Search

Summary: Protein phosphatase 2A (PP2A) is an essential Ser/Thr phosphatase. The PP2A holoenzyme complex comprises a scaffolding (A), regulatory (B), and catalytic (C) subunit, with PPP2CA being the principal catalytic subunit. The full scope of PP2A substrates in cells remains to be defined. To address this, we employed dTAG proteolysis-targeting chimeras to efficiently and selectively degrade dTAG-PPP2CA in homozygous knock-in HEK293 cells. Unbiased global phospho-proteomics identified 2,204 proteins with significantly increased phosphorylation upon dTAG-PPP2CA degradation, implicating them as potential PPP2CA substrates. A vast majority of these are novel. Bioinformatic analyses revealed involvement of the potential PPP2CA substrates in spliceosome function, cell cycle, RNA transport, and ubiquitin-mediated proteolysis. We identify a pSP/pTP motif as a predominant target for PPP2CA and confirm some of our phospho-proteomic data with immunoblotting. We provide an in-depth atlas of potential PPP2CA substrates and establish targeted degradation as a robust tool to unveil phosphatase substrates in cells.

Purpose: Assessing the long-term impact of cancer on people's lives is challenging due to confounding issues such as aging and comorbidities. We aimed to investigate this impact by comparing the outcomes of cancer survivors with a matched control cohort., Methods: This was a cross-sectional survey of breast, colorectal and ovarian cancer survivors approximately 5 years post-diagnosis and a cohort of age, sex and social deprivation-matched controls who had never had a cancer diagnosis. Eligible participants were invited by post to complete a survey assessing quality of life (QoL), health, identity, healthcare usage and finances., Results: A total of 2075 out of 5734 (36.2%) eligible participants participated (852 cancer survivors and 1223 matched controls). Cancer survivors had poorer QoL than matched controls as assessed by the Quality of Life of Adult Cancer Survivors (QLACS) summary score (p = 0.007); however, the effect size was modest (ω 2  = 0.121). The cancer survivors also reported worse outcomes across some individual domains of QoL and health, but not others, and differences were small. There were few differences between cohorts across healthcare usage and finances., Conclusions: Five years or more after diagnosis, the QoL, healthcare usage and finances of breast, colorectal and ovarian cancer survivors were generally similar to that of age, sex and IMD-matched controls., Implications for Cancer Survivors: This finding has important implications for people affected by cancer and those providing care who would benefit from greater information on outcomes and functioning beyond treatment. Despite this reassuring finding, it is important to note that there were some differences, on both physical and psychosocial issues, mandating the need for specialist service provision., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Implant survivorship in uncemented total ankle replacement (TAR) is dependent on achieving initial stability. This is because early micromotion between the implant and bone can disrupt the process of osseointegration, leading to poor long-term outcomes. Tibial implant fixation features are designed to resist micromotion, aided by bony sidewall retention and interference fit. The goal of this study was to investigate design-specific factors influencing implant-bone micromotion in TAR tibial components with interference fit., Methods: Three implant designs with fixation features representative of current TAR tibial components (ARC, SPIKES, KEEL) were virtually inserted into models of the distal tibias of 2 patients with end-stage ankle arthritis. Tibia models were generated from deidentified patient computed tomography scans, with material properties for modeling bone behavior and compaction during press-fit. Finite element analysis (FEA) was used to simulate 2 fixation configurations: (1) no sidewalls or interference fit, and (2) sidewalls with interference fit. Load profiles representing the stance phase of gait were applied to the models, and implant-bone micromotions were computed from FEA output., Results: Sidewalls and interference fit substantially influenced implant-bone micromotions across all designs studied. When sidewalls and interference fit were modeled, average micromotions were less than 11 µm, consistent across the stance phase of gait. Without sidewalls or interference fit, micromotions were largest near either heel strike or toe-off. In the absence of sidewalls and interference fit, the amount of micromotion generally aligned inversely with the size of implant fixation features; the ARC design had the largest micromotion (~540 µm average), whereas the KEEL design had the smallest micromotion (~15 µm)., Conclusion: This study presents new insights into the effect of TAR fixation features on implant-bone micromotion. With sidewalls and interference fit, micromotion is predicted to be minimal for implants, whereas with no sidewalls and no interference fit, micromotion depended primarily on the implant design., Clinical Relevance: This study presents new insights into the effect of TAR primary fixation features on implant-bone micromotion. Although design features heavily influenced implant stability in the model, their influence was greatly diminished when interference fit was introduced. The results of this study show the relative importance of design features and interference fit in the predicted initial stability of uncemented TAR, potentially a key factor in implant survivorship., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Disclosure forms for all authors are available online.

Abstract: Gilteritinib is the current standard of care for relapsed or refractory fms related receptor tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia in many countries, however outcomes for patients relapsing after contemporary first-line therapies (intensive chemotherapy with midostaurin, or nonintensive chemotherapy with venetoclax) are uncertain. Moreover, reported data on toxicity and health care resource use is limited. Here, we describe a large real-world cohort of 152 patients receiving single-agent gilteritinib in 38 UK hospitals. Median age was 61 years, and 36% had received ≥2 prior lines of therapy, including a FLT3 inhibitor in 41% and venetoclax in 24%. A median of 4 cycles of gilteritinib were administered, with 56% of patients requiring hospitalization in the first cycle (median, 10 days). Over half of patients required transfusion in each of the first 4 cycles. Complete remission (CR) was achieved in 21%, and CR with incomplete recovery (CRi) in a further 9%. Remission rates were lower for patients with FLT3-tyrosine kinase domain or adverse karyotype. Day-30 and day-60 mortality were 1% and 10.6%, respectively, and median overall survival was 9.5 months. On multivariable analysis, increasing age, KMT2A rearrangement, and complex karyotype were associated with worse survival whereas RUNX1 mutations were associated with improved survival. Twenty patients received gilteritinib as first salvage having progressed after first-line therapy with venetoclax, with CR/CRi achieved in 25% and median survival 4.5 months. Real-world results with gilteritinib mirror those seen in the clinical trials, but outcomes remain suboptimal, with more effective strategies needed., (© 2024 by The American Society of Hematology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Background: Alterations in gut-brain axis communication pathways and the gut microbiota ecosystem caused by early life stress have been extensively described as critical players in the pathophysiology of stress-induced disorders. However, the extent to which stress-induced gut microbiota alterations manifest in early life and contribute to the sex-specific susceptibility to distinct gut-brain phenotypes in adulthood has yet to be defined., Methods: Male and female Sprague-Dawley rat offspring underwent maternal separation (3h/day from postnatal day 2-12). Faecal samples were collected before weaning for gut microbiota 16S rRNA sequencing and metabolomic analysis. Visceral pain sensitivity and negative valence behaviours were assessed in adulthood using colorectal distension and the forced swim test respectively. Behavioural data were processed in a two-step cluster analysis to identify groupings within the dataset. Multi-omics analysis was carried out to investigate if the microbial signatures following early life stress were already defined according to the membership of the adult behavioural phenotypes., Results: Maternal separation resulted in increased visceral hypersensitivity while showing a trend for a sex-dependent increase in negative valence behaviour in adulthood. The cluster analysis revealed four clusters within the dataset representing distinct pathophysiological domains reminiscent of the behavioural consequences of early-life stress: 1. resilient, 2. pain, 3. immobile and 4. comorbid. The early life gut microbiota of each of these clusters show distinct alterations in terms of diversity, genus level differential abundance, and functional modules. Multi-omic integrations points towards a role for different metabolic pathways underlying each cluster-specific phenotype., Conclusion: Our study is the first to identify distinct phenotypes defined by susceptibility or resilience to gut-brain dysfunction induced by early life stress. The gut microbiota in early life shows sex-dependent alterations in each cluster that precede specific behavioural phenotypes in adulthood. Future research is warranted to determine the causal relationship between early-life stress-induced changes in the gut microbiota and to understand the trajectory leading to the manifestation of different behavioural phenotypes in adulthood., Competing Interests: 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. SMO’M has received funding from 10.13039/100006628Mead Johnson. JFC has spoken at conferences organised by Mead Johnson, Ordesa, and Yakult and has received research funding from Reckitt, Nutricia, Dupont/IFF, and Nestle. G.C. received honoraria from Janssen, Probi, and Apsen and research funding from Pharmavite and 10.13039/501100003144Fonterra and is a paid consultant for Yakult and Zentiva., (© 2024 The Authors.)

