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Comparison of reported proportions of men detected with incurable metastatic/stage VI prostate cancer through different detection strategies. These studies were done in different populations as indicted and based on different investigation indications
Article
Background Prostate cancer is an epidemic of the modern age, and despite efforts to improve awareness, it remains the case that mortality has hardly altered over the decades, driven largely by late presentation. There is a strong public perception that male urinary symptoms is one of the key indicators of prostate cancer, and this continues to be part of messaging from national guidelines and media health campaigns. This narrative, however, is not based on evidence and may be seriously hampering efforts to encourage early presentation. Discussion Anatomically, prostate cancer most often arises in the peripheral zone, while urinary symptoms result from compression of the urethra by prostatic enlargement more centrally. Biopsy studies show that mean prostate volume is actually lower in men found to have (early) prostate cancer compared to those with benign biopsies. This inverse relationship between prostate size and the probability of cancer is so strong that PSA density (PSA corrected for prostate volume) is known to be significantly more accurate in predicting a positive biopsy than PSA alone. Thus, this disconnect between scientific evidence and the current perception is very striking. There is also evidence that using symptoms for investigating possible cancer may lead to higher proportions of men presenting with locally advanced or metastatic disease compared to PSA testing or screening programmes. Concerns about overwhelming health care services if men are encouraged to get tested without symptoms may also be overstated, with recent newer approaches to reduce over-investigation and treatment. In this article, we explore the link between urinary symptoms and prostate cancer and propose that public and professional messaging needs to change. Conclusion If rates of earlier diagnosis are to improve, we call for strong clear messaging that prostate cancer is a silent disease especially in the curable stages and men should come forward for testing regardless of whether or not they have symptoms. This should be done in parallel with other ongoing efforts to raise awareness including targeting men at highest risk due to racial ancestry or family history. While the current resurgence in interest and debate about prostate cancer screening is timely, change of this message by guideline bodies, charities and the media can be a first simple step to improving earlier presentation and hence cures rates.
 
Article
Background Transparency and reproducibility are expected to be normative practices in clinical trials used for decision-making on marketing authorisations for new medicines. This registered report introduces a cross-sectional study aiming to assess inferential reproducibility for main trials assessed by the European Medicines Agency. Methods Two researchers independently identified all studies on new medicines, biosimilars and orphan medicines given approval by the European Commission between January 2017 and December 2019, categorised as ‘main studies’ in the European Public Assessment Reports (EPARs). Sixty-two of these studies were randomly sampled. One researcher retrieved the individual patient data (IPD) for these studies and prepared a dossier for each study, containing the IPD, the protocol and information on the conduct of the study. A second researcher who had no access to study reports used the dossier to run an independent re-analysis of each trial. All results of these re-analyses were reported in terms of each study’s conclusions, p -values, effect sizes and changes from the initial protocol. A team of two researchers not involved in the re-analysis compared results of the re-analyses with published results of the trial. Results Two hundred ninety-two main studies in 173 EPARs were identified. Among the 62 studies randomly sampled, we received IPD for 10 trials. The median number of days between data request and data receipt was 253 [interquartile range 182–469]. For these ten trials, we identified 23 distinct primary outcomes for which the conclusions were reproduced in all re-analyses. Therefore, 10/62 trials (16% [95% confidence interval 8% to 28%]) were reproduced, as the 52 studies without available data were considered non-reproducible. There was no change from the original study protocol regarding the primary outcome in any of these ten studies. Spin was observed in the report of one study. Conclusions Despite their results supporting decisions that affect millions of people’s health across the European Union, most main studies used in EPARs lack transparency and their results are not reproducible for external researchers. Re-analyses of the few trials with available data showed very good inferential reproducibility. Trial registration https://osf.io/mcw3t/
 
GO (Gene Ontology) enrichment analysis of the human and bacterial genes found to be associated and visualised in Fig. 2. Results are given for monomicrobial streptococcal (S. pyogenes) and for the polymicrobial NSTI. Gene names listed in blue indicate genes annotated by the GO term also indicated in blue, and gene names in red are annotated by the GO term in red. Genes given in purple colour are annotated by both GO terms. A different type of infection elicits different response patterns in the host
Figure of protein functions associated to the host-pathogen gene expression profiles derived from Dual RNA-seq of tissue biopsies of NSTI patients represented by the interactome network given in Fig. 2. The central column contains human genes, the left column contains S. pyogenes genes (i.e. bacterial genes found to be associated with human genes in monomicrobial NSTI), the right column contains genes from several bacterial species (i.e. bacterial genes found to be associated with human genes in polymicrobial NSTI). Nodes are colour coded by bacterial species. The node size is proportional to the node degree (connectivity, i.e. the number of associated genes; see Additional File 1, Equation S3). Red edges indicate positive partial correlation; blue edges indicate negative partial correlation; the colour intensity and the edge width are proportional to the value of the partial correlations
Abbreviations AMPs: Antimicrobial peptides; CTGF: Connective tissue growth factor; ECM: Extracellular matrix; GMM: Gaussian Graphical Model; GO: Gene Ontology; HSP: Heat shock protein; IgG: Immunoglobulin G; isp: Immunogenic secreted protein; LIONESS: Linear Interpolation to Obtain Network Estimates for Single Samples; lm: Laminin; NSTI: Necrotising soft tissue infection; PCLRC: Probabilistic Context Likelihood of Relatedness on Correlation; RF: Random forest.
Article
Background Necrotising soft tissue infections (NSTIs) are rapidly progressing bacterial infections usually caused by either several pathogens in unison (polymicrobial infections) or Streptococcus pyogenes (mono-microbial infection). These infections are rare and are associated with high mortality rates. However, the underlying pathogenic mechanisms in this heterogeneous group remain elusive. Methods In this study, we built interactomes at both the population and individual levels consisting of host-pathogen interactions inferred from dual RNA-Seq gene transcriptomic profiles of the biopsies from NSTI patients. Results NSTI type-specific responses in the host were uncovered. The S. pyogenes mono-microbial subnetwork was enriched with host genes annotated with involved in cytokine production and regulation of response to stress. The polymicrobial network consisted of several significant associations between different species ( S. pyogenes , Porphyromonas asaccharolytica and Escherichia coli ) and host genes. The host genes associated with S. pyogenes in this subnetwork were characterised by cellular response to cytokines. We further found several virulence factors including hyaluronan synthase, Sic1, Isp, SagF, SagG, ScfAB-operon, Fba and genes upstream and downstream of EndoS along with bacterial housekeeping genes interacting with the human stress and immune response in various subnetworks between host and pathogen. Conclusions At the population level, we found aetiology-dependent responses showing the potential modes of entry and immune evasion strategies employed by S. pyogenes , congruent with general cellular processes such as differentiation and proliferation. After stratifying the patients based on the subject-specific networks to study the patient-specific response, we observed different patient groups with different collagens, cytoskeleton and actin monomers in association with virulence factors, immunogenic proteins and housekeeping genes which we utilised to postulate differing modes of entry and immune evasion for different bacteria in relationship to the patients’ phenotype.
 
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart of the study selection process (presented according to the PRISMA guidelines)
Abbreviations BMI: Body mass index; CI: Confidence interval; HR: Hazard ratio; MET: Metabolic equivalent; n: Number; PA: Physical activity; RR: Relative risk; SD: Standard deviation.
Article
Background The associations of cancer with types of diets, including vegetarian, fish, and poultry-containing diets, remain unclear. The aim of this study was, therefore, to investigate the association of type of diet with all cancers and 19 site-specific incident cancers in a prospective cohort study and then in a meta-analysis of published prospective cohort studies. Methods A total of 409,110 participants from the UK Biobank study, recruited between 2006 and 2010, were included. The outcomes were incidence of all cancers combined and 19 cancer sites. Associations between the types of diets and cancer were investigated using Cox proportional hazards models. Previously published prospective cohort studies were identified from four databases, and a meta-analysis was conducted using random-effects models. Results The mean follow-up period was 10.6 years (IQR 10.0; 11.3). Compared with meat-eaters, vegetarians (hazard ratio (HR) 0.87 [95% CI: 0.79 to 0.96]) and pescatarians (HR 0.93 [95% CI: 0.87 to 1.00]) had lower overall cancer risk. Vegetarians also had a lower risk of colorectal and prostate cancers compared with meat-eaters. In the meta-analysis, vegetarians (Risk Ratio (RR): 0.90 [0.86 to 0.94]) and pescatarians (RR 0.91 [0.86; 0.96]) had lower risk of overall and colorectal cancer. No associations between the types of diets and prostate, breast, or lung cancers were found. Conclusions Compared with meat-eaters, vegetarians and pescatarians had a lower risk of overall, colorectal, and prostate cancer. When results were pooled in a meta-analysis, the associations with overall and colorectal cancer persisted, but the results relating to other specific cancer sites were inconclusive.
 
Article
Background Irritable bowel syndrome (IBS) is considered a disorder of gut-brain interaction (DGBI), presenting as chronic abdominal pain and altered defaecation. Symptoms are often food related. Much work in the field has focused on identifying physiological, immune and microbial abnormalities in the colon of patients; however, evidence of small intestinal immune activation and microbial imbalance has been reported in small studies. The significance of such findings has been largely underappreciated despite a growing body of work implicating small intestinal homeostatic imbalance in the pathogenesis of DGBIs. Main text Small intestinal mechanosensation is a characteristic feature of IBS. Furthermore, altered small intestinal barrier functions have been demonstrated in IBS patients with the diarrhoea-predominant subtype. Small intestinal bacterial overgrowth and increased populations of small intestinal mast cells are frequently associated with IBS, implicating microbial imbalance and low-grade inflammation in the pathogenesis of IBS. Furthermore, reports of localised food hypersensitivity responses in IBS patients implicate the small intestine as the site of immune-microbial-food interactions. Conclusions Given the association of IBS symptoms with food intake in a large proportion of patients and the emerging evidence of immune activation in these patients, the current literature suggests the pathogenesis of IBS is not limited to the colon but rather may involve dysfunction of the entire intestinal tract. It remains unclear if regional variation in IBS pathology explains the various symptom phenotypes and further work should consider the intestinal tract as a whole to answer this question.
 
Article
Targeted therapy is the key for improving overall survival while decreasing the undesirable adverse effects of cancer treatment. Patients who received matched targeted therapies showed dramatically improved overall survival (OS) and progression-free survival (PFS) compared to those without matched therapies. However, each patient responds to targeted therapy differently due to their unique genomic profile. The discrepancy of treatment response between clinical trials and real-world clinical practice highlights an unmet need to develop tailored therapies for individual patients. The development of cutting-edge technologies, such as next-generation sequencing, has enabled us to identify more actionable targets. In this special issue of BMC Medicine , a collection of highly translational and clinical oncology papers presented a series of studies on targeted therapies for a variety of cancer types, aiming to bridge the gap between genomic testing and precision medicine and spark innovations on improving the efficacy of targeted therapies.
 
Relationship between haemoglobin and time from administration of first antimalarial dose for A all age groups, B patients < 5 years old and C patients ≥ 5 years old. Figure derived from linear mixed effects model with fractional polynomial terms for time
Demographic and baseline characteristics
Article
Background Plasmodium falciparum malaria is associated with anaemia-related morbidity, attributable to host, parasite and drug factors. We quantified the haematological response following treatment of uncomplicated P. falciparum malaria to identify the factors associated with malarial anaemia. Methods Individual patient data from eligible antimalarial efficacy studies of uncomplicated P. falciparum malaria, available through the WorldWide Antimalarial Resistance Network data repository prior to August 2015, were pooled using standardised methodology. The haematological response over time was quantified using a multivariable linear mixed effects model with nonlinear terms for time, and the model was then used to estimate the mean haemoglobin at day of nadir and day 7. Multivariable logistic regression quantified risk factors for moderately severe anaemia (haemoglobin < 7 g/dL) at day 0, day 3 and day 7 as well as a fractional fall ≥ 25% at day 3 and day 7. Results A total of 70,226 patients, recruited into 200 studies between 1991 and 2013, were included in the analysis: 50,859 (72.4%) enrolled in Africa, 18,451 (26.3%) in Asia and 916 (1.3%) in South America. The median haemoglobin concentration at presentation was 9.9 g/dL (range 5.0–19.7 g/dL) in Africa, 11.6 g/dL (range 5.0–20.0 g/dL) in Asia and 12.3 g/dL (range 6.9–17.9 g/dL) in South America. Moderately severe anaemia (Hb < 7g/dl) was present in 8.4% (4284/50,859) of patients from Africa, 3.3% (606/18,451) from Asia and 0.1% (1/916) from South America. The nadir haemoglobin occurred on day 2 post treatment with a mean fall from baseline of 0.57 g/dL in Africa and 1.13 g/dL in Asia. Independent risk factors for moderately severe anaemia on day 7, in both Africa and Asia, included moderately severe anaemia at baseline (adjusted odds ratio (AOR) = 16.10 and AOR = 23.00, respectively), young age (age < 1 compared to ≥ 12 years AOR = 12.81 and AOR = 6.79, respectively), high parasitaemia (AOR = 1.78 and AOR = 1.58, respectively) and delayed parasite clearance (AOR = 2.44 and AOR = 2.59, respectively). In Asia, patients treated with an artemisinin-based regimen were at significantly greater risk of moderately severe anaemia on day 7 compared to those treated with a non-artemisinin-based regimen (AOR = 2.06 [95%CI 1.39–3.05], p < 0.001). Conclusions In patients with uncomplicated P. falciparum malaria, the nadir haemoglobin occurs 2 days after starting treatment. Although artemisinin-based treatments increase the rate of parasite clearance, in Asia they are associated with a greater risk of anaemia during recovery.
 
