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Background: Rotavirus was the leading cause of acute gastroenteritis among US children until vaccine introduction in 2006, after which, substantial declines in severe rotavirus disease occurred. We evaluated rotavirus vaccine effectiveness (VE) over 13 years (2009-2022)., Methods: We analyzed data from the New Vaccine Surveillance Network using a test-negative case-control design to estimate rotavirus VE against laboratory-confirmed rotavirus infections among children seeking care for acute gastroenteritis (≥3 diarrhea or ≥1 vomiting episodes within 24 hours) in the emergency department (ED) or hospital. Case-patients and control-patients were children whose stool specimens tested rotavirus positive or negative, respectively, by enzyme immunoassay or polymerase chain reaction assays. VE was calculated as (1-adjusted odds ratio)×100%. Adjusted odds ratios were calculated by multivariable unconditional logistic regression., Results: Among 16 188 enrolled children age 8 to 59 months, 1720 (11%) tested positive for rotavirus. Case-patients were less often vaccinated against rotavirus than control-patients (62% versus 88%). VE for receiving ≥1 dose against rotavirus-associated ED visits or hospitalization was 78% (95% confidence interval [CI] 75%-80%). Stratifying by a modified Vesikari Severity Score, VE was 59% (95% CI 49%-67%), 80% (95% CI 77%-83%), and 94% (95% CI 90%-97%) against mild, moderately severe, and very severe disease, respectively. Rotavirus vaccines conferred protection against common circulating genotypes (G1P[8], G2P[4], G3P[8], G9P[8], and G12[P8]). VE was higher in children <3 years (73% to 88%); protection decreased as age increased., Conclusions: Rotavirus vaccines remain highly effective in preventing ED visits and hospitalizations in US children., (Copyright © 2024 by the American Academy of Pediatrics.)

Clinical teachers do not acquire teaching skills through their traditional health professional education. Faculty development programmes are required to train these clinicians in essential educational theory and practical teaching skills. Such interventions are critical to successful clerkship experiences and preparedness for professional practice. However, sustained engagement in these programmes is challenging. Education and healthcare organisations have differing priorities often resulting in competing demands placed on clinical teachers. The twelve tips described in this article offer logical and simple approaches to designing large-scale faculty development programmes for clinical teachers. These tips emphasise the application of system theory to identify and address key regulatory, institutional, and individual barriers to implementation, risks to successful delivery and tools for upscaling faculty development programmes.

Background: Critical care beds are a limited resource, yet research indicates that recommendations for postoperative critical care admission based on patient-level risk stratification are not followed. It is unclear how prioritisation decisions are made in real-world settings and the effect of this prioritisation on outcomes., Methods: This was a prespecified analysis of an observational cohort study of adult patients undergoing inpatient surgery, conducted in 274 hospitals across the UK and Australasia during 2017. The primary outcome was postoperative morbidity at day 7. Logistic regression models were used to evaluate the relationship between critical care admission and patient and health system factors. The causal effect of critical care admission on outcome was estimated using variation in critical care occupancy as a natural experiment in an instrumental variable analysis., Results: A total of 19,491 patients from 248 hospitals were eligible for analysis, of whom 2107 were directly admitted to critical care postoperatively. Postoperative morbidity occurred in 2829/19,491 (15%) patients. Increasing surgical risk was associated with critical care admission, as was increased availability of critical care beds (odds ratio (95%CI) 1.04 (1.01-1.06), p = 0.002) per available bed; however, the probability of admission varied significantly between hospitals (median odds ratio 3.05). There was no evidence of a difference in postoperative morbidity with critical care admission (odds ratio (95%CI) 0.91 (0.57-1.45), p = 0.710)., Discussion: Postoperative critical care admission is variable and related to bed availability. Statistical methods that adjust for unobserved confounding lowered the estimates of harm previously reported to have been associated with postoperative critical care admission. Our findings provide a rationale for a clinical trial which would evaluate any potential benefits for postoperative critical care admission for patients in whom there is no absolute indication for admission., (© 2024 The Author(s). Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

Human norovirus (HuNoV) infection is a global health and economic burden. Currently, there are no licensed HuNoV vaccines or antiviral drugs available. The protease encoded by the HuNoV genome plays a critical role in virus replication by cleaving the polyprotein and is, therefore, an excellent target for developing small molecule inhibitors. While rupintrivir, a potent small-molecule inhibitor of several picornavirus proteases, effectively inhibits GI.1 protease, it is an order of magnitude less effective against GII protease. Other GI.1 protease inhibitors also tend to be less effective against GII proteases. To understand the structural basis for the potency difference, we determined the crystal structures of proteases of GI.1, pandemic GII.4 (Houston and Sydney), and GII.3 in complex with rupintrivir. These structures show that the open substrate pocket in GI protease binds rupintrivir without requiring significant conformational changes, whereas, in GII proteases, the closed pocket flexibly extends, reorienting arginine-112 in the BII-CII loop to accommodate rupintrivir. Structures of R112A protease mutants with rupintrivir, coupled with enzymatic and inhibition studies, suggest R112 is involved in displacing both substrate and ligands from the active site, implying a role in the release of cleaved products during polyprotein processing. Thus, the primary determinant for differential inhibitor potency between the GI and GII proteases is the increased flexibility in the BII-CII loop of the GII proteases caused by H-G mutation in this loop. Therefore, the inherent flexibility of the BII-CII loop in GII proteases is a critical factor to consider when developing broad-spectrum inhibitors for HuNoV proteases.

Building capacity for Health Policy and Systems Research (HPSR) is critical for advancing the field in lower- and middle-income countries (LMICs). The India HPSR fellowship program is a home-grown capacity-building initiative, anchored at the Health Systems Transformation Platform (HSTP), New Delhi, and developed in collaboration with a network of institutes in India and abroad. In this practice-oriented commentary, we provide an overview of the fellowship program and critically reflect upon the learnings from working with three cohorts of fellows between 2020 and 2023. This commentary draws on routine program documentation (guidelines, faculty meeting reports, minutes of meetings of curricula and course development) as well as the perspectives of faculty and program managers associated with the fellowship. We have had several important learnings in the initial years of program implementation. One, it is important to iteratively modify globally available curricula and pedagogies on HPSR to suit country-specific requirements and include a strong component of 'unlearning' in such fellowships. Secondly, the goals of such fellowship programs need to be designed with country-specific contextual realities in mind. For instance, should publication of fellows' work be an intended goal, then contextual deterrents to publication such as article processing fees, language barriers and work-related obligations of faculty and participants need to be addressed. Furthermore, to improve the policy translation of fellows' work, such programs need to make broader efforts to strengthen research-policy-practice interfaces. Lastly, fellowship programs are cost-intensive, and outputs from them, such as papers or policy translation, are less immediate and less visible to donors. In the absence of these outputs, consistent funding can be a roadblock to sustaining these fellowships in LMICs. The experience of our fellowship program suggests that LMIC-led capacity-building initiatives on HPSR have the potential to influence changes in health systems and build the capacity of researchers to generate evidence for policy-making. The sharing of resources and teaching material through the fellowship can enable learning for all institutions involved. Furthermore, such initiatives can serve as a launchpad for the creation of regional and international HPSR communities of practice, with a focus on LMICs, thereby challenging epistemic injustice in teaching and learning HPSR., (© 2024. The Author(s).)

