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The Australian, Chinese, European, Indian, and North American pulsar timing array (PTA) collaborations recently reported, at varying levels, evidence for the presence of a nanohertz gravitational-wave background (GWB). Given that each PTA made different choices in modeling their data, we perform a comparison of the GWB and individual pulsar noise parameters across the results reported from the PTAs that constitute the International Pulsar Timing Array (IPTA). We show that despite making different modeling choices, there is no significant difference in the GWB parameters that are measured by the different PTAs, agreeing within 1 σ . The pulsar noise parameters are also consistent between different PTAs for the majority of the pulsars included in these analyses. We bridge the differences in modeling choices by adopting a standardized noise model for all pulsars and PTAs, finding that under this model there is a reduction in the tension in the pulsar noise parameters. As part of this reanalysis, we “extended” each PTA’s data set by adding extra pulsars that were not timed by that PTA. Under these extensions, we find better constraints on the GWB amplitude and a higher signal-to-noise ratio for the Hellings–Downs correlations. These extensions serve as a prelude to the benefits offered by a full combination of data across all pulsars in the IPTA, i.e., the IPTA’s Data Release 3, which will involve not just adding in additional pulsars but also including data from all three PTAs where any given pulsar is timed by more than a single PTA.

Dedicator of cytokinesis 8 (DOCK8) deficiency underlies the majority of cases of patients with autosomal recessive form of the hyper-immunoglobulin E syndrome (HIES). Most DOCK8 mutations involve deletions and splice junction mutations that abrogate protein expression. However, a few patients whose presentation is reminiscent of DOCK8 deficiency have no identifiable mutations. Using Whole Exome Sequencing (WES), we identified a deep intronic homozygous DOCK8 variant located in intron 36 (c.4626 + 76 A > G) in two unrelated patients with features of HIES that resulted in an in-frame 75 base pair intronic sequence insertion in DOCK8 cDNA, resulting in a premature stop codon (p.S1542ins6Ter). This variant resulted in variable decrease in DOCK8 expression that was associated with impaired T cell receptor-triggered actin polymerization, decreased IL-6-induced STAT3 phosphorylation, reduced expression of the Th17 cell markers CCR6 and IL-17, and higher frequencies of GATA3 + T cells indicative of Th2 skewing. Our approach extends the reach of WES in identifying disease-related intronic variants. It highlights the role of non-coding mutations in immunodeficiency disorders, including DOCK8 deficiency, and emphasizes the need to explore these mutations in unexplained inborn errors of immunity., (Copyright © 2024 Elsevier Inc. All rights reserved.)

One in four older adults report difficulty walking, greatly increasing the risk of future disability and death. Though exercise improves mobility, too few older adults do it. While studies show that brief exercise sessions provide most of the benefit of longer sessions and that older adults note that "time" is a critical barrier to being active, what remains unknown is whether briefer RT sessions can improve mobility as well as, or better than, longer traditional sessions, possibly due to greater adherence. We present the design of a 12-month randomized controlled trial of 700 older adults with self-reported walking difficulty. Participants will be randomly assigned, in a 2 × 2 factorial design, to one of two home-based exercise programs: 1) Standard of Care: 45-min, three-times weekly sessions or 2) Experimental: 5-min daily sessions and to one of two doses of behavior change techniques (Standard or Enhanced) as part of their exercise program. The primary outcome measure is self-reported physical function. Secondary outcome measures include objectively measured lower extremity physical performance, walking endurance, balance, walking speed, strength and physical activity as well as self-reported falls, pain, fatigue and balance. This is one of the first studies to examine the clinical outcomes of brief exercise sessions, which may lead to a new generation of exercise programs that are optimized not only for impact, but for adherence as well., Competing Interests: Declaration of competing interest Dr. Sciamanna is part-owner of BandUp, Inc. and Play Fitness, LLC, formed to test the viability of various business models to disseminate findings from exercise studies. No other authors have competing interests., (Copyright © 2024. Published by Elsevier Inc.)

D-Xylitol is a naturally occurring sugar alcohol present in diverse plants that is used as an alternative sweetener based on a sweetness similar to sucrose and several health benefits compared to conventional sugar. However, current industrial methods for D-xylitol production are based on chemical hydrogenation of D-xylose, which is energy-intensive and environmentally harmful. However, efficient conversion of L-arabinose as an additional highly abundant pentose in lignocellulosic materials holds great potential to broaden the range of applicable feedstocks. Both pentoses D-xylose and L-arabinose are converted to D-xylitol as a common metabolic intermediate in the native fungal pentose catabolism.To engineer a strain capable of accumulating D-xylitol from arabinan-rich agricultural residues, pentose catabolism was stopped in the ascomycete filamentous fungus Aspergillus niger at the stage of D-xylitol by knocking out three genes encoding enzymes involved in D-xylitol degradation (ΔxdhA, ΔsdhA, ΔxkiA). Additionally, to facilitate its secretion into the medium, an aquaglyceroporin from Saccharomyces cerevisiae was tested. In S. cerevisiae, Fps1 is known to passively transport glycerol and is regulated to convey osmotic stress tolerance but also exhibits the ability to transport other polyols such as D-xylitol. Thus, a constitutively open version of this transporter was introduced into A. niger, controlled by multiple promoters with varying expression strengths. The strain expressing the transporter under control of the PtvdA promoter in the background of the pentose catabolism-deficient triple knock-out yielded the most favorable outcome, producing up to 45% D-xylitol from L-arabinose in culture supernatants, while displaying minimal side effects during osmotic stress. Due to its additional ability to extract D-xylose and L-arabinose from lignocellulosic material via the production of highly active pectinases and hemicellulases, A. niger emerges as an ideal candidate cell factory for D-xylitol production from lignocellulosic biomasses rich in both pentoses.In summary, we are showing for the first time an efficient biosynthesis of D-xylitol from L-arabinose utilizing a filamentous ascomycete fungus. This broadens the potential resources to include also arabinan-rich agricultural waste streams like sugar beet pulp and could thus help to make alternative sweetener production more environmentally friendly and cost-effective., (© 2024. The Author(s).)

Background : Of all adverse drug reactions, 35-45% are due to medication errors and would therefore be preventable. Thus, it is essential to implement effective strategies to prevent medication errors. However, it remains unclear whether medication reviews provide an additional benefit compared to medication reconciliation regarding medication safety. Aim : The present study aimed to evaluate whether medication reconciliation and medication reviews affect the incidence of preventable adverse drug reactions in elderly patients. Method : Non-elective patients 65 years and above admitted to the hospital, taking at least one high-risk drug, were eligible for participation in a three-armed randomized controlled trial. One group went through the medication reconciliation process, a second group received a comprehensive medication review, including medication reconciliation, and the third group did not receive any pharmaceutical intervention (control group). The incidence of preventable adverse drug reactions during hospitalization was set as the primary endpoint. The severity of the preventable adverse drug reactions and the number and clinical relevance of drug-related problems and discrepancies were defined as secondary endpoints. Results : In 207 patients, 74 preventable adverse drug reactions were detected. Neither medication reconciliation nor medication reviews showed a significant impact on the incidence of preventable adverse drug reactions compared to the control group. However, medication reviews significantly reduced the severity of preventable adverse drug reactions (p=0.017). Conclusion : The current study results suggest that medication reviews may have an impact on a clinically relevant outcome by reducing the severity of preventable adverse drug reactions. A significant impact of medication reconciliation on clinically relevant outcomes could not be demonstrated. Based on the results of this study, when deciding on a pharmaceutical intervention comprehensive medication reviews should be preferred over sole medication reconciliation whenever possible.

