Conservation of Tubulin-Binding Sequences in TRPV1 throughout Evolution

Transient Receptor Potential Vanilloid sub type 1 (TRPV1), commonly known as capsaicin receptor can detect multiple stimuli ranging from noxious compounds, low pH, temperature as well as electromagnetic wave at different ranges. In addition, this receptor is involved in multiple physiological and sensory processes. Therefore, functions of TRPV1 have direct influences on adaptation and further evolution also. Availability of various eukaryotic genomic sequences in public domain facilitates us in studying the molecular evolution of TRPV1 protein and the respective conservation of certain domains, motifs and interacting regions that are functionally important. analysis reveals that the TBS-1 and TBS-2 of TRPV1 can form helical structures and may play important role in TRPV1 function.Our analysis identifies the regions of TRPV1, which are important for structure – function relationship. This analysis indicates that tubulin binding sequence-1 (TBS-1) near the TRP-box forms a potential helix and the tubulin interactions with TRPV1 via TBS-1 have evolutionary significance. This interaction may be required for the proper channel function and regulation and may also have significance in the context of Taxol®-induced neuropathy

Lopinavir/ritonavir: is early administration better in Covid-19?

Background: To share the data of coronavirus 2019 (Covid-19) patients started on lopinavir-ritonavir (lopi/r) in relation to time period from the onset of symptoms.Method: Observational descriptive study of 23 Covid-19 patients admitted in a tertiary care center in India from March 2020 to May 2020. Patients categorized into 2 groups based on the timing of initiation of lopi/r from the onset of symptoms. Group 1 were given the drug early (≤7 days) and group 2 late (>7 days). The clinical events (oxygen requirement days and ICU stay) and outcomes of hospital stay between the two groups were evaluated.Results: Patients were started on lopi/r for a period of 14 days on admission, out of which 12 patients were in group 1 and 11 patients in group 2. Underlying co-morbidities were present in 15 patients (65.21%). The mean duration from onset of symptoms to lopi/r initiation was 4 days and 11.1 days in Group 1 and 2 respectively. Requirement for oxygen support (2.16 versus 6.54 days), mean duration of hospitalization (8.58 versus 11.54 days) and mean duration of obtaining first Covid-19 negative report from the onset of symptoms (10.5 versus 19.57 days) were all significantly lesser in group 1 (p<0.05). All patients belonging to Group 1 and eight patients of group 2 recovered completely and were discharged whereas 3 patients of group 2 expired. Diarrhea was the most commonly observed adverse effect of lopi/r in our patients.Conclusion: With no approved weapon to tackle the Covid-19 pandemic, we should keep lopi/r in our armamentarium of drugs and use it at the earliest. More clinical trials are needed in future to ascertain if lopi/r can reduce hospital stay, prompt faster recovery and result in better clinical outcome

Acute limb ischemia in COVID-19 patients and its rehabilitation: a case series from a tertiary care hospital in Central India

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and infectious virus. It belongs to the family coronavirus and it is a single strand positive sense virus. There are many theories which relate to the origin and transmission of this virus and hence the virus has been tagged with many names according to various taxonomical guidelines. The conventional clinical spectrum of this infection includes cough, fever, dyspnea, anorexia and gastrointestinal symptoms. It has been seen during the course of this disease that there are also some properties relating this virus to the hypercoagulability in the disease spectrum. The cases involving arterial and venous thromboembolism are not rare. This case series is a collection on three such cases from the red zone (zone separated for COVID-19 infected patients) of a tertiary care hospital in central India which showcase acute limb ischemia in patients infected with SARS-CoV-2

Molecular Phylogeny of OVOL Genes Illustrates a Conserved C2H2 Zinc Finger Domain Coupled by Hypervariable Unstructured Regions

OVO-like proteins (OVOL) are members of the zinc finger protein family and serve as transcription factors to regulate gene expression in various differentiation processes. Recent studies have shown that OVOL genes are involved in epithelial development and differentiation in a wide variety of organisms; yet there is a lack of comprehensive studies that describe OVOL proteins from an evolutionary perspective. Using comparative genomic analysis, we traced three different OVOL genes (OVOL1-3) in vertebrates. One gene, OVOL3, was duplicated during a whole-genome-duplication event in fish, but only the copy (OVOL3b) was retained. From early-branching metazoa to humans, we found that a core domain, comprising a tetrad of C2H2 zinc fingers, is conserved. By domain comparison of the OVOL proteins, we found that they evolved in different metazoan lineages by attaching intrinsically-disordered (ID) segments of N/C-terminal extensions of 100 to 1000 amino acids to this conserved core. These ID regions originated independently across different animal lineages giving rise to different types of OVOL genes over the course of metazoan evolution. We illustrated the molecular evolution of metazoan OVOL genes over a period of 700 million years (MY). This study both extends our current understanding of the structure/function relationship of metazoan OVOL genes, and assembles a good platform for further characterization of OVOL genes from diverged organisms