Human noroviruses (HuNoVs) are a significant cause of epidemic and sporadic acute gastroenteritis worldwide. The lack of a reproducible culture system hindered the study of HuNoV replication and pathogenesis for almost a half-century. This barrier was overcome with our successful cultivation of multiple HuNoV strains in human intestinal enteroids (HIEs), which has significantly advanced HuNoV research. We optimized culture media conditions and generated genetically-modified HIE cultures to enhance HuNoV replication in HIEs. Building upon these achievements, we now present new insights to this culture system, which involve testing different media, unique HIE lines, and additional virus strains. HuNoV infectivity was evaluated and compared in new HIE models, including HIEs generated from different intestinal segments of individual adult organ donors, HIEs from human intestinal organoids produced from directed differentiation of human embryonic stem cells into intestinal organoids that were transplanted and matured in mice before making enteroids (H9tHIEs), genetically-engineered (J4 FUT2 knock-in [ KI ], J2 STAT1 knock-out [ KO ]) HIEs, as well as HIEs derived from a patient with common variable immunodeficiency (CVID) and from infants. Our findings reveal that small intestinal HIEs, but not colonoids, from adults, H9tHIEs, HIEs from a CVID patient, and HIEs from infants support HuNoV replication with segment and strain-specific differences in viral infection. J4 FUT2-KI HIEs exhibit the highest susceptibility to HuNoV infection, allowing the cultivation of a broader range of GI and GII HuNoV strains than previously reported. Overall, these results contribute to a deeper understanding of HuNoVs and highlight the transformative potential of HIE cultures in HuNoV research., Importance: HuNoVs cause global diarrheal illness and chronic infections in immunocompromised patients. This manuscript reports approaches for cultivating HuNoVs in secretor positive human intestinal enteroids (HIEs). HuNoV infectivity was compared in new HIE models, including ones from i) different intestinal segments of single donors, ii) human embryonic stem cell-derived organoids transplanted into mice, iii) genetically-modified lines, and iv) a patient with chronic variable immunodeficiency disease. HIEs from small intestine, but not colon, support HuNoV replication with donor, segment and strain-specific variations. Unexpectedly, HIEs from one donor are resistant to GII.3 infection. The genetically-modified J4 FUT2-KI HIEs enable cultivation of a broad range of GI and GII genotypes. New insights into strain-specific differences in HuNoV replication in HIEs support this platform for advancing understanding of HuNoV biology and developing potential therapeutics.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in children worldwide, while human noroviruses (HuNoV) are a leading cause of epidemic and sporadic acute gastroenteritis. Generating full-length genome sequences for these viruses is crucial for understanding viral diversity and tracking emerging variants. However, obtaining high-quality sequencing data is often challenging due to viral strain variability, quality, and low titers. Here, we present a set of comprehensive oligonucleotide probe sets designed from 1,570 RSV and 1,376 HuNoV isolate sequences in GenBank. Using these probe sets and a capture enrichment sequencing workflow, 85 RSV positive nasal swab samples and 55 (49 stool and six human intestinal enteroids) HuNoV positive samples encompassing major subtypes and genotypes were characterized. The Ct values of these samples ranged from 17.0-29.9 for RSV, and from 20.2-34.8 for HuNoV, with some HuNoV having below the detection limit. The mean percentage of post-processing reads mapped to viral genomes was 85.1% for RSV and 40.8% for HuNoV post-capture, compared to 0.08% and 1.15% in pre-capture libraries, respectively. Full-length genomes were>99% complete in all RSV positive samples and >96% complete in 47/55 HuNoV positive samples-a significant improvement over genome recovery from pre-capture libraries. RSV transcriptome (subgenomic mRNAs) sequences were also characterized from this data. Probe-based capture enrichment offers a comprehensive approach for RSV and HuNoV genome sequencing and monitoring emerging variants.

Aim and Objective: The purpose of the study is to compare the effects of rocuronium priming with the combined technique of magnesium pretreatment and rocuronium priming and to investigate whether this pretreatment could further accelerate the onset of neuromuscular blockade during intubation., Materials and Methods:  A double-blinded randomized controlled trial (RCT) clinical study was done on patients at a tertiary care center for six months after obtaining approval from the institutional ethical committee. A total of 150 patients were randomly allocated as Group MP (infusion of 50 mg/kg of MgSo4 over 10 min was given 10 mins prior to premedication and dose of rocuronium 0.06 mg/kg given three minutes), Group P (priming dose of rocuronium 0.06 mg/kg given three minutes before the intubating dose), and Group C (control group with the same volume of 0.9% saline and rocuronium bolus of 0.6 mg/kg on intubation). Parameters such as demographic and hemodynamical data, American Society of Anesthesiologists (ASA) score, Mallampati scoring, neuromuscular monitoring, intubation grading, and number of successful/failed attempts were recorded., Results:  Our results showed that Group MP had a rapid onset of action of rocuronium with 58.90 +/- 4.77 seconds and a longer duration of action of rocuronium with 54.92 +/- 10.39 minutes, which are statistically significant compared to Group P (onset of action of ROC 106.70 +/- 4.24 seconds and duration of action rocuronium 45.88 +/- 6.22 minutes) and Group C (onset of action of ROC 154.56 +/- 11.39 seconds and duration of ROC 40.56 +/- 3.96 minutes). The maximum number of patients in Group MP (33 patients) showed good intubation conditions compared to Group P (23 patients) and Group C (16 patients), which was statistically significant., Conclusion: We conclude that magnesium sulfate pretreatment in combination with rocuronium priming (Group MP) considerably accelerates the onset of rocuronium action, increases the duration of action of rocuronium, and enhances the intubation procedure without any adverse effect of rocuronium and magnesium sulfate., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. SRM Medical College Hospital and Research Center Institutional Ethical Committee issued approval 8366(A)/IEC/2017. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Roy et al.)

Background: Human noroviruses are a leading cause of acute and sporadic gastroenteritis worldwide. The evolution of human noroviruses in immunocompromised persons has been evaluated in many studies. Much less is known about the evolutionary dynamics of human norovirus in healthy adults., Methods: We used sequential samples collected from a controlled human infection study with GI.1/Norwalk/US/68 virus to evaluate intra- and inter-host evolution of a human norovirus in healthy adults. Up to 12 samples from day 1 to day 56 post-challenge were sequenced using a norovirus-specific capture probe method., Results: Complete genomes were assembled, even in samples that were below the limit of detection of standard RT-qPCR assays, up to 28 days post-challenge. Analysis of 123 complete genomes showed changes in the GI.1 genome in all persons, but there were no conserved changes across all persons. Single nucleotide variants resulting in non-synonymous amino acid changes were observed in all proteins, with the capsid VP1 and nonstructural protein NS3 having the largest numbers of changes., Conclusions: These data highlight the potential of a new capture-based sequencing approach to assemble human norovirus genomes with high sensitivity and demonstrate limited conserved immune pressure-driven evolution of GI.1 virus in healthy adults.

