This study aims to explore whether and how positive and negative supercoiling contribute to the three-dimensional (3D) organization of the bacterial genome. We used recently published Escherichia coli GapR ChIP-seq and TopoI ChIP-seq (also called EcTopoI-seq) data, which marks positive and negative supercoiling sites, respectively, to study how supercoiling correlates with the spatial contact maps obtained from chromosome conformation capture sequencing (Hi-C and 5C). We find that supercoiled chromosomal loci have overall higher Hi-C contact frequencies than sites that are not supercoiled. Surprisingly, positive supercoiling corresponds to higher spatial contact than negative supercoiling. Additionally, positive, but not negative, supercoiling could be identified from Hi-C data with high accuracy. We further find that the majority of positive and negative supercoils coincide with highly active transcription units, with a minor group likely associated with replication and other genomic processes. Our results show that both positive and negative supercoiling enhance spatial contact, with positive supercoiling playing a larger role in bringing genomic loci closer in space. Based on our results, we propose new physical models of how the E. coli chromosome is organized by positive and negative supercoils.
Background Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States. While HPV is a vaccine-preventable illness, vaccine utilization rates in the United States remain low, particularly among adults. Methods The objective of this study was to assess the impact of an online, asynchronous educational module on HPV vaccination for adult primary care providers. We designed and implemented the module for family medicine, internal medicine, medicine/pediatrics, and obstetrics/gynecology providers in a community practice network affiliated with a large academic health system. We evaluated the effect of the module on provider knowledge, attitudes, and self-reported behaviors with pre-, post-, and delayed post-tests, using Likert-scales for measurement. We summarized data with descriptive statistics and compared changes in individuals using paired t-tests. Results One hundred forty-four out of 223 providers completed the module (response rate of 65%). At baseline, internists had the lowest knowledge scores compared to other specialties (pre-test mean of 3.6, out of 5, SD 1.2). Internists were also the least likely to counsel patients on HPV vaccination (mean 1.6, SD 0.9). There was a statistically significant improvement in knowledge from pre-test to post-test (from mean of 3.8 to 4.6, out of 5, p < .001) across all specialties. There was also statistically significant improvement in mean confidence for all providers from pre-test to post-test to identify patients aged 19–26 (3.3 to 3.7, p < .001) and patients aged 27–45 (2.7 to 3.5, p < .001) who needed vaccination. There was a statistically significant improvement in likelihood to counsel eligible patients on the risks of HPV infection (mean 2.3 to 2.8, p-value 0.002). The delayed post-test demonstrated retention of improved knowledge, confidence, and self-reported behavior. Conclusions This study demonstrated that an asynchronous online module was effective at improving confidence, knowledge, and self-reported behavior of adult primary care providers in recommending HPV immunization. Given the important role that healthcare providers play in vaccine uptake, this study suggests that an online educational intervention can be a powerful tool to encourage increased utilization and delivery of the HPV vaccine. Further efforts are needed to educate internists and providers who take care of the adult population on HPV vaccination.
Gene editing strategies for cystic fibrosis are challenged by the complex barrier properties of airway epithelia. We previously reported that the amphiphilic S10 shuttle peptide non-covalently combined with CRISPR-associated (Cas) ribonucleoprotein (RNP) enabled editing of human and mouse airway epithelial cells. Here, we derive the S315 peptide as an improvement over S10 in delivering base editor RNP. Following intratracheal aerosol delivery of Cy5-labeled peptide in rhesus macaques, we confirm delivery throughout the respiratory tract. Subsequently, we target CCR5 with co-administration of ABE8e-Cas9 RNP and S315. We achieve editing efficiencies of up-to 5.3% in rhesus airway epithelia. Moreover, we document persistence of edited epithelia for up to 12 months in mice. Finally, delivery of ABE8e-Cas9 targeting the CFTR R553X mutation restores anion channel function in cultured human airway epithelia. These results demonstrate the therapeutic potential of base editor delivery with S315 to functionally correct the CFTR R553X mutation in respiratory epithelia.
