Gene therapy for CNS disorders: modalities, delivery and translational challenges.

Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.

Polygenic risk score adds to a clinical risk score in the prediction of cardiovascular disease in a clinical setting.

BACKGROUND AND AIMS: A cardiovascular disease polygenic risk score (CVD-PRS) can stratify individuals into different categories of cardiovascular risk, but whether the addition of a CVD-PRS to clinical risk scores improves the identification of individuals at increased risk in a real-world clinical setting is unknown. METHODS: The Genetics and the Vascular Health Check Study (GENVASC) was embedded within the UK National Health Service Health Check (NHSHC) programme which invites individuals between 40-74 years of age without known CVD to attend an assessment in a UK general practice where CVD risk factors are measured and a CVD risk score (QRISK2) is calculated. Between 2012-2020, 44,141 individuals (55.7% females, 15.8% non-white) who attended an NHSHC in 147 participating practices across two counties in England were recruited and followed. When 195 individuals (cases) had suffered a major CVD event (CVD death, myocardial infarction or acute coronary syndrome, coronary revascularisation, stroke), 396 propensity-matched controls with a similar risk profile were identified, and a nested case-control genetic study undertaken to see if the addition of a CVD-PRS to QRISK2 in the form of an integrated risk tool (IRT) combined with QRISK2 would have identified more individuals at the time of their NHSHC as at high risk (QRISK2 10-year CVD risk of ≥10%), compared with QRISK2 alone. RESULTS: The distribution of the standardised CVD-PRS was significantly different in cases compared with controls (cases mean score .32; controls, -.18, P = 8.28×10-9). QRISK2 identified 61.5% (95% confidence interval [CI]: 54.3%-68.4%) of individuals who subsequently developed a major CVD event as being at high risk at their NHSHC, while the combination of QRISK2 and IRT identified 68.7% (95% CI: 61.7%-75.2%), a relative increase of 11.7% (P = 1×10-4). The odds ratio (OR) of being up-classified was 2.41 (95% CI: 1.03-5.64, P = .031) for cases compared with controls. In individuals aged 40-54 years, QRISK2 identified 26.0% (95% CI: 16.5%-37.6%) of those who developed a major CVD event, while the combination of QRISK2 and IRT identified 38.4% (95% CI: 27.2%-50.5%), indicating a stronger relative increase of 47.7% in the younger age group (P = .001). The combination of QRISK2 and IRT increased the proportion of additional cases identified similarly in women as in men, and in non-white ethnicities compared with white ethnicity. The findings were similar when the CVD-PRS was added to the atherosclerotic cardiovascular disease pooled cohort equations (ASCVD-PCE) or SCORE2 clinical scores. CONCLUSIONS: In a clinical setting, the addition of genetic information to clinical risk assessment significantly improved the identification of individuals who went on to have a major CVD event as being at high risk, especially among younger individuals. The findings provide important real-world evidence of the potential value of implementing a CVD-PRS into health systems.

Increased taxes and regulation of Indian cigarillos (bidi) industry: Effects on revenue and years of life lost.

INTRODUCTION: Indian cigarillos (bidi) are low-cost alternatives to cigarettes with only 22% imposed taxes, and turnover of upto INR 4 million per annum exempted from taxation. This paper estimates revenue implications and potential loss of life years (YLLs) averted, if bidi industry is subjected to increased regulations and taxation. METHODS: Revenue estimated at 10% increased regulation and 100% regulation were calculated, followed by estimates at taxes equivalent to cigarettes and World Health Organization - Framework Convention on Tobacco Control (WHO-FCTC) recommendation. Price elasticity was considered to assess demand. Price change in separate fractions (previously regulated and unregulated) were calculated to obtain potential YLLs averted. RESULTS: Current revenue of USD 59.25 million is projected to increase to USD 179.25 million with 695,159 averted YLLs at cigarette equivalent taxes and 10% increased regulation; USD 639.38 million with 4,527,597 averted YLLs with 100% regulation; USD 54.75 million, at WHO recommended taxes with 2,233,740 YLLs averted at 10% increased regulation, and 10,486,192 YLLs at 100% regulation. CONCLUSION: Proposed estimates are inline with WHO recommendations as they consider price elasticity and suggest substantial increase in revenue, while averting YLLs. A national action is needed to drive the policy decisions towards increased regulation and taxation and revision of India's tobacco control legislation. IMPLICATIONS: Our study presented empirical evidence of how the currently underutilized tool of taxation, as proposed in the WHO-FCTC, can be utilized to decrease bidi smoking prevalence and save measurable life years while generating government revenue simultaneously. While the revenue statistics counter the misleading tobacco industry narratives, the projected reduction in mortality will be seen as an irrefutable driving force for policy reforms, targeted at strategic increase in regulation and taxation of the traditional Indian cigarillos industry.

