Aims: We investigated whether a short period of tightly controlled low-carbohydrate diet (LCD) leads to higher time in range without increasing the associated risks in children and young people with diabetes (CYPwD). Methods: Thirty-five (CYPwD) were recruited into this randomized controlled cross-over study (20 female; 20 CSII; age 14.5 f 2.9 years; HbA1c 48.9 f 9.4 mmol/mol). The interventions were five and five weeks of readymade food box deliveries of isocaloric diets in random order: either LCD (94.5 f 4.7 g/day) or recommended carbohydrate diet (RCD) (191 f 19.2 g/day). The outcomes were continuous glucose monitoring parameters, anthropometric, laboratory and quality of life (QoL) data. Results: Time in range was significantly higher in the LCD than in the RCD period (77.1 % vs. 73.8 %, P=0.008). Times in hyperglycemia and average glycaemia were significantly lower in the LCD. There was no difference between the diets in time in hypoglycemia or glycemic variability. The subjects' body weight and BMI were significantly lower during the LCD. There was no significant difference in the LDL-cholesterol levels. No significant differences were observed in the self-assessed QoL. Conclusions: Short-term LCD led to an improvement of glycemic parameters without increasing time in hypoglycemia, disturbing the lipid profile or negatively affecting the quality of life of CYPwD.

INTRODUCTION:Men in sub-Saharan Africa are less likely than women to initiate antiretroviral therapy (ART) and more likely to have longer cycles of disengagement from ART programmes. Treatment interventions that meet the unique needs of men are needed, but they must be scalable. We will test the impact of various interventions on 6-month retention in ART programmes among men living with HIV who are not currently engaged in care (never initiated ART and ART clients with treatment interruption).METHODS AND ANALYSIS:We will conduct a programmatic, individually randomised, non-blinded, controlled trial. 'Non-engaged' men will be randomised 1:1:1 to either a low-intensity, high-intensity or stepped arm. The low-intensity intervention includes one-time male-specific counseling+facility navigation only. The high-intensity intervention offers immediate outside-facility ART initiation+male-specific counselling+facility navigation for follow-up ART visits. In the stepped arm, intervention activities build in intensity over time for those who do not re-engage in care with the following steps: (1) one-time male-specific counselling+facility navigation→(2) ongoing male mentorship+facility navigation→(3) outside-facility ART initiation+male-specific counselling+facility navigation for follow-up ART visits. Our primary outcome is 6-month retention in care. Secondary outcomes include cost-effectiveness and rates of adverse events. The primary analysis will be intention to treat with all eligible men in the denominator and all men retained in care at 6 months in the numerator. The proportions achieving the primary outcome will be compared with a risk ratio, corresponding 95% CI and p value computed using binomial regression accounting for clustering at facility level.ETHICS AND DISSEMINATION:The Institutional Review Board of the University of California, Los Angeles and the National Health Sciences Research Council in Malawi have approved the trial protocol. Findings will be disseminated rapidly in national and international forums and in peer-reviewed journals and are expected to provide urgently needed information to other countries and donors.TRIAL REGISTRATION NUMBER:NCT05137210.DATE AND VERSION:5 May 2023; version 3.

