Emergence of slip-ideal-slip behavior in tip-links serve as force filters of sound in hearing.

Tip-links in the inner ear convey force from sound and trigger mechanotransduction. Here, we present evidence that tip-links (collectively as heterotetrameric complexes of cadherins) function as force filters during mechanotransduction. Our force-clamp experiments reveal that the tip-link complexes show slip-ideal-slip bond dynamics. At low forces, the lifetime of the tip-link complex drops monotonically, indicating slip-bond dynamics. The ideal bond, rare in nature, is seen in an intermediate force regime where the survival of the complex remains constant over a wide range. At large forces, tip-links follow a slip bond and dissociate entirely to cut-off force transmission. In contrast, the individual tip-links (heterodimers) display slip-catch-slip bonds to the applied forces. While with a phenotypic mutant, we showed the importance of the slip-catch-slip bonds in uninterrupted hearing, our coarse-grained Langevin dynamics simulations demonstrated that the slip-ideal-slip bonds emerge as a collective feature from the slip-catch-slip bonds of individual tip-links.

Prevalence and Correlates of Malnutrition in Nuh District, Haryana State, India.

India has a substantial burden of undernutrition coupled with overweight and obesity at the other end of the spectrum of malnutrition. Nuh district, in the Haryana State in northern India, is an impoverished district in India. With an aim to investigate the problem of malnutrition in the community, a cross-sectional study was conducted in four villages of the Nuh district. Height/length, weight, and age data of children under 5 years were used to calculate three indices: weight-for-age, height-for-age, and weight-for-height. The body mass index was calculated for individuals older than 6 years. Associations between malnutrition and other factors were assessed using simple and multiple logistic regression to get adjusted coefficients. The total surveyed population comprised 11,496 individuals. Over 51% were female, and 13.2% of the surveyed population were children under 5 years. Almost half of the population was illiterate and unemployed. The prevalences of underweight, stunting, and wasting in children under 5 years were 37%, 53%, and 21%, respectively. The prevalences of underweight and stunting in the 6- to 19-year-old age group were 29% and 38%, respectively. The prevalence of overweight was 36% in the 20- to 40-year-old and > 60-year-old age groups, and 44% in the 41- to 60-year-old age group. Our findings reveal a considerable burden of undernutrition among children under 5 years and a dual burden of undernutrition and overnutrition in adults, highlighting the need to map these areas and sharpen our responses to mitigate the overwhelming and long-term consequences of malnutrition in the Nuh district.

Prevalence of isoniazid resistance in cases of rifampicin resistance detected on GeneXpert MTB/RIF assay.

Background: The fight against tuberculosis in our country has taken a new shape with the inclusion of rapid nucleic acid amplification tests like GeneXpert MTB/RIF assay which rapidly detects Mycobacterium tuberculosis and rifampicin resistance. Rifampicin resistance detected on GeneXpert has been considered as a sine qua non for the presence of isoniazid resistance and hence classified as multidrug-resistant tuberculosis (MDR-TB). However treatment of rifampicin-resistant, isoniazid-monoresistance, and MDR-TB are different. Our study was done with the aim of identification of the prevalence of isoniazid resistance on culture, in cases which had rifampicin resistance on GeneXpert. Methods: Pulmonary samples of patients of presumptive tuberculosis were subjected to GeneXpert testing and liquid MGIT (mycobacterium growth indicator tube) culture. On detection of rifampicin resistance on MTB/RIF assay, the patients were included in our study and cultures were followed-up for sensitivity to isoniazid. A total of 76 patients were included. Results: 76 patients of rifampicin resistance on GeneXpert MTB/RIF assay were followed-up for the sensitivity of isoniazid on culture media. Out of the 76 cases, 62 (81.57%) were found to have isoniazid resistance. Out of the 14 patients, the cultures showed no growth in 6, and in the rest, isoniazid was found to be sensitive. Conclusion: GeneXpert MTB/RIF assay is an excellent modality for the detection of M. tuberculosis and rifampicin resistance. The decision to exclude isoniazid from the treatment regimen in patients with rifampicin resistance should be made only after conducting further molecular/phenotypic tests.

