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Context: Lactation is associated with lower future risk of cardiovascular disease in women but the mechanism(s) underlying this relationship remain unclear., Objective: We sought to characterize the relationship between duration of exclusive breastfeeding and cardiovascular risk factors over the first 5-years postpartum., Design/setting/patients: In this prospective cohort study, 328 women underwent serial cardiometabolic characterization (anthropometry, blood pressure, lipids, fasting glucose, adiponectin, C-reactive protein (CRP)) at 1-year, 3-years, and 5-years postpartum., Outcome: Cardiovascular risk factors in 3 groups defined by duration of exclusive breastfeeding, as follows: <3 months (n=107), 3-6 months (n=101), and ≥6 months (n=120)., Results: The prevalence of metabolic syndrome did not differ between the groups at 3-years but, by 5-years postpartum, was higher in women who had exclusively breastfed <3 months than in those who did so for 3-6 and ≥6 months, respectively (14.0% vs 6.9% vs 4.2%; p=0.02). However, after adjustment for covariates (including BMI), there were no significant differences between groups in blood pressure, glucose, LDL cholesterol, HDL cholesterol, triglycerides or adiponectin. Indeed, the only cardiovascular risk factor difference that persisted after covariate adjustment was that women who had exclusively breastfed <3 months had higher CRP at both 3-years (p=0.04) and 5-years (p=0.01). Moreover, generalized estimating equation analyses with adjustment for covariates (including time-dependent BMI) showed that CRP remained higher over time in these women, as compared to their peers, from 1-year to 3-years to 5-years postpartum (p=0.03)., Conclusion: Sustained reduction of subclinical inflammation may contribute to the cardioprotective effect of lactation in women., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Aims: Rotational re-entries and ectopic foci, or 'drivers', are proposed mechanisms for persistent atrial fibrillation (persAF), but driver-based interventions have had mixed success in clinical trials. Selective targeting of drivers with multi-month stability may improve these interventions, but no prior work has investigated whether drivers can be stable on such a long timescale., Objective: We hypothesized that drivers could recur even several months after initial observation., Methods and Results: We performed serial electrophysiology studies on paced canines (n = 18, 27-35 kg) at 1-, 3-, and 6 months post-initiation of continual persAF. Using a high-density 64-electrode catheter, we captured endocardial electrograms in the left atrium (LA) and right atrium (RA) to determine the presence of drivers at each major anatomical site. We defined drivers that were repeatedly observed across consecutive studies to be recurrent. The mean probability that any driver would recur was 66% (LA: 73%, RA: 41%). We also found evidence of 'multi-recurring' drivers, i.e. those seen in all three studies. Multi-recurring drivers constituted 53% of initially observed drivers with at least one found in 92% of animals, and we found more multi-recurring drivers per animal than predicted by random chance (2.6 ± 1.5 vs. 1.2 ± 1.1, P < 0.001). Driver sites showed more enhancement than non-drivers during late gadolinium enhancement-magnetic resonance imaging (P = 0.04), but we observed no relationship between enhancement and driver recurrence type., Conclusion: We observed recurring drivers over a 6-month period at fixed locations, confirming our hypothesis. We also found drivers to be associated with fibrosis, implying a structural basis., Competing Interests: Conflict of interest: R.R. is a consultant for Abbott., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Hepatitis C virus (HCV) testing is recommended for all adults 18 years and older to increase identification of those with infection and facilitate prompt referral for curative antiviral therapy. While critical to promote elimination, this strategy excludes a key demographic group who are clearly at risk of undetected HCV infection and who could benefit from early treatment: adolescents. In this paper, we review the available data on the burden of HCV and the close association with injection drug use, discuss the rationale of universal testing in adolescents and, finally, present data from a quality improvement project implementing HCV testing into routine adolescent health visits., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Many older adults experience a major stressor at some point in their lives. The ability to recover well after a major stressor is known as resilience. An important goal of geriatric research is to identify factors that influence resilience to stressors. Studies of resilience in older adults are typically conducted with a single-arm where everyone experiences the stressor. The simplistic approach of regressing change versus baseline yields biased estimates due to mathematical coupling and regression to the mean (RTM). We develop a method to correct the bias. We extend the method to include covariates. Our approach considers a counterfactual control group and involves sensitivity analyses to evaluate different settings of control group parameters. Only minimal distributional assumptions are required. Simulation studies demonstrate the validity of the method. We illustrate the method using a large, registry of older adults (N  =7239) who underwent total knee replacement (TKR). We demonstrate how external data can be utilized to constrain the sensitivity analysis. Naive analyses implicated several treatment effect modifiers including baseline function, age, body-mass index (BMI), gender, number of comorbidities, income, and race. Corrected analysis revealed that baseline (pre-stressor) function was not strongly linked to recovery after TKR and among the covariates, only age and number of comorbidities were consistently and negatively associated with post-stressor recovery in all functional domains. Correction of mathematical coupling and RTM is necessary for drawing valid inferences regarding the effect of covariates and baseline status on pre-post change. Our method provides a simple estimator to this end., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. [br]For permissions, please e-mail: journals.permissions@oup.com.)

Colouterine fistulas are generally seen in post-menopausal patients and present with abdominal pain and non-physiologic vaginal drainage. A history of uterine pathology or diverticulitis is generally lacking. Visualization of the passage of contrast from the gastrointestinal tract to the uterus is not necessary to make the diagnosis. We present the case of a 44-year-old woman successfully treated for a colouterine fistula due to sigmoid diverticulitis. A variety of surgical approaches have been described to correct this fistula, and a minimally invasive colectomy without ileostomy or colostomy appears to be a safe approach., Competing Interests: None declared., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2024.)

We developed a Project ECHO® module to offer prenatal providers training on engaging in shared decision-making about hepatitis C virus (HCV) treatment during pregnancy. In this pilot program, the ECHO module addressing HCV during pregnancy and the potential benefits of treatment was associated with increases in self-efficacy scores among participants., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Lung cancer is the leading cause of cancer death in the US and globally. The mortality from lung cancer has been declining, due to a reduction in incidence and advances in treatment. Although recent success in developing targeted and immunotherapies for lung cancer has benefitted patients, it has also expanded the complexity of potential treatment options for health care providers. To aid in reducing such complexity, experts in oncology convened a conference (Bridging the Gaps in Lung Cancer) to identify current knowledge gaps and controversies in the diagnosis, treatment, and outcomes of various lung cancer scenarios, as described here. Such scenarios relate to biomarkers and testing in lung cancer, small cell lung cancer, EGFR mutations and targeted therapy in non-small cell lung cancer (NSCLC), early-stage NSCLC, KRAS/BRAF/MET and other genomic alterations in NSCLC, and immunotherapy in advanced NSCLC., (© The Author(s) 2024. Published by Oxford University Press.)