Spontaneous pneumothorax as a complication in COVID‐19 recovered male patient: a case report from a tertiary care centre in Central India

As the number of COVID-19 cases emerge new complications associated with the disease are recognised. This report records a case of pneumothorax in a COVID-19 patient. Our report justifies that pneumothorax can occur during different phases of disease in patients without any history of pulmonary comorbidity and is not necessarily associated to positive pressure ventilation or a severity of COVID-19. However debatable might be the exact mechanism of the process be, this observation might imply that extensive alveolar destruction due to COVID-19 may lead to bulla formation resulting in subsequent pneumothorax

Health System Capacity and Access Barriers to Diagnosis and Treatment of CVD and Diabetes in Nepal

Background: Universal access to essential medicines and routine diagnostics is required to combat the growing burden of cardiovascular disease (CVD) and diabetes. Evaluating health systems and various access dimensions – availability, affordability, accessibility, acceptability, and quality – is crucial yet rarely performed, especially in low- and middle-income countries. Objective: To evaluate health system capacity and barriers in accessing diagnostics and essential medicines for CVD and diabetes in Nepal. Methods: We conducted a WHO/HAI nationally-representative survey in 45 health-facilities (public sector: 11; private sector: 34) in Nepal to collect availability and price data for 21 essential medicines for treating CVD and diabetes, during May–July 2017. Data for 13 routine diagnostics were obtained in 12 health facilities. Medicines were considered unaffordable if the lowest paid worker spends >1 day’s wage to purchase a monthly supply. To evaluate accessibility, we conducted facility exit interviews among 636 CVD patients. Accessibility (e.g., private-public health facility mix, travel to hospital/pharmacy) and acceptability (i.e. Nepal’s adoption of WHO Essential Medicine List, and patient medication adherence) were summarized using descriptive statistics, and we conducted a systematic review of relevant literature. We did not evaluate medicine quality. Results: We found that mean availability of generic medicines is low (<50%) in both public and private sectors, and less than one-third medicines met WHO’s availability target (80%). Mean (SD) availability of diagnostics was 73.1% (26.8%). Essential medicines appear locally unaffordable. On average, the lowest-paid worker would spend 1.03 (public sector) and 1.26 (private sector) days’ wages to purchase a monthly medicine supply. For a person undergoing CVD secondary-prevention interventions in the private sector, the associated expenditure would be 7.5–11.2% of monthly household income. Exit interviews suggest that a long/expensive commute to health facilities and poor medicine affordability constrain access. Conclusions: This study highlights critical gaps in Nepal’s health system capacity to offer basic health services to CVD and diabetes patients, owing to low availability and poor affordability and accessibility. Research and policy initiatives are needed to ensure uninterrupted supply of affordable essential medicines and diagnostics

The platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure

Acetaminophen (APAP) is the main cause of acute liver failure in the West. Specific efficacious therapies for acute liver failure (ALF) are limited and time-dependent. The mechanisms that drive irreversible acute liver failure remain poorly characterized. Here we report that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage after toxic liver injury. Our data demonstrate that blocking platelet CLEC-2 signalling enhances liver recovery from acute toxic liver injuries (APAP and carbon tetrachloride) by increasing tumour necrosis factor-α (TNF-α) production which then enhances reparative hepatic neutrophil recruitment. We provide data from humans and mice demonstrating that platelet CLEC-2 influences the hepatic sterile inflammatory response and that this can be manipulated for therapeutic benefit in acute liver injury. Since CLEC-2 mediated platelet activation is independent of major haemostatic pathways, blocking this pathway represents a coagulopathy-sparing, specific and novel therapy in acute liver failure

Microduplications of 16p11.2 are associated with schizophrenia

Recurrent microdeletions and microduplications of a 600 kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders1-3. Here we report the strong association of 16p11.2 microduplications with schizophrenia in two large cohorts. In the primary sample, the microduplication was detected in 12/1906 (0.63%) cases and 1/3971 (0.03%) controls (P=1.2×10-5, OR=25.8). In the replication sample, the microduplication was detected in 9/2645 (0.34%) cases and 1/2420 (0.04%) controls (P=0.022, OR=8.3). For the series combined, microduplication of 16p11.2 was associated with 14.5-fold increased risk of schizophrenia (95% C.I. [3.3, 62]). A meta-analysis of multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia, bipolar disorder and autism. The reciprocal microdeletion was associated only with autism and developmental disorders. Analysis of patient clinical data showed that head circumference was significantly larger in patients with the microdeletion compared with patients with the microduplication (P = 0.0007). Our results suggest that the microduplication of 16p11.2 confers substantial risk for schizophrenia and other psychiatric disorders, whereas the reciprocal microdeletion is associated with contrasting clinical features

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Microduplications of 16p11.2 are associated with schizophrenia

Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders1,2,3. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 × 10−5, OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 × 10−7), bipolar disorder (P = 0.017) and autism (P = 1.9 × 10−7). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 × 10−13). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007)