mHealth based intervention by social care professionals to support family caregivers to persons with dementia living at home in Sweden (Caregiver Connect): a randomized controlled trial.

BACKGROUND: The majority of persons with dementia in Sweden reside in their own homes with support from family members. Approximately, 12% of persons with dementia have immigrant background. Within the next 20 years, the number of persons with dementia who are non-ethnic Swedes is said to double. Family caregivers with immigrant backgrounds are noted to receive less support in the community than ethnic Swedes and rate their health status lower than ethnic Swedish peers. The Swedish National Board of Health and Welfare have highlighted the importance of follow-up support for family caregivers with immigrant backgrounds as there is a recognized gap in research and available information tailored to meet the needs of this group. PURPOSE OF THE STUDY: The purpose of the study is to test effectiveness of an mHealth based intervention through which community social workers can improve caregiving competence of non-European immigrant family caregivers of people with dementia living at home in Sweden. The overarching aim is to reduce caregiver burden and depressive symptoms, and improve quality of life. METHODS: A randomized controlled trial (RCT) including wait list control group will be performed consisting of an intervention group (A, n = 44) and a wait list control group (B, n = 44), totaling a sample size of 88. On completion of the 10-weeks long intervention in the intervention group, the intervention will be delivered to group B. Effect of the intervention will be analyzed between and within groups over time. The content of the educational component of the intervention is inspired by the iSupport manual developed by the World Health Organization. The contents, in the form of a booklet, aims to equip the family caregivers with structured information on understanding dementia as a condition and its management at home, including self-care guidance designed specifically for family caregivers themselves. DISCUSSION: Similar telephone-delivered intervention studies targeted for family caregivers to persons with dementia are ongoing in Malaysia and will start in India using the same booklet adapted to the local context. These studies will provide evidence on the effectiveness of using digital technologies to deliver support to those who may not be reached or adequately served by the traditional healthcare system. TRIAL REGISTRATION: ISRCTN registry, Registration number ISRCTN64235563.

Estimating the weight of consumed tobacco product waste in various Indian states: a novel method to assess the potential burden of tobacco product waste.

INTRODUCTION: The direct morbidity and mortality caused by tobacco are well documented, but such products also contribute to a range of environmental pollutants resulting from tobacco product waste. No previous studies have yet quantified tobacco product waste in a low-income and middle-income country (LMIC). This study estimates the potential annual waste generated due to consumption of smoked and smokeless tobacco products in India and its states. METHODOLOGY: We systematically collected samples of smoked and smokeless tobacco products from 33 districts of 17 Indian states/union territories. Stratified weights of plastic, paper, foil and filter packaging components, and gross empty package weights were recorded. Prevalence of smoking and smokeless tobacco use at national and state-level estimates was derived from the Global Adult Tobacco Survey (2016-2017) to quantify waste potentially generated by tobacco products. RESULTS: We included 222 brands of tobacco products (70 cigarette, 94 bidi and 58 smokeless tobacco brands) in the final analysis. A total of 170 331 (±29 332) tonnes of waste was estimated to be generated annually, out of which 43.2% was plastic, 3.6% was foil and 0.8% was filter. Two-thirds of the overall waste was contributed by smokeless products alone. Maximum waste was generated in Uttar Pradesh (20.9%; 35 723.7±6151.6 tonnes), Maharashtra (8.9%; 15 116.84±2603.12 tonnes) and West Bengal (8.6%; 14 636.32±2520.37 tonnes). CONCLUSION: This study provides first of its kind national-level evidence on the types (plastic, paper, foil and filter) and quantity of waste potentially generated by use of tobacco products in India. Similar studies from other LMICs can serve to raise consciousness about many negative environmental impacts of tobacco products and need for policies to address them.