Effectiveness of high flow nasal cannula oxygen therapy in patients of acute pulmonary thromboembolism with acute hypoxemic respiratory failure.

Background: Acute Pulmonary thromboembolism (PTE) is associated with acute hypoxemic respiratory failure (AHRF), which is a leading cause of death in these patients. High-Flow Nasal Cannula (HFNC) oxygen therapy is a cornerstone of the treatment of respiratory failure. The aim of the present study is to explore the efficacy of HFNC in the treatment of patients of acute PTE with acute hypoxemic respiratory failure in India. Methods: This is a retrospective study of patients admitted to a tertiary care center with acute PTE with AHRF during the period from January 2018 to January 2020. After reviewing medical files, patients of acute PTE with AHRF treated with HFNC were included in the study. We analyzed the improvement in oxygenation parameters and respiratory rate, as well as outcome in these patients. Results: During the above specified period, 12 patients suffering from PTE with AHRF were treated with HFNC. After 1 h of the initiation of HFNC along with anticoagulation, the respiratory parameters of patients significantly improved. HFNC was applied for a period of 6-10 days. None of the patients required intubation for AHRF, and all patients were discharged from the hospital on oral anticoagulants. Conclusion: HFNC oxygen therapy in patients with acute PTE with AHRF showed rapid improvement of oxygenation and respiratory rate. HFNC oxygen therapy is an efficacious treatment for patients with AHRF secondary to acute PTE without any significant hemodynamic effect. It acts as a superior modality of oxygen therapy avoiding noninvasive and invasive ventilatory support.

Pulmonary embolism in coronavirus disease 2019: the silent killer.

BACKGROUND: Pulmonary embolism (PE) has been identified as one of the deadliest complications of coronavirus disease 2019 (COVID-19), especially in patients admitted to the intensive care unit (ICU). Western literature reminds us of the high prevalence of PE in COVID. Here, we report a series of 13 cases of PE diagnosed and managed at our hospital. METHODS: Retrospective analysis of medical records of 13 cases of PE admitted at our hospital from February 1, 2020, to September 31, 2020, were done. Their clinical, laboratory, and radiologic data were assessed in detail. RESULTS: Computed tomography pulmonary arteriography was used to make the diagnosis in eight patients (61.53%), and clinical findings with corroborative ultrasound and laboratory parameters were used to label PE in five patients (38.46%). Five patients were hemodynamically unstable, requiring thrombolysis with recombinant tissue plasminogen activator, and four patients (30.76%) suffered a fatal outcome. CONCLUSION: COVID-19 is a highly prothrombotic state, and all physicians should keep a high vigilance for PE. All hospitalized patients with COVID-19, especially those admitted in ICU, should be on prophylactic anticoagulation and, if there is any worsening, should be started on therapeutic regimen. Patients at the time of discharge should be switched to oral anticoagulation, which should be continued for at least 3-6 months.

Multidrug-resistant tuberculosis in COVID-19: Double trouble.

COVID-19 pandemic has changed the lives of many especially those living with chronic diseases. India has the highest burden of multidrug resistant tuberculosis (MDR TB) in the world. The pandemic and the lockdown created multiple bottlenecks in the provision of healthcare as well as the distribution of medications. The stigma of tuberculosis leads to mental trauma, suffering, delay in diagnosis, and non-compliance to therapy. Lockdown imposed due to COVID-19, aggravated the fears of each patient and had made medical care access difficult. Here we describe a patient with MDR TB and chronic hepatitis B and how the course of the disease and its management was affected by COVID-19.

A very unusual case of interstitial lung disease.

Cotton dust exposure has been implicated in causing diseases like byssinosis and obstructive airway diseases like COPD and asthma. Long-term exposure to cotton dust causing interstitial lung disease and pulmonary fibrosis has been sparsely reported in the literature. Here, we report a case of an individual with long-term cotton dust exposure who presented with typical symptoms of interstitial lung disease and was managed conservatively.