Stress and circadian systems are interconnected through the hypothalamic-pituitary-adrenal (HPA) axis to maintain responses to external stimuli. Yet, the mechanisms of how such signals are orchestrated remain unknown. Here, we uncover the gut microbiota as a regulator of HPA-axis rhythmicity. Microbial depletion disturbs the brain transcriptome and metabolome in stress-responding pathways in the hippocampus and amygdala across the day. This is coupled with a dysregulation of the circadian pacemaker in the brain that results in perturbed glucocorticoid rhythmicity. The resulting hyper-activation of the HPA axis at the sleep/wake transition drives time-of-day-specific impairments of the stress response and stress-sensitive behaviors. Finally, microbiota transplantation confirmed that diurnal oscillations of gut microbes underlie altered glucocorticoid secretion and that L. reuteri is a candidate strain for such effects. Our data offer compelling evidence that the microbiota regulates stress responsiveness in a circadian manner and is necessary to respond adaptively to stressors throughout the day., Competing Interests: Declaration of interests J.F.C. has been an invited speaker at conferences organized by Bromotech and Nestle and has received research funding from Nutricia, Dupont/IFF, and Nestle. G.C. has received honoraria from Janssen, Probi, and Apsen as an invited speaker; is in receipt of research funding from Pharmavite, Fonterra, Reckitt, Nestle, Tate, and Lyle; and is a paid consultant for Yakult, Zentiva, and Heel Pharmaceuticals. This support neither influenced nor constrained the contents of this article., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Red cell concentrates (RCCs) may be cryopreserved at Canadian Blood Services (CBS) for up to 10 years; however, inadvertent warming of these units over the prescribed storage temperature (≤ -65°C) may occur. These units may be discarded from inventory to avoid potential adverse transfusion outcomes. This study aimed to assess the quality of RCCs that experienced unintentional transient warming events (TWEs) related to freezer failures., Study Design: Thirty cryopreserved RCCs with known TWEs were selected for this study and classified into three different experimental groups (Event 1 (n = 5) TWE > -65°C for 34 min; Event 2 (n = 23) TWE > -65°C for 48 h; and both Event 1 and Event 2 (n = 2) TWE > -65°C for 34 min and 48 h). Ten additional RCCs with no known TWEs, cryopreserved over the same period, were selected as controls. Thawed RCCs were deglycerolized using the Haemonetics ACP 215, and in vitro quality was assessed throughout hypothermic storage., Results: RCCs from the control and all three experimental groups met the Canadian Standards Association (CSA) guidelines for hematocrit, total hemoglobin, and hemolysis at expiry. RCCs experiencing a singular TWE had similar in vitro quality to control RCCs., Discussion: This study's findings revealed that single exposures to specific documented TWEs did not significantly impact the quality of RCCs post-deglycerolization. While units should still be assessed on a case-by-case basis upon TWE, our work provides the first-ever evidence that supports a broader policy of unit retention by blood centers., (© 2024 The Author(s). Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Anti-KEL1 antigen (also referred to as anti-Kell, or anti-K) alloimmunisation is the second most common cause of severe haemolytic disease of the fetus and newborn, after anti-rhesus D antigen, and can cause substantial fetal morbidity and mortality. Both fetal erythropoietic suppression and haemolysis contribute to anaemia. Typically, once a clinically significant alloantibody is identified during pregnancy, antibody titration is performed as a screening test to predict the risk of anaemia and the need for maternal-fetal medicine referral. The titre is a semiquantitative laboratory method based on the underlying principle that increased maternal antibody concentrations are associated with an increased risk of fetal anaemia. Because some studies report that anti-K alloantibodies can lead to severe anaemia even at a low antibody titration, guidelines are inconsistent with respect to the role of titration testing. Some experts recommend maternal-fetal medicine referral and middle cerebral artery Doppler ultrasound without titration testing or with the use of a very low cutoff titre. This Viewpoint evaluates management for pregnancies affected by anti-K alloantibodies and highlights literature regarding the predictive value of anti-K titration testing., Competing Interests: Declaration of interests GC is a medical advisor to Perinatal Screening Ontario and has received travel support to international congresses from the International Society for Blood Transfusion. GC is the Secretary General for the International Society for Blood Transfusion. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Visceral hypersensitivity, a hallmark of disorders of the gut-brain axis, is associated with exposure to early-life stress (ELS). Activation of neuronal β3-adrenoceptors (AR) has been shown to alter central and peripheral levels of tryptophan and reduce visceral hypersensitivity. In this study, we aimed to determine the potential of a β3-AR agonist in reducing ELS-induced visceral hypersensitivity and possible underlying mechanisms. Here, ELS was induced using the maternal separation (MS) model, where Sprague Dawley rat pups were separated from their mother in early life (postnatal day 2-12). Visceral hypersensitivity was confirmed in adult offspring using colorectal distension (CRD). CL-316243, a β3-AR agonist, was administered to determine anti-nociceptive effects against CRD. Distension-induced enteric neuronal activation as well as colonic secretomotor function were assessed. Tryptophan metabolism was determined both centrally and peripherally. For the first time, we showed that CL-316243 significantly ameliorated MS-induced visceral hypersensitivity. Furthermore, MS altered plasma tryptophan metabolism and colonic adrenergic tone, while CL-316243 reduced both central and peripheral levels of tryptophan and affected secretomotor activity in the presence of tetrodotoxin. This study supports the beneficial role of CL-316243 in reducing ELS-induced visceral hypersensitivity, and suggests that targeting the β3-AR can significantly influence gut-brain axis activity through modulation of enteric neuronal activation, tryptophan metabolism, and colonic secretomotor activity which may synergistically contribute to offsetting the effects of ELS., (© 2023 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