Background: A national guideline on peripheral arterial disease management in England was issued in August 2012. The impact on revascularization rates was examined and variation with socioeconomic deprivation assessed., Methods: Annual hospital admissions for England over 10 years (2008-2009 to 2017-2018) were examined using interrupted time series analysis. A pragmatic approach was used to classify admissions for revascularization into moderate and severe categories., Results: There were 309 839 admissions (56% for moderate peripheral arterial disease), with an overall annual admission rate for revascularization of 86 per 100 000 population aged 25+ years. The rate for moderate peripheral arterial disease marginally increased by 0.29 per 100 000 per year (95% c.i. -0.22 to 0.80) from 2008-2009 to 2012-2013. Following guideline introduction, this rate decreased. The equivalent for severe peripheral arterial disease increased by 1.33 per 100 000 (0.78 to 1.88). Following guideline introduction, this rate plateaued. The change in rate (slope) for moderate peripheral arterial disease of -2.81 per 100 000 per year (-3.52 to -2.10) after guideline introduction was greater than the change in rate for severe peripheral arterial disease of -1.95 per 100 000 per year (-2.73 to -1.17). For moderate peripheral arterial disease, the annual rate in the most socioeconomically deprived category was 15.6 per 100 000 lower in 2017-2018 compared with 2012-2013 (24.3% decrease). The impact progressively diminished with decreasing deprivation. In the least deprived category, the reduction was 5.2 per 100 000 (12.9% decrease). For severe peripheral arterial disease, the decrease was 1.2 per 100 000 (3.1% reduction) with no consistent variation in relation to deprivation., Conclusion: Introduction of the national peripheral arterial disease management guideline in England was associated with a reduction in admission rates for revascularization, especially for moderate peripheral arterial disease, with greater reduction in rates for moderate peripheral arterial disease in more socioeconomically deprived areas. Association, however, does not necessarily imply causation and alternative explanations cannot be ruled out., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Objective: Time-restricted eating (TRE) which consists of restricting the eating window to typically 4-8h (while fasting for the remaining hours of the day) has been proposed as a non-pharmacological strategy with cardio-metabolic benefits but little is known about its metabolic impact in type 2 diabetes (T2DM). We evaluated whether TRE can improve pancreatic beta-cell function and metabolic status in overweight individuals with early T2DM., Research Design and Methods: In a randomized cross-over trial, 39 participants [mean 2.9 years of diabetes duration, baseline glycated hemoglobin (HbA1c) 6.6% ± 0.7% and body mass index (BMI) 32.4 ± 5.7 kg/m2] were randomized to either an initial intervention consisting of 6-weeks of TRE (20h-fasting/4h-eating) or standard lifestyle. The primary outcome of beta-cell function was assessed by Insulin Secretion-Sensitivity Index-2 (ISSI-2) derived from an oral glucose tolerance test. Trial registration: clinicaltrials.gov NCT05717127., Results: As compared to standard lifestyle, TRE induced a 14% increase in ISSI-2 (+14.0 ± 39.2%, p = 0.03) accompanied by 14% reduction of hepatic insulin resistance as evaluated by HOMA-IR [-11.6% (-49.3-21.9), p = 0.03]. Fasting glucose did not differ between interventions, but TRE yielded a significant reduction in HbA1c (-0.32 ± 0.48%, p <0.001). These metabolic improvements were coupled by a reduction of body weight of 3.86% (-3.86 ± 3.1%, p <0.001) and waist circumference of 3.8 cm (-3.8 ± 7.5 cm, p = 0.003)., Conclusion: TRE improved beta-cell function and insulin resistance in overweight patients with early diabetes, accompanied by beneficial effects on adiposity., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Plastic surgery sector has experienced significant growth, driven by an aging population's demand for minimally invasive procedures and technological innovation. Despite this, the role of venture capital (VC) in driving innovation within this sector remains underexplored. This study aimed to analyze the trends in VC investments in plastic surgery over the last 20 years, providing insights into the financial landscape of the sector. A retrospective cross-sectional analysis was conducted on VC investments in plastic and aesthetic surgery companies worldwide from January 1, 2003 to December 31, 2023, utilizing PitchBook (Seattle, WA). Companies were categorized into therapeutic and thematic areas, with investment trends analyzed by deal and company values, average investment size, and total capital invested. The study found 543 VC firms made 402 investments in 163 companies, totaling $1.98 billion, increasing by 15,143% over the study period, and focused on general plastic surgery and facial cosmetic procedures. Significant investments were also made in surgical software (25.3%), biotechnology and drug discovery (22.8%), and clinic and outpatient services (20.3%). Geographically, most investments were made in companies registered in Asia (45%) and North America (33.2%). VC investments have contributed to the growth and innovation in the plastic surgery sector, particularly in minimally invasive devices. The focus on general and facial cosmetic surgery aligns with market demand trends for aesthetic procedures. These findings underscore the importance of VC in shaping the future of plastic surgery and suggest the potential for strategic investments to further drive innovation., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Aesthetic Society.)

