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Abstract Background Diet is considered a first-line treatment option for prediabetes, a condition that affects 96 million United States (U.S.) adults. Diet patterns that prioritize whole foods (e.g., Mediterranean) are currently recommended to treat prediabetes. However, no studies have tested whether a U.S.-style diet pattern that prioritizes whole foods can be used to treat prediabetes. The purpose of this study was to assess the feasibility and acceptability of a whole foods diet for adults with prediabetes and their offspring prior to conducting a larger clinical trial. Methods A 2-week single-arm pre-post experimental controlled-feeding intervention of a 2020–2025 Dietary Guidelines for Americans adapted whole foods diet (e.g., primarily focused on foods that have undergone limited processing or refinement) was conducted in adults (25–59 years) with prediabetes and their biological offspring (6–17 years). Families received 2 weeks of menus and grocery delivery and weekly counseling by a registered dietitian. Families were invited to attend an optional focus group session. Feasibility was based on having a ≥ 50% family completion rate with ≥ 80% completion of study outcomes. Measures included adult–child anthropometrics (weight [kg], body mass index [BMI] including BMI% and Z-scores for offspring, waist circumference [cm]) and child diet quality estimated using the 2015 Healthy Eating Index (HEI) from a single random food record. Wilcoxon signed rank was used to compare differences between baseline and 2-week anthropometrics measures and offspring total HEI scores. Qualitative data were analyzed using thematic analysis to understand factors attributed to diet adherence and acceptability. Results Eight families enrolled (n = 8 adults, n = 12 offspring), with 7 families completing the study (12% attrition) and completing 100% of study outcome measures. Adults experienced a median weight loss of − 1.0 kg from baseline to 2 weeks (79.5 kg to 78.5 kg). Offspring had a 24-point increase in total 2015 HEI scores (median difference 50 to 74). Focus group participants (n = 4 adults) reported being satisfied with the program and expressed a willingness to continue the diet despite identified barriers. Conclusions A whole foods diet that provides dietary support was found to be feasible and acceptable for families at risk for T2D. Future studies are needed to test the effects of the diet on prediabetes outcomes, diet quality, and diet adherence in adults and families. Trial registration NCT05483972 at ClinicalTrials.gov. Registered July 25, 2022. https://clinicaltrials.gov/study/NCT05483972?cond=prediabetes&term=whole%20foods%20&rank=1

Abstract Background Criminal legal system-involved individuals with serious mental illness (SMI) experience more challenges accessing mental health and other community services than those without a history of criminal legal system involvement. A formative qualitative study was conducted to explore feasibility and acceptability and inform the adaptation of a mental health peer navigation intervention for individuals with SMI reentering the community after jail incarceration. Methods In-depth qualitative interviews and focus-group discussions were conducted with mental health peer navigators (i.e., certified mental health peer support specialists, peer recovery coaches) and individuals with lived experience of SMI and criminal legal system involvement (N = 20 total). Data were analyzed using applied thematic analysis. Results Four major themes emerged: (1) Feasibility and acceptability of peer-provided services: all participants reported that peer navigation services would be feasible and acceptable for individuals with SMI reentering the community after jail incarceration; (2) roles of peer navigators in addressing barriers to care: peers can address barriers to care experienced during community reentry and contribute towards service linkage/engagement; (3) shared identity and combating stigma: having a shared identity with peer navigators may minimize the impact of stigma and make it easier for clients with multiple marginalized identities to seek support; and (4) peer navigator skills and recommendations for the planned program: essential peer navigation skills include authenticity, reliability, active listening, advocacy, trauma-informed care, motivational interviewing, and empathy. Recommendations for the planned program include initiating services while clients are in custody, emphasizing the voluntary nature of peer support, knowing the limits of a peer navigation intervention, and offering support for peer navigators while on the job. Conclusion Participants saw peer navigation services for individuals with SMI with criminal legal system involvement as potentially feasible and acceptable. Such programs may enhance their impact by offering supportive supervision, emphasizing the voluntary nature of the service, and acknowledging recovery as a self-directed endeavor.

Abstract Background Islet transplantation is a recommended treatment for type 1 diabetes but is limited by donor organ shortage. This study introduces an innovative approach for improving the differentiation and functionality of insulin-producing cells (IPCs) from iPSCs using 3D spheroid formation and hydrogel matrix as an alternative pancreatic islet source. The extracellular matrix (ECM) is crucial for pancreatic islet functionality, but finding the ideal matrix for β-cell differentiation has been challenging. We aimed to advance IPC differentiation and maturation through an esterified collagen hydrogel, comparing its effectiveness with conventional basement membrane extract (BME) hydrogels. Methods iPSCs were differentiated into IPCs using a small molecule-based sequential protocol, followed by spheroid formation in concave microwells. Rheological analysis, scanning electron microscopy, and proteomic profiling were used to characterize the chemical and physical properties of each matrix. IPCs, both in single-cell form and as spheroids, were embedded in either ionized collagen or BME hydrogels, which was followed by assessments of morphological changes, pancreatic islet-related gene expression, insulin secretion, and pathway activation using comprehensive analytical techniques. Results Esterified collagen hydrogels markedly improved the structural integrity, insulin expression, and cell-cell interactions in IPC spheroids, forming densely packed insulin-expressing clusters, in contrast to the dispersed cells observed in BME cultures. Collagen hydrogel significantly enhanced the mRNA expression of crucial endocrine markers and maturation factors, with IPC spheroids showing accelerated differentiation from day 5, suggesting a faster differentiation compared to single cells in hydrogel encapsulation. Insulin secretion in response to glucose in collagen environments, with a GSIS index of 2.46 ± 0.05, exceeded those in 2D and BME, demonstrating superior pancreatic islet functionality. Pathway analysis highlighted enhanced insulin secretion capabilities, evidenced by the upregulation of genes like Secretogranin III and Chromogranin A in collagen cultures. In vivo transplantation results showed that collagen hydrogel enhanced cluster integrity, tissue integration, and insulin secretion compared to non-embedded IPCs and BME groups. Conclusion Esterified collagen hydrogels demonstrated superior efficacy over 2D and BME in promoting IPC differentiation and maturation, possibly through upregulation of the expression of key secretion pathway genes. Our findings suggest that using collagen hydrogels presents a promising approach to enhance insulin secretion efficiency in differentiating pancreatic β-cells, advancing cell therapy in diabetes cell therapy.

Abstract Background Age-related reproductive aging is a natural and irreversible physiological process, and delaying childbearing is increasingly common all over the world. Transplantation of mesenchymal stem cells (MSCs) is considered a new and effective therapy to restore ovarian function, but the relevant mechanisms remain unclear. Recently, it has been found that there is a local Renin–angiotensin system (RAS) in human ovary and it plays a key role. Methods After collecting follicular fluid from women who received oocyte retrieval for pure male factor infertility, the level of RAS components in it were detected, and the correlation analysis by linear regression. Then, the in vivo experiments on female C57BL/6 mice were designed to measure ovarian function, and the transcription and translation levels of RAS pathway were detected by molecular biology methods. Moreover, the role of RAS in regulating inflammation and oxidative stress in the co-culture system were explored in in vitro experiments on KGN cells. Results First, a total of 139 samples of analyzable follicular fluid were obtained. The local RAS of ovary, which is independent of systemic RAS (P > 0.05), is affected by age (Pearson r 0.05). Conclusions Together, our findings indicate that a novel possible mechanism to explain how stem cells restore age-related ovarian functional decline.

Abstract Background Kidney fibrosis is a hallmark of chronic kidney disease (CKD) and compromises the viability of transplanted human bone marrow-derived mesenchymal stromal cells (BM-MSCs). Hence, BM-MSCs were genetically-engineered to express the anti-fibrotic and renoprotective hormone, human relaxin-2 (RLX) and green fluorescent protein (BM-MSCs-eRLX + GFP), which enabled BM-MSCs-eRLX + GFP delivery via a single intravenous injection. Methods BM-MSCs were lentiviral-transduced with human relaxin-2 cDNA and GFP, under a eukaryotic translation elongation factor-1α promoter (BM-MSCs-eRLX + GFP) or GFP alone (BM-MSCs-eGFP). The ability of BM-MSCs-eRLX + GFP to differentiate, proliferate, migrate, produce RLX and cytokines was evaluated in vitro, whilst BM-MSC-eRLX + GFP vs BM-MSCs-eGFP homing to the injured kidney and renoprotective effects were evaluated in preclinical models of ischemia reperfusion injury (IRI) and high salt (HS)-induced hypertensive CKD in vivo. The long-term safety of BM-MSCs-RLX + GFP was also determined 9-months after treatment cessation in vivo. Results When cultured for 3- or 7-days in vitro, 1 × 106 BM-MSCs-eRLX + GFP produced therapeutic RLX levels, and secreted an enhanced but finely-tuned cytokine profile without compromising their proliferation or differentiation capacity compared to naïve BM-MSCs. BM-MSCs-eRLX + GFP were identified in the kidney 2-weeks post-administration and retained the therapeutic effects of RLX in vivo. 1–2 × 106 BM-MSCs-eRLX + GFP attenuated the IRI- or therapeutically abrogated the HS-induced tubular epithelial damage and interstitial fibrosis, and significantly reduced the HS-induced hypertension, glomerulosclerosis and proteinuria. This was to an equivalent extent as RLX and BM-MSCs administered separately but to a broader extent than BM-MSCs-eGFP or the angiotensin-converting enzyme inhibitor, perindopril. Additionally, these renoprotective effects of BM-MSCs-eRLX + GFP were maintained in the presence of perindopril co-treatment, highlighting their suitability as adjunct therapies to ACE inhibition. Importantly, no major long-term adverse effects of BM-MSCs-eRLX + GFP were observed. Conclusions BM-MSCs-eRLX + GFP produced greater renoprotective and therapeutic efficacy over that of BM-MSCs-eGFP or ACE inhibition, and may represent a novel and safe treatment option for acute kidney injury and hypertensive CKD.

