Social support and economic conditions among older migrants in India: do distance, duration, and streams of migration play a role in later life?

BACKGROUND: Being older and having a migrant feature might cause a double risk of vulnerability in poor economic, social support, and health status at the place of destination. This study examines the association of migration on the social support and economic condition of older persons in India. METHODS: Longitudinal Ageing Study in India (LASI) wave-I (2017-2018) data with total samples of 66,156 older adults aged 45 + with 30,869 and 35,287 male and female samples, respectively, used in this study. Descriptive and bivariate analyses have been performed to examine the pattern of older migrants, and multinomial logistic regression analysis has been used to establish the associations between migration, social support, and economic condition. RESULTS: Over half (57.5%) of the population aged 45 + in India had migrant characteristics; 80% migrated before 25 years. Of all migrants, about 90% migrated within one state (Intrastate), and 9% migrated to another (Interstate). The association between social support and migration by distance and the adjusted result showed that immigrants were less likely to have medium [RRR = 0.56 (CI; 0.46-0.68)] and high [RRR = 0.39 (CI; 0.30-0.50)] social support. The interstate migrants were also less likely to have high [RRR = 0.90 (CI; 0.83-0.98)] social support. The migrants with 0-9 years of duration were less likely to have high social support, and the urban to rural stream migrants were more likely to have high social support. The association between economic status and migration by distance and the adjusted result showed that more affluent immigrants were likelier to have [RRR = 1.41 (CI; 1.14-1.73)] better economic conditions than affluent non-migrants. Migrants with 0-9-year duration and urban to rural stream were found to be likelier to have better economic conditions. CONCLUSIONS: The findings of this study suggest that distance, duration, and migration stream have a significant association with social support and economic conditions in later life. In exploring migration's effect on social and economic status, policymakers should prioritize migrants in their agenda to maintain socio-economic and social support for older persons in India to achieve the sustainable goal of active and healthy ageing.

Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in obesity.

Overnutrition engenders the expansion of adipose tissue and the accumulation of immune cells, in particular, macrophages, in the adipose tissue, leading to chronic low-grade inflammation and insulin resistance. In obesity, several proinflammatory subpopulations of adipose tissue macrophages (ATMs) identified hitherto include the conventional "M1-like" CD11C-expressing ATM and the newly discovered metabolically activated CD9-expressing ATM; however, the relationship among ATM subpopulations is unclear. The ER stress sensor inositol-requiring enzyme 1α (IRE1α) is activated in the adipocytes and immune cells under obesity. It is unknown whether targeting IRE1α is capable of reversing insulin resistance and obesity and modulating the metabolically activated ATMs. We report that pharmacological inhibition of IRE1α RNase significantly ameliorates insulin resistance and glucose intolerance in diet-induced obesity mice. IRE1α inhibition also increases thermogenesis and energy expenditure, and hence protects against high fat diet-induced obesity. Our study shows that the "M1-like" CD11c + ATMs are largely overlapping with but yet non-identical to CD9 + ATMs in obese white adipose tissue. Notably, IRE1α inhibition diminishes the accumulation of obesity-induced metabolically activated ATMs and "M1-like" ATMs, resulting in the curtailment of adipose inflammation and ensuing reactivation of thermogenesis, without augmentation of the alternatively activated M2 macrophage population. Our findings suggest the potential of targeting IRE1α for the therapeutic treatment of insulin resistance and obesity.

Anti-Parkinson potential of hesperetin nanoparticles: in vivo and in silico investigations.

