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BackgroundObesity induces significant changes in lipid mediators, however, the extent to which these changes persist after weight loss has not been investigated.Subjects/methodsWe fed C57BL6 mice a high-fat diet to generate obesity and then switched the diet to a lower-fat diet to induce weight loss. We performed a comprehensive metabolic profiling of lipid mediators including oxylipins, endocannabinoids, sphingosines and ceramides in key metabolic tissues (including adipose, liver, muscle and hypothalamus) and plasma.ResultsWe found that changes induced by obesity were largely reversible in most metabolic tissues but the adipose tissue retained a persistent obese metabolic signature. Prostaglandin signaling was perturbed in the obese state and lasting increases in PGD2, and downstream metabolites 15-deoxy PGJ2 and delta-12-PGJ2 were observed after weight loss. Furthermore expression of the enzyme responsible for PGD2 synthesis (hematopoietic prostaglandin D synthase, HPGDS) was increased in obese adipose tissues and remained high after weight loss. We found that inhibition of HPGDS over the course of 5 days resulted in decreased food intake in mice. Increased HPGDS expression was also observed in human adipose tissues obtained from obese compared with lean individuals. We then measured circulating levels of PGD2 in obese patients before and after weight loss and found that while elevated relative to lean subjects, levels of this metabolite did not decrease after significant weight loss.ConclusionsThese results suggest that lasting changes in lipid mediators induced by obesity, still present after weight loss, may play a role in the biological drive to regain weight.

In 2023, Africa experienced 180 public health emergencies, of which 90% were infectious diseases and 75% were related to zoonotic diseases. Testing capacity for epidemic-prone diseases is essential to enable rapid and accurate identification of causative agents, and for action to prevent disease spread. Moreover, testing is pivotal in monitoring disease transmission, evaluating public health interventions and informing targeted resource allocation during outbreaks. An online, self-assessment survey was conducted in African Union Member States to identify major challenges in testing for epidemic-prone diseases. The survey assessed current capacity for diagnosing priority epidemic-prone diseases at different laboratory levels. It explored challenges in establishing and maintaining testing capacity to improve outbreak response and mitigate public health impact. Survey data analysed diagnostic capacity for priority infectious diseases, diagnostic technologies in use, existing surveillance programmes and challenges limiting diagnostic capacity, by country. The survey result from 15 Member States who responded to the survey, showed high variability in testing capacity and technologies across countries and diverse factors limiting testing capacity for certain priority diseases like dengue and Crimean-Congo haemorrhagic fever. At the same time diagnostic capacity is better for coronavirus disease 2019 (COVID-19), polio, and measles due to previous investments. Unfortunately, many countries are not utilizing multiplex testing, despite its potential to improve diagnostic access. The challenges of limited laboratory capacity for testing future outbreaks are indeed significant. Recent disease outbreaks in Africa have underscored the urgent need to strengthen diagnostic capacity and introduce cost-effective technologies. Small sample sizes and differing disease prioritisation within each country limited the analysis. These findings suggest the benefits of evaluating laboratory testing capacity for epidemic-prone diseases and highlight the importance of effectively addressing challenges to detect diseases and prevent future pandemics.

Background. Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus. Uganda confirmed the first case of COVID-19 on 21st March, 2020, which led to the first total lockdown in the country. During the lockdown, some factories remained operational; hence, there is a need for a study aimed at assessing the level of adherence to COVID-19 standard operating procedures (SOPs) in factories as a mitigator for the pandemic. Methods. A cross-sectional study to assess compliance of factories to COVID-19 SOPs was conducted in Wakiso, Mukono, Buikwe, and Jinja districts during the month of September, 2021. This involved visitation of factories and collection of data using the KoboCollect tool by interviewing general managers as well as human resource managers of the factories. A total of 39 factories were included in the study and were categorized into four major groups; food and beverages (15), plastics (5), construction (8), and others (11). Data analysis was done using STATA version 14.2. Results. Overall adherence to COVID-19 SOPs by the factories was 64.1% (95% CI = 49.1–79.1). Communication and training of employees (79.5%; 95% CI = 66.8–92.2), wearing personal protective equipment (PPE), and respiratory protection (79.5%; 95% CI = 66.8–92.2) as well as enhanced cleaning and disinfection of surfaces (74.4%; 95% CI = 60.6–88.1) were the most implemented SOPs in the factories. Implementation of the SOPs was the highest in Mukono district (88.9%; 95% CI = 68.4–100) and the least in Wakiso district (40.0%; 95% CI = 9.6–70.4). The COVID-19 SOPs were followed mostly in construction material factories (87.5%; 95% CI = 64.6–100) and least in food and beverage factories (40%; 95% CI = 15.2–64.8). There was no significant difference in the adherence of COVID-19 SOPs among the districts (X2 = 5.02 and P=0.17) and factories (X2 = 7.04 and P=0.07). Although good overall adherence to SOPs noted was not dependent on location and type of factory, adherence to some SOPs such as exposure control plan, presence of signages on COVID-19, maintenance of social distance, and implementation of a health control plan varied with location of the district. Likewise, exposure control plan, signages on COVID-19, and maintenance of social distance varied significantly with the type of factory. Conclusion. This study revealed moderately good overall adherence to COVID-19 SOPs by factories, with variations in the level of implementation of individual SOPs being observed.

Abstract Background Declines in malaria burden in Uganda have slowed. Modelling predicts that indoor residual spraying (IRS) and mass drug administration (MDA), when co-timed, have synergistic impact. This study investigated additional protective impact of population-based MDA on malaria prevalence, if any, when added to IRS, as compared with IRS alone and with standard of care (SOC). Methods The 32-month quasi-experimental controlled before-and-after trial enrolled an open cohort of residents (46,765 individuals, 1st enumeration and 52,133, 4th enumeration) of Katakwi District in northeastern Uganda. Consented participants were assigned to three arms based on residential subcounty at study start: MDA+IRS, IRS, SOC. IRS with pirimiphos methyl and MDA with dihydroartemisinin- piperaquine were delivered in 4 co-timed campaign-style rounds 8 months apart. The primary endpoint was population prevalence of malaria, estimated by 6 cross-sectional surveys, starting at baseline and preceding each subsequent round. Results Comparing malaria prevalence in MDA+IRS and IRS only arms over all 6 surveys (intention-to-treat analysis), roughly every 6 months post-interventions, a geostatistical model found a significant additional 15.5% (95% confidence interval (CI): [13.7%, 17.5%], Z = 9.6, p = 5e−20) decrease in the adjusted odds ratio (aOR) due to MDA for all ages, a 13.3% reduction in under 5’s (95% CI: [10.5%, 16.8%], Z = 4.02, p = 5e−5), and a 10.1% reduction in children 5–15 (95% CI: [8.5%, 11.8%], Z = 4.7, p = 2e−5). All ages residents of the MDA + IRS arm enjoyed an overall 80.1% reduction (95% CI: [80.0%, 83.0%], p = 0.0001) in odds of qPCR confirmed malaria compared with SOC residents. Secondary difference-in-difference analyses comparing surveys at different timepoints to baseline showed aOR (MDA + IRS vs IRS) of qPCR positivity between 0.28 and 0.66 (p < 0.001). Of three serious adverse events, one (nonfatal) was considered related to study medications. Limitations include the initial non-random assignment of study arms, the single large cluster per arm, and the lack of an MDA-only arm, considered to violate equipoise. Conclusions Despite being assessed at long time points 5–7 months post-round, MDA plus IRS provided significant additional protection from malaria infection over IRS alone. Randomized trials of MDA in large areas undergoing IRS recommended as well as cohort studies of impact on incidence. Trial registration: This trial was retrospectively registered 11/07/2018 with the Pan African Clinical Trials Registry (PACTR201807166695568).