Disclaimer: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time., Purpose: Elevated serum bromide levels can cause dermatological, gastrointestinal, and neurological abnormalities. As bromide and chloride are both halogens, bromide may interfere with chloride assays, causing a falsely high serum chloride concentration and a low or negative anion gap. There is a paucity of data describing bromide toxicity from high doses of pyridostigmine bromide (PB). This case report describes a patient with an elevated bromide level with neurological symptoms from a therapeutic dose of PB., Summary: A 37-year-old male with myasthenia gravis secondary to type B2 thymoma status following thymectomy presented in myasthenic crisis. He required mechanical ventilation and was managed with steroids, intravenous immune globulin, plasmapheresis, and PB. On day 9, the patient experienced acute agitation. He had an anion gap of 2 mEq/L and a chloride concentration of 109 mEq/L. The plasma creatinine concentration was 0.63 to 1.15 mg/dL and urine output was 0.76 to 1.79 mL/kg/h throughout his admission. All other laboratory values were normal. The daily dose of PB was 660 mg on day 9, but the patient received 76 mg of intravenous PB over the first few days of his admission with the largest dose in 24 hours equal to 48 mg. On day 10, the patient's bromide level was 37 μg/mL. His agitation was initially managed with quetiapine, followed by PB dose reduction. To our knowledge, there are 2 cases in the literature of bromide toxicity secondary to PB. These patients experienced neurological symptoms with bromide levels of 88 to 90 μg/mL. Bromide concentrations of more than 12 μg/mL are associated with a higher risk of neuronal dysfunction demonstrated as disturbances on an electroencephalogram, and levels greater than 50 μg/mL are considered toxic. While our patient's bromide level was not as high as those previously reported, no other causes for his agitation were identified., Conclusion: Elevated bromide levels from therapeutic PB can occur, and monitoring of these levels should be considered., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The management of hepatitis B virus (HBV) in pediatrics presents many challenges, given the potential sequelae of untreated infection including hepatic fibrosis, cirrhosis, and malignancy, and a lack of clear guidance on the timing of treatment initiation. The goal of this review is to feature common clinical scenarios that occur in the evaluation and treatment of HBV infection in children. Each vignette presents an opportunity to discuss guidelines and evidence-based practices as well as review landmark studies and evolving practices., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The genomes of the fungus Magnaporthe oryzae that causes blast diseases on diverse grass species, including major crops, have indispensable core-chromosomes and may contain supernumerary chromosomes, also known as mini-chromosomes. These mini-chromosomes are speculated to provide effector gene mobility, and may transfer between strains. To understand the biology of mini-chromosomes, it is valuable to be able to detect whether a M. oryzae strain possesses a mini-chromosome. Here, we applied recurrent neural network models for classifying DNA sequences as arising from core- or mini-chromosomes. The models were trained with sequences from available core- and mini-chromosome assemblies, and then used to predict the presence of mini-chromosomes in a global collection of M. oryzae isolates using short-read DNA sequences. The model predicted that mini-chromosomes were prevalent in M . oryzae isolates. Interestingly, at least one mini-chromosome was present in all recent wheat isolates, but no mini-chromosomes were found in early isolates collected before 1991, indicating a preferential selection for strains carrying mini-chromosomes in recent years. The model was also used to identify assembled contigs derived from mini-chromosomes. In summary, our study has developed a reliable method for categorizing DNA sequences and showcases an application of recurrent neural networks in predictive genomics., (© The Author(s) 2024. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Constitutive androstane receptor (CAR, Nr1i3), a liver nuclear receptor and xenobiotic sensor, induces drug, steroid, and lipid metabolizing enzymes, stimulates liver hypertrophy and hyperplasia, and ultimately, hepatocellular carcinogenesis. The mechanisms linking early CAR responses to later disease development are poorly understood. Here we show that exposure of CD-1 mice to TCPOBOP (1,4-bis[2-(3,5-dichloropyridyloxy)]benzene), a halogenated xenochemical and selective CAR agonist ligand, induces pericentral steatosis marked by hepatic accumulation of cholesterol and neutral lipid, and elevated circulating alanine aminotransferase, indicating hepatocyte damage. TCPOBOP-induced steatosis was weaker in the pericentral region but stronger in the periportal region in females compared with males. Early (1 day) TCPOBOP transcriptional responses were enriched for CAR-bound primary response genes, and for lipogenesis and xenobiotic metabolism and oxidative stress protection pathways; late (2 weeks) TCPOBOP responses included many CAR binding-independent secondary response genes, with enrichment for macrophage activation, immune response, and cytokine and reactive oxygen species production. Late upstream regulators specific to TCPOBOP-exposed male liver were linked to proinflammatory responses and hepatocellular carcinoma progression. TCPOBOP administered weekly to male mice using a high corn oil vehicle induced carbohydrate-responsive transcription factor (MLXIPL)-regulated target genes, dysregulated mitochondrial respiratory and translation regulatory pathways, and induced more advanced liver pathology. Overall, TCPOBOP exposure recapitulates histological and gene expression changes characteristic of emerging steatotic liver disease, including secondary gene responses in liver nonparenchymal cells indicative of transition to a more advanced disease state. Upstream regulators of both the early and late TCPOBOP response genes include novel biomarkers for foreign chemical-induced metabolic dysfunction-associated steatotic liver disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Idiopathic nephrotic syndrome (NS) in children poses treatment challenges, with a subset developing steroid-resistant nephrotic syndrome (SRNS). Genetic factors play a role, yet data on paediatric SRNS genetics in India are scarce. We conducted a prospective study using whole-exome sequencing to explore genetic variants and their clinical correlations., Methods: A single-centre prospective study (October 2018-April 2023) enrolled children with SRNS, undergoing renal biopsy and genetic testing per institutional protocol. Clinical, histological, and genetic data were recorded. DNA isolation and next-generation sequencing were conducted for genetic analysis. Data collection included demographics, clinical parameters, and kidney biopsy findings. Syndromic features were evaluated, with second-line immunosuppressive therapy administered. Patient and renal outcomes are presented for patients with and without genetic variants., Results: A total of 680 paediatric NS patients were analysed, with 121 (17.8%) having SRNS and 96 consent to genetic analysis. 69 (71.9%) had early SRNS, 27 (28.1%) late. Among participants, 62 (64.58%) had reportable genetic variants. The most common were in COL4A genes, with 20 (31.7%) positive. Renal biopsy showed focal segmental glomerulosclerosis in 31/42 (74%) with variants, 16/28 (57.1%) without variants. Second-line immunosuppressions varied, with CNIs the most common. Outcomes varied, with partial or complete remission achieved in some while others progressed to ESRD., Conclusion: The study underscores the importance of genetic analysis in paediatric SRNS, revealing variants in 65.7% of cases. COL4A variants were predominant. Variants correlated with varied renal outcomes, highlighting potential prognostic implications. These findings emphasize the value of personalized approaches and further research in managing paediatric SRNS., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Infectious diseases physicians are frequently called on to perform quality improvement and patient safety (QIPS) work. We describe a newly created faculty position at our institution that allows a faculty member with graduate training in quality and safety methodologies to address QIPS priorities at both the division and hospital levels., Competing Interests: Potential conflicts of interest. R. J. reports grants or contracts paid to institution from GSK, the Centers for Disease Control and Prevention, and the Agency for Healthcare Research and Quality; royalties or licenses to author from UpToDate; consulting fees to author from AstraZeneca, Seqirus, Sanofi, Gilead, and Dynavax; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events to author from Moderna; payment for expert testimony to author from Quinn Johnston, LLC; and a role as editor in chief for the Journal of the Pediatric Infectious Diseases Society. C. L. reports speaker reimbursement for IDWeek 2023 to author. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Although pre-clinical studies have shown a beneficial impact of omega-3 (n-3) polyunsaturated fatty acids (PUFAs) on adipose (AT) inflammation, the current literature from human studies is limited. Therefore, we aimed to evaluate the longitudinal associations of circulating levels of n-3 PUFAs with biomarkers of AT inflammation., Methods: Longitudinal data from participants in the PROMISE cohort (n = 474) were used. AT inflammation was measured using circulating biomarkers at baseline and up to 2 follow-up visits. n-3 PUFAs were measured at baseline in four serum lipid fractions. Generalized estimating equations (GEE) analyses evaluated longitudinal associations between n-3 PUFAs and AT inflammation, adjusting for covariates., Results: Fully adjusted GEE models indicated that higher baseline proportions of eicosapentaenoic acid (EPA), n-3 docosapentaenoic acid (n-3 DPA), and docosahexaenoic acid (DHA) in total serum were significantly inversely associated with longitudinal change in soluble CD163 (sCD163) (all p < 0.05). A significant positive association of n-3 DPA and DHA with longitudinal change in adiponectin (p < 0.05) was also observed. Generally consistent associations were observed between n-3 PUFAs and sCD163 and adiponectin in the four lipid fractions., Conclusions: These findings will add to the limited evidence on the potential role n-3 PUFAs have in the prevention and management of AT inflammation in humans and may help inform future interventions targeting chronic inflammation at the level of AT., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

We report a rare case of a pedunculated calcified amorphous tumor (CAT) of the left ventricle attached by a stalk to the membranous septum in a 74-year-old woman who presented with a cerebrovascular accident. We believe this is the first report of a CAT attached to the membranous septum., Competing Interests: None of the authors have conflicts of interest or disclosures., (Published by Oxford University Press and JSCR Publishing Ltd. 2024.)