Background Men experience twice the mortality of women while on ART in sub-Saharan Africa (SSA) largely due to late HIV diagnosis and poor retention. Here we propose to conduct an individually randomized control trial (RCT) to investigate the impact of three-month home-based ART (hbART) on viral suppression among men who were not engaged in care. Methods and design A programmatic, individually randomized non-blinded, non-inferiority-controlled trial design (ClinicalTrials.org NCT04858243). Through medical chart reviews we will identify “non-engaged” men living with HIV, ≥15years of age who are not currently engaged in ART care, including (1) men who have tested HIV-positive and have not initiated ART within 7 days; (2) men who have initiated ART but are at risk of immediate default; and (3) men who have defaulted from ART. With 1:1 computer block randomization to either hbART or facility-based ART (fbART) arms, we will recruit men from 10–15 high-burden health facilities in central and southern Malawi. The hbART intervention will consist of 3 home-visits in a 3-month period by a certified male study nurse ART provider. In the fbART arm, male participants will be offered counselling at male participant’s home, or a nearby location that is preferred by participants, followed with an escort to the local health facility and facility navigation. The primary outcome is the proportion of men who are virally suppressed at 6-months after ART initiation. Assuming primary outcome achievement of 24.0% and 33.6% in the two arms, 350 men per arm will provide 80% power to detect the stated difference. Discussion Identifying effective ART strategies that are convenient and accessible for men in SSA is a priority in the HIV world. Men may not (re-)engage in facility-based care due to a myriad of barriers. Two previous trials investigated the impact of hbART on viral suppression in the general population whereas this trial focuses on men. Additionally, this trial involves a longer duration of hbART i.e., three months compared to two weeks allowing men more time to overcome the initial psychological denial of taking ART.

Introduction Men in sub-Saharan Africa are less likely than women to initiate antiretroviral therapy (ART) and are more likely to have longer cycles of disengagement from ART programs. Treatment interventions that meet the unique needs of men are needed, but they must be scalable. We will conduct a study to test the impact of various interventions on six-month retention in ART programs among men living with HIV who are not currently engaged in care. Methods and Analysis We will conduct a programmatic, individually randomized, non-blinded, non-inferiority controlled trial. “Non-engaged” men will be randomized 1:1:1 to either a Stepped, Low-Intensity, or High-Intensity arm. In the Stepped arm, intervention activities build in intensity over time for those who do not reengage in care with the following steps: 1) one-time male-specific counseling + facility navigation ⟶ 2) ongoing male mentorship + facility navigation ⟶ outside-facility ART initiation + male-specific counseling + facility navigation for follow-up ART visits. The Low-Intensity Intervention includes one-time male-specific counseling + facility navigation only and the High-Intensity Intervention offers immediate outside-facility ART initiation + male-specific counseling + facility navigation for follow-up ART visits. Our primary outcome is 6-month retention in care. Secondary outcomes include cost-effectiveness and rates of adverse events. Ethics and Dissemination The Institutional Review Board of the University of California, Los Angeles and the National Health Sciences Research Council in Malawi have approved the trial protocol. Findings will be disseminated rapidly in national and international forums, as well as in peer-reviewed journals and are expected to provide urgently needed information to other countries and donors. Strengths and limitations ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT05137210 ### Funding Statement The work was supported by the Bill and Melinda Gates Foundation grant number INV-001423. KD was supported by National Institute of Mental Health of the National Institutes of Health grant number R01-MH122308, Fogarty International grant number K01-TW011484-01 and UCLA GSTTP. LL was supported by the National Institute of Mental Health of the National Institutes of Health under grant number K01MH119923. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This protocol manuscript used publicly available and can be found in the reference section. Collection of human subjects data for the trial was approved by the Institutional Review Board of the University of California, Los Angeles and the National Health Sciences Research Council in Malawi. Full findings from the trial will be publicly available upon the trials completion. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data used to draft this protocol manuscript are publicly available and can be found in the reference section.

