Economic burden and economic impact associated with non-communicable diseases among countries of World Health Organization South-East Asia Region - a systematic review protocol.

OBJECTIVE: The objective of this systematic review is to synthesize studies on economic burden and economic impact of noncommunicable diseases (NCDs) in the World Health Organization South-East Asian Region (WHO SEAR) countries. INTRODUCTION: WHO SEAR countries represent 8.6% of the world's population and 75% of all deaths in this region are attributable to NCDs. In addition, there is a pattern of low government spending on health in SEAR countries, leading to a high proportion of health financing by patients', risking impoverishment for households. INCLUSION CRITERIA: We will consider observational (cross-sectional, cohort, and case-control) and interventional (either single arm or comparative) studies that report economic burden (direct and indirect costs, out-of-pocket expenditure) and economic impact (catastrophic health expenditure, hardship financing, impoverishment, and gross domestic product impact at individual, household, and/or country levels). This includes government surveys, surveillance, and secondary data analyses for one or more NCDs prevalent in the WHO SEAR. METHODS: We will conduct a comprehensive search for relevant studies in databases, including PubMed (MEDLINE), Embase (Ovid), Scopus, Web of Science, Google Scholar, and gray literature with no date limits. Two independent reviewers will screen titles and abstracts, followed by full-text screening. Included studies will be critically appraised for quality. Data will be extracted accordingly and, if possible, random effects meta-analyses will be conducted on the pooled data for resource utilization and costs (including burden and impact), presenting the degree of variation between studies. The characteristics and results of the included studies will be narratively summarized with accompanying tables. REVIEW REGISTRATION: PROSPERO CRD42023421302.

Regulation of defective mitochondrial DNA accumulation and transmission in C. elegans by the programmed cell death and aging pathways.

The heteroplasmic state of eukaryotic cells allows for cryptic accumulation of defective mitochondrial genomes (mtDNA). 'Purifying selection' mechanisms operate to remove such dysfunctional mtDNAs. We found that activators of programmed cell death (PCD), including the CED-3 and CSP-1 caspases, the BH3-only protein CED-13, and PCD corpse engulfment factors, are required in C. elegans to attenuate germline abundance of a 3.1-kb mtDNA deletion mutation, uaDf5, which is normally stably maintained in heteroplasmy with wildtype mtDNA. In contrast, removal of CED-4/Apaf1 or a mutation in the CED-4-interacting prodomain of CED-3, do not increase accumulation of the defective mtDNA, suggesting induction of a non-canonical germline PCD mechanism or non-apoptotic action of the CED-13/caspase axis. We also found that the abundance of germline mtDNAuaDf5 reproducibly increases with age of the mothers. This effect is transmitted to the offspring of mothers, with only partial intergenerational removal of the defective mtDNA. In mutants with elevated mtDNAuaDf5 levels, this removal is enhanced in older mothers, suggesting an age-dependent mechanism of mtDNA quality control. Indeed, we found that both steady-state and age-dependent accumulation rates of uaDf5 are markedly decreased in long-lived, and increased in short-lived, mutants. These findings reveal that regulators of both PCD and the aging program are required for germline mtDNA quality control and its intergenerational transmission.

Effectiveness of a participatory approach to develop school health interventions in four low resource cities: study protocol of the 'empowering adolescents to lead change using health data' cluster randomised controlled trial.