Abstract Background Spinal cord injury (SCI) is a severe traumatic spinal condition with a poor prognosis. In this study, a scaffold called linearly ordered collagen aggregates (LOCAS) was created and loaded with induced pluripotent stem cells (iPSCs)-derived neural stem cells (NSCs) from human umbilical cord blood derived mesenchymal stem cells (hUCB-MSCs) to treat SCI in a rat model. Methods The rats underwent a complete transection SCI resulting in a 3-mm break at either the T9 or T10 level of the spinal cord. Results Scanning electron microscope analysis revealed a uniform pore structure on the coronal plane of the scaffold. The LOCAS had a porosity of 88.52% and a water absorption of 1161.67%. Its compressive modulus and stress were measured at 4.1 MPa and 205 kPa, respectively, with a degradation time of 10 weeks. After 12 weeks, rats in the LOCAS-iPSCs-NSCs group exhibited significantly higher BBB scores (8.6) compared to the LOCAS-iPSCs-NSCs group (5.6) and the Model group (4.2). The CatWalk analysis showed improved motion trajectory, regularity index (RI), and swing speed in the LOCAS-iPSCs-NSCs group compared to the other groups. Motor evoked potentials latency was lower and amplitude was higher in the LOCAS-iPSCs-NSCs group, indicating better neural function recovery. Histological analysis demonstrated enhanced neuronal differentiation of NSCs and nerve fiber regeneration promoted by LOCAS-iPSCs-NSCs, leading to improved motor function recovery in rats. The LOCAS scaffold facilitated ordered neurofilament extension and guided nerve regeneration. Conclusions The combination of LOCAS and iPSCs-NSCs demonstrated a positive therapeutic impact on motor function recovery and tissue repair in rats with SCI. This development offers a more resilient bionic microenvironment and presents novel possibilities for clinical SCI repair.

Abstract The human endometrium is a highly regenerative tissue capable of undergoing scarless repair during the menstruation and postpartum phases. This process is mediated by endometrial adult stem/progenitor cells. During the healing of endometrial injuries, swift reepithelization results in the rapid covering of the wound surface and facilitates subsequent endometrial restoration. The involvement of endogenous endometrial epithelial stem cells, stromal cells, and bone marrow-derived cells in the regeneration of the endometrial epithelium has been a subject of prolonged debate. Increasing evidence suggests that the regeneration of the endometrial epithelium mainly relies on epithelial stem cells rather than stromal cells and bone marrow-derived cells. Currently, no consensus has been established on the identity of epithelial stem cells in the epithelial compartment. Several markers, including stage-specific embryonic antigen-1 (SSEA-1), sex-determining region Y-box 9 (SOX9), neural-cadherin (N-cadherin), leucine-rich-repeat-containing G-protein-coupled receptor 5 (LGR5), CD44, axis inhibition protein 2 (Axin2), and aldehyde dehydrogenase 1A1 (ALDH1A1), have been suggested as potential candidate markers for endometrial epithelial stem cells. The identification of endometrial epithelial stem cells contributes to our understanding of endometrial regeneration and offers new therapeutic insights into diseases characterized by regenerative defects in the endometrium, such as intrauterine adhesion. This review explores different perspectives on the origins of human and mouse endometrial epithelial cells. It summarizes the potential markers, locations, and hierarchies of epithelial stem cells in both human and mouse endometrium. It also discusses epithelial cell-based treatments for intrauterine adhesion, hoping to inspire further research and clinical application of endometrial epithelial stem cells. Graphical abstract

Abstract Backgroud Intrauterine Adhesions (IUA) is a common gynecological disease which is seriously endangers the reproductive function of women without any ideal treatment. Some researchers found Menstrual Blood-derived Mesenchymal Stem Cells (MenSCs) can repair of damaged endometrium, however, has not been fully clarified. This study aims to evaluate the therapeutic effects of MenSCs in IUA and the repair mechanism in vivo. Methods This study is Laboratory-based study. To evaluate the therapeutic effects of MenSCs in IUA, We cultivated MenSCs, established mouse endometrial injury model, observed the uterine morphology and degree of endometrial fibrosis and compared the expression of CXC chemokine ligand-13 (CXCL13)、CXC chemokine receptor-5 (CXCR5)、Plasmin Activating Inhibitor-1(Pai-1), Transforming Growth Faction-β1(TGF- β1) and Matrix Metalloproteinase-9 (Mmp-9) among each groups. GraphPad Prism 8.0 was used for statistical processing. Data were expressed as mean ± SD. Statistical comparisons among groups were performed with one-way ANOVA. P

Abstract Background Liver fibrosis is a common pathological process of chronic liver disease, characterized by excessive deposition of extracellular matrix (ECM). Mesenchymal stem cells (MSCs) have been found to have potential therapy effect on liver fibrosis, but the mechanism involved was still unclear. The objective of this study is to investigate the therapeutic efficacy of adipose-derived mesenchymal stem cells (ADMSCs) on the treatment of liver fibrosis, with particular emphasis on elucidating the underlying mechanism of action through which ADMSCs inhibit the activation of hepatic stellate cells (HSCs). Methods ADMSCs were isolated from adipose tissue and injected intravenously into hepatic fibrosis model of rats. The histopathological changes, liver function, collagen deposition, the expression of fibroin and Hippo pathway were evaluated. In vitro, ADMSCs were co-cultured with HSCs activated by transforming growth factor beta 1 (TGF-β1), and the inhibitor of Hippo pathway was used to evaluate the therapeutic mechanism of ADMSCs transplantation. Results The results showed that after the transplantation of ADMSCs, the liver function of rats was improved, the degree of liver fibrosis and collagen deposition were reduced, and the Hippo signaling pathway was activated. In vitro, ADMSCs can effectively inhibit the proliferation and activation of HSCs induced by TGF-β1 treatment. However, the inhibitory effect of ADMSCs was weakened after blocking the Hippo signaling pathway. Conclusions ADMSCs inhibit HSCs activation by regulating YAP/TAZ, thereby promoting functional recovery after liver fibrosis. These findings lay a foundation for further investigation into the precise mechanism by which ADMSCs alleviate liver fibrosis.

Abstract Background South Africa is experiencing a persistent growth in non-communicable diseases. Diabetes is among the top ten causes of mortality, especially among women, which is partly driven by high levels of added sugar consumption and obesity. To reduce obesity rates and the incidence of diabetes, South Africa introduced a tax on sugar sweetened beverages (also known as the Health Promotion Levy (HPL)) in 2018. The tax is applicable to sugar-sweetened beverages but excludes 100% fruit juice. The government is currently considering extending the tax to include fruit juices. This study models the potential health and economic impact of taxing fruit juices at 20% of the retail price of one liter. Methods To analyze the distributional impact of the tax, this study uses extended cost-effectiveness analysis methodology. Data on price elasticities, healthcare cost, income, fruit juice consumption were sourced from the literature and representative national surveys. The potential impact of the tax on diabetes incidence, prevalence, mortality, and financial benefits were estimated for each income group (lowest, quintile 1 to highest, quintile 5). Findings We estimate that a 20% tax on fruit juice would avert 156,640 incident cases of type 2 diabetes mellitus over 20 years, with most disease averted occurring among the first- and fifth-income groups. Averted deaths from diabetes would average 2,000 deaths per quintile (for quintiles 1 to 4) and about 2,800 in quintile 5. The improved health resulting from averted incidence and deaths will reduce overall healthcare expenditure by R7.5 billion over 20 years, of which R2.3 billion will occur in the fifth quintile. The South African government will also save about R300 million in subsidizing diabetes-related healthcare cost as a result of prevention; and would raise R8.6 billion in tax revenues per annum. Out-of-pocket expenditure savings will be R303 million and a financial risk protection (money-metric value of insurance) of R4.6 billion over the 20-year period. Conclusion We conclude that an HPL that significantly raises the retail price of fruit juices would reduce consumption and diabetes-related morbidity and mortality. The tax will also provide significant financial benefits in the form of reduced healthcare costs for both government and households as well as providing financial risk protection to individuals. Health taxes are win-win policies that improve population health and generate revenue for governments to fund public health services delivery and thus improve overall health financing activities of the government. Therefore, population level disease prevention measures such as health taxes are important for achieving universal health coverage.

Abstract Background Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors affecting a quarter of the global population, with diet playing a significant role in its progression. The aim of this study is to compare the effectiveness of the Dietary Diabetes Risk Reduction Score (DDRRS) and the Macronutrient Quality Index (MQI) scoring systems in assessing the diet-related risk of metabolic syndrome. Methods In this cross-sectional study, data from 7431 individuals aged between 30 and 70 years, obtained from the Mashhad Cohort Study, were utilized to evaluate the risk factors of metabolic syndrome. A valid semi-quantitative food frequency questionnaire was used to assess participants’ dietary intake. The MQI was calculated based on carbohydrate, fat, and healthy protein components, while the DDRRS was also computed. Anthropometric measurements and blood samples were taken to determine the presence of metabolic syndrome. Logistic regression analyses were conducted to assess the association between MQI and DDRRS with metabolic syndrome and its components. Results According to the crude model, we observed lower odds of MetS in the highest quartile of DDRRS and MQI compared to the lowest quartile (P-trend

Abstract Background Poor dietary choices and consumption of unhealthy foods are major determinants of malnutrition among adolescents in Ethiopia. The school food environment is a valuable setting for exploring adolescents’ eating habits. Teachers have an important role in understanding factors that impact students’ dietary choices. The aim of this study is to explore secondary school teachers’ perceptions towards adolescents’ dietary habits in Ethiopia. Methods The study employed a qualitative research design. Four focus group discussions, involving a total of 13 teachers, were conducted at governmental and private schools in Addis Ababa, Ethiopia. Additionally, observations of the food environment in these four schools. The transcripts from the focus group discussions and photographs from observations were analyzed using thematic analysis. Triangulation of data sources and persistent observation of the data were employed to enhance the study’s trustworthiness. The study was approved by the Norwegian Center for Research Data and the Addis Ababa Health Bureau, and all participants provided informed consent. Result Teachers perceived adolescents’ dietary habits as unhealthy, characterized by the consumption of unsafe foods, limited variety, and reliance on processed foods. Factors negatively influencing adolescents’ dietary habits include a lack of awareness about a healthy diet among both students and parents. Low familial income levels were also identified as a barrier to eating a healthy diet. The unavailability of healthy foods and the advertising of unhealthy and processed foods as well as peer influence were hindrances to a healthy diet both at school and home. Conclusion This study provides additional evidence of the nutrition transition which is linked to the double burden of malnutrition among adolescents in low-income countries. Factors affecting adolescent diets at school are multileveled. Incorporating nutrition education into the school curriculum will likely improve dietary awareness mitigating peer influence. Regulating the school food environment and enforcing advertisement laws targeting adolescents can promote healthier school food environments. Providing short term nutrition trainings for biology or science teachers and strengthen their role in delivering nutrition education to children and their families, along with implementing measures to address food insecurity and restricting availability of unhealthy food at school need to be regarded as priorities.