Coronaviruses modify their single-stranded RNA genome with a methylated cap during replication to mimic the eukaryotic mRNAs. The capping process is initiated by several nonstructural proteins (nsp) encoded in the viral genome. The methylation is performed by two methyltransferases, nsp14 and nsp16, while nsp10 acts as a co-factor to both. Additionally, nsp14 carries an exonuclease domain which operates in the proofreading system during RNA replication of the viral genome. Both nsp14 and nsp16 were reported to independently bind nsp10, but the available structural information suggests that the concomitant interaction between these three proteins would be impossible due to steric clashes. Here, we show that nsp14, nsp10, and nsp16 can form a heterotrimer complex upon significant allosteric change. This interaction is expected to encourage the formation of mature capped viral mRNA, modulating nsp14's exonuclease activity, and protecting the viral RNA. Our findings show that nsp14 is amenable to allosteric regulation and may serve as a novel target for therapeutic approaches., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

More severe atopic dermatitis and psoriasis are associated with a higher cumulative impact on quality of life, multimorbidity and healthcare costs. Proactive, early intervention in those most at risk of severe disease may reduce this cumulative burden and modify the disease trajectory to limit progression. The lack of reliable biomarkers for this at-risk group represents a barrier to such a paradigm shift in practice. To expedite discovery and validation, the BIOMarkers in Atopic Dermatitis and Psoriasis (BIOMAP) consortium (a large-scale European, interdisciplinary research initiative) has curated clinical and molecular data across diverse study designs and sources including cross-sectional and cohort studies (small-scale studies through to large multicentre registries), clinical trials, electronic health records and large-scale population-based biobanks. We map all dataset disease severity instruments and measures to three key domains (symptoms, inflammatory activity and disease course), and describe important codependencies and relationships across variables and domains. We prioritize definitions for more severe disease with reference to international consensus, reference standards and/or expert opinion. Key factors to consider when analysing datasets across these diverse study types include explicit early consideration of biomarker purpose and clinical context, candidate biomarkers associated with disease severity at a particular point in time and over time and how they are related, taking the stage of biomarker development into account when selecting disease severity measures for analyses, and validating biomarker associations with disease severity outcomes using both physician- and patient-reported measures and across domains. The outputs from this exercise will ensure coherence and focus across the BIOMAP consortium so that mechanistic insights and biomarkers are clinically relevant, patient-centric and more generalizable to current and future research efforts., Competing Interests: Conflicts of interest S.M.L. has received funding from a Wellcome Trust Senior Research Fellowship in Clinical Science (205039/Z/16/Z). A.E. has received research funding from Almirall, Pfizer, Eli Lilly, Novartis, Bristol Myers Squibb, AbbVie, Janssen Pharmaceuticals, Boehringer Ingelheim, the Danish National Psoriasis Foundation, the Simon Spies Foundation and the Kgl Hofbundtmager Aage Bang Foundation, and honoraria as consultant and/or speaker from Amgen, AbbVie, Almirall, LEO Pharma, Zuellig Pharma Ltd., Galapagos NV, Sun Pharmaceuticals, Samsung Bioepis Co., Ltd., Pfizer, Eli Lilly and Company, Novartis, Union Therapeutics, Galderma, Dermavant, UCB, Mylan, Bristol Myers Squibb, McNeil Consumer Healthcare, Horizon Therapeutics, Boehringer Ingelheim and Janssen Pharmaceuticals. E.d.J. has received research grants for the department of dermatology of Radboud University Medical Centre Nijmegen from AbbVie, BMS, Janssen Pharmaceutica, LEO Pharma, Lilly, Novartis, UCB, ZonMw, KCE, NWO, the National Psoriasis Foundation USA and Horizon 2020 European funding (Immuniverse). She has acted as consultant and/or paid speaker for and/or participated in research sponsored by companies that manufacture drugs used for the treatment of psoriasis or eczema including AbbVie, Amgen, Almirall, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Galapagos, Janssen Pharmaceutica, Lilly, Novartis, LEO Pharma, Sanofi and UCB. All funding is not personal but goes to the Institution Radboud University Medical Center Nijmegen. M.A.M.-H. has carried out consultancy for Sanofi, Pfizer and LEO Pharma and is one of the main investigators of the TREAT NL registry. A.B. reports multiple grants from H2020 and HEurope with various industry partners. L.S. reports grants from Novartis, Bristol Myers Squibb, AbbVie, Janssen Pharmaceuticals, Sanofi, Almirall, the Danish National Psoriasis Foundation and the LEO Foundation and honoraria as consultant and/or speaker for AbbVie, Eli Lilly, Novartis, Pfizer, LEO Pharma, Janssen, UCB, Almirall, Bristol Myers Squibb, Galderma and Sanofi. S.K.M. has received research funding (but no personal payments) from Wellcome Trust, British Skin Foundation, European Lead Factory EU/IMI (multiple pharma participants), Charles Wolfson Charitable Trust, Rosetrees Trust, Stoneygate Trust, anonymous donations from people with eczema, Pfizer, AbbVie, Sosei Heptares, Janssen and Unilever. J.N.B. has received honoraria and/or research grants from AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Janssen, LEO Pharma, Lilly, Novartis, Samsung and Sun Pharma. C.H.S. reports grants from an MRC-funded stratified medicine consortium with multiple industry partners, grants from IMI (Horizon 2020-funded) European consortium with multiple industry partners, and other funding from AbbVie, Novartis, Pfizer, Sanofi, Boehringer Ingelheim and SOBI, outside the submitted work, and is Chair of UK guidelines on biologic therapy in psoriasis., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: Postoperative recurrence of Crohn's disease (CD) is common. While most patients undergo resection with undiverted anastomosis (UA), some individuals also have creation of an intended temporary diversion (ITD) with an ileostomy followed by ostomy takedown (OT) due to increased risk of anastomotic complications. We assessed the association of diversion with subsequent CD recurrence risk and the influence of biologic prophylaxis timing to prevent recurrence in this population., Methods: This was a retrospective cohort study of CD patients who underwent ileocolic resection between 2009 and 2020 at a large quaternary health system. Patients were grouped by continuity status after index resection (primary anastomosis or ITD). The outcomes of the study were radiographic, endoscopic, and surgical recurrence as well as composite recurrence postoperatively (after OT in the ITD group). Propensity score-weighted matching was performed based on risk factors for diversion and recurrence. Multivariable regression and a Cox proportional hazards model adjusting for recurrence risk factors were used to assess association with outcomes. Subgroup analysis in the ITD group was performed to assess the impact of biologic timing relative to OT (no biologic, biologic before OT, after OT) on composite recurrence., Results: A total of 793 CD patients were included (mean age 38 years, body mass index 23.7 kg/m2, 52% female, 23% active smoker, 50% penetrating disease). Primary anastomosis was performed in 67.5% (n = 535) and ITD in 32.5% (n = 258; 79% loop, 21% end) of patients. Diverted patients were more likely to have been males and to have had penetrating and perianal disease, prior biologic use, lower body mass index, and lower preoperative hemoglobin and albumin (all P < .01). After a median follow-up of 44 months, postoperative recurrence was identified in 83.3% patients (radiographic 40.4%, endoscopic 39.5%, surgical 13.3%). After propensity score matching and adjusting for recurrence risk factors, no significant differences were seen between continuity groups in radiographic (adjusted hazard ratio [aHR], 1.32; 95% confidence interval [CI], 0.91-1.91) or endoscopic recurrence (aHR, 1.196; 95% CI, 0.84-1.73), but an increased risk of surgical recurrence was noted in the ITD group (aHR, 1.61; 95% CI, 1.02-2.54). Most (56.1%) ITD patients started biologic prophylaxis after OT, 11.4% before OT, and 32.4% had no postoperative biologic prophylaxis. Biologic prophylaxis in ITD was associated with younger age (P < .001), perianal disease (P = .04), and prior biologic use (P < .001) but not in recurrence (P = .12). Despite higher rates of objective disease activity identified before OT, biologic exposure before OT was not associated with a significant reduction in composite post-OT recurrence compared with starting a biologic after OT (52% vs 70.7%; P = 0.09)., Conclusions: Diversion of an ileocolic resection is not consistently associated with a risk of postoperative recurrence and should be performed when clinically appropriate. Patients requiring diversion at time of ileocolic resection are at high risk for recurrence, and biologic initiation prior to stoma reversal may be considered., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The use of octreotide in managing intrathoracic chyle leak following esophagectomy has gained popularity in the adult population. While the benefits of octreotide have been confirmed in the pediatric population, there remains limited evidence to support its use in the adults post-esophagectomy. Thus, we performed a single-institution cohort study to characterize its efficacy. The study was performed using a prospective, single-center database, from which clinicopathologic characteristics were extracted of patients who had post-esophagectomy chyle leaks. Kaplan-Meier and multivariable Cox regression analyses were performed to investigate the effect of octreotide use on chest tube duration (CTD), hospital length of stay (LOS), and overall survival (OS). In our cohort, 74 patients met inclusion criteria, among whom 27 (36.5%) received octreotide. Kaplan-Meier revealed no significant effect of octreotide on CTD (P = 0.890), LOS (P = 0.740), or OS (P = 0.570). Multivariable Cox regression analyses further corroborated that octreotide had no effect on CTD (HR = 0.62, 95% confidence interval [CI]: 0.32-1.20, P = 0.155), LOS (HR = 0.64, CI: 0.34-1.21, P = 0.168), or OS (1.08, CI: 0.53-2.19, P = 0.833). Octreotide use in adult patients with chyle leak following esophagectomy lacks evidence of association with meaningful clinical outcomes. Level 1 evidence is needed prior to further consideration in this population., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