Purpose: The necessity of routine drain placement in pancreatic resections is controversial. Some randomized controlled trials have shown that the omission of drainage is safe for some patients, whereas reintervention rates and mortality rates are substantial for others. The present study aimed to assess fistula-associated outcomes in the setting of routine drain placement and drain irrigation on demand., Methods: Between 01/2017 and 12/2022, perioperative and outcome data from patients who underwent consecutive pancreatoduodenectomies (PD, n = 253) or distal pancreatectomies (DP, n = 72) were prospectively collected in the electronic StuDoQ database and analysed. All patients underwent intraoperative drain placement. Drains were removed starting at postoperative day 2 in PD or at day 5 in DP after testing for amylase concentration. In case of high amylase levels or macroscopically suspicious pancreatic fistulas, drain irrigation was started. Nondrained fluid collections underwent percutaneous radiologic or transluminal endoscopic evacuation., Results: Clinically relevant pancreatic fistulas were detected in 53 of 325 patients (POPF grade B 16.3%, grade C 1.2%). 43.3% of those had drain irrigation. Additional interventional or endoscopic drainage was necessary in 14 and 5 patients, respectively (overall 5.8%), and were observed in 4.0% of patients with PD and in 12.5% with DP (p = 0.009). Delayed fistula-associated postpancreatectomy haemorrhage (PPH) was present in 1.2% (4/325) of patients. The fistula- and delayed PPH-associated reoperation rate was 1.5% (5/325). The 30-day and in-hospital mortality rates were both 1.5% (5/325), and the rate of fistula-associated mortality was 0.6% (2/325). The overall 90-day mortality rate was 4.5%., Conclusions: In pancreatectomies, a standardized drainage protocol including on-demand drain irrigation results in very low fistula-associated morbidity and mortality and an infrequent need for interventional or surgical reintervention as compared to previously published drainage studies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Carbohydrate-binding modules (CBM) have emerged as useful tools for a wide range of tasks, including the use as purification tags or for cellulose fiber modification. For this purpose, the CBM needs to be attached to a target protein leading to large constructs. We investigated if short peptides from the carbohydrate binding site of CBMs can bind in a similar way as native, full-length CBMs to nanocrystalline cellulose (NCC) or cotton linter paper. We designed our cellulose-binding peptides to be less hydrophobic and shorter than those previously reported. Starting from the binding site of Cel7A-CBM1, we incorporated the essential amino acids involved in cellulose binding into our peptides. These peptides, as well as control peptides with scrambled sequences or a lack of essential amino acids, bound to cellulose with similar affinity as CBM regardless of their secondary structure, sequence, or hydrophobicity. This unspecific mode of cellulose binding displayed by the presented peptides may be exploited to functionalize cellulose-based biomaterials by means of peptide-conjugates.

Publicly available genomic databases and genetic constraint scores are crucial in understanding human population variation and the identification of variants that are likely to have a deleterious impact causing human disease. We utilized the one of largest publicly available databases, gnomAD, to determine genes that are highly constrained for only LoF, only missense, and both LoF/missense variants, identified their unique signatures, and explored their causal relationship with human conditions. Those genes were evaluated for unique patterns including their chromosomal location, tissue level expression, gene ontology analysis, and gene family categorization using multiple publicly available databases. Those highly constrained genes associated with human disease, we identified unique patterns of inheritance, protein size, and enrichment in distinct molecular pathways. In addition, we identified a cohort of highly constrained genes that are currently not known to cause human disease, that we suggest will be candidates to pursue as novel disease-associated genes. In summary, these insights not only elucidate biological pathways of highly constrained genes that expand our understanding of critical cellular proteins but also advance research in rare diseases.

Filamentous fungi with their diverse inventory of carbohydrate-active enzymes promise a holistic usage of lignocellulosic residues. A major challenge for application is the inherent repression of enzyme production by carbon catabolite repression (CCR). In the presence of preferred carbon sources, the transcription factor CreA/CRE-1 binds to specific but conserved motifs in promoters of genes involved in sugar metabolism, but the status of CCR is notoriously difficult to quantify. To allow for a real-time evaluation of CreA/CRE-1-mediated CCR at the transcriptional level, we developed a luciferase-based construct, representing a dynamic, highly responsive reporter system that is inhibited by monosaccharides in a quantitative fashion. Using this tool, CreA/CRE-1-dependent CCR triggered by several monosaccharides could be measured in Neurospora crassa, Aspergillus niger and Aspergillus nidulans over the course of hours, demonstrating distinct and dynamic regulatory processes. Furthermore, we used the reporter to visualize the direct impacts of multiple CreA truncations on CCR induction. Our reporter thus offers a widely applicable quantitative approach to evaluate CreA/CRE-1-mediated CCR across diverse fungal species and will help to elucidate the multifaceted effects of CCR on fungal physiology for both basic research and industrial strain engineering endeavours., (© 2024 The Author(s). Microbial Biotechnology published by John Wiley & Sons Ltd.)

Histone deacetylase 4 (HDAC4) contributes to gene repression by complex formation with HDAC3 and the corepressor silencing mediator for retinoid or thyroid hormone receptors (SMRT). We hypothesized that peptides derived from the class IIa specific binding site of SMRT would stabilize a specific conformation of its target protein and modulate its activity. Based on the SMRT-motif 1 (SM1) involved in the interaction of SMRT with HDAC4, we systematically developed cyclic peptides that exhibit K i values that are 9 to 56 times lower than that of the linear SMRT peptide. The peptide macrocycles stabilize the wildtype of the catalytic domain of HDAC4 (cHDAC4) considerably better than its thermally more stable 'gain-of-function' (GOF) variant, cHDAC4-H976Y. Molecular docking and mutagenesis studies indicated that the cyclic peptides bind in a similar but not identical manner as the linear SMRT peptide to a discontinuous binding site. Ion mobility mass spectrometry showed no major changes in the protein fold upon peptide binding. Consistent with these results, preliminary hydrogen-deuterium exchange mass spectrometry measurements indicated only minor conformational changes. Taken together, the cyclic SMRT peptides most likely stabilize the apo form of cHDAC4., (© 2024 The Authors. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.)