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is emerging as the most prevalent liver disease in overweight and obese children. While no cure exists, dietary and lifestyle modifications have been shown to improve the condition. This study investigates the relationship between fructose and fiber consumption, physical activity, and NAFLD in children. Methods A cross-sectional study was conducted on 378 overweight and obese children aged 6–13 years. NAFLD diagnosis was confirmed via ultrasound, and dietary intake was assessed using a 147-item food frequency questionnaire (FFQ). Physical activity was evaluated using the Modifiable Activity Questionnaire (MAQ). Multivariable logistic regression models were applied to determine the associations. Results After excluding 53 participants due to incomplete data, 325 were included in the final analysis. The mean age was 9.2 ± 1.7 years, and 35% had NAFLD. No significant association was found between fructose intake and NAFLD (OR: 0.67, 95% CI: 0.35–1.29, P = 0.221). However, higher intake of legume fiber (OR: 0.48, 95% CI: 0.26–0.90, P = 0.03) and nut fiber (OR: 0.52, 95% CI: 0.28–0.95, P = 0.04) was significantly associated with a reduced risk of NAFLD. Physical activity showed a trend towards reduced NAFLD risk but was not statistically significant after adjustments (OR: 0.53, 95% CI: 0.22–1.04, P = 0.07). Conclusions While fructose intake was not significantly linked to NAFLD in this population, fiber from legumes and nuts appeared protective. Further prospective studies are needed to confirm these findings and clarify the role of physical activity in NAFLD prevention.

Abstract Background Individuals with class II/III obesity have a high percentage of body fat. Assessing body composition in cases of severe obesity can be difficult and controversial both in clinical practice and scientific research. Thus, it is essential to explore the different aspects of evaluating body composition and to discuss the available methods to assess it in this population. Aims To summarise and discuss the methods used to measure body composition in adults with class II/III obesity and their potential in clinical practice and scientific research. Methods This is a narrative review using data from PubMed, Scielo, and Lilacs databases. Original articles on body composition analysis in adults with class II/III obesity i.e., a BMI ≥ 35 kg/m2 were eligible. Body composition assessment methods were analysed and described. Results Some imaging methods produced significantly accurate results. Dual-energy X-ray absorptiometry (DXA) significantly produces accurate results and has been used in clinical studies. However, due to its high cost, it is not applicable in clinical practice. Multifrequency bioelectrical impedance analysis (BIA) has good accuracy and is more appropriate for clinical practice than other methods. We have highlighted several aspects of the importance and applicability of performing body composition analysis in individuals with class II/III obesity. Conclusion DXA has been considered the most adequate method for clinical research. Multifrequency BIA may be a viable alternative to DXA for use in clinical practice. Assessing body composition and its components is important for people with class II/III obesity. It can help improve the effectiveness of interventions and clinical treatments, especially in reducing the risk of losing muscle mass. Muscle loss can cause sarcopenic obesity and other clinical complications, so understanding body composition is crucial. Assessing body composition can also help understand the impact of interventions on bones and avoid clinical complications.

Abstract Background With the rise of the triple burden of malnutrition, the changing nutrition situation in Sub-Saharan Africa may be associated with changes in pubertal timing of adolescents. The purpose of this review was to summarize the association between nutritional status and pubertal milestones among children in SSA. Method A search of publications was conducted in PubMed and Scopus on 1st April 2023. Observational studies with children aged 0 to 22 years, that reported nutritional status and association with pubertal milestones in SSA were selected for review. Risk of bias was assessed using the NOS and results were presented using the PRISMA. Results Twenty-three studies published from 1992 to 2021 reporting data from nine countries and a total of 21,853 children were included in this review. Mean menarche age relative to nutritional status varied from 17.2 years in stunted adolescents in Senegal to 13.3 (in the underweight), 13.9 (in normal weight girls), and 14.1 (in overweight girls) years in adolescents in Ethiopia. Adolescents who were not stunted in Kenya and those with higher height-for-age z-scores (HAZ) and body mass index (BMI) in South Africa had more advanced breast development. Pubic hair development was positively associated with HAZ and BMI z-scores (BMIZ) at 5 years in South Africa and overweight and obesity in adolescents in Nigeria. Attainment of voice break in adolescent boys in Nigeria was associated with lower likelihood of stunting and underweight. In a study in Zambia, earlier onset and more rapid progression of genital development assessed by testicular volume in boys was associated with increased height and arm muscle. Conclusions Higher BMI, height, weight, and triceps skinfolds are significantly associated with advanced pubertal development in SSA. In SSA, less than one-third of the countries have published any research studies on nutritional status and pubertal milestones. Future studies should focus on detailed assessment of pubertal development and associated nutritional factors in both male and female adolescents in SSA. PROSPERO registration CRD42022350048.

Abstract Severe tissue defects present formidable challenges to human health, persisting as major contributors to mortality rates. The complex pathological microenvironment, particularly the disrupted immune landscape within these defects, poses substantial hurdles to existing tissue regeneration strategies. However, the emergence of nanobiotechnology has opened a new direction in immunomodulatory nanomedicine, providing encouraging prospects for tissue regeneration and restoration. This review aims to gather recent advances in immunomodulatory nanomedicine to foster tissue regeneration. We begin by elucidating the distinctive features of the local immune microenvironment within defective tissues and its crucial role in tissue regeneration. Subsequently, we explore the design and functional properties of immunomodulatory nanosystems. Finally, we address the challenges and prospects of clinical translation in nanomedicine development, aiming to propose a potent approach to enhance tissue regeneration through synergistic immune modulation and nanomedicine integration.

Abstract Background Champions are integral across research in cancer, yet studies exploring their roles are limited and have produced mixed results. The current review examines and synthesizes descriptions of how champions emerged and the types of activities they most often performed. By examining evidence from across the translational research continuum, this scoping review aims to characterize the role of champions and strategies that facilitate their involvement in the implementation of cancer care interventions in both clinical and community-based settings. Methods This scoping review was designed and implemented in compliance with PRISMA-ScR. The review focused on peer-reviewed articles in English-language journals. We searched five databases: PubMed (including MEDLINE), Scopus (including EMBASE), CINAHL, PsycINFO, and the Cochrane Library. Articles published from 1971 to 2022 were included. Two members of the team reviewed in duplicate each article and then a single member of the team extracted the data in Covidence, with a second member comparing the extraction to the original article. Qualitative and quantitative data were extracted and then synthesized. These data were used to summarize core champion activities and implementation strategies and to characterize barriers and facilitators to using champions in research. Results A total of 74 articles were included in the review. The qualitative synthesis highlighted facilitators and barriers to the effective use of champions. Facilitators included consideration of an individual’s characteristics when identifying champions, time spent planning for the specific responsibilities of champions, working within a supportive environment, and identifying champions embedded in the target setting. Major barriers included constrained time, low self-efficacy among champions, inadequate training, high turnover rates of champions, and a lack of buy-in from organizational leadership toward the intervention. Champions also were mostly assigned their roles, had varied core activities, and used complementary strategies to empower their target populations. Champions’ most frequent core activities include facilitation, outreach/promotion, and recruitment of participants into studies. Conclusions Champions were used in research of many cancer types and often serve similar roles regardless of where they are located within the translational research process. Despite their critical role, evidence is lacking on the impact of champions specifically on outcomes of many of the research studies that include them. Future research is needed to understand the nuances of champion-driven approaches across diverse cancer care settings.

Abstract Background The knee is the most commonly afflicted weight-bearing joint. Osteoarthritis of the knee is regarded as one of the most commonly diagnosed causes of disability in the elderly. Knee joint replacement can be regarded as a final solution for Osteoarthritis of the knee in which the joint is worn out, accompanied by clinical symptoms such as pain, deformity, and limited movement. Aim this study sought to estimate the economic burden of knee joint replacement procedures carried out in Iran. Method This cross-sectional descriptive study utilized the Incidence-based approach to assess the economic burden of knee joint replacement surgeries conducted in Iran during 2022, estimating the costs of the disease from a societal perspective. The sampling method employed was random sampling, and the sample size consisted of 300 patients. Direct costs were calculated employing the top-down approach, while indirect costs were estimated using the human capital approach. Microsoft Excel was employed for data analysis. Result The average direct medical costs of the knee replacement procedure per patient were $10,076.87 and $13,099.93 in the public and private sectors, respectively. The average direct non-medical costs of knee joint replacement surgery are $1123.64, with companion costs constituting most of the direct non-medical costs. Finally, the economic burden of the knee joint replacement surgery was estimated at $67340417.28. Conclusion Despite insurance coverage, knee joint replacement surgery in Iran incurs substantial costs. With the anticipated rise in the elderly population, the frequency of these procedures is expected to increase, amplifying the economic burden on the Iranian public.