Parkinson's disease (PD) is characterised by the gradual demise of dopaminergic neurons. In recent years, there has been significant interest in herbal treatments. In this study, hesperetin nanoparticles (HTN) were developed and compared their anti-PD potential with hesperetin (HT) on rotenone induced PD rats. Molecular docking was also performed to evaluate the binding affinity of hesperetin on pathological protein, i.e. D2 dopamine receptors (DR2), using Auto Dock Vina tools. The results showed a higher binding relationship of HTN on dopamine receptors (-7.2 kcal/mol) compared to L-dopa (-6.4 kcal/mol), supporting their potential as drug candidates for PD therapy. HTN was effectively synthesised using the fabrication technique and characterised by zeta potential and SEM analysis. HTN had favourable characteristics, including a size of 249.8 ± 14.9 nm and a Z-potential of -32.9 mV. After being administered orally, HTN demonstrated a notable anti-Parkinsonian effects, indicated by the significant improvement in motor function as assessed by the rota rod test (p < .001***), pole test (p < .001***), stair test (p < .01**), wood walk test (p < .01**) and an increase in substantia nigra (SN) antioxidant levels, CAT (p < .001***), SOD (p < .001***), GSH (p < .01**). Additionally, HTN led to increased dopamine levels (p < .01**) and a decrease in the oxidant system, MDA levels (p < .01**). Furthermore, histopathological examination revealed decreased SN neuronal necrosis in diseased animals treated with HTN compared to those treated with HT in a rat model of Parkinson's disease. Therefore, HTN can be regarded as a viable platform for efficient therapy of PD.

Growth of diamond in liquid metal at 1 atm pressure.

Natural diamonds were (and are) formed (thousands of million years ago) in the upper mantle of Earth in metallic melts at temperatures of 900-1,400 °C and at pressures of 5-6 GPa (refs. 1,2). Diamond is thermodynamically stable under high-pressure and high-temperature conditions as per the phase diagram of carbon3. Scientists at General Electric invented and used a high-pressure and high-temperature apparatus in 1955 to synthesize diamonds by using molten iron sulfide at about 7 GPa and 1,600 °C (refs. 4-6). There is an existing model that diamond can be grown using liquid metals only at both high pressure and high temperature7. Here we describe the growth of diamond crystals and polycrystalline diamond films with no seed particles using liquid metal but at 1 atm pressure and at 1,025 °C, breaking this pattern. Diamond grew in the subsurface of liquid metal composed of gallium, iron, nickel and silicon, by catalytic activation of methane and diffusion of carbon atoms into and within the subsurface regions. We found that the supersaturation of carbon in the liquid metal subsurface leads to the nucleation and growth of diamonds, with Si playing an important part in stabilizing tetravalently bonded carbon clusters that play a part in nucleation. Growth of (metastable) diamond in liquid metal at moderate temperature and 1 atm pressure opens many possibilities for further basic science studies and for the scaling of this type of growth.

Understanding patients' mobility for treatment seeking in India.

Healthcare systems worldwide are grappling with the challenge of providing high-quality healthcare in the face of evolving disease patterns. India, like many other countries, faces a significant treatment gap for various curable impairments, non-communicable diseases (NCDs), and cardiovascular diseases (CVDs). To address their healthcare needs, individuals often relocate in search of better treatment options. However, no studies were conducted to understand the spatial mobility. This paper explores the determinants of spatial mobility for treatment in India using data from NSS 75th round (2017-2018). A total of 64,779 individual medical cases of different diseases were taken into consideration for our analysis. Fixed effect and multinomial regression models were used to understand diseases specific mobility for treatment. It was found that those with CVDs, NCDs, and disabilities are more prone to travel outside their district for medical care. Rural and economically disadvantaged individuals also tend to travel further for treatment. The key factors impacting treatment-seeking mobility include insurance coverage, hospital quality, cost of medicine, and cost of X-rays/surgeries. The study highlights the need for improved policies to address the gap between healthcare needs and infrastructure in India, with a focus on prioritizing the development of local healthcare facilities for disabilities, NCDs, and CVDs.

A Randomized, Double-Blind, Parallel-Group Phase III Trial Investigating the Glycemic Efficacy and Safety Profile of Fixed-Dose Combination Dapagliflozin and Linagliptin Over Linagliptin Monotherapy in Patients with Inadequately Controlled Type 2 Diabetes with Metformin.

