Synthesis, Characterization, and Antimicrobial Activity Screening of Some Novel 3-(2-(3-(Substituted benzyloxy)oxetan-3-yl)-3-fluorophenoxy)-8-fluoro-2-methylquinoline Derivatives as Potential Antimycobacterial Agents.

Microbial infections remain a grave threat to global health security due to increasing antibiotic resistance. The coronavirus pandemic has increased the risk of microbial infection. To combat these infections, the search for new therapeutic agents is in high demand. A series of new 3-(2-(3-(substituted benzyloxy)oxetan-3-yl)-3-fluorophenoxy)-8-fluoro-2-methylquinoline (9a-i) derivatives have been synthesized. The structure of synthesized compounds was analyzed by spectroscopic methods. The newly synthesized oxetanyl-quinoline derivatives were evaluated for in vitro antibacterial activity against Escherichia coli (NCIM 2574), Proteus mirabilis (NCIM 2388), Bacillus subtilis (NCIM 2063), Staphylococcus albus (NCIM 2178), and in vitro antifungal activity against Aspergillus niger (ATCC 504) and Candida albicans (NCIM 3100). Six oxetanyl-quinoline derivatives 9a, 9b, 9c, 9d, 9e, and 9h have shown good antibacterial activity against P. mirabilis with MIC 31.25-62.5 µM, 3-(((3-(2-fluoro-6-((8-fluoro-2-methylquinolin-3-yl)oxy)phenyl)oxetan-3-yl)oxy)methyl)benzonitrile (9f) reporting comparable activity against P. mirabilis with respect to the standard drug streptomycin. Compound 9a also showed good activity against B. subtilis with MIC 31.25 µM. The eight compounds 9a, 9b, 9d, 9e, 9f, 9g, 9h, and 9i have shown good antifungal activity against A. niger. The synthesized compounds were also screened for antimycobacterial activity against Mycobacterium tuberculosis H37Rv by MTT assay. Among the nine derivatives, compounds 9b, 9c, 9d, 9f, 9g, 9h, and 9i showed excellent antimycobacterial activity with MIC 3.41-12.23 µM, and two derivatives showed good activity with MIC 27.29-57.73 µM. All the derivatives were further evaluated for cytotoxicity against the Vero cell line and were found to be nontoxic. The in silico study of compounds 9a-i was performed against ATP synthase (PDB ID: 4V1F) and most of the compounds showed the stable and significant binding to ATP synthase, confirming their plausible mode of action as ATP synthase inhibitors. Thus, the significant antimycobacterial activity of 3-(2-(3-(substituted benzyloxy)oxetan-3-yl)-3-fluorophenoxy)-8-fluoro-2-methylquinoline derivatives has suggested that the oxatenyl-quinoline compounds could assist in the development of lead compounds to treat mycobacterial infections.

Potential Association of Hypernatremia With Mortality in Patients With Acute Kidney Injury and COVID-19.

Background The outcome of acute kidney injury (AKI) in patients with COVID-19 and the factors associated with its outcome, including mortality, are understudied among the Indian population. Objective The objective of this study is to determine the outcome of AKI in a cohort of patients with COVID-19 admitted to medical wards and associated intensive care unit (ICU) and the factors associated with its outcome, including mortality. Method This is a retrospective study of patients with COVID-19 and AKI admitted to a tertiary care hospital. A total of 1765 patients were admitted to a hospital with COVID-19 between March 23, 2021, and June 30, 2021, during the second wave of the pandemic chiefly attributed to SARS-Co-V-2 lineage B.1.617. Patients with AKI for whom a nephrology call was sought for management (N=60) were included. Measurements carried out were the stage of AKI, co-morbidities, ICU admission, mechanical ventilation, lab parameters, and mortality. We classified AKI by comparing the highest to lowest recorded serum creatinine in hospital and staged AKI based on the Kidney Disease: Improving Global Outcomes (KDIGO) system. We further developed stepwise logistic regression models to find independent factors associated with mortality.  Results Out of the 1765 patients hospitalized with COVID-19, a total of 60 (3.4%) patients with AKI were referred to nephrology for management. The observed mortality in this cohort was 41/60 (68.3%). AKI stage 3 was observed to be the most common (78.3%). Based on a univariate analysis of association, age, chronic kidney disease, admission to ICU, the requirement for vasopressor and ventilation, lactate dehydrogenase (LDH) DH, liver function tests (LFT), hypernatremia, and leucocytosis were associated with the mortality of patients (p<0.05) with AKI and COVID-19 infection. Multivariate analysis using logistic regression led to the identification of hypernatremia (OR 5.24 {0.95-42.31}) and multiple co-morbidities (OR 2.59 {1.03-8.75}, p<0.07) as potential factors independently associated with mortality. Conclusion The study indicates the potential association of hypernatremia with mortality in AKI, along with the simultaneous presence of multiple co-morbidities with COVID-19. As the statistical power of the association is weak, we are claiming the association as potential only. It needs to be confirmed in other larger studies.