Abstract Background While physicians are considered to be more susceptible to developing depressive symptoms, empirical data are lacking. The study aims to compare the risk of depressive symptoms between emergency physicians and the general population in China based on national data. Methods This was a national cross-sectional study. 10 457 emergency physicians and 101 120 participants from the general population were investigated from July 2018 to August 2018 and January 2019 to February 2019, respectively. PHQ-9 was used to measure depressive symptoms, and a score ≥ 10 indicates major depression. Propensity score matching was adopted to balance the characteristics between emergency physicians and the general population. Multinomial logistic regression model was used to examine the association between occupational groups and the severity of depressive symptoms. Binary logistic regression model was performed to explore the risk factors of major depression among emergency physicians. Results The prevalence of major depression among emergency physicians was 35.7%, whereas among the general population was 13.9%. Emergency physicians had a 3.65 times higher risk of major depression than the general population. And emergency physician was significantly associated with mild (OR: 3.12, 95% CI 2.95–3.30), moderate (OR: 4.94, 95% CI 4.60–5.30), moderately severe (OR: 9.48, 95% CI 8.61–10.44), and severe depressive symptoms (OR: 14.18, 95% CI 12.47–16.13) compared with none depressive symptoms. Even after matching, the results remained consistent. Factors associated with major depression among emergency physicians included bachelor degree or above (OR: 1.22, 95% CI 1.06–1.40), worked long years (OR: 1.26, 95% CI 1.08–1.46 for 1–5 years; OR: 1.56, 95% CI 1.32–1.84 for ≥ 6 years), experienced workplace violence (OR: 2.51, 95% CI 2.16–2.94), worked more night shifts per month (OR: 1.33, 95% CI 1.16–1.51 for 6–10 times; OR: 1.83, 95% CI 1.58–2.11 for ≥ 11 times), smoked (OR: 1.64, 95% CI 1.47–1.84), and effort-reward imbalance (OR: 4.18, 95% CI 3.62–4.85). Conclusions Emergency physicians had a higher risk of depressive symptoms than the general population. There is a need for greater awareness of the mental health issues faced by emergency physicians.

Abstract Background Primary healthcare, the first line of care in many countries, treats patients with diverse health problems. High workload, time pressure, poor job control and negative interpersonal experiences with supervisors have been documented in primary healthcare. The work environment in primary healthcare is also affected by several types of changes. Aim We aimed to explore the levels of job satisfaction, turnover intention, social support, leadership climate and change fatigue according to physicians in Swedish primary healthcare. We also aimed to identify and characterize physicians exhibiting both high turnover intention and low job satisfaction, i.e., “discontent with current job”. Methods A cross-sectional survey based on a random sample of physicians working in Swedish primary healthcare. Results Approximately one-quarter of the respondents were discontented with their current job. Discontent was negatively associated with poor general health and change fatigue among the respondents; social support from colleagues and a favorable leadership climate showed positive associations in terms of reducing the levels of discontent with current job. Conclusions The findings of this study highlight the association between low levels of job satisfaction and high levels of turnover intention (i.e., discontent with current job) among physicians in primary healthcare. Moreover, these variables exhibited a strong association with physicians’ general health; poor health significantly increased the likelihood of discontent with current job. Our findings also show that experiencing change fatigue is associated with discontent with current job among physicians in primary healthcare. This knowledge can help identify and improve shortcomings within the psychosocial work environment in Swedish primary healthcare.

Abstract Background Clinical trial registration is critical for research transparency and integrity. Since 2005, the Declaration of Helsinki has required prospective registration of trials before subject recruitment. In Israel, the MyTrial registry was established in 2015 to register interventional trials and became mandatory in 2016 for ethical approval. The study aimed to analyze the registration practices, challenges, and trends in clinical trial registration in Israel using the local registry “MyTrial”. Methods A total of 3,895 clinical trial records from 2011 to December 2022 were retrieved from the MyTrial platform and subjected to descriptive analysis. Results A significant increase occurred from 2016 to 2021 due to mandated registration, with a peak in 2020 (733 trials) and a decrease in 2022 (462 trials), likely due to COVID-19. Most of the trials included drugs (56%) or medical devices (33%). Geographically, 53% were from central Israel. Only 39% of the patients were registered at both MyTrial and ClinicalTrials.gov. 65% had no blinding. 47% featured unregistered products. 56% had not started recruitment. Since 2016, the number of advanced therapy trials has steadily increased, reaching 19 in 2022. There are gaps between registered trials and official government reports. Conclusion These findings provide valuable insights into the current landscape of clinical trial registration in Israel and highlight the need for improvements in compliance with prospective registration and adherence to the WHO-ICTRP standards.

Abstract Purpose We aim to thoroughly compare past and current methods that leverage baseline covariate information to estimate the average treatment effect (ATE) using data from of randomized clinical trials (RCTs). We especially focus on their performance, efficiency gain, and power. Methods We compared 6 different methods using extensive Monte-Carlo simulation studies: the unadjusted estimator, i.e., analysis of variance (ANOVA), the analysis of covariance (ANCOVA), the analysis of heterogeneous covariance (ANHECOVA), the inverse probability weighting (IPW), the augmented inverse probability weighting (AIPW), and the overlap weighting (OW) as well as the augmented overlap weighting (AOW) estimators. The performance of these methods is assessed using the relative bias (RB), the root mean square error (RMSE), the model-based standard error (SE) estimation, the coverage probability (CP), and the statistical power. Results Even with a well-executed randomization, adjusting for baseline covariates by an appropriate method can be a good practice. When the outcome model(s) used in a covariate-adjusted method is closer to the correctly specified model(s), the efficiency and power gained can be substantial. We also found that most covariate-adjusted methods can suffer from the high-dimensional curse, i.e., when the number of covariates is relatively high compared to the sample size, they can have poor performance (along with lower efficiency) in estimating ATE. Among the different methods we compared, the OW performs the best overall with smaller RMSEs and smaller model-based SEs, which also result in higher power when the true effect is non-zero. Furthermore, the OW is more robust when dealing with the high-dimensional issue. Conclusion To effectively use covariate adjustment methods, understanding their nature is important for practical investigators. Our study shows that outcome model misspecification and high-dimension are two main burdens in a covariate adjustment method to gain higher efficiency and power. When these factors are appropriately considered, e.g., performing some variable selections if the data dimension is high before adjusting covariate, these methods are expected to be useful.

Abstract Introduction Evaluation of implementation strategies is core to implementation trials, but implementation strategies often deviate from the original plan to adjust to the real-world conditions. The optimal approach to track modifications to implementation strategies is unclear, especially in low-resource settings. Using data from an implementation trial for people who inject drugs (PWID) with HIV in Vietnam, we describe the tracking of implementation strategy modifications and present findings of this process. Methods SNaP (Systems Navigation and Psychosocial Counseling) is a hybrid type-III effectiveness-implementation randomized controlled trial aiming to scale up the evidence-based intervention, integrated systems navigation and psychosocial counseling, for PWID with HIV in Vietnam. Forty-two HIV testing sites were randomized 1:1 to a standard or tailored arm. While the standard arm (SA) received a uniform package of strategies, implementation strategies for the tailored arm (TA) were tailored to address specific needs of each site. The central research team also met monthly with the TA to document how their tailored strategies were implemented over time. Five components were involved in the tracking process: describing the planned strategies; tracking strategy use; monitoring barriers and solutions; describing modifications; and identifying and describing any additional strategies. Results Our approach allowed us to closely track the modifications to implementation strategies in the tailored arms every month. TA sites originally identified 27 implementation strategies prior to implementation. During implementation, five strategies were dropped by four sites and two new strategies were added to twelve sites. Modifications of five strategies occurred at four sites to accommodate their changing needs and resources. Difficulties related to the COVID-19 pandemic, low number of participants recruited, high workload at the clinic, lack of resources for HIV testing and high staff turnover were among barriers of implementing the strategies. A few challenges to tracking modifications were noted, including the considerable amount of time and efforts needed as well as the lack of motivation from site staff to track and keep written documentations of modifications. Conclusions We demonstrated the feasibility of a systematic approach to tracking implementation strategies for a large-scale implementation trial in a low-resource setting. This process could be further enhanced and replicated in similar settings to balance the rigor and feasibility of implementation strategy tracking. Our findings can serve as additional guidelines for future researchers planning to report and track modifications to implementation strategies in large, complex trials. Trial registration : clinicaltrials.gov ID: NCT03952520 (first posted 2019-05-16).

Abstract Background Globorisk is one of the prediction tools for 10-year risk assessment of cardiovascular disease, featuring an office-based (non-laboratory-based) version. This version does not require laboratory tests for determining the CVD risk. The present study aims to determine the 10-year CVD risk using the office-based Globorisk model and factors associated with the 10-year CVD risk. Methods In this study, baseline data from 6810 individuals participating in the Fasa cohort study, with no history of CVD or stroke, were utilized. The risk equation of the office-based Globorisk model incorporates age, sex, systolic blood pressure (SBP), body mass index (BMI), and smoking status. The Globorisk model categorizes the risk into three groups: low risk (

Abstract Background Reference intervals, which define an interval in which a specific proportion of measurements from a healthy population are expected to fall, are commonly used in medical practice. Synthesizing information from multiple studies through meta-analysis can provide a more precise and representative reference interval than one derived from a single study. However, the current approaches for estimating the reference interval from a meta-analysis mainly rely on aggregate data and require parametric distributional assumptions that cannot always be checked. Methods With the availability of individual participant data (IPD), non-parametric methods can be used to estimate reference intervals without any distributional assumptions. Furthermore, patient-level covariates can be introduced to estimate personalized reference intervals that may be more applicable to specific patients. This paper introduces quantile regression as a method to estimate the reference interval from an IPD meta-analysis under the fixed effects model. Results We compared several non-parametric bootstrap methods through simulation studies to account for within-study correlation. Under fixed effects model, we recommend keeping the studies fixed and only randomly sampling subjects with replacement within each study. Conclusion We proposed to use the quantile regression in the IPD meta-analysis to estimate the reference interval. Based on the simulation results, we identify an optimal bootstrap strategy for estimating the uncertainty of the estimated reference interval. An example of liver stiffness measurements, a clinically important diagnostic test without explicitly established reference range in children, is provided to demonstrate the use of quantile regression in estimating both overall and subject-specific reference intervals.

Abstract Background Causal mediation analysis is widespread in applied medical research, especially in longitudinal settings. However, estimating natural mediational effects in such contexts is often difficult because of the presence of post-treatment confounding. Moreover, many models frequently used in applied research, like multilevel and latent growth models, present an additional difficulty, i.e. the presence of latent variables. In this paper, we propose a causal interpretation of these two classes of models based on a novel type of causal effects called separable, which overcome some of the issues of natural effects. Methods We formally derive conditions for the identifiability of separable mediational effects and their analytical expressions based on the g-formula. We carry out a simulation study to investigate how moderate and severe model misspecification, as well as violation of the identfiability assumptions, affect estimates. We also present an application to real data. Results The results show how model misspecification impacts the estimates of mediational effects, particularly in the case of severe misspecification, and that the bias worsens over time. The violation of assumptions affects separable effect estimates in a very different way for the mixed effect and the latent growth models. Conclusion Our approach allows us to give multilevel and latent growth models an appealing causal interpretation based on separable effects. The simulation study shows that model misspecification can heavily impact effect estimates, highlighting the importance of careful model choice.