Introduction Several studies have demonstrated dysbiosis in irritable bowel syndrome (IBS). Therefore, faecal microbiota transplantation, whose effect and safety have been proven in Clostridioides difficile infections, may hold promise in other conditions, including IBS. Our study will examine the effectiveness of stool transfer with artificially increased microbial diversity in IBS treatment. Methods and analysis A three-group, double-blind,randomised, cross-over, placebo-controlled study of two pairs of gut microbiota transfer will be conducted in 99 patients with diarrhoeal or mixed type of IBS. Patients aged 18–65 will be randomised into three equally sized groups: group A will first receive two enemas of study microbiota mixture (deep-frozen stored stool microbiota mixed from eight healthy donors); after 8 weeks, they will receive two enemas with placebo (autoclaved microbiota mixture), whereas group B will first receive placebo, then microbiota mixture. Finally, group C will receive placebos only. The IBS Severity Symptom Score (IBS-SSS) questionnaires will be collected at baseline and then at weeks 3, 5, 8, 11, 13, 32. Faecal bacteriome will be profiled before and regularly after interventions using 16S rDNA next-generation sequencing. Food records, dietary questionnaires, anthropometry, bioimpedance, biochemistry and haematology workup will be obtained at study visits during the follow-up period. The primary outcome is the change in the IBS-SSS between the baseline and 4 weeks after the intervention for each patient compared with placebo. Secondary outcomes are IBS-SSS at 2 weeks after the intervention and 32 weeks compared with placebo and changes in the number of loose stools, Bristol stool scale, abdominal pain and bloating, anthropometric parameters, psychological evaluation and the gut microbiome composition. Ethics and dissemination The study was approved by the Ethics Committee of Thomayer University Hospital, Czechia (G-18-26); study results will be published in peer-reviewed journals and presented at international conferences and patient group meetings. Trial registration number NCT04899869.

We previously detected indications that beta cell function is protected by gluten-free diet (GFD) introduced shortly after the onset of childhood type 1 diabetes. The present aim was to assess whether GFD was associated with changes in the gut bacteriome composition and in its functional capacity, and whether such changes mediated the observed effects of GFD on beta cell function. Forty-five children (aged 10.2 ± 3.3 years) were recruited into a self-selected intervention trial primarily focused on determining the role of GFD on beta cell preservation ( ClinicalTrials.gov NCT02867436). Stool samples were collected prior to the dietary intervention and then at 3-month intervals. A total of 128 samples from the GFD group and 112 from the control group were analysed for bacteriome 16S rDNA community profiles, the bacteriome functional capacity was predicted using PICRUSt2 and actual gut metabolome profiles measured using NMR. Intestinal permeability was assessed using serum zonulin concentrations at 1, 6 and 12 months and lactulose/mannitol tests at the end of intervention. Dietary questionnaires were used to ensure that the dietary intervention did not result in differences in energy or nutrient intake. The bacteriome community composition changed during the intervention with GFD: of abundant genera, a 3.3-fold decrease was noted for Bifidobacterium genus (adjusted p=1.4 × 10−4 in a DESeq2 model, p=0.026 in generalised estimating equations model), whereas a 2.4-fold increase was observed in Roseburia (adjusted p=0.02 in DESeq2 model, p=0.002 in generalised estimating equations model). The within-sample (alpha) diversity did not change, and there was no statistically significant clustering of GFD samples in the ordination graphs of beta diversity. Neither of the genera changes upon GFD intervention showed any association with the pace of beta cell loss (p>0.50), but of the remaining taxa, several genera of Bacteroidaceae family yielded suggestive signals. The faecal metabolome profile ordination correlated with that of bacteriomes but did not associate with GFD or categories of beta cell preservation. There was no indication of changes in gut permeability. The bacteriome reacted to GFD, but the changes were unrelated to the pace of beta cell capacity loss. The previously observed moderately protective effect of GFD is therefore mediated through other pathways.

BACKGROUND:Maintaining of remission early in the disease course of Crohn's disease (CD) is essential and has major impact on the future prognosis. This study aimed to identify baseline predictors to develop model allowing stratification of patients who will not benefit from long-term azathioprine (AZA) treatment and will require more intensive therapy. METHODS:This study was designed to develop clinical prediction rule using retrospective data analysis of pediatric CD patients included in prospective inception cohort. Clinical relapse was defined as necessity of re-induction of remission. Sequence of Cox models was fitted to predict risk of relapse. RESULTS:Out of 1190 CD patients from 13 European centers, 441 were included, 50.3% patients did not experience clinical relapse within 2 years of AZA treatment initiation. Median time to relapse was 2.11 (CI 1.59-2.46) years. Of all the tested parameters available at diagnosis, six were significant in multivariate analyses: C-reactive protein (p = 0.038), body mass index Z-score >0.8 SD (p = 0.002), abnormal sigmoid imaging (p = 0.039), abnormal esophageal endoscopy (p = 0.005), ileocolonic localization (p = 0.023), AZA dose in specific age category (p = 0.031). CONCLUSIONS:Although the possibility of predicting relapse on AZA treatment appears limited, we developed predictive model based on six baseline parameters potentially helpful in clinical decision. IMPACT:The possibility of predicting relapse on AZA treatment appears to be possible but limited. We identified six independent predictors available at diagnosis of early AZA/6-MP treatment failure in pediatric CD patients. Using combination of these factors, a model applicable to clinical practice was created. A web-based tool, allowing estimation of individual relapse risk in pediatric CD patients on a particular therapeutic regimen, has been developed.