Is telemedicine a holy grail in healthcare policy: clinicians' and patients' perspectives from an Apex Institution in Western India.

BACKGROUND: This study aimed to explore the perception of doctors regarding telemedicine consultations and the level of patient satisfaction with the services received through teleconsultations. METHODS: This cross-sectional study was conducted on clinicians who provided teleconsultations and patients who received teleconsultations in an Apex healthcare institution in Western India. Semi-structured interview schedules were used to record the quantitative and qualitative information. Clinicians' perceptions and patients' satisfaction were assessed using two different 5-point Likert scales. Data were analyzed using SPSS v.23 using non-parametric tests (Kruskal Wallis and Mann-Whitney U). RESULTS: A total of 52 clinicians who delivered teleconsultations and 134 patients who received teleconsultations from those doctors were interviewed in this study. For 69% of doctors, telemedicine was feasible to implement, and for the rest, it was challenging. Doctors believe telemedicine is convenient for patients (77%) and prevents the transmission of infection (94.2%). Difficulty in clinical evaluation (73%), communication (55.7%), network connectivity (34%), diagnosis and investigations (32%), and patients' e-illiteracy (32%) were the most common challenges faced by clinicians. Patients' experiences were positive in terms of ease of registration (82.1%), audio quality (100%), freedom to discuss medicine (94.8%), and comprehension of the diagnoses (88.1%). Patients expressed satisfaction with the length of the teleconsultation (81.4%), the advice and care they received (78.4%), and the manner and communication of the clinicians (78.4%). CONCLUSIONS: Though there were some challenges in the implementation of telemedicine, the clinicians perceived it quite helpful. The majority of the patients were satisfied with teleconsultation services. Difficulty in registration, lack of communication, and a deep-rooted mindset of physical consultations were the primary concerns from the patient side.

Musculoskeletal disorders among doctors and nursing officers : an occupational hazard of overstrained healthcare delivery system in western Rajasthan, India.

BACKGROUND: The present study was conducted to estimate the prevalence and distribution of MSDs in different anatomical regions among Doctors and NO and to determine their ergonomic risk factors and predictors. METHODS: This cross-sectional study was conducted in an apex institution in Western India. The socio-demographic information, medical and occupational history, and other personal and work-related attributes were captured using a semi-structured questionnaire, which was developed and finalized by piloting on 32 participants (who were not part of the study). Nordic Musculoskeletal and International Physical Activity Questionnaires were used to assess MSDs and Physical activity. Data were analyzed using SPSS v.23. Prevalence of Musculoskeletal Symptoms (M.S.), Multisite Musculoskeletal Symptoms (MMS), and Widespread Musculoskeletal Symptoms (WMS) were calculated. A comparison was made to estimate the burden and distribution of MSD among Doctors and Nursing officers. Logistic regression was applied to identify the predictors of MSDs and pinpoint the risk factors associated with MSDs. RESULTS: A total of 310 participants, of which 38.7% were doctors, and 61.3% were Nursing Officers (NOs) were included in the study. The mean age of the respondents was 31.63 ± 4.9 years. Almost 73% (95%CI: 67.9-78.1) of participants had MSD in the last 12 months, with approximately 41.6% (95%CI: 36.1-47.3) suffering from MSDs in the previous seven days of the survey. The lower back (49.7%) and the neck (36.5%) were the most affected sites. Working in the same position for a long time (43.5%) and not taking adequate breaks (31.3%) were the highest self-reported risk factors. Females had significantly higher odds of having pain in the upper back [aOR:2.49(1.27-4.85)], neck [aOR:2.15(1.22-3.77)], shoulder [aOR:2.8 (1.54-5.11)], hips [aOR:9.46 (3.95-22.68)] and knee [aOR:3.8(1.99-7.26)]. CONCLUSIONS: Females, who are NOs, work for > 48 h per week, and fall in the obese category were significantly at more risk of developing MSDs. Working in an awkward position, treating an excessive number of patients in a day, working in the same position for a long period, performing repeated tasks, and not having enough rest breaks were significant risk factors for MSDs.