Article
Background: Studies have suggested incremental short-term adverse events (AE) after repeated vaccination. In this report, we assessed occurrence and risk factors for short-term AEs following repeated SARS-CoV-2 vaccination in patients with various immune-mediated inflammatory diseases (IMIDs). Methods: Self-reported daily questionnaires on AEs during the first 7 days after vaccination were obtained of 2259 individuals (2081 patients and 178 controls) participating in an ongoing prospective multicenter cohort study on SARS-CoV-2 vaccination in patients with various IMIDs in the Netherlands (T2B-COVID). Relative risks were calculated for potential risk factors associated with clinically relevant AE (rAE), defined as AE lasting longer than 2 days or impacting daily life. Results: In total, 5454 vaccinations were recorded (1737 first, 1992 second and 1478 third vaccinations). Multiple sclerosis, Crohn's disease and rheumatoid arthritis were the largest disease groups. rAEs were reported by 57.3% (95% CI 54.8-59.8) of patients after the first vaccination, 61.5% (95% CI 59.2-63.7) after the second vaccination and 58% (95% CI 55.3-60.6) after the third vaccination. At day 7 after the first, second and third vaccination, respectively, 7.6% (95% CI 6.3-9.1), 7.4% (95% CI 6.2-8.7) and 6.8% (95% CI 5.4-8.3) of patients still reported AEs impacting daily life. Hospital admissions and allergic reactions were uncommon (<0.7%). Female sex (aRR 1.43, 95% CI 1.32-1.56), age below 50 (aRR 1.14, 95% CI 1.06-1.23), a preceding SARS-CoV-2 infection (aRR 1.14, 95% CI 1.01-1.29) and having an IMID (aRR 1.16, 95% CI 1.01-1.34) were associated with increased risk of rAEs following a vaccination. Compared to the second vaccination, the first vaccination was associated with a lower risk of rAEs (aRR 0.92, 95% CI 0.84-0.99) while a third vaccination was not associated with increased risk on rAEs (aRR 0.93, 95% CI 0.84-1.02). BNT162b2 vaccines were associated with lower risk on rAEs compared to CX-024414 (aRR 0.86, 95% CI 0.80-0.93). Conclusions: A third SARS-CoV-2 vaccination was not associated with increased risk of rAEs in IMID patients compared to the second vaccination. Patients with an IMID have a modestly increased risk of rAEs after vaccination when compared to controls. Most AEs are resolved within 7 days; hospital admissions and allergic reactions were uncommon. Trial registration: NL74974.018.20 , Trial ID: NL8900. Registered on 9 September 2020.
 
Article
Background Forecasting healthcare demand is essential in epidemic settings, both to inform situational awareness and facilitate resource planning. Ideally, forecasts should be robust across time and locations. During the COVID-19 pandemic in England, it is an ongoing concern that demand for hospital care for COVID-19 patients in England will exceed available resources. Methods We made weekly forecasts of daily COVID-19 hospital admissions for National Health Service (NHS) Trusts in England between August 2020 and April 2021 using three disease-agnostic forecasting models: a mean ensemble of autoregressive time series models, a linear regression model with 7-day-lagged local cases as a predictor, and a scaled convolution of local cases and a delay distribution. We compared their point and probabilistic accuracy to a mean-ensemble of them all and to a simple baseline model of no change from the last day of admissions. We measured predictive performance using the weighted interval score (WIS) and considered how this changed in different scenarios (the length of the predictive horizon, the date on which the forecast was made, and by location), as well as how much admissions forecasts improved when future cases were known. Results All models outperformed the baseline in the majority of scenarios. Forecasting accuracy varied by forecast date and location, depending on the trajectory of the outbreak, and all individual models had instances where they were the top- or bottom-ranked model. Forecasts produced by the mean-ensemble were both the most accurate and most consistently accurate forecasts amongst all the models considered. Forecasting accuracy was improved when using future observed, rather than forecast, cases, especially at longer forecast horizons. Conclusions Assuming no change in current admissions is rarely better than including at least a trend. Using confirmed COVID-19 cases as a predictor can improve admissions forecasts in some scenarios, but this is variable and depends on the ability to make consistently good case forecasts. However, ensemble forecasts can make forecasts that make consistently more accurate forecasts across time and locations. Given minimal requirements on data and computation, our admissions forecasting ensemble could be used to anticipate healthcare needs in future epidemic or pandemic settings.
 
Article
There is considerable variability in disease progression for patients with amyotrophic lateral sclerosis (ALS) including the age of disease onset, site of disease onset, and survival time. There is growing evidence that short structural variations (SSVs) residing in frequently overlooked genomic regions can contribute to complex disease mechanisms and can explain, in part, the phenotypic variability in ALS patients. Here, we discuss SSVs recently characterized by our laboratory and how these discoveries integrate into the current literature on ALS, particularly in the context of application to future clinical trials. These markers may help to identify and differentiate patients for clinical trials that have a similar ALS disease mechanism(s), thereby reducing the impact of participant heterogeneity. As evidence accumulates for the genetic markers discovered in SQSTM1 , SCAF4 , and STMN2 , we hope to improve the outcomes of future ALS clinical trials.
 
Flowchart of the study population
Central illustration: Changes from baseline to follow-up by treatment arm in (A): Flow mediated dilation (%FMD); (B): Peak cutaneous vascular conductance responses to acetylcholine (ACh); (C):Peak cutaneous vascular conductance responses to sodium nitroprusside (SNP); (D): Mean arterial pressure (MAP)
Article
  • Markos KlonizakisMarkos Klonizakis
  • Anil GumberAnil Gumber
  • Emma McIntoshEmma McIntosh
  • Leonie S. BroseLeonie S. Brose
Background Smoking is a major risk factor for cardiovascular disease and smoking cessation reduces excess risk. E-cigarettes are popular for smoking cessation but there is little evidence on their cardiovascular health effect. Our objective was to compare the medium- and longer-term cardiovascular effects in smokers attempting to quit smoking using e-cigarettes with or without nicotine or prescription nicotine replacement therapy (NRT). Methods This was a single-center, pragmatic three-arm randomized (1:1:1) controlled trial, which recruited adult smokers (≥ 10 cigarettes/day), who were willing to attempt to stop smoking with support ( n = 248). Participants were randomized to receive behavioral support with either (a) e-cigarettes with 18 mg/ml nicotine, (b) e-cigarettes without nicotine, and (c) NRT. Flow-mediated dilation (%FMD) and peak cutaneous vascular conductance (CVCmax) responses to acetylcholine (ACh) and sodium nitroprusside (SNP), mean arterial pressure (MAP), and other outcomes were recorded at baseline, 3, and 6 months after stopping smoking. Data were analyzed using generalized estimating equations (GEE). Results At 3- and 6-month follow-up, %FMD showed an improvement over baseline in all three groups (e.g., p < 0.0001 at 6 months). Similarly, ACh, SNP, and MAP improved significantly over baseline in all groups both at 3 and 6 months (e.g., ACh: p = 0.004, at 6 months). Conclusions Smokers attempting to quit experienced positive cardiovascular impact after both a 3- and 6-month period. None of the groups (i.e., nicotine-containing and nicotine-free e-cigarettes or NRT) offered superior cardiovascular benefits to the others. Trial registration ClinicalTrials.gov NCT03061253 . Registered on 17 February 2017.
 
The study selection flowchart. This flowchart shows the number of records and studies at each stage of the study selection process
(continued)
Risk of bias assessment results. The left section of this figure shows risk of bias judgements for each domain of the QUADAS-2 tool for each study and the right section shows applicability judgements for each concern domain of the QUADAS-2 tool for each study. Please see Additional file 4: Box S3 for all signalling questions used in the QUADAS-2 assessment and further considerations
Summary characteristics of the included studies
Result summaries of meta-analysis for levels of skin pigmentation and ethnic groups
Article
Background: During the COVID-19 pandemic, there have been concerns regarding potential bias in pulse oximetry measurements for people with high levels of skin pigmentation. We systematically reviewed the effects of skin pigmentation on the accuracy of oxygen saturation measurement by pulse oximetry (SpO2) compared with the gold standard SaO2 measured by CO-oximetry. Methods: We searched Ovid MEDLINE, Ovid Embase, EBSCO CINAHL, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform (up to December 2021) for studies with SpO2–SaO2 comparisons and measuring the impact of skin pigmentation or ethnicity on pulse oximetry accuracy. We performed meta-analyses for mean bias (the primary outcome in this review) and its standard deviations (SDs) across studies included for each subgroup of skin pigmentation and ethnicity; and used these pooled mean bias and SDs to calculate accuracy root-mean-square (Arms) and 95% limits of agreement. The review was registered with the Open Science Framework (https://osf.io/gm7ty). Results: We included 32 studies (6505 participants): 15 measured skin pigmentation and 22 referred to ethnicity. Compared with standard SaO2 measurement, pulse oximetry probably overestimates oxygen saturation in people with the high level of skin pigmentation (pooled mean bias 1.11%; 95% confidence interval 0.29% to 1.93%) and people described as Black/African American (1.52%; 0.95% to 2.09%) (moderate- and low-certainty evidence). The bias of pulse oximetry measurements for people with other levels of skin pigmentation, or those from other ethnic groups is either more uncertain or suggests no overestimation. Whilst the extent of mean bias is small or negligible for all subgroups evaluated, the associated imprecision is unacceptably large (pooled SDs > 1%). When the extent of measurement bias and precision is considered jointly, pulse oximetry measurements for all the subgroups appear acceptably accurate (with Arms < 4%). Conclusions: Pulse oximetry may overestimate oxygen saturation in people with high levels of skin pigmentation and people whose ethnicity is reported as Black/African American, compared with SaO2. The extent of overestimation may be small in hospital settings but unknown in community settings.
 
Data processing and analyses flow diagram of this study. Thirty-eight metabolites were significant following multiple testing in multi-variable cox proportional hazards models. For the development of a prediction model, participants were randomly assigned to the training and testing group for model development. After a 10-fold cross-validation test, 24 metabolites were assigned a nonzero coefficient in the elastic net regression model amongst the 249 included metabolites. Receiver operating characteristic (ROC) curve was created and area under curve (AUC) was calculated for predictive value comparison. Categorical net reclassification improvement (NRI) was calculated to investigate the reclassification ability
Adjusted HR (95% CI) of incident dementia for metabolites after multiple testing. Hazard ratios (HR) are per 1 standard deviation (SD) higher of Z-transformed metabolic marker and are adjusted for age, gender, education level, systolic pressure, anti-hypertension treatment, diabetes mellitus, smoking status, history of stroke, history of coronary heart disease, and APOE ε4 allele. CI, confidence interval; LDL, low-density lipoprotein; HDL, high-density lipoprotein; VLDL, very-low-density lipoprotein; IDL, intermediate-density lipoprotein
ROC and AUC analysis of incident dementia prediction model development and predictive value comparison. An elastic net regression model based on lasso penalty was used for dementia prediction. After 10-fold cross-validation, 24 of 249 metabolites were selected for the dementia prediction model. Xb1 curve used conventional risk factors as input signals, while the Xb2 curve was for 24 selected metabolites and Xb3 was for conventional risk factors and 24 selected metabolites. There was no clinically significant difference (P = 0.042) found between the AUC of Xb1 and Xb3. Conventional risk factors included age, gender, education level, systolic pressure, anti-hypertension treatment, diabetes mellitus, smoking status, history of stroke, history of coronary heart disease, and APOE ε4 allele. ROC, receiver operating characteristic; AUC, area under curve
Article
  • Xinyu ZhangXinyu Zhang
  • Wenyi HuWenyi Hu
  • Yueye WangYueye Wang
  • [...]
  • Zhuoting ZhuZhuoting Zhu
Background Plasma metabolomic profile is disturbed in dementia patients, but previous studies have discordant conclusions. Methods Circulating metabolomic data of 110,655 people in the UK Biobank study were measured with nuclear magnetic resonance technique, and incident dementia records were obtained from national health registers. The associations between plasma metabolites and dementia were estimated using Cox proportional hazard models. The 10-fold cross-validation elastic net regression models selected metabolites that predicted incident dementia, and a 10-year prediction model for dementia was constructed by multivariable logistic regression. The predictive values of the conventional risk model, the metabolites model, and the combined model were discriminated by comparison of area under the receiver operating characteristic curves (AUCs). Net reclassification improvement (NRI) was used to estimate the change of reclassification ability when adding metabolites into the conventional prediction model. Results Amongst 110,655 participants, the mean (standard deviation) age was 56.5 (8.1) years, and 51 186 (46.3%) were male. A total of 1439 (13.0%) developed dementia during a median follow-up of 12.2 years (interquartile range: 11.5–12.9 years). A total of 38 metabolites, including lipids and lipoproteins, ketone bodies, glycolysis-related metabolites, and amino acids, were found to be significantly associated with incident dementia. Adding selected metabolites (n=24) to the conventional dementia risk prediction model significantly improved the prediction for incident dementia (AUC: 0.824 versus 0.817, p =0.042) and reclassification ability (NRI = 4.97%, P = 0.009) for identifying high risk groups. Conclusions Our analysis identified various metabolomic biomarkers which were significantly associated with incident dementia. Metabolomic profiles also provided opportunities for dementia risk reclassification. These findings may help explain the biological mechanisms underlying dementia and improve dementia prediction.
 