INTRODUCTION: The aim of the study was to evaluate the efficacy and safety of fixed-dose combination (FDC) of dapagliflozin (10 mg) and linagliptin (5 mg) in comparison to linagliptin 5 mg (Trajenta) in patients with insufficiently controlled type 2 diabetes mellitus (T2DM) on metformin monotherapy. METHODS: The double-blind, randomized, multicentric, parallel-group phase III trial screened 287 adult patients with T2DM (age 18-65 years) from 16 sites across India. The recruited subjects were undergoing metformin monotherapy ≥ 1000 mg/day for at least 28 days. Patients with HbA1c of 7.5-10.5% (58-91 mmol/l) (n = 232) after 2 weeks of run-in period with linagliptin monotherapy and placebo dapagliflozin/linagliptin on metformin monotherapy were randomized (1:1) in parallel to once daily dapagliflozin/linagliptin 10/5 mg or linagliptin 5 mg for 16 weeks. Patients were stratified on the basis of HbA1c (≤ 9.0% and > 9.0%; ≤ 75 mmol/l and > 75 mmol/l)). A total of 225 subjects completed 16 weeks of treatment, 115 patients in the test group and 110 patients in the reference group. RESULTS: Dapagliflozin/linagliptin (p = 0.0003) exhibited a greater change in HbA1c from baseline than linagliptin (p < 0.0001) in 16 weeks (mean reduction, - 1.28% vs - 0.83%). Test group showed a significant decrease in fasting plasma glucose (FPG), postprandial plasma glucose (PPG) and body weight compared to the reference group. The FDC was well tolerated with adverse events being more frequent in the reference group. No serious adverse events (SAEs) were reported in the study. CONCLUSION: Dapagliflozin/linagliptin combination is a novel dipeptidyl peptidase 4 (DPP4)/sodium-glucose co-transporter 2 (SGLT2) inhibitor FDC approved in India for patients with T2DM. Potential limitations of this study are a small dose of dapagliflozin (10 mg) in the FDC, a short study duration (30 weeks) and a high minimum threshold for HbA1c (≤ 7.5%; ≤ 53 mmol/l). Results indicate the FDC to be a superior therapeutic option over linagliptin for patients with T2DM on metformin monotherapy. TRIAL REGISTRATION: CTRI/2022/08/044563; 01/08/2022.

Manganese-Doped Bimetallic (Co,Ni)2P Integrated CoP in N,S Co-Doped Carbon: Unveiling a Compatible Hybrid Electrocatalyst for Overall Water Splitting.

Rational design of highly efficient noble-metal-unbound electrodes for hydrogen and oxygen production at increased current density is crucial for robust water-splitting. A facile hydrothermal and room-temperature aging method is presented, followed by chemical vapor deposition (CVD), to create a self-sacrificed hybrid heterostructure electrocatalyst. This hybrid material, (Mn-(Co,Ni)2P/CoP/(N,S)-C), comprises manganese-doped cobalt nickel phosphide (Mn-(Co,Ni)2P) nanofeathers and cobalt phosphide (CoP) nanocubes embedded in a nitrogen and sulfur co-doped carbon matrix (N,S)-C on nickel foam. The catalyst exhibits excellent performance in both the hydrogen evolution reaction (HER; η10 = 61 mV) and oxygen evolution reaction (OER; η10 = 213 mV) due to abundant active sites, high porosity, and enhanced hetero-interface interaction between Mn-(Co2P-Ni2P) CoP, and (N,S)-C supported by significant synergistic effects observed among different phases through density functional theory (DFT) calculations. Impressively, (Mn-(Co,Ni)2P/CoP/(N,S)-C (+,-) shows an extra low cell voltage of 1.49 V@10 mA cm-2. Moreover, the catalyst exhibits remarkable stability at 100 and 300 mA cm-2 when operating as a single stack cell electrolyzer. The superior electrochemical activity is attributed to the enhanced electrode-electrolyte interface among the multiple phases of the hybrid structure.

Blocking of doublecortin-like kinase 1-regulated SARS-CoV-2 replication cycle restores cell signaling network.