Projected climate extremes over agro-climatic zones of Ganga River Basin under 1.5, 2, and 3° global warming levels.

Recurring floods, droughts, heatwaves, and other hydro-meteorological extreme events are likely to be increased under the climate change scenarios. The increased risk of these extreme events might have more exposure to the population; thus, it is important to discuss such extreme events and their projected behavior under a changing climate scenario. In the present study, we have computed the extreme precipitation and temperature indices over the 10 agro-climatic zones falling under the Ganga River Basin (GRB)utilizing a high-resolution daily gridded temperature and precipitation multi-model ensembled CMIP6 dataset (0.25° × 0.25°) under global warming levels of 1.5 °C, 2 °C, and 3 °C. We found that the annual daily minimum temperature (TNN) showed a higher rise of about 67% than the maximum temperature (TXX) of 48% in GRB. The basin also experiences a greater increase in the frequency of warm nights (TN90P) of about 67.71% compared to warm days (TX90P) of 29.1% for the 3 °C global warming level. Along with extreme indices, the population exposed due to the impact of the extreme maximum temperature has also been analyzed for progressive warming levels. Population exposure to extreme temperature event (TXX) has been analyzed with 20-year return period using GEV distribution method. The study concludes that the exposed population to extreme temperature event experienced an increase from 46.99 to 52.16% for the whole Ganga Basin. Consecutive dry days (CDD) and consecutive wet days (CWD) both show a significant increasing trend, but CWD has a significant increase in the majority of the zones, while CDD shows a significant decreasing trend for some of the zones for three warming levels periods. Extreme climate indices help to understand the frequency and intensity of extreme weather events such as heavy rainfall, droughts, and heatwaves to develop early warning systems and adaptation strategies to mitigate such events.

Intrinsic capacity of rural elderly in thar desert using world health organization integrated care for older persons screening tool: A pilot study.

Integrated Care for Older Persons (ICOPE) screening tool helps to address declines in physical and mental capacities in older people. In India, majority of the older population resides in rural areas and there is a paucity of studies that demonstrates the utility of the ICOPE screening tool in India. Thus, a cross-sectional study was conducted to demonstrate the feasibility of using the World Health Organization ICOPE screening tool in a rural population. Comprehensive geriatric assessment of intrinsic capacity revealed cognitive decline in 31.5% (n = 142) participants, diminished mobility 52.1% (n = 235) participants, eye problems in 49.4% (n = 223) participants, and hearing loss in 68.3% (n = 308) participants. Gender difference was statistically significant with mobility limitation (P = 0.005; χ2 = 7.95) and feeling of pain (P = 0.001; χ2 = 15.64), being more in females than males. This tool seems suitable in identifying the intrinsic capacity of the rural elderly.

Stanene-Based Nanosheets for ß-Elemene Delivery and Ultrasound-Mediated Combination Cancer Therapy.

Ultrasound (US)-mediated sonodynamic therapy (SDT) has emerged as a superior modality for cancer treatment owing to the non-invasiveness and high tissue-penetrating depth. However, developing biocompatible nanomaterial-based sonosensitizers with efficient SDT capability remains challenging. Here, we employed a liquid-phase exfoliation strategy to obtain a new type of two-dimensional (2D) stanene-based nanosheets (SnNSs) with a band gap of 2.3 eV, which is narrower than those of the most extensively studied nano-sonosensitizers, allowing a more efficient US-triggered separation of electron (e- )-hole (h+ ) pairs for reactive oxygen species (ROS) generation. In addition, we discovered that such SnNSs could also serve as robust near-infrared (NIR)-mediated photothermal therapy (PTT) agents owing to their efficient photothermal conversion, and serve as nanocarriers for anticancer drug delivery owing to the inherent 2D layered structure. This study not only presents general nanoplatforms for SDT-enhanced combination cancer therapy, but also highlights the utility of 2D SnNSs to the field of nanomedicine.