For patients with Biliary atresia, antibiotic prophylaxis after Kasai portoenterostomy is a common practice. Societal guidelines often cite one reference as supportive evidence for this practice. In this paper, we go back to review the quality of this evidence and suggest more research is required to demonstrate the efficacy of antibiotic prophylaxis in this population., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Unlike animals, variability in transcription factors (TFs) and their binding regions (TFBRs) across the plants species is a major problem that most of the existing TFBR finding software fail to tackle, rendering them hardly of any use. This limitation has resulted into underdevelopment of plant regulatory research and rampant use of Arabidopsis-like model species, generating misleading results. Here, we report a revolutionary transformers-based deep-learning approach, PTFSpot, which learns from TF structures and their binding regions' co-variability to bring a universal TF-DNA interaction model to detect TFBR with complete freedom from TF and species-specific models' limitations. During a series of extensive benchmarking studies over multiple experimentally validated data, it not only outperformed the existing software by >30% lead but also delivered consistently >90% accuracy even for those species and TF families that were never encountered during the model-building process. PTFSpot makes it possible now to accurately annotate TFBRs across any plant genome even in the total lack of any TF information, completely free from the bottlenecks of species and TF-specific models., (© The Author(s) 2024. Published by Oxford University Press.)

The HD-ZIP class I transcription factor Homeobox 1 (HvHOX1), also known as Vulgare Row-type Spike 1 (VRS1) or Six-rowed Spike 1, regulates lateral spikelet fertility in barley (Hordeum vulgare L.). It was shown that HvHOX1 has a high expression only in lateral spikelets, while its paralog HvHOX2 was found to be expressed in different plant organs. Yet, the mechanistic functions of HvHOX1 and HvHOX2 during spikelet development are still fragmentary. Here, we show that compared with HvHOX1, HvHOX2 is more highly conserved across different barley genotypes and Hordeum species, hinting at a possibly vital but still unclarified biological role. Using bimolecular fluorescence complementation, DNA-binding, and transactivation assays, we validate that HvHOX1 and HvHOX2 are bona fide transcriptional activators that may potentially heterodimerize. Accordingly, both genes exhibit similar spatiotemporal expression patterns during spike development and growth, albeit their mRNA levels differ quantitatively. We show that HvHOX1 delays the lateral spikelet meristem differentiation and affects fertility by aborting the reproductive organs. Interestingly, the ancestral relationship of the two genes inferred from their co-expressed gene networks suggested that HvHOX1 and HvHOX2 might play a similar role during barley spikelet development. However, CRISPR-derived mutants of HvHOX1 and HvHOX2 demonstrated the suppressive role of HvHOX1 on lateral spikelets, while the loss of HvHOX2 does not influence spikelet development. Collectively, our study shows that through the suppression of reproductive organs, lateral spikelet fertility is regulated by HvHOX1, whereas HvHOX2 is dispensable for spikelet development in barley., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Background and Aims: Vascular patterning is intimately related to plant form and function. Here, using barley (Hordeum vulgare) as a model, we studied the vascular anatomy of the spike-type inflorescence. The main aim of the present work was to clarify the relationship between rachis (spike axis) vasculature and spike size, to define vascular dynamics and to discuss the implications for transport capacity and its interaction with the spikelets., Methods: We used serial transverse internode sections to determine the internode area, vascular area and number of veins along the rachis of several barley lines., Key Results: Internode area and total vascular area show a clear positive correlation with spike size, whereas the number of veins is only weakly correlated. The lateral periphery of the rachis contains large mature veins of constant size, whereas the central part is occupied by small immature veins. Spikelet-derived veins entering the rachis often merge with the immature rachis veins but never merge with the mature veins. An increase in floret fertility through the conversion of a two-rowed barley into an isogenic six-rowed line, in addition to a decrease in floret fertility owing to enhanced pre-anthesis tip degeneration caused by the mutation tip sterile 2.b (tst2.b), significantly affected vein size but had limited to no effects on the number of veins or internode area., Conclusions: The rachis vasculature is the result of a two-step process involving an initial layout followed by size adjustment according to floret fertility/spike size. The restriction of large mature vessels to the periphery and that of small immature vessels to the centre of the rachis suggests that long-distance transport and local supply to spikelets are spatially separated processes. The identification of spikelet-derived veins entering the rachis without fusing with its vasculature indicates that a vascular continuity between rachis and spikelets might be non-essential., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Annals of Botany Company.)

