Colorectal cancer (CRC) is one of the most common malignancies and a leading cause of cancer morbidity and mortality worldwide¹. Many factors can impact survival including the presence of metastases. The most common site of colorectal cancer metastases is the liver, as almost 20 percent of patients with CRC have liver metastasis at presentation². Among patients without liver metastases at presentation, about 25 percent will develop metachronous liver metastasis at some point in their disease course³. Different treatment options are available for patients with CRC and colorectal liver metastases (CRLM) including locoregional and systemic therapies³. Surgical resection remains, however, the best chance at long-term survival and cure4,5. In this chapter, we aim to describe the different imaging modalities used to evaluate and stage patients with CRLM. We describe the role that each imaging modality plays and discuss the elements of hepatic imaging related to evaluation of response to preoperative therapy, as well as surgical planning.
Improvements in DNA sequencing technology and an expansion of available systemic therapies have together resulted in dramatic advances in personalized therapy for metastatic colorectal cancer. As a result, modern multidiscplinary management requires a thorough understanding of “prognostic biomarkers” associated with a likely cancer outcome independent of treatment, and “predictive biomarkers” associated with a differential treatment effect between positive and negative patients. Unique patient details currently utilized as prognostic or predictive biomarkers to inform the personalized multidisciplinary management of metastatic colorectal cancer include disease characteristics, histologic subtype, tumor sidedness, and molecular characterizations of patient pharmacogenetics and tumor tissue. Many additional biomarkers are under active investigation, including immunologic markers, the gut microbiome, circulating tumor cells and cell free DNA. The continuous development of targeted agents hand in hand with ongoing clinical trials evaluating novel systemic therapies on cohorts sharing common biomarkers, together offer promise for further improvements in survival over time.
The number of cancer survivors increases yearly in the United States, with over 1.5 million people now living with a past or current diagnosis of colorectal cancer. Survivorship care focuses on four core essential components of care in these patients. This includes surveillance for recurrence and screening for second primary cancers, assessment and management of physical and psychosocial effects of cancer and treatment, routine health promotion needs, and lastly coordination of care among specialists and primary care physicians. The emphasis on the importance of survivorship care has only emerged in the last 15 years. As a result, studies and guidelines are lacking, particularly in subgroups of patients such as those with colorectal liver metastases. This chapter outlines the present research on each essential component of this care, highlights limitations, and provides future directions for research.
Non-fasting lipidemia (nFL), mainly contributed by postprandial lipidemia (PL), has recently been recognized as an important cardiovascular disease (CVD) risk as fasting lipidemia (FL). PL serves as a common feature of dyslipidemia in Type 2 Diabetes (T2D), albeit effective therapies targeting on PL were limited. In this study, we aimed to evaluate whether the therapy combining probiotics (Prob) and berberine (BBR), a proven antidiabetic and hypolipidemic regimen via altering gut microbiome, could effectively reduce PL in T2D and to explore the underlying mechanism. Blood PL (120 min after taking 100 g standard carbohydrate meal) was examined in 365 participants with T2D from the Probiotics and BBR on the Efficacy and Change of Gut Microbiota in Patients with Newly Diagnosed Type 2 Diabetes (PREMOTE study), a random, placebo-controlled, and multicenter clinical trial. Prob+BBR was superior to BBR or Prob alone in improving postprandial total cholesterol (pTC) and low-density lipoprotein cholesterol (pLDLc) levels with decrement of multiple species of postprandial lipidomic metabolites after 3 months follow-up. This effect was linked to the changes of fecal Bifidobacterium breve level responding to BBR alone or Prob+BBR treatment. Four fadD genes encoding long-chain acyl-CoA synthetase were identified in the genome of this B. breve strain, and transcriptionally activated by BBR. In vitro BBR treatment further decreased the concentration of FFA in the culture medium of B. breve compared to vehicle. Thus, the activation of fadD by BBR could enhance FFA import and mobilization in B. breve and diliminish the intraluminal lipids for absorption to mediate the effect of Prob+BBR on PL. Our study confirmed that BBR and Prob (B. breve) could exert a synergistic hypolipidemic effect on PL, acting as a gut lipid sink to achieve better lipidemia and CVD risk control in T2D.