Endometriosis is often diagnosed in reproductive aged women with spontaneous ovarian activity. Here we described a case of endometriosis diagnosed in a patient with premature ovarian insufficiency (POI) due to prepubertal bone marrow transplant (BMT). The patient is a 22-year-old nulligravid female who presented with chronic pelvic pain. She had an inherited bone marrow failure syndrome (Diamond-Blackfan anemia), which required gonadotoxic chemotherapy for BMT at a young age prior to puberty. At age 13, she received hormone therapy with transdermal estrogen with subsequent addition of cyclic progestin and was later transitioned to combined oral contraceptive pills (COC). Endometriosis was suspected due to progressive dysmenorrhea and multiple cyclic systemic symptoms. She underwent a trial of elagolix, but could not tolerate it due to worsened arthralgia. Norethindrone acetate (NET-A) was then started, and she underwent diagnostic laparoscopy. Laparoscopy revealed scattered superficial endometriotic lesions in the pelvis. Histological studies showed florid endometriosis. Patient continues on NET-A 10mg and oral estradiol 0.5mg daily since the surgery and has experienced sustained improvement in her symptoms. Endometriosis should be considered as a possible cause for progressive dysmenorrhea or pelvic pain, even in the setting of POI. The balance between HT for overall health benefits in young women with POI and the risk of endometriosis exacerbation is delicate, but achievable., (© 2024. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Background & Aims: The protection provided by rotavirus (RV) vaccines is highly heterogeneous among individuals. We hypothesized that microbiota composition might influence RV vaccine efficacy., Methods: First, we examined the potential of segmented filamentous bacteria (SFB) colonization to influence RV vaccine efficacy in mice. Next, we probed the influence of human microbiomes on RV vaccination via administering mice fecal microbial transplants (FMTs) from children with robust or minimal RV vaccine responsiveness. Post-FMT, mice were subjected to RV vaccination followed by RV challenge., Results: SFB colonization induced a phenotype that was reminiscent of RV vaccine failure (ie, failure to generate RV antigens and, consequently, anti-RV antibodies following RV vaccination resulting in proneness to RV challenge after SFB levels diminished). FMTs from children to mice recapitulated donor vaccination phenotype. Specifically, mice receiving FMTs from high-responsive vaccinees copiously shed RV antigens and robustly generated anti-RV antibodies following RV vaccination. Concomitantly, such mice were impervious to RV challenge. In contrast, mice receiving FMTs from children who had not responded to RV vaccination exhibited only modest responses to RV vaccination and, concomitantly, remained prone to RV challenge. Microbiome analysis ruled out a role for SFB but suggested involvement of Clostridium perfringens. Oral administration of cultured C. perfringens to gnotobiotic mice partially recapitulated the RV vaccine non-responder phenotype. Analysis of published microbiome data found C. perfringens abundance in children modestly associated with RV vaccine failure., Conclusion: Microbiota composition influences RV vaccine efficacy with C. perfringens being one, perhaps of many, potential contributing taxa., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: None declared.

This series, "Primary health care in South Asia", is an effort to provide region-specific, evidence-based insights for reorienting health systems towards PHC. Led by regional thinkers, this series draws lessons from five countries in South Asia: Bangladesh, India, Nepal, Pakistan, and Sri Lanka. This is the last paper in the series that outlines points for future action. We call for action in three areas. First, the changing context in the region, with respect to epidemiological shifts, urbanisation, and privatisation, presents an important opportunity to appraise existing policies on PHC and reformulate them to meet the evolving needs of communities. Second, reorienting health systems towards PHC requires concrete efforts on three pillars-integrated services, multi-sectoral collaboration, and community empowerment. This paper collates nine action points that cut across these three pillars. These action points encompass contextualising policies on PHC, scaling up innovations, allocating adequate financial resources, strengthening the governance function of health ministries, establishing meaningful public-private engagements, using digital health tools, reorganising service delivery, enabling effective change-management processes, and encouraging practice-oriented research. Finally, we call for more research-policy-practice networks on PHC in South Asia that can generate evidence, bolster advocacy, and provide spaces for cross-learning., Funding: WHO SEARO funded this paper. This source did not play any role in the design, analysis or preparation of the manuscript., Competing Interests: We declare no conflict of interest., (© 2024 The Authors.)

Human intestinal enteroids (HIEs) are gaining recognition as physiologically relevant models of the intestinal epithelium. While HIEs from adults are used extensively in biomedical research, few studies have used HIEs from infants. Considering the dramatic developmental changes that occur during infancy, it is important to establish models that represent infant intestinal characteristics and physiological responses. We established jejunal HIEs from infant surgical samples and performed comparisons to jejunal HIEs from adults using RNA sequencing (RNA-Seq) and morphologic analyses. We then validated differences in key pathways through functional studies and determined whether these cultures recapitulate known features of the infant intestinal epithelium. RNA-Seq analysis showed significant differences in the transcriptome of infant and adult HIEs, including differences in genes and pathways associated with cell differentiation and proliferation, tissue development, lipid metabolism, innate immunity, and biological adhesion. Validating these results, we observed a higher abundance of cells expressing specific enterocyte, goblet cell, and enteroendocrine cell markers in differentiated infant HIE monolayers, and greater numbers of proliferative cells in undifferentiated 3D cultures. Compared to adult HIEs, infant HIEs portray characteristics of an immature gastrointestinal epithelium including significantly shorter cell height, lower epithelial barrier integrity, and lower innate immune responses to infection with an oral poliovirus vaccine. HIEs established from infant intestinal tissues reflect characteristics of the infant gut and are distinct from adult cultures. Our data support the use of infant HIEs as an ex vivo model to advance studies of infant-specific diseases and drug discovery for this population., Importance: Tissue or biopsy stem cell-derived human intestinal enteroids are increasingly recognized as physiologically relevant models of the human gastrointestinal epithelium. While enteroids from adults and fetal tissues have been extensively used for studying many infectious and non-infectious diseases, there are few reports on enteroids from infants. We show that infant enteroids exhibit both transcriptomic and morphological differences compared to adult cultures. They also differ in functional responses to barrier disruption and innate immune responses to infection, suggesting that infant and adult enteroids are distinct model systems. Considering the dramatic changes in body composition and physiology that begin during infancy, tools that appropriately reflect intestinal development and diseases are critical. Infant enteroids exhibit key features of the infant gastrointestinal epithelium. This study is significant in establishing infant enteroids as age-appropriate models for infant intestinal physiology, infant-specific diseases, and responses to pathogens., Competing Interests: The authors declare no conflict of interest.

Background: In addition to providing patient care, interprofessional health care teams work collaboratively on a variety of projects. These projects often benefit from using facilitated small group project discussion sessions, such as the Harvard Macy Institute's (HMI) Step Back Process (SBP). Although having a trained facilitator is an important component of the SBP, only a limited number of health care professionals can attend HMI courses in person or virtually, limiting its impact., Approach: We developed three video-based education (VBE) modules to deliver facilitator training on the SBP, informed by principles of Mayer's cognitive theory of multimedia learning. For module development, we used a five-step approach. We evaluated effectiveness of the modules as a self-directed method to enhance SBP facilitator training. An initial survey collected demographic data and module feedback, a follow-up survey collected feedback on the modules' impact on facilitation and interviews focused on the participants' overall experience., Evaluation: Survey results indicated that the modules were positively received and helped to improve participant confidence in facilitating. We identified four themes from the interviews: challenges of facilitating, value of group feedback, value of modules for experienced facilitators and the modules as part of a multi-modal approach to train new facilitators., Implications: This innovation provides insight on delivering facilitator training on the SBP using VBE. Health professions educators developing online facilitator training could adapt our development process and modify implementation guided by our results. Future work should evaluate the best methods to integrate VBE modules into a longitudinal virtual community and assess facilitation techniques., (© 2024 Association for the Study of Medical Education and John Wiley & Sons Ltd.)