Improving access to cancer clinical trials for patients from CALD backgrounds whose preferred language is not English - Results of a National Survey in Australia (Current Resources)

INTRODUCTION AND OBJECTIVES: Despite Australia having an extremely diverse population, research demonstrates that cancer patients from culturally and linguistically diverse ('CALD') communities are underrepresented in clinical trials. To inform future policy and strategy to address this inequity, we completed a national survey of the Australian clinical trials workforce evaluating current resources to address this issue, identified barriers and preferred solutions. This reports current resources in place. METHODS: An online survey was created using Redcap comprising a mix of 15 closed and open-ended items with an estimated completion time of 20 minutes. The survey was emailed to members of two peak bodies for oncology clinicians in Australia, the Clinical Oncology Society of Australia (COSA) and the Medical Oncology Group of Australia (MOGA) and all major cancer cooperative trial groups (12) in Australia. The survey was also promoted by the study team to relevant individuals and online via Twitter. Quantitative analysis was performed using Microsoft Excel and qualitative analysis of free text entries was performed using NVivo. RESULTS: 91 respondents completed the questionnaire, with representatives from each state - the majority of respondents were from NSW (53%) and Victoria (31%). 68% were clinicians and 16% were clinical trial coordinators. 55% of respondents reported that their trial catchment was comprised of over 20% patients from a CALD background - however, 62% reported that less than 20% of their trials had included CALD participants in the previous 12 months. 74% of respondents reported that their units do not routinely collect data on preferred language or ethnic background of trial patients. Qualitative analysis showed that the only resource routinely available to sites are in person interpreters used in standard of care, which additionally, have been difficult to access during the COVID pandemic leading to only phone interpreters. CONCLUSIONS: This representative survey of the Australian cancer clinical trials workforce confirms an ongoing inequity with disproportionately lower numbers of CALD patients on enrolled in cancer clinical trials compared to the catchments served. Most respondents stated that CALD data is not routinely collected, which inhibits ongoing monitoring of this issue. We did not find evidence of existing specific resources in place to support recruitment of CALD populations, apart from standard of care interpreters.

Predictors of Requirement of Inotrope Among Patients With Early Sepsis: Special Reference to Microcirculatory Parameters.

Introduction The management of septic shock and refractory septic shock is essential in preventing sepsis-related death. The handheld vital microscope is a new modality of investigation for sepsis for microcirculatory assessment. This study aimed to identify predictors of inotrope requirements among patients with early sepsis and impending septic shock with particular reference to sublingual microcirculation assessment parameters. Methodology We conducted an observational cross-sectional hospital-based study in central India. The formal sample size was calculated to be 52 patients using a convenient sampling technique. The study was initiated with ethics approval (IHEC-LOP/2019/ MD0090) with consent from the patients. We used the MicroScan (MicroVision Medical, Netherlands) Video Microscope System (No.16A00102) to obtain sidestream dark-field imaging along with the AVA 4.3C software (MicroVision Medical). Results Of 51 cases, 60.8% were women, and 39.2% were men, and the study population had a mean age of 41.0 ± 14.9 years. Patients were recruited from medical wards (64.7%) and emergency departments (35.3%). The most common site of infection was gastrointestinal (33.3%), followed by respiratory infections (25.5%) and genitourinary infections (11.8%). The quick sequential organ failure assessment score was 2.0 ± 0.1. Eight patients required inotropes, and six patients died. High respiratory rates and lactate levels were important predictors of inotrope requirements in patients with early sepsis. Sublingual microcirculatory parameters at baseline did not significantly affect the requirement of inotropes consequently. Conclusions Sublingual microscopy is a suggested tool for the management of sepsis. However, without clearly defined cut-off values, handheld vital microscopy could not predict fluid responsiveness among patients with early sepsis. Also, it would be difficult to incorporate this technology into regular practice without equipment upgrades and image acquisition software.