Abstract Background There is growing interest to add mass drug administration (MDA) to the already existing malaria prevention strategies, such as indoor residual spraying (IRS). However, successful MDA and IRS requires high population-wide coverage, emphasizing the importance of community acceptance. This study’s objectives were to identify community-level facilitators and barriers during the implementation of both MDA and IRS in communities with high malaria transmission intensity. Methods This was a qualitative study conducted in two sub-counties in Katakwi district. Kapujan sub-county residents received two rounds of IRS and MDA while Toroma sub-county residents received two rounds of IRS only. Key informant interviews and focus group discussions were conducted with key influential district and sub-county personnel and community members. Data were analysed using thematic analysis. Transcripts and interview notes from the in-depth interviews were analysed using a coding scheme developed from pre-defined topics together with themes emerging from the data. The Nvivo software program was used to aggregate the data by codes and to present study findings. Results Overall, 14 key informants were interviewed: 4 from Katakwi district and 5 each from Kapujan and Toroma sub-counties. Five focus group discussions were conducted: 4 with community members (men and women), 2 in each sub-county and one with medical staff of Toroma health centre IV. Important themes for consideration raised by the respondents include community sensitization, conducting implementation during the low activity dry season, involvement of government and local leadership, use of the competent locally composed team, community knowledge of malaria effects and consequences, combining interventions and evidence of malaria reduction from interventions. Potential barriers such as spreading of misinformation regarding interventions, the strong unpleasant smell from Actellic and inadequate duration of engagement with the community should be taken into consideration. Conclusion This study documents important community engagement strategies that need to be considered when implementing malaria MDA in combination with IRS, for malaria prevention in such settings. This information is useful for malaria programmes, especially during the design and implementation of such community level interventions.

Lightweight and strong ceramic materials are attractive for tissue engineering, aerospace, armor systems, and many high-temperature applications. Cuttlebone, primarily composed of bioceramics, features a unique S-shaped wall structure that contributes significantly to its remarkable mechanical properties. Here, we explore the hierarchical structure and components of the cuttlebone and reveal the high ceramic content in S-shaped walls. Inspired by the design of the cuttlebone, we developed a high ceramic loading slurry for three-dimensional printing cuttlebone-like structures. As shown in the compression test, the fabricated bioinspired ceramics exhibit excellent mechanical properties and can withstand 1.07 million times their own weight, outperforming traditional ceramic foams. The specific strength and modulus are 59.5 and 785.6 MPa/(g cm -3 ), 9 and 36 times that of the natural cuttlebone. The failure mechanisms are also systematically studied on the basis of tuning the structural parameters. These findings provide effective solutions and inspiration in fabricating high-performance ceramic structural materials.

In the quest for heightened protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, we engineered a prototype vaccine utilizing the plant expression system of Nicotiana benthamiana, to produce a recombinant SARS-CoV-2 virus-like particle (VLP) vaccine presenting the S-protein from the Beta (B.1.351) variant of concern (VOC). This innovative vaccine, formulated with either a squalene oil-in-water emulsion or a synthetic CpG oligodeoxynucleotide adjuvant, demonstrated efficacy in a golden Syrian Hamster challenge model. The Beta VLP vaccine induced a robust humoral immune response, with serum exhibiting neutralization not only against SARS-CoV-2 Beta but also cross-neutralizing Delta and Omicron pseudoviruses. Protective efficacy was demonstrated, evidenced by reduced viral RNA copies and mitigated weight loss and lung damage compared to controls. This compelling data instills confidence in the creation of a versatile platform for the local manufacturing of potential pan-sarbecovirus vaccines, against evolving viral threats., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background and Aims: Pulmonary rehabilitation (PR) improves dyspnoea, fatigue and healthcare-related quality of life (QoL) in patients with chronic lung disease (CLD). Non-English-speaking background (NESB) patients face language and cultural barriers that hinder their access to PR programmes, contributing to health disparities. Our trial aimed to demonstrate the effectiveness and feasibility of a Chinese language-specific PR programme on lung function, functional exercise capacity and QoL measures., Methods: A prospective cohort study was conducted over a 2-year period. Participants were enrolled in an 8-week PR programme with biweekly sessions conducted by Chinese-speaking physiotherapists. Baseline and post-rehabilitation testing included pulmonary function testing, 6-min walk test (6MWT), St. George Respiratory Questionnaire (SGQR) and Short Form Health Survey (SF-36)., Results: We enrolled 76 patients (58% male) with a median age of 77 years (interquartile range (IQR) 68-81) and achieved a completion rate of 86.8% (n = 66). CLD included chronic obstructive pulmonary disease (42%), asthma (15%) and interstitial lung disease (3%). Baseline median forced expiratory volume in 1 s (FEV1) was 1.63 L (IQR 1.17-2.05), and the median 6MWT was 282 m (IQR 232-332). Post-intervention median 6MWT increased to 332 m (IQR 290-390), and the median FEV1 was 1.99 L (IQR 1.3-2.1). Both QoL measures (SGQR and SF-36) showed significant improvement after intervention (P < 0.05)., Conclusion: Our study demonstrates that a language-specific PR programme is feasible, improving outcomes in NESB patients with CLD. The improvement in 6MWT and QoL measures was comparable to English-based programmes. Ensuring equal access to healthcare programmes, regardless of cultural background or language barriers, is crucial in promoting health equity., (© 2023 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Background: Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus. Uganda confirmed the first case of COVID-19 on 21st March, 2020, which led to the first total lockdown in the country. During the lockdown, some factories remained operational; hence, there is a need for a study aimed at assessing the level of adherence to COVID-19 standard operating procedures (SOPs) in factories as a mitigator for the pandemic., Methods: A cross-sectional study to assess compliance of factories to COVID-19 SOPs was conducted in Wakiso, Mukono, Buikwe, and Jinja districts during the month of September, 2021. This involved visitation of factories and collection of data using the KoboCollect tool by interviewing general managers as well as human resource managers of the factories. A total of 39 factories were included in the study and were categorized into four major groups; food and beverages (15), plastics (5), construction (8), and others (11). Data analysis was done using STATA version 14.2., Results: Overall adherence to COVID-19 SOPs by the factories was 64.1% (95% CI = 49.1-79.1). Communication and training of employees (79.5%; 95% CI = 66.8-92.2), wearing personal protective equipment (PPE), and respiratory protection (79.5%; 95% CI = 66.8-92.2) as well as enhanced cleaning and disinfection of surfaces (74.4%; 95% CI = 60.6-88.1) were the most implemented SOPs in the factories. Implementation of the SOPs was the highest in Mukono district (88.9%; 95% CI = 68.4-100) and the least in Wakiso district (40.0%; 95% CI = 9.6-70.4). The COVID-19 SOPs were followed mostly in construction material factories (87.5%; 95% CI = 64.6-100) and least in food and beverage factories (40%; 95% CI = 15.2-64.8). There was no significant difference in the adherence of COVID-19 SOPs among the districts ( X 2  = 5.02 and P =0.17) and factories ( X 2  = 7.04 and P =0.07). Although good overall adherence to SOPs noted was not dependent on location and type of factory, adherence to some SOPs such as exposure control plan, presence of signages on COVID-19, maintenance of social distance, and implementation of a health control plan varied with location of the district. Likewise, exposure control plan, signages on COVID-19, and maintenance of social distance varied significantly with the type of factory., Conclusion: This study revealed moderately good overall adherence to COVID-19 SOPs by factories, with variations in the level of implementation of individual SOPs being observed., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2024 Joseph M. Kungu et al.)