This AMEE guide discusses theoretical principles and practical strategies for health professions educators to promote impactful mentoring relationships. Traditional definitions are challenged, distinctions are made between roles such as mentor, advisor, coach and sponsor. As educational environments change and options for professional development expand, we argue that the traditional dyadic format of mentoring alone will not help mentees to maximise their professional growth. Newer formats of mentoring are discussed in detail and their advantages and disadvantages compared. We use a variety of theoretical concepts to anchor the practice of mentorship: self-focussed and other-focussed motives; psychological safety; personal interpretive framework; Daloz model for balancing support and challenge; zone of proximal development; communities of practice; and development along multiple layers of competence. Recommended strategies for effective mentoring are based on extensive review of literature, as well as combined professional mentoring experiences of the authors. We use key principles from the theories described and phases of mentoring relationships as foundations for the suggested best practices of mentorship. Finally, we emphasise the role of mentees in their own professional development and provide tips for them on seeking mentors, expanding their mentoring network and taking the lead in setting the agenda during mentoring meetings and formulating action plans for their own advancement.

Background: Among the most common mucosal viral infections in infants are rotavirus, one of the main causes of severe gastroenteritis in infants and children up to 5 years, and respiratory syncytial virus (RSV), one of the leading causes of lower respiratory tract infections. Both human milk and bovine milk derived factors may provide protection against mucosal viral infections. More recently, a similar activity of milk derived proteins was suggested for SARS-CoV-2. The goal of the current study was to test antiviral activity of the bovine milkfat globule membrane (MFGM) against rotavirus, RSV and SARS-CoV-2 and to further characterize MFGM-enriched whey to identify which components in MFGM-enriched whey may contribute to the inhibitory activity., Methods: The effects of MFGM-enriched whey, its whey protein isolate counterpart (WPI, obtained from the same production process) and a conventional whey protein concentrate (WPC) on rotavirus (strains Wa and SA114F), RSV (strain RSV-A2) and SARS-CoV-2 (Alpha variant) infectivity were determined using MA104 cells, human alveolar basal epithelial (A549) cells and monkey kidney (Vero E6) cells, respectively. The compounds were characterized in detail by LC-MS/MS and 31 P-NMR to determine protein and phospholipid composition, respectively., Results: Relative to its WPI counterpart, MFGM-enriched whey demonstrated a dose-dependent inhibition for both rotavirus and RSV whereas for SARS-CoV-2 inhibition was only observed at the highest concentration tested. Label-free quantification (LFQ) and intensity based absolute quantification (iBAQ) of identified proteins revealed a clear difference between MFGM-enriched whey and its controls including enrichment of known MFGM proteins and non-MFGM proteins that are enriched simultaneously, some of which have previously been demonstrated to display anti-viral activity. Although not completely absent from other whey protein preparations, MFGM-enriched whey had the highest specific and total phospholipid levels., Conclusion: MFGM-enriched whey displayed antiviral activity against multiple viruses of clinical importance. This study provides insights into the active components in MFGM-enriched whey and may contribute to previous clinical observations with MFGM-enriched formula demonstrating reduced respiratory and gastrointestinal infections in formula fed infants., Competing Interests: EK, VT, JB and TTL are employed by FrieslandCampina. MM is employed by Virology Research Services Ltd. The funder was involved in the study design, analysid, interpretation of the data, the writing of this article or the decision to submit it for publication. The remaining authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Kramer, Patil, Triantis, Bastiaans, Mazzon, Ramani and Lambers.)

Mechanistic investigation of host-microbe interactions in the human gut are hindered by difficulty of co-culturing microbes with intestinal epithelial cells. On one hand the gut bacteria are a mix of facultative, aerotolerant or obligate anaerobes, while the intestinal epithelium requires oxygen for growth and function. Thus, a coculture system that can recreate these contrasting oxygen requirements is critical step towards our understanding microbial-host interactions in the human gut. Here, we demonstrate Intestinal Organoid Physoxic Coculture (IOPC) system, a simple and cost-effective method for coculturing anaerobic intestinal bacteria with human intestinal organoids (HIOs). Using commensal anaerobes with varying degrees of oxygen tolerance, such as nano-aerobe Bacteroides thetaiotaomicron and strict anaerobe Blautia sp., we demonstrate that IOPC can successfully support 24-48 hours HIO-microbe coculture. The IOPC recapitulates the contrasting oxygen conditions across the intestinal epithelium seen in vivo. The IOPC cultured HIOs showed increased barrier integrity, and induced expression of immunomodulatory genes. A transcriptomic analysis suggests that HIOs from different donors show differences in the magnitude of their response to coculture with anaerobic bacteria. Thus, the IOPC system provides a robust coculture setup for investigating host-microbe interactions in complex, patient-derived intestinal tissues, that can facilitate the study of mechanisms underlying the role of the microbiome in health and disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Fofanova et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Recent research suggests that neurocognitive deficits in patients with schizophrenia may increase the risk of developing cognitive biases. As such, we set out to determine this predictive relationship as it pertains to the development of a first-episode psychosis. We hypothesized that poorer performance in processing speed would be associated with jumping to conclusions and an externalizing bias. Poorer performance in working memory would be associated with belief inflexibility and jumping to conclusions, and poorer performance in attention would be associated with attention to threat. We hypothesized that all cognitive biases would be associated with subsyndromal positive symptoms, and schizotypal traits would moderate these relationships. Undergraduate students (N = 130) completed the Schizotypal Personality Questionnaire, DAVOS Assessment of Cognitive Biases, Community Assessment of Psychic Experiences, and a computerized neuropsychological assessment battery. Processing speed had a small effect on externalizing bias, which in turn affected subsyndromal positive symptoms. There was no moderating effect of schizotypal traits on externalizing bias, but it was significantly associated with subsyndromal positive symptoms. Only the externalizing bias was associated with subsyndromal positive symptomatology, which might be explained by a restricted range and reduced variance in performance as a result of using a university student sample. This is one of few studies that sought to explain the mechanism responsible for the development of subsyndromal positive symptoms in a healthy sample using self-report measures.

Enteroids are in vitro models to study gastrointestinal pathologies and test personalized therapeutics; however, the inherent complexity of enteroids often renders standard gene editing approaches ineffective. Here, we introduce a refined lentiviral transfection protocol, ensuring sufficient lentiviral engagement with enteroids while considering spatiotemporal growth variability throughout the extracellular matrix. Additionally, we highlight a selection process for transduced cells, introduce a protocol to accurately measure transduction efficiency, and explore methodologies to gauge effects of gene knockdown on biological processes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background & Aims: The extent to which live orally-administered rotavirus (RV) vaccines elicit protective immunity is highly heterogeneous. We hypothesized microbiota composition might influence vaccine efficacy., Methods: We tested this concept by examining extent to which colonizing mice with segmented filamentous bacteria (SFB) influenced RV vaccine efficacy.Influence of human microbiomes on RV vaccination was studied via administering germ-free mice fecal microbial transplants (FMT) from children with robust or minimal RV vaccine responsiveness. Post-FMT, mice were subjected to vaccination and challenge doses of RV., Results: SFB administration resulted in a phenotype reminiscent of RV vaccine failure, i.e. minimal generation of RV antigens and, consequently, lack of anti-RV antibodies resulting in proneness to RV challenge once SFB levels diminished. Transplant of microbiomes from children to mice recapitulated donor vaccination phenotype. Specifically, mice receiving FMT from high-responding children exhibited high levels of fecal RV antigen shedding and RV antibodies in response to RV vaccination and, concomitantly, were impervious to RV challenge. In contrast, mice receiving FMT from children who had not responded to RV vaccination exhibited only modest responses to RV challenge and, accordingly, remained prone to RV challenge. Microbiome analysis ruled out a role for SFB but suggested that RV vaccine failure might involve Clostridium perfringens . Oral administration of cultured C. perfringens to gnotobiotic mice partially recapitulated the RV vaccine non-responder phenotype. Analysis of previously-reported microbiome data found C. perfringens abundance in children associated with RV vaccine failure., Conclusion: Microbiota composition influences RV vaccine virus infection and, consequently, protective immunity. C. perfringens may be one, perhaps of many, bacterial species harbored in the intestine of RV-vaccine non-responders that influences RV vaccine outcomes.