Human Factors Results for Fentanyl Iontophoretic Transdermal System (ITS) With Enhanced Controller for Postoperative Pain Management.

PURPOSE: The purpose of this analysis was to conduct summative usability evaluations, including behavioral and subjective evaluations, for the fentanyl iontophoretic transdermal system (ITS). DESIGN: Four usability studies were conducted in representative users. METHODS: The first three studies were conducted with (1) health care professionals (HCPs; N = 31), (2) patients who received placebo fentanyl ITS (N = 30), and (3) healthy volunteers (N = 30), and focused on the understanding and use of fentanyl ITS. The fourth study included HCPs (N = 31) and healthy volunteers (N = 30), and focused on the effectiveness of formal training regarding the use of fentanyl ITS. FINDINGS: Overall, user groups found the fentanyl ITS easy to use. There were no use errors that could potentially have safety implications. In the three early studies, there were some minor difficulties experienced; however, the introduction of a structured training reduced these difficulties. CONCLUSIONS: Patients, nurses, and pharmacists were able to use fentanyl ITS with ease.

EUS-guided pseudocyst drainage: prospective evaluation of early removal of fully covered self-expandable metal stents with pancreatic ductal stenting in selected patients.

BACKGROUND: EUS-guided pseudocyst drainage with fully covered self-expandable metal stents (FCSEMSs) was recently described. The appropriate period for stent removal is not known. OBJECTIVE: To assess the safety and efficacy of EUS-guided FCSEMS placement for 3 weeks, along with pancreatic ductal stenting in selected patients. STUDY DESIGN: Prospective, single-center evaluation. SETTING: Tertiary referral center. PATIENTS: Symptomatic pseudocysts in the body and tail region of the pancreas. INTERVENTIONS: EUS-guided transgastric placement of FCSEMS. MRCP was performed after 3 weeks. Patients with a suspected pancreatic duct leak underwent ERCP and plastic stent placement. The FCSEMSs were removed at 3 weeks. MAIN OUTCOME MEASUREMENTS: Success of FCSEMS placement, adverse events, and recurrence rate. RESULTS: Forty-seven patients met the eligibility criteria. Technical and functional success was achieved in 43 patients (intention to treat, 91.48% and 95.34% patients [per protocol, 41/43, respectively]). Adverse events occurred in 2 patients (cyst infections, 4.6%). Follow-up of 42 patients at 3 weeks was performed. MRCP detected a ductal leak in 3 patients (7.1%) and a disconnected duct in 2 patients (4.7%). ERCP and stenting were successful in all 3 patients with a ductal leak. During a median follow-up of 306 days in 42 patients, 2 recurrences (4.7%) were detected, both in patients with disconnected duct. Multivariate analysis showed that pancreatic ductal leak or disconnection was an independent factor affecting pseudocyst resolution at 3 weeks (P = .0001). LIMITATIONS: Single-center study. CONCLUSION: Short-term placement of FCSEMSs with pancreatic ductal stenting in selected patients appears safe and effective for the treatment of pseudocysts.

Geospatial analysis of toxic metal contamination in groundwater and associated health risks in the lower Himalayan industrial region.