Despite their high degree of effectiveness in the management of psychiatric conditions, exposure to antipsychotic drugs, including olanzapine and risperidone, is frequently associated with substantial weight gain and the development of diabetes. Even before weight gain, a rapid rise in circulating leptin concentrations can be observed in most patients taking antipsychotic drugs. To date, the contribution of this hyperleptinemia to weight gain and metabolic deterioration has not been defined. Here, with an established mouse model that recapitulates antipsychotic drug-induced obesity and insulin resistance, we not only confirm that hyperleptinemia occurs before weight gain but also demonstrate that hyperleptinemia contributes directly to the development of obesity and associated metabolic disorders. By suppressing the rise in leptin through the use of a monoclonal leptin-neutralizing antibody, we effectively prevented weight gain, restored glucose tolerance, and preserved adipose tissue and liver function in antipsychotic drug-treated mice. Mechanistically, suppressing excess leptin resolved local tissue and systemic inflammation typically associated with antipsychotic drug treatment. We conclude that hyperleptinemia is a key contributor to antipsychotic drug-associated weight gain and metabolic deterioration. Leptin suppression may be an effective approach to reducing the undesirable side effects of antipsychotic drugs.

Objective: Despite great advances in obesity therapeutics in recent years, there is still a need to identify additional therapeutic targets for the treatment of this disease. We previously discovered a signature of genes, including Chloride intracellular channel 1 (Clic1), whose expression was associated with drug-induced weight gain, and in these studies, we assess the effect of Clic1 inhibition on food intake and body weight in mice., Methods: We studied the impact of Clic1 inhibition in mouse models of binge-eating, diet-induced obese mice and genetic models of obesity (Magel2 KO mice)., Results: Clic1 knockout (KO) mice ate significantly less and had a lower body weight than WT littermates when either fed chow or high fat diet. Furthermore, pharmacological inhibition of Clic1 in diet-induced obese mice resulted in suppression of food intake and promoted highly efficacious weight loss. Clic1 inhibition also reduced food intake in binge-eating models and hyperphagic Magel2 KO mice. We observed that chronic obesity resulted in a significant change in subcellular localization of Clic1 with an increased ratio of Clic1 in the membrane in the obese state. These observations provide a novel therapeutic strategy to block Clic1 translocation as a potential mechanism to reduce food intake and lower body weight., Conclusions: These studies attribute a novel role of Clic1 as a driver of food intake and overconsumption. In summary, we have identified hypothalamic expression of Clic1 plays a key role in food intake, providing a novel therapeutic target to treat overconsumption that is the root cause of modern obesity., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

In obesity, CD11c+ innate immune cells are recruited to adipose tissue and create an inflammatory state that causes both insulin and catecholamine resistance. We found that ablation of Gnas, the gene that encodes Gαs, in CD11c expressing cells protects mice from obesity, glucose intolerance, and insulin resistance. Transplantation studies showed that the lean phenotype was conferred by bone marrow-derived cells and did not require adaptive immunity. Loss of cAMP signaling was associated with increased adipose tissue norepinephrine and cAMP signaling, and prevention of catecholamine resistance. The adipose tissue had reduced expression of catecholamine transport and degradation enzymes, suggesting that the elevated norepinephrine resulted from decreased catabolism. Collectively, our results identified an important role for cAMP signaling in CD11c+ innate immune cells in whole-body metabolism by controlling norepinephrine levels in white adipose tissue, modulating catecholamine-induced lipolysis and increasing thermogenesis, which, together, created a lean phenotype., Article Highlights: We undertook this study to understand how immune cells communicate with adipocytes, specifically, whether cAMP signaling in the immune cell and the adipocyte are connected. We identified a reciprocal interaction between CD11c+ innate immune cells and adipocytes in which high cAMP signaling in the immune cell compartment induces low cAMP signaling in adipocytes and vice versa. This interaction regulates lipolysis in adipocytes and inflammation in immune cells, resulting in either a lean, obesity-resistant, and insulin-sensitive phenotype, or an obese, insulin-resistant phenotype., (© 2023 by the American Diabetes Association.)

Background: Anorexia nervosa (AN) is a complex debilitating disease characterized by intense fear of weight gain and excessive exercise. It is the deadliest of any psychiatric disorder with a high rate of recidivism, yet its pathophysiology is unclear. The Activity-Based Anorexia (ABA) paradigm is a widely accepted mouse model of AN that recapitulates hypophagia and hyperactivity despite reduced body weight, however, not the chronicity., Methods: Here, we modified the prototypical ABA paradigm to increase the time to lose 25% of baseline body weight from less than 7 days to more than 2 weeks. We used this paradigm to identify persistently altered genes after weight restoration that represent a transcriptomic memory of under-nutrition and may contribute to AN relapse using RNA sequencing. We focused on adipose tissue as it was identified as a major location of transcriptomic memory of over-nutririon., Results: We identified 300 dysregulated genes that were refractory to weight restroration after ABA, including Calm2 and Vps13d, which could be potential global regulators of transcriptomic memory in both chronic over- and under-nutrition., Conclusion: We demonstrated the presence of peristent changes in the adipose tissue transcriptome in the ABA mice after weight restoration. Despite being on the opposite spectrum of weight perturbations, majority of the transcriptomic memory genes of under- and over-nutrition did not overlap, suggestive of the different mechanisms involved in these extreme nutritional statuses., (© 2023. The Feinstein Institute for Medical Research.)