Objective As part of a quality improvement project, we developed and employed an observation checklist to measure patient-centered behaviors during daily rounds to assess the frequency of patient-centered behaviors among a patient-centered care (PCC) team and standard team (ST) rounds. Patients and Methods On four general medicine service (GMS) teaching teams at an urban academic medical center in which housestaff rotate, we utilized an observation checklist to assess the occurrence of eight behaviors on inpatient daily rounds. The checklist covered domains of patient-centered communication, etiquette-based behaviors, and shared decision-making. One GMS team is guided by a PCC curriculum that emphasizes patient-centered communication strategies, but not specifically behaviors during bedside rounds. Results Between August 2018 and May 2019 a trained observer completed 448 observations of patient rounding encounters using the checklist. Across all teams, 46.0% of the 8 behaviors were performed when possible, with more done on the PCC team (58.0%) than ST (42.0%), p < 0.01. Conclusions Performance of patient-centered behaviors during daily rounds was low overall. Despite having no specific instruction on daily rounds, patient-centered behaviors were more frequent among the teams which were part of a PCC curriculum. However, the frequency of observed behaviors was modest, suggesting that more explicit efforts to change rounding behaviors are needed. Our observational checklist may be a tool to assist in future interventions to improve patient-centered behaviors on daily rounds.
Background Destination left ventricular assist device placement is increasing as a result of donor shortages and changing patient attitudes. As organ shortages become critical, LVAD programs become fundamental even in more remote regions of the world including island states. Here, we provide a look into the current state and availability of LVAD programs in island states. Main body A narrative review was performed using the World Health Organization Global Index Medicus and PubMed/MEDLINE databases to identify articles describing the island states having reported LVAD placements and programs. Additionally, INTERMACS reports were used. Data were retrieved and a review is presented describing the current state of LVADs in island states. The Caribbean region as a whole has a heart failure (HF) prevalence of 814 per 100,000 and Oceania 667 per 100,000 people. We estimate that over 3000 people in these islands need either a heart transplant or an LVAD. Short conclusion For HF patients living in island regions, special attention should be paid to the inability of having access to specialized mainland medical care. The continuous quest for a solution to HF in island regions should include the establishing of high-quality LVAD programs in a transfer-network centralized/regionalized system to care for those patients not candidates for long-distance air-bridging.
Objectives To assess volumetric DCE-MRI radiomics nomogram in predicting response to neoadjuvant chemotherapy (nCT) in EC patients. Methods This retrospective analysis of a prospective study enrolled EC patients with stage cT1N + M0 or cT2-4aN0-3M0 who received DCE-MRI within 7 days before chemotherapy, followed by surgery. Response assessment was graded from 1 to 5 according to the tumor regression grade (TRG). Patients were stratified into responders (TRG1 + 2) and non-responders (TRG3 + 4 + 5). 72 radiomics features and vascular permeability parameters were extracted from DCE-MRI. The discriminating performance was assessed with ROC. Decision curve analysis (DCA) was used for comparing three different models. Results This cohort included 82 patients, and 72 tumor radiomics features and vascular permeability parameters acquired from DCE-MRI. mRMR and LASSO were performed to choose the optimized subset of radiomics features, and 3 features were selected to create the radiomics signature that were significantly associated with response ( P < 0.001). AUC of combining radiomics signature and DCE-MRI performance in the training (n = 41) and validation (n = 41) cohort was 0.84 (95% CI 0.57–1) and 0.86 (95% CI 0.74–0.97), respectively. This combined model showed the best discrimination between responders and non-responders, and showed the highest positive and positive predictive value in both training set and test set. Conclusions The radiomics features are useful for nCT response prediction in EC patients.