Clinico-etiological characteristics of organizing pneumonia: A retrospective study.

INTRODUCTION: Organizing pneumonia (OP) is an idiopathic interstitial pneumonia characterized radiologically by the patchy peripheral areas of ground-glass opacities and consolidation. It is commonly associated with a variety of conditions such as connective tissue diseases (CTD), drugs, infections, malignancy, radiation exposure, post-transplant, and other interstitial pneumonia. There are no specific clinical manifestations unless there is an underlying etiology. We present a series of such cases. AIMS AND OBJECTIVES: The aim of the study was to identify the clinical characteristics and etiological spectrum of patients manifesting radiologically with OP pattern. MATERIALS AND METHODS: This was a retrospective analysis of clinico-radiological profile and etiological diagnosis of 23 patients, who had a radiological diagnosis of OP during the period of January 2017-September 2019. RESULTS: Our patients presented with nonspecific symptoms of cough, fever, breathlessness, and occasionally with hemoptysis. The various etiologies identified were CTD (n = 4), infection (n = 2), drugs (n = 4), radiation (n = 1), chronic aspiration syndrome (n = 1), malignancy (n = 2), hypersensitivity pneumonitis (n = 1), and chronic heart failure (n = 2), and in majority (n = 7), no underlying etiology was evident and were labeled as cryptogenic organizing pneumonia. CONCLUSION: OP is an underdiagnosed entity and is associated with numerous diseases varying from pulmonary tuberculosis to malignancy. Identification of the underlying disease process is of paramount importance as it enables the treating physician to implement necessary therapeutic interventions.

Immunogenicity and protective efficacy of inactivated SARS-CoV-2 vaccine candidate, BBV152 in rhesus macaques.

The COVID-19 pandemic is a global health crisis that poses a great challenge to the public health system of affected countries. Safe and effective vaccines are needed to overcome this crisis. Here, we develop and assess the protective efficacy and immunogenicity of an inactivated SARS-CoV-2 vaccine in rhesus macaques. Twenty macaques were divided into four groups of five animals each. One group was administered a placebo, while three groups were immunized with three different vaccine candidates of BBV152 at 0 and 14 days. All the macaques were challenged with SARS-CoV-2 fourteen days after the second dose. The protective response was observed with increasing SARS-CoV-2 specific IgG and neutralizing antibody titers from 3rd-week post-immunization. Viral clearance was observed from bronchoalveolar lavage fluid, nasal swab, throat swab and lung tissues at 7 days post-infection in the vaccinated groups. No evidence of pneumonia was observed by histopathological examination in vaccinated groups, unlike the placebo group which exhibited interstitial pneumonia and localization of viral antigen in the alveolar epithelium and macrophages by immunohistochemistry. This vaccine candidate BBV152 has completed Phase I/II (NCT04471519) clinical trials in India and is presently in phase III, data of this study substantiates the immunogenicity and protective efficacy of the vaccine candidates.

Diagnostic Yield and Safety of Bronchoscopic Lung Cryobiopsy in Evaluation of Lung Mass.

Background A mass lesion in the lung is a common finding seen on chest radiology. The prognosis of patients with mass lesions in the lung is capricious as malignancy is a consideration. It is essential to diagnose the underlying aetiology at the earliest with minimally invasive procedures for prompt treatment of the case. Bronchoscopic lung cryobiopsy (BLC) is a newer interventional technique in pulmonary medicine for the diagnosis of mass lesions in the lung. Materials and methods This is a retrospective study of patients reporting to a tertiary care centre who were radiologically (by computed tomography scan of the chest) diagnosed with a mass lesion of the lung and who underwent BLC during the period from January 2018 to January 2021. We analysed the diagnostic yield of the technique defined as a positive tissue diagnosis after the histopathological examination (HPE) along with the safety of the procedure. Results During the above period, we evaluated 70 patients who were diagnosed radiologically with mass lesions of the lung and underwent BLC. We obtained tissue diagnoses for 66 cases and the result of four cases was inconclusive. The diagnostic yield of the BLC procedure was 94.29%. There was no mortality and complications were minimal bleeding and small pneumothorax. Conclusion BLC is a newer technique for obtaining lung tissue via a flexible bronchoscope obviating the need for open lung biopsy. The main advantage of the technique is providing larger tissue samples with minimal or no side effects without undergoing multiple procedures as compared to other bronchoscopic or surgical methods for obtaining a diagnosis from lung tissue. BLC is a safer and promising technique in diagnosing mass lesions of the lung with better yield.