Background: The in vitro cultivation of human noroviruses allows a comparison of antibody levels measured in neutralization and histoblood group antigen (HBGA)-blocking assays., Methods: Serum samples collected during the evaluation of an investigational norovirus vaccine (HIL-214 [formerly TAK-214]) were assayed for neutralizing antibody levels against the vaccine's prototype Norwalk virus/GI.1 (P1) virus strain. Results were compared to those previously determined using HBGA-blocking assays., Results: Neutralizing antibody seroresponses were observed in 83% of 24 vaccinated adults, and antibody levels were highly correlated (r=0.81, P<0.001) with those measured by HBGA-blocking., Conclusions: GI.1-specific HBGA-blocking antibodies are a surrogate for neutralization of GI.1 norovirus., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

In vitro models, such as primary cells and continuous cell lines routinely used for evaluating drug candidates, have limitations in their translational relevance to human diseases. Organotypic cultures are increasingly being used to assess therapeutics for various cancers and infectious diseases. Monitoring drug cytotoxicity in cell cultures is crucial in drug development, and several commercially available kits for cytotoxicity assessment offer distinct advantages and limitations. Given the complexity of organoid cultures, including donor-driven variability, we investigated drug-treated, tissue stem cell-derived human intestinal organoid responses with commonly used cell cytotoxicity assay kits. Using seven different compounds, we compared the cytotoxicity assay performance of two different leaky membrane-based and two metabolism-based assays. Significant variability was seen in reported viability outcomes across assays and organoid lines. High baseline activity of lactate dehydrogenase (LDH) in four human intestinal organoid lines required modification of the standard LDH assay protocol. Additionally, the LDH assay reported unique resilience to damage in a genetically-modified line contrasting results compared to other assays. This study highlights factors that can impact the measurement of cell cytotoxicity in intestinal organoid models, which are emerging as valuable new tools for research and pre-clinical drug testing and suggest the need for using multiple assay types to ensure reliable cytotoxicity assessment., Competing Interests: “M.K.E. is named as an inventor on patents related to cloning of the Norwalk virus genome and HuNoV cultivation and has received research funding from Takeda Vaccines Business Unit (Cambridge, MA, USA) and Hillevax, Inc. and has served as a consultant to Hillevax, Inc. R.L.A. is named as an inventor on patents related to HuNoV cultivation and has received research support from Takeda Vaccines Business Unit (Cambridge, MA, USA) and Hillevax, Inc. and has served as a consultant to Hillevax, Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.”, (Copyright: © 2024 Lewis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The transition from medical school to residency is a critical developmental phase; coaching may help students prepare for this role transition., Aims: We explored whether near-peer coaching could improve a specific workplace skill prior to residency., Methods: A resident-as-coach program was piloted for the medicine sub-internship, an advanced acting internship rotation. Between March and June 2021, 26 students were assigned a resident coach ( n  = 16). Resident coaches completed one training session, and student-coach dyads met for one coaching session on 'pre-rounding'- gathering patient data before rounds. The program was evaluated through surveys and focus groups., Results: 20/26 students and 14/16 residents completed the survey. 19/20 students identified a pre-rounding challenge and reported increased pre-rounding efficiency; all committed to one actionable step for improvement. All 16 residents felt their coaching skills improved. In focus groups, students valued the program's focus on honing a relevant skill in a safe, near-peer setting. Residents expressed their intent to incorporate coaching into their future work., Conclusions: A resident-as-coach model can be effective in preparing students for residency, while concurrently building residents' coaching skills.

Background: Multiple sclerosis (MS) negatively impacts cognition and has been associated with deficits in social cognition, including emotion recognition. There is a lack of research examining emotion recognition from multiple modalities in MS. The present study aimed to employ a clinically available measure to assess multimodal emotion recognition abilities among individuals with MS., Method: Thirty-one people with MS and 21 control participants completed the Advanced Clinical Solutions Social Perceptions Subtest (ACS-SP), BICAMS, and measures of premorbid functioning, mood, and fatigue. ANCOVAs examined group differences in all outcomes while controlling for education. Correlational analyses examined potential correlates of emotion recognition in both groups., Results: The MS group performed significantly worse on the ACS-SP than the control group, F(1, 49) = 5.32, p = .025. Significant relationships between emotion recognition and cognitive functions were found only in the MS group, namely for information processing speed (r = 0.59, p < .001), verbal learning (r = 0.52, p = .003) and memory (r = 0.65, p < 0.001), and visuospatial learning (r = 0.62, p < 0.001) and memory (r = 0.52, p = .003). Emotion recognition did not correlate with premorbid functioning, mood, or fatigue in either group., Conclusions: This study was the first to employ the ACS-SP to assess emotion recognition in MS. The results suggest that emotion recognition is impacted in MS and is related to other cognitive processes, such as information processing speed. The results provide information for clinicians amidst calls to include social cognition measures in standard MS assessments., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Although most teaching around feedback focuses on the delivery, one must consider that the word 'feedback' is not a neutral word. It inflicts a range of emotions that, when used, may influence the effectiveness of the feedback process. A more profound understanding of health professions educators' perceptions regarding the word 'feedback' can help explain discrepancies between the provision, reception and acceptance of feedback., Methods: This is a qualitative inductive, reflective thematic analysis study. The authors interviewed 22 health professions educators participating in an online workshop to develop their feedback giving skills on their initial perspectives of the word 'feedback'., Results: We found four major themes: (1) Can I tell you a little story about my feedback experience? (2) It is probably going to be negative. (3) There is always something to learn if you are willing to hear the message. (4) It is like getting a report card. From the data, we suggest one key antecedent and two practical approaches one could take when giving feedback., Conclusion: In this article, the authors highlight barriers during the feedback process due to the mere perception of the nature of feedback and the connotations associated with the term itself and suggest approaches that can refocus conversations towards a shared meaning and purpose of improvement, despite the preconceptions of the word 'feedback'., (© 2023 John Wiley & Sons Ltd and The Association for the Study of Medical Education.)