Abstract Background Shapley values have been used extensively in machine learning, not only to explain black box machine learning models, but among other tasks, also to conduct model debugging, sensitivity and fairness analyses and to select important features for robust modelling and for further follow-up analyses. Shapley values satisfy certain axioms that promote fairness in distributing contributions of features toward prediction or reducing error, after accounting for non-linear relationships and interactions when complex machine learning models are employed. Recently, feature selection methods using predictive Shapley values and p-values have been introduced, including powershap. Methods We present a novel feature selection method, LLpowershap, that takes forward these recent advances by employing loss-based Shapley values to identify informative features with minimal noise among the selected sets of features. We also enhance the calculation of p-values and power to identify informative features and to estimate number of iterations of model development and testing. Results Our simulation results show that LLpowershap not only identifies higher number of informative features but outputs fewer noise features compared to other state-of-the-art feature selection methods. Benchmarking results on four real-world datasets demonstrate higher or comparable predictive performance of LLpowershap compared to other Shapley based wrapper methods, or filter methods. LLpowershap is also ranked the best in mean ranking among the seven feature selection methods tested on the benchmark datasets. Conclusion Our results demonstrate that LLpowershap is a viable wrapper feature selection method that can be used for feature selection in large biomedical datasets and other settings.

Abstract Background Hypertension and type 2 diabetes mellitus (T2DM) are important contributors to noncommunicable disease related morbidity and mortality. Health systems could benefit from exploring the use of Faith-Based Centres (FBC) to screen and link suspected cases for further care in order to help achieve Sustainable Development Goal (SDG) 3. The study investigated the role of faith-based screening for T2DM and hypertension and the linkage of cases to the healthcare system and examined the care cascade in the Kassena Nankana Districts of Northern Ghana. Methods We screened individuals from 6 FBCs for elevated blood pressure and hyperglycaemia. Suspected hypertension and T2DM cases were referred to health facilities for confirmation and subsequently followed them up for 3 months. We assessed the prevalence of behavioural and metabolic risk factors, including hypertension and T2DM, and the retention of referred cases in the healthcare system over follow up period. We further assessed levels of awareness, treatment and adequate control of hypertension and T2DM. Results A total of 631 participants were screened, (mean age 49 ± 16years, 73% female) from 6 Faith based Centres. More males than females reported smoking tobacco (14.5% vs. 0.7%) and been physically active (64.5% vs. 52.7%) while more females were obese (29.6 kg/m2 vs. 14.5 kg/m2) and had a higher mean waist circumference (89.0 cm IQR 75-116 cm vs. 84.2 cm IQR 72–107 cm), hip circumference (101.5 ± 10.6 cm vs. 96.4 ± 8.6 cm) and waist-to-hip ratio (0.86 ± 0.1 cm vs. 0.87 ± 0.1 cm) than males. The prevalence of confirmed hypertension and T2DM was 27.9% and 3.5% respectively with no observed sex differences. We observed deficits in the hypertension and T2DM care cascade with reported low awareness, treatment and uncontrolled levels. A 3-month follow up showed a retention in care of 100% in month one and 94.9% in the third month. There was an increase in treatment (39.4% in month-1 and 82.8% in month-3) and control (26.3% in month-1 and 76.3% in month-3) of hypertension and T2DM combined. Conclusion Faith-based centres have the potential to enhance the screening, linkage to the healthcare system, and management of hypertension and T2DM. This improvement over the routine system could lead to earlier diagnoses, a reduction in complications, and decreased premature mortality from cardiovascular diseases. Consequently, these efforts would contribute significantly to achieving SDG 3.

Abstract Background Limited information exists regarding the prevalence of bereavement care provision by general practitioners (GPs) and in what cases they provide this. Insights into the current practice of bereavement care provision by GPs can highlight areas for improvement of the bereavement care practice. Therefore, we examined in how many cases GPs contacted relatives regarding bereavement care, and which case-specific characteristics are associated. Methods This study had a retrospective cross-sectional design and used data from a clustered sample of 52 GP-practices in the Netherlands. Patient cases were included if they were one year or older and died between January 1st, 2018 and December 31st, 2022. The main outcome was whether the GP had had contact with relatives regarding bereavement care or planned to do so. Descriptive statistics were used, as well as logistic regression analyses with generalized estimating equations. Results Following 86.4% of deaths, GPs either had contact with or planned to have contact with relatives of their deceased patients regarding bereavement care. This likelihood was higher in non-sudden deaths compared to sudden deaths (odds ratio [OR] 1.60). In cases of non-sudden death, GPs were more likely to provide bereavement care if an informal caregiver was involved (OR 3.81), or if the GP was part of a palliative care at home group (PaTz) (OR 2.78). Conclusions In the majority of cases GPs reach out to the relatives of their deceased patients to offer bereavement care. Given their familiarity with the deceased person, particularly instances of non-sudden death, the GP seems to be well-positioned to provide bereavement care, especially support that focuses on reviewing the period leading up to the death.

Abstract Background In the UK, about 14% of community-dwelling adults aged 65 and over are estimated to be at risk of malnutrition. Screening older adults in primary care and treating those identified as ‘at risk’ may help reduce malnutrition risk and associated healthcare use, and improve quality of life. The aim of this study is to explore how primary care practitioners (PCPs) and older adults perceive, use and respond to an intervention to support those identified as ‘at risk’. Methods We developed and optimised an intervention (screen and treat protocol, online tools and printed materials) to support primary care practitioners to identify malnutrition risk among older adults, and intervene where necessary. We recruited older adults (described as ‘patients’ here) taking part in a feasibility study, and carried out semi-structured interviews to assess PCPs’ and patients’ engagement with the intervention, and identify any contextual issues that supported or undermined their engagement. Results Four themes were developed, encompassing patients’ and PCPs’ perceptions of undernutrition, study measures and appointments, constraints on PCPs’ enthusiasm to make a difference, and patients’ expectations of nutritional appointments. Key findings included patients commonly not accepting advice for undernutrition/malnutrition but welcoming support for their nutritional needs; checklists potentially distracting patients from recalling discussions about their nutritional needs; a tension between PCPs’ desire to recruit less-well patients and logistical difficulties in doing so; and patients compromising their nutritional needs to suit others. Conclusions Diverse factors influence whether an intervention succeeds in primary care. PCPs learn about an intervention/study in different ways, vary in how they understand and accept its aims, and desire to make a difference to their patients. Patients bring perceptions and expectations about the study’s aims, coloured by their habits and preferences, prior experience of research and healthcare, and pressure from social expectations. Each aspect must be considered when developing a successful primary care intervention that is viewed as relevant and meaningful, and presented using language that aligns with participants’ values and goals. Our findings suggest that references to ‘malnutrition risk’ should be avoided in any patient-facing materials/interactions as participants do not accept or identify with this label.

Abstract Background This study investigated the perceived barriers and potential facilitators for culturally sensitive care among general practitioners in Flanders. Understanding these dynamics is crucial for improving healthcare quality and equity. Methodology Twenty-one in-depth interviews were conducted with Flemish GPs. Braun and Clarke’s reflexive thematic analysis was employed to develop and interpret themes that elucidate shared underlying meanings and capture the nuanced challenges and strategies related to cultural sensitivity in healthcare. Results Two core themes were generated: GPs’ uncertainty and opposition. These themes manifest in emotional responses such as frustration, miscomprehension, and feelings of helplessness, influencing relational outcomes marked by patient disconnect and reduced motivation for cultural sensitivity. The barriers identified are exacerbated by resource scarcity and limited intercultural contact. Conversely, facilitators include structural elements like interpreters and individual strategies such as engagement, aimed at enhancing GPs’ confidence in culturally diverse encounters. A meta-theme of perceived lack of control underscores the challenges, particularly regarding language barriers and resource constraints, highlighting the critical role of GPs’ empowerment through enhanced intercultural communication skills. Conclusion Addressing GPs’ uncertainties and oppositions can mitigate related issues, thereby promoting comprehensive culturally sensitive care. Essential strategies include continuous education and policy reforms to dismantle structural barriers. Moreover, incentivizing culturally sensitive care through quality care financial incentives could bolster GP motivation. These insights are pivotal for stakeholders—practitioners, policymakers, and educators—committed to advancing culturally sensitive healthcare practices and, ultimately, for fostering more equitable care provision.

Abstract Background Long-term management of patients with hypothyroidism on thyroxine replacement requires thyroid function test (TFT) monitoring once every six–12 months as recommended by clinical practice guidelines. This study determined their thyroid function status during two-year follow-up visits in primary care, and the factors influencing their thyroid status, and assessed the optimal interval for TFTs. Methods A retrospective cohort study was conducted on adults with a clinical diagnosis code for hypothyroidism in their electronic health records taken from a group of polyclinics in Singapore between July 2017 and June 2020. The follow-up thyroid status was categorized as under-replacement (TSH ≥ 3.70mIU/L), over-replacement (TSH ≤ 0.65mIU/L) or euthyroid (TSH 0.65–3.70mIU/L). The patients’ demographic, clinical and TFT data were analyzed using appropriate statistical tests during the two-year follow-up. Stepwise logistic regression analysis identified the factors associated with suboptimal thyroid control. Kaplan–Meier analysis was used to compare their thyroid function status in association with the interval between TFT monitoring. Results Data from 5,749 eligible subjects (mean age 62.1 ± 13.29 years; 79% female; 79.7% Chinese) were analyzed. After a two-year follow-up, 61.9% (n = 3558) of all subjects were euthyroid, with 29.5% (n = 1694) being under-replaced and 8.6% (n = 497) over-replaced. However, thyroid status did not differ significantly with the various dose regimen (daily, segmented, or alternate days) (p = 0.193). Stepwise logistic regression showed that thyroxine under-replacement was significantly associated with the male gender (AOR = 1.25,95%CI = 1.03–1.51,p = 0.02) and obesity (AOR = 1.34,95%CI = 1.08–1.66,p = 0.008). Every unit (μg/kg body weight) increase in the mean daily thyroxine dose was associated with 2.72 times greater odds of over-replacement. When comparing thyroid function monitoring at intervals of 13-24 months, monitoring at shorter intervals (≤ 12 months) was less likely to detect thyroxine under-replacement (AOR = 0.57,95%CI = 0.44–0.74,p