Flow chart of the family-based designs. MBR, Medical Birth Register; MGR, Multi-Generation Register; LISA, Longitudinal Integrated Database for Health Insurance and Labor Market Studies; TPR, Total Population Register; NPR, National Patient Register; NDR, National Diabetes Register; NPDR, National Prescribed Drug Register; PIN, personal identity number
HRs/ORs (95% CIs) of type 1 diabetes for maternal smoking versus non-smoking during pregnancy in different study designs. HR, hazard ratio; OR, odds ratio; CI, confidence interval. Model 1 was adjusted for sex and year of birth. The model in the cohort analysis was fitted with a frailty component to take into account the non-independence among children born by the same mother. The model in the cousin (or sibling) analysis was conditioning on cousin (or sibling) groups. Model 2 was additionally adjusted for maternal education, paternal education, maternal age at delivery, maternal body mass index during pregnancy, maternal diabetes, paternal diabetes, and birth order on the basis of model 1. Model 3 was additionally adjusted for gestational age and birth weight for gestational age on the basis of model 2
Article
Background Maternal smoking during pregnancy was reported to be associated with a reduced risk of type 1 diabetes in the offspring. We investigated whether this association is consistent with a causal interpretation by accounting for familial (shared genetic and environmental) factors using family-based, quasi-experimental designs. Methods We included 2,995,321 children born in Sweden between 1983 and 2014 and followed them for a diagnosis of type 1 diabetes until 2020 through the National Patient, Diabetes and Prescribed Drug Registers. Apart from conducting a traditional cohort study, we performed a nested case–control study (quasi-experiment) comparing children with type 1 diabetes to their age-matched siblings (or cousins). Information on maternal smoking during pregnancy was retrieved from the Swedish Medical Birth Register. Multivariable adjusted Cox proportional hazards regression and conditional logistic regression were used. Results A total of 18,617 children developed type 1 diabetes, with a median age at diagnosis of 9.4 years. The sibling and cousin comparison design included 14,284 and 7988 of these children, respectively. Maternal smoking during pregnancy was associated with a 22% lower risk of offspring type 1 diabetes in the full cohort (hazard ratio 0.78, 95% confidence interval [CI] 0.75–0.82). The corresponding odds ratio was 0.78 (95% CI 0.69–0.88) in the sibling and 0.72 (95% CI 0.66–0.79) in the cousin comparison analysis. Conclusions This nationwide, family-based study provides support for a protective effect of maternal smoking on offspring type 1 diabetes. Mechanistic studies are needed to elucidate the underlying pathways behind this link.
 
Associations between genetically predicted IL-6R-mediated signaling and risk of incident cardiovascular disease across measured hsCRP levels. A Mendelian randomization analyses stratified by baseline hsCRP levels. The hazard ratios are scaled for 1 mg/dL increment in absolute hsCRP levels. The p-values for heterogeneity and for trend are derived from the Cochran Q statistic and linear meta-regression analyses across deciles of measured hsCRP. B, C Mendelian randomization analyses of genetically predicted IL6R-mediated signaling and CVD risk across B ln-transformed measured hsCRP levels and C absolute measured hsCRP levels. For B, C, results are obtained from fractional polynomial models across associations derived for deciles of measured hsCRP levels. The reference is set to the minimum hsCRP value in the UK Biobank sample (0.08 mg/dL). The p-values for non-linearity are 0.001 for ln-transformed hsCRP levels and 0.99 for absolute hsCRP levels. For all graphs, the residual values of hsCRP are used to stratify, as determined in models regressing the genetic risk score for IL-6 signaling on measured hsCRP levels
Association between genetically predicted IL-6R-mediated signaling activity and risk of cardiovascular disease across clinically relevant subgroups. The hazard ratios are scaled on 1 mg/dL increment in absolute hsCRP levels. The p-values for heterogeneity and for trend are derived from the Cochran Q statistic and linear meta-regression analyses across strata of the different measured variables. For all variables except for age and sex, the residual values are used to stratify, as determined in models regressing the genetic score for IL-6 signaling on these variables
Article
Background Interleukin 6 (IL-6) signaling is being investigated as a therapeutic target for atherosclerotic cardiovascular disease (CVD). While changes in circulating high-sensitivity C-reactive protein (hsCRP) are used as a marker of IL-6 signaling, it is not known whether there is effect heterogeneity in relation to baseline hsCRP levels or other cardiovascular risk factors. The aim of this study was to explore the association of genetically predicted IL-6 signaling with CVD risk across populations stratified by baseline hsCRP levels and cardiovascular risk factors. Methods Among 397,060 White British UK Biobank participants without known CVD at baseline, we calculated a genetic risk score for IL-6 receptor (IL-6R)-mediated signaling, composed of 26 variants at the IL6R gene locus. We then applied linear and non-linear Mendelian randomization analyses exploring associations with a combined endpoint of incident coronary artery disease, ischemic stroke, peripheral artery disease, aortic aneurysm, and cardiovascular death stratifying by baseline hsCRP levels and cardiovascular risk factors. Results The study participants (median age 59 years, 53.9% females) were followed-up for a median of 8.8 years, over which time a total of 46,033 incident cardiovascular events occurred. Genetically predicted IL-6R-mediated signaling activity was associated with higher CVD risk (hazard ratio per 1-mg/dL increment in absolute hsCRP levels: 1.11, 95% CI: 1.06–1.17). The increase in CVD risk was linearly related to baseline absolute hsCRP levels. There was no evidence of heterogeneity in the association of genetically predicted IL-6R-mediated signaling with CVD risk when stratifying the population by sex, age, body mass index, estimated glomerular filtration rate, or systolic blood pressure, but there was evidence of greater associations in individuals with low-density lipoprotein cholesterol ≥ 160 mg/dL. Conclusions Any benefit of inhibiting IL-6 signaling for CVD risk reduction is likely to be proportional to absolute reductions in hsCRP levels. Therapeutic inhibition of IL-6 signaling for CVD risk reduction should therefore prioritize those individuals with the highest baseline levels of hsCRP.
 
Risk of hip fracture in occasional meat-eaters, pescatarians, and vegetarians compared to regular meat-eaters in the UKWCS. The multivariable-adjusted model was adjusted for the following (all at recruitment): ethnicity (white, Asian, black, other); socio-economic status (professional/managerial, intermediate, routine/manual); marital status (married/living as married, separated/divorced, single/widowed); menopausal status (premenopausal, postmenopausal); number of children (continuous); prevalence of cardiovascular disease, cancer, or diabetes (yes, no); physical activity in hours per day (continuous); smoking status (current, former, never); alcohol consumption (> 1/week, ≤ 1/week, never); BMI (continuous); and any nutritional supplement use (yes, no). HR (95% CI), hazard ratio (95% confidence interval)
Risk of hip fracture in occasional meat-eaters, pescatarians, and vegetarians compared to regular meat-eaters by BMI in the UKWCS
Article
Background The risk of hip fracture in women on plant-based diets is unclear. We aimed to investigate the risk of hip fracture in occasional meat-eaters, pescatarians, and vegetarians compared to regular meat-eaters in the UK Women’s Cohort Study and to determine if potential associations between each diet group and hip fracture risk are modified by body mass index (BMI). Methods UK women, ages 35–69 years, were classified as regular meat-eaters (≥ 5 servings/week), occasional meat-eaters (< 5 servings/week), pescatarian (ate fish but not meat), or vegetarian (ate neither meat nor fish) based on a validated 217-item food frequency questionnaire completed in 1995–1998. Incident hip fractures were identified via linkage to Hospital Episode Statistics up to March 2019. Cox regression models were used to estimate the associations between each diet group and hip fracture risk over a median follow-up time of 22.3 years. Results Amongst 26,318 women, 822 hip fracture cases were observed (556,331 person-years). After adjustment for confounders, vegetarians (HR (95% CI) 1.33 (1.03, 1.71)) but not occasional meat-eaters (1.00 (0.85, 1.18)) or pescatarians (0.97 (0.75, 1.26)) had a greater risk of hip fracture than regular meat-eaters. There was no clear evidence of effect modification by BMI in any diet group ( p -interaction = 0.3). Conclusions Vegetarian women were at a higher risk of hip fracture compared to regular meat-eaters. Further research is needed to confirm this in men and non-European populations and to identify factors responsible for the observed risk difference. Further research exploring the role of BMI and nutrients abundant in animal-sourced foods is recommended. Trial registration ClinicalTrials.gov , NCT05081466
 
Outline of process for considering and justifying resources for an adaptive design
Major tasks required to run a clinical trial and how adaptive designs may affect them
Article
Adaptive designs are a class of methods for improving efficiency and patient benefit of clinical trials. Although their use has increased in recent years, research suggests they are not used in many situations where they have potential to bring benefit. One barrier to their more widespread use is a lack of understanding about how the choice to use an adaptive design, rather than a traditional design, affects resources (staff and non-staff) required to set-up, conduct and report a trial. The Costing Adaptive Trials project investigated this issue using quantitative and qualitative research amongst UK Clinical Trials Units. Here, we present guidance that is informed by our research, on considering the appropriate resourcing of adaptive trials. We outline a five-step process to estimate the resources required and provide an accompanying costing tool. The process involves understanding the tasks required to undertake a trial, and how the adaptive design affects them. We identify barriers in the publicly funded landscape and provide recommendations to trial funders that would address them. Although our guidance and recommendations are most relevant to UK non-commercial trials, many aspects are relevant more widely.
 
Article
Background Although cholesterol metabolism is a common pathway for the development of antitumor drugs, there are no specific targets and drugs for clinical use. Here, based on our previous study of sterol O-acyltransferase 1 (SOAT1) in hepatocelluar carcinoma, we sought to screen an effective targeted drug for precise treatment of hepatocelluar carcinoma and, from the perspective of cholesterol metabolism, clarify the relationship between cholesterol regulation and tumorigenesis and development. Methods In this study, we developed a virtual screening integrated affinity screening technology for target protein drug screening. A series of in vitro and in vivo experiments were used for drug activity verification. Multi-omics analysis and flow cytometry analysis were used to explore antitumor mechanisms. Comparative analysis of proteome and transcriptome combined with survival follow-up information of patients reveals the clinical therapeutic potential of screened drugs. Results We screened three compounds, nilotinib, ABT-737, and evacetrapib, that exhibited optimal binding with SOAT1. In particular, nilotinib displayed a high affinity for SOAT1 protein and significantly inhibited tumor activity both in vitro and in vivo. Multi-omics analysis and flow cytometry analysis indicated that SOAT1-targeting compounds reprogrammed the cholesterol metabolism in tumors and enhanced CD8+ T cells and neutrophils to suppress tumor growth. Conclusions Taken together, we reported several high-affinity SOAT1 ligands and demonstrated their clinical potential in the precision therapy of liver cancer, and also reveal the potential antitumor mechanism of SOAT1-targeting compounds.
 
Flowchart of the study population. Legend: Detailed presentation of the inclusion and exclusion criteria of the study participant selection process and how the final number of the study cohort was established
Associations of gestational age with daily sleep hours. Legend: Associations of gestational age with daily sleep hours: A Compared with full-term birth, preschool children born very-preterm, moderate-preterm, late-preterm, early-term and post-term were associated with lower daily sleep hours, all p < 0.01. B A fit spline described an inverse U-shape relationship of gestational age (weeks) with daily sleep hours (hours/day)
Associations of gestational age with CSHQ score and sleep disorder. Legend: Associations of gestational age with CSHQ scores and sleep disorder. A Compared with full-term birth, preschool children born very-preterm, moderate-preterm, late-preterm, early-term and post-term were associated with higher CSHQ scores, all p < 0.001. B A fit spline described a U-shape relationship of gestational age (weeks) with CSHQ scores. C Compared with full-term birth, preschool children born very-preterm, moderate-preterm, late-preterm and post-term were associated with a higher prevalence of pediatric sleep disorder, all p < 0.001
Article
Abstract Background Both sleep quality and quantity are essential for normal brain development throughout childhood; however, the association between preterm birth and sleep problems in preschoolers is not yet clear, and the effects of gestational age across the full range from preterm to post-term have not been examined. Our study investigated the sleep outcomes of children born at very-preterm (41 weeks). Methods A national retrospective cohort study was conducted with 114,311 children aged 3–5 years old in China. Children’s daily sleep hours and pediatric sleep disorders defined by the Children’s Sleep Habits Questionnaire (CSHQ) were reported by parents. Linear regressions and logistic regression models were applied to examine gestational age at birth with the sleep outcomes of children. Results Compared with full-term children, a significantly higher CSHQ score, and hence worse sleep, was observed in very-preterm (β = 1.827), moderate-preterm (β = 1.409), late-preterm (β = 0.832), early-term (β = 0.233) and post-term (β = 0.831) children, all p41) was also seen in very-preterm (adjusted odds ratio [AOR] = 1.287 95% confidence interval [CI] (1.157, 1.433)), moderate-preterm (AOR = 1.249 95% CI (1.110, 1.405)), late-preterm (AOR = 1.111 95% CI (1.052, 1.174)) and post-term (AOR = 1.139 95% CI (1.061, 1.222)), all p
 
Flowchart of the study selection. Steps and number of articles included and excluded per step during the study selection process
Literature summaries of association between medication use and risk of amyotrophic lateral sclerosis (25 articles including 7 drug categories)
Article
Background Studying whether medications act as potential risk factors for amyotrophic lateral sclerosis (ALS) can contribute to the understanding of disease etiology as well as the identification of novel therapeutic targets. Therefore, we conducted a systematic review to summarize the existing evidence on the association between medication use and the subsequent ALS risk. Methods A systematic review was conducted in Medline, Embase, and Web of Science from the date of database establishment to December 10, 2021. References of identified articles were further searched for additional relevant articles. Studies were included if (1) published in English, (2) explored medication use as exposure and development of ALS as outcome, and (3) the design was a human observational study. Clinical trials, reviews, comments, editorials, and case reports were excluded. Quality assessment was performed using a pre-validated tool for non-randomized studies, the Newcastle–Ottawa Assessment Scale (NOS). Results Of the 4760 studies identified, 25 articles, including 13 case–control studies, five nested case–control studies, six cohort studies, and one retrospective chart review, were included in the review. Among these studies, there were 22 distinct study populations that included 171,407 patients with ALS, seven classes of medication examined, and 23 studies with a NOS ≥ 5. There was a general lack of agreement between studies on the associations of cholesterol-lowering drugs, anti-inflammatory drugs, immunosuppressants, antibiotics, oral contraceptives (OCs) or hormone replacement therapy (HRT), antihypertensive drugs, antidiabetics, and drugs for psychiatric and neurological disorders with the subsequent risk of ALS. However, it appeared that statins, aspirin, OCs/HRT, antihypertensives, and antidiabetics were unlikely related to a higher risk of ALS. The positive associations noted for antibiotics, antidepressants, and skeletal muscle relaxants might be attributable to prodromal symptoms of ALS. Conclusions There is currently no strong evidence to link any medication use with ALS risk.
 
