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Abstract Background Pain is a significant problem for many people with advanced disease or a serious illness. Culture and ethnicity can affect the experience and management of pain. However, there is limited research in South Asian communities in the UK on their experiences of pain. The aim of this study is to explore the experiences and attitudes of patients and family carers from South Asian communities about pain and its management within advanced disease or serious illness. Methods Qualitative thematic analysis based on descriptive phenomenology (Sundler et al. 2019). Qualitative semi-structured interviews with patients or family carers from South Asian communities (N = 15). Interviews were recorded, transcribed and analysed using an inductive approach. Public and Patient Involvement representatives from British South Asian communities were consulted for guidance. Results There were five key themes from the interviews: The importance of communication about pain with healthcare professionals; Concerns about taking pain medication; Personal resilience, privacy and self-management; Gender, culture and pain; Home pain management as struggle and frustration. Conclusion To improve pain management for people from South Asian communities with advanced disease or a serious illness, there are a number of important issues for healthcare professionals from palliative and primary care services to address. These include: greater awareness around people’s fears and concerns about pain medication; their potential use of alternative pain management strategies; and cultural issues such as resilience, privacy, dignity and gender roles. Effective communication between doctors, patients and family members could be improved by using a ‘cultural humility’ model; providing clear and accessible pain medication information; understanding and taking account of people with both low, and medium levels, of English language proficiency; and improving patient trust. Additionally, improvements to out of hours services could improve pain management for all patients managing their pain at home.

Avian influenza (AI) is one of the most important viral diseases in poultry, wildlife and humans. Available data indicate that pigeons play a minimum role in the epidemiology of AI. However, a degree of variation exists in the susceptibility of pigeons to highly pathogenic AI viruses (HPAIVs), especially since the emergence of the goose/Guangdong H5 lineage. Here, the pathogenesis of H5N8 HPAIV in comparison with a H7N1 HPAIV and the role of pigeons in the epidemiology of these viruses were evaluated. Local and urban pigeons (Columba livia var. domestica) were intranasally inoculated with 105 ELD50 of A/goose/Spain/IA17CR02699/2017 (H5N8) or A/Chicken/Italy/5093/1999 (H7N1) and monitored during 14 days. Several pigeons inoculated with H5N8 or H7N1 seroconverted. However, clinical signs, mortality, microscopic lesions and viral antigen were only detected in a local pigeon inoculated with H5N8 HPAIV. This pigeon presented prostration and neurological signs that correlated with the presence of large areas of necrosis and widespread AIV antigen in the central nervous system, indicating that the fatal outcome was associated with neurological dysfunction. Viral RNA in swabs was detected in some pigeons inoculated with H7N1 and H5N8, but it was inconsistent, short-term and at low titres. The present study demonstrates that the majority of pigeons were resistant to H5N8 and H7N1 HPAIVs, despite several pigeons developing asymptomatic infections. The limited viral shedding indicates a minimum role of pigeons as amplifiers of HPAIVs, regardless of the viral lineage, and suggests that this species may represent a low risk for environmental contamination. RESEARCH HIGHLIGHTS H7N1 and H5N8 HPAIVs can produce subclinical infections in pigeons. The mortality caused by H5N8 HPAIV in one pigeon was associated with neurological dysfunction. Pigeons represent a low risk for environmental contamination by HPAIVs. [ABSTRACT FROM AUTHOR]

Probiotics may be a viable alternative to antibiotic growth promoters in controlling gastrointestinal infections in chickens. In order to be effective probiotics must be able to survive conditions in the gastrointestinal tract. This study investigated the survival of Lactobacillus salivarius NCIMB 41606 in an in vitro model of the chicken digestive process and the effect on the survival of Salmonella typhimurium nalr Sal1344. Lb. salivarius was administered either as a dry feed treatment (DF) or as fermented moist feed (FMF). Lb. salivarius survived passage through the digestive process with no loss of viability for control and dry feed. The presence of Lb. salivarius administered in dry feed had no significant effect on the survival of S. typhimurium compared with the control, in both cases there was a 1.3 log reduction in S. typhimurium numbers over the course if the digestive process. However, with FMF no S. typhimurium were detectable from the end of the gastric stage. FMF contained 175mmol/l lactic acid and it is likely that this contributed to its anti-salmonella activity. [ABSTRACT FROM AUTHOR]