Objectives Antigen tests have recently emerged as an interesting alternative to SARS-CoV-2 diagnostic PCR, thought to be valuable especially for the screening of bigger communities. To check appropriateness of the antigen based testing, we determined sensitivity of two point-of-care antigen tests when applied to a cohort of COVID-19 symptomatic, COVID-19 asymptomatic and healthy persons. Methods We examined nasopharyngeal swabs with antigen test 1 (Panbio Covid-19 Ag Rapid Test, Abbott) and antigen test 2 (Standard F Covid-19 Ag FIA, SD Biosensor). An additional nasopharyngeal and oropharyngeal swab of the same individual was checked with PCR (Allplex SARS-nCoV-2, Seegene). Within a 4-day period in October 2020, we collected specimens from 591 subjects. Of them, 290 had COVID-19 associated symptoms. Results While PCR positivity was detected in 223 cases, antigen test 1 and antigen test 2 were found positive in 148 (sensitivity 0.664, 95% CI 0.599 - 0.722) and 141 (sensitivity 0.623, 95% CI 0.558 - 0.684) patients, respectively. When only symptomatic patients were analysed, sensitivity increased to 0.738 (95% CI 0.667 - 0.799) for the antigen test 1 and to 0.685 (95% CI 0.611 - 0.750) for the antigen test 2. The substantial drop in sensitivity to 12.9% (95% CI 0.067 - 0.234) was observed for samples with the PCR threshold cycle above > 30. Conclusions Low sensitivity of antigen tests leads to the considerable risk of false negativity. It is advisable to implement repeated testing with high enough frequency if the antigen test is used as a frontline screening tool.

According to current guidelines, most paediatric patients in Europe diagnosed with Crohn′s disease (CD) are prescribed long-term immunosuppressive therapy with azathioprine (AZA). This study aimed to develop a predictive model allowing to stratify patients who will not benefit from AZA maintenance treatment and who require a more intensive therapeutic approach early after diagnosis.

To test whether a gluten‐free diet (GFD) is associated with the deceleration of the decline in beta‐cell capacity in non‐coeliac children with recently diagnosed type 1 diabetes.

Abstract Background According to current guidelines, most paediatric patients in Europe diagnosed with Crohn′s disease (CD) are prescribed long-term immunosuppressive therapy with azathioprine (AZA). This study aimed to develop a predictive model allowing to stratify patients who will not benefit from AZA maintenance treatment and who require a more intensive therapeutic approach early after diagnosis. Methods The study was designed to develop a clinical prediction rule using retrospective data analysis from patients included to prospective inception cohort, the EUROKIDS-IBD until 2017. In total, 1190 CD patients using AZA were selected from the registry in 13 European centres. Of these, 441 patients who responded to induction treatment, started AZA treatment within 6 weeks from the time of diagnosis and maintained remission at week 12 were entered into this multicentre study. The primary outcome was time to clinical relapse defined as a necessity of re-induction of remission. A sequence of Cox models was fitted to predict the risk of relapse. Variables appearing to be significant in univariate risk analyses were added to the model one by one and non-significant terms were dropped. Results More than 50 % of patients did not experience a clinical relapse within 2 years of AZA treatment (Figure 1). The median time to relapse was 2.11 (CI 1.59–2.46) years. Out of all tested parameters available at the time of diagnosis,8 were predictive in the context of early relapse. Only 4 of these variables, namely centre (p = 0.0009), age (HR = 1.389 95% CI (1.004–1.921), p = 0.047), CRP (HR = 1.504 95% CI (1.116–2.027), p = 0.008) and BMI Z-score (HR = 0.830 95% CI (0.742–0.928), p = 0.001), remained significant in multivariate analyses. Conclusion In paediatric CD patients achieving clinical remission after induction treatment at week 12, AZA was effective as maintenance treatment in over 50% of patients for 2 years. Due to low values of HR, the possibility to predict relapse on AZA treatment appears to be limited. Acknowledgement: This work was supported by the Grant Agency of Charles University in Prague [grant number 364617] and by Ministry of Health, Czech Republic-conceptual development of research organisation, Motol University Hospital, Prague, Czech Republic [00064203].