Background: A major hurdle to effectively treating glioblastoma (GBM) patients is the lack of longitudinal information about tumor progression, evolution, and treatment response., Methods: In this study, we report the use of a neural tract-inspired conduit containing aligned polymeric nanofibers (i.e., an aligned nanofiber device) to enable on-demand access to GBM tumors in 2 rodent models. Depending on the experiment, a humanized U87MG xenograft and/or F98-GFP+ syngeneic rat tumor model was chosen to test the safety and functionality of the device in providing continuous sampling access to the tumor and its microenvironment., Results: The aligned nanofiber device was safe and provided a high quantity of quality genomic materials suitable for omics analyses and yielded a sufficient number of live cells for in vitro expansion and screening. Transcriptomic and genomic analyses demonstrated continuity between material extracted from the device and that of the primary, intracortical tumor (in the in vivo model)., Conclusions: The results establish the potential of this neural tract-inspired, aligned nanofiber device as an on-demand, safe, and minimally invasive access point, thus enabling rapid, high-throughput, longitudinal assessment of tumor and its microenvironment, ultimately leading to more informed clinical treatment strategies., Competing Interests: S.M., B.B., R.B., and N.M. are licensing the aligned nanofiber technology discussed in this work to a private entity for translation and commercialization., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Introduction: Under the current policy landscapes, the lifetime health and economic burden of smokeless tobacco (ST) products, consumed by over 297 million ST users in South Asia, is unknown. The aim of this study was to estimate the lifetime health effects and costs attributable to current and future ST use in Bangladesh, India, and Pakistan where the majority of ST users live., Aims and Methods: We developed a Markov-based state-transition model (ASTRAMOD) to predict the lifetime costs of treatment of four diseases (oral, pharyngeal, esophageal cancers, and stroke) and disability-adjusted life years (DALYs), attributable to the current and future use of ST under existing ST policy scenario. Country-specific Global Adult Tobacco Surveys, life tables, and meta-analyses of South Asian and South East Asian studies were used to populate the model. A probabilistic sensitivity analysis evaluated the uncertainty in model predictions., Results: If there were no change in the current ST policies, the lifetime ST-attributable treatment costs would be over US$19 billion in India, over US$1.5 billion in Bangladesh, and over US$3 billion in Pakistan. For all countries, the attributable costs are higher for younger cohorts with costs declining with increasing age for those over 50. The model predicted that a typical 15-year-old male adoloscent would gain 0.07-0.18 life years, avert 0.07-0.19 DALYs, and generate a cost-savings of US$7-21 on healthcare spending if ST policies were changed to eliminate ST use., Conclusions: Policy interventions aimed at decreasing the uptake of ST and increasing quitting success have the potential to substantially decrease the economic and health burden of ST., Implications: This study provides the most comprehensive estimates of the lifetime health and economic burden of ST by 5-year age and sex cohorts. This is also the first study that highlights the scale of health and economic burden of ST in Bangladesh, India, and Pakistan if there were no changes in the current ST policies. Policymakers and practitioners can use the reported data to justify their decisions to improve current ST policies and practices in their country. Researchers can use the ASTRAMOD methodology to estimate the impact of future ST policy changes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.)

Background: There are no recent data on the prevalence of cardiovascular risk factors (CVDRFs) in Lesotho. This study aims to assess the prevalence of CVDRFs and their determinants., Methods: We conducted a household-based, cross-sectional survey among adults ≥18 y of age in 120 randomly sampled clusters in two districts., Results: Among 6061 participants, 52.2% were female and their median age was 39 y (interquartile range 27-58). The overall prevalence of overweight, diabetes, elevated blood pressure (BP) and tobacco use was 39.9%, 5.3%, 21.6% and 24.9%, respectively. Among participants, 34.6% had none, 45.2% had one and 20.2% had two or more CVDRFs. Women were more likely to have two or more CVDRFs (20.7% vs 12.3%). Overall, 7.5% of participants had elevated total cholesterol, 52.7% had low high-density lipoprotein cholesterol and 1.6% had elevated low-density lipoprotein cholesterol. Among younger participants (18-29 y), 16.1% reported tobacco use, 28.6% were overweight, 1.5% had diabetes and 3.5% had elevated BP. Household wealth positively correlated with the prevalence of elevated BP, overweight and diabetes, whereas tobacco use was higher among people in the lowest three wealth quintiles., Conclusions: CVDRFs are highly prevalent in Lesotho across age and sex groups, underlining the importance of strengthening prevention and care programs in Lesotho and similar settings in southern Africa., (© The Author(s) 2023. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Many analytical methods are reported for simultaneous estimation of pharmaceutical dosages form. However, only a few are reproducible at an industrial scale. The proposed research aims to establish a technology transfer (TT) protocol between two laboratories (Lab-X, originator) with binary and (Lab-Y, receiver) with quaternary high-performance liquid chromatography (HPLC) system. Thus, utilizing reverse-phase HPLC (RP-HPLC), a robust, sensitive and repeatable analytical method has been developed, validated and TT between two laboratories for simultaneous estimation of Andrographolide (AG) and Paclitaxel (PTX). The method has been developed on a Phenomenex Luna C18 column (150 x 4.6, 5) sustained at 40°C and validated under the International Conference on Harmonisation (ICH) Q2 (R1) regulatory guideline and TT USP chapter 1224. The mobile phase consisted of MilliQ (pH = 3) and a combination of acetonitrile and methanol (1:1) in the ratio 50:50 with a flow rate of 0.45 mL/min, linear gradient elution in both labs. The AG and PTX were detected on the PDA detector at 224 and 227 nm wavelength with retention time of 4.5 ± 0.34 and 8.2 ± 0.02 min and limit of detection was found 0.028 ± 0.004 μg/mL, and 0.028 ± 0.0007 μg/mL, whereas limit of quantification as 0.086 ± 0.011 μg/mL and 0.088 ± 0.0014 μg/mL respectively in both labs. Throughout, this approach we have proved that proposed method is repeatable in both labs, and it can be used to quantify AG and PTX in developed pharmaceutical nano-formulations., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