Background: Acute intracranial occlusion of the internal carotid artery (ICA) can be distinguished into (a) occlusion of the terminal ICA, involving the proximal segments of the middle or anterior cerebral artery (ICA-L/-T) and (b) non-terminal intracranial occlusions of the ICA with patent circle of Willis (ICA-I). While patients with ICA-L/-T occlusion were included in all randomized controlled trials on endovascular therapy (EVT) in anterior large vessel occlusion, data on EVT in ICA-I occlusion is scarce. We thus aimed to evaluate effectiveness and safety of EVT in ICA-I occlusions in comparison to ICA-L/-T occlusions., Methods: A large international multicentre cohort was searched for patients with intracranial ICA occlusion treated with EVT between 2014 and 2023. Patients were stratified by ICA occlusion pattern, differentiating ICA-I and ICA-L/-T occlusions. Baseline factors, technical (modified thrombolysis in cerebral infarction (mTICI) scale) and functional outcomes (modified Rankin scale [mRS] at 3 months) as well as rates of (symptomatic) intracranial hemorrhage ([s]ICH) were analyzed., Results: Of 13,453 patients, 1825 (13.6%) had isolated ICA occlusion. ICA-occlusion pattern was ICA-I in 559 (4.2%) and ICA-L/-T in 1266 (9.4%) patients. Age (years: 74 vs 73), sex (female: 45.8% vs 49.0%) and pre-stroke functional independency (pre-mRS ⩽ 2: 89.9% vs 92.2%) did not differ between the groups. Stroke severity was lower in ICA-I patients (NIHSS at admission: 14 [7-19] vs 17 [13-21] points). EVT was similarly successful with respect to technical (mTICI2b/3: 76.1% (ICA-I) vs 76.6% (ICA-L/-T); aOR 1.01 [0.76-1.35]) and functional outcome (mRS ordinal shift cOR 1.01 [0.83-1.23] in adjusted analyses. Rates of ICH (18.9% vs 34.5%; aOR 0.47 [0.36-0.62] and sICH (4.7% vs 7.3%; aOR 0.58 [0.35-0.97] were lower in ICA-I patients., Conclusion: EVT might be performed safely and similarly successful in patients with ICA-I occlusions as in patients with ICA-L/-T occlusions., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RRL received speaker honoraria from IscemaView, Boehringer Ingelheim, Pfizer, Jansen, Biogen, Medtronic and Abott and advisory board honoraria from Jansen and Bayer.STE has received funding for travel or speaker honoraria from Bayer, Boehringer Ingelheim and Daiichi-Sankyo. He has served on scientific advisory boards for Bayer, Boehringer Ingelheim, BMS/Pfizer, and MindMaze and on the editorial board of Stroke. His institutions have received an educational grant from Pfizer, compensation from Stago for educational efforts and research support from Daiichi-Sankyo, the Science Funds [Wissenschaftsfonds] of the University Hospital Basel, the University Basel, from the “Wissenschaftsfonds Rehabilitation” of the University Hospital for Geriatric Medicine Felix Platter, the “Freiwillige Akademische Gesellschaft Basel,” the Swiss Heart Foundation, and the Swiss National Science Foundation.HG has received research support from the Swiss National Science Foundation, advisory board honoraria from Daiichi Sankyo and funding for travel from BMS/Pfizer.AZ received speaker honoraria from CSL Behring, Boehringer-Ingelheim, Alexion-Astra Zeneca and Daiichi Sankyo and advisory board honoraria from Bayer, Astra Zeneca and Daiichi Sankyo.DRJ received speaker honoraria from Medtronic and Boehringer Ingelheim.VP received speaker honoraria from Medtronic and Boehringer Ingelheim.H.J.A. reports receiving personal fees from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, and Roche that all produce products for hyperacute stroke care.MRH reports grants from SITEM Research Support Funds and Swiss National Science Foundation, Swiss Heart Foundation, not directly related to this manuscript.AS received travel grants from NovoNordiskPM received grants from the Swiss National Science Foundation, the Swiss Heart Foundation, and Faculty of Biology and Medicine of the Lausanne UniversityCHN reports receiving speaker honoraria from Abbot, Alexion, AstraZeneca, Bristol-Meyers Squibb, Pfizer and Takeda, all outside the submitted work.All further authors declare no conflicts of interest related to the presented study.

Introduction: After positive findings in clinical trials the time window for endovascular thrombectomy (EVT) for patients with an acute ischemic stroke has been expanded up to 24 h from symptom onset or last seen well (LSW). We aimed to compare EVT patients' characteristics and outcomes in the early versus extended time window and to compare outcomes with the DAWN and DEFUSE 3 trial results., Patients and Methods: Consecutive EVT patients from 16 mostly European comprehensive stroke centers from the EVA-TRISP cohort were included. We compared rates of 90-day good functional outcomes (Modified Rankin Scale 0-2), symptomatic intracranial hemorrhage (sICH), and 90-day mortality between patients treated in the early (<6 h after onset or LSW) versus extended (6-24 h after onset or LSW) time windows., Results: We included 9313 patients, of which 6876 were treated in the early and 2437 in the extended time window. National Institutes of Health Stroke Scale (NIHSS) score at presentation was lower in patients treated in the extended time window (median 13 [IQR 7-18] vs 15 [IQR 9-19], p  < 0.001). The percentage of patients with good functional outcome was slightly lower in the extended time window (37.4% vs 42.2%, p  < 0.001). However, rates of successful recanalization, sICH, and mortality were similar. Good functional outcome rates after EVT were slightly lower for patients in the extended window in the EVA-TRISP cohort as compared to DAWN and DEFUSE 3., Discussion and Conclusion: According to this large multicenter cohort study reflecting daily clinical practice, EVT use in the extended time window appears safe and effective., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Ivana Berisavac: speaker honoraria from Medtronic. Visnja Padjen: speaker honoraria from Medtronic and Boehringer Ingelheim. Ronen R. Leker: received speaker honoraria from IscemaView, Boehringer Ingelheim, Pfizer, Jansen, Biogen, Medtronic and Abott and advisory board honoraria from Jansen and Filterlex. Andrea Zini: has received funding for speaker honoraria and consulting fees from Boehringer Ingelheim, Astra Zeneca, Daiichi Sankyo, CSL Behring, for scientific advisory board from Bayer, Astra Zeneca. Mirjam R. Heldner: reports grants from Swiss National Science Foundation, SITEM Research Support Funds and Swiss Heart Foundation, not directly related to this manuscript. Christian H Nolte: has received honoraria for lectures or speaker’s bureau from Alexion, AstraZeneca, BMS, Novartis and Pfizer. The other authors report nothing to disclose.