The ability to manipulate brain function through the communication between the microorganisms in the gastrointestinal tract and the brain along the gut-brain axis has emerged as a potential option to improve cognitive and emotional health. Dietary composition and patterns have demonstrated a robust capacity to modulate the microbiota-gut-brain axis. With their potential to possess pre-, pro-, post-, and synbiotic properties, dietary fibre and fermented foods stand out as potent shapers of the gut microbiota and subsequent signalling to the brain. Despite this potential, few studies have directly examined the mechanisms that might explain the beneficial action of dietary fibre and fermented foods on the microbiota-gut-brain axis, thus limiting insight and treatments for brain dysfunction. Herein, we evaluate the differential effects of dietary fibre and fermented foods from whole food sources on cognitive and emotional functioning. Potential mediating effects of dietary fibre and fermented foods on brain health via the microbiota-gut-brain axis are described. Although more multimodal research that combines psychological assessments and biological sampling to compare each food type is needed, the evidence accumulated to date suggests that dietary fibre, fermented foods, and/or their combination within a psychobiotic diet can be a cost-effective and convenient approach to improve cognitive and emotional functioning across the lifespan.

Background: Normothermic machine perfusion of donor livers has become standard practice in the field of transplantation, allowing the assessment of organs and safe extension of preservation times. Alongside its clinical uses, there has been expanding interest in extended normothermic machine perfusion (eNMP) of livers as a potential vehicle for medical research. Reproducible extended normothermic machine perfusion has remained elusive due to its increased complexity and monitoring requirements. We set out to develop a reproducible protocol for the extended normothermic machine perfusion of whole human livers., Methods: Human livers declined for transplantation were perfused using a blood-based perfusate at 36 °C using the Liver Assist device (XVIVO, Sweden), with continuous veno-venous haemofiltration in-parallel. We developed the protocol in a stepwise fashion., Results: Perfusion techniques utilised included: targeted physiological vascular flows, phosphate replacement (to prevent hypophosphataemia), N-acetylcysteine (to prevent methaemoglobin accumulation), and the utilisation of sodium lactate as both a nutritional source and real-time measure of hepatocyte function. All five human livers perfused with the developed protocol showed preserved function with a median perfusion time of 168 h (range 120-184 h), with preserved viability throughout., Conclusions: Livers can be reproducibly perfused in excess of 120 (range 121-184) hours with evidence of preserved hepatocyte and cholangiocyte function., (© 2024. The Author(s).)

We examined the effect of increased plasma ketones on left ventricular (LV) function, myocardial glucose uptake (MGU), and myocardial blood flow (MBF) in type 2 diabetes (T2DM) patients with heart failure (HF). Three groups (I,II,III) of T2DM (12 per group) with LV ejection fraction ≤50% received incremental infusions of β-OH-B for 3-6 hours to raise plasma β-OH-B concentration throughout the physiologic (Groups I and II) and pharmacologic (Group III) range. Cardiac MRI was performed at baseline and after each β-OH-B infusion to provide measures of cardiac function. On a separate day, Group II also received NaHCO3 infusion, thus serving as their own control for time, volume, and pH. Additionally, Group II underwent positron emission tomography study with 18F-fluoro-2-deoxyglucose to examine effect of hyperketonemia on MGU. Groups I, II, III achieved plasma β-OH-B levels of 0.7±0.3, 1.6±0.2, 3.2±0.2 mmol/L, respectively. Cardiac output, LVEF, and stroke volume increased significantly during β-OH-B infusion in Groups II (CO, 4.54 to 5.30; EF, 39.9 to 43.8; SV, 70.3 to 80.0) and III (CO, 5.93 to 7.16; EF, 41.1 to 47.5; SV, 89.0 to 108.4) and did not change with NaHCO3 infusion in Group II. The increase in LVEF was greatest in Group III (p<0.001 vs Group II). MGU and MBF were not altered by β-OH-B. In T2DM patients with LVEF≤50%, increased plasma β-OH-B significantly increased LV function dose-dependently. Since MGU did not change, the myocardial benefit of β-OH-B resulted from providing an additional fuel for the heart without inhibiting MGU., (© 2024 by the American Diabetes Association.)

Human microbiomes are essential to health throughout the lifespan and are increasingly recognized and studied for their roles in metabolic, immunological and neurological processes. Although the full complexity of these microbial communities is not fully understood, their clinical and industrial exploitation is well advanced and expanding, needing greater oversight guided by a consensus from the research community. One of the most controversial issues in microbiome research is the definition of a 'healthy' human microbiome. This concept is complicated by the microbial variability over different spatial and temporal scales along with the challenge of applying a unified definition to the spectrum of healthy microbiome configurations. In this Perspective, we examine the progress made and the key gaps that remain to be addressed to fully harness the benefits of the human microbiome. We propose a road map to expand our knowledge of the microbiome-health relationship, incorporating epidemiological approaches informed by the unique ecological characteristics of these communities., (© 2024. Springer Nature Limited.)

Objectives: In experimental models, the prenatal diet influences gut microbiota composition in mothers and offspring; however, it is unclear whether this occurs in humans. We investigated the effects of a gut-focused perinatal dietary intervention on maternal and infant gut microbiota composition four weeks after birth., Methods: This randomised controlled trial randomised pregnant women to receive dietary advice as part of standard care, or additionally receive a dietary intervention focused on the Australian Dietary Guidelines and increasing prebiotic and probiotic/fermented food intakes (ACTRN12616000936426). Study assessments occurred from gestation week 26 (baseline) to four weeks postpartum (follow-up). Faecal samples, collected at baseline for mothers, and follow-up for mothers and infants, underwent 16SrRNA sequencing. The primary outcome was a between-group mean difference in infant faecal Shannon index. Secondary outcomes included between-group differences in other microbiota measures, including maternal change from baseline CLR-transformed Prevotella abundance., Results: Forty-four women and 45 infants completed the study. The mean Shannon index of infants in the intervention group was -0.35 (95% CI: -0.64, -0.06, SD: 0.52) units lower than control group infants, corresponding to a medium effect size (Cohen's D: -0.74, 95% CI: -1.34, -0.13). The findings were similar using other metrics of α-diversity. There were no between-group differences in β-diversity, nor any differentially abundant taxa in infants. The intervention increased abundances of the genus Prevotella in mothers compared to controls., Discussion: This gut-focused perinatal dietary intervention was associated with differences in the maternal and infant gut microbiota composition. Larger studies are required to replicate and extend these findings.

Lactiplantibacillus plantarum is a commensal bacterial species often found within the human gut. To expand our knowledge about this human-associated taxon with potential probiotic properties, here we present the draft genome sequence of Lactiplantibacillus plantarum strain APC2688, isolated from a human fecal sample.