Purpose: The aims are to determine the feasibility of an online-delivered resistance exercise program among racially diverse breast cancer survivors and to conduct an exploratory analysis of the intervention on muscular strength, physical activity levels, health-related quality of life, and self-efficacy., Methods: A 2-arm randomized controlled trial study design with assessments at pre- and post-intervention was used. Participants (n = 52) were recruited from clinics at the host institution and randomized to either intervention (n = 28) or minimal contact control (MCC) conditions (n = 24). All participants received a 12-week individualized resistance exercise prescription based on their baseline functional strength assessment. Intervention participants exercised one-on-one once per week over Zoom with an exercise trainer. MCC participants received no supervision. Descriptive statistics were used to determine feasibility and acceptability (primary outcomes). Repeated measures ANOVAs were used to examine exploratory outcomes., Results: The intervention demonstrated high rates for feasibility outcomes of enrollment (80.0%) and post-intervention assessment completion (92.9%). Acceptability outcomes were high for session attendance (98.0%) and satisfaction (M score  = 4.87 out of 5, SD = .18). The intervention group increased upper- (p < .01) and lower- (p < .02) body strength compared to MCC condition., Conclusions: The intervention was feasible, acceptable, and demonstrated increases in muscular strength. Limitations include a small sample recruited from one cancer center. Future research is needed to determine longitudinal impacts of resistance exercise on survivorship outcomes. Online-delivered resistance exercise shows promising efficacy among racially diverse breast cancer survivors., Clinicaltrials: gov registration: NCT04562233 on September 18, 2020., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: 'Elderspeak' has been defined as a form of communication overaccommodation used with older adults that typically involves inappropriate simplified speech. One aspect of elderspeak is the use of terms of endearment such as 'honey', sweetie' and 'dear'. There is disagreement regarding the use of terms of endearment with older adults, with differing views on whether it is beneficial or harmful., Aim: To explore the perceptions of older adults residing in an assisted living facility on the use of terms of endearment by healthcare staff., Method: This qualitative study used a descriptive phenomenological design. Semi-structured interviews were undertaken with 15 older adults regarding their perceptions of the use of terms of endearment. The data were analysed to identify themes., Findings: Two themes emerged from the interview data: 'it's a matter of opinion' and 'context matters'. Not all older adults viewed terms of endearment negatively; some liked them, others were neutral and some viewed them as childish or disrespectful., Conclusion: Perceptions regarding the use of terms of endearment appear to differ among older adults. Therefore, the use of such terms should be individualised based on the preferences of the older adult., Competing Interests: None declared, (© 2024 RCN Publishing Company Ltd. All rights reserved. Not to be copied, transmitted or recorded in any way, in whole or part, without prior permission of the publishers.)

Background: Common variable immunodeficiency (CVID) is the most common symptomatic syndrome among inborn errors of immunity. Although several aspects of CVID immunopathology have been elucidated, predictive factors for mortality are incompletely defined. A genetic cause can be identified only in approximately 30% of patients., Objective: We sought to develop a mortality predictive score on the basis of the immunophenotypes and genotypes of patients with CVID., Methods: Twenty-one patients diagnosed with CVID in Córdoba, Argentina, were analyzed for clinical and laboratory data. Immunophenotyping was done by flow cytometry. CVID-associated mutations were identified by whole-exome sequencing., Results: Alive (15) and deceased (6) patients were compared. Univariate analysis showed significant differences in CD4 + T cells ( P  = .002), natural killer (NK) cells ( P  = .001), and memory switched B cells ( P  = .001) between groups. Logistic regression analysis showed a negative correlation between CD4 + , NK, and memory switched B - cell counts and probability of survival over a 10-year period (CD4 + T cells: odds ratio [OR], 1.01; 95% CI, 1.001-1.020; NK cells: OR, 1.07; 95% CI, 1.02-1.17; and memory switched B cells: OR, 26.23; 95% CI, 2.06-2651.96). Receiver-operating characteristic curve analysis identified a survival cutoff point for each parameter (CD4 + T cells: 546 cells/mL; AUC, 0.87; sensitivity, 60%; specificity, 100%; memory switched B cells: 0.84 cells/mL; AUC, 0.92; sensitivity, 100%; specificity, 85%; and NK cells: 45 cells/mL; AUC, 0.92; sensitivity, 83%; specificity, 100%). Genetic analysis on 14 (9 female and 5 male) patients from the cohort revealed mutations associated with inborn errors of immunity in 6 patients., Conclusions: A score to predict mortality is proposed on the basis of CD4 + T, NK, and memory switched B-cell counts in patients with CVID., Competing Interests: This study was funded by the 10.13039/100000002National Institutes of Health/10.13039/100000060National Institute of Allergy and Infectious Diseases (grant no. 5R01AI128976), Agencia Nacional de Promoción Científica y Tecnológica (grant no. PICT 2021-0840), and Secretaría de Ciencia y Tecnología de la Universidad Nacional de Córdoba (grant no. 33620180100584CB). Disclosure of potential conflict of interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 The Authors.)

Background and Aims: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations to the CF transmembrane conductance regulator (CFTR). Symptoms and severity of the disease can be quite variable suggesting modifier genes play an important role., Materials and Methods: Exome sequencing was performed on six individuals carrying homozygous deltaF508 for CFTR genotype but present with rapidly progressing CF (RPCF). Data was analyzed using an unbiased genome-wide genetic burden test against 3076 controls. Single cell RNA sequencing data from LungMAP was utilized to evaluate unique and co-expression of candidate genes, and structural modeling to evaluate the deleterious effects of identified candidate variants., Results: We have identified solute carrier family 26 member 9 (SLC26A9) as a modifier gene to be associated with RPCF. Two rare missense SLC26A9 variants were discovered in three of six individuals deemed to have RPCF: c.229G > A; p.G77S (present in two patients), and c.1885C > T; p.P629S. Co-expression of SLC26A9 and CFTR mRNA is limited across different lung cell types, with the highest level of co-expression seen in human (6.3 %) and mouse (9.0 %) alveolar type 2 (AT2) cells. Structural modeling suggests deleterious effects of these mutations as they are in critical protein domains which might affect the anion transport capability of SLC26A9., Conclusion: The enrichment of rare and potentially deleterious SLC26A9 mutations in patients with RPCF suggests SLC26A9 may act as an alternative anion transporter in CF and is a modifier gene associated with this lung phenotype., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Two major etiologies of hyperbilirubinemia include hemolysis and cholestasis. Although rare, the former can give rise to the latter through the formation of pigment gallstones and subsequent biliary tree obstruction. We report a case of a 57-year-old woman with systemic lupus erythematosus who presented with dyspnea and right upper quadrant abdominal pain. She was found to have hepatolithiasis and choledocholithiasis secondary to warm autoimmune hemolytic anemia in the setting of COVID-19. In patients with symptomatic anemia secondary to acute hemolysis and concomitant right upper quadrant abdominal pain, elevated hepatocellular laboratory results should prompt a high clinical suspicion for biliary tree pigment stones., (© 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

