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Abstract The gut microbiome is implicated in the pathogenesis of colorectal cancer (CRC), but the full scope of this dialogue is unknown. Here we aimed to define the scale and membership of the body of CRC- and health-associated gut bacteria in global populations. We performed a microbiome-CRC correlation analysis of published ultra-deep shotgun metagenomic sequencing data from global microbiome surveys, utilizing a de novo (reference-agnostic) gene-level clustering approach to identify protein-coding co-abundant gene (CAGs) clusters. We link an unprecedented ~ 23–40% of gut bacteria to CRC or health, split nearly evenly as CRC- or health-associated. These microbes encode 2319 CAGs encompassing 427,261 bacterial genes significantly enriched or depleted in CRC. We identified many microbes that had not previously been linked to CRC, thus expanding the scope of “known unknowns” of CRC-associated microbes. We performed an agnostic CAG-based screen of bacterial isolates and validated predicted effects of previously unimplicated bacteria in preclinical models, in which we observed differential induction of precancerous adenomas and field effects. Single-cell RNA sequencing disclosed microbiome-induced senescence-associated gene expression signatures in discrete colonic populations including fibroblasts. In organoid co-cultures, primary colon fibroblasts from mice with microbiomes promoted significantly greater growth than fibroblasts from microbiome-depleted mice. These results offer proof-of-principle for gene-level metagenomic analysis enabling discovery of microbiome links to health and demonstrate that the microbiome can drive precancer states, thereby potentially revealing novel cancer prevention opportunities.

Abstract Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is a rare but life-threatening cutaneous drug reaction mediated by human leukocyte antigen (HLA) class I-restricted CD8+ T cells. For unbiased assessment of cellular immunopathogenesis, here we perform single-cell (sc) transcriptome, surface proteome, and T cell receptor (TCR) sequencing on unaffected skin, affected skin, and blister fluid from 15 SJS/TEN patients. From 109,888 cells, we identify 15 scRNA-defined subsets. Keratinocytes express markers indicating HLA class I-restricted antigen presentation and appear to trigger the proliferation of and killing by cytotoxic CD8+ tissue-resident T cells that express granulysin, granzyme B, perforin, LAG3, CD27, and LINC01871, and signal through the PKM, MIF, TGFβ, and JAK-STAT pathways. In affected tissue, cytotoxic CD8+ T cells express private expanded and unexpanded TCRαβ that are absent or unexpanded in unaffected skin, and mixed populations of macrophages and fibroblasts express pro-inflammatory markers or those favoring repair. This data identifies putative cytotoxic TCRs and therapeutic targets.

Abstract Background The choroid plexus (CP) is an understudied tissue in the central nervous system and is primarily implicated in cerebrospinal fluid (CSF) production. CP also produces numerous neurotrophic factors (NTF) which circulate to different brain regions. Regulation of NTFs in the CP during natural aging is largely unknown. Here, we investigated the age and gender-specific transcription of NTFs along with the changes in the tight junctional proteins (TJPs) and the water channel protein Aquaporin (AQP1). Methods Male and female mice were used for our study. Age-related transcriptional changes were analyzed using quantitative PCR at three different time points: mature adult, middle-aged, and aged. Transcriptional changes during aging were further confirmed with digital droplet PCR. Additionally, we used immunohistochemical analysis (IHC) for the evaluation of in vivo protein expression. We further investigated the cellular phenotype of these NTFS, TJP, and water channel proteins in the mouse CP by co-labeling them with the classical vascular marker, Isolectin B4, and epithelial cell marker, Plectin. Results Aging significantly altered NTF gene expression in the CP. Brain-derived neurotrophic factor (BDNF), Midkine (MDK), VGF, Insulin-like growth factor (IGF1), IGF2, Klotho (KL), Erythropoietin (EPO), and its receptor (EPOR) were reduced in the aged CP of males and females. Vascular endothelial growth factor (VEGF) transcription was gender-specific; in males, gene expression was unchanged in the aged CP, while females showed an age-dependent reduction. Age-dependent changes in VEGF localization were evident, from vasculature to epithelial cells. IGF2 and klotho localized in the basolateral membrane of the CP and showed an age-dependent reduction in epithelial cells. Water channel protein AQP1 localized in the tip of epithelial cells and showed an age-related reduction in mRNA and protein levels. TJP’s JAM, CLAUDIN1, CLAUDIN2 and CLAUDIN5 were reduced in aged mice. Conclusions Our study highlights transcriptional level changes in the CP during aging. The age-related transcriptional changes exhibit similarities as well as gene-specific differences in the CP of males and females. Altered transcription of the water channel protein AQP1 and TJPs could be involved in reduced CSF production during aging. Importantly, reduction in the neurotrophic factors and longevity factor Klotho can play a role in regulating brain aging. Graphical Abstract

Abstract The growth factor Neuregulin-1 (NRG1) has pleiotropic roles in proliferation and differentiation of the stem cell niche in different tissues. It has been implicated in gut, brain and muscle development and repair. Six isoform classes of NRG1 and over 28 protein isoforms have been previously described. Here we report a new class of NRG1, designated NRG1-VII to denote that these NRG1 isoforms arise from a myeloid-specific transcriptional start site (TSS) previously uncharacterized. Long-read sequencing was used to identify eight high-confidence NRG1-VII transcripts. These transcripts presented major structural differences from one another, through the use of cassette exons and alternative stop codons. Expression of NRG1-VII was confirmed in primary human monocytes and tissue resident macrophages and induced pluripotent stem cell-derived macrophages (iPSC-derived macrophages). Isoform switching via cassette exon usage and alternate polyadenylation was apparent during monocyte maturation and macrophage differentiation. NRG1-VII is the major class expressed by the myeloid lineage, including tissue-resident macrophages. Analysis of public gene expression data indicates that monocytes and macrophages are a primary source of NRG1. The size and structure of class VII isoforms suggests that they may be more diffusible through tissues than other NRG1 classes. However, the specific roles of class VII variants in tissue homeostasis and repair have not yet been determined.

Abstract Background With a median age at diagnosis of 70, lung cancer remains a significant public health challenge for older Americans. Surgery is a key component in treating most patients with non-metastatic lung cancer. These patients experience postoperative pain, fatigue, loss of respiratory capacity, and decreased physical function. Data on quality of life (QOL) in older adults undergoing lung cancer surgery is limited, and few interventions are designed to target the needs of older adults and their family caregivers (FCGs). The primary aim of this comparative effectiveness trial is to determine whether telephone-based physical activity coaching before and after surgery will be more beneficial than physical activity self-monitoring alone for older adults and their FCGs. Methods In this multicenter comparative effectiveness trial, 382 older adults (≥ 65 years) with lung cancer and their FCGs will be recruited before surgery and randomized to either telephone-based physical activity coaching or physical activity self-monitoring alone. Participants allocated to the telephone-based coaching comparator will receive five telephone sessions with coaches (1 pre and 4 post surgery), an intervention resource manual, and a wristband pedometer. Participants in the self-monitoring only arm will receive American Society of Clinical Oncology (ASCO) physical activity information and wristband pedometers. All participants will be assessed at before surgery (baseline), at discharge, and at days 30, 60, and 180 post-discharge. The primary endpoint is the 6-minute walk test (6MWT) at 30 days post-discharge. Geriatric assessment, lower extremity function, self-reported physical function, self-efficacy, and QOL will also be assessed. Discussion The trial will determine whether this telephone-based physical activity coaching approach can enhance postoperative functional capacity and QOL outcomes for older adults with lung cancer and their FCGs. Trial results will provide critical findings to inform models of postoperative care for older adults with cancer and their FCGs. Trial Registration ClinicalTrials.gov Identifier: NCT06196008.