Article
Background Early detection of breast cancer (BC) through mammography screening (MAM) is known to reduce mortality. We examined the differential effect that mammography has on BC characteristics and overall survival and the sociodemographic determinants of MAM utilization in a multi-ethnic Asian population. Methods This study included 3739 BC patients from the Singapore Breast Cancer Cohort (2010–2018). Self-reported sociodemographic characteristics were collected using a structured questionnaire. Clinical data were obtained through medical records. Patients were classified as screeners (last screening mammogram ≤ 2 years before diagnosis), non-screeners (aware but did not attend or last screen > 2years), and those unaware of MAM. Associations between MAM behaviour (MB) and sociodemographic factors and MB and tumour characteristics were examined using multinomial regression. Ten-year overall survival was modelled using Cox regression. Results Patients unaware of screening were more likely diagnosed with late stage (OR stage III vs stage I (Ref) [95% CI]: 4.94 [3.45–7.07], p < 0.001), high grade (OR poorly vs well-differentiated (reference) : 1.53 [1.06–2.20], p = 0.022), nodal-positive, large size (OR >5cm vs ≤2cm (reference) : 5.06 [3.10–8.25], p < 0.001), and HER2-positive tumours (OR HER2-negative vs HER2-positive (reference) : 0.72 [0.53–0.97], p = 0.028). Similar trends were observed between screeners and non-screeners with smaller effect sizes. Overall survival was significantly shorter than screeners in the both groups (HR non-screeners : 1.89 [1.22–2.94], p = 0.005; HR unaware : 2.90 [1.69–4.98], p < 0.001). Non-screeners and those unaware were less health conscious, older, of Malay ethnicity, less highly educated, of lower socioeconomic status, more frequently ever smokers, and less physically active. Among screeners, there were more reported personal histories of benign breast surgeries or gynaecological conditions and positive family history of breast cancer. Conclusions Mammography attendance is associated with more favourable BC characteristics and overall survival. Disparities in the utility of MAM services suggest that different strategies may be needed to improve MAM uptake.
 
Hospitals providing data for model derivation and external validation represented by the dots. The hospitals that cluster west of the map are in moderate to high malaria transmission zone while the cluster at the centre of the map is in moderate to low malaria transmission zones
Calibration curves for the SENSS and NETS model in the external validation dataset. SENSS, Score for Essential Neonatal Symptoms and Signs; NETS, Neonatal Essential Treatment Score; RCS, restricted cubic splines; CL, confidence limits (95%). Calibration curves generated using the CalibrationCurves package in R [36]
Calibration curves for the updated SENSS and NETS model in the external validation dataset. SENSS, Score for Essential Neonatal Symptoms and Signs; NETS, Neonatal Essential Treatment Score; RCS, restricted cubic splines; CL, confidence limits (95%). Calibration curves generated using the CalibrationCurves package in R [36]
Heterogeneity in model performance from internal–external cross-validation (IECV) approach. SENSS, Score for Essential Neonatal Symptoms and Signs; NETS, Neonatal Essential Treatment Score
Article
Background Two neonatal mortality prediction models, the Neonatal Essential Treatment Score (NETS) which uses treatments prescribed at admission and the Score for Essential Neonatal Symptoms and Signs (SENSS) which uses basic clinical signs, were derived in high-mortality, low-resource settings to utilise data more likely to be available in these settings. In this study, we evaluate the predictive accuracy of two neonatal prediction models for all-cause in-hospital mortality. Methods We used retrospectively collected routine clinical data recorded by duty clinicians at admission from 16 Kenyan hospitals used to externally validate and update the SENSS and NETS models that were initially developed from the data from the largest Kenyan maternity hospital to predict in-hospital mortality. Model performance was evaluated by assessing discrimination and calibration. Discrimination, the ability of the model to differentiate between those with and without the outcome, was measured using the c-statistic. Calibration, the agreement between predictions from the model and what was observed, was measured using the calibration intercept and slope (with values of 0 and 1 denoting perfect calibration). Results At initial external validation, the estimated mortality risks from the original SENSS and NETS models were markedly overestimated with calibration intercepts of − 0.703 (95% CI − 0.738 to − 0.669) and − 1.109 (95% CI − 1.148 to − 1.069) and too extreme with calibration slopes of 0.565 (95% CI 0.552 to 0.577) and 0.466 (95% CI 0.451 to 0.480), respectively. After model updating, the calibration of the model improved. The updated SENSS and NETS models had calibration intercepts of 0.311 (95% CI 0.282 to 0.350) and 0.032 (95% CI − 0.002 to 0.066) and calibration slopes of 1.029 (95% CI 1.006 to 1.051) and 0.799 (95% CI 0.774 to 0.823), respectively, while showing good discrimination with c-statistics of 0.834 (95% CI 0.829 to 0.839) and 0.775 (95% CI 0.768 to 0.782), respectively. The overall calibration performance of the updated SENSS and NETS models was better than any existing neonatal in-hospital mortality prediction models externally validated for settings comparable to Kenya. Conclusion Few prediction models undergo rigorous external validation. We show how external validation using data from multiple locations enables model updating and improving their performance and potential value. The improved models indicate it is possible to predict in-hospital mortality using either treatments or signs and symptoms derived from routine neonatal data from low-resource hospital settings also making possible their use for case-mix adjustment when contrasting similar hospital settings.
 
Article
Chronic kidney disease (CKD) in people with diabetes is becoming an increasing major public health concern, disproportionately burdening low- and middle-income countries (LMICs). This rising burden is due to various factors, including the lack of disease awareness that results in late referral and the cost of screening and consequent treatment of the comorbid conditions, as well as other factors endemic to LMICs relating to inadequate management of risk factors. We critically assessed the extant literature, by performing searches of Medline via PubMed, EBSCOhost, Scopus, and Web of Science, for studies pertaining to screening, diagnosis, and prediction of CKD amongst adults with diabetes in LMICs, using relevant key terms. The relevant studies were summarized through key themes derived from the Wilson and Jungner criteria. We found that screening for CKD in people with diabetes is generally infrequent in LMICs. Also, LMICs are ill-equipped to appropriately manage diabetes-associated CKD, especially its late stages, in which supportive care and kidney replacement therapy (KRT) might be required. There are acceptable and relatively simple tools that can aid diabetes-associated CKD screening in these countries; however, these tools come with limitations. Thus, effective implementation of diabetes-associated CKD screening in LMICs remains a challenge, and the cost-effectiveness of such an undertaking largely remains to be explored. In conclusion, for many compelling reasons, screening for CKD in people with diabetes should be a high policy priority in LMICs, as the huge cost associated with higher mortality and morbidity in this group and the cost of KRT offers a compelling economic incentive for improving early detection of diabetes in CKD.
 
Study design and participants
Differences in the vaginal microbiome with different pregnancy outcomes. A, B PCoA analysis based on Jaccard distance: PC 1, PC2, and PC3 could explain 33.33%, 9.07%, and 8.58% of the variation, respectively. C Lefse analysis; the threshold of LDA value was 4.0. D The rank of the Gini index from the random forest model. PCoA, principal coordinate analysis; Lefse, linear discriminant analysis effect size
Scatter diagrams showing the relative abundances of the genera between the pregnant and non-pregnant groups. The middle lines represent the median, while the error bars represent the interquartile range. P values were acquired by the Kruskal-Wallis test
Types of vaginal microbiome and fecundability. A Clustering analysis based on the absolute loads of five bacterial species, based on the z-score of the log10(absolute load). B Kaplan-Meier plots for the cumulative pregnancy rate across different vaginal microbiome types
Article
Background Although sexually transmitted infections are regarded as the main cause of tubal infertility, the association between the common vaginal microbiome and female fecundability has yet to be determined. The objective of this study was to find convincing evidence relating to the impact of the vaginal bacterial structure on the fecundability of women planning pregnancy. Methods We recruited women who took part in the Free Pre-pregnancy Health Examination Project from 13 June 2018 to 31 October 2018 (n = 89, phase I) and from 1 November 2018 to 30 May 2020 (n = 389, phase II). We collected pre-pregnancy vaginal swabs from each subject; then, we followed up each subject to acquire the pregnancy-planning outcome in 1 year. In phase I, 16S rRNA gene sequencing was performed to investigate the vaginal bacterial content between the pregnancy and non-pregnancy groups. These findings were verified in phase II by applying a quantitative real-time polymerase chain reaction for the measurement of the absolute abundance of specific species. Cox models were used to estimate fecundability ratios (FR) for each vaginal microbiome type. Results In phase I, 59.6% (53/89) of women became pregnant within 1 year. The principal coordinate analysis showed that the pre-pregnancy vaginal microbial community structures of the pregnant and non-pregnant groups were significantly different (PERMANOVA test, R² = 0.025, P = 0.049). The abundance of the genus Lactobacillus in the pregnancy group was higher than that of the non-pregnant group (linear discriminant analysis effect size (LDA) > 4.0). The abundance of the genus Gardnerella in the non-pregnant group was higher than those in the pregnant group (LDA > 4.0). In phase II, female fecundability increased with higher absolute loads of Lactobacillus gasseri (quartile Q4 vs Q1, FR = 1.71, 95%CI 1.02–2.87) but decreased with higher absolute loads of Fannyhessea vaginae (Q4 vs Q1, FR = 0.62, 95%CI 0.38–1.00). Clustering analysis showed that the vaginal microbiome of type D (characterized by a higher abundance of Lactobacillus iners, a lower abundance of Lactobacillus crispatus and Lactobacillus gassri) was associated with a 55% reduction of fecundability (FR = 0.45, 95%CI 0.26–0.76) compared with type A (featuring three Lactobacillus species, low Gardnerella vaginalis and Fannyhessea vaginae abundance). Conclusions This cohort study demonstrated an association between the pre-pregnancy vaginal microbiome and female fecundability. A vaginal microbiome characterized by a higher abundance of L. iners and lower abundances of L. crispatus and L. gasseri appeared to be associated with a lower fecundability. Further research now needs to confirm whether manipulation of the vaginal microenvironment might improve human fecundability.
 
of clinical presentation of children with acute hepatitis with unknown aetiology. Adapted from UKHSA analysis of 144 cases in England presenting up until 16 May [5]
Timeline of the public health response to severe, acute hepatitis of unknown aetiology among children. Image created using Canva [18]
Data on the distribution of cases globally (as of 26 May 2022). Data source: World Health Organization (27 May 2022). Acute hepatitis of unknown aetiology in children—multi-country [4]
Article
The ongoing investigations into clusters of children affected by severe acute hepatitis of unknown aetiology have put our global capacity for a coordinated, effective response to the test. The global health community have rapidly convened to share data and inform the response. In the UK, where most cases were initially identified, a coordinated public health and clinical research response was rapidly initiated. Since then, cases have been reported from other countries, predominantly from higher-income countries. While agencies are keeping an open mind to the cause, the working hypothesis and case notifications raise important questions about our capacity to detect emerging cases in lower-resourced settings with a recognised lack of access to diagnostics even for commonly circulating viruses such as hepatitis A. The limited capability to generate integrated global pathogen surveillance data is a challenge for the outbreak investigations, highlighting an urgent need to strengthen access to diagnostics, with a focus on lower-resourced settings, to improve the capacity to detect emerging diseases to inform care and to improve outcomes and outbreak control.
 
Flowchart of patient enrollment and study design
The association of LRP1B mutation at baseline with clinical outcomes of ICIs plus chemotherapy. A Objective response rate (ORR) (left) and durable clinical benefit (DCB) rate (right) between patients with LRP1B mutant and wild type. B The association of LRP1B mutation with PD-L1, tumor size at baseline, CRP level, and bTMB, respectively. Fisher’s exact test was used for statistical analysis. C Multivariate COX analysis of LRP1B mutation, bTMB, PD-L1, CRP, and tumor size at baseline. Mut, mutant; WT, wild-type; ORR, objective response rate; DCB, durable clinical benefit; CRP, C-reactive protein; bTMB, blood-based tumor mutational burden
Association of the change of bITH scores after ICIs plus chemotherapy with clinical outcomes. A Kaplan-Meier curve for progression-free survival (PFS) according to bITH change status. bITH up was defined as a ≥ 10% increase in bITH score from baseline, with a second confirmatory measurement after treatment. Log-rank test was used for statistical analysis. B Objective response rate (ORR) (left) and durable clinical benefit (DCB) rate (right) among bITH up and bITH stable or down. Fisher’s exact test was used for statistical analysis. C Waterfall plot of bITH score change and the maximum change in tumor size from baseline. bITH, blood-based intratumor heterogeneity; HR, hazard ratio; ORR, objective response rate; DCB, durable clinical benefit; BOR, best overall response; PD, progressive disease; SD, stable disease; PR, partial response. MSAF, maximum somatic allele frequency
Case analysis of two patients with MSAF decreased but bITH up after treatment experienced disease progression as the best response to treatment. A, C The timeline, treatment history, and radiographic response to treatment of the patient P12 (A) and P03 (C). B, D The changes of bITH score, tumor size, and detected somatic mutations at baseline and after two cycles of therapy in patient P12 (B) and P03 (D). Hierarchical clustering method was used to cluster somatic mutations detected at two time points. bITH, blood-based intratumor heterogeneity; PD, progressive disease; MSAF, maximum somatic allele frequency; MAF, mutant allele frequency
Case analysis of patient with dynamic ctDNA detection at baseline, after two cycles of treatment, and after disease progression. A The timeline, treatment history, and radiographic response to treatment of the patient P57. B The changes of bITH score, tumor size, and detected somatic mutations at baseline and after two cycles of therapy in patient P57. Hierarchical clustering method was used to cluster somatic mutations detected at multiple time points. bITH, blood-based intratumor heterogeneity; SD, stable disease; PD, progressive disease; MSAF, maximum somatic allele frequency; MAF, mutant allele frequency
Article
Background The combination of immune checkpoint inhibitors (ICIs) and chemotherapy has been the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) patients with driver-gene negative. However, efficacy biomarkers for ICIs-based combination therapy are lacking. We aimed to identify potential factors associated with outcomes of ICIs plus chemotherapy at baseline and dynamic changes in peripheral blood. Methods We collected plasma samples of 51 advanced NSCLC patients without EGFR/ALK/ROS1 alteration at baseline and/or after two treatment cycles of ICIs plus chemotherapy. A blood-based intratumor heterogeneity (bITH) score was calculated based on the allele frequencies of somatic mutations using a 520-gene panel. bITH-up was defined as a ≥ 10% increase in bITH score from baseline, with a second confirmatory measurement after treatment. Results At baseline, the number of metastatic organs and lung immune prognostic index (LIPI) were significantly associated with shorter progression-free survival (PFS) of ICIs plus chemotherapy, while bITH and other common molecular biomarkers, including ctDNA level, blood-based tumor mutational burden (bTMB), and PD-L1 expression, had no effect on PFS. LRP1B mutation at baseline was significantly associated with favorable outcomes to ICIs plus chemotherapy. There were 37 patients who had paired samples at baseline and after two cycles of treatment, with the median interval of 53 days. Intriguingly, patients with bITH-up had significant shorter PFS (HR, 4.92; 95% CI, 1.72–14.07; P = 0.001) and a lower durable clinical benefit rate (0 vs 41.38%, P = 0.036) than those with bITH-stable or down. Case studies indicated that bITH was promising to predict disease progression. Conclusions The present study is the first to report that increased bITH is associated with unfavorable outcomes of ICIs plus chemotherapy in advanced NSCLC patients.
 