Background: Participants' recruitment and retention into community-based interventions can be challenging, especially in research involving ethnic minorities and migrants. Despite known challenges, there are limited reviews that probe recruitment and retention strategies involving ethnic minorities and migrants in the Organisation for Economic Cooperation and Development (OECD) countries. This systematic review aimed to measure recruitment and retention rates and identify the barriers and facilitators to effective recruitment and retention of ethnic minorities and migrants in community-based obesity prevention Randomised Control Trials (RCTs) in OECD countries., Methods: This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Five databases (CINAHL, Cochrane, Embase, Medline and PsychInfo) were searched from January 2000 to March 2022, in addition to Google and Google Scholar. Methodological quality and risk of bias were assessed, and pooled analysis and meta-ethnographic analysis were conducted on the included studies., Results: Twenty-five studies were included in the review. The pooled analysis found a 64% rate of recruitment of ethnic minorities in RCTs, with a retention rate of 71%. Key facilitators identified were-use of multiple communication channels, incentives, recruiting community champions, participant convenience and employing culturally sensitive strategies. Key barriers to participation were limited access to study sites, time constraints, limited trust, perceived fear, and anxiety., Conclusion: Findings suggest the importance of undertaking culturally appropriate recruitment and retention strategies to minimise barriers and facilitate effective recruitment and retention of low-income ethnic minorities and migrants in community-based research., (© 2024. The Author(s).)

The assembly and disassembly of biomolecular condensates are crucial for the subcellular compartmentalization of biomolecules in the control of cellular reactions. Recently, a correlation has been discovered between the phase transition of condensates and their maturation (aggregation) process in diseases. Therefore, modulating the phase of condensates to unravel the roles of condensation has become a matter of interest. Here, we create a peptide-based phase modulator, JSF1, which forms droplets in the dark and transforms into amyloid-like fibrils upon photoinitiation, as evidenced by their distinctive nanomechanical and dynamic properties. JSF1 is found to effectively enhance the condensation of purified fused in sarcoma (FUS) protein and, upon light exposure, induce its fibrilization. We also use JSF1 to modulate the biophysical states of FUS condensates in live cells and elucidate the relationship between FUS phase transition and FUS proteinopathy, thereby shedding light on the effect of protein phase transition on cellular function and malfunction., (© 2024. The Author(s).)