Several related progeroid disorders are caused by defective post-translational processing of prelamin A, the precursor of the nuclear scaffold protein lamin A, encoded by LMNA. Prelamin A undergoes farnesylation and additional modifications at its C-terminus. Subsequently, the farnesylated C-terminal segment is cleaved off by the zinc metalloprotease ZMPSTE24. The premature aging disorder Hutchinson Gilford progeria syndrome (HGPS) and a related progeroid disease, mandibuloacral dysplasia (MAD-B), are caused by mutations in LMNA and ZMPSTE24, respectively, that result in failure to process the lamin A precursor and accumulate permanently farnesylated forms of prelamin A. The farnesyl transferase inhibitor (FTI) lonafarnib is known to correct the aberrant nuclear morphology of HGPS patient cells and improves lifespan in children with HGPS. Importantly, and in contrast to a previous report, we show here that FTI treatment also improves the aberrant nuclear phenotypes in MAD-B patient cells with mutations in ZMPSTE24 (P248L or L425P). As expected, lonafarnib does not correct nuclear defects for cells with lamin A processing-proficient mutations. We also examine prelamin A processing in fibroblasts from two individuals with a prevalent laminopathy mutation LMNA-R644C. Despite the proximity of residue R644 to the prelamin A cleavage site, neither R644C patient cell line shows a prelamin A processing defect, and both have normal nuclear morphology. This work clarifies the prelamin A processing status and role of FTIs in a variety of laminopathy patient cells and supports the FDA-approved indication for the FTI Zokinvy for patients with processing-deficient progeroid laminopathies, but not for patients with processing-proficient laminopathies.
HIV incidence in eastern and southern Africa has historically been concentrated among girls and women aged 15–24 years. As new cases decline with HIV interventions, population-level infection dynamics may shift by age and gender. Here, we integrated population-based surveillance of 38,749 participants in the Rakai Community Cohort Study and longitudinal deep-sequence viral phylogenetics to assess how HIV incidence and population groups driving transmission have changed from 2003 to 2018 in Uganda. We observed 1,117 individuals in the incidence cohort and 1,978 individuals in the transmission cohort. HIV viral suppression increased more rapidly in women than men, however incidence declined more slowly in women than men. We found that age-specific transmission flows shifted: whereas HIV transmission to girls and women (aged 15–24 years) from older men declined by about one-third, transmission to women (aged 25–34 years) from men that were 0–6 years older increased by half in 2003 to 2018. Based on changes in transmission flows, we estimated that closing the gender gap in viral suppression could have reduced HIV incidence in women by half in 2018. This study suggests that HIV programmes to increase HIV suppression in men are critical to reduce incidence in women, close gender gaps in infection burden and improve men’s health in Africa.
TRPV1 is an ion channel that transduces noxious heat and chemical stimuli and is expressed in small fiber primary sensory neurons that represent almost half of skin nerve terminals. Tissue injury and inflammation result in the sensitization of TRPV1 and sustained activation of TRPV1 can lead to cellular toxicity though calcium influx. To identify signals that trigger TRPV1 sensitization after a 24-h exposure, we developed a phenotypic assay in mouse primary sensory neurons and performed an unbiased screen with a compound library of 480 diverse bioactive compounds. Chemotherapeutic agents, calcium ion deregulators and protein synthesis inhibitors were long-acting TRPV1 sensitizers. Amongst the strongest TRPV1 sensitizers were proteasome inhibitors, a class that includes bortezomib, a chemotherapeutic agent that causes small fiber neuropathy in 30–50% of patients. Prolonged exposure of bortezomib produced a TRPV1 sensitization that lasted several days and neurite retraction in vitro and histological and behavioral changes in male mice in vivo. TRPV1 knockout mice were protected from epidermal nerve fiber loss and a loss of sensory discrimination after bortezomib treatment. We conclude that long-term TRPV1 sensitization contributes to the development of bortezomib-induced neuropathy and the consequent loss of sensation, major deficits experienced by patients under this chemotherapeutic agent.
