Ribosomal protein S6 mRNA is a biomarker upregulated in multiple sclerosis, downregulated by interferon treatment, and affected by season

Background

Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans.

Fluoropyrimidines are the first-line treatment for colorectal cancer, but their efficacy is highly variable between patients. We queried whether gut microbes, a known source of inter-individual variability, impacted drug efficacy. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed three-way high-throughput screens that unraveled the complexity underlying host-microbe-drug interactions. We report that microbes can bolster or suppress the effects of fluoropyrimidines through metabolic drug interconversion involving bacterial vitamin B6, B9, and ribonucleotide metabolism. Also, disturbances in bacterial deoxynucleotide pools amplify 5-FU-induced autophagy and cell death in host cells, an effect regulated by the nucleoside diphosphate kinase ndk-1. Our data suggest a two-way bacterial mediation of fluoropyrimidine effects on host metabolism, which contributes to drug efficacy. These findings highlight the potential therapeutic power of manipulating intestinal microbiota to ensure host metabolic health and treat disease

Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans

Fluoropyrimidines are the first-line treatment for colorectal cancer, but their efficacy is highly variable between patients. We queried whether gut microbes, a known source of inter-individual variability, impacted drug efficacy. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed three-way high-throughput screens that unraveled the complexity underlying host-microbe-drug interactions. We report that microbes can bolster or suppress the effects of fluoropyrimidines through metabolic drug interconversion involving bacterial vitamin B-6, B-9, and ribonucleotide metabolism. Also, disturbances in bacterial deoxynucleotide pools amplify 5-FU-induced autophagy and cell death in host cells, an effect regulated by the nucleoside diphosphate kinase ndk-1. Our data suggest a two-way bacterial mediation of fluoropyrimidine effects on host metabolism, which contributes to drug efficacy. These findings highlight the potential therapeutic power of manipulating intestinal microbiota to ensure host metabolic health and treat disease.Peer reviewe

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Knowledge, Attitudes, and Practices of Poultry Farmers on Antimicrobial Use and Resistance in Kitwe, Zambia: Implications on Antimicrobial Stewardship

The inappropriate antimicrobial usage (AMU) in chicken production has led to an increase in the prevalence of antimicrobial resistance (AMR). In Zambia, there is little information documented regarding the knowledge, attitude, and practices of poultry farmers on AMU and AMR. Therefore, this study assessed the knowledge, attitude and practices regarding AMU and AMR among poultry farmers in Kitwe, Zambia. Methods: This was a cross-sectional study conducted among 106 poultry farmers from November to December 2021 using a structured questionnaire. Data analysis was done using IBM Statistical Package for Social Sciences (SPSS) version 26. Results: Overall, of the 106 participants, 90.6% knew what antimicrobials were, but only 29.2% were aware of AMR. The study showed that 46.2% of the participants had low knowledge, 71.7% had negative attitudes, and 61.3% had poor practices regarding AMR. The prevalence of antibiotic use in poultry production was 83%. The most used antimicrobials were tetracycline (84%) and gentamicin (35.2%). The commonly reported reason for the use of antimicrobials was for the treatment (93.2%) and prevention (89.8%) of diseases. Further, 76.9% of the administered antimicrobials were usually done without veterinarian consultation or prescription. Conclusion: The study shows that there was high AMU in poultry farms in Kitwe. However, there was low knowledge, negative attitude, and poor practices towards AMU and AMR. Therefore, there is a need for educational and sensitisation programmes regarding AMU and AMR among poultry farmers in Kitwe, Zambia. Alongside this, antimicrobial stewardship and surveillance systems should be strengthened in the livestock production sector. This will ensure food safety and public health

Preferences for services in a patient’s first six months on antiretroviral therapy for HIV in South Africa and Zambia (PREFER): research protocol for a prospective observational cohort study [version 2; peer review: 2 approved]