The COVID-19 pandemic has underscored the changing role of scientists, clinicians, ethicists, and educators in advocacy as they rapidly translate their findings to inform practice and policy. Critical efforts have been directed towards understanding child well-being, especially with pandemic-related educational disruptions. While school closures were part of early widespread public health measures to curb the spread of COVID-19, they have not been without consequences for all children, and especially for children from disadvantaged backgrounds. In a recent Isr J Health Policy Res perspective, Paltiel and colleagues demonstrate the integral role of academic activism to promote child well-being during the pandemic by highlighting work of the multidisciplinary academic group on children and coronavirus (MACC). In this commentary, we explore parallels to MACC’s work in an international context by describing the efforts of a multidisciplinary team at Johns Hopkins University in Baltimore, Maryland, United States, to aggregate data, conduct analyses, and offer training tools intended to minimize health and educational inequities for children throughout the COVID-19 pandemic. As both MACC and our work collectively demonstrates, multidisciplinary partnerships and public-facing data-driven initiatives are crucial to advocating for children's equitable access to quality health and education. This will likely not be the last pandemic that children experience in their lifetime. As such, efforts should be made to apply the lessons learned during the current pandemic to strengthen multidisciplinary academic-public partnerships which will continue to play a critical role in the future.
Background Spinal cord motor neurons (MNs) from human iPS cells (iPSCs) have wide applications in disease modeling and therapeutic development for amyotrophic lateral sclerosis (ALS) and other MN-associated neurodegenerative diseases. We need highly efficient MN differentiation strategies for generating iPSC-derived disease models that closely recapitulate the genetic and phenotypic complexity of ALS. An important application of these models is to understand molecular mechanisms of action of FDA-approved ALS drugs that only show modest clinical efficacy. Novel mechanistic insights will help us design optimal therapeutic strategies together with predictive biomarkers to achieve better efficacy. Methods We induce efficient MN differentiation from iPSCs in 4 days using synthetic mRNAs coding two transcription factors (Ngn2 and Olig2) with phosphosite modification. These MNs after extensive characterization were applied in electrophysiological and neurotoxicity assays as well as transcriptomic analysis, to study the neuroprotective effect and molecular mechanisms of edaravone, an FDA-approved drug for ALS, for improving its clinical efficacy. Results We generate highly pure and functional mRNA-induced MNs (miMNs) from control and ALS iPSCs, as well as embryonic stem cells. Edaravone alleviates H 2 O 2 -induced neurotoxicity and electrophysiological dysfunction in miMNs, demonstrating its neuroprotective effect that was also found in the glutamate-induced miMN neurotoxicity model. Guided by the transcriptomic analysis, we show a previously unrecognized effect of edaravone to induce the GDNF receptor RET and the GDNF/RET neurotrophic signaling in vitro and in vivo, suggesting a clinically translatable strategy to activate this key neuroprotective signaling. Notably, edaravone can replace required neurotrophic factors (BDNF and GDNF) to support long-term miMN survival and maturation, further supporting the neurotrophic function of edaravone-activated signaling. Furthermore, we show that edaravone and GDNF combined treatment more effectively protects miMNs from H 2 O 2 -induced neurotoxicity than single treatment, suggesting a potential combination strategy for ALS treatment. Conclusions This study provides methodology to facilitate iPSC differentiation and disease modeling. Our discoveries will facilitate the development of optimal edaravone-based therapies for ALS and potentially other neurodegenerative diseases. Graphical abstract
Soft tissue reconstruction remains an intractable clinical challenge as current surgical options and synthetic implants may produce inadequate outcomes. Soft tissue deficits may be surgically reconstructed using autologous adipose tissue, but these procedures can lead to donor site morbidity, require multiple procedures, and have highly variable outcomes. To address this clinical need, we developed an “off-the-shelf” adipose extracellular matrix (ECM) biomaterial from allograft human tissue (Acellular Adipose Tissue, AAT). We applied physical and chemical processing methods to remove lipids and create an injectable matrix that mimicked the properties of lipoaspirate. Biological activity was assessed using cell migration and adipogenesis assays. Characterization of regenerative immune properties in a murine muscle injury model revealed that allograft and xenograft AAT induced pro-regenerative CD4 ⁺ T cells and macrophages with xenograft AAT additionally attracting eosinophils secreting interleukin 4 (Il4). In immunocompromised mice, AAT injections retained similar volumes as human fat grafts but lacked cysts and calcifications seen in the fat grafts. The combination of AAT with human adipose-derived stem cells (ASCs) resulted in lower implant volumes. However, tissue remodeling and adipogenesis increased significantly in combination with ASCs. Larger injected volumes of porcine-derived AAT demonstrated biocompatibility and greater retention when applied allogeneicly in Yorkshire cross pigs. AAT was implanted in healthy volunteers in abdominal tissue that was later removed by elective procedures. AAT implants were well tolerated in all human subjects. Implants removed between 1 and 18 weeks demonstrated increasing cellular infiltration and immune populations, suggesting continued tissue remodeling and the potential for long-term tissue replacement.