Abstract Background Lyme borreliosis is by far the most common vector-borne infection in Western Europe. The most severe manifestation of Lyme borreliosis is Lyme neuroborreliosis (LNB). In LNB symptoms vary from mild to severe and may include late complications that involve both physical and/or neurocognitive constraints. An estimated 25–28% of the LNB population suffers from late complications. This study investigates patient and relative perspectives on everyday life with LNB symptoms, diagnosis, and treatment to identify areas for improvement of healthcare. Methods A focus group was conducted at Odense University Hospital, Denmark. The focus group comprised 16 participants, nine patients diagnosed with LNB who had been treated at the Clinical Center for Emerging and Vector-borne Infections, and seven relatives of the patients’ choice. The focus group lasted 2 ½ hours and was audio recorded as well as documented in field notes. Results Data analysis was grounded in the conceptual framework of critical psychology and resulted in three main themes: (1) Burden of LNB symptoms in everyday life, (2) A break in the conduct of everyday life caused by LNB and (3) Need for transparent pathways to specialist knowledge. Conclusions Before diagnosis and treatment, each patient reported varying degrees of non-treatable pain, and cognitive and/or musculoskeletal symptoms. Visible physical symptoms were rare. All patients had experienced that their bodily symptoms remained unaddressed throughout numerous encounters with the healthcare system. The course of LNB comes with a break in patients’ everyday lives and self-understandings affecting their ability to work and manage everyday activities. Patients and relatives strongly recommend a specialised LNB clinic.

Abstract Background Practice facilitation (PF) is an evidence-based multicomponent in-person implementation strategy. COVID-19-related lockdowns caused many implementation initiatives to rapidly shift to virtual settings, but there is limited evidence on PF deployed exclusively using virtual meeting platforms. Our objective was to assess the feasibility and acceptability of virtual PF used in a primary care setting to implement interdisciplinary opioid safety committees (OSCs) to improve care for patients using opioid medicines for persistent pain and reduce high-dose opioid prescribing. We also describe alignment of virtual PF with the core functions of PF and fidelity of participating clinics to the OSC intervention. Methods We applied qualitative and quantitative methods to evaluate virtual PF used to implement a quality improvement project at Kaiser Permanente Washington, an integrated health system in Washington State. We established interdisciplinary OSCs in primary care clinics using virtual PF. OSCs were tasked with promoting opioid safety and high-quality pain care through population management and chart reviews. We used administrative data to calculate feasibility measures including attendance and retention. Acceptability data came from interviews with OSC members conducted by evaluators. Measures of fidelity to the OSC intervention were abstracted from meeting notes and administrative data. We used qualitative methods to assess the adherence of virtual PF to the core functions of PF. Results Facilitators carried out a comprehensive PF approach virtually and demonstrated adherence to the core functions of PF. We established OSCs in eight clinics and conducted an average of 17.5 virtual PF meetings over eight months of PF for each clinic. Average attendance was 75% and we had 84% retention. OSC members were highly satisfied with virtual PF. Facilitators effectively supported teams through implementation and technical challenges and OSC members gained skills through virtual PF. We implemented OSCs with high fidelity, suggesting virtual PF is an effective implementation strategy. Conclusions We found virtual PF is a feasible and acceptable implementation strategy for this intervention and identified strategies to support care teams through challenges. Our findings can help inform future implementation efforts, especially those hoping to engage geographically dispersed clinics or remote clinical staff. Trial registration Not applicable.

Abstract Background Animation has promise for teaching complex health content through smartphone applications. However, smartphones have had limited use in Thailand for health literacy improvement among adults with chronic diseases. This study aims to explore the perceptions of adults with diabetes and/or hypertension resulting from 2D short animated videos for literacy against chronic disease that are available via smartphones. Methods Four animated videos were initially developed based on clinical practice guidelines and nursing experience. Physicians, an expert in health education, and an animation team developed and revised scripts and storyboards of the animated videos. Lastly, videos were validated by physicians and health educators for content breadth and depth and by media experts for motion graphics and illustration. Each video presents a different situation in diabetes, hypertension, missing appointments, and obesity, ranging from 2.18 to 4.14 min in duration. The inclusion criteria were adults 35–70 years old with diabetes or hypertension who received care from primary care units. Thematic analysis was performed on the extracted data. Results Twenty participants with a mean age of 58.4 years (SD 6.7; ranged 41–68) were focus-group interviewed. Three animation elements were assessed, including presentation, impacts, and suggestions. Participants had positive responses regarding the presentation (suitability of images and smooth motion graphics, short length of videos, simple language, understandable content, and clear sound) and impacts (recalling information, enhancing engagement, and motivating health awareness and behavior change). Suggested improvements were for a bigger font size for subtitles and considering the use of spoken text instead of on-screen text for recommendations at the end of the animations. Conclusions Animated videos are acceptable for delivering health information. Pilot testing animated videos for promoting literacy against chronic diseases in adults with diabetes and hypertension is needed for optimal utility.

Abstract Aim To describe where clinical information is contemporarily and commonly found in UK primary care, what is favoured by clinicians, and whether this is (1) publicly funded (2) has commercial potential conflicts of interest. Design and setting A mixed methods study, consisting of (1) site visits to general practices in Scotland, (2) online questionnaire, focused on UK general practice (3) analysis of materials cited by professionals. Methods Data about sources of clinical information used was obtained verbally, visually and via search histories on computers from visits. This was used to inform a questionnaire in which primary care clinicians in the four nations of the UK were invited to participate. This obtained data about the information sources used and preferred by clinicians. This information was searched for data about funding and conflicts of interest. Results Over 2022, four practices were visited. 337 clinicians, 280 of whom were general practitioners completed an online questionnaire. 136 different resources were identified. These were mainly websites but sources of information included colleagues, either in practice or through online networks, apps, local guidelines, health charities, and learning resources aimed at GPs. Of these, 70 were not publicly funded, and were a mixture of membership organisations, charities, or sponsored venues. Conclusions Primary care clinicians obtain information for themselves and patients from a wide variety of sources. Funding is from a variety of sources and some contain advertising and/or sponsorship, risking commercial bias. Protocol Pre-published at https://osf.io/wrzqk .

Abstract Background Telemedicine holds immense potential to revolutionise healthcare delivery, particularly in resource-limited settings and for patients with chronic diseases. Despite proven benefits and policy reforms, the use of telemedicine remains low due to several patient, technology, and system-level barriers. Assisted telemedicine employs trained health professionals to connect patients with physicians, which can improve access and scope of telemedicine. The study aims to describe the design, service utilisation and chronic disease outcomes following the implementation of an assisted telemedicine initiative. Methods This is an observational implementation study. Barriers and potential solutions to the implementation of telemedicine were identified through interviews with key stakeholders. The assisted telemedicine solution using an interoperable platform integrating electronic health records, point-of-care diagnostics, and electronic clinical decision support systems was designed and piloted at three telemedicine clinics in Tamil Nadu, India. Nurses were trained in platform use and facilitation of tele-consultations. Health records of all patients from March 2021 to June 2023 were included in the analysis. Data were analysed to assess the utilisation of clinic services and improvements in health outcomes in patients with diabetes mellitus and hypertension. Results Over 2.4 years, 11,388 patients with a mean age of 45 (± 20) years and median age of 48 years, predominantly female (59.3%), accessed the clinics. The team completed 15,437 lab investigations and 26,998 consultations. Among 5542 (48.6%) patients that reported chronic conditions, diabetes mellitus (61%) and hypertension (45%) were the most frequent. In patients with diabetes mellitus and hypertension, 43% and 75.3% were newly diagnosed, respectively. Diabetes mellitus and hypertension patients had significant reductions in fasting blood sugar (-33.0 mg/dL (95% CI (-42.4, -23.7, P

Abstract Background At least 10% of Covid-19 recovered individuals experience persistent symptoms (Long Covid). Primary healthcare and general practitioners (GPs) are at the forefront in their care. In this study, GPs’ knowledge, perceptions and experiences with Long Covid, and the definition used in two countries, are investigated to provide insight into GPs’ care for Long Covid patients at a cross-country level. Methods A cross-sectional study targeted towards GPs was conducted in Belgium and Malta during spring and early summer 2022. An online survey consisting of 15 questions on Long Covid was disseminated. Additionally, country-specific practice and demographic characteristics were collected. Descriptive and logistic regression analyses were performed. Results A total of 150 GPs (Belgium = 105; Malta = 45) responded. Female GPs represented 58.0%, median age was 49 years (IQR: 37–61). Concerning GPs’ knowledge and perception on Long Covid, in both countries, most GPs reported insufficient scientific knowledge and information on Long Covid diagnosis and treatment. Access to educational material was limited and an awareness-rising campaign on Long Covid was deemed necessary. Moreover, two out of three GPs stated that Long Covid patients were not well followed up by primary healthcare in mid-2022. For diagnosing Long Covid, 54.7% required a positive Covid-19 test, more often among Belgian GPs than Maltese (64.3% vs. 45.2%, p = 0.036). To assess Long Covid, GPs mainly applied diagnostic criteria by themselves (47.3%) in combination with persistent symptoms (4 weeks to 5 months). Most GPs had experience with Long Covid patients in their practice, regardless of practice type and GPs’ country, sex or age (p = 0.353; p = 0.241; p = 0.194; p = 0.058). Although most GPs (94.7%) stated that Long Covid patients should follow multidisciplinary approach, 48.3% reported providing care for these patients themselves or with GP colleagues and only 29.8% by multidisciplinary cooperation. Conclusions GPs frequently provide (multidisciplinary) care to Long Covid patients and GPs’ care showed similarities at cross-country level. Although GPs perceive lack of scientific knowledge and educational material on Long Covid, similar diagnostic criteria among GPs were noted. Uniform evidence-based guidelines, scientific support and training for GP across Europe must be a priority to enhance their treatment approach to Long Covid.