Introduction: Culture is the gold-standard diagnosis for urinary tract infections (UTIs). However, most hospitals in low-resource countries lack adequately equipped laboratories and relevant expertise to perform culture and, therefore, rely heavily on dipstick tests for UTI diagnosis., Research Gap: In many Kenyan hospitals, routine evaluations are rarely done to assess the accuracy of popular screening tests such as the dipstick test. As such, there is a substantial risk of misdiagnosis emanating from inaccuracy in proxy screening tests. This may result in misuse, under-use or over-use of antimicrobials., Aim: The present study aimed to assess the accuracy of the urine dipstick test as a proxy for the diagnosis of UTIs in selected Kenyan hospitals., Methods: A hospital-based cross-sectional method was used. The utility of dipstick in the diagnosis of UTIs was assessed using midstream urine against culture as the gold standard., Results: The dipstick test predicted 1416 positive UTIs, but only 1027 were confirmed positive by culture, translating to a prevalence of 54.1 %. The sensitivity of the dipstick test was better when leucocytes and nitrite tests were combined (63.1 %) than when the two tests were separate (62.6 and 50.7 %, respectively). Similarly, the two tests combined had a better positive predictive value (87.0 %) than either test alone. The nitrite test had the best specificity (89.8 %) and negative predictive value (97.4 %) than leucocytes esterase (L.E) or both tests combined. In addition, sensitivity in samples from inpatients (69.2 %) was higher than from outpatients (62.7 %). Furthermore, the dipstick test had a better sensitivity and positive predictive value among female (66.0 and 88.6 %) than male patients (44.3 and 73.9 %). Among the various patient age groups, the dipstick test's sensitivity and positive predictive value were exceptionally high in patients ≥75 years old (87.5 and 93.3 %)., Conclusion: Discrepancies in prevalence from the urine dipstick test and culture, the gold standard, indicate dipstick test inadequacy for accurate UTI diagnosis. The finding also demonstrates the need for urine culture for accurate UTI diagnosis. However, considering it is not always possible to perform a culture, especially in low-resource settings, future studies are needed to combine specific UTI symptoms and dipstick results to assess possible increases in the test's sensitivity. There is also a need to develop readily available and affordable algorithms that can detect UTIs where culture is not available., Competing Interests: The author(s) declare that there are no conflicts of interest, (© 2023 The Authors.)

Antipsychotic (AP) drugs are efficacious treatments for various psychiatric disorders, but excessive weight gain and subsequent development of metabolic disease remain serious side effects of their use. Increased food intake leads to AP-induced weight gain, but the underlying molecular mechanisms remain unknown. In previous studies, we identified the neuropeptide Agrp and the transcription factor nuclear receptor subfamily 5 group A member 2 (Nr5a2) as significantly upregulated genes in the hypothalamus following AP-induced hyperphagia. While Agrp is expressed specifically in the arcuate nucleus of the hypothalamus and plays a critical role in appetite stimulation, Nr5a2 is expressed in both the CNS and periphery, but its role in food intake behaviors remains unknown. In this study, we investigated the role of hypothalamic Nr5a2 in AP-induced hyperphagia and weight gain. In hypothalamic cell lines, olanzapine treatment resulted in a dose-dependent increase in gene expression of Nr5a2 and Agrp. In mice, the pharmacological inhibition of NR5A2 decreased olanzapine-induced hyperphagia and weight gain, while the knockdown of Nr5a2 in the arcuate nucleus partially reversed olanzapine-induced hyperphagia. Chromatin-immunoprecipitation studies showed for the first time that NR5A2 directly binds to the Agrp promoter region. Lastly, the analysis of single-cell RNA seq data confirms that Nr5a2 and Agrp are co-expressed in a subset of neurons in the arcuate nucleus. In summary, we identify Nr5a2 as a key mechanistic driver of AP-induced food intake. These findings can inform future clinical development of APs that do not activate hyperphagia and weight gain., (© 2023. The Author(s).)

The outbreak of the SARS-CoV-2 global pandemic heightened the pace of vaccine development with various vaccines being approved for human use in a span of 24 months. The SARS-CoV-2 trimeric spike (S) surface glycoprotein, which mediates viral entry by binding to ACE2, is a key target for vaccines and therapeutic antibodies. Plant biopharming is recognized for its scalability, speed, versatility, and low production costs and is an increasingly promising molecular pharming vaccine platform for human health. We developed Nicotiana benthamiana-produced SARS-CoV-2 virus-like particle (VLP) vaccine candidates displaying the S-protein of the Beta (B.1.351) variant of concern (VOC), which triggered cross-reactive neutralising antibodies against Delta (B.1.617.2) and Omicron (B.1.1.529) VOCs. In this study, immunogenicity of the VLPs (5 µg per dose) adjuvanted with three independent adjuvants i.e. oil-in-water based adjuvants SEPIVAC SWE TM (Seppic, France) and "AS IS" (Afrigen, South Africa) as well as a slow-release synthetic oligodeoxynucleotide (ODN) adjuvant designated NADA (Disease Control Africa, South Africa) were evaluated in New Zealand white rabbits and resulted in robust neutralising antibody responses after booster vaccination, ranging from 1:5341 to as high as 1:18204. Serum neutralising antibodies elicited by the Beta variant VLP vaccine also showed cross-neutralisation against the Delta and Omicron variants with neutralising titres ranging from 1:1702 and 1:971, respectively. Collectively, these data provide support for the development of a plant-produced VLP based candidate vaccine against SARS-CoV-2 based on circulating variants of concern., 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 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Declines in malaria burden in Uganda have slowed. Modelling predicts that indoor residual spraying (IRS) and mass drug administration (MDA), when co-timed, have synergistic impact. This study investigated additional protective impact of population-based MDA on malaria prevalence, if any, when added to IRS, as compared with IRS alone and with standard of care (SOC)., Methods: The 32-month quasi-experimental controlled before-and-after trial enrolled an open cohort of residents (46,765 individuals, 1st enumeration and 52,133, 4th enumeration) of Katakwi District in northeastern Uganda. Consented participants were assigned to three arms based on residential subcounty at study start: MDA+IRS, IRS, SOC. IRS with pirimiphos methyl and MDA with dihydroartemisinin- piperaquine were delivered in 4 co-timed campaign-style rounds 8 months apart. The primary endpoint was population prevalence of malaria, estimated by 6 cross-sectional surveys, starting at baseline and preceding each subsequent round., Results: Comparing malaria prevalence in MDA+IRS and IRS only arms over all 6 surveys (intention-to-treat analysis), roughly every 6 months post-interventions, a geostatistical model found a significant additional 15.5% (95% confidence interval (CI): [13.7%, 17.5%], Z = 9.6, p = 5e-20) decrease in the adjusted odds ratio (aOR) due to MDA for all ages, a 13.3% reduction in under 5's (95% CI: [10.5%, 16.8%], Z = 4.02, p = 5e-5), and a 10.1% reduction in children 5-15 (95% CI: [8.5%, 11.8%], Z = 4.7, p = 2e-5). All ages residents of the MDA + IRS arm enjoyed an overall 80.1% reduction (95% CI: [80.0%, 83.0%], p = 0.0001) in odds of qPCR confirmed malaria compared with SOC residents. Secondary difference-in-difference analyses comparing surveys at different timepoints to baseline showed aOR (MDA + IRS vs IRS) of qPCR positivity between 0.28 and 0.66 (p < 0.001). Of three serious adverse events, one (nonfatal) was considered related to study medications. Limitations include the initial non-random assignment of study arms, the single large cluster per arm, and the lack of an MDA-only arm, considered to violate equipoise., Conclusions: Despite being assessed at long time points 5-7 months post-round, MDA plus IRS provided significant additional protection from malaria infection over IRS alone. Randomized trials of MDA in large areas undergoing IRS recommended as well as cohort studies of impact on incidence., Trial Registration: This trial was retrospectively registered 11/07/2018 with the Pan African Clinical Trials Registry (PACTR201807166695568)., (© 2023. The Author(s).)

