A Zn-dependent structural transition of SOD1 modulates its ability to undergo phase separation.

The misfolding and mutation of Cu/Zn superoxide dismutase (SOD1) is commonly associated with amyotrophic lateral sclerosis (ALS). SOD1 can accumulate within stress granules (SGs), a type of membraneless organelle, which is believed to form via liquid-liquid phase separation (LLPS). Using wild-type, metal-deficient, and different ALS disease mutants of SOD1 and computer simulations, we report here that the absence of Zn leads to structural disorder within two loop regions of SOD1, triggering SOD1 LLPS and amyloid formation. The addition of exogenous Zn to either metal-free SOD1 or to the severe ALS mutation I113T leads to the stabilization of the loops and impairs SOD1 LLPS and aggregation. Moreover, partial Zn-mediated inhibition of LLPS was observed for another severe ALS mutant, G85R, which shows perturbed Zn-binding. By contrast, the ALS mutant G37R, which shows reduced Cu-binding, does not undergo LLPS. In addition, SOD1 condensates induced by Zn-depletion exhibit greater cellular toxicity than aggregates formed by prolonged incubation under aggregating conditions. Overall, our work establishes a role for Zn-dependent modulation of SOD1 conformation and LLPS properties that may contribute to amyloid formation.

India Hypertension Control Initiative: decentralization of hypertension care to health wellness centres in Punjab and Maharashtra, India, 2018-2022.

INTRODUCTION: The India Hypertension Control Initiative (IHCI) emphasizes decentralized patient-centric care to boost hypertension control in public healthcare facilities. We documented the decentralization process, enrolment pattern by facility type, and treatment outcomes in nine districts of Punjab and Maharashtra states, India, from 2018-2022. METHODS: We detailed the shift in hypertension care from higher facilities to Health and Wellness Centres (HWCs) using the World Health Organization (WHO) health system pillar framework. We reviewed hypertension treatment records in 4,045 public facilities from nine districts in the two states, focusing on indicators including registration numbers, the proportion of controlled, uncontrolled blood pressure (BP), and missed visits among those under care. RESULTS: The decentralization process involved training, treatment protocol provision, supervision, and monitoring. Among 394,038 individuals registered with hypertension from 2018-2021, 69% were under care in 2022. Nearly half of those under care (129,720/273,355) received treatment from HWCs in 2022. Care of hypertensive individuals from district hospitals (14%), community health centres (20%), and primary health centres (24%) were decentralized to HWCs. Overall BP control rose from 20% (4,004/20,347) in 2019 to 58% (157,595/273,355) in 2022, while missed visits decreased from 61% (12,394/20,347) in 2019 to 26% (70,894/273,355) in 2022. This trend was consistent in both states. HWCs exhibited the highest BP control and the lowest missed visits throughout the study period compared to other facility types. CONCLUSION: We documented an increase in decentralized access to hypertension treatment and improved treatment outcomes over four years. We recommend operationalizing hypertension care at HWCs to other districts in India to improve BP control.

Comprehensive evaluation on progressive development strategies in DENV surveillance and monitoring infection rate among vector population.

The elevated rise in dengue infection rate has been a health burden worldwide and it will continue to impact global health for years to come. Accumulated literature holds accountable the geographical expansion of the mosquito species transmitting the dengue virus DENV. The frequency of this viral disease outbreaks has increased rapidly in the recent years, owing to various geo-climatic and anthropological activities. Due to scarcity of any effective control measures, there has been a continuous traceable rise in mortality and morbidity rates. However, it has been reported that the spate of incidences is directly related to density of the virus infected vector (mosquito) population in a given region. In such a scenario, systems capable of detecting virus infected vector population would aid in estimating prediction of outbreak, as well as provide time to deploy suitable management strategies for vector control, and to break the vector-human transmission chain. This would also help in identifying areas, where much improvement is needed for vector management. To this context, we illustrate an exhaustive overview of both gold standards and as well as emerging advents for sensitive and specific mosquito population strategized viral detection technologies. We summarize the cutting-edge technologies and the challenges faced in pioneering to field application. Regardless the proven popularity of the gold standards for detection purpose, they offer certain limitations. Thus with the surge in the infection rate globally, approaches for development of newer advancements and technique upgradation to arrest the infection escalation and for early detection as a part of vector management should be prioritized.

Discovery, development, and deployment of a user-centered point-of-care digital information system to treat and track hypertension and diabetes patients under India Hypertension Control Initiative 2019-2022, India.

