Vitamin D supplementation and clinical outcomes in COVID-19: a systematic review and meta-analysis.

PURPOSE: To provide a precise summary and collate the hitherto available clinical evidence on the effect of vitamin D supplementation on clinical outcomes in COVID-19 patients. METHODS: PubMed/MEDLINE, Scopus, and Web of Science databases were systematically searched using appropriate keywords till June 8, 2021, to identify observational studies and randomized controlled trials (RCTs) reporting adverse clinical outcomes (ICU admission and/or mortality) in COVID-19 patients receiving vitamin D supplementation vs. those not receiving the same. Both prior use and use of vitamin D after COVID-19 diagnosis were considered. Unadjusted/adjusted pooled odds ratio (OR) with 95% confidence intervals (CI) were calculated (PROSPERO registration number CRD42021248488). RESULTS: We identified 13 studies (10 observational, 3 RCTs) pooling data retrieved from 2933 COVID-19 patients. Pooled analysis of unadjusted data showed that vitamin D use in COVID-19 was significantly associated with reduced ICU admission/mortality (OR 0.41, 95% CI: 0.20, 0.81, p = 0.01, I2 = 66%, random-effects model). Similarly, on pooling adjusted risk estimates, vitamin D was also found to reduce the risk of adverse outcomes (pooled OR 0.27, 95% CI: 0.08, 0.91, p = 0.03, I2 = 80%, random-effects model). Subgroup analysis showed that vitamin D supplementation was associated with improved clinical outcomes only in patients receiving the drug post-COVID-19 diagnosis and not in those who had received vitamin D before diagnosis. CONCLUSIONS: Vitamin D supplementation might be associated with improved clinical outcomes, especially when administered after the diagnosis of COVID-19. However, issues regarding the appropriate dose, duration, and mode of administration of vitamin D remain unanswered and need further research.

Immune Regulation by T Regulatory Cells in Hepatitis B Virus-Related Inflammation and Cancer.

Hepatocellular carcinoma (HCC) is the leading cause of cancer death, and hepatitis B virus (HBV) infection is one of the commonest causes in Asian countries. India has the second largest pool after China for hepatitis B-infected subjects. HBV clearance is T cell dependent, and one of the reasons for T cells hyporesponsiveness is due to mass production of regulatory T cells (Tregs) through activation of Notch signalling, which suppress CD4/CD8 T cells. Tregs are important to maintain cellular homoeostasis; however, during viral infection increase of Tregs is inversely proportional to HBV DNA titres. Tregs exert their suppressive effect either via cell-to-cell contact or through release of interleukin (IL)-2, IL-10, TGF-ß and IL-35. In Chronic hepatitis B virus CHBV infection, PD-1 pathway also gets activated and is involved in promoting tolerance. However, with Tregs induction, virus-specific T cell responses also get decreased. Circulatory and intratumoural Tregs promote development of HBV-specific HCC more by decreasing and impairing the effector functions of CD8 T cells. Antiviral therapies and PD-1 blockade strategy had shown the inhibition of Tregs and reduction in HBV DNA. However, inhibition of HBV-specific Tregs is major challenge for future therapies. New cytokine blockade therapies have emerged as potential therapeutic potentials.

Immune balance in Hepatitis B Infection: Present and Future Therapies.

Chronic hepatitis B virus (HBV) infection affects millions of people worldwide and about half a million people die every year. India represents the second largest pool of chronic HBV infections with an estimated 40 million chronically infected patients. Persistence or clearance of HBV infection mainly depends upon host immune responses. Chronically infected individuals remain in immune tolerant phase unless HBV flares and leads to the development of chronic active hepatitis or acute-on-chronic liver failure. Strategies based on inhibition of viral replication (nucleoside analogues) or immune modulation (interferons) as monotherapy, or in combination in sequential therapies, are currently being used globally for reducing HBV viral load and mediating HBsAg clearance. However, the immune status and current therapies for promoting sustained virological responses in HBV-infected patients remain suboptimal. Elimination of cccDNA is major challenge for future therapies, and new molecules such as NTCP, Toll-like receptor (TLR)7 agonist (GS9620) and cyclophilin have emerged as potential targets for preventing HBV entry and replication. Other than these, HBV cccDNA elimination is the major target for future therapies.

Public health matters: Innovative approaches for engaging medical students.