Human noroviruses (HuNoVs) are the leading cause of acute gastroenteritis worldwide. Currently, there are no targeted antivirals for the treatment of HuNoV infection. Histo-blood group antigens (HBGAs) on the intestinal epithelium are cellular attachment factors for HuNoVs; molecules that block the binding of HuNoVs to HBGAs thus have the potential to be developed as antivirals. Human milk oligosaccharides (HMOs) are glycans in human milk with structures analogous to HBGAs. HMOs have been shown to act as decoy receptors to prevent the attachment of multiple enteric pathogens to host cells. Previous X-ray crystallography studies have demonstrated the binding of HMO 2'-fucosyllactose (2'FL) in the same pocket as HBGAs for some HuNoV strains. We evaluated the effect of 2'FL on the replication of a globally dominant GII.4 Sydney [P16] HuNoV strain using human intestinal enteroids (HIEs) from adults and children. A significant reduction in GII.4 Sydney [P16] replication was seen in duodenal and jejunal HIEs from multiple adult donors, all segments of the small intestine from an adult organ donor and in two pediatric duodenal HIEs. However, 2'FL did not inhibit HuNoV replication in two infant jejunal HIEs that had significantly lower expression of α1-2-fucosylated glycans. 2'FL can be synthesized in large scale, and safety and tolerance have been assessed previously. Our data suggest that 2'FL has the potential to be developed as a therapeutic for HuNoV gastroenteritis.

A GII.2 outbreak in an efficacy study of a bivalent virus-like particle norovirus vaccine, TAK-214, in healthy US adults provided an opportunity to examine GII.4 homotypic vs GII.2 heterotypic responses to vaccination and infection. Three serologic assays-virus-like particle binding, histoblood group antigen blocking, and neutralizing-were performed for each genotype. Results were highly correlated within a genotype but not between genotypes. Although the vaccine provided protection from GII.2-associated disease, little GII.2-specific neutralization occurred after vaccination. Choice of antibody assay can affect assessments of human norovirus vaccine immunogenicity., Competing Interests: Potential conflicts of interest. R. L. A. and M. K. E. received grant support from Takeda Vaccines, Inc; have served as consultants to HilleVax, Inc; and are named as inventors on patents related to HuNoV cultivation. M. K. E. is named as an inventor on patents related to cloning of the Norwalk virus genome. L. L. and R. S. B. hold patents on norovirus vaccine design and ongoing collaborations with Vaxart, Takeda Vaccines, HilleVax, and BioNTech that are unrelated to this report. R. S. B. is a member of the advisory committee for Vaxart and Invivyd. A. B., R. B., and J. S. were full-time employees of Takeda Vaccines, Inc at the time that these studies were performed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In very low birth weight (VLBW) infants, human milk cream added to standard human milk fortification is used to improve growth. This study aimed to evaluate the impact of cream supplement on the intestinal microbiome of VLBW infants., Methods: Whole genome shotgun sequencing was performed on stool (n = 57) collected from a cohort of 23 infants weighing 500-1250 grams (control = 12, cream = 11). Both groups received an exclusive human milk diet (mother's own milk, donor human milk, and donor human milk-derived fortifier) with the cream group receiving an additional 2 kcal/oz cream at 100 mL/kg/day of fortified feeds and then 4 kcal/oz if poor growth., Results: While there were no significant differences in alpha diversity, infants receiving cream significantly differed from infants in the control group in beta diversity. Cream group samples had significantly higher prevalence of Proteobacteria and significantly lower Firmicutes compared to control group. Klebsiella species dominated the microbiota of cream-exposed infants, along with bacterial pathways involved in lipid metabolism and metabolism of cofactors and amino acids., Conclusions: Cream supplementation significantly altered composition of the intestinal microbiome of VLBW infants to favor increased prevalence of Proteobacteria and functional gene content associated with these bacteria., Impact: We report changes to the intestinal microbiome associated with administration of human milk cream; a novel supplement used to improve growth rates of preterm very low birth weight infants. Since little is known about the impact of cream on intestinal microbiota composition of very low birth weight infants, our study provides valuable insight on the effects of diet on the microbiome of this population. Dietary supplements administered to preterm infants in neonatal intensive care units have the potential to influence the intestinal microbiome composition which may affect overall health status of the infant., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Purpose: Internal medicine residents care for clinically complex older adults and may experience increased moral distress due to knowledge gaps, time constraints, and institutional barriers. We conducted a phenomenological study to explore residents' experiences and challenges through the lens of uncertainty., Methods: Between January and March 2022, six focus groups were conducted comprising a total of 13 internal medicine residents in postgraduate years 2 and 3, who had completed a required 2-week geriatrics rotation. Applying the Beresford taxonomy of uncertainty as a conceptual model, data were analyzed using the framework method., Results: All challenging experiences described by residents caring for older adults were linked to uncertainty. Sources of uncertainty were categorized and mapped to the Beresford taxonomy: (1) lack of geriatrics knowledge or clinical guidelines (technical); (2) difficulty applying knowledge to complex older adults (conceptual); and (3) lack of longitudinal relationship with the older patient (personal). Residents identified capacity evaluation and discharge planning as two major geriatric knowledge areas linked with uncertainty. While the majority of residents reacted to uncertainty with some degree of distress, several reported positive coping strategies., Conclusions: Internal medicine residents face uncertainty when caring for older adults, particularly related to technical and conceptual factors. Strategies for mitigating uncertainty in the care of older adults are needed given links with moral distress and trainee well-being., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

The Watch List (WL) is a monitoring program under the European Water Framework Directive (WFD) to obtain high-quality Union-wide monitoring data on potential water pollutants for which scarce monitoring data or data of insufficient quality are available. The main purpose of the WL data collection is to determine if the substances pose a risk to the aquatic environment at EU level and subsequently to decide whether a threshold, the Environmental Quality Standards (EQS) should be set for them and, potentially to be listed as priority substance in the WFD. The first WL was established in 2015 and contained 10 individual or groups of substances while the 4th WL was launched in 2022. The results of monitoring the substances of the first WL showed that some countries had difficulties to reach an analytical Limit of Quantification (LOQ) below or equal to the Predicted No-Effect Concentrations (PNEC) or EQS. The Joint Research Centre (JRC) of the European Commission (EC) organised a series of workshops to support the EU Member States (MS) and their activities under the WFD. Sharing the knowledge among the Member States on the analytical methods is important to deliver good data quality. The outcome and the discussion engaged with the experts are described in this paper, and in addition a literature review of the most important publications on the analysis of 17-alpha-ethinylestradiol (EE2), amoxicillin, ciprofloxacin, metaflumizone, fipronil, metformin, and guanylurea from the last years is presented., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Teaching hospitals are fast-paced health care environments where clinical supervisors constantly balance teaching and patient care. Although hospital-based clinicians in acute care settings regularly teach trainees, views regarding their teaching roles and how this relates to professional satisfaction are less well studied. We explored perspectives of physicians who teach trainees in medical intensive care units (MICUs), to understand whether their engagement in teaching has any impact on professional (job) satisfaction., Methods: This qualitative study used focus groups of MICU fellows (postgraduate clinical trainees) and attending physicians (consultants) to explore participants' perceptions of their teaching roles. Focus groups were audiotaped and transcribed; thematic analysis was conducted on de-identified transcripts., Findings: Four focus groups were held; two with MICU attendings (n = 13) and two with MICU fellows (n = 12). We identified four key themes: two challenges of teaching (being a chameleon; calibrating learner abilities), one benefit of teaching (facilitating learners' eureka moments) and a call for professional development (peer coaching to enhance teaching skills)., Discussion: Although teaching in acute clinical environments requires balancing dynamic learner needs and complex patient care needs, participants found it highly rewarding. They called for peer coaching initiatives to enhance professional development as teachers and demonstrate departmental commitment to teaching., Conclusion: While teaching in acute clinical settings is challenging for many reasons, clinical teachers emphasise that it is very satisfying when learners see the 'light'. Overt institutional support and recognition for clinical teachers along with peer coaching and debriefing may tilt the balance towards the rewards side of the equation and foster professional satisfaction., (© 2023 Association for the Study of Medical Education and John Wiley & Sons Ltd.)