The management and processing of synchrotron and neutron computed tomography data can be a complex, labor-intensive and unstructured process. Users devote substantial time to both manually processing their data (i.e. organizing data/metadata, applying image filters etc.) and waiting for the computation of iterative alignment and reconstruction algorithms to finish. In this work, we present a solution to these problems: TomoPyUI, a user interface for the well known tomography data processing package TomoPy. This highly visual Python software package guides the user through the tomography processing pipeline from data import, preprocessing, alignment and finally to 3D volume reconstruction. The TomoPyUI systematic intermediate data and metadata storage system improves organization, and the inspection and manipulation tools (built within the application) help to avoid interrupted workflows. Notably, TomoPyUI operates entirely within a Jupyter environment. Herein, we provide a summary of these key features of TomoPyUI, along with an overview of the tomography processing pipeline, a discussion of the landscape of existing tomography processing software and the purpose of TomoPyUI, and a demonstration of its capabilities for real tomography data collected at SSRL beamline 6-2c.

Background: Proximal humerus fractures are a common injury, predominantly affecting older adults. This study aimed to develop risk-prediction models for prolonged length of hospital stay (LOS), serious adverse complications, and readmission within 30 days of surgically treated proximal humerus fractures using machine learning (ML) techniques. Methods: Adult patients (age >18) who underwent open reduction internal fixation (ORIF), hemiarthroplasty, or total shoulder arthroplasty for proximal humerus fracture between 2016 and 2021 were included. Preoperative demographic and clinical variables were collected for all patients and used to establish ML-based algorithms. The model with optimal performance was selected according to area under the curve (AUC) on the receiver operating curve (ROC) curve and overall accuracy, and the specific predictive features most important to model derivation were identified. Results: A total of 7473 patients were included (72.1% male, mean age 66.2 ± 13.7 years). Models produced via gradient boosting performed best for predicting prolonged LOS and complications. The model predicting prolonged LOS demonstrated good discrimination and performance, as indicated by (Mean: 0.700, SE: 0.017), recall (Mean: 0.551, SE: 0.017), accuracy (Mean: 0.717, SE: 0.010), F1-score (Mean: 0.616, SE: 0.014), AUC (Mean: 0.779, SE: 0.010), and Brier score (Mean: 0.283, SE: 0.010) Preoperative hematocrit, preoperative platelet count, and patient age were considered the strongest predictive features. The model predicting serious adverse complications exhibited comparable discrimination [precision (Mean: 0.226, SE: 0.024), recall (Mean: 0.697, SE: 0.048), accuracy (Mean: 0.811, SE: 0.010), F1-score (Mean: 0.341, SE: 0.031)] and superior performance relative to the LOS model [AUC (Mean: 0.806, SE: 0.024), Brier score (Mean: 0.189, SE: 0.010), noting preoperative hematocrit, operative time, and patient age to be most influential. However, the 30-day readmission model achieved the weakest relative performance, displaying low measures of precision (Mean: 0.070, SE: 0.012) and recall (Mean: 0.389, SE: 0.053), despite good accuracy (Mean: 0.791, SE: 0.009). Conclusion: Predictive models constructed using ML techniques demonstrated favorable discrimination and satisfactory-to-excellent performance in forecasting prolonged LOS and serious adverse complications occurring within 30 days of surgical intervention for proximal humerus fracture. Modifiable preoperative factors such as hematocrit and platelet count were identified as significant predictive features, suggesting that clinicians could address these factors during preoperative patient optimization to enhance outcomes. Overall, these findings highlight the potential for ML techniques to enhance preoperative management, facilitate shared decision-making, and enable more effective and personalized orthopedic care by exploring alternative approaches to risk stratification.

Abstract Elevated atmospheric carbon dioxide (eCO2) can affect plant growth and physiology, which can, in turn, impact herbivorous insects, including by altering pollen or plant tissue nutrition. Previous research suggests that eCO2 can reduce pollen nutrition in some species, but it is unknown whether this effect is consistent across flowering plant species. We experimentally quantified the effects of eCO2 across multiple flowering plant species on plant growth in 9 species and pollen chemistry (%N an estimate for protein content and nutrition in 12 species; secondary chemistry in 5 species) in greenhouses. For pollen nutrition, only buckwheat significantly responded to eCO2, with %N increasing in eCO2; CO2 treatment did not affect pollen amino acid composition but altered secondary metabolites in buckwheat and sunflower. Plant growth under eCO2 exhibited two trends across species: plant height was taller in 44% of species and flower number was affected for 63% of species (3 species with fewer and 2 species with more flowers). The remaining growth metrics (leaf number, above-ground biomass, flower size, and flowering initiation) showed divergent, species-specific responses, if any. Our results indicate that future eCO2 is unlikely to uniformly change pollen chemistry or plant growth across flowering species but may have the potential to alter ecological interactions, or have particularly important effects on specialized pollinators.

Abstract Microspherical structures find broad application in chemistry and materials science, including in separations and purifications, energy storage and conversion, organic and biocatalysis, and as artificial and bioactive scaffolds. Despite this utility, the systematic diversification of their morphology and function remains hindered by the limited range of their molecular building blocks. Drawing upon the design principles of reticular synthesis, where diverse organic molecules generate varied porous frameworks, we show herein how analogous microspherical structures can be generated under mild conditions. The assembly of simple organic molecules into microspherical structures with advanced morphologies represents a grand challenge. Beginning with a partially condensed Schiff base which self-assembles into a hierarchical organic microsphere, we systematically synthesized sixteen microspheres from diverse molecular building blocks. We subsequently explicate the mechanism of hierarchical assembly through which these hierarchical organic microspheres are produced, isolating the initial monomer, intermediate substructures, and eventual microspheres. Furthermore, the open cavities present on the surfaces of these constructs provided distinctive adsorptive properties, which we harnessed for the immobilization of enzymes and bacteriophages. Holistically, these hierarchical organic microspheres provide an approach for designing multi-functional superstructures with advanced morphologies derived from simple organic molecules, revealing an extended length scale for reticular synthesis.

Abstract This study examines the presence of bisphenol A (BPA), S (BPS), F (BPF), and M (BPM) in various recycled plastics readily available on the market (LDPE, HDPE, PET, and PP), in light of European Food Safety Authority (EFSA) limits. Twenty samples of different origin are analyzed, cleaning treatments are applied, and the migration potential of these bisphenols into food is studied. BPM is absent in all samples, but a post-consumer recycled LDPE sample reveals high bisphenol concentrations, raising concerns, reaching 8540 ng/g, 370 ng/g, and 29 ng/g of BPA, BPS, and BPF, respectively. Migration tests show substantial migration of these contaminants into food simulants. Using a cleaning treatment with polyethylene glycol (PEG 400) reduces BPA in LDPE, HDPE, PP, and PET samples by 95%, 99%, 97% and 28%, respectively, highlighting the importance of cleaning treatments across various polymers in plastic recycling. These findings not only protect food safety but addressing environmental challenges associated with plastic recycling.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with strong genetic heterogeneity and more prevalent in males than females. We and others hypothesize that diminished activity-dependent neural signaling is a common molecular pathway dysregulated in ASD caused by diverse genetic mutations. Brain-derived neurotrophic factor (BDNF) is a key growth factor mediating activity-dependent neural signaling in the brain. A common single nucleotide polymorphism (SNP) in the pro-domain of the human BDNF gene that leads to a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met) significantly decreases activity-dependent BDNF release without affecting basal BDNF secretion. By using mice with genetic knock-in of this human BDNF methionine (Met) allele, our previous studies have shown differential severity of autism-like social deficits in male and female BDNF+/Met mice. Pyramidal neurons are the principal neurons in the prefrontal cortex (PFC), a key brain region for social behaviors. Here, we investigated the impact of diminished activity-dependent BDNF signaling on the intrinsic excitability of pyramidal neurons in the PFC. Surprisingly, diminished activity-dependent BDNF signaling significantly increased the intrinsic excitability of pyramidal neurons in male mice, but not in female mice. Notably, significantly decreased thresholds of action potentials were observed in male BDNF+/Met mice, but not in female BDNF+/Met mice. Voltage-clamp recordings revealed that the sodium current densities were significantly increased in the pyramidal neurons of male BDNF+/Met mice, which were mediated by increased transcriptional level of Scn2a encoding sodium channel NaV 1.2. Medium after hyperpolarization (mAHP), another important parameter to determine intrinsic neuronal excitability, is strongly associated with neuronal firing frequency. Further, the amplitudes of mAHP were significantly decreased in male BDNF+/Met mice only, which were mediated by the downregulation of Kcnn2 encoding small conductance calcium-activated potassium channel 2 (SK2). This study reveals a sexually dimorphic signature of diminished activity-dependent BDNF signaling on the intrinsic neuronal excitability of pyramidal neurons in the PFC, which provides possible cellular and molecular mechanisms underpinning the sex differences in idiopathic ASD patients and human autism victims who carry BDNF Val66Met SNP.