Background For patients on HIV treatment in sub-Saharan Africa, the highest risk for loss from care remains the first six months after antiretroviral (ART) initiation, when patients are not yet eligible for differentiated service delivery (DSD) models that offer lower-burden, patient-centred care and thus improve treatment outcomes. To reduce early disengagement from care, the PREFER study will use a sequential mixed-methods approach to describe the characteristics, needs, concerns, and preferences of patients in South Africa and Zambia 0-6 months after ART initiation or re-initiation. Protocol PREFER is an observational, prospective cohort study of adults on ART for ≤6 months at 12 public healthcare facilities in Zambia and 18 in South Africa. Its objective is to describe and understand the needs and preferences of initiating and re-initiating ART clients to inform the design of DSD models for the early HIV treatment period, improve early treatment outcomes, and distinguish the barriers encountered by naïve patients from those facing re-initiators. It has four components: 1) survey of clients 0-6 months after ART initiation (identify characteristics and preferences of clients starting ART); 2) follow up through routinely collected medical records for <24 months after enrollment (describe resource utilization and patterns and predictors of engagement in care); 3) focus group discussions and discrete choice experiment (explore reported barriers to and facilitators of retention); and 4) in South Africa only, collection of blood samples (assess the prevalence of ARV metabolites indicating prior ART use). Conclusions PREFER aims to understand why the early treatment period is so challenging and how service delivery can be amended to address the obstacles that lead to early disengagement from care. It will generate information about client characteristics and preferences to help respond to patients’ needs and design better strategies for service delivery and improve resource allocation going forward

Advanced HIV disease during the first six months on antiretroviral therapy in Zambia: research protocol for a prospective, observational, multi-cohort study [version 1; peer review: awaiting peer review]

Background The proportion of HIV-positive individuals who present for initiation or re-initiation of antiretroviral therapy (ART) with advanced HIV disease (AHD) and are at risk for morbidity and mortality remains high throughout sub-Saharan Africa. In Zambia, where 20% of ART initiators are diagnosed with AHD, little is known about the characteristics of those starting ART with AHD, why treatment initiation is delayed, how AHD clinical management influences clinical and non-clinical outcomes, or implementation of national AHD guidelines at facility level. Protocol AHD-Zambia is a mixed-methods observational study to describe AHD clients and care during the first six months after starting or re-starting ART in Zambia. The study will be conducted at 24 public sector primary health facilities in four provinces. It will enroll ART clients screened for AHD during a three-month data collection period (Cohort 1), clients screened for AHD in the 12 months prior to the data collection period (Cohort 2), patients hospitalized for AHD-related conditions (Cohort 3); and clinical providers at the study sites who manage clients with AHD (Cohort 4). Data collection will include quantitative surveys, medical record review during the 12 months before and after enrollment, qualitative interviews, and focus group discussions. Facility-level indicators will also be collected. Outcomes will include detailed profiles of AHD clients and their 6 and 12-month retention in care and viral suppression, provider and client views on barriers to and preferences for AHD care, and assessment of facility fidelity to AHD guidelines. Discussion This study will generate a comprehensive profile of clients presenting with AHD in Zambia, including clinical, demographic, social, and behavioral characteristics, treatment outcomes, and barriers to providing guideline-compliant care. Findings will provide insight into the delivery of AHD services, identify gaps in implementation, and support improvements to retention and care during the early treatment period. Registration Clinicaltrials.gov NCT06904456

Preferences for services in a patient’s first six months on antiretroviral therapy for HIV in South Africa and Zambia (PREFER): research protocol for a prospective observational cohort study

Study protocol and supplementary files for protocol manuscript in Gates Open Research.BACKGROUND: For patients on HIV treatment in sub-Saharan Africa (SSA), the highest risk for loss from care consistently remains the first six months after antiretroviral (ART) initiation, when patients are not yet eligible for most existing differentiated service delivery (DSD) models. To reduce disengagement from care during this period, we must gain a comprehensive understanding of patients’ needs, concerns, resources, and preferences for service delivery during this period. The PREFER study will use a sequential mixed-methods approach to survey a sample of patients in South Africa and Zambia 0-6 months after ART initiation to develop a detailed profile of patient characteristics and needs. PROTOCOL: PREFER is an observational, prospective cohort study of adult patients on ART for ≤6 months at 12 public sector healthcare facilities in Zambia and 18 in South Africa that aims to inform the design of DSD models for the early HIV treatment period. It has four components: 1) survey of clients 0-6 months after ART initiation; 2) follow up through routinely collected medical records for <12 or <24 months after enrollment; 3) focus group discussions to explore specific issues raised in the survey; and 4) in South Africa only, collection of blood samples self-reported naïve participants to assess the prevalence of ARV metabolites indicating prior ART use. Results will include demographic and clinical characteristics of patients, self-reported HIV care histories, preferences for treatment delivery, and predictors of disengagement. CONCLUSIONS: PREFER aims to understand why the early treatment period is so challenging and how service delivery can be amended to address the obstacles that lead to early disengagement from care and to distinguish the barriers encountered by naïve patients to those facing re-initiators. The information collected by PREFER will help respond to patients’ needs and design better strategies for service delivery and improve resource allocation going forward.Bill & Melinda Gates Foundation, INV-031690 to Boston Universit