Allogeneic hematopoietic cell transplantation (HCT) survivors may benefit from routine screening for post-transplant complications. However, the impact of formal survivorship efforts to promote screening adherence is uncertain. The effect of a formal HCT survivorship program to promote screening adherence was evaluated. We conducted a retrospective analysis of an academic formal HCT survivorship program with primary and specialty consult components. We included patients who underwent allogeneic HCT and were alive and relapse-free 1-year post-HCT. We excluded patients who died <2-year post-HCT or transferred care. We measured screening adherence to cardiovascular, pulmonary, ocular, secondary cancer, and endocrine evaluations. The primary outcome was proportion of patients completing ≥1 evaluation per screening domain prior to 2-year post-HCT. We examined screening adherence during 3 time periods: presurvivorship (2012 to 2014) and 2 postsurvivorship (2016 to 2018 and 2019 to 2021) using multivariate logistic and Cox proportional hazards regression. Four hundred ten patients (2012 to 2014: n = 136, 2016 to 2018: n = 153, 2019 to 2021: n = 121) were included. Compared to the presurvivorship period (16.9%), patients in 2016 to 2018 (47.7%, odds ratio [OR] = 4.9, P < .0001) and 2019 to 2021 (34.7%, OR = 2.7, P = .001) were more likely to complete ≥1 evaluation per screening domain. Except for pulmonary function tests in 2019 to 2021, median time to completion of survivorship evaluations was shorter in the survivorship periods compared to presurvivorship. Patients who completed a formal HCT survivorship consult in 2016 to 2018 and 2019 to 2021 were more likely to complete ≥1 evaluation per screening domain (OR = 5.1, P = .0004). Survivorship consult had similar effect on the primary screening outcome in 2016 to 2018 and 2019 to 2021 (consult × time interaction OR: 2.5, P = .2). However, patients who received a consult in 2019 to 2021 were more likely to complete all screenings (consult × time interaction: OR = 5.7, P = .03). Our HCT survivorship program with primary and specialty components improved screening adherence. Additional studies are needed to evaluate efficacy, dissemination, and implementation of formal HCT survivorship programs., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Lyophilized human amniotic membrane (HAM) and silver nanoparticles (AgNPs) have multispectral applications as a biological dressing. The present study focuses on the safety aspects of HAM coated with colistin and AgNPs (HACoN) dressing in relation to its structural and hematological changes. Four dressing groups were designed for the study, HAM, HAM coated with colistin (HACo), HAM coated with AgNPs (HAN), and HAM coated with colistin (HACo) and HACoN. Scanning electron microscopy (SEM) and Fourier-transform infrared spectroscopy (FTIR) were utilized for constitutional analysis. Biological safety was checked by applying HAM of all groups on open excisional burn wounds on Sprague-Dawley rats for 21 days. The skin, kidneys, liver, and spleen were removed, and histological analysis was performed for detailed structural analysis. Oxidative stress was assessed using homogenate from newly generated skin. No structural or biochemical change was observed in any of the study groups as observed by SEM and FTIR. After 21 days of grafting, wounds were healed properly with normal skin, and no anomaly was observed in related to kidneys, spleen, and liver. Some of antioxidant enzymes were increased, while malondialdehyde which is a reactive oxygen species was reduced in the skin tissue homogenate of HACoN group. Impregnation of colistin and AgNPs in combination on HAM has no effects on hematological and structural constitution of HAM. It leaves no obvious change in vital organs of rats and improves oxidative stress and inflammation. Hence, it can be claimed that HACoN is a biologically safe antibacterial dressing., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3 -/- ; ttn.1 +/- ) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases., (© 2024. The Author(s).)

Aortic aneurysms, which may dissect or rupture acutely and be lethal, can be a part of multisystem disorders that have a heritable basis. We report four patients with deficiency of selenocysteine-containing proteins due to selenocysteine Insertion Sequence Binding Protein 2 (SECISBP2) mutations who show early-onset, progressive, aneurysmal dilatation of the ascending aorta due to cystic medial necrosis. Zebrafish and male mice with global or vascular smooth muscle cell (VSMC)-targeted disruption of Secisbp2 respectively show similar aortopathy. Aortas from patients and animal models exhibit raised cellular reactive oxygen species, oxidative DNA damage and VSMC apoptosis. Antioxidant exposure or chelation of iron prevents oxidative damage in patient's cells and aortopathy in the zebrafish model. Our observations suggest a key role for oxidative stress and cell death, including via ferroptosis, in mediating aortic degeneration., (© 2023. The Author(s).)

Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for estrogen receptor-positive (ER+) breast cancer, as they achieve greater inhibition of ER-driven cancers than current ETs and overcome key resistance mechanisms. In this study, we evaluated the preclinical pharmacology and efficacy of the next-generation oral SERD camizestrant (AZD9833) and assessed ER-co-targeting strategies by combining camizestrant with CDK4/6 inhibitors (CDK4/6i) and PI3K/AKT/mTOR-targeted therapy in models of progression on CDK4/6i and/or ET. Camizestrant demonstrated robust and selective ER degradation, modulated ER-regulated gene expression, and induced complete ER antagonism and significant antiproliferation activity in ESR1 wild-type (ESR1wt) and mutant (ESR1m) breast cancer cell lines and patient-derived xenograft (PDX) models. Camizestrant also delivered strong antitumor activity in fulvestrant-resistant ESR1wt and ESR1m PDX models. Evaluation of camizestrant in combination with CDK4/6i (palbociclib or abemaciclib) in CDK4/6-naive and -resistant models, as well as in combination with PI3Kαi (alpelisib), mTORi (everolimus), or AKTi (capivasertib), indicated that camizestrant was active with CDK4/6i or PI3K/AKT/mTORi and that antitumor activity was further increased by the triple combination. The response was observed independently of PI3K pathway mutation status. Overall, camizestrant shows strong and broad antitumor activity in ER+ breast cancer as a monotherapy and when combined with CDK4/6i and PI3K/AKT/mTORi., Significance: Camizestrant, a next-generation oral SERD, shows promise in preclinical models of ER+ breast cancer alone and in combination with CDK4/6 and PI3K/AKT/mTOR inhibitors to address endocrine resistance, a current barrier to treatment., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: South Asia continues to host the triple burden of child malnutrition with high levels of child undernutrition, hidden hunger (micronutrient deficiencies) and childhood overweight/obesity. To combat malnutrition, the international community along with the National governments have launched initiatives to track the country's progress towards achieving the Global Nutrition targets by 2025. This review captures the country-specific efforts of nutrition-specific and nutrition-sensitive sectoral programs and policies towards achieving these targets for eight South Asian countries., Methods: A systematic internet search was undertaken to search relevant policies and programs from Government websites and twelve International Organisations working in the region. The authors developed a template to map the policies against the following criteria: (i) enabling supportive environment; (ii) Initiatives targeted at nutrition-specific interventions; and (iii) Initiatives targeted at nutrition-specific interventions that impact child malnutrition. A narrative descriptive approach was used to present findings., Results: All eight countries had relevant policies and programs to address child malnutrition and macronutrient deficiencies with targets for significant reductions in stunting and improved breastfeeding. However, despite the outlined there are major challenges of implementation, monitoring, evaluation and quality that persist with increased dependency on international donors and organisations for funding and/or implementation of nutrition plans., Conclusion: There is a need to contextualise efforts designated to donors and governments to improve the tracking of efforts that impact nutrition., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background and Objectives: Australia's population is growing, aging, and becoming more ethnically diverse, resulting in barriers and challenges around social inclusion for non-English-speaking migrants and refugees. This scoping review investigates the experiences of aging within Australia among older adults from culturally and linguistically diverse (CALD) migrant and refugee backgrounds to identify barriers to social integration., Research Design and Methods: A scoping review of English language literature and gray literature on the experiences of aging among CALD migrants and refugees living in Australia was conducted from January 2000 to January 2021, according to Arksey and O'Malley's review process. A total of 34 studies were identified for analysis., Results: Three primary themes were identified: (a) sociocultural similarities in settlement experiences, (b) engagement with technology for social connection, and (c) engagement with family and community networks., Discussion and Implications: Aging, language, sociocultural, and technology contexts shape attitudes to belonging, as well as access to sociomedical services. We argue a cultural well-being framework may assist in developing policy for improved social integration of older CALD adults. As the focus is on social and cultural experiences, all studies with a primary focus on medical and other chronic conditions were excluded. Future studies could include health-related articles to present a more comprehensive approach regarding older CALD adult needs. Follow-up research could focus on the impact of the coronavirus disease 2019 pandemic on the experiences of older adults in Australia, in particular those of CALD backgrounds., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America.)