Since the 1980s, fish farming (aquaculture) has been an important contributor to Scotland's economy, but there are concerns that nutrient-rich food waste and excreta from these farms are causing eutrophication. Water quality monitoring preceding the arrival and subsequent expansion of the industry is limited. Therefore, to better understand the impacts of in-lake fish farms on the quality of freshwater ecosystems, we examined the diatom records in sediment cores from seven freshwater lochs in Scotland over a timescale of c.100-200 years, spanning the period before and after installation of the fish cages at these sites. At three lochs (A, C, E) we observed marked diatom assemblage shifts indicative of eutrophication, coincident with arrival of the fish farms, at two lochs (B, G) there was evidence of enrichment over a longer timescale although with some further enrichment occurring with the advent of the fish farms, and at the other two lochs (D, F), diatom shifts were subtle and showed no sign of eutrophication. Thus, while marked ecological shifts are shown to occur with the arrival of fish farms in some sites, this is not always the case. The natural background conditions, the scale of operations, the siting of the fish cages in relation to location of inflows and outflows, the role of flushing rate and additional sources of nutrients are discussed as potential factors for the variable impacts observed across the seven lochs. Such factors should be considered when planning future installation and expansion of fish farms to ensure sustainable development of these resources. Our study provides an understanding of baseline conditions and long-term water quality trajectories in freshwater lakes with fish farms and demonstrates the value of paleolimnology in supporting management decisions with respect to fisheries., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Helen Bennion reports financial support was provided by Marine Harvest Limited. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Red cell concentrate (RCC) cryopreservation allows for long-term storage of RCCs with rare phenotypes. Currently, tubing segments are not produced for these frozen units. Pre-transfusion compatibility testing therefore requires thawing and deglycerolization of the whole unit. A study was conducted to demonstrate the feasibility of using segments for compatibility testing, including circumstances where segments would require shipment to a reference laboratory. Study Design and Methods: RCCs produced using the red cell filtration method from citrate-phosphate-dextrose whole blood collections were glycerolized (40%) at day 21 post-collection and segments were generated prior to freezing. Room temperature (RT, 18°C-20°C) or water bath (WB, 37°C) thawing of segments was performed prior to storage at RT or at refrigerated temperatures (cold, 1°C -6°C) for 0, 24, 48, or 72 hours followed by deglycerolization and hemolysis testing. Additional segments were thawed and shipped in temperature-controlled containers at either RT or 1°C -10°C for antibody screening. Results: Hemolysis and RBC recovery results did not show significant differences over the storage period or between thawing and storage conditions. RBC recovery ranged from 46% to 64%. Hemoglobin (Hb) recovery ranged from 56% to 96%; for RT-thawed segments, recovery was significantly higher at 24 hours and lower at 72 hours for RT storage compared with cold storage. WB-thawed, cold-stored segments had higher Hb recoveries at 48 hours. Phenotype assessment was successful for all segments regardless of thawing method or shipping condition. Discussion: The shipment of thawed segments containing glycerolized red cells is feasible for the purpose of conducting pretransfusion phenotype evaluations or pretransfusion compatibility checks.

Objective: Safety planning for suicide prevention is an important quality metric for Zero Suicide implementation. We describe the development, validation, and application of electronic health record (EHR) programs to measure uptake of safety planning practices across six integrated healthcare systems as part of a Zero Suicide evaluation study., Methods: Safety planning was documented in narrative notes and structured EHR templates using the Stanley Brown Safety Planning Intervention (SBSPI) in response to a high-risk cutoff score on the Columbia Suicide Severity Rating Scale (CSSRS). Natural Language Processing (NLP) metrics were developed and validated using chart review to characterize practices documented in narrative notes. We applied NLP to measure frequency of documentation in the narrative text and standard programming methods to examine structured SBSPI templates from 2010-2022., Results: Chart reviews found three safety planning practices documented in narrative notes that were delivered to at least half of patients at risk: professional contacts, lethal means counseling for firearms, and lethal means counseling for medication access/storage. NLP methods were developed to identify these practices in clinical text with high levels of accuracy (Sensitivity, Specificity, & PPV ≥ 82%). Among visits with a high-risk CSSRS, 40% (Range 2-73% by health system) had an SBSPI template within 1 year of implementation., Conclusions: This is one of the first reports describing development of measures that leverage electronic health records to track use of suicide prevention safety plans. There are opportunities to use the methods developed here in future evaluations of safety planning.

Introduction: In light of the COVID-19 (Coronovirus Disease 2019) pandemic, the use of personal protective equipment has become essential to reduce viral transmission and maintain public health. Viruses, particularly human coronavirus and influenza, pose significant challenges because of their various transmission routes. UMF Corporation's innovation, Micrillon, aims to address these challenges by creating durable, antiviral technology for textiles without harmful chemicals, reducing viral transmission risks., Materials and Methods: The study followed ISO Standard 18184:2019, testing Micrillon textiles against Human Coronavirus OC43 and H1N1 Influenza A virus using MDCK and HCT-8 cell lines. Cell propagation, viral application, TCID50 (Median Tissue Culture Infectious Dose) testing, and maintenance protocols were rigorously implemented to assess antiviral efficacy., Results: Micrillon gloves, fabrics, and fibers exhibited high antiviral efficacy against both viruses across various contact times. Gloves demonstrated exceptional antiviral activity against H1N1 (99.88%) and OC43 (99.67%) at 120 minutes. Rolled fabrics showed strong efficacy against H1N1 (99.42% at 30 minutes) and OC43 (>97%) at all time points. Bundled fibers displayed substantial efficacy against H1N1 (99.17% at 120 minutes) and OC43 (>98%) at all time points., Conclusions: The study demonstrates that Micrillon technology effectively inhibits viral activity, particularly in gloves, fabrics, and fibers. The innovation not only shows high antiviral efficacy against both Human Coronavirus and Influenza but also promises a reusable, sustainable solution, mitigating environmental impact and reducing the use of harmful chemicals in personal protective equipment. The technology holds promise for widespread use in health care and hospitality, offering a layer of protection while being environmentally conscious. Further development of such technologies can significantly reduce infection risks while minimizing environmental harm., (© The Association of Military Surgeons of the United States 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Background: Inequities in palliative and end-of-life care access exist, with evidence of lower uptake of these services among people from the British Muslim community. Little research exists exploring the experiences of British Muslims with palliative care needs and their families during the pandemic or before., Aim: To coproduce peer research exploring the experiences of British Muslims with palliative care needs and their families during the COVID-19 pandemic., Design: A collaborative peer research interview study. Peer researchers were recruited and trained to undertake qualitative interviewing. Data were analysed using reflective thematic analysis., Setting/participants: 3 peer researchers conducted 11 telephone interviews (10 in English and 1 in Urdu) between August and September 2021 with 12 participants (5 people with palliative care needs and 7 family carers)., Results: Four themes were identified: (1) issues in accessing healthcare exacerbated by the COVID-19 pandemic, (2) the impact on family carers, (3) variation in support from community groups and (4) social and information exclusion. The COVID-19 pandemic exacerbated existing challenges to accessing healthcare services for British Muslims with palliative care needs. Family members experienced the cumulative impact of supporting people with palliative needs while also advocating for and supporting them to access the care they required. Language barriers, digital exclusion and uncertainly about how to access information, in addition to the apparent lack of consideration of important festivals in the Muslim calendar in the implementation of policies around lockdowns, culminated in a sense of exclusion from COVID-19-related policies and messaging for this population., Conclusions: These findings support the need to involve people from diverse backgrounds in the design and delivery of healthcare services and policies. Learning from this unique time in our histories should be used to shape future delivery of culturally aware and inclusive care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The prevalence of brain disorders, including stress-related neuropsychiatric disorders and conditions with cognitive dysfunction, is rising. Poor dietary habits contribute substantially to this accelerating trend. Conversely, healthy dietary intake supports mood and cognitive performance. Recently, the communication between the microorganisms within the gastrointestinal tract and the brain along the gut-brain axis has gained prominence as a potential tractable target to modulate brain health. The composition and function of the gut microbiota is robustly influenced by dietary factors to alter gut-brain signalling. To reflect this interconnection between diet, gut microbiota and brain functioning, we propose that a diet-microbiota-gut-brain axis exists that underpins health and well-being. In this Review, we provide a comprehensive overview of the interplay between diet and gut microbiota composition and function and the implications for cognition and emotional functioning. Important diet-induced effects on the gut microbiota for the development, prevention and maintenance of neuropsychiatric disorders are described. The diet-microbiota-gut-brain axis represents an uncharted frontier for brain health diagnostics and therapeutics across the lifespan., (© 2024. Springer Nature Limited.)