IMPORTANCE: Severe COVID-19 and post-acute sequelae often afflict patients with underlying co-morbidities. There is a pressing need for highly effective treatment, particularly in light of the emergence of SARS-CoV-2 variants. In a previous study, we demonstrated that DCLK1, a protein associated with cancer stem cells, is highly expressed in the lungs of COVID-19 patients and enhances viral production and hyperinflammatory responses. In this study, we report the pivotal role of DCLK1-regulated mechanisms in driving SARS-CoV-2 replication-transcription processes and pathogenic signaling. Notably, pharmacological inhibition of DCLK1 kinase during SARS-CoV-2 effectively impedes these processes and counteracts virus-induced alternations in global cell signaling. These findings hold significant potential for immediate application in treating COVID-19.

Gastrointestinal Duplications: A Decade's Experience.

Context: Gastrointestinal (GI) duplications are rare congenital malformations with diverse presentations. They usually present in the pediatric age, especially in the first 2 years of life. Aims: To present our experience with GI duplication (cysts) at a pediatric surgery tertiary care teaching institute. Settings and Design: It is a retrospective observational study undertaken in the department of pediatric surgery at our center between 2012 and 2022 for GI duplications. Materials and Methods: All children were analyzed for their age, sex, presentation, radiological evaluation, operative management, and outcomes. Results: Thirty-two patients were diagnosed with GI duplication. Slight male predominance was present in the series (M: F ≈ 4:3). Fifteen (46.88%) patients presented in the neonatal age group; 26 (81.25%) patients were under 2 years. In the majority of cases (n = 23, 71.88%), the presentation was acute onset. Double duplication cysts on opposite sides of the diaphragm were present in one case. The most common location was ileum (n = 17), followed by gallbladder (n = 6), appendix (n = 3), gastric (n = 1), jejunum (n = 1), esophagus (n = 1), ileocecal junction (n = 1), duodenum (n = 1), sigmoid (n = 1), and anal canal (n = 1). Multiple associations (malformations/surgical pathologies) were present. Intussusception (n = 6) was the most common, followed by intestinal atresia (n = 5), anorectal malformation (n = 3), abdominal wall defect (n = 3), hemorrhagic cyst (n = 1), Meckel's diverticulum (n = 1), and sacrococcygeal teratoma (n = 1). Four cases were associated with intestinal volvulus, three cases with intestinal adhesions, and two with intestinal perforation. Favorable outcomes were present in 75% of cases. Conclusion: GI duplications have varied presentations depending on site, size, type, local mass effect, mucosal pattern, and associated complications. The importance of clinical suspicion and radiology cannot be underrated. Early diagnosis is required to prevent postoperative complications. Management is individualized as per the type of duplication anomaly and its relation with the involved GI tract.

Utility of Narrow-band Imaging Bronchoscopy in the Diagnosis of Endobronchial Sarcoidosis.

BACKGROUND: There are few reports on the utility of bronchoscopic narrow-band imaging (NBI) for visualizing endobronchial abnormalities in sarcoidosis. Our primary objective was to compare the sensitivity of finding endobronchial abnormality using NBI versus white light bronchoscopy (WLB) in patients with sarcoidosis. The secondary aim was to evaluate the sensitivity of NBI in diagnosing endobronchial sarcoidosis against a reference standard of positive endobronchial biopsy (EBB). METHODS: We retrospectively included subjects with sarcoidosis, where we sequentially recorded WLB and NBI videos to visualize the endobronchial mucosa. We collected data on the demographic findings, sarcoidosis stage, and the histopathological findings of transbronchial needle aspiration, EBB, and transbronchial lung biopsy. Three experienced bronchoscopists viewed the video recordings and noted the abnormalities of the airway mucosa separately on WLB and NBI. RESULTS: We included 28 subjects (mean age, 42.9 y; 53.6% men; 14 each, stages 1 and 2) with a final diagnosis of sarcoidosis. Granulomas were detected on EBB in 11 (39.3%) subjects. We identified endobronchial nodules in 10 and 15 subjects on WLB and NBI. The sensitivity of finding endobronchial abnormality using WLB and NBI was 35.7% (10/28) and 53.6% (15/28), respectively (χ 2 =1.77, df=1, P =0.18). The sensitivity of NBI in diagnosing endobronchial sarcoidosis against a positive EBB was 63.6% (7/11 subjects). There was excellent agreement (Κ=0.86) for detecting nodules on NBI among the 3 observers. CONCLUSION: NBI might allow the identification of additional abnormalities not detected on WLB in sarcoidosis. Larger studies are required to confirm our observations.