Background The contemporary frameworks for clinical research require informed consent for research participation that includes disclosure of material information, comprehension of disclosed information and voluntary consent to research participation. There is thus an urgent need to test, and an ethical imperative, to test, modify or refine medications or healthcare plans that could reduce patient morbidity, lower healthcare costs or strengthen healthcare systems. Methods Conceptual review. Discussion Although some allocation principles seem better than others, no single moral principle allocates interventions justly, necessitating combining the moral principles into multiprinciple allocation systems. The urgency notwithstanding, navigating ethical challenges related to conducting corona virus disease (COVID-19) clinical trials is mandatory, in order to safeguard the safety and welfare of research participants, ensure autonomy of participants, reduce possibilities for exploitation and ensure opportunities for research participation. The ethical challenges to can be categorized as challenges in allocation of resources for research; challenges of clinical equipoise in relation to the research questions; challenges of understanding disclosed information in potential participants; and challenges in obtaining informed consent. Conclusion To navigate these challenges, stakeholders need a delicate balance of moral principles during allocation of resources for research. Investigators need to apply information processing theories to aid decision-making about research participation or employ acceptable modifications to improve the informed consent process. Research and ethics committees should strengthen research review and oversight to ensure rigor, responsiveness and transparency.
The World Magnetic Model (WMM) is a geomagnetic main field model that is widely used for navigation by governments, industry and the general public. In recent years, the model has been derived using high accuracy magnetometer data from the Swarm mission. This study explores the possibility of developing future WMMs in the post-Swarm era using data from the Iridium satellite constellation. Iridium magnetometers are primarily used for attitude control, so they are not designed to produce the same level of accuracy as magnetic data from scientific missions. Iridium magnetometer errors range from 30 nT quantization to hundreds of nT errors due to spacecraft contamination and calibration uncertainty, whereas Swarm measurements are accurate to about 1 nT. The calibration uncertainty in the Iridium measurements is identified as a major error source, and a method is developed to calibrate the spacecraft measurements using data from a subset of the INTERMAGNET observatory network producing quasi-definitive data on a regular basis. After calibration, the Iridium data produced main field models with approximately 20 nT average error and 40 nT maximum error as compared to the CHAOS-7.2 model. For many scientific and precision navigation applications, highly accurate Swarm-like measurements are still necessary, however, the Iridium-based models were shown to meet the WMM error tolerances, indicating that Iridium is a viable data source for future WMMs. Graphical Abstract
Background DNA methylation alterations have emerged as hallmarks of cancer and have been proposed as screening, prognostic, and predictive biomarkers. Traditional approaches for methylation analysis have relied on bisulfite conversion of DNA, which can damage DNA and is not suitable for targeted gene analysis in low-input samples. Here, we have adapted methyl-CpG-binding domain protein 2 (MBD2)-based DNA enrichment for use on a semi-automated exclusion-based sample preparation (ESP) platform for robust and scalable enrichment of methylated DNA from low-input samples, called SEEMLIS. Results We show that combining methylation-sensitive enzyme digestion with ESP-based MBD2 enrichment allows for single gene analysis with high sensitivity for GSTP1 in highly impure, heterogenous samples. We also show that ESP-based MBD2 enrichment coupled with targeted pre-amplification allows for analysis of multiple genes with sensitivities approaching the single cell level in pure samples for GSTP1 and RASSF1 and sensitivity down to 14 cells for these genes in highly impure samples. Finally, we demonstrate the potential clinical utility of SEEMLIS by successful detection of methylated gene signatures in circulating tumor cells (CTCs) from patients with prostate cancer with varying CTC number and sample purity. Conclusions SEEMLIS is a robust assay for targeted DNA methylation analysis in low-input samples, with flexibility at multiple steps. We demonstrate the feasibility of this assay to analyze DNA methylation in prostate cancer cells using CTCs from patients with prostate cancer as a real-world example of a low-input analyte of clinical importance. In summary, this novel assay provides a platform for determining methylation signatures in rare cell populations with broad implications for research as well as clinical applications.