The carnivorous mushroom Pleurotus ostreatus uses an unknown toxin to rapidly paralyze and kill nematode prey upon contact. We report that small lollipop-shaped structures (toxocysts) on fungal hyphae are nematicidal and that a volatile ketone, 3-octanone, is detected in these fragile toxocysts. Treatment of Caenorhabditis elegans with 3-octanone recapitulates the rapid paralysis, calcium influx, and neuronal cell death arising from fungal contact. Moreover, 3-octanone disrupts cell membrane integrity, resulting in extracellular calcium influx into cytosol and mitochondria, propagating cell death throughout the entire organism. Last, we demonstrate that structurally related compounds are also biotoxic to C. elegans , with the length of the ketone carbon chain being crucial. Our work reveals that the oyster mushroom has evolved a specialized structure containing a volatile ketone to disrupt the cell membrane integrity of its prey, leading to rapid cell and organismal death in nematodes.

Background: Pregnenolone (P5) is a neurosteroid that promotes microtubule polymerization. It also reduces stress and negative symptoms of schizophrenia, promotes memory, as well as recovery from spinal cord injury. P5 is the first substance in the steroid-synthetic pathway; it can be further metabolized into other steroids. Therefore, it is difficult to differentiate the roles of P5 versus its metabolites in the brain. To alleviate this problem, we synthesized and screened a series of non-metabolizable P5 derivatives for their ability to polymerize microtubules similar to P5., Results: We identified compound #43 (3-beta-pregnenolone acetate), which increased microtubule polymerization. We showed that compound #43 modified microtubule dynamics in live cells, increased neurite outgrowth and changed growth cone morphology in mouse cerebellar granule neuronal culture. Furthermore, compound #43 promoted the formation of stable microtubule tracks in zebrafish developing cerebellar axons., Conclusions: We have developed compound #43, a nonmetabolized P5 analog, that recapitulates P5 functions in vivo and can be a new therapeutic candidate for the treatment of neurodevelopmental diseases., (© 2022. The Author(s).)