Eating behaviour and circadian rhythms are closely related. The type, timing, and quantity of food consumed, and host circadian rhythms, directly influence the intestinal microbiota, which in turn impacts host circadian rhythms and regulates food intake beyond homeostatic eating. This Opinion discusses the impact of food intake and circadian disruptions induced by an obesogenic environment on gut-brain axis signalling. We also explore potential mechanisms underlying the effects of altered gut microbiota on food intake behaviour and circadian rhythmicity. Understanding the crosstalk between gut microbiota, circadian rhythms, and unhealthy eating behaviour is crucial to addressing the obesity epidemic, which remains one of the biggest societal challenges of our time., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The human gut microbiome can be impacted by a range of environmental and lifestyle factors including diet, antibiotics, physical fitness and acute and chronic stressors. There is also evidence to suggest that specific compositional and/or functional features of the gut microbiome are mediators of aspects of health and performance including disease susceptibility, cognitive and physical states and the immune response. Therefore, understanding microbe-to-microbe and nutrient-to-microbe interactions in the gut and how they interact with host biology (eg, via the gut-brain axis) could enable better design of interventions aimed at modulating the gut microbiome to improve the health and performance of the military. Accordingly, this review summarises a thematic session hosted at the 6th International Conference on Soldier Physical Performance which provided an overview of military-relevant research related to the gut microbiome. It articulates a timely opportunity to leverage this rapidly advancing area to improve personnel health and military performance., Competing Interests: Competing interests: GC has received honoraria from Janssen, Probi and Apsen as an invited speaker, is in receipt of research funding from Pharmavite, Reckitt, Tate and Lyle, Nestle and Fonterra and has received payments as a consultant from Yakult, Zentiva and Heel Pharmaceuticals. This support neither influenced nor constrained the content of this article. All other authors have no competing interests to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Prenatal maternal stressors ranging in severity from everyday occurrences/hassles to the experience of traumatic events negatively impact neurodevelopment, increasing the risk for the onset of psychopathology in the offspring. Notably, the timing of prenatal stress exposure plays a critical role in determining the nature and severity of subsequent neurodevelopmental outcomes. In this review, we evaluate the empirical evidence regarding temporal windows of heightened vulnerability to prenatal stress with respect to motor, cognitive, language, and behavioural development in both human and animal studies. We also explore potential temporal windows whereby several mechanisms may mediate prenatal stress-induced neurodevelopmental effects, namely, excessive hypothalamic-pituitary-adrenal axis activity, altered serotonin signalling and sympathetic-adrenal-medullary system, changes in placental function, immune system dysregulation, and alterations of the gut microbiota. While broadly defined developmental windows are apparent for specific psychopathological outcomes, inconsistencies arise when more complex cognitive and behavioural outcomes are considered. Novel approaches to track molecular markers reflective of the underlying aetiologies throughout gestation to identify tractable biomolecular signatures corresponding to critical vulnerability periods are urgently required., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: The authors measured implementation of Zero Suicide (ZS) clinical practices that support identification of suicide risk and risk mitigation, including screening, risk assessment, and lethal means counseling, across mental health specialty and primary care settings., Methods: Six health care systems in California, Colorado, Michigan, Oregon, and Washington participated. The sample included members ages ≥13 years from 2010 to 2019 (N=7,820,524 patients). The proportions of patients with suicidal ideation screening, suicide risk assessment, and lethal means counseling were estimated., Results: In 2019, patients were screened for suicidal ideation in 27.1% (range 5.0%-85.0%) of mental health visits and 2.5% (range 0.1%-35.0%) of primary care visits among a racially and ethnically diverse sample (44.9% White, 27.2% Hispanic, 13.4% Asian, and 7.7% Black). More patients screened positive for suicidal ideation in the mental health setting (10.2%) than in the primary care setting (3.8%). Of the patients screening positive for suicidal ideation in the mental health setting, 76.8% received a risk assessment, and 82.4% of those identified as being at high risk received lethal means counseling, compared with 43.2% and 82.4%, respectively, in primary care., Conclusions: Six health systems that implemented ZS showed a high level of variation in the proportions of patients receiving suicide screening and risk assessment and lethal means counseling. Two opportunities emerged for further study to increase frequency of these practices: expanding screening beyond patients with regular health care visits and implementing risk assessment with lethal means counseling in the primary care setting directly after a positive suicidal ideation screening., Competing Interests: The authors report no financial relationships with commercial interests.

Background: Women who are over 50 years are drinking alcohol in higher quantities and more frequently than in previous decades. Good engagement with primary care is crucial for women's physical and psychological health, particularly if they use alcohol. However, there is little known about the alcohol use of women over 50 and their use of primary care., Methods: A systematic search was conducted on six databases; CINAHL, Medline, PsycINFO, Academic Search Complete, EMBASE and Web of Science to identify literature on primary health care engagement of women 50 years and older (50+) who use alcohol. Titles and abstracts were reviewed and full texts were independently reviewed by two researchers. A narrative review, critical appraisal and synthesis of the eligible studies produced common themes and key findings., Results: After excluding 3822 articles, 13 articles were deemed eligible for the review. For this age group (50+), findings were: 1) women who drink heavily were less likely than men to attend General Practitioners (GPs), moderate drinkers were more likely than abstainers to attend mammogram screening, 2) GPs were less likely to ask questions or discuss alcohol with women than with men, 3) GPs offered less advice on alcohol to women than to men, and 4) less women than men received alcohol screening from their GP., Discussion: While women 50+ are drinking more, their alcohol use is underreported and insufficiently provided for in primary health. As women's life expectancy increases, improved GP engagement will benefit women's health and reduce future healthcare costs.