The advancements in the detection and characterization of circulating tumor DNA (ctDNA) have revolutionized precision medicine and are likely to transform standard clinical practice. The non-invasive nature of this approach allows for molecular profiling of the entire tumor entity, while also enabling real-time monitoring of the effectiveness of cancer therapies as well as the identification of resistance mechanisms to guide targeted therapy. Although the field of ctDNA studies offers a wide range of applications, including in early disease, in this review we mainly focus on the role of ctDNA in the dynamic molecular characterization of unresectable locally advanced and metastatic BC (mBC). Here, we provide clinical practice guidance for the rapidly evolving field of molecular profiling of mBC, outlining the current landscape of liquid biopsy applications and how to choose the right ctDNA assay. Additionally, we underline the importance of exploring the clinical relevance of novel molecular alterations that potentially represent therapeutic targets in mBC, along with mutations where targeted therapy is already approved. Finally, we present a potential roadmap for integrating ctDNA analysis into clinical practice., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Autosomal-recessive mutations in SPEG (striated muscle preferentially expressed protein kinase) have been linked to centronuclear myopathy with or without dilated cardiomyopathy (CNM5). Loss of SPEG is associated with defective triad formation, abnormal excitation-contraction coupling, calcium mishandling and disruption of the focal adhesion complex in skeletal muscles. To elucidate the underlying molecular pathways, we have utilized multi-omics tools and analysis to obtain a comprehensive view of the complex biological processes and molecular functions., Methods: Skeletal muscles from 2-month-old SPEG-deficient (Speg-CKO) and wild-type (WT) mice were used for RNA sequencing (n = 4 per genotype) to profile transcriptomics and mass spectrometry (n = 4 for WT; n = 3 for Speg-CKO mice) to profile proteomics and phosphoproteomics. In addition, interactomics was performed using the SPEG antibody on pooled muscle lysates (quadriceps, gastrocnemius and triceps) from WT and Speg-CKO mice. Based on the multi-omics results, we performed quantitative real-time PCR, co-immunoprecipitation and immunoblot to verify the findings., Results: We identified that SPEG interacts with myospryn complex proteins CMYA5, FSD2 and RyR1, which are critical for triad formation, and that SPEG deficiency results in myospryn complex abnormalities (protein levels decreased to 22 ± 3% for CMYA5 [P < 0.05] and 18 ± 3% for FSD2 [P < 0.01]). Furthermore, SPEG phosphorylates RyR1 at S2902 (phosphorylation level decreased to 55 ± 15% at S2902 in Speg-CKO mice; P < 0.05), and its loss affects JPH2 phosphorylation at multiple sites (increased phosphorylation at T161 [1.90 ± 0.24-fold], S162 [1.61 ± 0.37-fold] and S165 [1.66 ± 0.13-fold]; decreased phosphorylation at S228 and S231 [39 ± 6%], S234 [50 ± 12%], S593 [48 ± 3%] and S613 [66 ± 10%]; P < 0.05 for S162 and P < 0.01 for other sites). On analysing the transcriptome, the most dysregulated pathways affected by SPEG deficiency included extracellular matrix-receptor interaction (P < 1e -15 ) and peroxisome proliferator-activated receptor signalling (P < 9e -14 )., Conclusions: We have elucidated the critical role of SPEG in the triad as it works closely with myospryn complex proteins (CMYA5, FSD2 and RyR1), it regulates phosphorylation levels of various residues in JPH2 and S2902 in RyR1, and its deficiency is associated with dysregulation of several pathways. The study identifies unique SPEG-interacting proteins and their phosphorylation functions and emphasizes the importance of using a multi-omics approach to comprehensively evaluate the molecular function of proteins involved in various genetic disorders., (© 2024 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Advances in bioinformatic tools paired with the ongoing accumulation of genetic knowledge and periodic reanalysis of genomic sequencing data have led to an improvement in genetic diagnostic rates. Candidate gene variants (CGVs) identified during sequencing or on reanalysis but not yet implicated in human disease or associated with a phenotypically distinct condition are often not revisited, leading to missed diagnostic opportunities. Here, we revisited 33 such CGVs from our previously published study and determined that 16 of them are indeed disease-causing (novel or phenotype expansion) since their identification. These results emphasize the need to focus on previously identified CGVs during sequencing or reanalysis and the importance of sharing that information with researchers around the world, including relevant functional analysis to establish disease causality., (© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Diphthamide is a modified histidine residue unique for eukaryotic translation elongation factor 2 (eEF2), a key ribosomal protein. Loss of this evolutionarily conserved modification causes developmental defects through unknown mechanisms. In a patient with compound heterozygous mutations in Diphthamide Biosynthesis 1 (DPH1) and impaired eEF2 diphthamide modification, we observe multiple defects in neural crest (NC)-derived tissues. Knockin mice harboring the patient's mutations and Xenopus embryos with Dph1 depleted also display NC defects, which can be attributed to reduced proliferation in the neuroepithelium. DPH1 depletion facilitates dissociation of eEF2 from ribosomes and association with p53 to promote transcription of the cell cycle inhibitor p21, resulting in inhibited proliferation. Knockout of one p21 allele rescues the NC phenotypes in the knockin mice carrying the patient's mutations. These findings uncover an unexpected role for eEF2 as a transcriptional coactivator for p53 to induce p21 expression and NC defects, which is regulated by diphthamide modification., (© 2024. The Author(s).)