Objective Health care has increasingly expanded into a hybrid in-person/telehealth model. Patients with a variety of health conditions, including cerebellar ataxia, have received virtual health evaluations; however, it remains unknown whether some outcome measures clinicians utilize in the telehealth setting are reliable and valid. The goal of this project is to evaluate the psychometric properties of the Scale for Assessment and Rating of Ataxia (SARA) for patients with cerebellar ataxia in the telehealth setting. Methods Nineteen individuals with cerebellar impairments were recruited on a voluntary basis. Participants completed two 30-minute testing sessions during which a clinical examination and the SARA were performed. One session was performed in person and the other session was assessed remotely. Outcome measure performance was video recorded in both environments and independently scored by 4 additional raters with varying levels of clinical experience (ranging from 6 months to 29 years). Concurrent validity was assessed with the Spearman rank order correlation coefficient (α < .05), comparing the virtual SARA scores to their gold standard in-person scores. Interrater reliability was evaluated with the ICC(2,4) (α < .05). Results Fourteen of the 19 participants completed both in-person and telehealth SARA evaluations. We found that the in-person SARA and the telehealth SARA have large concurrent validity (Spearman rho significant at the 2-tailed α of .01 = 0.90; n = 14). Additionally, raters of varying years of experience had excellent interrater reliability for both the in-person SARA [ICC(2,4) = 0.97; n = 19] and the telehealth SARA [ICC(2,4) = 0.98; n = 14]. Conclusion Our results show that the telehealth SARA is comparable to the in-person SARA. Additionally, raters of varying years of clinical experience were found to have excellent interrater reliability scores for both remote and in-person SARA evaluations. Impact Our study shows that the SARA can be used in the telehealth setting for patients with ataxia.
Since the start of the pandemic, over 15 million youth have tested positive for COVID-19 (American Academy of Pediatrics [AAP], 2023), but less is known about the impact of COVID-19 in children compared to adults. While children generally experience fewer and less severe acute symptoms, a subgroup of children may become quite ill with COVID-19 or multisystem inflammatory syndrome in children (MIS-C). Like adults, a minority of children also go on to develop what is now known as “pediatric long COVID”. Research in children with COVID-19 is limited, but emerging studies suggest that, like adults, children with more severe or persisting forms of COVID-19, including long COVID, may be at risk for a range of physical, cognitive, and emotional/behavioral symptoms. Pediatric neuropsychologists are uniquely positioned to assess neurocognitive functioning in children with COVID-19, help children and families understand the factors affecting the child’s functioning, and provide recommendations for appropriate interventions and management at home, at school, and in the community.
Patient-reported outcomes (PROs) describe measures of a patient’s experience throughout medical care as reported by the patient (Mercieca-Bebber et al. in Patient Relat Outcome Meas, 2018). Various PRO instruments exist. It is challenging to select appropriate instruments given the absence of an organizational framework which describes all measurable PROs in dermatologic surgery and represents which instruments measure which outcomes. Our objective was to systematically review all validated PRO instruments in dermatologic surgery and use qualitative analysis to develop an organizational framework representing PRO measures and instruments. PubMed/MEDLINE, Embase, CINAHL, PsycINFO, and Cochrane databases were searched to retrieve validated PRO instruments in the dermatologic surgery population. The constant comparative method of qualitative analysis was used to develop an organizational framework representing all PROs in dermatologic surgery. All instruments were sorted into this framework. The search identified 3195 articles; 35 validated instruments were extracted and qualitatively analyzed. The organizational framework sorted all instruments into 36 PRO measures aligned with the National Institutes of Health Patient-Reported Outcomes Measurement Information System (Gershon RC, Rothrock N, Hanrahan R, et al (2010) The use of PROMIS and assessment center to deliver patient-reported outcome measures in clinical research). Measures were grouped into four categories (expectations, satisfaction, quality of life, needs) describing how patients experience these outcomes and lenses through which researchers can evaluate them. In conclusion, we have proposed an organizational framework for use in choosing validated instruments to develop and answer PRO research questions.