Background: Platelet inventory constraints necessitate ABO-incompatible platelet transfusion. Many minimize the hemolytic impact by confirming low titre (LT) donor isohemagglutinins. This process is costly. Pathogen-reduced platelets (PRP) in platelet additive solutions (PAS) will dilute plasma and decrease high-titre isohemagglutinins (HT). We determined the proportion of HT platelets and incompatible transfusions for units suspended in plasma to reassess the need for titres following introduction of PRP/PAS., Study Design and Methods: Our titre method is manual tube (1:50) dilution of platelet supernatant from apheresis or whole blood derived buffy coat pools suspended in plasma, tested with A1/B red cells. Testing included 49,058 pooled and 11,738 apheresis platelets over 4 years. The HT proportion, rate of out-of-group transfusions, and hemolytic reactions were determined. The impact of PAS dilution was estimated., Results: Totally 60,796 platelet units were tested. Group O pooled and group B apheresis platelets had HT in 6.6% and 5.7%, respectively. Group A pooled and apheresis platelets included 2% with HT. Approximately 25% of platelets transfused were ABO-incompatible and no hemolytic reactions were reported. Based on the proportions of PAS-E and plasma for PRP platelets, plasma from each donor comprises 11 mL (6% of total volume) vs 20-257 mL in untreated pools. PAS-E will replace and dilute residual plasma by at least 50%., Discussion: Rare platelet pools may demonstrate HT. PRP platelets with PAS will reduce titres and may abrogate the need for titration. A strategy of group specific transfusion or transfusion of group A PRP platelet transfusions may be a safe alternative., (© 2024 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Aim: To assess patient socio-demographic and disease characteristics associated with the initiation, timing, and completion of emergency care and treatment planning in a large UK-based hospital trust., Methods: Secondary retrospective analysis of data across 32 months extracted from digitally stored Recommended Summary Plan for Emergency Care and Treatment (ReSPECT) plans within the electronic health record system of an acute hospital trust in England, UK., Results: Data analysed from ReSPECT plans (n = 23,729), indicate an increase in the proportion of admissions having a plan created from 4.2% in January 2019 to 6.9% in August 2021 (mean = 8.1%). Forms were completed a median of 41 days before death (a median of 58 days for patients with capacity, and 21 days for patients without capacity). Do not attempt cardiopulmonary resuscitation was more likely to be recorded for patients lacking capacity, with increasing age (notably for patients aged over 74 years), being female and the presence of multiple disease groups. 'Do not attempt cardiopulmonary resuscitation' was less likely to be recorded for patients having ethnicity recorded as Asian or Asian British and Black or Black British compared to White. Having a preferred place of death recorded as 'hospital' led to a five-fold increase in the likelihood of dying in hospital., Conclusion: Variation in the initiation, timing, and completion of ReSPECT plans was identified by applying an evaluation framework. Digital storage of ReSPECT plan data presents opportunities for assessing trends and completion of the ReSPECT planning process and benchmarking across sites. Further research is required to monitor and understand any inequity in the implementation of the ReSPECT process in routine care., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The current study estimated effects of intervention dose (attendance) of a cognitive behavioral prevention (CBP) program on depression-free days (DFD) in adolescent offspring of parents with a history of depression. As part of secondary analyses of a multi-site randomized controlled trial, we analyzed the complete intention-to-treat sample of 316 at-risk adolescents ages 13-17. Youth were randomly assigned to the CBP program plus usual care (n=159) or to usual care alone (n=157). The CBP program involved 8 weekly acute sessions and 6 monthly continuation sessions. Results showed that higher CBP program dose predicted more DFDs, with a key threshold of approximately 75% of a full dose in analyses employing instrumental variable methodology to control multiple channels of bias. Specifically, attending at more than 75% of acute phase sessions led to 45.3 more DFDs over the 9-month period post randomization, which accounted for over 12% of the total follow-up days. Instrument sets were informed by study variables and external data including weather and travel burden. In contrast, conventional analysis methods failed to find a significant dose-outcome relation. Application of the instrumental variable approach, which better controls the influence of confounding, demonstrated that higher CBP program dose resulted in more DFDs., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Red blood cell (RBC) transfusion is a critical therapy for those with sickle cell disease (SCD). Alloimmunization is frequent for those with SCD and may limit the availability of matched RBC. Cryopreserved RBCs, from family members or donors with a similar RBC antigen profile could provide a viable alternative to avoid further alloimmunization and prevent hemolytic transfusion-related events. However, cryopreserved SCD and Sickle Cell trait (S-trait) donor RBC units suffer from reduced recovery following deglycerolization. This study proposes and tests a modified deglycerolization protocol using an automated cell processor to mitigate RBC loss. Six red cell concentrates (RCC) from donors with S-trait and six control RCCs were glycerolized, frozen (<-65 °C) and deglycerolized on the ACP 215 using modified parameters (decreased hypertonic solution flow rate (100 mL/min) and hypertonic equilibration delay (120 s), and increased NaCl dilution volumes (500 mL). Quality testing included: hematocrit (HCT), hemolysis, indices, extracellular potassium, morphology, osmotic fragility, osmotic gradient ektacytometry, hemoglobin (HGB), and recovery. Canadian standards (CS) indicate that acceptable deglycerolized units for transfusion require a HCT ≤0.80 L/L, HGB ≥35 g/unit, and hemolysis <0.8 % in 90 % of units tested. No significant differences in HGB or RBC recovery were observed between study groups. Significant differences between study groups were identified in osmotic fragility and osmotic gradient ektacytometry parameters. Of the 6 S-trait RCCs, 3/6 units were within the HCT, HGB and hemolysis thresholds set by the CS. The modified deglycerolization protocol provides a path for the routine cryopreservation of S-trait RBCs., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The group and screen (G&S) are performed in early pregnancy to identify clinically significant antibodies (CSA) that may necessitate fetal monitoring for hemolysis/anemia or affect RhIg eligibility. Guidelines vary, including differences between RhD-positive and negative patients, but typically, the G&S is repeated at 28 weeks, and sometimes pre-delivery. We reviewed data showing a low risk (0.01%-0.43%) of detecting a new CSA in late gestation (late alloimmunization) and the risk of late alloimmunization causing severe hemolysis/anemia is even lower at <0.01%. Routinely repeating a G&S at 28 weeks and delivery may not be necessary for healthy, low-risk pregnancies., (Copyright © 2024 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Chronic stress disrupts microbiota-gut-brain axis function and is associated with altered tryptophan metabolism, impaired gut barrier function, and disrupted diurnal rhythms. However, little is known about the effects of acute stress on the gut and how it is influenced by diurnal physiology. Here, we used germ-free and antibiotic-depleted mice to understand how microbiota-dependent oscillations in tryptophan metabolism would alter gut barrier function at baseline and in response to an acute stressor. Cecal metabolomics identified tryptophan metabolism as most responsive to a 15-min acute stressor, while shotgun metagenomics revealed that most bacterial species exhibiting rhythmicity metabolize tryptophan. Our findings highlight that the gastrointestinal response to acute stress is dependent on the time of day and the microbiome, with a signature of stress-induced functional alterations in the ileum and altered tryptophan metabolism in the colon., Competing Interests: Declaration of interests J.F.C. has spoken at conferences organized by Mead Johnson, Ordesa, and Yakult and has received research funding from Reckitt, Nutricia, Dupont/IFF, and Nestle. G.C. received honoraria from Janssen, Probi, and Apsen and research funding from Pharmavite and Fonterra and is a paid consultant for Yakult and Zentiva. This support did not influence or constrain this preview. The authors’ views do not reflect the official guidance or position of the United States Government, the Department of Defense, or the United States Air Force. Approved for public release; distribution is unlimited. Case no. AFRL-2022-5638, December 2, 2022., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: This guideline provides recommendations for the prevention of Rh D alloimmunization (isoimmunization) in pregnancy, including parental testing, routine postpartum and antepartum prophylaxis, and other clinical indications for prophylaxis. Prevention of red cell alloimmunization in pregnancy with atypical antigens (other than the D antigen), for which immunoprophylaxis is not currently available, is not addressed in this guideline., Target Population: All Rh D-negative pregnant individuals at risk for Rh D alloimmunization due to potential exposure to a paternally derived fetal Rh D antigen., Outcomes: Routine postpartum and antepartum Rh D immunoprophylaxis reduces the risk of Rh D alloimmunization at 6 months postpartum and in a subsequent pregnancy., Benefits, Harms, and Costs: This guideline details the population of pregnant individuals who may benefit from Rho(D) immune globulin (RhIG) immunoprophylaxis. Thus, those for whom the intervention is not required may avoid adverse effects, while those who are at risk of alloimmunization may mitigate this risk for themselves and/or their fetus., Evidence: For recommendations regarding use of RhIG, Medline and Medline in Process via Ovid and Embase Classic + Embase via Ovid were searched using both the trials and observational studies search strategies with study design filters. For trials, the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects via Ovid were also searched. All databases were searched from January 2000 to November 26, 2019. Studies published before 2000 were captured from the grey literature of national obstetrics and gynaecology specialty societies, luminary specialty journals, and bibliographic searching. A formal process for the systematic review was undertaken for this update, as described in the systematic review manuscript published separately., Validation Methods: The authors rated the quality of evidence and strength of recommendations using the SOGC's modified GRADE approach. See Appendix A (Tables A1 for definitions and A2 for interpretations of strong and conditional [weak] recommendations)., Intended Audience: The intended users of this guideline include prenatal care providers such as obstetricians, midwives, family physicians, emergency room physicians, and residents, as well as registered nurses and nurse practitioners., Tweetable Abstract: An updated Canadian guideline for prevention of Rh D alloimmunization addresses D variants, cffDNA for fetal Rh type, and updates recommendations on timing of RhIG administration., Summary Statements: RECOMMENDATIONS., (Copyright © 2024. Published by Elsevier Inc.)