INTRODUCTION: Comprehensive local data on adolescent health are often lacking, particularly in lower resource settings. Furthermore, there are knowledge gaps around which interventions are effective to support healthy behaviours. This study generates health information for students from cities in four middle-income countries to plan, implement and subsequently evaluate a package of interventions to improve health outcomes. METHODS AND ANALYSIS: We will conduct a cluster randomised controlled trial in schools in Fez, Morocco; Jaipur, India; Saint Catherine Parish, Jamaica; and Sekondi-Takoradi, Ghana. In each city, approximately 30 schools will be randomly selected and assigned to the control or intervention arm. Baseline data collection includes three components. First, a Global School Health Policies and Practices Survey (G-SHPPS) to be completed by principals of all selected schools. Second, a Global School-based Student Health Survey (GSHS) to be administered to a target sample of n=3153 13-17 years old students of randomly selected classes of these schools, including questions on alcohol, tobacco and drug use, diet, hygiene, mental health, physical activity, protective factors, sexual behaviours, violence and injury. Third, a study validating the GSHS physical activity questions against wrist-worn accelerometry in one randomly selected class in each control school (n approximately 300 students per city). Intervention schools will develop a suite of interventions using a participatory approach driven by students and involving parents/guardians, teachers and community stakeholders. Interventions will aim to change existing structures and policies at schools to positively influence students' behaviour, using the collected data and guided by the framework for Making Every School a Health Promoting School. Outcomes will be assessed for differential change after a 2-year follow-up. ETHICS AND DISSEMINATION: The study was approved by WHO's Research Ethics Review Committee; by the Jodhpur School of Public Health's Institutional Review Board for Jaipur, India; by the Noguchi Memorial Institute for Medical Research Institutional Review Board for Sekondi-Takoradi, Ghana; by the Ministry of Health and Wellness' Advisory Panel on Ethics and Medico-Legal Affairs for St Catherine Parish, Jamaica, and by the Comité d'éthique pour la recherche biomédicale of the Université Mohammed V of Rabat for Fez, Morocco. Findings will be shared through open access publications and conferences. TRIAL REGISTRATION NUMBER: NCT04963426.

Performance of equations for estimation of 24-hour urinary sodium from morning fasting urine samples in a multisite study in India.

Background Dietary salt intake is an important modifiable risk factor for cardiovascular diseases. Estimation of 24-hour salt intake using morning urine samples needs to be validated in the Indian context. We examined the performance of INTERSALT, Tanaka and Kawasaki equations for the estimation of 24-hour urinary sodium from morning fasting urine (MFU) samples. Methods We enrolled 486 adults aged 18-69 years from four regions of India with equal rural/urban and sex representation to provide 24-hour urine samples. The next day, a MFU sample was obtained. Based on the volume and sodium content of the 24-hour urine sample, 24-hour sodium excretion (reference method) was calculated. Sodium levels in the MFU samples were measured along with other parameters required, and the above equations were used to estimate 24-hour urinary sodium levels. Intraclass correlation coefficient (ICC) was used to assess the degree of agreement between the estimates from the reference method and the three equations. Bland-Altman (BA) plots were used to identify systematic bias and limits of agreement. A difference of 1 g of salt (0.39 g of sodium) between the mean salt intake by 24-hour urine and as estimated by equations was considered acceptable. Results A total of 346 participants provided both the samples. The mean (SD) daily salt intake estimated by the 24-hour urine sample method was 9.9 (5.8) g. ICC was low for all the three equations: highest for Kawasaki (0.16; 95% CI 0.05-0.26) and least for Tanaka (0.12; 0.02-0.22). Only Tanaka equation provided estimates within 1 g of measured 24-hour salt intake (-0.36 g). BA plots showed that as the mean values increased, all the three equations provided lower estimates of salt intake. Conclusion Tanaka equation provided acceptable values of 24-hour salt intake at the population level. However, poor performance of all the equations highlights the need to understand the reasons and develop better methods for the measurement of sodium intake at the population level.

Feedforward regulatory logic controls the specification-to-differentiation transition and terminal cell fate during Caenorhabditis elegans endoderm development.