Objective: To investigate associations between postpartum depression in fathers and children's behaviors at age 5 in a national high-risk U.S. sample., Study Design: A secondary data analysis of 1,796 children in a national birth cohort study that oversampled non-marital births was conducted. Paternal depression was assessed 1 year after the child was born and children's behaviors were assessed by their primary caregivers when the children were 5 years old. Unadjusted and adjusted negative binomial regression models of associations between paternal depression and child behavior scores and logistic regression models of associations between paternal depression and high scores (at least 1.5 or 2.0 standard deviations above the mean) were estimated., Results: In negative binomial regression models that adjusted for child, paternal, and family characteristics and maternal depression, paternal depression was associated with a 17% higher total externalizing behavior score (Incidence Rate Ratio (IRR): 1.17; 95% Confidence Interval (CI): 1.07-1.27), a 17% higher aggressive subscale score (IRR: 1.17; 95% CI: 1.08-1.27), and an 18% higher delinquent subscale score (IRR: 1.18; 95% CI: 1.03-1.35). In adjusted logistic regression models for scores ≥2.0 standard deviations above the mean, paternal depression was associated with high total externalizing scores (e.g., Odds Ratio (OR): 3.09; 95% CI: 1.77-5.41), high aggressive behavior scores (OR: 2.40; 95% CI: 1.30-4.43), and high delinquent behavior scores (OR: 2.08; 95% CI: 1.01-4.27). There were suggestive but non-robust associations between paternal depression and attention problems and no associations between paternal depression and internalizing behaviors or social problems., Conclusion: Fathers' depression at age 1 was associated with children's externalizing behaviors at age 5, an important developmental stage when children transition to school. These findings suggest a need to identify and support fathers with depressive symptoms to promote optimal child development., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Schmitz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Introduction: The American College of Sports Medicine provided guidelines for exercise prescriptions in cancer survivors for specific cancer- and treatment-related health outcomes. However, there was insufficient evidence to generate exercise prescriptions for 10 health outcomes of cancer treatment. We sought to update the state of evidence., Methods: We conducted a systematic review of these 10 understudied health outcomes (bone health, sleep, cardiovascular function, chemotherapy-induced peripheral neuropathy (CIPN), cognitive function, falls and balance, nausea, pain, sexual function, and treatment tolerance) and provided an update of evidence., Results: While the evidence base for each outcome has increased, there remains insufficient evidence to generate exercise prescriptions. Common limitations observed across outcomes included: variability in type and quality of outcome measurement tools, variability in definitions of the health outcomes, a lack of phase III trials, and a majority of trials investigating breast or prostate cancer survivors only., Conclusion: We identified progress in the field of exercise oncology for several understudied cancer- and treatment-related health outcomes. However, we were not able to generate exercise prescriptions due to continued insufficient evidence base. More work is needed to prescribe exercise as medicine for these understudied health outcomes, and our review highlights several strategies to aid in research acceleration within these areas of exercise oncology., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Over the past two years, coronavirus disease (COVID-19) has greatly altered medical student education as well as daily life. Medical schools across the world were disrupted and had to immediately adapt the educational experience to the online environment in order to continue the delivery of quality medical education. However, COVID-19 was not the only recent pandemic. This posed the question, were similar disruptions and adaptations also seen in recent past pandemics such as Severe Acute Respiratory Syndrome (SARS) or Middle East Respiratory Syndrome (MERS) that could have prepared medical educators for COVID-19? This scoping review investigated the educational and personal impact of recent pandemics on medical students., Methods: This review followed the PRISMA-ScR guidelines for scoping reviews. Nine databases including PubMed, ERIC, and EMBASE were systematically searched using keywords and subject headings related to medical students and SARS, H1N1, MERS, Ebola, Zika, and COVID-19. Studies were limited to research studies published between 2000 and 2020 and in English. Based on exclusion and inclusion criteria, all studies were independently screened by two reviewers first by the title/abstract and then via full text. Data were extracted from the included studies and analyzed qualitatively using thematic analysis., Results: A total of 174 studies fit the criteria. Seven major themes emerged from those studies: educational adaptations and online modifications, knowledge and attitudes of students, mental wellness of students, student involvement and use of telehealth, student vaccination, physical wellness of students, and stigma., Conclusion: This review provided insights into how medical students were affected by recent pandemics and their perceptions of pivoting to online education, mental health, and knowledge of the diseases. Additionally, this review showcases the various educational adaptations that emerged uniquely during the COVID-19 pandemic, such as telehealth services or video conferencing tools, that can be utilized in a post-pandemic environment.