Background: Hypertension affects 28.5% of Indians aged 18-69. Real-time registration and follow-up of persons with hypertension are possible with point-of-care digital information systems. We intend to describe herein the experiences of discovering, developing, and deploying a point-of-care digital information system for public health facilities under the India Hypertension Control Initiative. Methods: We have adopted an agile and user-centered approach in each phase in selected states of India since 2017. A multidisciplinary team adopted a hybrid approach with quantitative and qualitative methods, such as contextual inquiries, usability testing, and semi-structured interviews with healthcare workers, to document and monitor utility and usability. Results: During the discovery phase, we adopted a storyboard technique to understand the requirement of a digital information system. The participatory approach in discovery phase co-designed the information system with the nurses and doctors at Punjab state of India. Simple, which is the developed information system, has a front-end Android mobile application for healthcare workers and a backend dashboard for program managers. As of October 2022, over 24,31,962 patients of hypertension and 8,99,829 diabetes were registered in the information system of 10,017 health facilities. The median duration of registering a new patient was 50 seconds, and for recording a follow-up visit was 14 seconds in the app. High satisfaction was reported in 100 app users' quarterly interviews. Conclusion: Simple was implemented by administering a user-centered approach and agile techniques. It demonstrated high utility and usability among users, highlighting the benefits of a user-centered approach for effective digital health solutions.

India Hypertension Control Initiative: Blood Pressure Control Using Drug and Dose-Specific Standard Treatment Protocol at Scale in Punjab and Maharashtra, India, 2022.

Background: Hypertension treatment coverage is low in India. A stepwise simple treatment protocol is one of the strategies to improve hypertension treatment in primary care. We estimated the effectiveness of various protocol steps to achieve blood pressure (BP) control in public sector health facilities in Punjab and Maharashtra, India, where the India Hypertension Control Initiative (IHCI) was implemented. Methods: We analyzed the records of people enrolled for hypertension treatment and follow-up under IHCI between January 2018 and December 2021 in public sector primary and secondary care facilities across 23 districts from two states. Each state followed a different treatment protocol. We calculated the proportion with controlled BP at each step of the protocol. We also estimated the mean decline in BP pre- and post-treatment. Results: Of 281,209 patients initiated on amlodipine 5 mg, 159,292 continued on protocol drugs and came for a follow-up visit during the first quarter of 2022. Of 33,450 individuals who came for the follow-up in Punjab and 125,842 in Maharashtra, 70% and 76% had controlled BP, respectively, at the first step with amlodipine 5 mg. In Punjab, at the second step with amlodipine 10 mg, the cumulative BP control increased to 75%. A similar 5% (76%-81%) increase was seen in the second step after adding telmisartan 40 mg in Maharashtra. Overall, the mean (SD) systolic blood pressure (SBP) decreased by 16 mmHg from 148 (15) mmHg at the baseline in Punjab. In Maharashtra, the decline in the mean (SD) SBP was about 15 mmHg from the 144 (18) mmHg baseline. Conclusion: Simple drug- and dose-specific protocols helped achieve a high control rate among patients retained in care under program conditions. We recommend treatment protocols starting with a single low-cost drug and escalating with the same or another antihypertensive drug depending on the cost and availability.

Diverse utilization of surfactants in coal-floatation for the sustainable development of clean coal production and environmental safety: a review.

The rapidly increasing modern industrial world demands a huge uninterrupted energy supply, where high-quality coal (HQC) is one of the major sources of the required energy. In this regard, a gigantic amount of solid waste including ash and toxic chemicals, such as heavy metals, nitrate and sulphur, gases including NOx and SOx are emitted during the direct incineration process of low-rank coal. About 10 Gt of CO2 and about one-fifth of total greenhouse gases in the world are emitted each year due to coal combustion in power plants, making it the single largest cause of climate change. The UN proposed that OECD countries stop producing electricity from coal by 2030 and the rest of the world by 2040. Herein, we discuss the development of modern technologies that can convert low-quality coal (LQC) into high-quality coal (HQC) to minimize the impact of fossil fuel burn, climate change, premature death of animals and all other related environmental hazards. Amongst the many established technologies, flotation pre-treatment is the most common and effective method used worldwide due to its lower energy input than other methods. In this review, we attempt to present an up-to-date understanding of the applications and utilities of surfactants in coal floating. We also demonstrate the possible modernization of this surfactant chemistry and its prospects.

A multisource database tracking the impact of the COVID-19 pandemic on the communities of Boston, MA, USA.