BackgroundIn the United States, innovation is needed to address the increasing need for mental health care services and widen the patient-to-provider ratio. Despite the benefits of digital mental health interventions (DMHIs), they have not been effective in addressing patients’ behavioral health challenges as stand-alone treatments. ObjectiveThis study evaluates the implementation and effectiveness of precision behavioral health (PBH), a digital-first behavioral health care model embedded within routine primary care that refers patients to an ecosystem of evidence-based DMHIs with strategically placed human support. MethodsPatient demographic information, triage visit outcomes, multidimensional patient-reported outcome measure, enrollment, and engagement with the DMHIs were analyzed using data from the electronic health record and vendor-reported data files. The RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework was used to evaluate the implementation and clinical effectiveness outcomes of PBH. ResultsPBH had a 47.58% reach rate, defined as patients accepting the PBH referral from their behavioral health integrated clinician. PBH patients had high DMHI registration rates (79.62%), high activation rates (76.54%), and high retention rates at 15 days (57.69%) and 30 days (44.58%) compared to literature benchmarks. In total, 74.01% (n=168) of patients showed clinical improvement, 22.47% (n=51) showed no clinical change, and 3.52% (n=8) showed clinical deterioration in symptoms. PBH had high adoption rates, with behavioral health integrated clinicians referring on average 4.35 (SD 0.46) patients to PBH per month and 90%-100% of clinicians (n=12) consistently referring at least 1 patient to PBH each month. A third (32%, n=1114) of patients were offered PBH as a treatment option during their triage visit. ConclusionsPBH as a care model with evidence-based DMHIs, human support for patients, and integration within routine settings offers a credible service to support patients with mild to moderate mental health challenges. This type of model has the potential to address real-life access to care problems faced by health care settings.

Meniscus tissue is commonly injured due to sports-related injuries and age-related degeneration and approximately 50% of individuals with a meniscus tear will develop post-traumatic osteoarthritis (PTOA). Given that the meniscus has limited healing potential, new therapeutic strategies are required to enhance meniscus repair. Porcine meniscus-derived matrix (MDM) scaffolds improve meniscus integrative repair, but sources of human meniscus tissue have not been investigated. Therefore, the objectives of this study were to generate healthy and osteoarthritic (OA) MDM scaffolds and to compare meniscus cellular responses and integrative repair. Meniscus cells showed high viability on both healthy and OA scaffolds. While DNA content was higher in cell-seeded OA scaffolds than cell-seeded healthy scaffolds, CCK-8, and both sGAG and collagen content were similar between scaffold types. After 28 days in an ex vivo meniscus defect model, healthy and OA scaffolds had similar DNA, sGAG, and collagen content. However, the shear strength of repair was reduced in defects containing OA scaffolds compared to healthy scaffolds. In conclusion, healthy human allograft tissue is a useful source for generating MDM scaffolds that can support cellular growth, ECM production, and ex vivo integrative repair of the meniscus, highlighting the potential suitability for tissue engineering approaches to improve meniscus repair.

Purpose: Alcohol consumption is a strong risk factor for both cirrhosis and esophageal squamous cell carcinoma (ESCC). Few studies have been conducted on the treatment of ESCC in patients with cirrhosis. This study aimed to analyze the clinical outcomes of ESCC in patients with cirrhosis. Materials and methods: Medical records of patients with esophageal cancer between January 2009 and December 2023 were retrospectively reviewed. A total of 479 patients with ESCC were included and divided into cirrhotic (n = 69) and non-cirrhotic (n = 410) groups. Clinical outcomes and survival according to treatment were compared between these groups. Results: The cirrhotic group was younger (median age 64 years vs. 69 years, p = 0.022) and had a higher proportion of male (97.1 % vs. 88.3 %, p = 0.042) than the non-cirrhotic group. Patients with cirrhosis were less likely to undergo surgery (31.9 % vs. 47.8 %, p = 0.015) and were more likely to receive no active cancer treatment (26.1 % vs. 13.7 %, p = 0.010). Overall survival was lower in the cirrhotic group (hazard ratio [HR], 1.41; 95 % confidence interval [CI], 1.01–1.99; p = 0.045), however, no difference was found between Child-Pugh class A patients and those in the non-cirrhotic group (HR, 1.04 [95 % CI, 0.69–1.56]; p = 0.864). Postoperative mortality was significantly higher in cirrhotic group (27.3 % vs. 8.7 %, p = 0.011). Upon performing concurrent chemoradiotherapy (CRT), the clinical complete response rate (84.2 % vs. 43.3 %, p = 0.004) was better in the cirrhotic group. CRT yielded better overall survival for patients with cancer in the resectable stages in the cirrhotic group compared to surgery (HR, 0.19 [95 % CI, 0.42–0.84]; p = 0.029]. Conclusions: In patient with ESCC and cirrhosis, chemoradiotherapy may be a better treatment option than surgery.

Background: Relatives of probands diagnosed with familial hypercholesterolemia (FH) should undergo cascade testing for FH. Objectives: The purpose of this study was to evaluate probands’ choices of innovative strategies to communicate their FH result with relatives and facilitate cascade testing uptake. Methods: Probands with an FH genetic result from the MyCode Community Health Initiative could choose to share their FH result with adult blood relatives via the Family and Healthcare Professional Packet (packet), family sharing and cascade chatbots (chatbot), and/or FH Outreach and Support Program (direct contact). Cascade testing uptake was measured as reported completion of genetic or cholesterol testing. Generalized estimating equations models were used to identify factors associated with testing. Results: One hundred seventy five probands received an FH result, median age was 58.9 (IQR: 44.9-69.3), and 58.9% were female. Probands shared information about 1,915 adult and 163 minor relatives (11.9 relatives per proband). Seventy percent of probands (121/175) selected at least one strategy for at least one adult relative. An average of 1.2 strategies was selected per adult relative. Cascade testing was completed for 26.6% (144/541) of adults with at least one strategy selected, 2.4% (33/1,374) of adults without a strategy selected, and 25.2% (41/163) of minor relatives. Factors associated with increased cascade testing uptake were selection of at least one strategy (6.32 higher odds), specifically, selection of direct contact (16.78 higher odds). Conclusions: Strategies implemented improved FH cascade testing uptake compared to previous estimates and in families where no strategy was selected. Overall uptake remains insufficient, which can be attributed to probands reluctance to select a strategy for many relatives.

Background Hidradenitis suppurativa (HS) is associated with a high prevalence of psychiatric disorders. However, no studies examine how psychiatric disorders influence surgical and financial outcomes. This study aimed to assess impact of a psychiatric diagnosis on patients treated for HS.

Ascaris-induced intestinal obstruction is a rare complication primarily seen in children in areas with a high prevalence of worm infestations. It can occur through 2 mechanisms: immune-mediated reactions releasing neurotoxins that cause contractions and inflammation in the small intestine (aperistalsis), or mechanical obstruction by adult worms, commonly at the ileocecal valve. Partial obstructions are managed conservatively, while complete obstructions often require surgical intervention. In a recent case, a 19-year-old male presented with persistent abdominal pain, vomiting, and inability to pass stools, and gas. Imaging revealed partial obstruction, and conservative management with fluids, a nasogastric tube, and antibiotics led to the spontaneous passage of worms, relieving symptoms. The patient was discharged with anthelmintics and advised on follow-up and sanitary measures. This case is notable for the uncommon occurrence of Ascaris-induced intestinal obstruction in adults and the successful conservative management resulting in early worm expulsion.