Background: The burden of Non-Communicable Diseases (NCDs) in urban informal settlements across Lower and Middle Income Countries is increasing. In recognition, there has been interest in fine-tuning policies on NCDs to meet the unique needs of people living in these settlements. To inform such policy efforts, we studied the care-seeking journeys of people living in urban informal settlements for two NCDs-diabetes and hypertension. The study was done in the Mumbai Metropolitan Region, India., Methods: This qualitative study was based on interviews with patients having diabetes and hypertension, supplemented by interactions with the general community, private doctors, and public sector staff. We conducted a total of 47 interviews and 6 Focus Group Discussions. We synthesized data thematically and used the qualitative software NVivo Version 10.3 to aid the process. In this paper, we report on themes that we, as a team, interpreted as striking and policy-relevant features of peoples' journeys., Results: People recounted having long and convoluted care-seeking journeys for the two NCDs we studied. There were several delays in diagnosis and treatment initiation. Most people's first point of contact for medical care were local physicians with a non-allopathic degree, who were not always able to diagnose the two NCDs. People reported seeking care from a multitude of healthcare providers (public and private), and repeatedly switched providers. Their stories often comprised multiple points of diagnosis, re-diagnosis, treatment initiation, and treatment adjustments. Advice from neighbors, friends, and family played an essential role in shaping the care-seeking process. Trade-offs between saving costs and obtaining relief from symptoms were made constantly., Conclusion: Our paper attempts to bring the voices of people to the forefront of policies on NCDs. People's convoluted journeys with numerous switches between providers indicate the need for trusted "first-contact" points for NCD care. Integrating care across providers-public and private-in urban informal settlements-can go a long way in streamlining the NCD care-seeking process and making care more affordable for people. Educating the community on NCD prevention, screening, and treatment adherence; and establishing local support mechanisms (such as patient groups) may also help optimize people's care-seeking pathways., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ramani, Bahuguna, Spencer, Pathak, Shende, Pantvaidya, D’Souza and Jayaraman.)

Background: Health professions education (HPE) must keep pace with rapid shifts in learning and societal contexts, control of resources, knowledge and environmental concerns. Sustainability is increasingly seen as complex, balancing the three pillars of economy, society and the environment and addressing the current generation's needs without compromising future generations' needs. We aim to orient three-pillar sustainability in (HPE) from a decolonial global perspective., Conferences as Truth-Regimes: Future-proofing imperatives compel HPE to respond to sustainability calls in contexts of globalisation and internationalisation. International conferences are sites of power in knowledge production and dissemination because themes and invited speakers determine who experts in the field are and what knowledge is important. Scholarly communities, dominating the discourse, determine the nature of reality or 'truth' (ontology), theoretical foundations of that reality and approaches to knowing (epistemology). Using one international conference as a case study, we found few scholarly presentations on sustainability, especially economic disparities. Discourse in HPE is still dominated by Global North 'experts'., Implications: Conferences are important discursive spaces for knowledge production and exchange. Increasing attention to social justice and planetary health must include a global perspective on three-pillar sustainability. Historical and contemporary perspectives about disparities on health should exceed Eurocentric epistemologies alone. These are areas ripe for innovative research in HPE. Promisingly, there is increasing attention to curricula around health equity, disparities and clinical rotations in rural and underserved communities among educational institutions around the world., Conclusions: Future-proofing HPE requires addressing three sustainability pillars simultaneously. Conferences as influential knowledge production spaces are mostly characterised by Global North to South flow of knowledge. Global North-dominated discourse fails to reflect on the impact of historical disparities including colonialism that thwart equivalence. Transforming HPE can occur through a sustainability perspective that advances three-pillar global approaches for inclusive global legitimacy in HPE narratives and standards., (© 2023 The Authors. Medical Education published by Association for the Study of Medical Education and John Wiley & Sons Ltd.)

Cholesterol is a risk factor for age-related hearing loss (ARHL). However, the effect of cholesterol on the organ of Corti during the onset of ARHL is unclear. We established a mouse model for the ARHL group (24 months, n = 12) and a young group (6 months, n = 12). Auditory thresholds were measured in both groups using auditory brainstem response (ABR) at frequencies of 8, 16, and 32 kHz. Subsequently, mice were sacrificed and subjected to histological analyses, including transmission electron microscopy (TEM), H&E, Sudan Black B (SBB), and Filipin staining, as well as biochemical assays such as IHC, enzymatic analysis, and immunoblotting. Additionally, mRNA extracted from both young and aged cochlea underwent RNA sequencing. To identify the mechanism, in vitro studies utilizing HEI-OC1 cells were also performed. RNA sequencing showed a positive correlation with increased expression of genes related to metabolic diseases, cholesterol homeostasis, and target of rapamycin complex 1 (mTORC1) signaling in the ARHL group as compared to the younger group. In addition, ARHL tissues exhibited increased cholesterol and lipofuscin aggregates in the organ of Corti, lateral walls, and spiral ganglion neurons. Autophagic flux was inhibited by the accumulation of damaged lysosomes and autolysosomes. Subsequently, we observed a decrease in the level of transcription factor EB (TFEB) protein, which regulates lysosomal biosynthesis and autophagy, together with increased mTORC1 activity in ARHL tissues. These changes in TFEB and mTORC1 expression were observed in a cholesterol-dependent manner. Treatment of ARHL mice with atorvastatin, a cholesterol synthesis inhibitor, delayed hearing loss by reducing the cholesterol level and maintaining lysosomal function and autophagy by inhibiting mTORC1 and activating TFEB. The above findings were confirmed using stress-induced premature senescent House Ear Institute organ of Corti 1 (HEI-OC1) cells. The findings implicate cholesterol in the pathogenesis of ARHL. We propose that atorvastatin could prevent ARHL by maintaining lysosomal function and autophagy by inhibiting mTORC1 and activating TFEB during the aging process.

Background Preoperative fasting for six hours and accepting clear fluids till two hours of surgery is followed as a regular practice. Carbohydrate-rich fluids antagonize catabolism and are claimed to be tolerated better. This study aims to compare the effect of carbohydrate-rich drinks on gastric volume and blood sugar control in diabetic and non-diabetic patients undergoing elective surgery with plain water. Methods Two hundred forty patients aged 40 to 65 undergoing elective surgery under regional anesthesia were randomized into diabetic control, diabetic study, non-diabetic control, and non-diabetic study. Control groups were given 400 ml of plain water, while the study group received 50 grams of dextrose dissolved in 400 ml of water two hours prior to surgery. Gastric volume was evaluated using USG, and thirst and discomfort were assessed using the Likert scale. Perioperatively, blood sugar values were monitored and kept under control using insulin. Results Mean gastric volume (ml) in diabetic control (35.3±12.95 ml), diabetic study (31.2±11.75 ml), non-diabetic control (29±11.42 ml), and non-diabetic study (30.4±9.12 ml) showed no statistically significant difference (p>0.05). Capillary blood glucose (CBG) values two hours post fluid intake showed a significant increase in CBG levels in the diabetic study (183.2±28.67 mg/dl) compared to the diabetic control group (138.66±15.81 mg/dl). The values returned to baseline within six hours. Thirst and discomfort were significantly lower in the study group of diabetic and non-diabetic populations. Conclusion We conclude that carbohydrate loading does not affect gastric volume in diabetics and non-diabetics. However, the sugar values do increase which may warrant hourly checking and administration of insulin in diabetics., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Vishak et al.)