Once known for its clean and natural environment, the lower Himalayan region is now no exception to human-induced disturbances. Rapid industrial growth in Baddi-Barotiwala (BB) industrial region has led to degradation of groundwater resources in the area. Groundwater samples were collected from 37 locations to study the groundwater chemistry, geospatial variation of 15 toxic metals in groundwater, source apportionment, metals of concern and associated health risks in the region. The results showed rock dominated hydrogeology with decreasing order of anion and cation abundance as HCO3- > Cl- > SO42- > NO3- > Br- > F- and Ca+ > Na+ > Mg2+ > K+ > Li+ respectively. Concentrations of Iron (BDL-3.6 mg/l), Nickel (BDL-0.023 mg/l), Barium (0.22-0.89 mg/l), Lead (0.0001-0.085 mg/l) and Zinc (0.006-21.4 mg/l) were found above the permissible limits at few locations. Principal component analysis (PCA) and coefficient of variance (CV) showed both geogenic and anthropogenic origin of metals in groundwater of the BB industrial region. A consistent concentration of Uranium was detected at all the sampling locations with an average value of 0.0039 mg/l and poor spatial variation indicating its natural presence. Overall, non-carcinogenic (N-CR) risk in the study area via oral pathway was high for adults and children (Hazard Index > 1) with geogenic Uranium as the major contributor (Hazard Quotient > 1) followed by Zinc, Lead and Cobalt. Carcinogenic (CR) risk in the region was high for adults having mean value above the threshold (1E-04) with Nickel and Chromium as the metals of major concern. Spatial variation of health risks was overlayed on village boundaries of the region to identify the potential industrial sources of the metals of major concern. The results highlight the need for immediate remediation of groundwater resources in order to achieve a harmonious coexistence between industrialization and human well-being.

Flow and contaminant transport dynamics in clay-amended barriers through flushing experiments and multi-porosity-based modeling.

Clay-amended barriers are widely used to prevent hazardous leachate percolation from landfill to subsurface. The performance of these barriers is mostly evaluated through numerical simulations with limited experimental investigation through leachate flushing experiments. To bridge this gap, contaminant loading and its flushing experiments were carried out to assess the performance of clay-amended composite materials as landfill liners. River sand (Sa), loamy soil (Ns), and alternative waste materials like fly ash (Fa) and flushed silt (Si) were used to prepare the composites. Composites fulfilling the hydraulic conductivity (<10-7 cm/s) and compressive strength (200 kPa) criteria were selected for contaminant loading and its flushing experiments to understand the fate of fluoride ions. The experimentally determined hydraulic conductivity (Ks) values for all the composites were in the order of 10-8 cm/s. The experimental breakthrough curves exhibited skewed shape, long tailing, and dual peaks. Dual porosity and dual permeability with immobile water models were employed to simulate these curves, revealing that preferential flow pathways and random chemical sorption sites significantly affect solute transport in clay-amended barriers. Further, scanning electron microscopy and energy-dispersive X-ray spectroscopy were employed to trace the preferred path of fluoride ions through the barrier. The removal efficiency and temporal moments were used to determine the percentage mass retained, mean arrival time, and spreading within the barrier. The highest solute mass was retained by sand-clay barrier (SaB30) (91%), followed by loam-clay barrier (NsB30) (59%), fly ash-clay barrier (FaB30) (38%), and silt-clay barrier (SiB30) (4%) with the least mass. The lowest mean arrival time was calculated for NsB30 (269 h) and the highest for SaB30 (990 h), with FaB30 (384 h) and SiB30 (512 h) having values in between. This study concludes that validating the design hypothesis of clay-amended barriers through contaminant loading and its flushing studies leads to an effective and sustainable design.

Return to Sports in Stress Reaction and Stress Fractures in Indian Athletes: A Case Series.

Introduction: A stress fracture is a painful condition which occurs when the adaptive ability of the bone is unbalanced. This imbalance predominantly occurs due to increased intensity, frequency, or duration of training. Identifying the etiology of stress fracture and its proper treatment prevents recurrence. Besides, evidence-based and supervised rehabilitation is indispensable for permanent remission of pain and return to sports to preinjury functional levels. The case series discusses the continuum of stress reaction to stress fracture in athletes, causes of stress fractures, their management, and return to sport. The paper aims to give a clear discussion about the management with rehabilitation guidelines for metabolic causes of stress fractures. Case Report: This study was a case series of five cases coming to Sports Medicine outpatient clinic of Sports Injury Centre, VMMC and Safdarjung Hospital, New Delhi, and physical medicine and rehabilitation outpatient clinic of Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow over a period of 1 year. The discussed cases are young Indian athletes, both male and females, who have presentation along the continuum of medial tibial stress syndrome (MTSS) to stress reactions and stress fracture. Conclusion: The findings of the paper highlight the significance of rehabilitation for individuals suffering from MTSS. Accurate diagnosis with targeted rehabilitation leads to quicker return to sports. The rehabilitation program comprises of identifying and treating the cause of stress fracture, removing any risk factors, biomechanical correction wherever indicated, structured exercise program, training in underwater treadmill, cyclical increase in loading, reducing activity every 3rd week.