It has long been known that some patients with type 2 diabetes (T2DM) can experience sustained metabolic improvement to near-normal levels of glycemia either spontaneously or after medical intervention. Now recognized as remission of diabetes, this intriguing state is currently more feasible than ever before due to profound advances in metabolic surgery, pharmacologic therapy, and regimens of lifestyle modification. This enhanced capacity to induce remission has revealed new pathophysiologic insights, including the presence of a reversible component of the pancreatic beta-cell dysfunction that otherwise drives the chronic progressive nature of T2DM. In doing so, it has changed the therapeutic landscape by offering new potential management objectives and considerations for patients and providers. However, the excitement around these developments must also be tempered by the sobering realities of our current understanding of remission, including the recognition that this condition may not be permanent (resulting in glycemic relapse over time) and that beta-cell function may not be normalized in the setting of remission. These limitations highlight both the many gaps in our current understanding of remission and the caution with which clinical discussions must be handled for clear patient-directed communication of the pros and cons of targeting this outcome in practice. In this mini-review, we consider this rapidly growing literature, including its implications and its limitations, and thereby seek to provide objective balanced perspectives on targeting remission of T2DM in current clinical care., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Advanced Practice Providers (APPs) are a rapidly growing segment of the pediatric infectious diseases workforce. APPs offer many advantages to divisions that are struggling to counter a smaller fellowship applicant pool and faculty workforce transitions as a result of the pandemic. Many divisions still have yet to incorporate APPs into their inpatient or outpatient teams. This review will discuss the diverse pool of APPs, summarize how APPs are currently being used in the field, discuss the financial considerations of hiring APPs, and highlight future needs for embracing APPs as critical members of the pediatric ID workforce., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Fecal calprotectin (FC) is a reliable predictor of active bowel inflammation in postoperative Crohn's disease (CD), but cutoffs vary between studies. Recent guidelines recommend a cutoff of <50 ug/g to avoid routine endoscopy in patients at low pretest probability for CD recurrence. We evaluated the performance of this threshold in a real-world CD cohort after ileocolic resection (ICR)., Methods: In this retrospective study, patients with CD post-ICR between 2009 to 2020 with FC > 60 days but < 1 year of surgery were included from a multicenter database. Established risk factors and/or biologic prophylaxis (biologic within 90 days of surgery) defined pretest probability. Those without postoperative colonoscopy were excluded. Rates of endoscopic recurrence, defined as Rutgeerts score ≥ i2b at any time after surgery, were compared between FC < 50 versus  ≥ 50 ug/g. Student's t -test and Fisher's exact test were utilized for statistical analysis. All postoperative FCs were matched to closest colonoscopy within 1 year to calculate sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV)., Results: Thirty-seven patients categorized as either low-risk or high-risk and received biologic prophylaxis and had postoperative colonoscopy were included. Median time to first FC was 217 days (IQR 131-288). 15 (41%) patients had initial FC < 50 ug/g versus 22 (59%) ≥50 ug/g. Median time to first colonoscopy was 234 days (IQR 189-369). Compared to initial FC ≥ 50 ug/g, FC < 50ug/g experienced less endoscopic recurrence (0% vs. 36%, P  = .005). Median time to first endoscopic recurrence in FC ≥ 50 ug/g was 145 days. There were 39 matched pairs of FC and colonoscopy. At an FC cutoff of 50 ug/g, calculated sensitivity was 90% and NPV was 93%, whereas specificity and PPV were 48% and 38%, respectively., Conclusions: In this real-world cohort, FC < 50 ug/g is a useful cutoff to exclude endoscopic recurrence in a post-ICR CD population that is at low pretest probability of recurrence., Competing Interests: Jordan E. Axelrad reports receiving research grants from Genentech and BioFire Diagnostics; consultancy fees or honorarium from Abbvie, Adiso, Bristol Myers Squibb, BioFire Diagnostics, Fresenius, Pfizer, and Janssen; and holds U.S. patent 2012/0052124A1. Edward Barnes reports consulting for Target RWE. Benjamin Click reports consulting for AbbVie, BMS, Janssen, Prometheus, Pfizer, Takeda, TARGET-RWE. Benjamin L. Cohen, M.D. receives the following financial support: Consultant for TARGET RWE; Educational Grant: Pfizer. Terry Li has no disclosures. Ravi Shah has no disclosures. Salam Bachour has no disclosures. Abel Joseph has no disclosures. Jessica Hu has no disclosures. Susell Contreras has no disclosures. Elizabeth Li has no disclosures. BC holds the position of Associate Editor for Crohn’s & Colitis 360 and has been recused from reviewing or making decisions for the manuscript., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn's & Colitis Foundation.)

Background: This systematic review aimed to investigate central nervous system (CNS) involvement in leprosy by analysing multiple cohort studies, individual cases and case series., Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. PubMed, Scopus and Embase databases were searched up to 8 July 2023, using a predefined search strategy. Inclusion criteria included patients diagnosed with leprosy with evidence of CNS involvement. The quality of the included cases was evaluated using the Joanna Briggs Institute checklist., Results: A total of 34 records were identified, including 18 cohort studies and 16 reports describing 27 isolated cases. Autopsies revealed macroscopic changes in the spinal cord, neurofibrillary tangles and senile plaques. Mycobacterium leprae was detected in neurons of the medulla oblongata and spinal cord using PCR and phenolic glycolipid 1 staining. Cerebrospinal fluid (CSF) analysis showed inflammatory changes, increased gamma globulins and detection of Mycobacterium leprae antigens and antibodies. In 21 patients (78%), spinal cord/brachial plexus abnormities were detected. In the majority, MRI revealed T2/fluid-attenuated inversion recovery (FLAIR) hyperintensity in the cervical cord. In patients with brainstem involvement, T2/FLAIR hyperintensity was noted in the cerebellar peduncles, facial nerve nuclei and/or other cranial nerve nuclei. Brain parenchymal involvement was noted in three patients., Conclusions: This systematic review provides evidence of CNS involvement in leprosy, based on autopsy findings, neuroimaging, CSF analysis and neurophysiological studies., (© The Author(s) 2023. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

The freshwater bodies of India are highly biodiverse but still understudied, especially concerning ciliates. Ciliates constitute a significant portion of eukaryotic diversity and play crucial roles in microbial loops, nutrient recycling, and ecosystem maintenance. The present study aimed to elucidate ciliate diversity in three freshwater sites in the Delhi region of India: Okhla Bird Sanctuary (OBS), Sanjay Lake (SL), and Raj Ghat pond (RJ). This study represents the first investigation into the taxonomic diversity and richness of freshwater ciliates in India using a high-throughput DNA metabarcoding approach. For the analysis, total environmental DNA was extracted from the three freshwater samples, followed by sequencing of the 18S V4 barcode region and subsequent phylogenetic analyses. Operational taxonomic units (OTU) analyses revealed maximum species diversity in OBS (106), followed by SL (104) and RJ (99) sites. Ciliates from the classes Oligohymenophorea, Prostomatea, and Spirotrichea were dominant in the three sites. The study discusses the ability of the metabarcoding approach to uncover unknown and rare species. The study highlights the need for refined reference databases and cautious interpretation of the high-throughput sequencing-generated data while emphasizing the complementary nature of molecular and morphological approaches in studying ciliate diversity., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of FEMS.)