Background Men in sub-Saharan Africa are less likely than women to get tested for HIV, less likely to present for treatment, less likely to be maintained in treatment, more likely to have detectable viral load, more likely to transmit HIV with unprotected intercourse, and more likely to progress to AIDS and die sooner from HIV. The ultimate objective of this research is to provide evidence-based strategies to improve HIV testing and treatment of HIV-infected men. Methods This study is being conducted in the Greater Edendale Area and Vulindlela region in KwaZulu-Natal, South Africa. It is a two-stage design of a cluster-randomised trial and an individual randomised trial to test how structural and individual-level interventions address the demand-side factors that affect HIV testing and treatment for hard-to reach, high-risk men. It combines male-focused mobilization, community-based mobile HIV Testing Services and a small incentive to determine if the strategies singly and in combination can result in more men diagnosed with HIV, and more men linked to and maintained in care with undetectable viral load. Discussion A priority for sub-Sahara Africa is developing and evaluating novel and cost-effective strategies for identifying hard-to-reach groups such as men, linking them to HIV testing and care services and maintaining them in care to the point of viral suppression. We propose a combination prevention intervention that addresses men’s individual, interpersonal, and structural barriers to testing and care. This includes male-led mobilization to encourage uptake of testing and treatment; male-focused testing venues; male-only counselors; developing counseling models that are flexible and responsive to men; and strategies for adhering to clinic visits without missing work and navigating the health care system. By thoughtfully combining male-focused mobilization, testing and addressing some of the barriers to male engagement with health facilities, this study hopes to add to the growing evidence based about how to reach, test, link and maintain a hard to reach group such as men in HIV treatment and care services.

Objectives: Data on the role of gluten in type 1 diabetes (T1D) are scarce. We aimed to test whether gluten-free diet (GFD) can decelerate the decline in beta-cell capacity in newly diagnosed non-celiac T1D children. Methods: Forty-six children (aged 10.2±3.3 years) were recruited into this non-randomized self-selected intervention trial: 26 started with GFD whereas 20 remained on standard diet. Main outcomes were the decline in C-peptide area under the curve (AUC) in mixed-meal tolerance tests and the differences in insulin dose, insulin dose adjusted A1c (IDAA1c) and HbA1c at 12 months. Data were analyzed as intention-to-treat by linear regression models adjusted for baseline parameters. The adherence to GFD was tested by immunoreactive gluten in stool. Results: Mean decrease in C-peptide AUC was 293 vs.484 pmol/L (p=0.3) at 6 months, and 567 vs. 919 pmol/L (p=0.1) at 12 months in GFD and control group, respectively. The GFD group had a lower insulin dose by 0.22 U/kg/day (p=0.007), lower IDAA1c by 1.5 (p=0.003) and lower mean HbA1c by 7.5 mmol/mol (p=0.01) at 12 months (Figure 1). There was no difference in daily carbohydrate intake between the groups (p=0.4). Immunoreactive gluten was found in the stool of only 3 patients. Conclusions: GFD kept over the first year after T1D diagnosis was associated with lower insulin demand and lower HbA1c, although the groups did not differ in the C-peptide dynamics. Disclosure V. Neuman: None. S. Pruhova: None. M. Kulich: None. S. Koloušková: None. J. Vosahlo: None. M. Romanova: None. L. Petruzelkova: None. B. Obermannova: None. O. Cinek: None. Z. Sumnik: None. Funding Ministry of Health of the Czech Republic (16-27994A)