BACKGROUND: Public health faces the paradox of being increasingly emphasized by the key health and social care regulators and stakeholders, while remaining a largely under-represented discipline in the context of medical curricula. Enhancing medical student engagement in public health teaching is one way to address this concern. METHODS: We discuss four key solutions to the challenges faced by public health educators in medical schools, and present five case studies which demonstrate innovative approaches to engaging medical students in our discipline. RESULTS: Four different approaches have been piloted by members of the Public Health Educators in Medical Schools (PHEMS) network: (i) ensuring social accountability, (ii) demonstrating clinical relevance, (iii) mapping the core curriculum, and (iv) using technology enhanced learning. Preliminary student feedback suggests that these approaches can be used to position public health as an enabler of modern medical practice, and promote a more holistic understanding of medicine by linking patient-centred care to the population level. CONCLUSIONS: The zeitgeist in both academia and the healthcare system supports the teaching of public health within the medical curriculum; there is also consensus at the political and pedagogical level. The challenge of ensuring engagement now needs to be met at the student-teacher interface.

Sugar before bed: a simple dietary risk factor for caries experience.

Clinical care pathways have placed renewed emphasis on caries risk assessment and the ability to predict and prevent further disease. With diet considered a key factor in the development of caries, the level of caries risk posed by dietary habits, such as the frequency of intake and timing of free sugars is questioned. OBJECTIVE: To identify reliable and simple dietary risk factors for caries experience. RESEARCH DESIGN: A cross-sectional observational study of a convenience sample with data gained from clinical examinations, questionnaire and a 24 hour dietary-recall interview. PARTICIPANTS: 128 subjects aged 11-12 from comprehensive schools in Greater Manchester and Newcastle upon-Tyne, UK. OUTCOME MEASURES: free sugars consumed between meals, before bed and total % of total free sugars consumed were assessed from dietary assessments led by a dietitian. D4-6MFT was generated with a caries threshold of ICDAS stage 4 from clinical examinations. RESULTS: Analysis revealed no significant differences in caries experience when looking specifically at caries into dentine, referred to as the cavity group (split at D4-6MFT), between high and low deprivation, consumption of free sugars between meals and free sugars (%). The consumption of free sugars within the hour before bed revealed a statistically significant difference between the cavity/no cavity groups (p=0.002). Logistic regression analysis on the cavity/no cavity groups revealed an odds ratio of 2.4 (95%CI 1.3,4.4) for free sugars consumption before bedtime. CONCLUSIONS: The study suggests that the consumption of free sugars before bedtime may be an important risk factor for adolescent caries into dentine experience.

The VCDQ--a Questionnaire for symptom monitoring in vocal cord dysfunction.

BACKGROUND: Vocal cord dysfunction (VCD) typically involves abnormal adduction of the vocal cords during inspiration, mimics the symptoms of asthma and leads to the prescription of ineffective medications. OBJECTIVE: We aimed to develop a clinical tool to monitor symptoms and response to treatment in confirmed VCD. METHODS: We collated symptoms of VCD from focus groups comprising patients and healthcare professionals; phrases describing these symptoms were assessed for face validity and internal correlation and rated for importance. The resultant 12-item questionnaire (VCDQ) rated the impact of each on a 5-point Likert scale (total score range 12-60) and was tested for reliability, concurrent validity and performance in 31 patients with endoscopically confirmed VCD (± asthma), 29 asthmatics with no history of VCD and 14 healthy controls. We assessed response to speech and language therapy and the minimal important difference by measuring the VCDQ pre- and post- therapy in a 20 new patients. RESULTS: The VCDQ had excellent test-retest reliability and differentiated VCD vs. healthy (Mann-Whitney U-test: z = -5.390, P < 0.001) and asthma (z = -5.730, P < 0.001). All patients improved post-therapy, assessed both by a global rating of change score (GRCS) and by the VCDQ [median (IQR) score pre-therapy 50.5 (48.0 - 54.8), post-therapy 35.0 (29.3 - 41.8), P < 0.001]. The minimal important difference in the VCDQ associated with a rating of 'minimally better' on the GRCS was 4 points. CONCLUSIONS AND CLINICAL RELEVANCE: The VCDQ is a valid and responsive tool suitable for measuring changes in symptoms in patients with VCD. It also gives insight into which symptoms are important to patients and could guide future therapy refinements. Future assessments of novel therapies for this condition should use an appropriately validated tool such as the VCDQ to measure response.

Multi-camera imaging to characterize jet and liner uniformity on the Plasma Liner Experiment (PLX).