The architecture of gene regulatory networks determines the specificity and fidelity of developmental outcomes. We report that the core regulatory circuitry for endoderm development in Caenorhabditis elegans operates through a transcriptional cascade consisting of six sequentially expressed GATA-type factors that act in a recursive series of interlocked feedforward modules. This structure results in sequential redundancy, in which removal of a single factor or multiple alternate factors in the cascade leads to a mild or no effect on gut development, whereas elimination of any two sequential factors invariably causes a strong phenotype. The phenotypic strength is successfully predicted with a computational model based on the timing and levels of transcriptional states. We found that one factor in the middle of the cascade, END-1, which straddles the distinct events of specification and differentiation, functions in both processes. Finally, we reveal roles for key GATA factors in establishing spatial regulatory state domains by repressing other fates, thereby defining boundaries in the digestive tract. Our findings provide a paradigm that could account for the genetic redundancy observed in many developmental regulatory systems.

Interstellar space biology via Project Starlight.

Our ability to explore the cosmos by direct contact has been limited to a small number of lunar and interplanetary missions. However, the NASA Starlight program points a path forward to send small, relativistic spacecraft far outside our solar system via standoff directed-energy propulsion. These miniaturized spacecraft are capable of robotic exploration but can also transport seeds and organisms, marking a profound change in our ability to both characterize and expand the reach of known life. Here we explore the biological and technological challenges of interstellar space biology, focusing on radiation-tolerant microorganisms capable of cryptobiosis. Additionally, we discuss planetary protection concerns and other ethical considerations of sending life to the stars.

A New Force Myography-Based Approach for Continuous Estimation of Knee Joint Angle in Lower Limb Amputees and Able-Bodied Subjects.

In this paper, we present a new method for estimating knee joint angle using force myography. The technique utilized force myogram signals from thigh muscles while subjects walked on a treadmill at different speeds, i.e., slow, medium, fast, and run. An eight-channel in-house force myography (FMG) data acquisition system was developed to collect the data wirelessly from seven healthy subjects and a transfemoral amputee. An artificial neural network was employed to estimate the knee joint angle from force myogram signals. The root-mean-square error across the healthy subjects was 6.9±1.5° at slow (1.5 km/hr), 6.5±1.3° at medium (4 km/hr), 7.4±2.2° at fast (6 km/hr) speeds, and 8.1±2.2° while running (8 km/hr). The root-mean-square error, across the trials, for the transfemoral amputee was 4.0±1.2° at slow (1 km/hr), 3.2±0.6° at medium (2 km/hr) and 3.8±0.9° at fast (3 km/hr) speeds. The proposed approach is useful in real-time gait analysis. The system is easily wearable, convenient in out-door use, portable, and commercially viable.

Intertwined Functions of Separase and Caspase in Cell Division and Programmed Cell Death.

Timely sister chromatid separation, promoted by separase, is essential for faithful chromosome segregation. Separase is a member of the CD clan of cysteine proteases, which also includes the pro-apoptotic enzymes known as caspases. We report a role for the C. elegans separase SEP-1, primarily known for its essential activity in cell division and cortical granule exocytosis, in developmentally programmed cell death when the predominant pro-apoptotic caspase CED-3 is compromised. Loss of SEP-1 results in extra surviving cells in a weak ced-3(-) mutant, and suppresses the embryonic lethality of a mutant defective for the apoptotic suppressor ced-9/Bcl-2 implicating SEP-1 in execution of apoptosis. We also report apparent non-apoptotic roles for CED-3 in promoting germ cell proliferation, meiotic chromosome disjunction, egg shell formation, and the normal rate of embryonic development. Moreover, loss of the soma-specific (CSP-3) and germline-specific (CSP-2) caspase inhibitors result in CED-3-dependent suppression of embryonic lethality and meiotic chromosome non-disjunction respectively, when separase function is compromised. Thus, while caspases and separases have evolved different substrate specificities associated with their specialized functions in apoptosis and cell division respectively, they appear to have retained the residual ability to participate in both processes, supporting the view that co-option of components in cell division may have led to the innovation of programmed cell suicide early in metazoan evolution.

Corrosive Esophageal Strictures: From Dilatation to Replacement: A Retrospective Cohort Study.