Abstract Background Worldwide, mild traumatic brain injury, synonymous with concussion, affects more than 30–50 million each year. The incidence of concussion in Denmark is estimated to be about 20,000 yearly. Although complete resolution normally occurs within a few weeks, up to a third develop persistent post-concussion symptoms (PPCS) beyond 3 months. Evidence for effective treatment strategies is scarce. The objective of this study is to evaluate the efficacy of the novel intervention GAIN Lite added to enhanced usual care (EUC) for adults with mild-to-moderate PPCS compared to EUC only. Methods An open-label, parallel-group, two-arm randomised controlled superiority trial (RCT) with 1:1 allocation ratio. Potential participants will be identified through the hospital’s Business Intelligence portal of the Central Denmark Region or referred by general practitioners within 2–4 months post-concussion. Participants with mild-to-moderate PPCS will be randomly assigned to either (1) EUC or (2) GAIN Lite added to EUC. GAIN Lite is characterised as a complex intervention and has been developed, feasibility-tested and process evaluated before effect evaluation in the RCT. GAIN Lite contains an initial remote interview, self-administrated e-learning videos and voluntary remote counselling with an allocated occupational- or physiotherapist. Sixty-six participants will be recruited to each group. Primary outcomes are mean changes in PPCS and limitations in daily life from baseline to 24 weeks after baseline. Discussion GAIN Lite is a low-intensity intervention for adults with mild-to-moderate PPCS. Offering a remote intervention may improve access to rehabilitation and prevent chronification for individuals with mild-to-moderate PPCS. Moreover, GAIN Lite will facilitate access to healthcare, especially for those with transportation barriers. Overall, GAIN Lite may provide an accessible, flexible and convenient way to receive treatment based on sound theories and previous evidence of effective interventions for adults with mild-to-moderate PPCS. Trial registration ClinicalTrials.gov NCT05233475. Registered on February 10, 2022.

Abstract Background Australia’s clinical trials sector is highly productive with continued sector investment needed to enhance research impact. Generating economic evidence alongside trials has the potential to facilitate the implementation of trial results into practice. Ascertaining the use of health economic evaluations alongside clinical trials can assist in determining whether clinical trials fully realize and operationalize their potential to change policy and practice. The aims of this study were to ascertain the uptake of health economic evaluations alongside Australian-led clinical trials and explore associations between uptake and trial characteristics. Methods This observational study comprised a descriptive analysis of clinical trials registries, a cross-sectional survey of Australian Clinical Trials Alliance (ACTA) networks, and a subgroup analysis of completed acute care trials. Descriptive analyses of trial registrations were conducted, with logistic regressions used to identify predictors of proposing and subsequently publishing a health economic evaluation alongside acute care trials. Results Few randomized Australian-led clinical trials (11% of 9251) and ACTA network trials (43% of 227) proposed a health economic evaluation. In the subgroup analysis, 22% of the 324 acute care trials and 53% of the 38 ACTA network acute care trials proposed a health economic evaluation. Acute care trials funded by government bodies were significantly more likely to propose and publish a health economic evaluation than those funded by hospitals, universities, and other funders, after adjusting for phase, registration year, primary sponsor type, and comparator. Conclusions Current uptake of health economic evaluations alongside Australian-led clinical trials is low, with uptake higher among the subset of ACTA network trials. This is despite economic evidence playing an increasingly prominent role in health system management, as well as rising health expenditure, limited budgets, and competing demands. There is significant opportunity to embed health economic evaluations alongside clinical trials, particularly phase 3 trials, to increase research outputs and optimize research translation. Investing in clinical trial networks that support funding for a health economist or a health economic evaluation may be an effective strategy to increase the uptake of health economic evaluations alongside trials.

Abstract Background and aim Depression in Parkinson’s disease (DPD) has a high incidence rate among patients with Parkinson’s disease (PD). It is a common nonmotor symptom of PD that seriously affects the quality of life of patients. Thus, improving DPD is important for improving the quality of life of patients. Psychotherapy for depression is limited for many reasons, and only a few patients are able to benefit from this therapy. Several studies have demonstrated that relaxation therapy, playing, and exercise therapy are effective treatments for depression. In recent years, virtual reality (VR) has rapidly developed as a form of rehabilitation due to its immersive characteristics and accessibility. It has also been applied in the psychological treatment of phobia and anxiety. However, no relevant research on the treatment of DPD has been conducted using VR. This study aims to assess the effects of immersive VR-assisted training on patients with DPD. Methods This single-blind randomized controlled trial will recruit 74 patients with DPD. The patients will then be randomly allocated into two groups. The patients in the VR group (n = 37) will receive VR-assisted training (40 min) three times a week for 8 weeks. The patients in the non-VR training group (n = 37) will receive treatment as usual. The outcome measures will be assessed before intervention, and after 8 weeks, 3 months, and 6 months of the intervention. The primary outcomes will include the Hamilton Depression Scale-24. The secondary outcomes will include the 36-Item Short-Form Health Survey questionnaire, neuroinflammation factors (brain-derived neurotrophic factor, interleukin-6, and C-reactive protein), and functional magnetic resonance imaging. Discussion The traditional treatment of depression has limited resources and requires a lot of time and energy. It is not suitable for patients with PD having mobility difficulties and residing in remote areas. VR can make up for limitations in traditional treatment methods. An advantage of VR is that it makes patients more invested in active participation. This study may provide an improved method for the clinical treatment of patients with DPD, which is suitable for clinical decision-making and future practice. Trial registration The study has been registered in the Chinese Clinical Trial Registry ChiCTR2200065843, November 16, 2022. https://www.chictr.org.cn/showproj.html?proj=174551 {2a and 2b}

Abstract Background Perinatal anxiety is common: up to 40% of pregnant women and new mothers experience high levels of anxiety. Given its prevalence, interventions that are low-intensity, highly accessible and cost-efficient, and target modifiable risk factors for anxiety are needed. Repetitive negative thinking (RNT)—such as worrying about ways things will go wrong in the future or ruminating about past negative events—is a risk factor for the development of anxiety. RNT is maintained by the tendency to generate negative interpretations of ambiguous situations. Methods A parallel two-arm randomised controlled trial will assess the efficacy of adding interpretation training (RELAX) to usual maternity care. Participants (N = 268) will be randomised to (i) 12 sessions of online interpretation training (RELAX) plus usual care, or (ii) usual care alone. We will assess anxiety, depression, RNT, and work and social adjustment at baseline, plus 4, 8 and 36 weeks later. Discussion Should the intervention result in lower levels of anxiety than usual care, it could be an accessible, cost-effective way to help women who are vulnerable to experiencing anxiety in the perinatal period. Trial registration ISRCTN 12754931. Registered 25th May 2023, prior to recruitment.

Abstract Background Latinx children in the United States experience disparities in asthma control and asthma-related functional outcomes compared to non-Latinx White children, including more school absences, emergency department visits, and hospitalizations for asthma. Stress appears to play a role in asthma control, but interventions designed to address the role of stress in asthma control for Latinx children are limited. Method The current randomized controlled trial tests the effects of Adapt 2 Asthma (A2A), a family-based coping skills and asthma management intervention tailored to the stressors, strengths, and cultural beliefs of Latinx families, compared to an asthma self-management control arm (the Asthma Plan for Kids; APK). Latinx families of children ages 8 to 14 years old with asthma (target N = 280) are identified and enrolled from primary care clinics and randomly assigned to either A2A or APK. The intervention is delivered by lay health workers trained and receiving ongoing consultation from the study team. The primary outcome is child- and parent-reported asthma control, while secondary outcomes are child’s quality of life, lung function, school absences, and emergency department visits, and child and parent coping and family asthma management behaviors. Participants will be assessed at baseline, post-intervention, and at 6- and 12-month follow-up timepoints. Discussion This study has the potential to provide new evidence regarding the effects of culturally relevant coping and asthma management intervention strategies for Latinx children with asthma. Trial Registration Clinicaltrials.gov NCT05118282 . Registered on 11 November 2021.

Abstract Background Senescent immune cells exhibit altered gene expression and resistance to apoptosis. The prevalence of these cells increases with age and emerging data implicate senescence-associated maladaptive signaling as a potential contributor to sepsis and septic shock. The senolytic drug fisetin promotes clearance of senescent cells and is hypothesized to mitigate septic responses to infection. Methods We are conducting a multi-center, randomized, double-blinded, adaptive allocation phase 2 clinical trial to assess the efficacy of the senolytic drug fisetin in preventing clinical deterioration of elderly patients diagnosed with sepsis. We intend to enroll and randomize 220 elderly patients (age > 65) with the clinical diagnosis of sepsis to receive either fisetin as a single oral dose of 20 mg/kg, fisetin in two oral doses of 20 mg/kg each spaced 1 day apart, or placebo. The primary outcome will be changed in the composite of cardiovascular, respiratory, and renal sequential organ failure assessment scores at 7 days from enrollment. Secondary outcomes include quantification of senescent CD3 + cells at 7 days, and 28-day assessments of organ failure-free days, days in an intensive care unit, and all-cause mortality. Discussion This multi-center, randomized, double-blinded trial will assess the efficacy of fisetin in preventing clinical deterioration in elderly patients with sepsis and measure the effects of this drug on the prevalence of senescent immune cells. We intend that the results of this phase 2 trial will inform the design of a larger phase 3 study. Trial registration This trial is registered to ClinicalTrials.gov under identifier NCT05758246, first posted on March 7, 2023.