Pediatric cardiac surgery patients are predisposed to blood loss. Blood product administration can lead to complications. Prothrombin complex concentrates (PCCs) offer potential advantages of factor composition, small volume, decreased immunogenicity/infectious risks, and accessibility. The objective of this study was to describe dosing, monitoring, blood product utilization, and thromboembolic complications of administering four-factor PCC (4F-PCC) in pediatric cardiac surgery. We performed a retrospective review of patients aged <18 years undergoing cardiac surgery from June 2020 to May 2022 (inclusive) who received 4F-PCC. Outcomes of interest included 4F-PCC dosing (units/kg) and number of doses administered, chest tube output, blood product administration, donor exposure, length of stay, and thromboembolic events. Eighty-six patients met eligibility criteria. The median (range) age and weight were 0.37 (0.01–16.3) years and 5.3 (1.6–98) kg, respectively. Median (range) total 4F-PCC dose per patient was 25 (9.2–50) units/kg, with 6 patients (7%) receiving a total of two doses. Median (range) 24-hour postoperative packed red blood cells, platelet, plasma, and cryoprecipitate administration volumes were 0 (0–2.57) mL/kg/24 h, 0 (0–1.09), 0 (0–2.64), and 0 (0–0.28 mL/kg/24 h), respectively. Median (range) length of stay and 24-hour postoperative chest tube output were 10 (6–26) days and 1.1 (0.1–4.2) mL/kg/h, respectively. Two (2%) patients experienced a thromboembolic event within 30 days of 4F-PCC administration. These retrospective findings suggest no worsening of hemostatic parameters, a mild median improvement in fibrinogen, low blood product utilization, and low thromboembolism rates following 4F-PCC use in pediatric cardiac surgery.
Purpose: Severe side effects prevent the utilization of otherwise promising drugs in treatments. These side effects arise when drugs affect untargeted tissues due to poor target specificity. In photopharmacology, light controls the timing and the location of drug delivery, improving treatment specificity and pharmacokinetic control. Photopharmaceuticals have not seen widespread adoption in part because researchers do not always have access to reliable and reproducible light delivery devices at prices which fit within the larger research budget. Method: In this work, we present a customizable photomodulator for use in both wearable and implantable devices. For experimental validation of the photomodulator, we photolyse JF-NP-26 in rats. Results: We successfully drive in vivo photopharmacology with a tethered photomodulator and demonstrate modifications which enable the photomodulator to operate wirelessly. Conclusion: By documenting our photomodulator development, we hope to introduce researchers to a simple solution which significantly lowers the engineering barriers to photopharmacology research. Researchers present a photomodulator, a device designed to facilitate in vivo photopharmacology. They demonstrate the in vivo capabilities of the photomodulator by photoreleasing raseglurant, an mGluR5 inhibitor, to treat pain in an acute rat model and follow this study by showing how to reconfigure the photomodulator to work wirelessly and interface with other biomedical devices.
Background This systematic review and meta-analysis were conducted to objectively evaluate the evidence of machine learning (ML) in the patient diagnosis of Intracranial Hemorrhage (ICH) on computed tomography (CT) scans. Methods Until May 2023, systematic searches were conducted in ISI Web of Science, PubMed, Scopus, Cochrane Library, IEEE Xplore Digital Library, CINAHL, Science Direct, PROSPERO, and EMBASE for studies that evaluated the diagnostic precision of ML model-assisted ICH detection. Patients with and without ICH as the target condition who were receiving CT-Scan were eligible for the research, which used ML algorithms based on radiologists' reports as the gold reference standard. For meta-analysis, pooled sensitivities, specificities, and a summary receiver operating characteristics curve (SROC) were used. Results At last, after screening the title, abstract, and full paper, twenty-six retrospective and three prospective, and two retrospective/prospective studies were included. The overall (Diagnostic Test Accuracy) DTA of retrospective studies with a pooled sensitivity was 0.917 (95% CI 0.88–0.943, I ² = 99%). The pooled specificity was 0.945 (95% CI 0.918–0.964, I ² = 100%). The pooled diagnostic odds ratio (DOR) was 219.47 (95% CI 104.78–459.66, I ² = 100%). These results were significant for the specificity of the different network architecture models ( p -value = 0.0289). However, the results for sensitivity ( p -value = 0.6417) and DOR ( p -value = 0.2187) were not significant. The ResNet algorithm has higher pooled specificity than other algorithms with 0.935 (95% CI 0.854–0.973, I ² = 93%). Conclusion This meta-analysis on DTA of ML algorithms for detecting ICH by assessing non-contrast CT-Scans shows the ML has an acceptable performance in diagnosing ICH. Using ResNet in ICH detection remains promising prediction was improved via training in an Architecture Learning Network (ALN).