Endoscopic dilatation is the recommended primary therapy for chronic corrosive esophageal strictures (ES), and surgery is reserved for failed dilatation. Through this study, we intend to analyze the efficacy and long-term outcomes of both endoscopic and surgical interventions in corrosive ES. A retrospective cohort analysis of patients with chronic corrosive ES, managed with endoscopic or surgical procedures at a tertiary teaching institute in North India from December 2009 to December 2016, was performed from a prospectively maintained database. The primary outcome measure was the absence of dysphagia following dilatation or surgery. During the study period, 64 patients with ES underwent surgical or endoscopic treatment. Associated gastric strictures and pharyngeal strictures were present in 39 (60%) and 22 patients (28.9%), respectively. The mean age was 28.8 years and mean BMI was 14.2 kg/m2. Acid was the most common corrosive substance. Endoscopic dilatation using Savary-Gilliard (SG) dilators was successful in achieving persistent symptom relief in 46 patients (71.8%) after a total of 358 sessions (mean number of dilatations were 5.2 ± 1.2) of dilatations over 2 years. The dilatation therapy failed in 18 patients (28.1%) including technical failures (15.6%), perforations (3.1%), refractory stricture (1.5%) and recurrent strictures (7.8%). Increasing stricture length (more than 6 cm) was associated with poor outcome of endoscopic dilatation (p < 0.001). Only eleven patients (17%) required esophageal replacement (resection: 0, bypass: 11) for failed dilatations including seven gastric pull-ups and four pharyngo-coloplasty. The stricture rate after surgery was 36.3% (4/11). The median follows up was 32 months. Endoscopic dilatation of corrosive ES is safe and effective therapy and should be the first-line therapy for these patients and surgery should be considered only in patients who have unsuccessful outcome following dilatation therapy.

Extensive intraspecies cryptic variation in an ancient embryonic gene regulatory network.

Innovations in metazoan development arise from evolutionary modification of gene regulatory networks (GRNs). We report widespread cryptic variation in the requirement for two key regulatory inputs, SKN-1/Nrf2 and MOM-2/Wnt, into the C. elegans endoderm GRN. While some natural isolates show a nearly absolute requirement for these two regulators, in others, most embryos differentiate endoderm in their absence. GWAS and analysis of recombinant inbred lines reveal multiple genetic regions underlying this broad phenotypic variation. We observe a reciprocal trend, in which genomic variants, or knockdown of endoderm regulatory genes, that result in a high SKN-1 requirement often show low MOM-2/Wnt requirement and vice-versa, suggesting that cryptic variation in the endoderm GRN may be tuned by opposing requirements for these two key regulatory inputs. These findings reveal that while the downstream components in the endoderm GRN are common across metazoan phylogeny, initiating regulatory inputs are remarkably plastic even within a single species.

Feasibility of measuring sodium, potassium and creatinine from urine sample on dried filter paper.

Aim: To develop a bioassay for estimation of sodium, potassium and creatinine in dried urine strips and comparing with their respective concentration in liquid urine samples. Materials & methods: Urine was collected on filter paper strips, dried at room temperature and, eluted for estimation of sodium, potassium by indirect ion selective electrode method and creatinine by Jaffé method. Result: This bioassay was validated based on the US FDA guidelines for bioanalytical method validation and was linear, sensitive, accurate and precise with acceptable recovery and matrix effects. Analytes were stable in dried urine strips during 1 year of storage at 4°C. Conclusion: We conclude that the dried urine is suitable for analysis of sodium, potassium and creatinine and offers a convenient alternative for monitoring dietary salt intake.

Blumgart's technique of pancreaticojejunostomy: Analysis of safety and outcomes.