Methylation Array Signals are Predictive of Chronological Age Without Bisulfite Conversion.

DNA methylation data has been used to make "epigenetic clocks" which attempt to measure chronological and biological aging. These models rely on data derived from bisulfite-based measurements, which exploit a semi-selective deamination and a genomic reference to determine methylation states. Here, we demonstrate how another hallmark of aging, genomic instability, influences methylation measurements in both bisulfite sequencing and methylation arrays. We found that non-methylation factors lead to "pseudomethylation" signals that are both confounding of epigenetic clocks and uniquely age predictive. Quantifying these covariates in aging studies will be critical to building better clocks and designing appropriate studies of epigenetic aging.

How We Do It: Whole Lung Lavage.

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disorder characterized by the accumulation of surfactant in the alveolar spaces resulting in hypoxemic respiratory failure. Whole lung lavage (WLL), the preferred treatment for PAP, physically removes the lipoproteinaceous material from the alveolar spaces. Since its initial description in 1963, the WLL procedure has undergone various modifications. However, the procedure has not been standardized yet. After securing a double lumen endotracheal tube, we perform WLL under general anesthesia. One lung is ventilated, while the other is lavaged using one-liter aliquots of pre-warmed saline. We use gravity-assisted drainage of the lavaged lung after each cycle till the milky white and opaque fluid becomes clear (usually 15-20 cycles). Herein, we describe the step-by-step procedure, precautions, and monitoring of WLL. We also provide videos demonstrating one-lung ventilation and bronchoscopic confirmation of lung isolation.

Targeting Doublecortin-Like Kinase 1 (DCLK1)-Regulated SARS-CoV-2 Pathogenesis in COVID-19.

Host factors play critical roles in SARS-CoV-2 infection-associated pathology and the severity of COVID-19. In this study, we systematically analyzed the roles of SARS-CoV-2-induced host factors, doublecortin-like kinase 1 (DCLK1), and S100A9 in viral pathogenesis. In autopsied subjects with COVID-19 and pre-existing chronic liver disease, we observed high levels of DCLK1 and S100A9 expression and immunosuppressive (DCLK1+S100A9+CD206+) M2-like macrophages and N2-like neutrophils in lungs and livers. DCLK1 and S100A9 expression were rarely observed in normal controls, COVID-19-negative subjects with chronic lung disease, or COVID-19 subjects without chronic liver disease. In hospitalized patients with COVID-19, we detected 2 to 3-fold increased levels of circulating DCLK1+S100A9+ mononuclear cells that correlated with disease severity. We validated the SARS-CoV-2-dependent generation of these double-positive immune cells in coculture. SARS-CoV-2-induced DCLK1 expression correlated with the activation of ß-catenin, a known regulator of the DCLK1 promoter. Gain and loss of function studies showed that DCLK1 kinase amplified live virus production and promoted cytokine, chemokine, and growth factor secretion by peripheral blood mononuclear cells. Inhibition of DCLK1 kinase blocked pro-inflammatory caspase-1/interleukin-1ß signaling in infected cells. Treatment of SARS-CoV-2-infected cells with inhibitors of DCLK1 kinase and S100A9 normalized cytokine/chemokine profiles and attenuated DCLK1 expression and ß-catenin activation. In conclusion, we report previously unidentified roles of DCLK1 in augmenting SARS-CoV-2 viremia, inflammatory cytokine expression, and dysregulation of immune cells involved in innate immunity. DCLK1 could be a potential therapeutic target for COVID-19, especially in patients with underlying comorbid diseases associated with DCLK1 expression. IMPORTANCE High mortality in COVID-19 is associated with underlying comorbidities such as chronic liver diseases. Successful treatment of severe/critical COVID-19 remains challenging. Herein, we report a targetable host factor, DCLK1, that amplifies SARS-CoV-2 production, cytokine secretion, and inflammatory pathways via activation of ß-catenin(p65)/DCLK1/S100A9/NF-κB signaling. Furthermore, we observed in the lung, liver, and blood an increased prevalence of immune cells coexpressing DCLK1 and S100A9, a myeloid-derived proinflammatory protein. These cells were associated with increased disease severity in COVID-19 patients. Finally, we used a novel small-molecule inhibitor of DCLK1 kinase (DCLK1-IN-1) and S100A9 inhibitor (tasquinimod) to decrease virus production in vitro and normalize hyperinflammatory responses known to contribute to disease severity in COVID-19.