Peripheral T-cell lymphoma (PTCL) represents a rare group of heterogeneous diseases in urgent need of effective treatments. A scarcity of disease-relevant preclinical models hinders research advances. Here, we isolated a novel mouse (m)PTCL by serially transplanting a lymphoma from a germinal center B-cell hyperplasia model (Cγ1-Cre Blimp1 fl/fl ) through immune-competent mice. Lymphoma cells were identified as clonal TCRβ+ T-helper cells expressing T-follicular helper markers. We also observed coincident B-cell activation and development of a de novo B-cell lymphoma in the model, reminiscent of B-cell activation/lymphomagenesis found in human PTCL. Molecular profiling linked the mPTCL to the high-risk "GATA3" subtype of PTCL, showing GATA3 and Th2 gene expression, PI3K/mTOR pathway enrichment, hyperactivated MYC, and genome instability. Exome sequencing identified a human-relevant oncogenic β-catenin mutation possibly involved in T-cell lymphomagenesis. Prolonged treatment responses were achieved in vivo by targeting ATR in the DNA damage response (DDR), a result corroborated in PTCL cell lines. This work provides mechanistic insight into the molecular and immunological drivers of T-cell lymphomagenesis and proposes DDR inhibition as an effective and readily translatable therapy in PTCL., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Antimicrobials used to treat burn wound infections have become multidrug-resistant, thus delaying wound healing. When combined with silver nanoparticles, antibiotics create a multifaceted antibacterial mechanism of action to which bacteria are incapable of developing resistance. Similarly, the amniotic membrane has been found to lower the bacterial number. The purpose of the current study was to observe the antibacterial activity of combined topical colistin with silver nanoparticles and decellularized human amniotic membrane as a dressing in burn wounds infected with bacteria with the goal of promoting faster healing. Bacteria commonly isolated from burn wounds and the most sensitive topical antibiotic were identified. Colistin, silver nanoparticles and combined colistin with silver nanoparticles were impregnated into decellularized human amniotic membranes. These wound dressings were evaluated in third-degree multidrug-resistant bacterial infected thermal burns induced in rats. Out of a total of 708 pus samples from burn wounds, Pseudomonas aeruginosa was the most prevalent pathogen 308 (43.5%), followed by Klebsiella pneumoniae 300 (42.4%). Topical colistin was 100% sensitive for both bacteria. Overall, maximum wound contraction (p < 0.05), and increased collagen deposition (+++) with no isolation of bacteria from wound swabs were noted on day 21 for the combined colistin with silver nanoparticle-loaded human amniotic membrane dressing group. Our study concluded that the increased antimicrobial activity of the novel combination of colistin and silver nanoparticle-loaded decellularized human amniotic membrane manifested its potential as an effective burn wound dressing., (© 2022. The Author(s).)

Background: Colorectal cancer (CRC) is a worldwide cancer with rising annual incidence. New medications for patients with CRC are still needed. Recently, fluorescent chemical probes have been developed for cancer imaging and therapy. Signal transducer and activator of transcription 1 (STAT1) has complex functions in tumorigenesis and its role in CRC still needs further investigation., Methods: RNA sequencing datasets in the NCBI GEO repository were analyzed to investigate the expression of STAT1 in patients with CRC. Xenograft mouse models, tail vein injection mouse models, and azoxymethane/dextran sodium sulfate (AOM/DSS) mouse models were generated to study the roles of STAT1 in CRC. A ligand-based high-throughput virtual screening approach combined with SWEETLEAD chemical database analysis was used to discover new STAT1 inhibitors. A newly designed and synthesized fluorescently labeled 4',5,7-trihydroxyisoflavone (THIF) probe (BODIPY-THIF) elucidated the mechanistic actions of STAT1 and THIF in vitro and in vivo. Colonosphere formation assay and chick chorioallantoic membrane assay were used to evaluate stemness and angiogenesis, respectively., Results: Upregulation of STAT1 was observed in patients with CRC and in mouse models of AOM/DSS-induced CRC and metastatic CRC. Knockout of STAT1 in CRC cells reduced tumor growth in vivo. We then combined a high-throughput virtual screening approach and analysis of the SWEETLEAD chemical database and found that THIF, a flavonoid abundant in soybeans, was a novel STAT1 inhibitor. THIF inhibited STAT1 phosphorylation and might bind to the STAT1 SH2 domain, leading to blockade of STAT1-STAT1 dimerization. The results of in vitro and in vivo binding studies of THIF and STAT1 were validated. The pharmacological treatment with BODIPY-THIF or ablation of STAT1 via a CRISPR/Cas9-based strategy abolished stemness and angiogenesis in CRC. Oral administration of BODIPY-THIF attenuated colitis symptoms and tumor growth in the mouse model of AOM/DSS-induced CRC., Conclusions: This study demonstrates that STAT1 plays an oncogenic role in CRC. BODIPY-THIF is a new chemical probe inhibitor of STAT1 that reduces stemness and angiogenesis in CRC. BODIPY-THIF can be a potential tool for CRC therapy as well as cancer cell imaging., (© 2022. The Author(s).)

RNA sequencing allows for the quantification of the transcriptome of embryos to investigate transcriptional responses to various perturbations ( e.g ., mutations, infections, drug treatments). Previous protocols either lack the option to genotype individual samples, or are laborious and therefore difficult to do at a large scale. We have developed a protocol to extract total nucleic acid from individual zebrafish embryos. Individual embryos are lysed in 96-well plates and nucleic acid is extracted using SPRI beads. The total nucleic acid can be genotyped and then DNase I treated to produce RNA samples for sequencing. This protocol allows for processing large numbers of individual samples, with the ability to genotype each sample, which makes it possible to undertake transcriptomic analysis on mutants at timepoints before the phenotype is visible. Graphic abstract: Extraction of total nucleic acid from individual zebrafish embryos for genotyping and RNA-seq., Competing Interests: Competing interestsThe authors declare no competing interests., (Copyright © The Authors; exclusive licensee Bio-protocol LLC.)