BACKGROUND: Blumgart's pancreaticojejunostomy (PJ) has been described with low pancreatic leak rates. This study aimed to evaluate our experience with this technique regarding the pancreatic leak and other perioperative outcomes. METHODS: We performed a single-center retrospective analysis of a cohort of 81 patients who underwent pancreaticoduodenectomy in our department from January 2011 to February 2018. The primary endpoint was the occurrence of a clinically relevant postoperative pancreatic fistula (CR-POPF) and analysis of its risk factors. RESULTS: The CR-POPF rate was 12.3%. Fistula risk score (FRS) was the only significant risk factor for the occurrence of overall POPF in multivariate analysis. However, none of the other factors including FRS was found to be significantly associated with CR-POPF risk. A strong positive correlation was found between the CR-POPF and the incidence of delayed gastric emptying, post-pancreatectomy hemorrhage and increased length of hospital stay. CONCLUSION: Blumgart's technique is a safe technique of pancreatico-enteric anastomosis with low rates of CR-POPF. CR-POPF with this technique is independent of most of the preoperative and intraoperative factors. Therefore, this technique can be used for all types of the pancreas with consistently good results.

Per anal endoscopic rectopexy for treatment of complete rectal prolapse: A preliminary report.

We describe Per Anal Endoscopic Rectopexy (PAER), a new treatment for complete rectal prolapse, which involves fixing the anterior rectal wall to the under-surface of the anterior abdominal wall and posterior rectal wall to the sacrum, through a submucosal tunnel (both endoluminally). This is a prospective single-centre pilot study done at a tertiary care centre. A total of 12 patients with a mean age of 48 years underwent the procedure. Constipation and incontinence were present in 8 and 4 patients, respectively and a significant improvement was seen in both following the procedure. A significant decrease in anorectal angle and its descent was also observed on post procedure magnetic resonance defecography. One patient had partial recurrence of prolapse. No major morbidity was observed. PAER is a minimally invasive and safe option for rectal prolapse, which needs to be validated in more patients over a longer follow up period.

Management of post cholecystectomy vascular injuries.

INTRODUCTION: Vasculobiliary and vascular injuries following cholecystectomy are the most serious complications requiring complex surgical management resulting in greater patient morbidity and mortality. METHODOLOGY: The study was performed at a tertiary teaching hospital of North India. Records of patients referred for biliary or vascular injury sustained during cholecystectomy were reviewed retrospectively to identify patients with vascular injury between January 2009 and March 2018. Clinical profile, hospital course and outcome of these patients were analysed. RESULTS: Over nine years, 117 patients were referred for cholecystectomy related complications. Total incidence of vascular injury was 5.1% (6/117). Combined vasculobiliary injury (VBI) occurred in 3.4% (4/117) while isolated vascular injury was present in 1.7% patients (2/117). Most (5/6) patients were operated for uncomplicated gall stone disease. Incidences of portal vein (PV) and right hepatic artery (RHA) injuries were equal (3/6). PV injuries were repaired either during cholecystectomy (1/3) or during re-exploration after damage control packing (2/3). RHA injuries presented as pseudoaneurysm and were managed surgically (2/3) or by coil embolization (1/3). All VBI referrals (4/117) were following open cholecystectomy. In VBI patients, vascular injury was diagnosed intra-operatively in two while it was diagnosed several weeks after cholecystectomy in two others. Biliary injury manifested as bile leak post-operatively in all four of them. Nature of biliary injury could be characterized in only 50% (2/4) patients. Definitive repair of biliary injury was performed in one patient only. There was one mortality in our series. CONCLUSION: Vascular injury is an uncommon complication of cholecystectomy with catastrophic outcome if not managed timely and properly. Adequate surgeon training, keeping the possibility of aberrant vasculobiliary anatomy in all cases, and proper surgical technique is crucial for prevention of such injuries. However in such an event, proper documentation and referral to tertiary centre will help in decreasing morbidity and further litigation.

Laparoscopic ventral rectopexy: A viable option in procidentia with redundant sigmoid - An Indian perspective.