Background: Post-exposure prophylaxis (PEP) with varicella immunoglobulin is recommended to minimize risk of varicella complications for high-risk children. However, providers frequently use alternatives like acyclovir or intravenous immunoglobulin., Methods: A retrospective cohort study was conducted of PEP for varicella in children from January 2009 to December 2019. Data were provided by 47 children's hospitals who participate in the Pediatric Health Information Systems database. Patients with clinical encounters for varicella exposure were reviewed. Choice of varicella PEP regimens, including differences by underlying condition and institution, and incidence of varicella disease were determined., Results: A total of 1704 patients with first clinical encounters for varicella met inclusion criteria. Of these patients, 509 (29.9%) were prescribed PEP after varicella exposure, and 65 (3.8%) ultimately had a subsequent encounter for varicella disease. Of 509 patients who received PEP, acyclovir was most frequently prescribed (n = 195, 38.3%), followed by varicella immunoglobulin (n = 146, 28.7%), IVIG (n = 115, 22.6%), and combination therapy (n = 53, 10.4%). The highest proportion of varicella immunoglobulin use (10/20, 50%) was amongst children with diagnoses of rheumatological/gastrointestinal conditions. The highest proportion of acyclovir use (29/684, 4.2%) was amongst children with diagnoses of oncology/stem cell transplant conditions. The proportion of patients who subsequently had clinical encounters for varicella disease was highest for Acyclovir (30/195, 15.4%) followed by varicella immunoglobulin (5/146, 3.4%), combination therapy (2/53, 3.8%), and intravenous immunoglobulin alone (0/115) (P < .0001)., Conclusions: Varicella PEP in high-risk children was highly varied among children's hospitals. In our dataset, use of acyclovir was associated with a higher rate of subsequent encounters for Varicella disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Above and below knee amputation (AKA, BKA) are treatments of last resort for peripheral arterial disease (PAD). The aim was to examine amputation rates, AKA:BKA ratios, previous revascularization and minor amputation, lengths of stay in hospital, mortality following amputation, and regional variation in people with and without diabetes in England., Methods: The study used population-based ecological and cohort study designs, 31 672 census areas, hospital admissions from 2006 to 2018 and Poisson, logistic and Cox regression., Results: There were 47 249 major lower limb amputations (50.7% AKA; 48% had diabetes), giving an annual PAD-related amputation rate of 11 per 100 000 in the population aged 25+ years. Amputation rates were higher in men and substantially higher in people with diabetes. The AKA:BKA ratio was 0.63 in patients with diabetes (n = 22 702) and 1.62 in patients without diabetes (n = 24 547). Of patients having AKA, 25.3% died within 90 days of amputation compared with 11.9% for BKA. Median survival following amputation ranged from only 1.68 years following AKA in patients with diabetes to 5.72 years following BKA in patients without diabetes. Amputation rates decreased over time mainly in the population with diabetes. Short-term mortality and lengths of stay in hospital also decreased over time, while the percentage with previous revascularization generally increased. Amputation rates and AKA:BKA ratios were highest in the North. Adjustment for age, sex and deprivation did not substantially alter geographical patterns. Adjusted 90-day mortality was generally higher in the North and the Midlands but also high in London. There were also regional variations in adjusted duration from admission to amputation, duration from amputation to discharge or death in hospital, previous revascularization and previous minor amputation., Conclusions: There were large variations in amputation rates and survival following amputation in relation to diabetes status and amputation level, and regional variations which remained after adjustment for deprivation., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Society Ltd.)

Competing Interests: Conflicts of interest The authors declare no conflicts of interest.

Background: Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas originating from cellular components within the nerve sheath. The incidence of MPNST is highest in people with neurofibromatosis type 1 (NF1), and MPNST is the leading cause of death for these individuals. Complete surgical resection is the only curative therapeutic option, but is often unfeasible due to tumor location, size, or presence of metastases. Evidence-based choices of chemotherapy for recurrent/refractory MPNST remain elusive. To address this gap, we conducted a retrospective analysis of our institutional experience in treating patients with relapsed MPNST in order to describe patient outcomes related to salvage regimens., Methods: We conducted a retrospective electronic health record analysis of patients with MPNST who were treated at Johns Hopkins Hospital from January 2010 to June 2021. We calculated time to progression (TTP) based on salvage chemotherapy regimens., Results: Sixty-five patients were included in the analysis. Upfront therapy included single or combined modalities of surgery, chemotherapy, or radiotherapy. Forty-eight patients received at least 1 line of chemotherapy, which included 23 different regimens (excluding active clinical studies). Most patients ( n = 42, 87.5%) received a combination of doxorubicin, ifosfamide, or etoposide as first-line chemotherapy. Salvage chemotherapy regimens and their TTP varied greatly, with irinotecan/temozolomide-based regimens having the longest average TTP (255.5 days, among 4 patients)., Conclusions: Patients with advanced or metastatic MPNST often succumb to their disease despite multiple lines of therapy. These data may be used as comparative information in decision-making for future patients and clinical trials., Competing Interests: K.M.L is an inventor on the patent (WO2022046910) for prodrugs of 6-Mercaptopurine (not relevant to the current manuscript). C.A.P. is an inventor on the patent application (WO2022234409A1) held/submitted by the Johns Hopkins University and Novartis that covers compounds and compositions for the treatment of MPNST (not relevant to the current manuscript). C.A.P. is a recipient of research grants from Novartis (not relevant to the current manuscript) and Kura Oncology (not relevant to the current manuscript) and has received consulting fees from Day One Therapeutics and Genentech (not relevant to the current manuscript). C.F.M. received royalties from UpToDate (not relevant to the current manuscript). J.O.B is a national co-investigator for clinical trials supported by Alexion, SpringWorks, and Takeda (none are relevant to this current manuscript). The other co-authors declare that they have no competing interests., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)