Introduction: Currently, there are no FDA-approved medications to treat methamphetamine addiction, including the inflammatory, neurotoxic, and adverse neuropsychiatric effects. We have shown that partial (p)MHC class II constructs (i.e., Recombinant T-cell receptor Ligand - RTL1000), comprised of the extracellular α1 and β1 domains of MHC class II molecules linked covalently to myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide, can address the neuroimmune effects of methamphetamine addiction through its ability to bind to and down-regulate CD74 expression, block macrophage migration inhibitory factor (MIF) signaling, and reduce levels of pro-inflammatory chemokine ligand 2 (CCL2). The present study evaluated the effects of our third-generation pMHC II construct, DRmQ, on cognitive function and concentration of inflammatory cytokines in the frontal cortex, a region critical for cognitive functions such as memory, impulse control, and problem solving., Methods: Female and male C57BL/6J mice were exposed to methamphetamine (or saline) via subcutaneous (s.c.) injections administered four times per day every other day for 14 days. Following methamphetamine exposure, mice received immunotherapy (DRmQ or ibudilast) or vehicle s.c. injections daily for five days. Cognitive function was assessed using the novel object recognition test (NORT). To evaluate the effects of immunotherapy on inflammation in the frontal cortex, multiplex immunoassays were conducted. ANOVA was used to compare exploration times on the NORT and immune factor concentrations., Results: Post hoc analysis revealed increased novel object exploration time in MA-DRmQ treated mice, as compared to MA-VEH treated mice (non-significant trend). One-way ANOVA detected a significant difference across the groups in the concentration of macrophage inflammatory protein-2 (MIP-2) ( p  = 0.03). Post hoc tests indicated that mice treated with methamphetamine and DRmQ or ibudilast had significantly lower levels of MIP-2 in frontal cortex, as compared to mice treated with methamphetamine and vehicle ( p  > 0.05)., Discussion: By specifically targeting CD74, our DRQ constructs can block the signaling of MIF, inhibiting the downstream signaling and pro-inflammatory effects that contribute to and perpetuate methamphetamine addiction., Competing Interests: Author RS was employed by company Virogenomics BioDevelopment, Inc. The Department of Veterans Affairs (VA) and Oregon Health & Science University (OHSU) own the RTL technology used in the RTL research that is described in this report. The VA, OHSU, JL and AV have rights to royalties from the licensing agreement with Artielle Immunotherapeutics. These potential conflicts of interest have been reviewed and managed by the Conflict of Interest Committees at the VA Portland Health Care System and OHSU. Virogenomics BioDevelopment, Inc. and RS have a financial interest in Artielle Immunotherapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Loftis, Ramani, Firsick, Hudson, Le-Cook, Murnane, Vandenbark and Shirley.)

Human noroviruses (HuNoVs) are the leading cause of acute gastroenteritis. In immunocompetent hosts, symptoms usually resolve within 3 days; however, in immunocompromised persons, HuNoV infection can become persistent, debilitating, and sometimes life-threatening. There are no licensed therapeutics for HuNoV due to a near half-century delay in its cultivation. Treatment for chronic HuNoV infection in immunosuppressed patients anecdotally includes nitazoxanide, a broad-spectrum antimicrobial licensed for treatment of parasite-induced gastroenteritis. Despite its off-label use for chronic HuNoV infection, nitazoxanide has not been clearly demonstrated to be an effective treatment. In this study, we standardized a pipeline for antiviral testing using multiple human small intestinal enteroid lines representing different intestinal segments and evaluated whether nitazoxanide inhibits replication of five HuNoV strains in vitro . Nitazoxanide did not exhibit high selective antiviral activity against any HuNoV strain tested, indicating it is not an effective antiviral for HuNoV infection. Human intestinal enteroids are further demonstrated as a model to serve as a preclinical platform to test antivirals against HuNoVs to treat gastrointestinal disease. Abstr., Competing Interests: M.K.E. is named as an inventor on patents related to cloning of the Norwalk virus genome and HuNoV cultivation and has received research funding from Takeda Vaccines Business Unit (Cambridge, MA, USA). R.L.A. is named as an inventor on patents related to HuNoV cultivation and has received research support from Takeda Vaccines Business Unit (Cambridge, MA, USA).

The National Center for Advancing Translational Sciences (NCATS) Assay Guidance Manual (AGM) Workshop on 3D Tissue Models for Antiviral Drug Development, held virtually on 7-8 June 2022, provided comprehensive coverage of critical concepts intended to help scientists establish robust, reproducible, and scalable 3D tissue models to study viruses with pandemic potential. This workshop was organized by NCATS, the National Institute of Allergy and Infectious Diseases, and the Bill and Melinda Gates Foundation. During the workshop, scientific experts from academia, industry, and government provided an overview of 3D tissue models' utility and limitations, use of existing 3D tissue models for antiviral drug development, practical advice, best practices, and case studies about the application of available 3D tissue models to infectious disease modeling. This report includes a summary of each workshop session as well as a discussion of perspectives and challenges related to the use of 3D tissues in antiviral drug discovery., Competing Interests: Potential conflicts of interest. A. A. is a shareholder in Biorg, Inc (Winston-Salem, NC). D. E. I. is a shareholder in Emulate, Inc (Boston, MA). E. A. R. is a shareholder in RUMI Viro, Inc and RUMI Scientific, Inc (New York, NY). T. H. is a shareholder in AxoSim, LLC (New Orleans, LA). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Competing Interests: No potential conflict of interest was reported by the authors.

Laboratory studies of host-microbe interactions have historically been carried out using transformed cell lines and animal models. Although much has been learned from these models, recent advances in the development of multicellular, physiologically active, human intestinal organoid (HIO) cultures are allowing unprecedented discoveries of host-microbe interactions. Here, we review recent literature using HIOs as models to investigate the pathogenesis of clinically important enteric bacteria and viruses and study commensal intestinal microbes. We also discuss limitations of current HIO culture systems and how technical advances and innovative engineering approaches are providing new directions to improve the model. The studies discussed here highlight the potential of HIOs for studying microbial pathogenesis, host-microbe interactions, and for preclinical development of therapeutics and vaccines., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Much of the current global health publishing landscape is restricted in its epistemological diversity, relying heavily on a biomedical lens to examine and report on global health issues. In this Viewpoint, we argue that the space within global health journals needs to be expanded to include diverse forms of research scholarship, thereby shifting the kinds of stories that get told in these spaces. We particularly call for the inclusion of deeper research that values the tacit, experiential knowledge possessed by actors (eg, communities, health-care workers, policy makers, activisits, and researchers) in low-income and middle-income countries, and legitimises the perspectives of local doers and thinkers; research that pays careful attention to context, and does not treat local realities as mere background occurrences; and research that draws on alternative, counter-dominant epistemologies, that allow for the crucial examination of power imbalances, and that challenge hegemonic discourses in global health. To decolonise academic work in the global health field, we should look beyond diversity in research authorship. We need to tackle other unconscious biases such as presumptions about the superiority of particular forms of evidence over others, and thereby expand the plurality of perspectives in global health., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)