Impact of COVID-19 Pandemic on People with Locomotor Disability in North India: A Cross-Sectional Analysis.

OBJECTIVE: To assess, analyse, and infer the impact of the coronavirus disease 2019 (COVID-19) pandemic on people living with locomotor disability in North India. METHODS: Patients with locomotor disabilities who met the inclusion criteria received a questionnaire that had already undergone testing and validation. It covered topics highlighting the effect of the pandemic on general health, financial burden, psychological and mental health, social life and behaviour, disability and comorbidity management, transportation, and healthcare accessibility during the pandemic. In order to gauge the pandemic's effects on the population of people with locomotor disabilities, the answers to the questions were collected and analyzed. RESULTS: The COVID-19 pandemic has adversely affected people living with locomotor disability, ranging from loss of wages and financial crisis to anxiety, depression and lack of sleep. People with disabilities had limited reach to health and community services that were vital for them, including basic life and functional needs, besides risks of mistreatment and other psychological consequences. CONCLUSION: This analysis suggests that the root cause of pandemic disparities is the lack of disability-inclusive planning and, more significantly, the pre-existing socioeconomic disparities and challenges that disabled people have been experiencing for a long time. We suggest that unambiguous public health and policy responses should be incorporated, and health, social participation, and socioeconomic disparity causes for disabled people should be addressed in tandem.

Progress and challenges in intravesical drug delivery.

INTRODUCTION: Intravesical drug delivery (IDD) has gained recognition as a viable approach for treating bladder-related diseases over the years. However, it comes with its set of challenges, including voiding difficulties and limitations in mucosal and epithelial penetration. These challenges lead to drug dilution and clearance, resulting in poor efficacy. Various strategies for drug delivery have been devised to overcome these issues, all aimed at optimizing drug delivery. Nevertheless, there has been minimal translation to clinical settings. AREAS COVERED: This review provides a detailed description of IDD, including its history, advantages, and challenges. It also explores the physical barriers encountered in IDD, such as voiding, mucosal penetration, and epithelial penetration, and discusses current strategies for overcoming these challenges. Additionally, it offers a comprehensive roadmap for advancing IDD into clinical trials. EXPERT OPINION: Physical bladder barriers and limitations of conventional treatments result in unsatisfactory efficacy against bladder diseases. Nevertheless, substantial recent efforts in this field have led to significant progress in overcoming these challenges and have raised important attributes for an optimal IDD system. However, there is still a lack of well-defined steps in the workflow to optimize the IDD system for clinical settings, and further research is required to establish more comprehensive in vitro and in vivo models to expedite clinical translation.

Precise modulation and use of reactive oxygen species for immunotherapy.

Reactive oxygen species (ROS) play an important role in regulating the immune system by affecting pathogens, cancer cells, and immune cells. Recent advances in biomaterials have leveraged this mechanism to precisely modulate ROS levels in target tissues for improving the effectiveness of immunotherapies in infectious diseases, cancer, and autoimmune diseases. Moreover, ROS-responsive biomaterials can trigger the release of immunotherapeutics and provide tunable release kinetics, which can further boost their efficacy. This review will discuss the latest biomaterial-based approaches for both precise modulation of ROS levels and using ROS as a stimulus to control the release kinetics of immunotherapeutics. Finally, we will discuss the existing challenges and potential solutions for clinical translation of ROS-modulating and ROS-responsive approaches for immunotherapy, and provide an outlook for future research.