BMI during the randomized controlled trial. Results of the intention to treat analysis of BMI of the control (open circles) and intervention group (filled squares) during the maintenance period (month 0 to month 12) and follow-up (up to 48 months). Results were presented as mean ± 95%CI. *p < 0.05 control vs. intervention group, for comparison of least square means adjusted for age, sex, and BMI after weight loss
Article
Background: Behavioral weight loss interventions are frequently hampered by long-term inefficacy. As metabolic improvements and health-related quality of life (HRQoL) are diminished by weight regain, effective long-term strategies are highly desirable. We aimed to analyze whether an additional weight maintenance intervention could delay body weight regain and can induce a long-term improvement of metabolism and HRQoL for up to 48 months in humans. Given the short-term metabolic effects of natriuretic peptides (NP), we also investigated the role of the adipose atrial NP (ANP) system in this long-term context. Methods: After a successful 12-week weight reduction program 143 subjects (age>18; BMI≥27 kg/m2) were randomized (1:1) to a control group or a 12-month multimodal weight maintenance intervention focusing on nutritional counseling and physical exercises. Secondary trial outcomes including course of BMI, HOMA-IR, glucose response after oGTT (glucoseAUC), and HRQoL (SF-36) were analyzed yearly for 48 months. Adipose ANP receptor mRNA expression was analyzed during weight loss. Results: Initial weight loss (- 4.7±1.5 kg/m2) improved glucoseAUC, HOMA-IR, and HRQoL. Although BMI was still reduced after 48 months (-1.98 [95% CI -2.61, -1.35] kg/m2), benefits on HOMA-IR, glucoseAUC, and mental health disappeared after 36 (-0.49 [-1.00, 0.02]), 18 (0.61 [-9.57, 10.79] mg dl-1 min-1), and 18 months (2.06 [-0.08, 4.20]), respectively, while improved physical health persisted up to months 48 (2.95 [0.49, 5.40]). Weight maintenance intervention inhibited weight regain and delayed impairment of HOMA-IR and glucoseAUC (but not HRQoL) for up to 12 months. However, no metabolic long-term effect was seen beyond the intervention period. Lower adipose NPR-C and higher NPR-A mRNA expression after weight loss predicted smaller regain of weight (r=0.398; p<0.05)/fat mass (FM) (r=0.391; p<0.05) and longer improvement of HOMA-IR (r=-0.422; p<0.05), respectively. Conclusions: Additional benefits of a behavioral 12-month weight maintenance intervention after weight loss regarding body weight regain and metabolic improvement does not persist beyond the intervention period. However, weight loss-induced modulation of the adipose ANP system is probably involved in the long-term control of body weight regain and insulin sensitivity. Trial registration: ClinicalTrials.gov NCT00850629 . Registered on February 25, 2009.
 
Neonatal severe inflammation leads to long-lasting cognitive impairment in adolescent rats. (A) Schematic illustrating the chronological order used for the establishment of the inflammation model and cognitive testing. Five litters were used in this cohort of experiment. (B) The development of body weight in rats (n = 8). (C) The survival curve of rats. (D) Learning curve for the escape latency. (E) Representative traces for the MWM test. (F) The time spent in the target quadrant (n = 15–19). (G) Distance spent in the target quadrant (n = 15–19). (H) Number of platform crossings (n = 15–19). (I) Mean velocity during the spatial probe test (n = 15–19). (J) The experimental protocol for FC. (K) The freezing time of rats during FC training. (L) The freezing time of rats in the context FC test (n = 15–19). (M) The freezing time of rats in the cued FC test (n = 15–19). LPS: lipopolysaccharide; NS: normal saline; MWM: Morris water maze; FC: fear conditioning; Panels B, D, and K were compared by two-way ANOVA with repeated measures followed by a Bonferroni post hoc test; Panel C was compared by log-rank test; Panels F, G, H, I, L, and M were compared by unpaired two-tailed Student’s t test; *P < 0.05, **P < 0.01, and ***P < 0.001, n.s.: no significance; Error bars indicate SD
Neonatal severe inflammation induces sustained elevation of IL-1β in the rat hippocampus. (A) Schematic illustrating the chronological order used for the proinflammatory cytokine test after neonatal inflammation. Fourteen litters were used in this cohort of experiment. (B, D, F) ELISA results showing the protein levels of TNF (B), IL-6 (D), and IL-1β (F) in peripheral blood serum at 2 h (n = 6), 4 h (n = 6), 6 h (n = 6), and 24 h (n = 6). (C, E, G) PCR results showing the mRNA levels of hippocampal TNF (C) and IL-6 (E) at 6 h after LPS injection (n = 6), P5 (n = 6), P7 (n = 6), and P14 (n = 6), and IL-1β after LPS injection (G) at 6 h (n = 6), P5 (n = 6), P7 (n = 6), P14 (n = 6), and P30 (n = 6). LPS: Lipopolysaccharide, NS: Normal saline, Panels B, C, D, E, F, and G were compared by unpaired two-tailed Student’s t test or Mann–Whitney U test; **P < 0.01 and ***P < 0.001, n.s.: no significance; Error bars indicate SD
Sustained elevation of hippocampal IL-1β levels contributes to long-term cognitive impairment after neonatal severe inflammation. (A) Schematic illustrating the chronological order used for siRNA delivery, LPS administration and cognitive testing. Eight litters were used in this cohort of experiment. (B) PCR results showing the knockdown efficiency of IL-1β-siRNA (n = 6). (C) Learning curve for the escape latency. (D) Time spent in the target quadrant (n = 15–24). (E) Distance spent in the target quadrant (n = 15–24). (F) Number of platform crossings (n = 15–24). (G) Mean velocity during the spatial probe test (n = 15–24). (H) The freezing time of rats in FC training. (I) The freezing time of rats in the context FC test (n = 15–24). (J) The freezing time of rats in the cued FC test (n = 15–24). LPS: lipopolysaccharide; NS: normal saline; MWM: Morris water maze; FC: fear conditioning; Panel B was compared by unpaired two-tailed Student’s t test; Panels C and H were compared by two-way ANOVA with repeated measures followed by a Bonferroni post hoc test; Panels D, E, F, G, I, and J were compared by one-way ANOVA with repeated measures followed by a Tukey post hoc test; **P < 0.01 and ***P < 0.001, n.s.: no significance; Error bars indicate SD
KCC2 mediates the effects of IL-1β on neonatal severe inflammation-induced cognitive impairment. (A) Schematic illustrating the chronological order used for the establishment of the inflammation model and KCC2 level testing. Five litters were used in this cohort of experiment. (B) The protein levels of KCC2 in P7 (left panel, n = 6), P14 (middle panel, n = 6), and P30 (right panel, n = 6) rats after LPS injection. (C) Schematic illustrating the chronological order used for siRNA injection, establishment of the inflammation model, and cognitive testing. Nine litters were used in this cohort of experiment. (D) The knockdown efficiency of KCC2-siRNA by PCR (n = 6). (E) Learning curve for the escape latency. (F) Time spent in the target quadrant (n = 10–15). (G) Distance spent in the target quadrant (n = 10–15). (H) Number of platform crossings (n = 10–15). (I) Mean velocity during the spatial probe test (n = 10–15). (J) The freezing time of rats during FC training. (K) The freezing time of rats in the context FC test (n = 10–15). (L) The freezing time of rats in the cued FC test (n = 10–15). LPS: lipopolysaccharide; NS: normal saline; MWM: Morris water maze; FC: fear conditioning; Panels B and D were compared by unpaired two-tailed Student’s t test; Panels F, G, H, I, K and L were compared by one-way ANOVA with repeated measures followed by a Tukey post hoc test; *P < 0.05, **P < 0.01, and ***P < 0.001, n.s.: no significance; Error bars indicate SD
EGABA is hyperpolarized in CA1 pyramidal neurons of rats after neonatal severe inflammation. (A) Schematic illustrating the chronological order used for siRNA delivery, LPS administration and perforated patch recordings. Fifteen litters were used in this cohort of experiment. (B) Representative traces of GABA-induced currents to the holding potential from –80 to –30 mV in 10 mV increments of hippocampal neurons at P7-P10. (C) Current–voltage (I-V) curve of GABA-induced currents recorded at different holding potentials from − 80 to − 30 mV in 10 mV increments of pyramidal neurons at P7-P10. (D) EGABA values per cell obtained from all I-V curves indicating a hyperpolarizing shift in septic rats at P7-P10 (n = 10–12 cells from 4–5 rats). (E) RMP values showing a hyperpolarizing shift in septic rats at P7-10 (n = 9–14 cells from 5–6 rats). (F) Representative traces of GABA-induced currents to the holding potential from –80 to –30 mV in 10 mV increments of hippocampal neurons at P14-P16. (G) Current–voltage (I-V) curve of GABA-induced currents recorded at different holding potentials from − 80 to − 30 mV in 10 mV increments of pyramidal neurons at P14. (H) EGABA values per cell obtained from all I-V curves indicating a hyperpolarizing shift in septic rats at P14-P16 (n = 7 cells from 3–4 rats). (I) RMP values showing a hyperpolarizing shift in septic rats at P14-P16 (n = 10–13 cells from 4–5 rats). (J) Current–voltage (I-V) curve of spontaneous GABA-induced currents recorded at different holding potentials from − 80 to − 30 mV in 10 mV increments of pyramidal neurons at P28-P32. (K) EGABA values per cell obtained from all I-V curves indicating a hyperpolarizing shift in septic rats at P28-32 (n = 6–7 cells from 3–4 rats). (L) RMP values showing a hyperpolarizing shift in septic rats at P28-P32 (n = 8–10 cells from 4–5 rats). (M) Representative traces of GABA-induced currents to the holding potential from − 80 to − 30 mV in 10 mV increments of hippocampal neurons at P7-P10 after siRNA injection. (N) Current–voltage (I-V) curve of GABA-induced currents recorded at different holding potentials from − 80 to − 30 mV in 10 mV increments of pyramidal neurons at P7-P10 after siRNA injection. (O) EGABA values per cell obtained from all I-V curves at P7-P10 after siRNA injection (n = 7–8 cells from 3–4 rats). (P) RMP values at P7-P10 after siRNA injection (n = 7–11 cells from 4–5 rats). (Q) Current–voltage (I-V) curve of GABA-induced currents recorded at different holding potentials from − 80 to − 30 mV in 10 mV increments of pyramidal neurons at P14-P16 after siRNA injection. (R) EGABA values per cell obtained from all I-V curves at P14-P16 after siRNA injection (n = 5–7 cells from 3–4 rats). (S) RMP values at P14-P16 after siRNA injection (n = 7–9 cells from 3–4 rats). LPS: lipopolysaccharide; NS: normal saline; EGABA: GABA reversal potential; Panels D, E, H, I, K, and L were compared by unpaired two-tailed Student’s t test; Panels O, P, R, and S were compared by one-way ANOVA with repeated measures followed by a Tukey post hoc test; *P < 0.05, **P < 0.01, and ***P < 0.001, n.s.: no significance; Error bars indicate SD
Article
Background Neonatal sepsis can induce long-term cognitive impairment in adolescence or adulthood, but the underlying molecular mechanism is not fully understood. The expression of K⁺-Cl– co-transporter 2 (KCC2) plays a pivotal role in the GABAergic shift from depolarizing to hyperpolarizing during early postnatal development. In this study, we aimed to determine whether neonatal severe inflammation-induced cognitive impairment was associated with the expression of KCC2 during early development. Methods Neonatal severe inflammation was established by intraperitoneal injection of high dose lipopolysaccharide (LPS, 1 mg kg–1) in postnatal day 3 (P3) rats. The Morris water maze task and fear conditioning test were used to investigate long-term cognitive functions. ELISA, RT-PCR and Western blotting were used to examine the expression levels of proinflammatory cytokines and KCC2. Perforated patch-clamping recordings were used to determine the GABAergic shift. Results Neonatal severe inflammation led to long-term cognitive impairment in rats. Meanwhile, sustained elevation of interleukin-1 beta (IL-1β) levels was found in the hippocampus until P30 after LPS injection. Elevated expression of KCC2 and hyperpolarized GABA reversal potential (EGABA) were observed in CA1 hippocampal pyramidal neurons from the P7-P10 and P14-P16 rats after LPS injection. Specific knockdown of IL-1β mRNA expression rescued the elevated expression of KCC2 and the hyperpolarized EGABA at P7-P10 and P14-P16. Accordingly, specific knockdown of IL-1β or KCC2 expression improved the cognitive impairment induced by neonatal severe inflammation. Conclusions Sustained elevation of IL-1β in the hippocampus may induce cognitive impairment by upregulation of KCC2 during early development.
 