Relation of diabetes mellitus (DM) to the various stages of corneal nerve fiber damage is well accepted. A possible association between changes in the cornea of diabetic patients and diabetic retinopathy (DR), DM duration, and age at the time of DM diagnosis were evaluated. The study included 60 patients with DM type 1 (DM1) and 20 healthy control subjects. The density of basal epithelial cells, keratocytes and endothelial cells, and the status of the subbasal nerve fibers were evaluated using in vivo corneal confocal microscopy. Basal epithelial cell density increased with age (p=0.026), while stromal and endothelial cell density decreased with age (p=0.003, p=0.0005, p<0.0001). After the DM1 diagnosis was established, this association with age weaken. We showed nerve fiber damage in DM1 patients (p<0.0001). The damage correlated with the degree of DR. DM1 patients with higher age at DM1 diagnosis had a higher nerve fiber density (p=0.0021). These results indicated that age at DM1 diagnosis potentially has an important effect on final nerve fiber and corneal cell density.

Youth represent a large proportion of new HIV infections worldwide, yet their utilization of HIV testing and counseling (HTC) remains low. Using the post-intervention, cross-sectional, population-based household survey done in 2011 as part of HPTN 043/NIMH Project Accept, a cluster-randomized trial of community mobilization and mobile HTC in South Africa (Soweto and KwaZulu Natal), Zimbabwe, Tanzania and Thailand, we evaluated age-related differences among socio-demographic and behavioral determinants of HTC in study participants by study arm, site, and gender. A multivariate logistic regression model was developed using complete individual data from 13,755 participants with recent HIV testing (prior 12 months) as the outcome. Youth (18-24 years) was not predictive of recent HTC, except for high-risk youth with multiple concurrent partners, who were less likely (aOR 0.75; 95% CI 0.61-0.92) to have recently been tested than youth reporting a single partner. Importantly, the intervention was successful in reaching men with site specific success ranging from aOR 1.27 (95% CI 1.05-1.53) in South Africa to aOR 2.30 in Thailand (95% CI 1.85-2.84). Finally, across a diverse range of settings, higher education (aOR 1.67; 95% CI 1.42, 1.96), higher socio-economic status (aOR 1.21; 95% CI 1.08-1.36), and marriage (aOR 1.55; 95% CI 1.37-1.75) were all predictive of recent HTC, which did not significantly vary across study arm, site, gender or age category (18-24 vs. 25-32 years).

The lung in cystic fibrosis (CF) is home to numerous pathogens that shorten the lives of patients. The aim of the present study was to assess changes in the lung bacteriome following antibiotic therapy targeting Pseudomonas aeruginosa in children with CF. The study included nine children (9-18 years) with CF who were treated for their chronic or intermittent positivity for Pseudomonas aeruginosa. The bacteriomes were determined in 16 pairs of sputa collected at the beginning and at the end of a course of intravenous antibiotic therapy via deep sequencing of the variable region 4 of the 16S rRNA gene, and the total bacterial load and selected specific pathogens were assessed using quantitative real-time PCR. The effect of antipseudomonal antibiotics was observable as a profound decrease in the total 16S rDNA load (p = 0.001) as well as in a broad range of individual taxa including Staphylococcus aureus (p = 0.03) and several members of the Streptococcus mitis group (S. oralis, S. mitis, and S. infantis) (p = 0.003). Improvements in forced expiratory volume (FEV1) were associated with an increase in Granulicatella sp. (p = 0.004), whereas a negative association was noted between the total bacterial load and white blood cell count (p = 0.007). In conclusion, the data show how microbial communities differ in reaction to antipseudomonal treatment, suggesting that certain rare species may be associated with clinical parameters. Our work also demonstrates the utility of absolute quantification of bacterial load in addition to the 16S rDNA profiling.