Prevalence of adolescent mental disorders in Kenya, Indonesia, and Viet Nam measured by the National Adolescent Mental Health Surveys (NAMHS):a multi-national cross-sectional study

BackgroundMental disorders are the leading global cause of health burden among adolescents. However, prevalence data for mental disorders among adolescents in low-income and middle-income countries are scarce with often limited generalisability. This study aimed to generate nationally representative prevalence estimates for mental disorders in adolescents in Kenya, Indonesia, and Viet Nam.MethodsAs part of the National Adolescent Mental Health Surveys (NAMHS), a multinational cross-sectional study, nationally representative household surveys were conducted in Kenya, Indonesia, and Viet Nam between March and December, 2021. Adolescents aged 10–17 years and their primary caregiver were interviewed from households selected randomly according to sampling frames specifically designed to elicit nationally representative results. Six mental disorders (social phobia, generalised anxiety disorder, major depressive disorder, post-traumatic stress disorder, conduct disorder, and attention-deficit hyperactivity disorder) were assessed with the Diagnostic Interview Schedule for Children, Version 5. Suicidal behaviours and self-harm in the past 12 months were also assessed. Prevalence in the past 12 months and past 4 weeks was calculated for each mental disorder and collectively for any mental disorder (ie, of the six mental disorders assessed). Prevalence of suicidal behaviours (ie, ideation, planning, and attempt) and self-harm in the past 12 months was calculated, along with adjusted odds ratios (aORs) to show the association with prevalence of any mental disorder in the past 12 months. Inverse probability weighting was applied to generate national estimates with corresponding 95% CIs.FindingsFinal samples consisted of 5155 households (ie, adolescent and primary caregiver pairs) from Kenya, 5664 households from Indonesia, and 5996 households from Viet Nam. In Kenya, 2416 (46·9%) adolescents were male and 2739 (53·1%) were female; in Indonesia, 2803 (49·5%) adolescents were male and 2861 (50·5%) were female; and in Viet Nam, 3151 (52·5%) were male and 2845 (47·4%) were female. Prevalence of any mental disorder in the past 12 months was 12·1% (95% CI 10·9–13·5) in Kenya, 5·5% (4·3–6·9) in Indonesia, and 3·3% (2·7–4·1) in Viet Nam. Prevalence in the past 4 weeks was 9·4% (8·3–10·6) in Kenya, 4·4% (3·4–5·6) in Indonesia, and 2·7% (2·2–3·3) in Viet Nam. The prevalence of suicidal behaviours in the past 12 months was low in all three countries, with suicide ideation ranging from 1·4% in Indonesia (1·0–2·0) and Viet Nam (1·0–1·9) to 4·6% (3·9–5·3) in Kenya, suicide planning ranging from 0·4% in Indonesia (0·3–0·8) and Viet Nam (0·2–0·6) to 2·4% (1·9–2·9) in Kenya, and suicide attempts ranging from 0·2% in Indonesia (0·1–0·4) and Viet Nam (0·1–0·3) to 1·0% (0·7–1·4) in Kenya. The prevalence of self-harm in the past 12 months was also low in all three countries, ranging from 0·9% (0·6–1·3) in Indonesia to 1·2% (0·9–1·7) in Kenya. However, the prevalence of suicidal behaviours and self-harm in the past 12 months was significantly higher among those with any mental disorder in the past 12 months than those without (eg, aORs for suicidal ideation ranged from 7·1 [3·1–15·9] in Indonesia to 14·7 [7·5–28·6] in Viet Nam).InterpretationNAMHS provides the first national adolescent mental disorders prevalence estimates for Kenya, Indonesia, and Viet Nam. These data can inform mental health and broader health policies in low-income and middle-income countries.FundingThe University of Queensland in America (TUQIA) through support from Pivotal Ventures, a Melinda French Gates company. Previous article in issu