Road accidents on Indian National highways, ambulance reachability and transportation of injured to trauma facility: Survey-based introspection of golden hour.

Background: The transportation system plays a crucial role in the context of socioeconomic development, whereas the highway infrastructure acts as a base for the transportation system. In recent years, a rich impetus has been given to the development of road infrastructure by Indian governance. There is a need to introspect how well the prevailing highway infrastructure is equipped with emergency rescue management during road accidents. Lack of ambulance service and trauma facilities along the highways results in a steady loss of lives and injuries and increases people's exposure to risks. Objective: This study aims to determine the response time of ambulance reachability to the accident spot on Indian national highways associated with heavy commercial transportation. Also, determining the time to transport the injured to the nearest trauma facility is another factor included as an objective in this investigation. Methods: The study adopted survey-based research, whereby the variables in the questionnaire were designed to record and assess the time for an ambulance to reach the accident spot and, from there, to transport the injured to the trauma management facility on Indian highways. Two hundred twenty-five participants who were either victims/relatives of victims or those involved in the rescue of the injured have participated in the survey. The dates of the accident events were 2017 and 2022. Results: The survey resulted in the identification of two categories of highway accidents. The first category of accidents happened on the highways near city limits/dense settlements, and the second category occurred on the core highways. The percentage of accidents caused on the highways either adjacent to or passing through the city limits/dense settlements was reported to be higher than the accidents on the core highways. Ninety percent of the participants reported successful contact with the ambulance call/service centre, but only ~75% success rate exists for ambulances to reach the accident scene. On the core highways, the time taken for the ambulance to arrive at the accident scene is 25-35 minutes. The results from the survey ascertained that the patients were prioritised for treatment in the nearest hospitals (irrespective of having a trauma facility) at a distance of ~12-20 km, for which the time taken is ~15-25 minutes. Importantly, from the interviews, it is understood that in many cases, these hospitals have further referred to specialty hospitals located in nearby cities or trauma centres with greater facilities. Occasions exist where the injured were taken directly to hospitals 30-40 km from the accident spot, for which the time was more than 40 minutes. Conclusions: The results provide evidence that in either of the accident cases on the highways that are adjacent to/passing through the city limits or on the core highways, the total time for emergency care accessibility is nearly 60 minutes or greater; this implies that in the majority of cases, there is very meagre time left to provide emergency medical care to the needy and injured on the Indian highways to abide by the concept of golden hour. Plausible reforms backed by technology for enabling highways into 'emergency rescuable highways' are highly needed to guarantee a safer and more sustainable transportation system in India.

A Mechanically Resilient Soft Hydrogel Improves Drug Delivery for Treating Post-Traumatic Osteoarthritis in Physically Active Joints.

Intra-articular delivery of disease-modifying osteoarthritis drugs (DMOADs) is likely to be most effective in early post-traumatic osteoarthritis (PTOA) when symptoms are minimal and patients are physically active. DMOAD delivery systems therefore must withstand repeated mechanical loading without affecting the drug release kinetics. Although soft materials are preferred for DMOAD delivery, mechanical loading can compromise their structural integrity and disrupt drug release. Here, we report a mechanically resilient soft hydrogel that rapidly self-heals under conditions resembling human running while maintaining sustained release of the cathepsin-K inhibitor L-006235 used as a proof-of-concept DMOAD. Notably, this hydrogel outperformed a previously reported hydrogel designed for intra-articular drug delivery, used as a control in our study, which neither recovered nor maintained drug release under mechanical loading. Upon injection into mouse knee joints, the hydrogel showed consistent release kinetics of the encapsulated agent in both treadmill-running and non-running mice. In a mouse model of aggressive PTOA exacerbated by treadmill running, L-006235 hydrogel markedly reduced cartilage degeneration. To our knowledge, this is the first hydrogel proven to withstand human running conditions and enable sustained DMOAD delivery in physically active joints, and the first study demonstrating reduced disease progression in a severe PTOA model under rigorous physical activity, highlighting the hydrogel's potential for PTOA treatment in active patients.