Objective: To report our initial experience with on-table extubation following cardiac surgery for congenital heart disease, assessing its efficacy and safety, and the potential for fast-tracking these patients through the intensive care unit (ICU)., Methods: We decided to implement a multidisciplinary protocol aiming toward on-table extubation following congenital cardiac surgery at our hospital. Between December 2018 and January 2020, 376 patients underwent congenital cardiac surgery. The management strategy involved choosing the patients preoperatively, a specific anesthetic technique, application of a standard extubation protocol, multidisciplinary team approach, and perioperative echocardiogram for assessment of surgical repair. Relevant data were collected and analyzed., Results: Out of the 376 patients who underwent congenital cardiac surgery during the study period, 44 patients were extubated on-table. Although a majority of these patients belonged to Risk Adjustment for Congenital Heart Surgery-1 score (RACHS-1) 1 and 2 categories, 18% of the patients who were extubated on-table were of RACHS-3 category. This included a wide spectrum of anatomical substrates such as endocardial cushion defects, pulmonary venous anomalies, single ventricle physiology, valvular defects, and others such as cor triatriatum and sinus of Valsalva aneurysm. There was no in-hospital mortality related to on-table extubation. Only one patient was reintubated following on-table extubation resulting in a reintubation rate of 2.27% among those patients extubated on-table. The patients extubated on-table had a shorter ICU stay (25.89 ± 7.20 h) compared with those patients who underwent delayed extubation (59.30 ± 6.80 h). The duration of the hospital stay was also significantly reduced in these patients (91.09 ± 20.40 h) leading to an earlier discharge compared with those patients who underwent delayed extubation (134.40 ± 16.20 h)., Conclusion: On-table extubation is an attractive alternative in limited-resource environments to enhance recovery in patients following congenital cardiac malformations. Owing to the lack of significant comorbidities such as Chronic Obstructive Pulmonary Disease (COPD) in this patient population, corrective surgery for cardiac malformation usually optimizes the cardiorespiratory status. This results in more chances of successful extubation immediately following surgery. However, this requires proper perioperative planning, a careful discussion about the choice of patients, adoption of an extubation protocol, and most importantly, a multidisciplinary team approach. It is associated with low morbidity and mortality, with reduced length of stay in the ICU and hospital. This preliminary study demonstrated that on-table extubation is feasible following congenital cardiac surgery at our center and greatly reduces the intensive care requirements. This article focuses mainly on the decision-making process which determines the ideal candidates for on-table extubation and the anesthetic protocol implemented in a low-resource environment to enable the same.

Energy metabolism becomes dysregulated in individuals with obesity and many of these changes persist after weight loss and likely play a role in weight regain. In these studies, we use a mouse model of diet-induced obesity and weight loss to study the transcriptional memory of obesity. We found that the 'metabolic memory' of obesity is predominantly localized in adipocytes. Utilizing a C. elegans-based food intake assay, we identify 'metabolic memory' genes that play a role in food intake regulation. We show that expression of ATP6v0a1, a subunit of V-ATPase, is significantly induced in both obese mouse and human adipocytes that persists after weight loss. C. elegans mutants deficient in Atp6v0A1/unc32 eat less than WT controls. Adipocyte-specific Atp6v0a1 knockout mice have reduced food intake and gain less weight in response to HFD. Pharmacological disruption of V-ATPase assembly leads to decreased food intake and less weight re-gain. In summary, using a series of genetic tools from invertebrates to vertebrates, we identify ATP6v0a1 as a regulator of peripheral metabolic memory, providing a potential target for regulation of food intake, weight loss maintenance and the treatment of obesity., (© 2022. The Author(s).)

Antipsychotic drugs (AP) are highly efficacious treatments for psychiatric disorders but are associated with significant metabolic side-effects. The circadian clock maintains metabolic homeostasis by sustaining daily rhythms in feeding, fasting and hormone regulation but how circadian rhythms interact with AP and its associated metabolic side-effects is not well-known. We hypothesized that time of AP dosing impacts the development of metabolic side-effects. Weight gain and metabolic side-effects were compared in C57Bl/6 mice and humans dosed with APs in either the morning or evening. In mice, AP dosing at the start of the light cycle/rest period (AM) resulted in significant increase in food intake and weight gain compared with equivalent dose before the onset of darkness/active period (PM). Time of AP dosing also impacted circadian gene expression, metabolic hormones and inflammatory pathways and their diurnal expression patterns. We also conducted a retrospective examination of weight and metabolic outcomes in patients who received risperidone (RIS) for the treatment of serious mental illness and observed a significant association between time of dosing and severity of RIS-induced metabolic side-effects. Time restricted feeding (TRF) has been shown in both mouse and some human studies to be an effective therapeutic intervention against obesity and metabolic disease. We demonstrate, for the first time, that TRF is an effective intervention to reduce AP-induced metabolic side effects in mice. These studies identify highly effective and translatable interventions with potential to mitigate AP-induced metabolic side effects., (© 2022. The Author(s).)

Community delivery of Antiretroviral therapy (ART) is a novel innovation to increase sustainable ART coverage for People living with HIV (PLHIV) in resource limited settings. Within a nested cluster-randomised sub-study in two urban communities that participated in the HPTN 071 (PopART) trial in Zambia we investigated individual acceptability and preferences for ART delivery models. Stable PLHIV were enrolled in a cluster-randomized trial of three different models of ART: Facility-based delivery (SoC), Home-based delivery (HBD) and Adherence clubs (AC). Consenting individuals were asked to express their stated preference for ART delivery options. Those assigned to the community models of ART delivery arms could choose ("revealed preference") between the assigned arm and facility-based delivery. In total 2489 (99.6%) eligible individuals consented to the study and 95.6% chose community models of ART delivery rather than facility-based delivery when offered a choice. When asked to state their preference of model of ART delivery, 67.6% did not state a preference of one model over another, 22.8% stated a preference for HBD, 5.0% and 4.6% stated a preference for AC and SoC, respectively. Offering PLHIV choices of community models of ART delivery is feasible and acceptable with majority expressing HBD as their stated preferred option., (© 2021. The Author(s).)