Abstract Chemical pesticide delivery is a fundamental aspect of agriculture. However, the extensive use of pesticides severely endangers the ecosystem because they accumulate on crops, in soil, as well as in drinking and groundwater. New frontiers in nano-engineering have opened the door for precision agriculture. We introduced Tobacco mild green mosaic virus (TMGMV) as a viable delivery platform with a high aspect ratio and favorable soil mobility. In this work, we assess the use of TMGMV as a chemical nanocarrier for agriculturally relevant cargo. While plant viruses are usually portrayed as rigid/solid structures, these are “dynamic materials,” and they “breathe” in solution in response to careful adjustment of pH or bathing media [e.g., addition of solvent such as dimethyl sulfoxide (DMSO)]. Through this process, coat proteins (CPs) partially dissociate leading to swelling of the nucleoprotein complexes—allowing for the infusion of active ingredients (AI), such as pesticides [e.g., fluopyram (FLP), clothianidin (CTD), rifampicin (RIF), and ivermectin (IVM)] into the macromolecular structure. We developed a “breathing” method that facilitates inter-coat protein cargo loading, resulting in up to ~ 1000 AIs per virion. This is of significance since in the agricultural setting, there is a need to develop nanoparticle delivery strategies where the AI is not chemically altered, consequently avoiding the need for regulatory and registration processes of new compounds. This work highlights the potential of TMGMV as a pesticide nanocarrier in precision farming applications; the developed methods likely would be applicable to other protein-based nanoparticle systems.

Abstract Background Men who have sex with men (MSM) are a key population group disproportionately affected by HIV and other sexually transmitted infections (STIs) worldwide. In Rwanda, the HIV epidemic remains a significant public health concern, and understanding the burden of HIV and hepatitis B and C coinfections among MSM is crucial for designing effective prevention and control strategies. This study aims to determine the prevalence of HIV, hepatitis B, and hepatitis C infections among MSM in Rwanda and identify correlates associated with HIV infection within this population. Methods We used respondent-driven sampling (RDS) to recruit participants between November and December 2021. A face-to-face, structured questionnaire was administered. Testing for HIV infection followed the national algorithm using two rapid tests: Alere Combo and STAT PAK as the first and second screening tests, respectively. Hepatitis B surface antigen (HBsAg) and anti-HCV tests were performed. All statistics were adjusted for RDS design, and a multivariable logistic regression model was constructed to identify factors associated with HIV infection. Results The prevalence of HIV among MSM was 6·9% (95% CI: 5·5–8·6), and among HIV-positive MSM, 12·9% (95% CI: 5·5–27·3) were recently infected. The prevalence of hepatitis B and C was 4·2% (95% CI: 3·0–5·7) and 0·7% (95% CI: 0·4–1·2), respectively. HIV and hepatitis B virus coinfection was 0·5% (95% CI: 0·2–1·1), whereas HIV and hepatitis C coinfection was 0·1% (95% CI: 0·0–0·5), and no coinfection for all three viruses was observed. MSM groups with an increased risk of HIV infection included those who ever suffered violence or abuse because of having sex with other men (AOR: 3·42; 95% CI: 1·87–6·25), those who refused to answer the question asking about ‘ever been paid money, goods, or services for sex’ (AOR: 10·4; 95% CI: 3·30–32·84), and those not consistently using condoms (AOR: 3·15; 95% CI: 1·31–7·60). Conclusion The findings suggest more targeted prevention and treatment approaches and underscore the importance of addressing structural and behavioral factors contributing to HIV vulnerability, setting interventions to reduce violence and abuse against MSM, promoting safe and consensual sexual practices, and expanding access to HIV prevention tools such as condoms and preexposure prophylaxis (PrEP).

Background The human gut microbiome develops rapidly during infancy, a key window of development coinciding with the maturation of the adaptive immune system. However, little is known about the microbiome growth dynamics over the first few months of life and whether there are any generalizable patterns across human populations. We performed metagenomic sequencing on stool samples (n = 94) from a cohort of infants (n = 15) at monthly intervals in the first 6 months of life, augmenting our dataset with seven published studies for a total of 4,441 metagenomes from 1,162 infants.Results Strain-level de novo analysis was used to identify 592 of the most abundant organisms in the infant gut microbiome. Previously unrecognized consortia were identified which exhibited highly correlated abundances across samples and were composed of diverse species spanning multiple genera. Analysis of a published cohort of infants with cystic fibrosis identified one such novel consortium of diverse Enterobacterales which was positively correlated with weight gain. While all studies showed an increased community stability during the first year of life, microbial dynamics varied widely in the first few months of life, both by study and by individual.Conclusion By augmenting published metagenomic datasets with data from a newly established cohort, we were able to identify novel groups of organisms that are correlated with measures of robust human development. We hypothesize that the presence of these groups may impact human health in aggregate in ways that individual species may not in isolation.

Hinge constructs can be used in revision total knee arthroplasty in cases of major collateral ligament deficiency, global knee instability, repeated failure of constrained implants, or large bone defects. Although the success of this construct in revision total knee arthroplasty varies depending on the type of surgery and bone quality, hinged implants can solve a wide array of complex problems while preserving stable flexion-extension motion for ambulation. The most common reasons for re-revision include patellofemoral complications, aseptic loosening, and infection. Most cases of mechanical failure for these hinged constructs occur at the hinge component. Here, we report the first instance of catastrophic femoral component failure in a modular rotating hinge via a low-energy mechanism.

Background: Less than half of adults with mental health disorders in the United States receive appropriate or timely care. Digital Mental Health Interventions (DMHIs) have the potential to bridge this gap. However, real-world adoption of DMHIs is impeded by patient and provider-level technological barriers. Care navigators have the potential to address these challenges by providing technical support and enhancing patients' experience with DMHIs. Objective: This study explores the effect of a digital care navigator (DCN) on patient registration latency and rates of DMHIs implemented as part of a digital-first behavioral health care model integrated within routine care at a large multispecialty group medical practice. Methods: Data were collected from electronic medical records and DMHI registration data were obtained from the DMHI vendors. Descriptive statistics were used to describe the DCN's efforts to help patients register with their DMHIs. Moods median tests evaluated differences in registration latency and weekly registration rate pre- and post- DCN implementation. Change in registration likelihood as a function of DCN outreach latency was investigated using a Kaplan-Meier plot. Results: During the first eight months, the DCN made 1306 phone calls to 680 unique patients, successfully connecting with 66 %. DCN implementation also increased the median registration rate from 61.9 % to 76.9 %. Results showed that the expediency by which the DCN outreached patients directly impacted registration rate such that of those who were outreached by the DCN on the day of their referral to a DMHI, 96.86 % registered. This number was reduced to 76.15 % if the DCN reached them 1-day following referral, and 41.39 % 5-days after their referral. Conclusions: Use of a DCN shows promise for enhancing patient registration rates with DMHIs in routine healthcare settings.

In South Africa, high unemployment rates persist, particularly among the country's youth and rural residents, exacerbating socio-economic challenges such as food insecurity and poverty. Despite government initiatives aimed at promoting entrepreneurship to combat youth joblessness, participation in agriculture remains low due to negative perceptions regarding the field's status and potential earnings. This study examines the socio-economic impact of youth involvement in agriculture, with a focus on job creation and poverty alleviation in the Umzimvubu Local Municipality, Eastern Cape Province. Data was collected from 210 youth using a stratified random sampling method, and analysis was conducted using logit regression and propensity score matching techniques. The results indicate that youth engage in agriculture to enhance employment opportunities and household food security, making significant contributions to farm income and poverty reduction. Recommendations include government interventions such as mentorship programs and skills training to support youth in agricultural enterprises. These findings highlight the pressing need for targeted strategies to address youth poverty and vulnerability in South Africa.