Superior Proton-Transfer Catalytic Promiscuity of Cytochrome†c in Self-Organized Media.

Evolutionarily elderly proteins commonly feature greater catalytic promiscuity. Cytochrome c is among the first set of proteins in evolution to have known prospects in electron transport and peroxidative properties. Here, we report that cyt c is also a proficient proton-transfer catalyst and enhances the Kemp elimination (KE; model reaction to show proton transfer catalytic property) by ∼750-fold on self-organized systems like micelles and vesicles. The self-organized systems mimic the mitochondrial environment in vitro for cyt c. Using an array of biophysical and biochemical mutational assays, both acid-base and redox mechanistic pathways have been explored. The histidine moiety close to hemin group (His18) is mainly responsible for proton abstraction to promote the concerted E2 pathway for KE catalysis when cyt c is in its oxidized form; this has also been confirmed by a H18A mutant of cyt c. However, the redox pathway is predominant under reducing conditions in the presence of dithiothreitol over the pH range 6-7.4. Interestingly, we found almost 750-fold enhanced KE catalysis by cyt c compared to aqueous buffer. Overall, in addition to providing mechanistic insights, the data reveal an unprecedented catalytic property of cyt c that could be of high importance in an evolutionary perspective considering its role in delineating the phylogenic tree and also towards generating programmable designer biocatalysts.

DC type 2 polarization depends on both the allergic status of the individual and protease activity of Per a 10.

Cockroach proteases are important risk factors for asthma development in predisposed individuals. In the present study, effect of allergic status of patients on DCs polarization in response to protease allergen Per a 10 was investigated. Cockroach-allergic, other-allergic patients and healthy individuals were selected following the guidelines of ATS/ARIA. Monocyte-derived dendritic cells (DCs) were generated from the selected individuals and stimulated with Per a 10. Flow cytometric analysis showed a significantly high expression of CD80 and CD86 on DCs from cockroach-allergic patients after Per a 10 stimulation as compared to healthy individuals or other-allergic patients (P<0.05). Per a 10 induced comparable level of CD83 expression on DCs from all the 3 groups, showing it was irrespective of the allergic status. CD40 expression was significantly low (P<0.05) on the DCs from cockroach-allergic patients as compared to healthy individuals or other-allergic patients. Further, proteolytically active Per a 10 induced lower CD40 expression on DCs than the heat-inactivated Per a 10 (P<0.05) indicating role of protease activity in the generation of an immune response. The sCD40 level in active Per a 10 stimulated DC cultures was significantly higher than in heat-inactivated Per a 10 (P<0.05). There was two-fold decrease (P<0.05) in IL-12 production by active Per a 10-stimulated DCs than heat-inactivated Per a 10-stimulated DCs. Per a 10-stimulated DCs from cockroach-allergic patients secreted high levels of IL-5, IL-6, TNF-α than that from healthy individuals or other-allergic patients (P<0.05). Furthermore, Per a 10-stimulated DCs from cockroach-allergic patients induced increased secretions of IL-4, IL-5, IL-6, TNF-α and low IL-12 by T cells as compared to those from other groups (P<0.05). Thus, in presence of Per a 10 allergen, polarization of DCs shifts toward type 2 in cockroach-allergic patients but not in the healthy individuals or other-allergic patients. In conclusion, both allergic status of the individual and protease activity of Per a 10 are important parameters that participate in DCs polarization.