Study cohort
Effect of citalopram on total body weight by CYP2C19 phenotype. *p = 0.001
Article
Background Prescription medications such as selective serotonin reuptake inhibitors (SSRIs), commonly used to treat depression, are associated with weight gain. The role of pharmacogenomics in predicting SSRI-induced weight gain is unclear. Methods In this retrospective cohort study from participants in the Mayo Clinic RIGHT study who were prescribed citalopram, paroxetine, sertraline, or fluoxetine, our aim was to evaluate the association of metabolizer phenotype and total body weight after 6 months of SSRIs initiation. We evaluated the metabolizer phenotypes (poor/intermediate, normal, and rapid/ultra-rapid) of the cytochromes P450 enzymes genes: CYP2C9, CYP2C19, and CYP2D6 known to influence the metabolism of SSRI medications: CYP2C19 for citalopram, CYP2D6 for paroxetine, CYP2D6 and CYP2C19 for sertraline, and CYP2D6 and CYP2C9 fluoxetine. In addition, we assessed the association of metabolizer phenotype and total body weight change at six months following SSRI prescription using parametric analysis of covariance adjusted for baseline body weight and multivariate regression models. Results CYP2C19 poor/intermediate metabolizers prescribed citalopram gained significantly more weight than normal or rapid/ultra-rapid metabolizers at 6 months (TBWG %: 2.6 [95% CI 1.3—4.1] vs. 0.4 [95% CI -0.5 – 1.3] vs. -0.1 [-95% CI -1.5—1.1]; p = 0.001). No significant differences in weight outcomes at six months of treatment with paroxetine, sertraline, or fluoxetine were observed by metabolizer status. Conclusions Weight gain observed with citalopram may be mediated by CYP2C19 metabolizer status.
 
Temporal and developmental alterations to the circulatory lipids in the GUSTO cohort: A Antenatal and postnatal plasma collection time points for mother-offspring dyads in GUSTO cohort. B PCA plot of lipidomics data (n=2491). C Postnatal vs. antenatal changes in maternal lipidomic profiles. D Comparison of maternal antenatal plasma with cord blood (CB) lipidomic profiles. E Changes in child lipidomic profiles between birth and 6 years of age. F Comparison of pediatric (6-year-old child) and adult (postnatal mothers) plasma lipidomes. The most significant lipid species based on adjusted p-values are labeled in c-f. Effect size is shown as log2 of fold change. Error bars indicate 95% confidence interval. Diamond—Padj ≥ 0.05 or |FC|≤1.5 (gray), circle—Padj <0.05 and |FC|>1.5, and square—Padj <1.00E−10 and |FC|>1.5
Association of maternal and child adiposity with plasma lipidomic profiles: A Association of pre-pregnancy BMI with antenatal plasma lipidome (pregnant state). B Association of maternal BMI with postnatal plasma lipidome (non-pregnant state). C Association of birth weight (BW) with cord blood plasma lipidome. D Association of child BMI with plasma lipidome at 6 years of age. The top 20 lipid species with the directionality of association (10 positive and 10 negative) with adiposity measures in each study group are shown in volcano plots. The horizontal dotted line indicates Padj=0.05 in each volcano plot. Effect sizes are shown as % change in lipid concentration per unit change in BMI, or per 100 g change in birth weight. Error bars indicate 95% confidence interval. Diamond—Padj ≥ 0.05 (gray), circle—Padj <0.05, and square—Padj <1.00E−5 in forest plots
Comparison of plasma lipidomic profiles associated with mother and child adiposity: A Pie chart comparing the percent overlap and directionality of association in the four studies. B Venn-diagram of lipids species that passed significance in the four association studies. C Effect sizes of 41 lipid species that overlapped between the four studies
Replication of GUSTO identified ppBMI and BW lipid signatures in Barwon Infant Study (BIS). A Sample collection at two time points. B PCA plot of lipidomics data (n=1935). C Association of pre-pregnancy BMI (ppBMI) with antenatal plasma lipidome. D Scatter plot of effect sizes in GUSTO and BIS for ppBMI study. E Association of birth weight (BW) with cord blood plasma lipidome. The most significant lipid species based on adjusted p-values are labeled in C and E. Effect sizes are shown as % change in lipid concentration per unit change in BMI, or per 100 g change in birth weight. Error bars indicate 95% confidence interval. Diamond—Padj ≥ 0.05 (gray), circle—Padj <0.05, and square—Padj <1.00E−5. F Scatter plot of effect sizes in GUSTO and BIS for BW study. Red—significant in both cohorts, purple—only significant in GUSTO, yellow—only significant in BIS, and gray—not significant in both cohorts
Article
Background Lipids play a vital role in health and disease, but changes to their circulating levels and the link with obesity remain poorly characterized in expecting mothers and their offspring in early childhood. Methods LC-MS/MS-based quantitation of 480 lipid species was performed on 2491 plasma samples collected at 4 time points in the mother-offspring Asian cohort GUSTO (Growing Up in Singapore Towards healthy Outcomes). These 4 time points constituted samples collected from mothers at 26–28 weeks of gestation (n=752) and 4–5 years postpartum (n=650), and their offspring at birth (n=751) and 6 years of age (n=338). Linear regression models were used to identify the pregnancy and developmental age-specific variations in the plasma lipidomic profiles, and their association with obesity risk. An independent birth cohort (n=1935), the Barwon Infant Study (BIS), comprising mother-offspring dyads of Caucasian origin was used for validation. Results Levels of 36% of the profiled lipids were significantly higher (absolute fold change > 1.5 and Padj < 0.05) in antenatal maternal circulation as compared to the postnatal phase, with phosphatidylethanolamine levels changing the most. Compared to antenatal maternal lipids, cord blood showed lower concentrations of most lipid species (79%) except lysophospholipids and acylcarnitines. Changes in lipid concentrations from birth to 6 years of age were much higher in magnitude (log2FC=−2.10 to 6.25) than the changes observed between a 6-year-old child and an adult (postnatal mother) (log2FC=−0.68 to 1.18). Associations of cord blood lipidomic profiles with birth weight displayed distinct trends compared to the lipidomic profiles associated with child BMI at 6 years. Comparison of the results between the child and adult BMI identified similarities in association with consistent trends (R²=0.75). However, large number of lipids were associated with BMI in adults (67%) compared to the children (29%). Pre-pregnancy BMI was specifically associated with decrease in the levels of phospholipids, sphingomyelin, and several triacylglycerol species in pregnancy. Conclusions In summary, our study provides a detailed landscape of the in utero lipid environment provided by the gestating mother to the growing fetus, and the magnitude of changes in plasma lipidomic profiles from birth to early childhood. We identified the effects of adiposity on the circulating lipid levels in pregnant and non-pregnant women as well as offspring at birth and at 6 years of age. Additionally, the pediatric vs maternal overlap of the circulating lipid phenotype of obesity risk provides intergenerational insights and early opportunities to track and intervene the onset of metabolic adversities. Clinical trial registration This birth cohort is a prospective observational study, which was registered on 1 July 2010 under the identifier NCT01174875.
 
The association of HRD scores with IDC-P and other clinicopathological characteristics. A Boxplots showing HRD score distribution in various clinicopathological characteristic settings (metastatic status, visceral metastasis, IDC-P, IDC-P pattern, ISUP grade, age, baseline PSA). B Stacking histogram showing that IDC-P and non-IDC-P tumors display different proportions of HRD scores (divided by threshold (21, 30)) in the total, localized, and metastatic cohorts, respectively. C Boxplots showing the distribution of HRD score, as well as LOH score, LST score, and TAI score, in IDC-P (negative/positive), IDC-P pattern (negative/1/2), metastatic status (negative/positive), and ISUP grade (1–3/4–5) groups in the total cohorts. D, E Boxplots showing the distribution of HRD score, as well as LOH score, LST score, and TAI score, in IDC-P (negative/positive), IDC-P pattern (negative/1/2), in the M0 and M1 cohorts, respectively. M0, localized; M1, de novo metastatic; IDC-P, intraductal carcinoma of the prostate, PSA, prostate-specific antigen; ISUP, International Society of Urological Pathology; HRD, homologous recombination deficiency
Heatmap showing the genomic alterations in this cohort grouped by clinicopathological characteristics (age, baseline PSA, metastatic status, visceral metastasis, IDC-P, IDC-P pattern, ISUP grade) and HRD score. M0, localized; M1, de novo metastatic; IDC-P, intraductal carcinoma of the prostate; PSA, prostate-specific antigen; ISUP, International Society of Urological Pathology; HRD, homologous recombination deficiency
A–C The correlation analyses of the top mutated genes (genes mutated in ≥5 cases) and HRD scores in the total, IDC-P, and non-IDC-P cohorts. D–F Histograms showing the HRD score of each patient in the IDC-P and non-IDC-P cohorts. Different colors represent the mutation status of MYC (D), TP53 (E), and HRR pathway genes (F): yellow=mutated, blue=wild type. IDC-P, intraductal carcinoma of the prostate; HRR, homologous recombination repair
Prognostic value of HRD score. A, B HRD score in predicting CFS and OS time in the total cohort. C, D HRD score in predicting CFS and OS time in the M0 cohort. E, F HRD score in predicting CFS and OS time in the M1 cohort. M0, localized; M1, de novo metastatic; IDC-P, intraductal carcinoma of the prostate; CFS, CRPC-free survival; MFS, metastasis-free survival; OS, overall survival; HRD, homologous recombination deficiency
Article
Background Intraductal carcinoma of the prostate (IDC-P) is a subtype of prostate cancer featured by poor prognosis. Previous studies suggested IDC-P could have a potentially unstable genome. Homologous recombination deficiency (HRD) score is a result-oriented method to describe the genomic instability status. This study investigates the association of HRD scores with IDC-P and other clinicopathological factors and the prognostic implication of HRD scores in an aggressive prostate cancer cohort. Methods This study involved 123 PCa patients, including high-risk localized (M0) and de novo metastatic (M1) diseases. HRD score is calculated based on over 10,000 single-nucleotide polymorphisms distributed across the human genome. We explored the association between HRD scores and clinicopathological characteristics, genomic alterations, and patients’ prognoses using rank-sum tests, chi-square tests, Kaplan-Meier curves, and Cox proportional hazards method. Results The median HRD score of this cohort is 21.0, with 65 (52.8%) patients showing HRD score≥21. Tumors with IDC-P displayed higher HRD scores than adenocarcinoma (P=0.002); other high HRD score-related factors included M1 (P =0.008) and high ISUP grades (4–5) (P=0.001). MYC mutations were associated with high HRD scores (P<0.001) in the total cohort. TP53 mutations (P=0.010) and HRR pathway mutations (P=0.028) corresponded to high HRD scores in IDC-P positive and non-IDC-P patients, respectively, but not vice versa. HRD scores higher than 21 indicated significantly worse survival in the total cohort. Conclusions M1, high Gleason score, and IDC-P pathology represent higher HRD scores in PCa. Tumors with IDC-P might have different driven mechanisms for high HRD scores than non-IDC-P. HRD score displayed prognostic value in this aggressive prostate cancer cohort.
 
Article
Background The protective effect of T cell-mediated immunity against influenza virus infections in natural settings remains unclear, especially in seasonal epidemics. Methods To explore the potential of such protection, we analyzed the blood samples collected longitudinally in a community-based study and covered the first wave of pandemic H1N1 (pH1N1), two subsequent pH1N1 epidemics, and three seasonal H3N2 influenza A epidemics (H3N2) for which we measured pre-existing influenza virus-specific CD4 and CD8 T cell responses by intracellular IFN-γ staining assay for 965 whole blood samples. Results Based on logistic regression, we found that higher pre-existing influenza virus-specific CD4 and CD8 T cell responses were associated with lower infection odds for corresponding subtypes. Every fold increase in H3N2-specific CD4 and CD8 T cells was associated with 28% (95% CI 8%, 44%) and 26% (95% CI 8%, 41%) lower H3N2 infection odds, respectively. Every fold increase in pre-existing seasonal H1N1 influenza A virus (sH1N1)-specific CD4 and CD8 T cells was associated with 28% (95% CI 11%, 41%) and 22% (95% CI 8%, 33%) lower pH1N1 infection odds, respectively. We observed the same associations for individuals with pre-epidemic hemagglutination inhibition (HAI) titers < 40. There was no correlation between pre-existing influenza virus-specific CD4 and CD8 T cell response and HAI titer. Conclusions We demonstrated homosubtypic and cross-strain protection against influenza infections was associated with T cell response, especially CD4 T cell response. These protections were independent of the protection associated with HAI titer. Therefore, T cell response could be an assessment of individual and population immunity for future epidemics and pandemics, in addition to using HAI titer.
 
Article
Background Acute kidney injury (AKI) is common and associated with adverse outcomes as well as important healthcare costs. However, evidence examining the epidemiology of acute kidney disease (AKD)—recently defined as AKI persisting between 7 and 90 days—remains limited. The aims of this study were to establish the rates of early AKI recovery, progression to AKD and non-recovery; examine risk factors associated with non-recovery and investigate the association between recovery timing and adverse outcomes, in a population-based cohort. Methods All adult residents of Tayside & Fife, Scotland, UK, with at least one episode of community or hospital-managed AKI using KDIGO creatinine-based definition during the period 1 January 2010 to 31 December 2018 were identified. Logistic regression was used to examine factors associated with non-recovery, and Cox modelling was used to establish associations between AKI recovery timing and risks of mortality and development of de novo CKD. Results Over 9 years, 56,906 patients with at least one AKI episode were identified with 18,773 (33%) of these progressing to AKD. Of those progressing to AKD, 5059 (27%) had still not recovered at day 90 post AKI diagnosis. Risk factors for AKD included: increasing AKI severity, pre-existing cancer or chronic heart failure and recent use of loop diuretics. Compared with early AKI recovery, progression to AKD was associated with increased hazard of 1-year mortality and de novo CKD (HR = 1.20, 95% CI 1.13 to 1.26 and HR = 2.21, 95% CI 1.91 to 2.57 respectively). Conclusions These findings highlight the importance of early AKI recognition and management to avoid progression to AKD and long-term adverse outcomes.
 