Background and Objectives: South Asia hosts the largest proportion of undernourished children in the world. Hidden hunger and undernutrition continue to be a major global health concern in the region. A systematic review looking at factors and drivers for hidden hunger and child undernutrition was undertaken., Methods and Study Design: This review was conducted using the 2020 Preferred Reporting Items for Systematic reviews and Meta- Analysis guidelines. Five computerized databases were searched: CINAHL, EMBASE, PubMed, PsycINFO and Scopus, in addition to various grey literature sources., Results: A total of 3601 articles were retrieved from databases and 25 studies from grey literature, 98 studies met our inclusion criteria. Included studies were assessed for quality by validated tools. A Meta-ethnographic narrative approach was used to analyse the findings. The most commonly reported factors for child undernutrition were maternal education, poor dietary diversity and rural residence., Conclusions: Based on findings we propose a model to mainstream context specific nutrition behavioural change along with nutrition specific and sensitive interventions aimed at targeting gender, social and cultural factors and norms. Findings from the review add to the extant literature of child undernutrition to inform policy and program.

This systematic review and meta-analysis aimed to assess the robustness of designs and tools used in nutrition social behaviour change communication (NSBCC) interventions and establish their effectiveness. EBSCOhost as an umbrella database including Medline (Ovid) and CINAHL, EMBASE, and ProQUEST databases were searched for peer-reviewed articles from January 1960 to October 2018. Additional sources were searched to identify all relevant studies including grey literature. Studies' biases were assessed according to Cochrane handbook. Pooled estimate of effectiveness of interventions on infant and young child feeding (IYCF) practices and child nutritional status with 95% confidence intervals were measured using random-effects models. Eighty studies were included in this review: Fifty-one (64%) were cluster randomised controlled trials (RCTs), 13 (16%) were RCTs and 16 (20%) quasi-experimental. Of the included studies, 22 (27%) measured early initiation of breastfeeding, 38 (47%) measured exclusive breastfeeding, 29 (36%) measured minimum dietary diversity, 21 (26%) measured minimum meal frequency, 26 (32%) measured height for age z-scores (HAZ), 23 (29%) measured weight for height z-scores (WHZ), 27 (34%) measured weight for age z-scores (WAZ), 20 (25%) measured stunting, 14 (17%) measured wasting, and 11 (14%) measured underweight. The overall intervention's effect was significant for exclusive breastfeeding (EBF) (odds ratio = 1.73; 95% confidence interval [CI]: 1.35-2.11, p < 0.001), HAZ (standardized mean differences [SMD] = 0.19; 95% CI: 0.17-0.21; p < 0.001), WHZ (SMD = 0.02; 95% CI: 0.004-0.04; p < 0.001), and WAZ (SMD = 0.04; 95% CI: 0.02-0.06; p < 0.001). Evidence shows the effectiveness of NSBCC in improving EBF and child anthropometric outcomes. Further research should test the impact on child nutritional status with clearly specified and detailed NSBCC interventions., (© 2021 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

People living with HIV (PLWH) are often culturally and linguistically diverse populations; these differences are associated with differing barriers to antiretroviral therapy (ART) adherence. Cultural competence measures the extent to which trial design recognises this diversity. This systematic review aimed to determine whether adherence trial participants represent the diversity of PLWH. Randomised Controlled Trials in Organisation for Economic Co-operation and Development countries to improve ART adherence were eligible. We searched MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews. For all included trials, we searched for their development, testing and evaluation studies. We compared trial participant characteristics with nationally reported PLWH data. We appraised trial cultural competence against ten criteria; scoring each criterion as 0, 1 or 2 indicating cultural blindness, pre-competence or competence respectively. For 80 included trials, a further 13 studies presenting development/testing/evaluation data for the included trials were identified. Only one of the 80 included studies reported trial participants representative of the country's population of PLWH. The median (IQ) cultural competence score was 2.5 (1.0, 4.0) out of 20. HIV adherence trial participants are not reflective of the population with HIV, which may be due to limited adoption of culturally competent research methods.

Suppressive myeloid cells mediate resistance to immune checkpoint blockade. PI3Kγ inhibition can target suppressive macrophages, and enhance efficacy of immune checkpoint inhibitors. However, how PI3Kγ inhibitors function in different tumor microenvironments (TME) to activate specific immune cells is underexplored. The effect of the novel PI3Kγ inhibitor AZD3458 was assessed in preclinical models. AZD3458 enhanced antitumor activity of immune checkpoint inhibitors in 4T1, CT26, and MC38 syngeneic models, increasing CD8 + T-cell activation status. Immune and TME biomarker analysis of MC38 tumors revealed that AZD3458 monotherapy or combination treatment did not repolarize the phenotype of tumor-associated macrophage cells but induced gene signatures associated with LPS and type II INF activation. The activation biomarkers were present across tumor macrophages that appear phenotypically heterogenous. AZD3458 alone or in combination with PD-1-blocking antibodies promoted an increase in antigen-presenting (MHCII + ) and cytotoxic (iNOS + )-activated macrophages, as well as dendritic cell activation. AZD3458 reduced IL-10 secretion and signaling in primary human macrophages and murine tumor-associated macrophages, but did not strongly regulate IL-12 as observed in other studies. Therefore, rather than polarizing tumor macrophages, PI3Kγ inhibition with AZD3458 promotes a cytotoxic switch of macrophages into antigen-presenting activated macrophages, resulting in CD8 T-cell-mediated antitumor activity with immune checkpoint inhibitors associated with tumor and peripheral immune activation., (©2021 American Association for Cancer Research.)