Background: Non-facility-based antiretroviral therapy (ART) delivery for people with stable HIV might increase sustainable ART coverage in low-income and middle-income countries. Within the HPTN 071 (PopART) trial, two interventions, home-based delivery (HBD) and adherence clubs (AC), which included groups of 15-30 participants who met at a communal venue, were compared with standard of care (SoC). In this trial we looked at the effectiveness and feasibility of these alternative models of care. Specifically, this trial aimed to assess whether these models of care had similar virological suppression to that of SoC 12 months after enrolment., Methods: This was a three-arm, cluster-randomised, non-inferiority trial, done in two urban communities in Lusaka, Zambia included in the HPTN 071 trial. The two communities were split into zones, which were randomly assigned (1:1:1) to the three treatment strategies: 35 zones to the SoC group, 35 zones to the HBD group, and 34 zones to the AC group. ART and adherence support were delivered once every 3 months at home for the HBD group, in groups of 15-30 people in the AC group, or in the clinic for the SoC group. Adults with HIV who were receiving first-line ART for at least 6 months, virally suppressed using national HIV guidelines in the last 12 months, had no other health conditions requiring the clinicians attention, live in the study catchment area, and provided written informed consent, were eligible for inclusion. The primary endpoint was viral suppression at 12 months (with a 6 month final measurement window [ie, 9-15 months]), defined as less than 1000 HIV RNA copies per mL, with a non-inferiority margin of 5%., Findings: Between May 5 and Dec 19, 2017, 9900 individuals were screened for inclusion, of whom 2489 (25·1%) participants were enrolled into the trial: 781 (31%) in the SoC group, 852 (34%) in the HBD group, and 856 (34%) in the AC group. A higher proportion of participants had viral load measurements in the primary outcome window in the HBD (581 [61%]of 852 participants) and AC (485 [57%] of 856 participants) groups than in the SoC (390 [50%] of 781 patients) group (p=0·0021). Of the 1096 missing observations, 152 (13·8%) were attributable to either deaths (25 [16%] participants), relocations (37 [24%] participants), or lost to follow-up (90 [59%]); 690 (63·0%) participants had viral load results outside the window period; and 254 (23·2%) did not have a viral load result. The prevalence of viral suppression was estimated to be 98·3% (95% CI 96·6 to 99·7) in the SoC group, 98·7% (97·5 to 99·6) in the HBD group, and 99·2% (98·4 to 99·8) in the AC group. This gave an estimated risk difference of 0·3% (95% CI -1·5 to 2·4) for the HBD group compared with the SoC group and 0·9% (-0·8 to 2·8) for the AC group compared with the SoC group. There was strong evidence (p<0·0001) that both community ART models were non-inferior to the SoC group (p<0·0001)., Interpretation: Community models of ART delivery were as effective as facility-based care in terms of viral suppression., Funding: National Institute of Allergy and Infectious Diseases, The International Initiative for Impact Evaluation (3ie), the Bill & Melinda Gates Foundation, National Institute on Drug Abuse, National Institute of Mental Health, and President's Emergency Plan for AIDS Relief., Competing Interests: Declaration of interests HA reports grants from The Bill & Melinda Gates Foundation, National Institutes of Allergy and Infectious Diseases (NIAID), National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), International Initiative for Impact Evaluation (3ie), and the US President's Emergency Plan for AIDS Relief (PEPFAR) during the study; is a member of the technical review panel for the Global Fund to Fight AIDS, Tuberculosis, and Malaria; and reports honoraria payment from global fund outside the submitted work. SFi reports grants from The Bill & Melinda Gates Foundation, NIAID, NIMH, NIDA, and 3ie during the study; is affiliated with the clinical trial HIVCORE006, St Marys Development Trust board, SHM Foundation charitable trust board; and SFi reports consulting fees from Immunocore, outside the submitted work. SFl and DM reports grants from The Bill & Melinda Gates Foundation, NIAID, NIMH, NIDA, and 3ie during the study. All other authors declare no competing interests., (Copyright © 2022 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.)

Although antipsychotics, such as olanzapine, are effective in the management of psychiatric conditions, some patients experience excessive antipsychotic-induced weight gain (AIWG). To illuminate pathways underlying AIWG, we compared baseline blood gene expression profiles in two cohorts of mice that were either prone (AIWG-P) or resistant (AIWG-R) to weight gain in response to olanzapine treatment for two weeks. We found that transcripts elevated in AIWG-P mice relative to AIWG-R are enriched for high-confidence transcriptional targets of numerous inflammatory and immunomodulatory signaling nodes. Moreover, these nodes are themselves enriched for genes whose disruption in mice is associated with reduced body fat mass and slow postnatal weight gain. In addition, we identified gene expression profiles in common between our mouse AIWG-P gene set and an existing human AIWG-P gene set whose regulation by immunomodulatory transcription factors is highly conserved between species. Finally, we identified striking convergence between mouse AIWG-P transcriptional regulatory networks and those associated with body weight and body mass index in humans. We propose that immunomodulatory transcriptional networks drive AIWG, and that these networks have broader conserved roles in whole body-metabolism., (© 2021. The Author(s).)

Preclinical studies in mice often rely on invasive protocols, such as injections or oral gavage, to deliver drugs. These stressful routes of administration have significant effects on important metabolic parameters including food intake and body weight. Although an attractive option to circumvent this is to compound the drug in rodent food or dissolve it in water, these approaches also have limitations as they are affected by drug stability at room temperature for extended periods of time, the drug's solubility in water, and that the dosing is highly dependent on timing of food or water intake. The constant availability of the drug also limits translational relevance on how drugs are administered to patients. To overcome these limitations, drugs can be mixed with highly palatable food, such as peanut butter, allowing mice to self-administer compounds. Mice reliably and reproducibly consume the drug/peanut butter pellet in a short time frame. This approach facilitates a delivery approach with minimal stress compared with an injection or gavage. This protocol demonstrates the approach of drug preparation, animal acclimatization to placebo delivery, and drug delivery. The implications of this approach are discussed in studies related to timing of drug administration and the circadian rhythm.

Antipsychotic drugs (AP) are used to treat a multitude of psychiatric conditions including schizophrenia and bipolar disorder. However, APs also have metabolic side effects including increased food intake and body weight, but the underlying mechanisms remain unknown. We previously reported that minocycline (MINO) co-treatment abrogates olanzapine (OLZ)-induced hyperphagia and weight gain in mice. Using this model, we investigated the changes in the pharmacometabolome in the plasma and hypothalamus associated with OLZ-induced hyperphagia and weight gain. Female C57BL/6 mice were divided into groups and fed either i) control, CON (45% fat diet) ii) CON + MINO, iii) OLZ (45% fat diet with OLZ), iv) OLZ + MINO. We identified one hypothalamic metabolite indoxylsulfuric acid and 389 plasma metabolites (including 19 known metabolites) that were specifically associated with AP-induced hyperphagia and weight gain in mice. We found that plasma citrulline, tricosenoic acid, docosadienoic acid and palmitoleic acid were increased while serine, asparagine and arachidonic acid and its derivatives were decreased in response to OLZ. These changes were specifically blocked by co-treatment with MINO. These pharmacometabolomic profiles associated with AP-induced hyperphagia and weight gain provide candidate biomarkers and mechanistic insights related to the metabolic side effects of these widely used drugs.