Aims: Cardiac fibrosis drives the progression of heart failure in ischaemic and hypertrophic cardiomyopathy. Therefore, the development of specific anti-fibrotic treatment regimens to counteract cardiac fibrosis is of high clinical relevance. Hence, this study examined the presence of persistent fibroblast activation during longstanding human heart disease at a single-cell resolution to identify putative therapeutic targets to counteract pathological cardiac fibrosis in patients., Methods and Results: We used single-nuclei RNA sequencing with human tissues from two samples of one healthy donor, and five hypertrophic and two failing hearts. Unsupervised sub-clustering of 7110 nuclei led to the identification of 7 distinct fibroblast clusters. De-convolution of cardiac fibroblast heterogeneity revealed a distinct population of human cardiac fibroblasts with a molecular signature of persistent fibroblast activation and a transcriptional switch towards a pro-fibrotic extra-cellular matrix composition in patients with established cardiac hypertrophy and heart failure. This sub-cluster was characterized by high expression of POSTN, RUNX1, CILP, and a target gene adipocyte enhancer-binding protein 1 (AEBP1) (all P < 0.001). Strikingly, elevated circulating AEBP1 blood level were also detected in a validation cohort of patients with confirmed cardiac fibrosis and hypertrophic cardiomyopathy by cardiac magnetic resonance imaging (P < 0.01). Since endogenous AEBP1 expression was increased in patients with established cardiac hypertrophy and heart failure, we assessed the functional consequence of siRNA-mediated AEBP1 silencing in human cardiac fibroblasts. Indeed, AEBP1 silencing reduced proliferation, migration, and fibroblast contractile capacity and α-SMA gene expression, which is a hallmark of fibroblast activation (all P < 0.05). Mechanistically, the anti-fibrotic effects of AEBP1 silencing were linked to transforming growth factor-beta pathway modulation., Conclusion: Together, this study identifies persistent fibroblast activation in patients with longstanding heart disease, which might be detected by circulating AEBP1 and therapeutically modulated by its targeted silencing in human cardiac fibroblasts., Competing Interests: Conflict of interest: E.N. has received speaker fees educational grants from Bayer AG., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Despite the overall reduction in the HIV mother-to-child transmission (MTCT) rate in South Africa, poor adherence and retention in care during breastfeeding contribute to this period being a major driver of MTCT in South Africa. To improve this retention, postnatal clubs were created as an integrated, differentiated model of care providing psychosocial support and comprehensive care for the mother-infant pairs (MIP), including HIV and under-5-child services. We describe the implementation of these facility-based clubs and examine its health outcomes in a peri-urban primary health care setting in Cape Town, South Africa., Methods: In this prospective cohort study, conducted between June 2016 and December 2019, MIPs were recruited into postnatal clubs between 6 weeks and 6 months of age and followed-up until 18 months of age. Outcomes including maternal Viral Load (VL), and children's HIV testing were compared to a historical control group. Children's immunizations and maternal sexual and reproductive health outcomes are also described., Results: During the implementation of the postnatal club study period, 484 MIP were recruited with 84% overall attendance, 95% overall viral load suppression, and 98% overall uptake of HIV infant testing. Compared to historical controls, the club infant rapid test uptake was 1.6 times higher (95% CI: 1.4-1.9) at 9 months and 2.0 times higher at 18 months (95% CI: 1.6-2.6). Through 12 months and between 12-18 months, maternal VL monitoring was higher in the club group compared to the historical control by 1.5 times (95% CI: 1.3-1.6) and 2.6 times (95% CI: 2.1-3.2), respectively, with similar maternal VL suppression. Of 105 infants attending the 12 months visit, 99% were fully vaccinated by one year., Conclusion: MIP in the postnatal clubs showed better PMTCT outcomes than historical controls with high levels of retention in care. Other outcomes such as immunisation results suggest that integration of services, such as in the postnatal club, is feasible and beneficial for MIPs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Nelson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Autosomal recessive dedicator of cytokinesis 8 (DOCK8 -/- ) and autosomal dominant signal transducer and activator of transcription 3 (STAT3 -/+ ) deficiencies are inborn errors of immunity (IEI) disorders present with the classic features of eczema and create a dilemma during differentiation from atopic dermatitis (AD). Therefore, an appropriate approach is required for eczema to diagnose DOCK8 -/- and STAT3 -/+  early. Here, we described a set of clinical and immunological variables, including atypical AD localizations and lymphocyte subsets, to differentiate DOCK8 -/- or STAT3 -/+ from AD., Methods: This multicenter study involved 100 patients with DOCK8 -/- and STAT3 -/+ and moderate/severe AD. We recruited disease manifestations, including detailed localizations of eczema, infections, and allergy. Principle component analysis (PCA) was used to discriminate DOCK8 -/- or STAT3 -/+ from AD., Results: There were 43 patients with DOCK8 -/- , 23 with STAT3 -/+ , and 34 with AD. Pneumonia, severe infections, mucocutaneous candidiasis, and skin abscesses were commonly observed in DOCK8 and STAT3 deficiencies. Atypical skin involvement with neonatal rash, retro auricular, axillary, sacral, and genital eczema discriminate DOCK8 -/- and STAT3 -/+ from AD with high specificity ranges between 73.5 and 94.1% and positive predictive index ranges between 55 and 93.1%. Together with using absolute numbers of CD3 + , CD4 + , and CD8 + T cells, the combined clinical and laboratory features showed perfect differentiation between DOCK8 -/- or STAT3 -/+ and AD via PCA., Conclusions: The described features can be easily implemented by physicians providing early diagnosis of DOCK8 and STAT3 deficiencies., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Previous studies identified physical function limitations in older cancer survivors, but few have included objective measures and most focused on breast and prostate cancer survivors. The current study compared patient-reported and objective physical function measures between older adults with and without a cancer history., Methods: Our cross-sectional study used a nationally representative sample of community-dwelling, Medicare beneficiaries from the 2015 National Health and Aging Trends Study (n = 7495). Data collected included patient-reported physical function, including a composite physical capacity score and limitations in strength, mobility, and balance, and objectively measured physical performance metrics, including gait speed, five time sit-to-stand, tandem stand, and grip strength. All analyses were weighted to account for the complex sampling design., Results: Thirteen percent of participants (n = 829) reported a history of cancer, of which more than half (51%) reported a diagnosis other than breast or prostate cancer. In models adjusted for demographics and health history, older cancer survivors had lower Short Physical Performance Battery scores (unstandardized beta [B] = -0.36; 95% CI: -0.64, -0.08), slower gait speed (B = -0.03; 95% CI: -0.05, -0.01), reduced grip strength (B = -0.86; 95% CI: -1.44, -0.27), worse patient-reported composite physical capacity (B = -0.43; 95% CI: -0.67, -0.18) and patient-reported upper extremity strength (B = 1.27; 95% CI: 1.07, 1.50) compared to older adults without cancer. Additionally, the burden of physical function limitations was greater in women than in men, which may be explained by cancer type., Conclusions: Our results extend studies in breast and prostate cancer to show worse objective and patient-reported physical function outcomes in older adults with a range of cancer types compared to those without a cancer history. Moreover, these burdens seem to disproportionately affect older adult women, underscoring the need for interventions to address functional limitations and prevent further health consequences of cancer and its treatment., (© 2023 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Introduction: Children who are HIV-exposed and uninfected (CHEU) are a growing population at potential risk of poor neurocognitive development. We tested a nurturing care intervention on children's neurocognitive development and maternal depressive symptoms (primary) with mediation through caregiving activities (secondary)., Methods: This study was conducted among six intervention and nine comparison antenatal-care/prevention of vertical transmission (ANC/PVT) HIV clinics in eSwatini. We enrolled pregnant women and measured infant development at 9 and 18 months. mothers2mothers (m2m) designed and implemented the clinic-home-community-based intervention. We measured infants' neurodevelopment, maternal depressive symptoms and caregiving activities with the Mullen Scales of Early Learning (MSEL), Edinburgh Postnatal Depression Scale, HOME Inventory and Family Care Indicators. We fitted linear mixed effects regression models with clinic random effects to compare intervention versus comparison arms, and generalised structural equation models to evaluate mediation, adjusting for confounders., Results: Mother-infant pairs (n = 429) participated between January 2016 through May 2018. Socio-demographic characteristics were balanced between arms except for higher rates of peri-urban versus rural residence and single versus married mothers in the comparison group. The 18 month retention was 82% (180/220) intervention, 79% (166/209) comparison arm, with 25 infant deaths. Intervention MSEL scores were significantly, and modestly, higher in receptive language (55.7 [95% CI 54.6, 56.9] vs. 53.7 [95% CI 52.6, 54.8]), expressive language (42.5 [95% CI 41.6, 39.8] vs. 40.8 [95% CI 39.8, 41.7]) and composite MSEL (85.4 [95% CI 83.7, 84.5] vs. 82.7 [95% CI 81.0, 84.5]), with no difference in maternal depressive symptoms or in observations of mother-child interactions. Intervention book-sharing scores were higher (0.63 vs. 0.41) and mediated the effect on MSEL scores (indirect effect, p-values ≤ 0.024). The direct effects on visual reception and expressive language scores were significantly higher in the intervention compared to the comparison arm (coefficients 1.93 [95% CI 0.26, 3.60] and 1.66 [95% CI 0.51, 2.79, respectively])., Conclusions: Nurturing care interventions can be integrated into ANC/PVT clinic-home-community programmes. The intervention, mediated through interactive caregiving activities, increased language development scores among CHEU. Partnering with a local team, m2m, to design and implement a culturally relevant intervention illustrates the ability to impact parent-child play and learning activities that are associated with children's neurodevelopment., (© 2023 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Aging is a major risk factor for impaired cardiovascular health. Because the aging myocardium is characterized by microcirculatory dysfunction, and because nerves align with vessels, we assessed the impact of aging on the cardiac neurovascular interface. We report that aging reduces nerve density in the ventricle and dysregulates vascular-derived neuroregulatory genes. Aging down-regulates microRNA 145 (miR-145) and derepresses the neurorepulsive factor semaphorin-3A. miR-145 deletion, which increased Sema3a expression or endothelial Sema3a overexpression, reduced axon density, mimicking the aged-heart phenotype. Removal of senescent cells, which accumulated with chronological age in parallel to the decline in nerve density, rescued age-induced denervation, reversed Sema3a expression, preserved heart rate patterns, and reduced electrical instability. These data suggest that senescence-mediated regulation of nerve density contributes to age-associated cardiac dysfunction.