Background: This study aimed to assess the association between social resources and dependency, and explored the effect of social support in modifying important risk factors for dependency among the elderly., Methods: This was a population-based cross-sectional study. A total of 950 participants aged ≥60 years were selected using a complex multistage sampling design from 22 locations in China. All data were collected using questionnaires by face-to-face interviews. Dependency was assessed using the Minnesota Multiphasic Personality Inventory-II, and social resource status with the Chinese version of the Older American Resources and Services (OARS) questionnaire. Logistic regression analysis was used to evaluate the association between dependency and social resources. Analysis of covariance was performed to evaluate the effect of social support on modifications of important risk factors for dependency., Results: A total of 913 participants were included in the analysis, and 10.3% of the males and 14.4% of the females were identified as in dependency. The results of logistic regression analysis showed a significant negative association between the levels of social resources and dependency. The odds ratio was 0.78 (95% confidence interval, 0.73-0.84) after adjusting for important confounding factors. The results of analysis of covariance showed differences in the mean dependency scores between different groups defined by chronic disease status and social support level., Conclusions: Levels of social resources were negatively associated with dependency. Our results suggest that social support has both a direct effect on dependency and an indirect effect through modifying chronic disease status and individual income., (© 2021 Japanese Psychogeriatric Society.)

Child wasting continues to be a major public health concern in South Asia, having a prevalence above the emergency threshold. This paper aimed to identify factors associated with wasting among children aged 0-23 months, 24-59 months, and 0-59 months in South Asia. A weighted sample of 564,518 children aged 0-59 months from the most recent demographic and health surveys (2014-2018) of five countries in South Asia was combined. Multiple logistic regression analyses that adjusted for clustering and sampling weights were used to examine associated factors. Wasting prevalence was higher for children aged 0-23 months (25%) as compared to 24-59 months (18%), with variations in prevalence across the South Asian countries. The most common factor associated with child wasting was maternal BMI [adjusted odds ratio (AOR) for 0-23 months = 2.02; 95% CI: (1.52, 2.68); AOR for 24-59 months = 2.54; 95% CI: (1.83, 3.54); AOR for 0-59 months = 2.18; 95% CI: (1.72, 2.77)]. Other factors included maternal height and age, household wealth index, birth interval and order, children born at home, and access to antenatal visits. Study findings suggest need for nutrition specific and sensitive interventions focused on women, as well as adolescents and children under 2 years of age.

This case report describes the first ex situ full-right/full-left splitting of a liver from a pediatric deceased donor in the Middle East with an excellent outcome for both recipients. The left lateral split-liver transplant requires division of the deceased donor liver into a left lateral lobe for a pediatric recipient and an extended right lobe for an adult recipient, thus producing only 1 graft for a pediatric recipient. Full-right/full-left liver transplant, which splits the liver along the line of Cantlie, is a much more complex and challenging surgery, even though the technique is fully developed, and is theoretically able to produce 2 sizeable grafts for 2 pediatric recipients. However, the full-right/full-left liver transplant remains limited because of the small vascular structures and therefore was not recommended and was not previously described in the literature.

South Asia continues to be the global hub for child undernutrition with 35% of children still stunted in 2017. This paper aimed to identify factors associated with stunting among children aged 0-23 months, 24-59 months, and 0-59 months in South Asia. A weighted sample of 564,518 children aged 0-59 months from the most recent Demographic and Health Surveys (2014-2018) was combined of five countries in South Asia. Multiple logistic regression analyses that adjusted for clustering and sampling weights were used to examine associated factors. The common factors associated with stunting in three age groups were mothers with no schooling ([adjusted odds ratio (AOR) for 0-23 months = 1.65; 95% CI: (1.29, 2.13)]; [AOR for 24-59 months = AOR = 1.46; 95% CI: (1.27, 1. 69)] and [AOR for 0-59 months = AOR = 1.59; 95% CI: (1.34, 1. 88)]) and maternal short stature (height < 150 cm) ([AOR for 0-23 months = 2.00; 95% CI: (1.51, 2.65)]; [AOR for 24-59 months = 3.63; 95% CI: (2.87, 4.60)] and [AOR for 0-59 months = 2.87; 95% CI: (2.37, 3.48)]). Study findings suggest the need for a balanced and integrated nutrition strategy that incorporates nutrition-specific and nutrition-sensitive interventions with an increased focus on interventions for children aged 24-59 months.