G protein-coupled receptor 120 (GPR120) and PPARγ agonists each have insulin sensitizing effects. But whether these two pathways functionally interact and can be leveraged together to markedly improve insulin resistance has not been explored. Here, we show that treatment with the PPARγ agonist rosiglitazone (Rosi) plus the GPR120 agonist Compound A leads to additive effects to improve glucose tolerance and insulin sensitivity, but at lower doses of Rosi, thus avoiding its known side effects. Mechanistically, we show that GPR120 is a PPARγ target gene in adipocytes, while GPR120 augments PPARγ activity by inducing the endogenous ligand 15d-PGJ2 and by blocking ERK-mediated inhibition of PPARγ. Further, we used macrophage- (MKO) or adipocyte-specific GPR120 KO (AKO) mice to show that GRP120 has anti-inflammatory effects via macrophages while working with PPARγ in adipocytes to increase insulin sensitivity. These results raise the prospect of a safer way to increase insulin sensitization in the clinic., Competing Interests: Declaration of Interests The authors declare no competing financial interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

While both men and women gain weight as a side effect of antipsychotic (AP) treatment, studies in mice have found only female mice are susceptible to weight gain. Therefore, to we set out to identify a strain of male mice that gain significant weight in response to APs which could better model AP-induced weight gain observed in humans. These studies determined that male Balb/c mice developed late onset olanzapine-induced weight gain. Patients often take APs for many years and thus understanding AP-mediated changes in food intake, energy expenditure and body weight regulation is particularly important., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Antipsychotic drugs (APD) have clinically important, adverse effects on metabolism that limit their therapeutic utility. Pancreatic beta cells produce dopamine and express the D 2 dopamine receptor (D2R). As D2R antagonists, APDs alter glucose-stimulated insulin secretion, indicating that dopamine likely plays a role in APD-induced metabolic dysfunction. Insulin secretion from beta cells is also modulated by the circadian clock. Disturbed circadian rhythms cause metabolic disturbances similar to those observed in APD-treated subjects. Given the importance of dopamine and circadian rhythms for beta cells, we hypothesized that the beta cell dopamine system and circadian clock interact and dually regulate insulin secretion, and that circadian manipulations may alter the metabolic impact of APDs. We measured circadian rhythms, insulin release, and the impact of dopamine upon these processes in beta cells using bioluminescent reporters. We then assessed the impact of circadian timing on weight gain and metabolic outcomes in mice treated with the APD sulpiride at the onset of light or dark. We found that molecular components of the dopamine system were rhythmically expressed in beta cells. D2R stimulation by endogenous dopamine or the agonist bromocriptine reduced circadian rhythm amplitude, and altered the temporal profile of insulin secretion. Sulpiride caused greater weight gain and hyperinsulinemia in mice when given in the dark phase compared to the light phase. D2R-acting drugs affect circadian-dopamine interactions and modulate beta cell metabolic function. These findings identify circadian timing as a novel and important mechanism underlying APD-induced metabolic dysfunction, offering new possibilities for therapeutic interventions., (Published by Elsevier Ltd.)

Insulin resistance is a key feature of obesity and type 2 diabetes. PU.1 is a master transcription factor predominantly expressed in macrophages but after HFD feeding PU.1 expression is also significantly increased in adipocytes. We generated adipocyte specific PU.1 knockout mice using adiponectin cre to investigate the role of PU.1 in adipocyte biology, insulin and glucose homeostasis. In HFD-fed obese mice systemic glucose tolerance and insulin sensitivity were improved in PU.1 AKO mice and clamp studies indicated improvements in both adipose and liver insulin sensitivity. At the level of adipose tissue, macrophage infiltration and inflammation was decreased and glucose uptake was increased in PU.1 AKO mice compared with controls. While PU.1 deletion in adipocytes did not affect the gene expression of PPARg itself, we observed increased expression of PPARg target genes in eWAT from HFD fed PU.1 AKO mice compared with controls. Furthermore, we observed decreased phosphorylation at serine 273 in PU.1 AKO mice compared with fl/fl controls, indicating that PPARg is more active when PU.1 expression is reduced in adipocytes. Therefore, in obesity the increased expression of PU.1 in adipocytes modifies the adipocyte PPARg cistrome resulting in impaired glucose tolerance and insulin sensitivity.

Serine rich splicing factor 3 (SRSF3) plays a critical role in liver function and its loss promotes chronic liver damage and regeneration. As a consequence, genetic deletion of SRSF3 in hepatocytes caused progressive liver disease and ultimately led to hepatocellular carcinoma. Here we show that SRSF3 is decreased in human liver samples with non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or cirrhosis that was associated with alterations in RNA splicing of known SRSF3 target genes. Hepatic SRSF3 expression was similarly decreased and RNA splicing dysregulated in mouse models of NAFLD and NASH. We showed that palmitic acid-induced oxidative stress caused conjugation of the ubiquitin like NEDD8 protein to SRSF3 and proteasome mediated degradation. SRSF3 was selectively neddylated at lysine11 and mutation of this residue (SRSF3-K11R) was sufficient to prevent both SRSF3 degradation and alterations in RNA splicing. Finally prevention of SRSF3 degradation in vivo partially protected mice from hepatic steatosis, fibrosis and inflammation. These results highlight a neddylation-dependent mechanism regulating gene expression in the liver that is disrupted in early metabolic liver disease and may contribute to the progression to NASH, cirrhosis and ultimately hepatocellular carcinoma.

Objective: In a motor vehicle crash, compressive forces from the lap component of the seat belt may produce an abdominal abrasion/contusion known as the 'seat belt sign', and is associated with abdominal and lumbar injuries. Previous research has not taken into account the position of this sign in relation to the anterior superior iliac spine (ASIS). Our aim was to demonstrate an association between the seat belt sign position in relation to ASIS and the presence of abdominal/lumbar injury., Methods: A mixed prospective and retrospective observational study of patients involved in a motor vehicle crash was conducted. The presence of a seat belt sign was recorded as above ASIS, at/below ASIS, or none. Injury data were extracted from discharge summaries, radiology reports and operation reports. Proportions of patients with injuries were compared across the three groups., Results: Four hundred and sixty-four participants were enrolled. For participants with a seat belt sign above ASIS, compared to those with no seat belt sign, the positive likelihood ratio for a seat belt related injury was 4.2 (95% CI 2.6-6.8). When the seat belt sign was at/below the level of ASIS the positive likelihood ratio was 1.5 (95% CI 0.4-5.7)., Conclusion: The seat belt sign is associated with abdominal and lumbar injury; however, the location is important. This association is strong when the seat belt sign is above ASIS, but when the sign is at/below the ASIS the injury rate is similar to participants with no seat belt sign. Routine imaging of the abdomen may be appropriate only for those with a seat belt sign above ASIS., (© 2018 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine.)