At Plasma Liner Experiment, a set of 36 coaxial plasma guns are deployed quasi-uniformly over a 9 ft diameter spherical chamber and are used to form a high-Z spherically compressive plasma liner. Simulations indicate that for the concept to ultimately achieve optimal target density and temperature, a high degree of timing uniformity is required between all guns. To aid in quantifying and correcting gun-to-gun nonuniformities, a key diagnostic will consist of up to six fisheye-view CCD cameras positioned inside the main chamber such that each has all plasma guns within its view. The individual cameras can be triggered at different times to determine each plasma jet's muzzle velocity and structure for different operating conditions. This camera array is currently under development, and the implementation needs and challenges for this camera array are discussed here. Additionally, we detail the analysis methodology for determining jet-to-jet uniformity deviations and how we can correct them, thereby improving overall liner uniformity.

Post chikungunya brain stem encephalitis.

Chikungunya is an arthropod born acute febrile arbo viral illness characterized by acute severe polyarthralgia. During last few years there has been scattered out breaks with associated neurological complications in India. Here we report a case of post chikungunya reversible demyelinating encephalitis who presented with vertigo, dysarthria and ataxia. There was complete clinical as well as radiological improvement with steroids.

Evaluation of hospital environment for presence of Mucorales during COVID-19-associated mucormycosis outbreak in India - a multi-centre study.

BACKGROUND: An unprecedented rise in the number of COVID-19-associated mucormycosis (CAM) cases has been reported in India. Myriad hypotheses are proposed for the outbreak. We recently reported uncontrolled diabetes and inappropriate steroid therapy as significant risk factors for the outbreak. However, Mucorales contamination of hospital environment was not studied. AIM: To perform a multi-centre study across India to determine possible Mucorales contamination of hospital environment during the outbreak. METHODS: Eleven hospitals from four zones of India representing high to low incidence for mucormycosis cases were included in the study. Samples from a variety of equipment used by the patients and ambient air were collected during May 19th, 2021 through August 25th, 2021. FINDINGS: None of the hospital equipment sampled was contaminated with Mucorales. However, Mucorales were isolated from 11.1% air-conditioning vents and 1.7% of patients' used masks. Other fungi were isolated from 18% of hospital equipment and surfaces, and 8.1% of used masks. Mucorales grew from 21.7% indoor and 53.8% outdoor air samples. Spore counts of Mucorales in air were significantly higher in the hospitals of North and South zones compared to West and East zones (P < 0.0001). Among Mucorales isolated from the environment, Rhizopus spp. were the most frequent genus. CONCLUSION: Contamination of air-conditioning vents and hospital air by Mucorales was found. Presence of Mucorales in these areas demands regular surveillance and improvement of hospital environment, as contamination may contribute to healthcare-associated mucormycosis outbreaks, especially among immunocompromised patients.

Tooth cleaning frequency in relation to socio-demographic variables and personal hygiene measures among school children of Udaipur district, India.

OBJECTIVE: The aim of the study was to determine if frequency of tooth cleaning varies with social group, family size, bedtime and other personal hygiene habits among school children. METHODS: Target population comprised schoolchildren aged 8-16 years of Udaipur district attending public schools. A two stage cluster random sampling procedure was executed to collect the representative sample, consequently final sample size accounted to 852 children. Data were collected by means of structured questionnaires which consisted of questions related to oral hygiene habits including a few general hygiene habits, bed time, family size, family income and dental visiting habits. RESULTS: The results show that 30.5% of the total sample cleaned their teeth twice or more daily and there was no significant difference between the genders for tooth cleaning frequency. Logistic regression analysis revealed that older children and those having less than two siblings were more likely to clean their teeth twice a day than the younger ones and children with more than two siblings. Furthermore, frequency of tooth cleaning was significantly lower among children of parents with low level of education and less annual income as compared with those of high education and more annual income. In addition, tooth cleaning habits were more regular in children using tooth paste and regularly visiting to the dentist. CONCLUSIONS: This study observed that tooth cleaning is not an isolated behaviour, but is a part of multifarious pattern of various social and behavioural factors.

Comparison of skin prick tests with specific serum immunoglobulin E in the diagnosis of fungal sensitization in patients with severe asthma.