Flow diagram of the study selection process
Geographic locations of study settings and number of studies in each setting. Legend: We mapped out countries where the studies were conducted and the respective number of studies identified for each country. The color codes show the different levels of country income, according to the World Bank classification in 2021
Log10 transformed costs of multimorbidity per log10 transformed country GDP per capita. Legend: Log10 transformed cost per capita of multimorbidity was plotted against log10 transformed country GDP per capita using a fixed-effects model. The red line depicts the relationship
Article
Background Multimorbidity is a rising global phenomenon, placing strains on countries’ population health and finances. This systematic review provides insight into the costs of multimorbidity through addressing the following primary and secondary research questions: What evidence exists on the costs of multimorbidity? How do costs of specific disease combinations vary across countries? How do multimorbidity costs vary across disease combinations? What “cost ingredients” are most commonly included in these multimorbidity studies? Methods We conducted a systematic review (PROSPERO: CRD42020204871) of studies published from January 2010 to January 2022, which reported on costs associated with combinations of at least two specified conditions. Systematic string-based searches were conducted in MEDLINE, The Cochrane Library, SCOPUS, Global Health, Web of Science, and Business Source Complete. We explored the association between costs of multimorbidity and country Gross Domestic Product (GDP) per capita using a linear mixed model with random intercept. Annual mean direct medical costs per capita were pooled in fixed-effects meta-analyses for each of the frequently reported dyads. Costs are reported in 2021 International Dollars (I$). Results Fifty-nine studies were included in the review, the majority of which were from high-income countries, particularly the United States. (1) Reported annual costs of multimorbidity per person ranged from I$800 to I$150,000, depending on disease combination, country, cost ingredients, and other study characteristics. (2) Our results further demonstrated that increased country GDP per capita was associated with higher costs of multimorbidity. (3) Meta-analyses of 15 studies showed that on average, dyads which featured Hypertension were among the least expensive to manage, with the most expensive dyads being Respiratory and Mental Health condition (I$36,840), Diabetes and Heart/vascular condition (I$37,090), and Cancer and Mental Health condition in the first year after cancer diagnosis (I$85,820). (4) Most studies reported only direct medical costs, such as costs of hospitalization, outpatient care, emergency care, and drugs. Conclusions Multimorbidity imposes a large economic burden on both the health system and society, most notably for patients with cancer and mental health condition in the first year after cancer diagnosis. Whether the cost of a disease combination is more or less than the additive costs of the component diseases needs to be further explored. Multimorbidity costing studies typically consider only a limited number of disease combinations, and few have been conducted in low- and middle-income countries and Europe. Rigorous and standardized methods of data collection and costing for multimorbidity should be developed to provide more comprehensive and comparable evidence for the costs of multimorbidity.
 
Article
Background At present, the extent and clinical relevance of epigenetic differences between upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) remain largely unknown. Here, we conducted a study to describe the global DNA methylation landscape of UTUC and UCB and to address the prognostic value of DNA methylation subtype and responses to the DNA methyltransferase inhibitor SGI-110 in urothelial carcinoma (UC). Methods Using whole-genome bisulfite sequencing ( n = 49 samples), we analyzed epigenomic features and profiles of UTUC ( n = 36) and UCB ( n = 9). Next, we characterized potential links between DNA methylation, gene expression ( n = 9 samples), and clinical outcomes. Then, we integrated an independent UTUC cohort (Fujii et al., n = 86) and UCB cohort (TCGA, n = 411) to validate the prognostic significance. Furthermore, we performed an integrative analysis of genome-wide DNA methylation and gene expression in two UC cell lines following transient DNA methyltransferase inhibitor SGI-110 treatment to identify potential epigenetic driver events that contribute to drug efficacy. Results We showed that UTUC and UCB have very similar DNA methylation profiles. Unsupervised DNA methylation classification identified two epi-clusters, Methy-High and Methy-Low, associated with distinct muscle-invasive statuses and patient outcomes. Methy-High samples were hypermethylated, immune-infiltrated, and enriched for exhausted T cells, with poor clinical outcome. SGI-110 inhibited the migration and invasion of Methy-High UC cell lines (UMUC-3 and T24) by upregulating multiple antitumor immune pathways. Conclusions DNA methylation subtypes pave the way for predicting patient prognosis in UC. Our results provide mechanistic rationale for evaluating SGI-110 in treating UC patients in the clinic.
 
Article
Background: Family history (FamH) of type 2 diabetes might indicate shared genotypes, environments, and/or behaviors. We hypothesize that FamH interacts with unhealthy behaviors to increase the risk of early onset of diabetes and poor cardiometabolic control. Methods: In a cross-sectional analysis of the prospective Joint Asia Diabetes Evaluation Register including patients from 427 clinics in 11 Asian countries/regions in 2007-2021, we defined positive FamH as affected parents/siblings and self-management as (1) healthy lifestyles (balanced diet, non-use of alcohol and tobacco, regular physical activity) and (2) regular self-monitoring of blood glucose (SMBG). Results: Among 86,931 patients with type 2 diabetes (mean±SD age: 56.6±11.6 years; age at diagnosis of diabetes: 49.8±10.5 years), the prevalence of FamH ranged from 39.1% to 85.3% in different areas with FamH affecting mother being most common (32.5%). The FamH group (n=51,705; 59.5%) was diagnosed 4.6 years earlier than the non-FamH group [mean (95% CI): 47.9 (47.8-48.0) vs. 52.5 (52.4-52.6), logrank p<0.001]. In the FamH group, patients with both parents affected had the earliest age at diagnosis [44.6 (44.5-44.8)], followed by affected single parent [47.7 (47.6-47.8)] and affected siblings only [51.5 (51.3-51.7), logrank p<0.001]. The FamH plus ≥2 healthy lifestyle group had similar age at diagnosis [48.2 (48.1-48.3)] as the non-FamH plus <2 healthy lifestyle group [50.1 (49.8-50.5)]. The FamH group with affected parents had higher odds of hyperglycemia, hypertension, and dyslipidemia than the FamH group with affected siblings, with the lowest odds in the non-FamH group. Self-management (healthy lifestyles plus SMBG) was associated with higher odds of attaining HbA1c<7%, blood pressure<130/80mmHg, and LDL-C<2.6 mmol/L especially in the FamH group (FamH×self-management, pinteraction=0.050-0.001). Conclusions: In Asia, FamH was common and associated with young age of diagnosis which might be delayed by healthy lifestyle while self management was associated with better control of cardiometabolic risk factors especially in those with FamH.
 
Article
Background Height is an important anthropometric measurement and is associated with many health-related outcomes. Genome-wide association studies (GWASs) have identified hundreds of genetic loci associated with height, mainly in individuals of European ancestry. Methods We performed genome-wide association analyses and replicated previously reported GWAS-determined single nucleotide polymorphisms (SNPs) in the Taiwanese Han population (Taiwan Biobank; n = 67,452). A genetic instrument composed of 251 SNPs was selected from our GWAS, based on height and replication results as the best-fit polygenic risk score (PRS), in accordance with the clumping and p -value threshold method. We also examined the association between genetically determined height (PRS 251 ) and measured height (phenotype). We performed observational (phenotype) and genetic PRS 251 association analyses of height and health-related outcomes. Results GWAS identified 6843 SNPs in 89 genomic regions with genome-wide significance, including 18 novel loci. These were the most strongly associated genetic loci ( EFEMP1 , DIS3L2 , ZBTB38 , LCORL , HMGA1 , CS , and GDF5 ) previously reported to play a role in height. There was a positive association between PRS 251 and measured height ( p < 0.001). Of the 14 traits and 49 diseases analyzed, we observed significant associations of measured and genetically determined height with only eight traits ( p < 0.05/[14 + 49]). Height was positively associated with body weight, waist circumference, and hip circumference but negatively associated with body mass index, waist-hip ratio, body fat, total cholesterol, and low-density lipoprotein cholesterol ( p < 0.05/[14 + 49]). Conclusions This study contributes to the understanding of the genetic features of height and health-related outcomes in individuals of Han Chinese ancestry in Taiwan.
 
Flowchart of the literature search and evaluation process returning 10 systematic reviews and meta-analyses
Number of systematic reviews or meta-analyses of observational studies reporting health outcomes among PEH by category of health outcome
Characteristics of the included SRs or MAs of observational and interventional studies
continued)
Article
Background Homelessness has been associated with multiple detrimental health outcomes across observational studies. However, relatively few randomized controlled trials (RCTs) have been conducted on people who experience homelessness (PEH). Thus, this umbrella review ranked the credibility of evidence derived from systematic reviews (SRs) and meta-analyses (MAs) of observational studies investigating the associations between homelessness and any health outcome as well as RCTs targeting health needs in this population. Methods Several databases were systematically searched from inception through April 28, 2021. Any SR and/or MA reporting quantitative data and providing a control group were eligible for inclusion. The credibility of the evidence derived from observational studies was appraised by considering the significance level of the association and the largest study, the degree of heterogeneity, the presence of small-study effects as well as excess significance bias. The credibility of evidence was then ranked in five classes. For SRs and/or MAs of RCTs, we considered the level of significance and whether the prediction interval crossed the null. The AMSTAR-2 and AMSTAR-plus instruments were adopted to further assess the methodological quality of SRs and/or MAs. The Newcastle-Ottawa Scale (NOS) was employed to further appraise the methodological quality of prospective cohort studies only; a sensitivity analysis limited to higher quality studies was conducted. Results Out of 1549 references, 8 MAs and 2 SRs were included. Among those considering observational studies, 23 unique associations were appraised. Twelve of them were statistically significant at the p ≤0.005 level. Included cases had worst health-related outcomes than controls, but only two associations reached a priori-defined criteria for convincing (class I) evidence namely hospitalization due to any cause among PEH diagnosed with HIV infection, and the occurrence of falls within the past year among PEH. According to the AMSTAR-2 instrument, the methodological quality of all included SRs and/or MAs was “critically low.” Interventional studies were scant. Conclusion While homelessness has been repeatedly associated with detrimental health outcomes, only two associations met the criteria for convincing evidence. Furthermore, few RCTs were appraised by SRs and/or MAs. Our umbrella review also highlights the need to standardize definitions of homelessness to be incorporated by forthcoming studies to improve the external validity of the findings in this vulnerable population.
 
Rationale for the identification and characterization of GC’s immune microenvironment according to CLDN18.2 expression. A Study follow chart. B The merged and single-stained images for four representative panels of multiplex IHC. Scale bar: 100 μm. C Overview of the analysis design
The association of CLDN18.2 positivity with clinicopathological and prognostic features in GC. A Comparison of CLDN18.2 expression between tumor and tumor adjacent normal area. Proportion: the proportion of CLDN18.2-positive tumor cells in the tumor region. Student t-test. * P < 0.05. ns: not significant. B The CLDN18.2 expression grouped by clinicopathologic features. Student t-test. * P < 0.05. ns: not significant. C The comparison of CLDN18.2 expression between EBV status in our cohort and TCGA cohort. Student t-test. *** P < 0.001. ns: not significant. D Overall survival, immunotherapy related OS, immunotherapy related PFS of patients based on CLDN18.2 expression in tumor core. Log-rank (Mantel-Cox) test. HR: hazard ratio
Unique immune cell subtypes in CLDN18.2-positive GC and normal tissues. A, B The rate of immune cell subtypes in tumor core based on CLDN18.2 expression and other clinicopathological features. Blue bars: CLDN18.2-negative; Red bars: CLDN18.2-positive. *P < 0.05, **P < 0.01, ***P < 0.001 and not significant (ns). Student t-test. C The rate of immune cell subtypes in tumor-adjacent normal regions grouped by CLDN18.2 expression. Blue dots: CLDN18.2-negative; Red dots: CLDN18.2-positive. * P < 0.05, ** P < 0.01, *** P < 0.001 and not significant (ns). Student t-test
Unique spatial distribution of immune cell subtypes in CLDN18.2-positive GC. A Illustration of the spatial analysis involving tumor cell and immune cell. Red dots and green dots represent tumor cells and immune cells, respectively. White line connecting a red dot and a green dot means that the distance between two cells are less than 20 microns. ES: effective score. EP: effective percent. Comparison of the effective scores (B) and effective percent (C) between the CLDN18.2-positive group and CLDN18.2-negative group (central cells: tumor cells; peripheral cells: immune cells; radius range: 20 microns). Red points and lines: CLDN18.2-positive; blue points and lines: CLDN18.2-negative
A graphical abstract for the major conclusions of the study. The immune microenvironmental features of GC stratified by CLDN18.2 indicated different therapeutic expectations to anti-PD-1/PD-L1 or CAR-T therapy. The blue area on the left represents the CLDN18.2-negative tumor microenvironment, where tumor cells expose few CLDN18.2 binding sites. The yellow area on the right represents the CLDN18.2-positive tumor microenvironment, where tumor cells expose more CLDN18.2 sites and CD8 + PD-1- T cells are enriched compared with CLDN18.2-negative gastric cancer
Article
Background The FAST study identified claudin-18 (CLDN18.2) as a promising novel therapeutic target for gastric cancer (GC). However, the tumor immune microenvironment and clinicopathological features of CLDN18.2-positive GC are unclear, making it difficult to develop and optimize CLDN18.2-targeted treatments. Methods This study included 80 GC patients, 60 of whom received anti-PD-1/PD-L1 treatment. CD4/CD8/CD20/CD66b/CD68/CD163/PD-1/PD-L1/TIM-3/LAG-3/FoxP3/CTLA-4/HLA-DR/STING, and CLDN18.2 were labeled using multiplex immunohistochemistry (m-IHC) to decipher the rate and spatial distribution of T cells, B cells, macrophages, and neutrophils in formalin-fixed, paraffin-embedded tumor tissues isolated from these patients. Tumor immune-microenvironmental features and patient survival stratified by CLDN18.2 expression were analyzed using two independent-sample t-tests and log-rank tests, respectively. Results We considered moderate-to-strong CLDN18.2 expression ≥ 40% of tumor cells as the cut-off for positivity. The proportion of CD8⁺PD-1⁻, CD8⁺LAG-3⁻, and CD8⁺TIM-3⁻ T cells was significantly higher in CLDN18.2-positive tumors than in negative tumors (0.039 vs. 0.026, P = 0.009; 0.050 vs.0.035, P = 0.024; 0.045 vs. 0.032, P = 0.038, respectively). In addition, the number of neutrophils (CD66b⁺) was higher in the CLDN18.2-positive group than in the negative group (0.081 vs. 0.055, P = 0.031, respectively), while the rates of M1 (CD68⁺CD163⁻HLA-DR⁺), M2 macrophages (CD68⁺CD163⁺HLA-DR⁻), and B cells (CD20⁺) were comparable between the CLDN18.2-positive and negative groups. The average numbers of CD8⁺PD-1⁻, CD8⁺LAG-3⁻, and CD8⁺TIM-3⁻T cells surrounding tumor cells within a 20-μm range were higher in CLDN18.2-positive tumors than in the CLDN18.2-negative tumors (0.16 vs. 0.09, P = 0.011; 0.20 vs. 0.12, P = 0.029; 0.18 vs. 0.12, P = 0.047, respectively). In addition, in the CLDN18.2-positive group, tumor cells surrounded by CD8⁺PD-1⁻, CD8⁺LAG-3⁻ T cells, or M1 macrophages within a 20-μm range accounted for a higher proportion of all tumor cells than those in the CLDN18.2-negative group (10.79% vs. 6.60%, P = 0.015; 12.68% vs. 8.70%, P = 0.049; 9.08% vs. 6.56%, P = 0.033, respectively). These findings suggest that CLDN18.2-positive GC harbors complex immune-microenvironmental features. Additionally, CLDN18.2-positive group had shorter OS and irOS than CLDN18.2-negative group (median OS: 23.33 vs.36.6 months, P < 0.001; median irOS: 10.03 vs. 20.13 months, P = 0.044, respectively). Conclusions CLDN18.2-positive GC displayed unique immune-microenvironmental characteristics, which is of great significance for the development of CLDN18.2-targeted therapies. However, the impact of CLDN18.2-related microenvironmental features on prognosis requires further investigation.
 