INTRODUCTION: Laparoscopic ventral mesh rectopexy (LVMR) has gained widespread acceptance for the management of complete rectal prolapse (CRP). However, there have been concerns considering its use in patients with a redundant sigmoid colon. This study was conducted to evaluate the anatomical and functional results following LVMR, particularly in cases of CRP with a redundant sigmoid colon. MATERIALS AND METHODS: Retrospective analysis of 25 patients who underwent LVMR from January 2011 to September 2016 was performed. Patients were divided into two groups according to the duration of follow-up. Group A (long-term) with follow-up >3 years and Group B (mid-term) <3 years. RESULTS: The study included 25 patients (M:F = 1.5:1) with a median age of 38 years. Eighty-eight percent of the patients had a redundant sigmoid colon. Significant improvement in post-operative Wexner score as compared to pre-operative values was seen in patients with pre-existing constipation (P < 0.0001). In patients presenting with faecal incontinence (FI), significant improvement in post-operative St. Mark's incontinence score was observed. Functional outcomes remain consistent in long-term follow-up (>3 years). CONCLUSIONS: LVMR seems to be a feasible surgical procedure with minimum morbidity and good long-term functional outcomes. It provides satisfactory results in patients with redundant sigmoid colon and improves pre-existing constipation and FI.

The multipotency-to-commitment transition in Caenorhabditis elegans-implications for reprogramming from cells to organs.

In animal embryos, cells transition from a multipotential state, with the capacity to adopt multiple fates, into an irreversible, committed state of differentiation. This multipotency-to-commitment transition (MCT) is evident from experiments in which cell fate is reprogrammed by transcription factors for cell type-specific differentiation, as has been observed extensively in Caenorhabditis elegans. Although factors that direct differentiation into each of the three germ layer types cannot generally reprogram cells after the MCT in this animal, transcription factors for endoderm development are able to do so in multiple differentiated cell types. In one case, these factors can redirect the development of an entire organ in the process of "transorganogenesis". Natural transdifferentiation also occurs in a small number of differentiated cells during normal C. elegans development. We review these reprogramming and transdifferentiation events, highlighting the cellular and developmental contexts in which they occur, and discuss common themes underlying direct cell lineage reprogramming. Although certain aspects may be unique to the model system, growing evidence suggests that some mechanisms are evolutionarily conserved and may shed light on cellular plasticity and disease in humans.

Liver hydatid cyst with cystobiliary communication: Laparoscopic surgery remains an effective option.

INTRODUCTION: Most centres offer laparoscopic treatment for liver hydatid cyst (LHC). There have been concerns about the management of intra-peritoneal spillage, bleeding, and cystobiliary communication (CBC) during laparoscopic surgery for LHC. CBC can exist in 13%-37% of cases of LHC. No randomised studies have compared open versus laparoscopic approach for the treatment of LHC. We specifically analysed the outcomes of laparoscopic treatment of LHC with special reference to associated biliary complications. PATIENTS AND METHODS: We analysed our prospectively collected data of patients undergoing laparoscopic treatment of LHC from 2009 to 2016. Patients undergoing open surgery or interventional radiology procedures were not included. Data analysed included demographic profile, investigational parameters, intra-operative findings and postoperative results with special reference to biliary complications and presence/management of CBC. RESULTS:: A total of 41 patients underwent laparoscopic treatment of LHC. History of jaundice was present in 5 (12.2%) patients. CBC was documented in 16 (39.02%) patients. In 11 patients, CBC was detected intra-operatively as visible communication, which was suture ligated or clipped. Five patients had occult CBC, detected as bile leak in the post-operative period. The leak resolved spontaneously in 7 patients and with biliary stenting in 2 patients. Only one patient had a persistent biliary leak. Postoperative bile leak was more common in patients with raised alkaline phosphatase. No statistically significant association was seen with size or location of the cyst, number of cysts and World Health Organisation classification. CONCLUSION: Laparoscopic treatment of LHC with associated CBC provides acceptable results.