BACKGROUND: It has been shown that patients with allergic bronchopulmonary aspergillosis (ABPA) and patients with severe asthma with fungal sensitization (SAFS) can benefit from antifungal therapy. It is not known whether allergy skin prick tests (SPT) or specific IgE tests are more sensitive in the identification of patients who are sensitized to fungi and who are therefore candidates for antifungal therapy. OBJECTIVES: To compare SPT and specific serum IgE tests for fungal sensitization in patients with severe asthma. METHODS: We have undertaken SPT and specific serum IgE tests to six fungi (Aspergillus fumigatus, Candida albicans, Penicillium notatum, Cladosporium herbarum, Alternaria alternata and Botrytis cineria) and specific serum IgE test for Trichophyton in 121 patients with severe asthma (British Thoracic Society/SIGN steps 4 and 5). RESULTS: Sixty-six percent of patients were sensitized to one or more fungi based on SPT and/or specific serum IgE results. Positivity to SPT and/or specific serum IgE was as follows: A. fumigatus 45%, C. albicans 36%, P. notatum 29%, C. herbarum 24%, A. alternata 22%, B. cineria 18%, Trichophyton 17% (specific serum IgE only). Concordance between the tests was 77% overall but only 14-56% for individual fungi. Twenty-nine (24%) patients were sensitized to a single fungus and seven (6%) were sensitized to all seven fungal species. Fifty percent of patients were sensitized to fungal and non-fungal extracts, 21% were sensitized only to non-fungal extracts, 16% were sensitized only to fungal extracts and 13% had no positive tests. CONCLUSION: This study is consistent with previous reports that fungal sensitization is common in patients with severe asthma. At present, it remains necessary to undertake both SPT and specific serum IgE testing to identify all cases of fungal sensitization. This may be important in the identification of patients with ABPA and SAFS who may benefit from antifungal therapy.

Costs and operation management of community outreach program for tuberculosis in tribal populations in India.

OBJECTIVE: To evaluate costs of an active case finding (ACF) program with tuberculosis (TB) treatment delivery and monitoring, which targeted a rural tribal population in India. METHOD: A time and motion study was conducted to evaluate operations and workload. Costs from the program perspective were assessed using both the bottom-up and top-down costing methods, exclusive of routine TB care costs. The impact of ACF on routine TB laboratory workloads was measured based on the changes in available staff time per smear at nine designated microscopy centers before and after program implementation. RESULTS: A majority (53.2%) of the community health-care worker's time was spent in traveling to communities, with an average of 22 TB patients (95% CI 19.14-24.94) seen per day per person. Costs (at 2015 $US rates) were US$1.85-US$2.42 per patient screened and submitting sputum, US$2.51-US$4.74 per person diagnosed with TB, and US$22.52-US$34.13 per TB patient completing treatment. Total smear volumes increased significantly after the ACF program, with more than a 15% reduction in available staff time per sputum smear test in most laboratories. CONCLUSION: This low-cost, ACF program has the potential to be highly cost-effective in addressing gaps in TB care problems in rural India.

Community-based active case-finding to reach the most vulnerable: tuberculosis in tribal areas of India.

India has the world's largest indigenous/tribal population. Many areas with large tribal populations suffer from weak infrastructure and services. Surveys have shown a high prevalence of TB among Saharia communities, who rarely access public services. We evaluated a community-based active TB case-finding intervention. Community health workers screened people for TB symptoms in Saharia communities, made referrals, collected sputum for transport to laboratories, and initiated and supported anti-tuberculosis treatment. Microscopy testing was performed at government laboratories. The intervention tracked the people screened, referrals, the people tested, laboratory results, treatment initiation and outcomes. Community health workers verbally screened 65 230 people, 8723 (13%) of whom had symptoms. Of these, 5600 were tested, 964 (17%) of whom were smear-positive. During the intervention, we observed a +52% increase in people tested at laboratories and an +84% increase in TB case notifications. Pre-treatment loss to follow-up decreased and treatment success increased slightly. In India, particularly among tribal populations, many people with TB are missed by current approaches due to poor access. Community-based active case-finding can help identify more people with TB in tribal and remote rural areas by addressing barriers to health seeking as well as help reach ambitious country and global notification targets. .

Microvesicles in hepatic and peripheral vein can predict nonresponse to corticosteroid therapy in severe alcoholic hepatitis.

BACKGROUND: Severe alcoholic hepatitis patients have high mortality and limited response to corticosteroids. Microvesicles reflect cellular stress and disease conditions. AIMS: To investigate whether microvesicles are associated with severity, response to steroid therapy and inflammation in severe alcoholic hepatitis. METHODS: Microvesicles originating from different cells were studied pre-therapy in 101 patients; (71 responder to corticosteroid therapy and 30 nonresponders) and 20 healthy controls. Microvesicles and cells were determined in peripheral and hepatic vein samples using flow cytometry and correlated with outcomes. Inflammatory signalling pathways and functional alterations of immune cells after stimulation with microvesicles were also investigated. RESULTS: Microvesicles mean levels were higher in nonresponders for T cells (CD3+ CD4+ ; 10.1 MV/µL vs 5.4; P = 0.06), macrophages (CD68+ CD11b+ ; 136.5 vs 121.9 MV/µL; P = 0.01), haematopoietic stem-cells (CD45+ CD34+ ; 116.8 vs 13.4 MV/µL; P = 0.0001) and hepatocytes (ASGPR+ ; 470 vs 361 MV/µL; P = 0.01); the latter two predicting steroid nonresponse in 94% patients at baseline in peripheral plasma. Microvesicle levels correlated with histological and liver disease severity indices. Whereas, in non-responders hepatic vein CD34+ cells were lower (P = 0.02), the CD34+ microvesicles there from were higher (P = 0.04), thus suggesting impaired regeneration. Also, microvesicles of 0.2-0.4 µm size were higher in nonresponders (P < 0.03) at baseline. Microvesicles from patients trigger more (P = 0.04) ROS generation, TNF-α production (P = 0.04) and up-regulate pro-inflammatory cytokine related genes in neutrophils in vitro. CONCLUSIONS: Pre-therapy peripheral plasma levels of CD34+ and ASGPR+ microvesicles are reliable non-invasive markers of steroid nonresponse and mortality in patients with severe alcoholic hepatitis.