Stroke is a well-characterized complication of isolated heart and lung transplantation but has not been described in combined heart-lung transplantation (HLTx). We retrospectively reviewed national U.S. data to describe the incidence, risk factors, and impact of postoperative stroke in HLTx recipients. Of 871 heart-lung recipients between 1994-2022, 35 (4.0%) experienced stroke, and the incidence increased over time, trending toward significance (p-trend = .07). After adjustment, extracorporeal membrane oxygenation (ECMO) (Adjusted odds ratio [aOR] = 2.63, 95%CI = [1.13-6.11]) and pre-transplant implantable defibrillator (aOR = 2.86, 95%CI = [1.20-6.81]) were independent risk factors for stroke. Postoperative stroke is common and is increasing in an era where organ allocation is driven by mechanical circulatory support (MCS) bridging. K E Y W O R D S heart-lung transplantation, mechanical circulatory support, stroke
To determine the diagnostic value of axial T1-weighted imaging for patients suffering from lower back pain. In this retrospective study, 100 consecutive lumbar spine MRIs obtained in patients with chronic low back pain were reviewed in two sessions: First, readers viewed core sequences (sagittal T1-weighted, STIR and T2-weighted, and axial T2-weighted) with axial T1-weighted sequences, and second, readers viewed cores sequences alone. Readers recorded the presence of disc degeneration, nerve root compromise, facet joint arthritis, and stenosis at each lumbar spine level as well as the presence of lipoma of filum terminale (LFT), spondylolisthesis, transitional vertebrae, and fractures. The McNemar, Wilcoxon signed-rank, and student T tests were utilized. For 100 studies, 5 spine levels were evaluated (L1–L2 through L5–S1). There were cases of disc disease (444/500 bulges, 56/500 herniations), nerve root compromise (1/500 nerve enlargement, 36/500 contact only, 20/500 displacement or compression), facet arthritis (438/500), stenosis (58/500 central canal, 64/500 lateral recess, 137/500 neuroforaminal), 6/100 LFTs, and other abnormalities (58/500 spondylolisthesis, 10/100 transitional vertebrae, 10/500 fracture/spondylolysis). There was no difference in diagnostic performance between the interpretation sessions (with and without axial T1-weighted imaging) at any level (p > 0.05), although four small additional LFTs were identified with axial T1-weighted imaging availability. There was no clinically significant difference in the interpretation of lumbar spine MRI viewed with and without axial T1-weighted imaging, suggesting that the axial T1-weighted sequence does not add diagnostic value to routine lumbar spine MRI.
Introduction Recent studies have introduced elevated lipoprotein(a) (Lp(a)) as a risk factor for coronary heart disease (CHD). This study investigated whether the addition of Lp(a) as a novel biomarker to the Framingham Risk Score (FRS) model improves CHD risk prediction. Methods The study included 1101 Iranian subjects (443 non-diabetic and 658 diabetic patients) who were followed for 10 years (2003–2013). Lp(a) levels and CHD events were recorded for each participant. Results The Net Reclassification Index (NRI) after adding Lp(a) to the FRS model was 19.57% and the discrimination slope was improved (0.160 vs. 0.173). The Akaike Information Criterion (AIC), a measure of model complexity, decreased significantly after adding Lp(a) to the FRS model (691.9 vs. 685.4, P value: 0.007). Conclusions The study concluded that adding Lp(a) to the FRS model improves CHD risk prediction in an Iranian population without making the model too complex. This could help clinicians to better identify individuals who are at risk of developing CHD and to implement appropriate preventive measures.
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