Objective: The purpose of this study was to determine whether sleep characteristics are associated with incidence of treated diabetes in postmenopausal individuals., Methods: Postmenopausal participants ages 50-79 years reported sleep duration, sleep-disordered breathing, or insomnia at baseline and again in a subsample 3 years later. The primary outcome was self-reported new diagnosis of diabetes treated with oral drugs or insulin at any time after baseline. Multivariable Cox proportional hazards models were used., Results: In 135,964 participants followed for 18.1 (± 6.3) years, there was a nonlinear association between sleep duration and risk of treated diabetes. Participants sleeping ≤5 hours at baseline had a 21% increased risk of diabetes compared with those sleeping 7 hours (adjusted hazard ratio [aHR] 1.21; 95% confidence interval [CI], 1.00-1.47). Those who slept for ≥9 hours had a nonsignificant 6% increased risk of diabetes compared with those sleeping 7 hours (aHR 1.06; 95% CI, 0.97-1.16). Participants whose sleep duration had decreased at 3 years had a 9% (aHR 1.09; 95% CI, 1.02-1.16) higher risk of diabetes than participants with unchanged sleep duration. Participants who reported increased sleep duration at 3 years had a risk of diabetes (HR 1.01; 95% CI, 0.95-1.08) similar to those with no sleep duration change. Participants at high risk of sleep-disordered breathing at baseline had a 31% higher risk of diabetes than those without (aHR 1.31; 95% CI, 1.26-1.37). No association was found between self-reported insomnia score and diabetes risk., Conclusions: Sleep-disordered breathing and short or long sleep duration were associated with higher diabetes risk in a postmenopausal population., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Alzheimer's disease is a complex and progressive condition that affects essential neurological functions such as memory and reasoning. In the brain, neuronal loss, synaptic dysfunction, proteinopathy, neurofibrillary tangles, and neuroinflammation are the hallmarks of Alzheimer's disease pathophysiology. In addition, recent evidence has highlighted that microbes, whether commensal or pathogenic, also have the ability to interact with their host and to regulate its immune system, therefore participating in the exchanges that lead to peripheral inflammation and neuropathology. Because of this intimate relationship, bacteria, viruses, fungi, and protozoa have been implicated in the development of Alzheimer's disease. Here, we bring together current and most recent evidence of the role of microbes in Alzheimer's disease, raising burning questions that need to be addressed to guide therapeutic approaches and potential prophylactic strategies., (© 2024 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd.)

Objective: To examine the effect of empagliflozin on liver fat content in individuals with and without type 2 diabetes (T2D) and the relationship between the decrease in liver fat and other metabolic actions of empagliflozin., Research Design and Methods: Thirty individuals with T2D and 27 without were randomly assigned to receive in double-blind fashion empagliflozin or matching placebo (2:1 ratio) for 12 weeks. Participants underwent 75-g oral glucose tolerance testing and measurement of liver fat content with MRS before therapy and at study end. Hepatic glucose production before the start of therapy was measured with 3-3H-glucose., Results: Empagliflozin caused an absolute reduction of 2.39% ± 0.79% in liver fat content compared with an increase of 0.91% ± 0.64% in participants receiving placebo (P < 0.007 with ANOVA). The decrease in liver fat was comparable in both individuals with diabetes and those without (2.75% ± 0.81% and 1.93% ± 0.78%, respectively; P = NS). The decrease in hepatic fat content caused by empagliflozin was strongly correlated with baseline liver fat content (r = -0.62; P < 0.001), decrease in body weight (r = 0.53; P < 0.001), and improvement in insulin sensitivity (r = -0.51; P < 0.001) but was not related to the decrease in fasting plasma glucose or HbA1c or the increase in hepatic glucose production., Conclusions: Empagliflozin is effective in reducing liver fat content in individuals with and without T2D. The decrease in liver fat content is independent of the decrease in plasma glucose concentration and is strongly related to the decrease in body weight and improvement in insulin sensitivity., (© 2024 by the American Diabetes Association.)