Background Rising global obesity rates are linked with inflammation and associated morbidities. These negative outcomes are generally more common in low-resource communities within high-income countries; however, it is unclear how frequent infectious disease exposures in these settings may influence the relationship between adiposity and inflammation.Aim We test associations between adiposity measures and distinct forms of inflammation among adults (n = 80) living in low-resource U.S. communities experiencing high levels of obesity and pathogen exposure.Subjects and methods Adiposity measures included BMI and percent body fat. Inflammation measures included systemic inflammation (C-reactive protein [CRP]) and localised intestinal inflammation (faecal calprotectin [FC]). The relationship between a condition characterised by elevated inflammation (Helicobacter pylori infection) and adiposity was also considered.Results Adiposity was not significantly related to FC concentration. However, both adiposity measures were positively related with odds of CRP elevation and H. pylori infection was associated with significantly lower adiposity measures (all p

Abstract Expendable Bathythermographs (XBTs) are oceanographic instruments that fall through the ocean's water column and measure ocean temperature with depth. In many instances, however, XBTs continue to record temperature after they impact the seabed. Here we show evidence that XBTs produce unique temperature responses when they impact the seabed that depend directly on seabed physical properties. Specifically, standard‐use XBTs (e.g., T‐4s and T‐5s), when deployed above a mud‐rich seabed, require significant time (tens of minutes) to equilibrate to steady‐state seafloor temperatures after seabed impact. In contrast, XBTs deployed above sand‐rich sediments equilibrate to seabed temperatures rapidly (644k XBT measurements exist publicly (via the National Oceanographic and Atmospheric Administration website), and >74,000 XBTs record temperatures post seabed impact, we suggest that XBT data represents a large, low‐cost, and currently untapped data set for characterizing seabed physical properties globally.

Reduction of amyloid beta (Aβ) has been shown to be effective in treating Alzheimer's disease (AD), but the underlying assumption that neurons are the main source of pathogenic Aβ is untested. Here, we challenge this prevailing belief by demonstrating that oligodendrocytes are an important source of Aβ in the human brain and play a key role in promoting abnormal neuronal hyperactivity in an AD knock-in mouse model. We show that selectively suppressing oligodendrocyte Aβ production improves AD brain pathology and restores neuronal function in the mouse model in vivo. Our findings suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for treating AD.

Circular RNAs represent a class of endogenous RNAs that regulate gene expression and influence cell biological decisions with implications for the pathogenesis of several diseases. Here, we disclose a novel gene-regulatory role of circHIPK3 by combining analyses of large genomics datasets and mechanistic cell biological follow-up experiments. Using time-course depletion of circHIPK3 and specific candidate RNA-binding proteins, we identify several perturbed genes by RNA sequencing analyses. Expression-coupled motif analyses identify an 11-mer motif within circHIPK3, which also becomes enriched in genes that are downregulated upon circHIPK3 depletion. By mining eCLIP datasets and combined with RNA immunoprecipitation assays, we demonstrate that the 11-mer motif constitutes a strong binding site for IGF2BP2 in bladder cancer cell lines. Our results suggest that circHIPK3 can sequester IGF2BP2 as a competing endogenous RNA (ceRNA), leading to target mRNA stabilization. As an example of a circHIPK3-regulated gene, we focus on the STAT3 mRNA as a specific substrate of IGF2BP2 and validate that manipulation of circHIPK3 regulates IGF2BP2-STAT3 mRNA binding and, thereby, STAT3 mRNA levels. Surprisingly, absolute copy number quantifications demonstrate that IGF2BP2 outnumbers circHIPK3 by orders of magnitude, which is inconsistent with a simple 1:1 ceRNA hypothesis. Instead, we show that circHIPK3 can nucleate multiple copies of IGF2BP2, potentially via phase separation, to produce IGF2BP2 condensates. Our results support a model where a few cellular circHIPK3 molecules can induce IGF2BP2 condensation, thereby regulating key factors for cell proliferation.

Background: intestinal parasitic infections are the most common infections in the world, with the most prevalent burden occurring in poverty-stricken areas. Intestinal parasitic infections are endemic in certain parts of Nigeria as a result of poor hygiene practices and pollution, which result in contamination of food and water. In semi-urban and rural communities where the dwellers are generally poor and uneducated and lack basic amenities like potable water supply and good sanitary facilities, intestinal parasitic infections cause major health problems. This study was to evaluate the influence of socio-demographic factors in the transmission of intestinal parasitoses among the residents of Ekemkpon and Idim Ita Communities of Cross River State, Nigeria. Materials and Methods: this was a cross-sectional survey between April 2019 and August 2019. Samples were obtained from 359 participants in the study areas and examined for stool analysis using direct microscopy and brine floatation technique. Socio-demographic data of the study subjects were obtained using questionnaires. Results: the prevalence of intestinal parasites was higher in Ekemkpon (41.0%) than in Idim Ita (14.9%). Participants with mixed infections in Ekemkpon were 7.9%, while those in Idim Ita were 2.2%. The study has shown that level of education had an influence on the transmission of intestinal parasites in Ekemkpon (p

Abstract Africa and the United States are both large, heterogeneous geographies with a diverse range of ecologies, climates and mosquito species diversity which contribute to disease transmission and nuisance biting. In the United States, mosquito control is nationally, and regionally coordinated and in so much as the Centers for Disease Control (CDC) provides guidance, the Environmental Protection Agency (EPA) provides pesticide registration, and the states provide legal authority and oversight, the implementation is usually decentralized to the state, county, or city level. Mosquito control operations are organized, in most instances, into fully independent mosquito abatement districts, public works departments, local health departments. In some cases, municipalities engage independent private contractors to undertake mosquito control within their jurisdictions. In sub–Saharan Africa (SSA), where most vector-borne disease endemic countries lie, mosquito control is organized centrally at the national level. In this model, the disease control programmes (national malaria control programmes or national malaria elimination programmes (NMCP/NMEP)) are embedded within the central governments’ ministries of health (MoHs) and drive vector control policy development and implementation. Because of the high disease burden and limited resources, the primary endpoint of mosquito control in these settings is reduction of mosquito borne diseases, primarily, malaria. In the United States, however, the endpoint is mosquito control, therefore, significant (or even greater) emphasis is laid on nuisance mosquitoes as much as disease vectors. The authors detail experiences and learnings gathered by the delegation of African vector control professionals that participated in a formal exchange programme initiated by the Pan-African Mosquito Control Association (PAMCA), the University of Notre Dame, and members of the American Mosquito Control Association (AMCA), in the United States between the year 2021 and 2022. The authors highlight the key components of mosquito control operations in the United States and compare them to mosquito control programmes in SSA countries endemic for vector-borne diseases, deriving important lessons that could be useful for vector control in SSA.

Abstract Sickle cell disease (SCD) affects millions worldwide, yet there are few therapeutic options. To develop effective treatments, preclinical models that recapitulate human physiology and SCD pathophysiology are needed. SCD arises from a single Glu-to-Val substitution at position 6 in the β subunit of hemoglobin (Hb), promoting Hb polymerization and subsequent disease. Sheep share important physiological and developmental characteristics with humans, including the same developmental pattern of fetal to adult Hb switching. Herein, we investigated whether introducing the SCD mutation into the sheep β-globin locus would recapitulate SCD’s complex pathophysiology by generating high quality SWISS-MODEL sheep Hb structures and performing MD simulations of normal/sickle human (huHbA/huHbS) and sheep (shHbB/shHbS) Hb, establishing how accurately shHbS mimics huHbS behavior. shHbS, like huHbS, remained stable with low RMSD, while huHbA and shHbB had higher and fluctuating RMSD. shHbB and shHbS also behaved identically to huHbA and huHbS with respect to β2-Glu6 and β1-Asp73 (β1-Asn72 in sheep) solvent interactions. These data demonstrate that introducing the single SCD-causing Glu-to-Val substitution into sheep β-globin causes alterations consistent with the Hb polymerization that drives RBC sickling, supporting the development of a SCD sheep model to pave the way for alternative cures for this debilitating, globally impactful disease.

Abstract When multiple influential covariates need to be balanced during a clinical trial, stratified blocked randomization and covariate-adaptive randomization procedures are frequently used in trials to prevent bias and enhance the validity of data analysis results. The latter approach is increasingly used in practice for a study with multiple covariates and limited sample sizes. Among a group of these approaches, the covariate-adaptive procedures proposed by Pocock and Simon are straightforward to be utilized in practice. We aim to investigate the optimal design parameters for the patient treatment assignment probability of their developed three methods. In addition, we seek to answer the question related to the randomization performance when additional covariates are added to the existing randomization procedure. We conducted extensive simulation studies to address these practically important questions.