A pandemic, like other disasters, changes how systems work. In order to support research on how the COVID-19 pandemic impacted the dynamics of a single metropolitan area and the communities therein, we developed and made publicly available a "data-support system" for the city of Boston. We actively gathered data from multiple administrative (e.g., 911 and 311 dispatches, building permits) and internet sources (e.g., Yelp, Craigslist), capturing aspects of housing and land use, crime and disorder, and commercial activity and institutions. All the data were linked spatially through BARI's Geographical Infrastructure, enabling conjoint analysis. We curated the base records and aggregated them to construct ecometric measures (i.e., descriptors of a place) at various geographic scales, all of which were also published as part of the database. The datasets were published in an open repository, each accompanied by a detailed documentation of methods and variables. We anticipate updating the database annually to maintain the tracking of the records and associated measures.

Factors affecting non-adherence to medical appointments among patients with hypertension at public health facilities in Punjab, India.

Daily adherence to antihypertensive medications is necessary to control hypertension. Under the State hypertension control program, hypertensive patients are enrolled in public health settings, provided with 30-day medication prescriptions, and advised to return to the health facility monthly. However, at least 50-60% of patients do not visit the health facility for their scheduled follow-up appointments. The authors aimed to document the major reasons for missed appointments and to characterize patient and health system barriers. By telephone, the authors interviewed 300 randomly selected patients who missed appointments for more than three consecutive months. Out of the 300, 206 were interviewed using a pre-structured questionnaire to explore patients' experiences along with medical record reviews from the patient database. Not feeling sick or not experiencing any symptoms (24.8%) was the major reason why patients did not return to the clinic, followed by far distance from the facility (22.3%). Among other reasons for missing follow-up appointments, lack of instructions/guidance from the facility (15.3%), acute illness among patients (8.3%), and long waiting time at the facilities (7%) were also documented. Most of these patients (55.4%) continued treatment from other sources, and a majority (54%) preferred private clinics. These results suggest the need for a more patient-centered care model, including education about hypertension as an asymptomatic but life-threatening condition and addressing the barrier of travel distance between a patient's home and the health facility. Further, introducing a reminder system using telephone calls, text messages, or home visits by health workers may increase the follow-up rate among patients.

The metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in an in vitro ALS model.

Aggregation of Cu-Zn superoxide dismutase (SOD1) is implicated in the motor neuron disease, amyotrophic lateral sclerosis (ALS). Although more than 140 disease mutations of SOD1 are available, their stability or aggregation behaviors in membrane environment are not correlated with disease pathophysiology. Here, we use multiple mutational variants of SOD1 to show that the absence of Zn, and not Cu, significantly impacts membrane attachment of SOD1 through two loop regions facilitating aggregation driven by lipid-induced conformational changes. These loop regions influence both the primary (through Cu intake) and the gain of function (through aggregation) of SOD1 presumably through a shared conformational landscape. Combining experimental and theoretical frameworks using representative ALS disease mutants, we develop a 'co-factor derived membrane association model' wherein mutational stress closer to the Zn (but not to the Cu) pocket is responsible for membrane association-mediated toxic aggregation and survival time scale after ALS diagnosis.

Amyotrophic lateral sclerosis, or ALS, is an incurable neurodegenerative disease in which a person slowly loses specialized nerve cells that control voluntary movement. It is not fully understood what causes this fatal disease. However, it is suspected that clumps, or aggregates, of a protein called SOD1 in nerve cells may play a crucial role. More than 140 mutations in the gene for SOD1 have been linked to ALS, with varying degrees of severity. But it is still unclear how these mutations cause SOD1 aggregation or how different mutations influence the survival rate of the disease. The protein SOD1 contains a copper ion and a zinc ion, and it is possible that mutations that affect how these two ions bind to SOD1 influences the severity of the disease. To investigate this, Sannigrahi, Chowdhury, Das et al. genetically engineered mutants of the SOD1 protein which each contain only one metal ion. Experiments on these mutated proteins showed that the copper ion is responsible for the protein's role in neutralizing harmful reactive molecules, while the zinc ion stabilizes the protein against aggregation. Sannigrahi et al. found that when the zinc ion was removed, the SOD1 protein attached to a structure inside the cell called the mitochondria and formed toxic aggregates. Sannigrahi et al. then used these observations to build a computational model that incorporated different mutations that have been previously associated with ALS. The model suggests that mutations close to the site where zinc binds to the SOD1 protein increase disease severity and shorten survival time after diagnosis. This model was then experimentally validated using two disease variants of ALS that have mutations close to the sites where zinc or copper binds. These findings still need to be tested in animals and humans to see if these mechanisms hold true in a multicellular organism. This discovery could help design new ALS treatments that target the zinc binding site on SOD1 or disrupt the protein's interactions with the mitochondria.