In many countries, assessing food and nutrient intake for research and surveillance purposes is difficult due to the lack of comprehensive, country-specific food and nutrient databases and/or a dietary analysis software program. In this case study, we describe the approach used to adapt a United States (US) dietary analysis software and nutrient database (Nutrition Data System for Research [NDSR]) for use in analyzing 24-hour dietary recalls collected for the Brazil Kids Nutrition and Health Study (KNHS). A team of experts that included individuals knowledgeable about Brazil and US eating traditions was assembled to devise solutions for between-country differences in eating habits, food supply, food nomenclature, and language. Solutions devised relied on several key resources, including the Brazilian Food Composition Table (TBCA) and a list of 200 foods commonly consumed in Brazil. These solutions included creating data entry rules that specified how each reported food should be entered into NDSR, creation of User Recipes for foods lacking a close nutritionally matching food in the NDSR database, and adjustment for food fortification differences as part of the analysis of study data. This case study illustrates that NDSR can be adapted for use outside of the United States through a structured process.

Objective: To assess whether video laryngoscopy (VL) for tracheal intubation of neonates results in a higher first-attempt success rate and fewer adverse tracheal intubation-associated events (TIAEs) when compared with direct laryngoscopy (DL)., Design: Single-centre, parallel group, randomised controlled trial., Setting: University Medical Centre Mainz, Germany., Patients: Neonates <44 0/7 weeks postmenstrual age in whom tracheal intubation was indicated either in the delivery room or in the neonatal intensive care unit., Intervention: Intubation encounters were randomly assigned to either VL or DL at first attempt., Primary Outcome: First-attempt success rate during tracheal intubation., Results: Of 121 intubation encounters assessed for eligibility, 32 (26.4%) were either not randomised (acute emergencies (n=9), clinicians' preference for either VL (n=8) or DL (n=2)) or excluded from the analysis (declined parental consent (n=13)). Eighty-nine intubation encounters (41 in the VL and 48 in the DL group) in 63 patients were analysed. First-attempt success rate was 48.8% (20/41) in the VL group compared with 43.8% (21/48) in the DL group (OR 1.22, 95% CI 0.51 to 2.88).The frequency of adverse TIAEs was 43.9% (18/41) and 47.9% (23/48) in the VL and DL group, respectively (OR 0.85, 95% CI 0.37 to 1.97). Oesophageal intubation with concomitant desaturation never occurred in the VL group but in 18.8% (9/48) of intubation encounters in the DL group., Conclusion: This study provides effect sizes for first-attempt success rates and frequency of TIAEs with VL compared with DL in the neonatal emergency setting. This study was underpowered to detect small but clinically important differences between the two techniques. The results of this study may be useful in planning future trials., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Inborn errors of immunity have been implicated in causing immune dysregulation, including allergic diseases. STAT6 is a key regulator of allergic responses., Objectives: This study sought to characterize a novel gain-of-function STAT6 mutation identified in a child with severe allergic manifestations., Methods: Whole-exome and targeted gene sequencing, lymphocyte characterization, and molecular and functional analyses of mutated STAT6 were performed., Results: This study reports a child with a missense mutation in the DNA binding domain of STAT6 (c.1114G>A, p.E372K) who presented with severe atopic dermatitis, eosinophilia, and elevated IgE. Naive lymphocytes from the affected patient displayed increased T H 2- and suppressed T H 1- and T H 17-cell responses. The mutation augmented both basal and cytokine-induced STAT6 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reversed STAT6 hyperresponsiveness to IL-4, normalized T H 1 and T H 17 cells, suppressed the eosinophilia, and improved the patient's atopic dermatitis., Conclusions: This study identified a novel inborn error of immunity due to a STAT6 gain-of-function mutation that gave rise to severe allergic dysregulation. Janus kinase inhibitor therapy could represent an effective targeted treatment for this disorder., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Receptor-derived peptides have played an important role in elucidating chemokine-receptor interactions. For the inflammatory chemokine CXC-class chemokine ligand 8 (CXCL8), a site II-mimetic peptide has been derived from parts of extracellular loops 2 and 3 and adjacent transmembrane helices of its receptor CXC-class chemokine receptor 1 (Helmer et al., RSC Adv., 2015, 5, 25657). The peptide sequence with a C-terminal glutamine did not bind to CXCL8, whereas one with a C-terminal glutamate did but with low micromolar affinity. We sought to improve the affinity and protease stability of the latter peptide through cyclization while also cyclizing the former for control purposes. To identify a cyclization strategy that permits a receptor-like interaction, we conducted a molecular dynamics simulation of CXCL8 in complex with full-length CXC-class chemokine receptor 1. We introduced a linker to provide an appropriate spacing between the termini and used an on-resin side-chain-to-tail cyclization strategy. Upon chemokine binding, the fluorescence intensity of the tetramethylrhodamine (TAMRA)-labeled cyclic peptides increased whereas the fluorescence anisotropy decreased. Additional molecular dynamics simulations indicated that the fluorophore interacts with the peptide macrocycle so that chemokine binding leads to its displacement and observed changes in fluorescence. Macrocyclization of both 18-amino acid-long peptides led to the same low micromolar affinity for CXCL8. Likewise, both TAMRA-labeled linear peptides interacted with CXCL8 with similar affinities. Interestingly, the linear TAMRA-labeled peptides were more resistant to tryptic digestion than the unlabeled counterparts, whereas the cyclized peptides were not degraded at all. We conclude that the TAMRA fluorophore tends to interact with peptides altering their protease stability and behavior in fluorescence-based assays., (© 2023 The Authors. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.)

A chiral chemical potential present in the early Universe can source helical hypermagnetic fields through the chiral plasma instability. If these hypermagnetic fields survive until the electroweak phase transition, they source a contribution to the baryon asymmetry of the Universe. In this Letter, we demonstrate that lepton flavor asymmetries above |μ|/T∼9×10^{-3} trigger this mechanism even for vanishing total lepton number. This excludes the possibility of such large lepton flavor asymmetries present at temperatures above 10^{6}  GeV, setting a constraint which is about 2 orders of magnitude stronger than the current CMB and BBN limits.