Cellular Carcinogenesis: Role of Polarized Macrophages in Cancer Initiation.

Inflammation is an essential hallmark of cancer. Macrophages are key innate immune effector cells in chronic inflammation, parainflammation, and inflammaging. Parainflammation is a form of subclinical inflammation associated with a persistent DNA damage response. Inflammaging represents low-grade inflammation due to the dysregulation of innate and adaptive immune responses that occur with aging. Whether induced by infection, injury, or aging, immune dysregulation and chronic macrophage polarization contributes to cancer initiation through the production of proinflammatory chemokines/cytokines and genotoxins and by modulating immune surveillance. This review presents pre-clinical and clinical evidence for polarized macrophages as endogenous cellular carcinogens in the context of chronic inflammation, parainflammation, and inflammaging. Emerging strategies for cancer prevention, including small molecule inhibitors and probiotic approaches, that target macrophage function and phenotype are also discussed.

Eliciting relative preferences for the attributes of health insurance schemes among rural consumers in India.

There is a limited understanding of the preferences of rural consumers in India for health insurance schemes. In this article, we investigate the preferences of the rural population for the attributes of a health insurance scheme by implementing a discrete choice experiment (DCE). We identified six attributes through qualitative and quantitative study: enrollment, management, benefit package, coverage, transportation facility, and monthly premium. A D-efficient design of 18 choices has been constructed, each comprising two health insurance choices. We collected the representative sample from 675 household heads of the rural population through personal interviews. The preferences for the attributes and attribute levels were estimated using the multinomial logit (MNL) and random-parameter logit (RPL) models. The analysis shows that all attribute levels significantly affect the choice behavior (P < 0.05). The relative order of preferences for attributes are; enrollment, benefit package, monthly premium, management, coverage, and transportation.

Real-time prediction of smoking activity using machine learning based multi-class classification model.

Smoking cessation efforts can be greatly influenced by providing just-in-time intervention to individuals who are trying to quit smoking. Detecting smoking activity accurately among the confounding activities of daily living (ADLs) being monitored by the wearable device is a challenging and intriguing research problem. This study aims to develop a machine learning based modeling framework to identify the smoking activity among the confounding ADLs in real-time using the streaming data from the wrist-wearable IMU (6-axis inertial measurement unit) sensor. A low-cost wrist-wearable device has been designed and developed to collect raw sensor data from subjects for the activities. A sliding window mechanism has been used to process the streaming raw sensor data and extract several time-domain, frequency-domain, and descriptive features. Hyperparameter tuning and feature selection have been done to identify best hyperparameters and features respectively. Subsequently, multi-class classification models are developed and validated using in-sample and out-of-sample testing. The developed models obtained predictive accuracy (area under receiver operating curve) up to 98.7% for predicting the smoking activity. The findings of this study will lead to a novel application of wearable devices to accurately detect smoking activity in real-time. It will further help the healthcare professionals in monitoring their patients who are smokers by providing just-in-time intervention to help them quit smoking. The application of this framework can be extended to more preventive healthcare use-cases and detection of other activities of interest. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11042-022-12349-6.