India Hypertension Control Initiative-Hypertension treatment and blood pressure control in a cohort in 24 sentinel site clinics.

The India Hypertension Control Initiative (IHCI) is a multi-partner initiative, implementing and scaling up a public health hypertension control program across India. A cohort of 21,895 adult hypertension patients in 24 IHCI sentinel site facilities in four Indian states (Punjab, Madhya Pradesh, Maharashtra, and Telangana), registered from January 2018 until June 2019 were assessed at baseline and then followed up for blood pressure (BP) control and antihypertensive medication use. Among all registrations, 11 274 (51%) of the patients returned for a follow-up visit between July 2019 and September 2019. Among patients returning for follow-up, 26.3% had BP controlled at registration, and 59.8% had BP controlled at follow-up (p < .001). The absolute improvement in BP control was more than two times greater in primary care (48.1 percentage point increase) than secondary care facilities (22.9 percentage point increase). Most IHCI patients received prescriptions according to state-specific treatment protocols. This study demonstrates that a scalable public health hypertension control program can yield substantial BP control improvements, especially in primary care settings. However, high loss to follow-up limits population health impact; future efforts should focus on improving systems to increase the likelihood that patients will return to the clinic for routine hypertension care.

Rebound of Cotton leaf curl Multan virus and its exclusive detection in cotton leaf curl disease outbreak, Punjab (India), 2015.

Cotton leaf curl disease (CLCuD) outbreaks caused by CLCuD associated begomoviruses (CABs) significantly constrain cotton production in India and Pakistan. In comparison to the CABs circulating in Pakistan, molecular epidemiology, evolution and recombination patterns of CABs circulating in India are less studied. In this work, we characterized CAB complex sequences obtained from the most recent outbreak (Punjab, India, 2015), and rigorously analyzed them with reference to GenBank sequences, submitted from India, Pakistan and other neighbouring countries, using contemporary bioinformatics approaches. In this manuscript, we illustrate the detection of a recombinant, phylogenetically distinct clade of Cotton leaf curl Multan virus (CLCuMuV), suggesting rebound of CLCuMuV in this region. Interestingly, we could not detect Cotton leaf curl Kokhran virus-Burewala strain (CLCuKoV-Bu), which was prevalent in this region, until now. Our study thus indicates substitution of the 'virulent resistance breaking' CLCuKoV-Bu by the re-emerging CLCuMuV recombinants. Our findings corroborate with that of a very recent study from Pakistan and we here discuss epidemiological links between the CAB complexes reported in these two studies. Taken together, these observations signify a shifting epidemiology of CABs, and seem to correlate with the recent prediction of the 'third epidemic' of CLCuD in the Indian subcontinent.

IgG4-related intraocular inflammation masquerading as ciliary body melanoma in a young girl.

Immunoglobulin G4 (IgG4-related diseases) affects various tissues and organs of the human body. Orbital, adnexal, and scleral inflammations were already reported in the medical literature. To the best of our knowledge, we report the first case of intraocular IgG4-associated inflammatory mass in the ciliary body mimicking as a melanoma in a 23-year-old female from Northeast India. Characteristic histopathology, immunohistochemistry in the tissue, protein chemistry, and raised serum IgG4 were supportive for the diagnosis. As this newly diagnosed disease has multi-organ affection and little is known about its pathogenesis particularly in eye and adnexa, the present case will open many challenges in clinico-pathological diagnosis and research in the future.

Next-generation sequencing in clinical virology: Discovery of new viruses.

Viruses are a cause of significant health problem worldwide, especially in the developing nations. Due to different anthropological activities, human populations are exposed to different viral pathogens, many of which emerge as outbreaks. In such situations, discovery of novel viruses is utmost important for deciding prevention and treatment strategies. Since last century, a number of different virus discovery methods, based on cell culture inoculation, sequence-independent PCR have been used for identification of a variety of viruses. However, the recent emergence and commercial availability of next-generation sequencers (NGS) has entirely changed the field of virus discovery. These massively parallel sequencing platforms can sequence a mixture of genetic materials from a very heterogeneous mix, with high sensitivity. Moreover, these platforms work in a sequence-independent manner, making them ideal tools for virus discovery. However, for their application in clinics, sample preparation or enrichment is necessary to detect low abundance virus populations. A number of techniques have also been developed for enrichment or viral nucleic acids. In this manuscript, we review the evolution of sequencing; NGS technologies available today as well as widely used virus enrichment technologies. We also discuss the challenges associated with their applications in the clinical virus discovery.