Article
This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/1741-7015-10-40.
 
Article
Background Umbrella clinical trials in precision oncology are designed to tailor therapies to the specific genetic changes within a tumor. Little is known about the risk/benefit ratio for umbrella clinical trials. The aim of our systematic review with meta-analysis was to evaluate the efficacy and safety profiles in cancer umbrella trials testing targeted drugs or a combination of targeted therapy with chemotherapy. Methods Our study was prospectively registered in PROSPERO (CRD42020171494). We searched Embase and PubMed for cancer umbrella trials testing targeted agents or a combination of targeted therapies with chemotherapy. We included solid tumor studies published between 1 January 2006 and 7 October 2019. We measured the risk using drug-related grade 3 or higher adverse events (AEs), and the benefit by objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). When possible, data were meta-analyzed. Results Of the 6207 records identified, we included 31 sub-trials or arms of nine umbrella trials ( N = 1637). The pooled overall ORR was 17.7% (95% confidence interval [CI] 9.5–25.9). The ORR for targeted therapies in the experimental arms was significantly lower than the ORR for a combination of targeted therapy drugs with chemotherapy: 13.3% vs 39.0%; p = 0.005. The median PFS was 2.4 months (95% CI 1.9–2.9), and the median OS was 7.1 months (95% CI 6.1–8.4). The overall drug-related death rate (drug-related grade 5 AEs rate) was 0.8% (95% CI 0.3–1.4), and the average drug-related grade 3/4 AE rate per person was 0.45 (95% CI 0.40–0.50). Conclusions Our findings suggest that, on average, one in five cancer patients in umbrella trials published between 1 January 2006 and 7 October 2019 responded to a given therapy, while one in 125 died due to drug toxicity. Our findings do not support the expectation of increased patient benefit in cancer umbrella trials. Further studies should investigate whether umbrella trial design and the precision oncology approach improve patient outcomes.
 
A Multivariable logistic regression model demonstrating risk factors associated with post-COVID-19 condition in adults at 6-month follow-up. Odds ratios and 95% CIs are presented. B Multivariable logistic regression model demonstrating risk factors associated with post-COVID-19 condition in adults at 12-month follow-up. Odds ratios and 95% CIs are presented. C Multivariable logistic regression model demonstrating risk factors associated with post-COVID-19 condition in children at 6-month follow-up. Odds ratios and 95% CIs are presented. D Multivariable logistic regression model demonstrating risk factors associated with post-COVID-19 condition in children at 12-month follow-up. Odds ratios and 95% CIs are presented
Article
Background: Previous studies assessing the prevalence of COVID-19 sequelae in adults and children were performed in the absence of an agreed definition. We investigated prevalence of post-COVID-19 condition (PCC) (WHO definition), at 6- and 12-months follow-up, amongst previously hospitalised adults and children and assessed risk factors. Methods: Prospective cohort study of children and adults with confirmed COVID-19 in Moscow, hospitalised between April and August, 2020. Two follow-up telephone interviews, using the International Severe Acute Respiratory and Emerging Infection Consortium survey, were performed at 6 and 12 months after discharge. Results: One thousand thirteen of 2509 (40%) of adults and 360 of 849 (42%) of children discharged participated in both the 6- and 12-month follow-ups. PCC prevalence was 50% (95% CI 47-53) in adults and 20% (95% CI 16-24) in children at 6 months, with decline to 34% (95% CI 31-37) and 11% (95% CI 8-14), respectively, at 12 months. In adults, female sex was associated with PCC at 6- and 12-month follow-up (OR 2.04, 95% CI 1.57 to 2.65) and (OR 2.04, 1.54 to 2.69), respectively. Pre-existing hypertension (OR 1.42, 1.04 to 1.94) was associated with post-COVID-19 condition at 12 months. In children, neurological comorbidities were associated with PCC both at 6 months (OR 4.38, 1.36 to 15.67) and 12 months (OR 8.96, 2.55 to 34.82) while allergic respiratory diseases were associated at 12 months (OR 2.66, 1.04 to 6.47). Conclusions: Although prevalence of PCC declined one year after discharge, one in three adults and one in ten children experienced ongoing sequelae. In adults, females and persons with pre-existing hypertension, and in children, persons with neurological comorbidities or allergic respiratory diseases are at higher risk of PCC.
 
Article
Background Previous findings on the associations of thiazide use with skin cancers were conflicting. This study aimed to examine the associations of individual thiazide use with skin cancer risk, differentiated by subtypes of skin cancers, geographic regions, and cumulative doses of individual thiazides. Methods We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials for relevant studies on January 5, 2022, scanned the references of included studies, and consulted experts. We included case-control and cohort studies or randomized trials reporting the associations of individual thiazide or thiazide-like diuretics use with skin cancers. Non-melanoma skin cancer (NMSC) and melanoma were analysed separately. A random-effects model meta-analysis was conducted for pooled odds ratio (OR) and hazard ratio (HR) for skin cancers related to individual thiazide use. Results We included 15, 5, and 5 case-control or cohort studies reporting the risk for skin cancers associated with hydrochlorothiazide, bendroflumethiazide, and indapamide use, respectively, with 17,848,313 participants. The meta-analysis showed associations of hydrochlorothiazide use with increased risk of NMSC (OR 1.16, 95% CI 1.08–1.24; HR 1.26, 95% CI 1.04–1.54), squamous cell carcinoma (SCC) (OR 1.32, 95% CI 1.06–1.65; HR 1.61, 95% CI 0.97–2.67), and melanoma (OR 1.11, 95% CI 1.02–1.20; HR 1.03, 95% CI 0.93–1.14). The increased risks for SCC were associated with high cumulative doses of hydrochlorothiazide (OR 2.56, 95% CI 1.43–4.57; HR 1.20, 95% CI 1.00–1.45). Hydrochlorothiazide use was associated with different subtypes of melanoma including superficial spreading (OR 1.18, 95% CI 1.05–1.33), nodular (OR 1.23, 95% CI 1.08–1.39), and lentigo maligna melanoma (OR 1.33, 95% CI 1.08–1.65). Various cumulative doses of hydrochlorothiazide were associated with increased odds for melanoma. However, the associations of hydrochlorothiazide use with increased risk of NMSC and melanoma only appeared in non-Asian countries. No meaningful increase in the risk for skin cancers was associated with bendroflumethiazide and indapamide. Conclusions Hydrochlorothiazide is associated with an increased risk for NMSC (especially SCC) and melanoma in non-Asian countries, whereas bendroflumethiazide and indapamide are not associated with a meaningful risk for skin cancers. Healthcare professionals and patients should be informed of the different risk profiles of skin cancers associated with different thiazides, cumulative doses, and regions. Trial registration PROSPERO CRD42021234317.
 
Survival curves for the cumulative incidence rate of all-cause mortality to 30 days. Model 1 was unadjusted; model 2 was adjusted for age only; model 3 was adjusted for age, sex, education, hospital levels, BMI, family history of CAD, prior history of stroke, prior history of COPD, and pre-admission aspirin; model 4 was further adjusting for presenting characteristics including onset-to-arrival time, pre-admission cardiac arrest, heart rate, systolic blood pressure, plasma creatinine, Killip class, and anterior myocardial infarction; model 5 was further adjusted for in-hospital medical treatment including reperfusion strategies and evidence-based medications (aspirin, P2Y12-receptor inhibitor, statin, ACEI/ARB, and β-blocker). SMuRF, standard modifiable cardiovascular risk factor; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker
Article
Background Recent publications reported a paradoxical finding that there was an inverse association between the number of standard modifiable risk factors (SMuRFs; smoking, hypertension, diabetes, and hyperlipidemia) and mortality in patients with myocardial infarction. However, the current evidence is only limited to those highly developed countries with advanced medical management systems. Methods The China Acute Myocardial Infarction registry is a prospective observational study including patients with acute myocardial infarction from three-level hospitals across 31 administrative regions throughout mainland China. A total of 16,228 patients with first-presentation ST-elevation myocardial infarction (STEMI) admitted to hospitals from January 2013 to September 2014 were enrolled in the current analysis. Cox proportional hazard models adjusting for baseline characteristics, clinical profiles at presentation, and in-hospital treatments were used to assess the association of the number of SMuRFs with all-cause mortality at 30 days after STEMI presentation. Results A total of 1918 (11.8%), 11,503 (70.9%), and 2807 (17.3%) patients had 0, 1–2, and 3–4 SMuRFs at presentation, respectively. Patients with fewer SMuRFs were older and more likely to be females, experienced longer pre-hospital delays, and were less likely to receive primary percutaneous coronary intervention and evidence-based medications. Compared with those without any SMuRF, patients with 1–2 SMuRFs and 3–4 SMuRFs were associated with an HR of 0.74 (95% CI, 0.63–0.87) and 0.63 (0.51–0.77) for all-cause mortality up to 30 days in the unadjusted model (Ptrend < 0.0001). However, after multivariate adjustment, the number of SMuRFs was positively associated with increased mortality risk (HR for 1–2 SMuRFs, 1.15 [0.95–1.39]; HR for 3–4 SMuRFs, 1.31 [1.02–1.68]; Ptrend = 0.03), and the association was only significant among patients admitted to hospitals beyond 12 h from onset (HR for 1–2 SMuRFs, 1.39 [1.03–1.87]; HR for 3–4 SMuRFs, 2.06 [1.41–3.01]) but not their counterparts (Pinteraction = 0.01). Conclusions The increased crude mortality risk among patients without SMuRFs is explained by confounding factors related to their poor risk profiles (old age, longer pre-hospital delays, and poor clinical management). After multivariate adjustment, a higher risk-factor burden was associated with poor prognosis among patients with STEMI.
 
Inclusion/exclusion flowchart
Kaplan-Meir plot for positive SARS-CoV-2 test over time, by priority group
Article
Background: While the vaccines against COVID-19 are highly effective, COVID-19 vaccine breakthrough is possible despite being fully vaccinated. With SARS-CoV-2 variants still circulating, describing the characteristics of individuals who have experienced COVID-19 vaccine breakthroughs could be hugely important in helping to determine who may be at greatest risk. Methods: With the approval of NHS England, we conducted a retrospective cohort study using routine clinical data from the OpenSAFELY-TPP database of fully vaccinated individuals, linked to secondary care and death registry data and described the characteristics of those experiencing COVID-19 vaccine breakthroughs. Results: As of 1st November 2021, a total of 15,501,550 individuals were identified as being fully vaccinated against COVID-19, with a median follow-up time of 149 days (IQR: 107-179). From within this population, a total of 579,780 (<4%) individuals reported a positive SARS-CoV-2 test. For every 1000 years of patient follow-up time, the corresponding incidence rate (IR) was 98.06 (95% CI 97.93-98.19). There were 28,580 COVID-19-related hospital admissions, 1980 COVID-19-related critical care admissions and 6435 COVID-19-related deaths; corresponding IRs 4.77 (95% CI 4.74-4.80), 0.33 (95% CI 0.32-0.34) and 1.07 (95% CI 1.06-1.09), respectively. The highest rates of breakthrough COVID-19 were seen in those in care homes and in patients with chronic kidney disease, dialysis, transplant, haematological malignancy or who were immunocompromised. Conclusions: While the majority of COVID-19 vaccine breakthrough cases in England were mild, some differences in rates of breakthrough cases have been identified in several clinical groups. While it is important to note that these findings are simply descriptive and cannot be used to answer why certain groups have higher rates of COVID-19 breakthrough than others, the emergence of the Omicron variant of COVID-19 coupled with the number of positive SARS-CoV-2 tests still occurring is concerning and as numbers of fully vaccinated (and boosted) individuals increases and as follow-up time lengthens, so too will the number of COVID-19 breakthrough cases. Additional analyses, to assess vaccine waning and rates of breakthrough COVID-19 between different variants, aimed at identifying individuals at higher risk, are needed.
 
Top-cited authors
Douglas Altman
  • University of Oxford
Michael Berk
  • Deakin University
Trisha Greenhalgh
  • University of Oxford
Kevin Eliceiri
  • University of Wisconsin–Madison
Patricia J Keely
  • University of Wisconsin–Madison