Abstract RNA binding proteins (RBPs) are key regulators of RNA processing and cellular function. Technologies to discover RNA targets of RBPs such as TRIBE (targets of RNA binding proteins identified by editing) and STAMP (surveying targets by APOBEC1 mediated profiling) utilize fusions of RNA base-editors (rBEs) to RBPs to circumvent the limitations of immunoprecipitation (CLIP)-based methods that require enzymatic digestion and large amounts of input material. To broaden the repertoire of rBEs suitable for editing-based RBP-RNA interaction studies, we have devised experimental and computational assays in a framework called PRINTER (protein-RNA interaction-based triaging of enzymes that edit RNA) to assess over thirty A-to-I and C-to-U rBEs, allowing us to identify rBEs that expand the characterization of binding patterns for both sequence-specific and broad-binding RBPs. We also propose specific rBEs suitable for dual-RBP applications. We show that the choice between single or multiple rBEs to fuse with a given RBP or pair of RBPs hinges on the editing biases of the rBEs and the binding preferences of the RBPs themselves. We believe our study streamlines and enhances the selection of rBEs for the next generation of RBP-RNA target discovery.

Abstract Prioritizing disease-critical cell types by integrating genome-wide association studies (GWAS) with functional data is a fundamental goal. Single-cell chromatin accessibility (scATAC-seq) and gene expression (scRNA-seq) have characterized cell types at high resolution, and studies integrating GWAS with scRNA-seq have shown promise, but studies integrating GWAS with scATAC-seq have been limited. Here, we identify disease-critical fetal and adult brain cell types by integrating GWAS summary statistics from 28 brain-related diseases/traits (average N = 298 K) with 3.2 million scATAC-seq and scRNA-seq profiles from 83 cell types. We identified disease-critical fetal (respectively adult) brain cell types for 22 (respectively 23) of 28 traits using scATAC-seq, and for 8 (respectively 17) of 28 traits using scRNA-seq. Significant scATAC-seq enrichments included fetal photoreceptor cells for major depressive disorder, fetal ganglion cells for BMI, fetal astrocytes for ADHD, and adult VGLUT2 excitatory neurons for schizophrenia. Our findings improve our understanding of brain-related diseases/traits and inform future analyses.

El cultivo de uva (Vitis vinifera L.) en la región Piura, es infestado por plagas como Spodoptera eridania Stoll, especie polífaga originaria de los trópicos sudamericanos. El objetivo de realizar el trabajo de investigación fue conocer aspectos básicos sobre su morfología y biología, debido a que no se encontraban registros de los mismos en este cultivo, ni en otros de la región. Se realizaron observaciones diarias para determinar la duración del periodo de incubación de huevos, del desarrollo larval, e igualmente del estado de pupa y la longevidad de los adultos. Emergidos los adultos, se aparearon para establecer el ritmo de oviposición, y capacidad reproductiva, todos estos parámetros se evaluaron durante tres generaciones. Se determinó que, bajo condiciones de laboratorio, el ciclo de desarrollo de S. eridania fue de 34,90 días para la primera generación, 31,16 y 28,60 días para la segunda y tercera, con un registro promedio de temperatura de 27,97 °C y humedad relativa del 71,86%. Los resultados muestran que puede desarrollarse en plantaciones de vid, y serán de utilidad en la planificación de las labores propias del cultivo y en el establecimiento de estrategias de manejo integrado de plagas para reducir las infestaciones cuando estas se presenten.

Abstract Background Knowledge, attitudes and substitution laws of biosimilars are not consistent across countries. Biosimilar acceptance among patients and healthcare professionals may be suffering from gaps in knowledge and understanding about biosimilars and their regulatory approval process. Pharmacists' roles and responsibilities changed considerably during the COVID-19 pandemic. Thus, they might have gained new skills and self-confidence in counseling and substitution of biosimilars. Aims To examine and compare the knowledge, perceptions and information needs of German and Swiss pharmacists regarding original biologicals and biosimilars in 2020 and 2022. Methods We conducted an online survey among Swiss and German community pharmacies in February 2020 (before) and August 2022 (after the COVID-19 pandemic). Descriptive statistics were calculated and the Chi-Square test was used for comparisons among categorical variables. Results A total of 764 pharmacists took part in the survey (390 in 2020 and 374 in 2022) with comparable demographics. The frequency of dispensing biologicals remained similar between German and Swiss pharmacists in 2020 and 2022, but the Swiss dispensation of biosimilars increased significantly in 2022 compared to 2020. Concerning the understanding of the term biosimilars, knowledge remained moderate in both countries in both years. Participants were equally familiar with the term and most felt sufficiently informed. In both countries, substitution with a biosimilar showed the least confidence of all attitudes. A third of the participants indicated correct substitution rules in their country. In both years, around 85% of the participants were highly interested in additional training on this topic. Discussion/Conclusion The results indicate that similarities and differences between Germany and Switzerland regarding knowledge and attitudes towards biologicals and biosimilars remained unchanged before and after the COVID-19 pandemic. An influence of the pandemic is unlikely. There is still a clear lack of knowledge among community pharmacists on biosimilars, especially regarding the substitution rules. Due to a rising market with many benefits but also big challenges to overcome, the topic of biosimilars should receive more attention in the future. This requires additional training for pharmacists.

Within the phylum Cnidaria, sea anemones (class Anthozoa) express a rich diversity of ion-channel peptide modulators with biomedical applications, but corollary discoveries from jellyfish (subphylum Medusozoa) are lacking. To bridge this gap, bioactivities of previously unexplored proteinaceous and small molecular weight (~15 kDa to 5 kDa) venom components were assessed in a mouse dorsal root ganglia (DRG) high-content calcium-imaging assay, known as constellation pharmacology. While the addition of crude venom led to nonspecific cell death and Fura-2 signal leakage due to pore-forming activity, purified small molecular weight fractions of venom demonstrated three main, concentration-dependent and reversible effects on defined heterogeneous cell types found in the primary cultures of mouse DRG. These three phenotypic responses are herein referred to as phenotype A, B and C: excitatory amplification (A) or inhibition (B) of KCl-induced calcium signals, and test compound-induced disturbances to baseline calcium levels (C). Most notably, certain Alatina alata venom fractions showed phenotype A effects in all DRG neurons; Physalia physalis and Chironex fleckeri fractions predominantly showed phenotype B effects in small- and medium-diameter neurons. Finally, specific Physalia physalis and Alatina alata venom components induced direct excitatory responses (phenotype C) in glial cells. These findings demonstrate a diversity of neuroactive compounds in jellyfish venom potentially targeting a constellation of ion channels and ligand-gated receptors with broad physiological implications.

Medulloblastoma, a malignant brain tumor primarily affecting children, poses significant challenges to patients and clinicians due to its complex treatment and potential long-term cognitive consequences. While recent advancements in treatment have significantly improved survival rates, survivors often face cognitive impairments, particularly in reading, impacting their quality of life. According to the double deficit theory, reading impairments are caused by deficits in one or both of two independent reading-related functions: phonological awareness and rapid visual naming. This longitudinal study investigates neurofunctional changes related to reading in medulloblastoma survivors in comparison to controls using functional MRI acquired during rapid automatized naming tasks over three annual visits. Support vector machine classification of functional MRI data reveals a progressive divergence in brain activity patterns between medulloblastoma survivors and healthy controls over time, suggesting delayed effects of cancer treatment on brain function. Alterations in brain regions involved in visual processing and orthographic recognition during rapid naming tasks imply disruptions in the ventral visual pathway associated with normal orthographic processing. These alterations are correlated with performance in tasks involving sound awareness, reading fluency, and word attack. These findings underscore the dynamic nature of post-treatment neurofunctional alterations and the importance of early identification and intervention to address cognitive deficits in survivors.