Background: There is growing interest to add mass drug administration (MDA) to the already existing malaria prevention strategies, such as indoor residual spraying (IRS). However, successful MDA and IRS requires high population-wide coverage, emphasizing the importance of community acceptance. This study's objectives were to identify community-level facilitators and barriers during the implementation of both MDA and IRS in communities with high malaria transmission intensity., Methods: This was a qualitative study conducted in two sub-counties in Katakwi district. Kapujan sub-county residents received two rounds of IRS and MDA while Toroma sub-county residents received two rounds of IRS only. Key informant interviews and focus group discussions were conducted with key influential district and sub-county personnel and community members. Data were analysed using thematic analysis. Transcripts and interview notes from the in-depth interviews were analysed using a coding scheme developed from pre-defined topics together with themes emerging from the data. The Nvivo software program was used to aggregate the data by codes and to present study findings., Results: Overall, 14 key informants were interviewed: 4 from Katakwi district and 5 each from Kapujan and Toroma sub-counties. Five focus group discussions were conducted: 4 with community members (men and women), 2 in each sub-county and one with medical staff of Toroma health centre IV. Important themes for consideration raised by the respondents include community sensitization, conducting implementation during the low activity dry season, involvement of government and local leadership, use of the competent locally composed team, community knowledge of malaria effects and consequences, combining interventions and evidence of malaria reduction from interventions. Potential barriers such as spreading of misinformation regarding interventions, the strong unpleasant smell from Actellic and inadequate duration of engagement with the community should be taken into consideration., Conclusion: This study documents important community engagement strategies that need to be considered when implementing malaria MDA in combination with IRS, for malaria prevention in such settings. This information is useful for malaria programmes, especially during the design and implementation of such community level interventions.

Antipsychotic (AP) drugs are used to treat psychiatric disorders but are associated with significant weight gain and metabolic disease. Increased food intake (hyperphagia) appears to be a driving force by which APs induce weight gain but the mechanisms are poorly understood. Here we report that administration of APs to C. elegans induces hyperphagia by a mechanism that is genetically distinct from basal food intake. We exploit this finding to screen for adjuvant drugs that suppress AP-induced hyperphagia in C. elegans and mice. In mice AP-induced hyperphagia is associated with a unique hypothalamic gene expression signature that is abrogated by adjuvant drug treatment. Genetic analysis of this signature using C. elegans identifies two transcription factors, nhr-25/Nr5a2 and nfyb-1/NFYB to be required for AP-induced hyperphagia. Our study reveals that AP-induced hyperphagia can be selectively suppressed without affecting basal food intake allowing for novel drug discovery strategies to combat AP-induced metabolic side effects.

Skeletal muscle is the major site of postprandial peripheral glucose uptake, but in obesity-induced insulin-resistant states insulin-stimulated glucose disposal is markedly impaired. Despite the importance of skeletal muscle in regulating glucose homeostasis, the specific transcriptional changes associated with insulin-sensitive vs. -resistant states in muscle remain to be fully elucidated. Herein, using an RNA-seq approach we identified 20 genes differentially expressed in an insulin-resistant state in skeletal muscle, including cysteine- and glycine-rich protein 3 ( Csrp3), which was highly expressed in insulin-sensitive conditions but significantly reduced in the insulin-resistant state. CSRP3 has diverse functional roles including transcriptional regulation, signal transduction, and cytoskeletal organization, but its role in glucose homeostasis has yet to be explored. Thus, we investigated the role of CSRP3 in the development of obesity-induced insulin resistance in vivo. High-fat diet-fed CSRP3 knockout (KO) mice developed impaired glucose tolerance and insulin resistance as well as increased inflammation in skeletal muscle compared with wild-type (WT) mice. CSRP3-KO mice had significantly impaired insulin signaling, decreased GLUT4 translocation to the plasma membrane, and enhanced levels of phospho-PKCα in muscle, which all contributed to reduced insulin-stimulated glucose disposal in muscle in HFD-fed KO mice compared with WT mice. CSRP3 is a highly inducible protein and its expression is acutely increased after fasting. After 24h fasting, glucose tolerance was significantly improved in WT mice, but this effect was blunted in CSRP3-KO mice. In summary, we identify a novel role for Csrp3 expression in skeletal muscle in the development of obesity-induced insulin resistance.

Insulin increases glucose uptake into adipose tissue and muscle by increasing trafficking of the glucose transporter Glut4. In cultured adipocytes, the exocytosis of Glut4 relies on activation of the small G protein RalA by insulin, via inhibition of its GTPase activating complex RalGAP. Here, we evaluate the role of RalA in glucose uptake in vivo with specific chemical inhibitors and by generation of mice with adipocyte-specific knockout of RalGAPB. RalA was profoundly activated in brown adipose tissue after feeding, and its inhibition prevented Glut4 exocytosis. RalGAPB knockout mice with diet-induced obesity were protected from the development of metabolic disease due to increased glucose uptake into brown fat. Thus, RalA plays a crucial role in glucose transport in adipose tissue in vivo., Competing Interests: The authors declare no conflict of interest.

Highly inbred C57BL/6 mice show wide variation in their degree of insulin resistance in response to diet-induced obesity even though they are almost genetically identical. Here we employed transcriptional profiling by RNA sequencing (RNA-Seq) of visceral adipose tissue (VAT) and liver in young mice to determine how gene expression patterns correlate with the later development of high-fat diet (HFD)-induced insulin resistance in adulthood. To accomplish this goal, we partially removed and banked tissues from pubertal mice. Mice subsequently received HFD followed by metabolic phenotyping to identify two well-defined groups of mice with either severe or mild insulin resistance. The remaining tissues were collected at study termination. We then applied RNA-Seq to generate transcriptome profiles associated with worsened insulin resistance before and after the initiation of HFD. We found 244 up- and 109 downregulated genes in VAT of the most insulin-resistant mice even before HFD exposure. Downregulated genes included serine protease inhibitor, major urinary protein, and complement genes; upregulated genes represented mostly muscle constituents. These gene families were also differentially expressed in VAT of mice with high or low insulin resistance after HFD. Inflammatory genes predicted insulin resistance in liver, but not in VAT. In contrast, when we compared VAT of all mice before and after HFD, differentially expressed genes were predominantly composed of immune response genes. These data show a distinct set of gene transcripts in young mice correlates with the severity of insulin resistance in adulthood, providing insight into the pathogenesis of insulin resistance in early life.