The effects of toxoplasma infection on rodent behavior are dependent on dose of the stimulus.

Parasite Toxoplasma gondii blocks the innate aversion of rats for cat urine, putatively increasing the likelihood of a cat predating a rat. This is thought to reflect an adaptive behavioral manipulation, because toxoplasma can reproduce only in cat intestines. While it will be adaptive for the parasite to cause an absolute behavioral change, fitness costs associated with the manipulation itself suggest that the change is optimized and not maximized. We investigate these conflicting suggestions in the present report. Furthermore, exposure to cat odor causes long-lasting acquisition of learnt fear in the rodents. If toxoplasma manipulates emotional valence of cat odor rather than just sensory response, infection should affect learning driven by the aversive properties of the odor. As a second aim of the present study, we investigate this assertion. We demonstrate that behavioral changes in rodents induced by toxoplasma infection do not represent absolute all-or-none effects. Rather, these effects follow a non-monotonous function dependent on strength of stimulus, roughly resembling an inverted-U curve. Furthermore, infection affects conditioning to cat odor in a manner dependent upon strength of unconditioned stimulus employed. Non-monotonous relationship between behavioral manipulation and strength of cat odor agrees with the suggestion that a dynamic balance exists between benefit obtained and costs incurred by the parasite during the manipulation. This report also demonstrates that toxoplasma affects emotional valence of the cat odor as indicated by altered learned fear induced by cat odor.

Dietary advice for treatment of type 2 diabetes mellitus in adults.

BACKGROUND: While initial dietary management immediately after formal diagnosis is an 'accepted' cornerstone of treatment of type 2 diabetes mellitus, a formal and systematic overview of its efficacy and method of delivery is not currently available. OBJECTIVES: To assess the effects of type and frequency of different types of dietary advice for adults with type 2 diabetes. SEARCH STRATEGY: We carried out a comprehensive search of The Cochrane Library, MEDLINE, EMBASE, CINAHL, AMED, bibliographies and contacted relevant experts. SELECTION CRITERIA: All randomised controlled trials, of six months or longer, in which dietary advice was the main intervention. DATA COLLECTION AND ANALYSIS: The lead investigator performed all data extraction and quality scoring with duplication being carried out by one of the other six investigators independently with discrepancies resolved by discussion and consensus. Authors were contacted for missing data. MAIN RESULTS: Thirty-six articles reporting a total of eighteen trials following 1467 participants were included. Dietary approaches assessed in this review were low-fat/high-carbohydrate diets, high-fat/low-carbohydrate diets, low-calorie (1000 kcal per day) and very-low-calorie (500 kcal per day) diets and modified fat diets. Two trials compared the American Diabetes Association exchange diet with a standard reduced fat diet and five studies assessed low-fat diets versus moderate fat or low-carbohydrate diets. Two studies assessed the effect of a very-low-calorie diet versus a low-calorie diet. Six studies compared dietary advice with dietary advice plus exercise and three other studies assessed dietary advice versus dietary advice plus behavioural approaches. The studies all measured weight and measures of glycaemic control although not all studies reported these in the articles published. Other outcomes which were measured in these studies included mortality, blood pressure, serum cholesterol (including LDL and HDL cholesterol), serum triglycerides, maximal exercise capacity and compliance. The results suggest that adoption of regular exercise is a good way to promote better glycaemic control in type 2 diabetic patients, however all of these studies were at high risk of bias. AUTHORS' CONCLUSIONS: There are no high quality data on the efficacy of the dietary treatment of type 2 diabetes, however the data available indicate that the adoption of exercise appears to improve glycated haemoglobin at six and twelve months in people with type 2 diabetes. There is an urgent need for well-designed studies which examine a range of interventions, at various points during follow-up, although there is a promising study currently underway.