Abstract The Northern muriqui (Brachyteles hypoxanthus) is one of the world's most critically endangered primates, with only ~1000 mature individuals remaining in the wild. Habitat loss and hunting have led to its sharp decline, making conservation efforts crucial. Analyses of gut microbiomes in wild populations can provide valuable information on host health and vulnerability, and ultimately, contribute to baseline knowledge toward improving conservation programs and reintroduction efforts. In this study, we analyzed the microbiome (16S rRNA metabarcoding) of fecal samples belonging to 53 uniquely genotyped individuals from three social groups from the Caparaó National Park, aiming to provide the first assessment of the microbiome diversity and composition for this species. Our results showed the muriqui gut microbiome was predominantly composed of the phyla Bacteroidetes and Firmicutes, with the dominant classes represented by Bacteroidia and Clostridia. High similarity in bacterial diversity and composition was found for individuals from distinct groups, suggesting a negligible geographical effect at the fine spatial scale analyzed. No significant effect of host genotype heterozygosity levels on microbiota diversity was recovered, but a significant influence of genetic distance on microbiota community structure and composition was demonstrated. Our findings stress the importance of considering associations between host genetics and the microbiome and suggest that the analyzed populations host a similar microbiome composition. This detailed microbiome assessment can aid conservation actions, including future anthropogenic impact assessments and animal reintroductions.

Summary: In the 80s, radiolabeled cells helped understand the pathology of hemato-oncology. In the 90s, pre-clinical trials evaluated radiolabeled immunotherapy with monoclonal antibodies (MoAbs) such as anti-CD20 agents labeled with Iodine-131 (Bexxar®) or Yttrium-90 (Zevalin®). Due to the safe and durable responses of radiolabeled-MoAbs, the FDA approved these agents in the 2000s. Despite radioimmunotherapy's long journey, its application has recently decreased. This review will discuss the historical timeline of radioimmunotherapy, debate on advantages and difficulties, and explore trials. Furthermore, we will examine future directions of radioimmunotherapy in hemato-oncology, considering emerging molecules that may become the next theragnostic trend. Conclusão: Since the 1980s, radiolabeled cells have been instrumental in understanding the pathological dynamics of hemato-oncological diseases. The evolution of this approach traversed the hybridoma technique in the 1990s, leading to numerous pre-clinical trials involving Monoclonal Antibodies (MoAbs). Subsequent clinical trials, predominantly in the 2000s, extensively explored MoAbs, focusing on anti-CD20 agents labeled with either 131I (Bexxar) or 90Y (Zevalin). The FDA approved these therapies in 2002 and 2003, marking significant milestones recognizing their safety and enduring therapeutic responses. Despite this journey, there has been a consistent decline in prescriptions. Various factors contribute to this trend, encompassing availability issues, reimbursement challenges, regulatory complexities, the need for trained personnel, and intricate logistics. Recent pre-clinical and clinical trials have shifted the spotlight onto novel antibodies, peptides, and further applications of known tracers. This renewed exploration may incentivize new suppliers to redirect their attention, potentially heralding the next wave of theragnostic trends in the near future.

Patterns of within-host influenza A virus (IAV) diversity and evolution have been described in natural human infections, but these patterns remain poorly characterized in non-human hosts. Elucidating these dynamics is important to better understand IAV biology and the evolutionary processes that govern spillover into humans. Here, we sampled an IAV outbreak in pigs during a week-long county fair to characterize viral diversity and evolution in this important reservoir host. Nasal wipes were collected on a daily basis from all pigs present at the fair, yielding up to 421 samples per day. Subtyping of PCR-positive samples revealed the co-circulation of H1N1 and H3N2 subtype swine IAVs. PCR-positive samples with robust Ct values were deep-sequenced, yielding 506 sequenced samples from a total of 253 pigs. Based on higher-depth re-sequenced data from a subset of these initially sequenced samples (260 samples from 168 pigs), we characterized patterns of within-host IAV genetic diversity and evolution. We find that IAV genetic diversity in single-subtype infected pigs is low, with the majority of intrahost Single Nucleotide Variants (iSNVs) present at frequencies of

Suspected adverse drug reactions (ADRs) during treatment with clozapine often prompt therapeutic drug monitoring (TDM) in clinical practice. Currently, there is no official recommendation for pharmacogenetic (PGx) testing in the context of clozapine therapy. In this case report, we demonstrate and discuss the challenges of interpreting PGx and TDM results highlighting the possibilities and limitations of both analytical methods. A 36-year-old male patient with catatonic schizophrenia was treated with clozapine. He experienced multiple hospitalizations due to elevated creatine kinase (CK) levels (up to 9000 U/L, reference range: 30-200 U/L). With no other medical explanation found, physicians suspected clozapine-induced ADRs. However, plasma levels of clozapine were consistently low or subtherapeutic upon admission, prompting us to conduct a PGx analysis and retrospectively review the patient’s TDM data, progress notes, and discharge reports. We investigated two possible hypotheses to explain the symptoms despite low clozapine plasma levels: Hypothesis i. suggested the formation and accumulation of a reactive intermediate metabolite due to increased activity in cytochrome P450 3A5 and reduced activity in glutathione S-transferases 1, leading to myotoxicity. Hypothesis ii. proposed under-treatment with clozapine, resulting in ineffective clozapine levels, leading to a rebound effect with increased catatonic symptoms and CK levels. After considering both data sources (PGx and TDM), hypothesis ii. appeared more plausible. By comprehensively assessing all available TDM measurements and examining them in temporal correlation with the drug dose and clinical symptoms, we observed that CK levels normalized when clozapine plasma levels were raised to the therapeutic range. This was achieved through hospitalization and closely monitored clozapine intake. Therefore, we concluded that the symptoms were not an ADR due to altered clozapine metabolism but rather the result of under-treatment. Interpreting TDM and PGx results requires caution. Relying solely on isolated PGx or single TDM values can result in misinterpretation of drug reactions. We recommend considering the comprehensive patient history, including treatment, dosages, laboratory values, clinic visits, and medication adherence.

Abstract Background This systematic review and meta‐analysis aimed to summarize evidence regarding the effectiveness and safety of oral antibiotic intervention for chronic low back pain (CLBP) patients with/without type‐1 Modic changes (MC1). Methods AMED, CINAHL, Cochrane Library, Embase, and Medline were searched from inception to March 3, 2023. Randomized controlled trials (RCTs) or non‐RCTs that investigated the effectiveness or safety of oral antibiotics in treating CLBP patients were eligible for inclusion. Two independent reviewers screened abstracts, full‐text articles, and extracted data. The methodological quality of each included article were evaluated by RoB2 and NIH quality assessment tools. The quality of evidence was appraised by GRADE. Meta‐analyses were performed, where applicable. A subgroup analysis was conducted to evaluate the RCTs and case series separately, and to evaluate the effect of removing a low‐quality RCT. Results Three RCTs and four case series were included. All Amoxicillin‐clavulanate/Amoxicillin treatments lasted for approximately 3 months. Moderate‐ and low‐quality evidence suggested that antibiotic was significantly better than placebo in improving disability and quality of life in CLBP patients with MC1 at 12‐month follow‐up, respectively. Low‐quality evidence from meta‐analyses of RCTs showed that oral antibiotic was significantly better than placebo in improving pain and disability in CLBP patients with MC1 immediately post‐treatment. Very low‐quality evidence from the case series suggested that oral Amoxicillin‐clavulanate significantly improved LBP/leg pain, and LBP‐related disability. Conversely, low‐quality evidence found that oral Amoxicillin alone was not significantly better than placebo in improving global perceived health in patients with CLBP at the 12‐month follow‐up. Additionally, oral antibiotic users had significantly more adverse effects than placebo users. Conclusions Although oral antibiotics were statistically superior to placebo in reducing LBP‐related disability in patients with CLBP and concomitant MC1, its clinical significance remains uncertain. Future large‐scale high‐quality RCTs are warranted to validate the effectiveness of antibiotics in individuals with CLBP.