Clinical exome/genome sequencing is increasingly being utilized by clinicians to diagnose various likely genetic conditions, but many cases remain undiagnosed. In a subset of those undiagnosed cases, a single heterozygous variant in an autosomal recessive (AR) condition with consistent phenotype may be identified, raising the question if a second variant is missing. Here, we report two cases of recessive conditions in which only one heterozygous variant was initially reported by clinical exome sequencing, and on research reanalysis a second heterozygous variant in trans was identified. We performed a review of the existing exome reanalysis literature and found that this aspect is often not emphasized. These findings highlight the importance of data reanalysis in undiagnosed cases where only a single disease-associated variant is identified in an AR condition with a strong link to presenting phenotype., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)

Background & Aims: Cardiorespiratory fitness and liver fibrosis are independently associated with poor outcomes in patients with nonalcoholic steatohepatitis (NASH), however, conflicting reports exist about their relationship. We aimed to better characterize the relationship between cardiorespiratory fitness and liver histology in a cross-sectional study of patients with biopsy-proven NASH., Methods: Participants aged 18-75 years completed VO 2peak fitness assessment using symptom-limited graded exercise testing. Participants were compared by liver fibrosis stage and NAFLD Activity Score (NAS). Multivariable models were constructed to assess factors related to relative VO 2peak , including liver fibrosis and NAS., Results: Thirty-five participants with mean age 48 ± 12 years and body mass index 33.5 ± 7.6 kg/m 2 were enrolled. Seventy-four percent of participants were female and 49% had diabetes. A dose-dependent relationship was found between relative VO 2peak and liver fibrosis. Relative VO 2peak was significantly lower in participants with advanced fibrosis (F3 disease- 15.7 ± 5.3 vs. ≤ F2 disease- 20.7 ± 5.9 mL/kg/min, p = 0.027). NAS > 5 was also associated with lower relative VO 2peak (22.6 ± 5.7 vs. 16.5 ± 5.1 mL/kg/min, p = 0.012) compared to NAS ≤ 5. With multivariable modeling, advanced fibrosis remained independently predictive of relative VO 2peak while NAS trended towards significance., Discussion and Conclusions: Advanced liver fibrosis is independently associated with cardiorespiratory fitness in patients with NASH. This may explain the incremental increase in mortality as liver fibrosis stage increases. Further research is needed to determine if exercise training can improve cardiorespiratory fitness across multiple stages of liver fibrosis and directly reduce morbidity and mortality in patients with NASH., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

(1) Background: The main objectives of our study are (i) to determine the prevalence of NTRK ( neurotrophic tyrosine kinase ) fusions in a routine diagnostic setting in NSCLC (non-small cell lung cancer) and (ii) to investigate the feasibility of screening approaches including immunohistochemistry (IHC) as a first-line test accompanied by fluorescence in situ hybridization (FISH) and RNA-(ribonucleic acid-)based next-generation sequencing (RNA-NGS). (2) Methods: A total of 1068 unselected consecutive patients with NSCLC were screened in two scenarios, either with initial IHC followed by RNA-NGS ( n = 973) or direct FISH testing ( n = 95). (3) Results: One hundred and thirty-three patients (14.8%) were IHC positive; consecutive RNA-NGS testing revealed two patients (0.2%) with NTRK fusions ( NTRK1-EPS15 ( epidermal growth factor receptor pathway substrate 15 ) and NTRK1-SQSTM1 ( sequestosome 1 )). Positive RNA-NGS was confirmed by FISH, and NTRK -positive patients benefited from targeted treatment. All patients with direct FISH testing were negative. RNA-NGS- or FISH-positive results were mutually exclusive with alterations in EGFR ( epidermal growth factor receptor ), ALK ( anaplastic lymphoma kinase ), ROS1 ( ROS proto-oncogene 1 ), BRAF ( proto-oncogene B-Raf ), RET ( rearranged during transfection ) or KRAS ( kirsten rat sarcoma viral oncogene ). Excluding patients with one of these alterations raised the prevalence of NTRK -fusion positivity among panTrk-(tropomyosin receptor kinase-) IHC positive samples to 30.5%. (4) Conclusions: NTRK fusion-positive lung cancers are exceedingly rare and account for less than 1% of patients in unselected all-comer populations. Both RNA-NGS and FISH are suitable to determine clinically relevant NTRK fusions in a real-world setting. We suggest including panTrk-IHC in a diagnostic workflow followed by RNA-NGS. Excluding patients with concurrent molecular alterations to EGFR/ALK/ROS1/BRAF/RET or KRAS might narrow the target population.

Introduction: Mother's own milk is the best nutrition for every newborn and especially for vulnerable infants such as preterm infants with a very low birth weight below 1,500 grams (VLBW). If no MOM is available, human donor milk is the alternative of choice. Mothers of preterm born infants face challenging conditions that impair sufficient milk production. For this reason, it is particularly important to provide structural lactation support and, at the same time, to promote the establishment of human donor milk banks., Methods and Analysis: Via a multidisciplinary approach the Neo-MILK study will develop an intervention for structured breastfeeding and lactation support. This will be based on a comprehensive status quo and needs assessment. In addition, the implementation of human donor milk banks (HDMB) will be supported by the development of standards., Ethics and Dissemination: Intervention development is participatory, involving different disciplines and stakeholders. All surveys are subject to approval by the ethics committee. During the course of the project, the results will be communicated to the scientific community and the general public via publications, the project homepage and social media., Trial Registration Number: DRKS00024799 (German Clinical Trials Register)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Scholten et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Complications associated with secondary displacement and migration of the lesser trochanter fragment in trochanteric fractures are rare. The complaints expressed by the patient may be misunderstood and attributed to implant-associated or patient-specific problems likely to occur after surgery. This series illustrates potentially dangerous late complications caused by secondary migration of the lesser trochanter. It may help focus the surgeon's attention on possible functional impairment and severe late complications caused by displacement of the lesser trochanter in trochanteric fractures that require prompt intervention., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background Digoxin acutely increases cardiac output in patients with pulmonary arterial hypertension (PAH) and right ventricular failure; however, the effects of chronic digoxin use in PAH are unclear. Methods and Results Data from the Minnesota Pulmonary Hypertension Repository were used. The primary analysis used likelihood of digoxin prescription. The primary end point was a composite of all-cause mortality or heart failure (HF) hospitalization. Secondary end points included all-cause mortality, HF hospitalization, and transplant-free survival. Multivariable Cox proportional hazards analyses determined the hazard ratios (HR) and 95% CIs for the primary and secondary end points. Among 205 patients with PAH in the repository, 32.7% (n=67) were on digoxin. Digoxin was more often prescribed to patients with severe PAH and right ventricular failure. After propensity score-matching, 49 patients were digoxin users, and 70 patients were nonusers; of these 31 (63.3%) in the digoxin group and 41 (58.6%) in nondigoxin group met the primary end point during a median follow-up time of 2.1 (0.6-5.0) years. Digoxin users had a higher combined all-cause mortality or HF hospitalization (HR, 1.82 [95% CI, 1.11-2.99]), all-cause mortality (HR, 1.92 [95% CI, 1.06-3.49]), HF hospitalization (HR, 1.89 [95% CI, 1.07-3.35]), and worse transplant-free survival (HR, 2.00 [95% CI, 1.12-3.58]) even after adjusting for patient characteristics and severity of PAH and right ventricular failure. Conclusions In this retrospective, nonrandomized cohort, digoxin treatment was associated with greater all-cause mortality and HF hospitalization, even after multivariate correction. Future randomized controlled trials should assess the safety and efficacy of chronic digoxin use in PAH.