The use of probiotics, prebiotics, synbiotics or fermented foods can modulate the gut-brain axis and constitute a potentially therapeutic intervention in psychiatric disorders. This systematic review aims to identify current evidence regarding these interventions in the treatment of patients with DSM/ICD psychiatric diagnoses. Forty-seven articles from 42 studies met the inclusion criteria. Risk of bias was assessed in all included studies. Major depression was the most studied disorder (n = 19 studies). Studies frequently focused on schizophrenia (n = 11) and bipolar disorder (n = 5) and there were limited studies in anorexia nervosa (n = 4), ADHD (n = 3), Tourette (n = 1), insomnia (n = 1), PTSD (n = 1) and generalized anxiety disorder (n = 1). Except in MDD, current evidence does not clarify the role of probiotics and prebiotics in the treatment of mental illness. Several studies point to an improvement in the immune and inflammatory profile (e.g. CRP, IL6), which may be a relevant mechanism of action of the therapeutic response identified in these studies. Future research should consider lifestyle and dietary habits of patients as possible confounders that may influence inter-individual treatment response., Competing Interests: Declaration of Competing Interest CR has received honoraria from Angelini and Italfarmaco. GC has received honoraria from Janssen, Probi and Apsen as an invited speaker, is in receipt of research funding from Pharmavite, Reckitt, Tate and Lyle, Nestle, and Fonterra, and has received payments as a consultant from Yakult, Zentiva and Heel Pharmaceuticals. VB-M has received honoraria from Angelini during the last 3 years. This did not influence or constrain the writing of the manuscript. All other authors have no competing interests to report., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Objectives: The practice regarding the selection and preparation of red blood cells (RBCs) for intrauterine transfusion (IUT) is variable reflecting historical practice and expert opinion rather than evidence-based recommendations. The aim of this survey was to assess Canadian hospital blood bank practice with respect to red cell IUT., Materials and Methods: A survey was sent to nine hospital laboratories known to perform red cell IUT. Questions regarding component selection, processing, foetal pre-transfusion testing, transfusion administration, documentation and traceability were assessed., Results: The median annual number of IUTs performed in Canada was 109 (interquartile range, 103-118). RBC selection criteria included allogeneic, Cytomegalovirus seronegative, irradiated, fresh units with most sites preferentially providing HbS negative, group O, RhD negative, Kell negative and units lacking the corresponding maternal antibody without extended matching to the maternal phenotype. Red cell processing varied with respect to target haematocrit, use of saline reconstitution (n = 4), use of an automated procedure for red cell concentration (n = 1) and incorporation of a wash step (n = 2). Foetal pre-transfusion testing uniformly included haemoglobin measurement, but additional serologic testing varied. A variety of strategies were used to link the IUT event to the neonate post-delivery, including the creation of a unique foetal blood bank identifier at three sites., Conclusion: This survey reviews current practice and highlights the need for standardized national guidelines regarding the selection and preparation of RBCs for IUT. This study has prompted a re-examination of priorities for RBC selection for IUT and highlighted strategies for transfusion traceability in this unique setting., (© 2023 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.)

Background: The gut microbiota has been extensively implicated in health and disease. The functional outputs of the gut microbiota, such as microbial metabolites, are considered particularly important in this regard. Significant associations exist between alterations in the relative abundance of specific microbial taxa and mental health disorders. Dietary fiber has the potential to alter gut microbiota composition and function, modifying bacterial enzymatic function and the production of metabolites. As many taxa of microorganisms have enzymes capable of producing or degrading neurochemicals i.e. neuroactive gut brain modules, new predictive tools can be applied to existing datasets such as those harvested from dietary fiber interventions. We endeavor to perform a systematic review in order to identify studies reporting compositional gut microbiota alterations after interventions with dietary fiber in healthy individuals. We aim to also extract from the selected studies publicly available microbial genomic sequence datasets for reanalysis with a consistent bioinformatics pipeline, with the ultimate intention of identifying altered gut brain modules following dietary fiber interventions., Methods: Interventional trials and randomized controlled studies that are originally published, including cross-over and non-crossover design and involving healthy adult humans will be included. A systematic search of PubMed/MEDLINE and EMBASE, two electronic databases, will be completed., Discussion: Various types of dietary fiber have an impact on the gut microbiota composition, with some promoting the growth of particular taxa while others are reduced in relative abundance. Our search focuses on the impact of this food component on the microbiota of healthy individuals. Compositional gut microbial changes have been reported and our review will compile and update these observations after reanalysis of their datasets with a consistent bioinformatic pipeline. From this it may be possible to predict more detailed functional consequences in terms of neuroactive gut brain modules, of the compositional alterations in gut microbial taxa., Competing Interests: Competing interests: JFC has been an invited speaker at conferences organized by Mead Johnson, Ordesa, and Yakult, and has received research funding from Reckitt, Nutricia, Dupont/IFF, and Nestle. GC has received honoraria from Janssen, Probi, and Apsen as an invited speaker; is in receipt of research funding from Pharmavite, Reckitt, Tate and Lyle, Nestle and Fonterra; and is a paid consultant for Yakult and Zentiva. This support neither influenced nor constrained the contents of this paper. DAL, BV, TB and AL declare no competing interests., (Copyright: © 2024 Lachmansingh DA et al.)

Social anxiety disorder (SAD) is a crippling psychiatric disorder characterized by intense fear or anxiety in social situations and their avoidance. However, the underlying biology of SAD is unclear and better treatments are needed. Recently, the gut microbiota has emerged as a key regulator of both brain and behaviour, especially those related to social function. Moreover, increasing data supports a role for immune function and oxytocin signalling in social responses. To investigate whether the gut microbiota plays a causal role in modulating behaviours relevant to SAD, we transplanted the microbiota from SAD patients, which was identified by 16S rRNA sequencing to be of a differential composition compared to healthy controls, to mice. Although the mice that received the SAD microbiota had normal behaviours across a battery of tests designed to assess depression and general anxiety-like behaviours, they had a specific heightened sensitivity to social fear, a model of SAD. This distinct heightened social fear response was coupled with changes in central and peripheral immune function and oxytocin expression in the bed nucleus of the stria terminalis. This work demonstrates an interkingdom basis for social fear responses and posits the microbiome as a potential therapeutic target for SAD., Competing Interests: Competing interests statement:The authors declare no competing interest.