Introduction Seasonal malaria chemoprevention (SMC) involves repeated administrations of sulfadoxine-pyrimethamine plus amodiaquine to children below the age of 5 years during the peak transmission season in areas of seasonal malaria transmission. While highly impactful in reducing Plasmodium falciparum malaria burden in controlled research settings, the impact of SMC on infection prevalence is moderate in real-life settings. It remains unclear what drives this efficacy decay. Recently, the WHO widened the scope for SMC to target all vulnerable populations. The Ministry of Health (MoH) in Burkina Faso is considering extending SMC to children below 10 years old. We aim to assess the impact of SMC on clinical incidence and parasite prevalence and quantify the human infectious reservoir for malaria in this population.Methods and analysis We will perform a cluster randomised trial in Saponé Health District, Burkina Faso, with three study arms comprising 62 clusters of three compounds: arm 1 (control): SMC in under 5-year-old children, implemented by the MoH without directly observed treatment (DOT) for the full course of SMC; arm 2 (intervention): SMC in under 5-year-old children, with DOT for the full course of SMC; arm 3 (intervention): SMC in under 10-year-old children, with DOT for the full course of SMC. The primary endpoint is parasite prevalence at the end of the malaria transmission season. Secondary endpoints include the impact of SMC on clinical incidence. Factors affecting SMC uptake, treatment adherence, drug concentrations, parasite resistance markers and transmission of parasites will be determined.Ethics and dissemination The London School of Hygiene & Tropical Medicine’s Ethics Committee (29193) and the Burkina Faso National Medical Ethics Committee (Deliberation No 2023-05-104) approved this study. The findings will be presented to the community; disease occurrence data and study outcomes will also be shared with the Burkina Faso MoH. Findings will be published irrespective of their results.Trial registration number NCT05878366.

ABSTRACTManagement of urinary tract infection (UTI) in postmenopausal women can be challenging. The recent rise in resistance to most of the available oral antibiotic options together with high recurrence rate in postmenopausal women has further complicated treatment of UTI. As such, intravesical instillations of antibiotics like gentamicin are being investigated as an alternative to oral antibiotic therapies. This study evaluates the efficacy of the candidate intravesical therapeutic VesiX, a solution containing the cationic detergent Cetylpyridinium chloride, against a broad range of uropathogenic bacterial species clinically isolated from postmenopausal women with recurrent UTI (rUTI). We also evaluate the cytotoxicity of VesiX against cultured bladder epithelial cells and find that low concentrations of 0.0063% and 0.0125% provide significant bactericidal effect toward diverse bacterial species including uropathogenic Escherichia coli (UPEC), Klebsiella pneumoniae, Enterococcus faecalis, Pseudomonas aeruginosa, and Proteus mirabilis while minimizing cytotoxic effects against cultured 5637 bladder epithelial cells. Lastly, to begin to evaluate the potential utility of using VesiX in combination therapy with existing intravesical therapies for rUTI, we investigate the combined effects of VesiX and the intravesical antibiotic gentamicin. We find that VesiX and gentamicin are not antagonistic and are able to reduce levels of intracellular UPEC in cultured bladder epithelial cells.IMPORTANCEWhen urinary tract infections (UTIs), which affect over 50% of women, become resistant to available antibiotic therapies dangerous complications like kidney infection and lethal sepsis can occur. New therapeutic paradigms are needed to expand our arsenal against these difficult to manage infections. Our study investigates VesiX, a Cetylpyridinium chloride (CPC)-based therapeutic, as a candidate broad-spectrum antimicrobial agent for use in bladder instillation therapy for antibiotic-resistant UTI. CPC is a cationic surfactant that is FDA-approved for use in mouthwashes and is used as a food additive but has not been extensively evaluated as a UTI therapeutic. Our study is the first to investigate its rapid bactericidal kinetics against diverse uropathogenic bacterial species isolated from postmenopausal women with recurrent UTI and host cytotoxicity. We also report that together with the FDA-approved bladder-instillation agent gentamicin, VesiX was able to significantly reduce intracellular populations of uropathogenic bacteria in cultured bladder epithelial cells.

Brief episodes of low oxygen breathing (therapeutic acute intermittent hypoxia; tAIH) may serve as an effective plasticity-promoting primer to enhance the effects of transcutaneous spinal stimulation-enhanced walking therapy (WALKtSTIM) in persons with chronic (>1 year) spinal cord injury (SCI). Pre-clinical studies in rodents with SCI show that tAIH and WALKtSTIM therapies harness complementary mechanisms of plasticity to maximize walking recovery. Here, we present a multi-site clinical trial protocol designed to examine the influence of tAIH + WALKtSTIM on walking recovery in persons with chronic SCI. We hypothesize that daily (eight sessions, 2 weeks) tAIH + WALKtSTIM will elicit faster, more persistent improvements in walking recovery than either treatment alone. To test our hypothesis, we are conducting a placebo-controlled clinical trial on 60 SCI participants who randomly receive one of three interventions: tAIH + WALKtSTIM; Placebo + WALKtSTIM; and tAIH + WALKtSHAM. Participants receive daily tAIH (fifteen 90-sec episodes at 10% O2 with 60-sec intervals at 21% O2) or daily placebo (fifteen 90-sec episodes at 21% O2 with 60-sec intervals at 21% O2) before a 45-min session of WALKtSTIM or WALKtSHAM. Our primary outcome measures assess walking speed (10-Meter Walk Test), endurance (6-Minute Walk Test), and balance (Timed Up and Go Test). For safety, we also measure pain levels, spasticity, sleep behavior, cognition, and rates of systemic hypertension and autonomic dysreflexia. Assessments occur before, during, and after sessions, as well as at 1, 4, and 8 weeks post-intervention. Results from this study extend our understanding of the functional benefits of tAIH priming by investigating its capacity to boost the neuromodulatory effects of transcutaneous spinal stimulation on restoring walking after SCI. Given that there is no known cure for SCI and no single treatment is sufficient to overcome walking deficits, there is a critical need for combinatorial treatments that accelerate and anchor walking gains in persons with lifelong SCI. Trial Registration: ClinicalTrials.gov, NCT05563103.

Plants recruit diverse microbial communities from the soil to their roots. Intermicrobial interactions and connectivity in the root microbiome play essential roles in plant health by promoting resistance to soilborne pathogens. However, the understanding of these interactions under field conditions is still scarce. Using a strawberry crop model, we characterized the prokaryotic and the fungal communities in the rhizosphere and the roots of three strawberry cultivars grown under field conditions and displaying varying degrees of resistance to the soilborne fungal pathogen Macrophomina phaseolina. We tested the hypothesis that resistant cultivars assemble distinct bacterial and fungal communities that foster microbial connectivity and mediate disease resistance. Our results show that the soilborne pathogen M. phaseolina does not alter the root microbiome of the three strawberry cultivars. Microbiome comparative analysis indicated that the highly susceptible cultivar Sweet Ann assembled a distinct rhizosphere and root microbiome, whereas the microbiome of the strawberry cultivars Marquis and Manresa were more similar and enriched with potential beneficial microbes. Cooccurrence network analysis revealed that the fungal pathogen M. phaseolina was more peripheral in the microbial network of Sweet Ann compared with Manresa and Marquis. Collectively, these results stress the role of the plant microbiome in mediating resistance against soilborne pathogens and further suggest the role of plant genetic traits in the assembly of beneficial microbiome members. Our study reinforces the eminent role of the plant microbiome as trait selection in breeding programs and the need for further understanding of the genetic and biological mechanisms that mediate microbiome assembly. Uncovering these mechanisms will be key for the future success of plant breeding programs in their fight against soilborne pathogens. [Graphic: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Background: Immune checkpoint inhibitor (ICI)-based therapy such as atezolizumab plus bevacizumab or durvalumab plus tremelimumab became mainstream first-line systemic treatment in advanced hepatocellular carcinoma (HCC) patients since remarkably superior efficacy of ICI-based therapy compared to tyrosine kinase inhibitors (TKIs) was reported in two recent randomized controlled trials (RCTs) (IMbrave150, HIMALAYA). However, the optimal second-line therapy after treatment failure of first-line ICI-based therapy remains unknown as no RCT has examined this issue. Summary: Therefore, at present, most clinicians are empirically treating patients with TKIs or retrial of ICI or locoregional treatment (LRT) modality such as transarterial therapy, radiofrequency ablation, and radiation therapy in this clinical setting without solid evidence. In this review, we will discuss current optimal strategies for second-line treatment after the failure of first-line ICI-based therapy by reviewing published studies and ongoing prospective trials. Key Messages: Clinicians should consider carefully whether to treat the patients with TKI, other ICI-based therapy, or LRT in this situation by considering several factors including liver function reserve, performance status, adverse events of previous therapy, and presence of lesion that can consider LRT such as oligoprogression and vascular invasion. In the meantime, we await the results of ongoing prospective trials to elucidate the best management options.