Background The US guidelines recommend avoiding marijuana during breastfeeding given concerns about infant’s neurodevelopment. In this setting, some physicians and hospitals recommend against or prohibit breastfeeding when marijuana use is detected during pregnancy. However, breastfeeding is beneficial for infants and women, and stigmatization of substance use in pregnancy has been historically linked to punitive approaches with a disproportionate impact on minority populations. We advance an empirically informed ethical analysis of this issue. Methods First, we performed a retrospective cross-sectional qualitative study of prenatal and postpartum records from a random sample of 150 women delivered in an academic hospital system in 2017 to provide evidence and context regarding breastfeeding management in relation to marijuana use. We then perform a scoping literature review on infant risks from breastmilk marijuana exposure and risks associated with not breastfeeding for infants and women. Finally, we analyze this issue vis-a-vis ethical principles of beneficence, autonomy, and justice. Results (1) Medical records reveal punitive language pertaining to the medicinal use of marijuana in pregnancy and misinterpretation of national guidelines, e.g., “patient caught breastfeeding and instructed to stop.” (2) Though there are plausible neurodevelopmental harms from breastmilk exposure to THC, evidence of infant effects from breastmilk exposure to marijuana is limited and largely confounded by concomitant pregnancy exposure and undisclosed exposures. By contrast, health benefits of breastfeeding for women and infants are well-established, as are harms of forgoing breastfeeding. (3) Discouraging breastfeeding for women with marijuana use in pregnancy contradicts beneficence, as it neglects women’s health considerations and incorrectly assumes that risks exceed benefits for infants. Restrictive hospital practices (e.g., withholding lactation support) compromise maternal autonomy and exploit power asymmetry between birthing persons and institutions, particularly when compulsory toxicology screening prompts child welfare investigations. Finally, recommending against breastfeeding during prenatal care and imposing restrictions during postpartum hospitalization may exacerbate racial disparities in breastfeeding and related health outcomes. Conclusions Policy interpretations which discourage rather than encourage breastfeeding among women who use of marijuana may cause net harm, compromise autonomy, and disproportionately threaten health and wellbeing of underserved women and infants.
Background Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are characterized by shared exposures and clinical features, but distinct genetic and pathologic features exist. These features have not been well-studied using large-scale gene expression datasets. We hypothesized that there are divergent gene, pathway, and cellular signatures between COPD and IPF. Methods We performed RNA-sequencing on lung tissues from individuals with IPF (n = 231) and COPD (n = 377) compared to control (n = 267), defined as individuals with normal spirometry. We grouped the overlapping differential expression gene sets based on direction of expression and examined the resultant sets for genes of interest, pathway enrichment, and cell composition. Using gene set variation analysis, we validated the overlap group gene sets in independent COPD and IPF data sets. Results We found 5010 genes differentially expressed between COPD and control, and 11,454 genes differentially expressed between IPF and control (1% false discovery rate). 3846 genes overlapped between IPF and COPD. Several pathways were enriched for genes upregulated in COPD and downregulated in IPF; however, no pathways were enriched for genes downregulated in COPD and upregulated in IPF. There were many myeloid cell genes with increased expression in COPD but decreased in IPF. We found that the genes upregulated in COPD but downregulated in IPF were associated with lower lung function in the independent validation cohorts. Conclusions We identified a divergent gene expression signature between COPD and IPF, with increased expression in COPD and decreased in IPF. This signature is associated with worse lung function in both COPD and IPF.
Granulomatous lobular mastitis (GLM) is a rare and chronic benign inflammatory disease of the breast. Difficulties exist in the management of GLM for many front-line surgeons and medical specialists who care for patients with inflammatory disorders of the breast. This consensus is summarized to establish evidence-based recommendations for the management of GLM. Literature was reviewed using PubMed from January 1, 1971 to July 31, 2020. Sixty-six international experienced multidisciplinary experts from 11 countries or regions were invited to review the evidence. Levels of evidence were determined using the American College of Physicians grading system, and recommendations were discussed until consensus. Experts discussed and concluded 30 recommendations on historical definitions, etiology and predisposing factors, diagnosis criteria, treatment, clinical stages, relapse and recurrence of GLM. GLM was recommended as a widely accepted definition. In addition, this consensus introduced a new clinical stages and management algorithm for GLM to provide individual treatment strategies. In conclusion, diagnosis of GLM depends on a combination of history, clinical manifestations, imaging examinations, laboratory examinations and pathology. The approach to treatment of GLM should be applied according to the different clinical stage of GLM. This evidence-based consensus would be valuable to assist front-line surgeons and medical specialists in the optimal management of GLM.