Abstract Background Most children with developmental disabilities (DD) live in low- and middle-income countries, but access to services is limited, impacting their ability to thrive. Pilot study findings of the World Health Organization’s Caregiver Skills Training (WHO CST) intervention, which equips caregivers with strategies to facilitate learning and adaptive behaviours in children with DD, are promising but evidence from an appropriately powered trial delivered by non-specialist facilitators is lacking. This study will investigate the effectiveness and the resource impacts and costs and consequences of the WHO CST intervention in four sites in rural and urban Kenya and Ethiopia. Methods This is a 2-arm multi-site hybrid type-1 effectiveness implementation cluster randomised controlled superiority trial. After baseline assessments (T0) are completed by participants in clusters comprising 7 to 10 caregiver-child dyads, the clusters will be randomised to either the WHO CST intervention arm or a waitlist enhanced care as usual control arm. Further assessments will be completed at endpoint (T1, 18 ± 2 weeks after randomisation) and follow-up (T2, 44 ± 2 weeks after randomisation). The intervention comprises three individualised home visits and nine group sessions with trained non-specialist facilitators. Participants in the control arm will receive the intervention after completing follow-up assessments. We aim to recruit 544 child-caregiver dyads, evenly distributed across the two arms and countries. The co-primary outcomes are the child-focused Child Behavior Checklist (assessing emotional and behavioural problems) and the caregiver-focused Pediatric Quality of Life Inventory (assessing caregiver quality of life), both assessed at endpoint. Secondary outcome measures comprise the two co-primary outcomes at follow-up and ten additional outcome measures at endpoint, assessing stigma-based experiences, depressive symptoms, household food insecurity, child disciplinary strategies and beliefs, CST knowledge and skill competencies, caregiver and child quality of life, social support, and children’s communication modes and functions. After quantitative follow-up assessments are completed, a mixed-methods evaluation approach will be used to investigate implementation processes and acceptability, feasibility, and potential sustainability of the intervention. Discussion The study’s findings will provide evidence of the effectiveness and resource impacts and costs and consequences of a non-specialist-delivered intervention in under-resourced contexts in one low-income and one middle-income country in East Africa. Findings will inform future research, intervention, and policy efforts to support children with DD and their families in under-resourced majority world contexts. Trial registration Pan African Clinical Trial Registry PACTR202310908063134. Registered on October 16, 2023.

Abstract Background The Structured Days Hypothesis posits that structure protects children against obesogenic behaviors (e.g., physical inactivity, unhealthy dietary intake) and, ultimately, prevents the occurrence of excessive weight gain. The hours following school (i.e., 3–6 pm school days) and summer vacation are two “windows of vulnerability” when children may experience less structure. Programs that provide a healthy structured environment and may prevent BMI gain exist for both time periods (i.e., after-school programs and summer day camps). Unfortunately, these programs are cost prohibitive for children from low-income families to attend. This study will test the impact of providing vouchers to access existing, community-operated after-school and summer programs on BMI z-score, body composition, and obesogenic behaviors (i.e., physical activity, screen use, diet, and sleep) of children (5–12 years) from schools that primarily serve families with low income. Methods The study will employ a 2x2 factorial design. Participants (N = 480) attending 4 elementary schools in one school district will be randomly assigned to a no treatment control, after-school program voucher only, summer day camp voucher only, or after-school and summer day camp vouchers. Vouchers will cover the full cost of attending a pre-existing community-based after-school or summer camp program. The primary outcome (BMI z-score) will be measured at baseline (before end of school year, ~ May), 3-month follow-up (after summer, ~ August), and 12-month follow-up (end the following school year, ~ May). Secondary outcomes include body composition (i.e., whole-body fat mass, fat free mass, and percent body fat) and obesogenic behaviors (i.e., physical activity, sedentary time, sleep, screen-time, and diet). The study will also employ a rigorous process evaluation which will consider after-school and summer camp program attendance and content. Analyses will examine differences between the four groups in BMI z-score, body composition, and obesogenic behaviors. Incremental cost effectiveness ratios will determine the cost effectiveness of the intervention. Discussion The current study will provide critical information for researchers, practitioners, and policy makers seeking to combat the childhood obesity epidemic in children from families with low-income during the school year and summer. Trial registration NCT05880901 . Registered 27 May 2023.

Abstract Introduction Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has been established as an effective treatment for peritoneal cancer (PC). However, this kind of combination therapy is associated with a high lactate level. Moreover, studies have suggested that the rate of complications early after surgery directly increased with elevated lactate levels. Glucose-insulin-potassium (GIP), a potent cardioprotective intervention, has been demonstrated to adjust blood glucose (BG) levels and reduce lactate levels. However, the insulin-glucose ratio should be adjusted according to the surgery performed. Here, we aimed to evaluate the advantages of using modified GIP during CRS/HIPEC to reduce the lactate level at the end of surgery and further reduce the incidence of early postoperative complications. Methods and analysis The modified GIP versus conventional management during surgery study is a single-center, randomized, single-blinded outcome assessment clinical trial of 80 patients with PC who are between 18 and 64 years old and undergoing CRS/HIPEC. Participants will be randomly allocated to receive modified GIP or conventional treatment (1:1). The primary outcome will be the plasma lactate level at the end of surgery. The secondary outcomes will include the highest levels and fluctuation ranges of lactate and BG during surgery, extubation time, APACHE-II score 24 h after surgery, postoperative defecation and exhaust time, postoperative lactate clearance time, postoperative liver and kidney function, incidence of complications within 7 days after surgery, length of intensive care unit stay (LIS), length of hospital stay (LHS), and total cost of hospitalization. Ethics and dissemination The trial protocol was approved by the Scientific Research Ethics Committee of Beijing Shijitan Hospital Affiliated with Capital Medical University, approval number sjtky11-1x-2022(118). The results will be published in international peer-reviewed journals. Trial registration ChiCTR2200057258. Registered on March 5, 2022.

Abstract Background Patient education is a crucial strategy for promoting prevention and diabetes self-management since glycemic control achievement involves taking medications, medical nutrition therapy, physical exercise, and behavior changes. However, patient education programs are still barely implemented in low- and middle-income countries. This trial aims to investigate whether a lifestyle education intervention added to physical exercising is superior to sole physical exercising regarding functional capacity, disease-related knowledge, health behaviors, cardiometabolic health parameters, quality of life, depression, and diet quality in individuals with prediabetes or diabetes. Methods Multicenter double-blinded randomized controlled trial with two parallel arms involving 12-week intervention and 6-month follow-up. The eligible individuals (≥ 18 years, living with prediabetes or diabetes, literate, no clinical decompensation and/or physical and/or mental limitations that contraindicate physical exercising, written physician permission for exercise, no cognitive impairment, no vision limitations for reading, no confirmed diagnosis of unstable coronary disease or heart failure, no pacemaker and/or implantable cardioverter-defibrillator, no complex ventricular arrhythmias, no intermittent claudication, no recent cardiovascular event or cardiac surgery, and no currently enrolled in a structured exercise program) were recruited from two Brazilian cities and randomized to either (1) an Exercise and Lifestyle Education Program (ExLE) or (2) an Exercise Program (Ex), which can be delivered on-site or remotely based on the participants’ internet access and technology literacy. The primary outcomes will be changes in functional capacity and disease-related knowledge. The secondary outcomes will involve changes in health behaviors (health literacy, physical activity level, exercise self-efficacy, and medication adherence) and cardiometabolic health parameters (glycemic control, anthropometric measures, and cardiac autonomic control). Program adherence, satisfaction with the program, diabetes-related morbidity, and changes in quality of life, depression, and diet quality will be the tertiary outcomes. Assessments will occur at baseline, post-intervention, and after 6-month follow-up. Discussion If superior effectiveness of ExLE compared to Ex program to improve the outcomes measures is found, this program could be delivered broadly in the Brazilian health system, especially in the primary care facilities where most individuals living with prediabetes and diabetes in our country are assisted. Trial registration ClinicalTrials.gov, NCT03914924 . Registered on April 16, 2019.

Abstract Background Balance dysfunction affects 70% of stroke patients. Emerging neurophysiological approaches, such as virtual reality therapy (VRT) and repetitive transcranial magnetic stimulation (rTMS), have been proven by clinical studies that the balance function of stroke patients can be improved when applied alone, but there are relatively few studies on the combined treatment of balance dysfunction after stroke. This study aimed to evaluate the impact of a 4-week intensive intervention combining VRT and rTMS on both balance function and brain plasticity among stroke patients. Methods This single-blind, randomized controlled trial was conducted at the Rehabilitation Medical Center of the Rehabilitation General Hospital of Ningxia Medical University. A cohort of 136 stroke patients, with durations of 2 to 24 weeks post-stroke, were enrolled in the study. Participants were randomly allocated in a 1:1:1:1 ratio to four groups: the VR group (n = 34), the rTMS group (n = 34), the combined treatment group receiving both VR and rTMS (n = 34), and the control group undergoing traditional balance training (n = 34). All patients underwent a standardized inpatient rehabilitation program over 4 weeks. The VR group received daily 30-min sessions of VR therapy for 20 days. The rTMS group underwent daily sessions of rTMS stimulation for 20 min, targeting the motor imagery region in the affected hemisphere. The combination group received VR therapy after completing their rTMS treatment. The control group received conventional balance training, with each session lasting 30 min. Additionally, all patients received an extra 60 min of standard rehabilitation therapy twice daily. Assessments were conducted at baseline, 2 weeks, and 4 weeks post-treatment, using the Berg Balance Scale (BBS) as the primary measure, and secondary measures including the Timed Up-and-Go Test (TUGT), Fugl-Meyer Assessment-Lower Extremity (FMA-LE), and 6-m walking test (6MWT), as well as assessments for brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VGEF), tyrosine receptor kinase (TrκB), motor-evoked potential latency (PL), central motor conduction time (CMCT), and amplitude. Discussion The widespread application of VR technology and rTMS in clinical settings is well-established. However, the potential synergistic effects of combining these modalities on balance function and neuroplasticity in stroke patients remain uncertain. Our hypothesis suggests that the integration of VR with rTMS may result in more pronounced improvements in both balance function and neuroplasticity among stroke patients, surpassing the outcomes achievable with VR alone, rTMS alone, or traditional therapy. The possible mechanism is that VR-based training combined with rTMS plays a superimposed effect, promoting better repair of damaged neurons and ultimately improving balance function in stroke patients. The positive results anticipated from this trial could provide objective evidence advocating for the concurrent use of VR and rTMS in clinical interventions. Trial registration The study protocol underwent review and approval by the Medical Research Ethics Committee of the General Hospital of Ningxia Medical University on January 26, 2024 (No. KYLL-2024–0162). Subsequently, it was registered in the Chinese Clinical Trial Registry on March 11, 2024 (registration number: ChiCTR2400081775). Currently, the study is still ongoing.