Advances in cardiac surgical operative techniques and myocardial protection have dramatically improved outcomes in the past two decades. An unfortunate and unintended consequence is that 80% of the preventable morbidity and mortality following cardiac surgery now originates outside of the operating room. Our hope is that a renewed emphasis on evidence-based best practice and standardized perioperative care will reduce overall morbidity and mortality and improve patient-centric care. The Perioperative Quality Initiative (POQI) and Enhanced Recovery After Surgery–Cardiac Society (ERAS® Cardiac) have identified significant evidence gaps in perioperative medicine related to cardiac surgery, defined as areas in which there is significant controversy about how best to manage patients. These five areas of focus include patient blood management, goal-directed therapy, acute kidney injury, opioid analgesic reduction, and delirium.
The cerebellum’s anatomical and functional organization and network interactions between the cerebellum and the cerebral cortex and subcortical structures are dynamic across the lifespan. Executive, emotional and social (EES) functions have likewise evolved during human development from contributing to primitive behaviors during infancy and childhood to being able to modulate complex actions in adults. In this review, we address how the importance of the cerebellum in the processing of EES functions might change across development. This evolution is driven by the macroscopic and microscopic modifications of the cerebellum that are occurring during development including its increasing connectivity with distant supra-tentorial cortical and sub-cortical regions. As a result of anatomical and functional changes, neuroimaging and clinical data indicate that the importance of the role of the cerebellum in human EES-related networks shifts from being crucial in newborns and young children to being only supportive later in life. In early life, given the immaturity of cortically mediated EES functions, EES functions and motor control and perception are more closely interrelated. At that time, the cerebellum due to its important role in motor control and sequencing makes EES functions more reliant on these computational properties that compute spatial distance, motor intent, and assist in the execution of sequences of behavior related to their developing EES expression. As the cortical brain matures, EES functions and decisions become less dependent upon these aspects of motor behavior and more dependent upon high-order cognitive and social conceptual processes. At that time, the cerebellum assumes a supportive role in these EES-related behaviors by computing their motor and sequential features. We suspect that this evolving role of the cerebellum has complicated the interpretation of its contribution to EES computational demands.
Background We previously showed that continued folic acid (FA) supplementation beyond the first trimester of pregnancy appears to have beneficial effects on neurocognitive performance in children followed for up to 11 years, but the biological mechanism for this effect has remained unclear. Using samples from our randomized controlled trial of folic acid supplementation in second and third trimester (FASSTT), where significant improvements in cognitive and psychosocial performance were demonstrated in children from mothers supplemented in pregnancy with 400 µg/day FA compared with placebo, we examined methylation patterns from cord blood (CB) using the EPIC array which covers approximately 850,000 cytosine–guanine (CG) sites across the genome. Genes showing significant differences were verified using pyrosequencing and mechanistic approaches used in vitro to determine effects on transcription. Results FA supplementation resulted in significant differences in methylation, particularly at brain-related genes. Further analysis showed these genes split into two groups. In one group, which included the CES1 gene, methylation changes at the promoters were important for regulating transcription. We also identified a second group which had a characteristic bimodal profile, with low promoter and high gene body (GB) methylation. In the latter, loss of methylation in the GB is linked to decreases in transcription: this group included the PRKAR1B / HEATR2 genes and the dopamine receptor regulator PDE4C . Overall, methylation in CB also showed good correlation with methylation profiles seen in a published data set of late gestation foetal brain samples. Conclusion We show here clear alterations in DNA methylation at specific classes of neurodevelopmental genes in the same cohort of children, born to FA-supplemented mothers, who previously showed improved cognitive and psychosocial performance. Our results show measurable differences at neural genes which are important for transcriptional regulation and add to the supporting evidence for continued FA supplementation throughout later gestation. This trial was registered on 15 May 2013 at www.isrctn.com as ISRCTN19917787.
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