Outcome of post-COVID-19 fungal pyelonephritis: A single Indian tertiary center experience.

Introduction: COVID-19 pandemic is associated with secondary opportunistic fungal infections. These have an aggressive course with a high mortality rate. We present our experience of seven cases of post-COVID-19 fungal pyelonephritis. Methods: An observational study over a period of 8 months of May to December 2021 was carried out at our tertiary care hospital, including all patients with features of fungal pyelonephritis in post-COVID-19 setting. The patient demographics, details of previous COVID-19 infection, details of present admission and management were collected. The endpoints were either discharge from the hospital or death. Results: Seven patients were included. Mean age of presentation was 42 years (range: 20-63 years, standard deviation ± 14.2). Male-to-female ratio was 6:1. One patient was diabetic. Two patients were asymptomatic, one had mild infection, and four patients had severe COVID-19 infection as per National Institute of Health criteria. In the present admission, all patients had symptomatic pyelonephritis with laboratory parameters showing elevated D dimer, C reactive protein, and total leukocyte counts. In all seven patients, ultrasound of kidney ureter bladder region showed bulky kidney, color Doppler showed main renal arterial thrombosis in two patients, segmental arterial thrombosis in another patient. Computed tomography scan was suggestive of changes of pyelonephritis in all patients with multiple renal hypodense areas. All patients required nephrectomy with biopsy suggestive of changes of necrotizing fungal inflammation. Three patients expired. Conclusion: Management of post-COVID-19 fungal pyelonephritis should be aggressive and suspicious laboratory and imaging findings should be treated by early nephrectomy.

Adequate Antithrombin III Level Predicts Survival in Severe COVID-19 Pneumonia.

Critically ill patients with COVID-19 are at an increased thrombotic risk, hence thromboprophylaxis with heparin is considered mandatory. Antithrombin III (ATIII) is the most potent endogenous anticoagulant and is required for the clinical efficacy of heparin. Profound hypercoagulable and inflammatory state associated with COVID-19 can result in decreased ATIII levels and ineffective heparin treatment resulting in increased mortality. The present study evaluated ATIII levels in critically ill patients of COVID-19 and correlated them with other coagulation parameters and disease outcomes. A retrospective review of those critically ill COVID-19 patients was performed who were on a therapeutic dose of low molecular weight heparin (LMWH) and had serial measurements of ATIII, anti-factor Xa (antiFXa) assay and other routine coagulation parameters. A total of 27 critically ill COVID-19 patients were identified, out of these, 12 survived and 15 had disease-induced mortality. ATIII levels were found to be significantly lower in non-survivors on the third day of serial measurement along with worsening of other coagulation parameters. AntiFXa levels were found to be higher in non-survivors as compared to survivors. Further studies are required to establish ATIII as a prognostic marker and to determine the utility of monitoring antiFXa levels in COVID-19 patients on LMWH therapy.

Obstructive sleep apnea is highly prevalent in COVID19 moderate to severe ARDS survivors: Findings of level I Polysomnography in a tertiary care hospital (preprint)

Study ObjectivesStudies have found Obstructive Sleep Apnea (OSA) as a risk factor for increased risk for COVID19 Acute respiratory Distress Syndrome (ARDS); but most of the studies were done in already known patients of OSA. This study was done to find prevalence of OSA in patients with COVID-19 related acute respiratory distress syndrome. MethodologyA hospital based longitudinal study was conducted among COVID 19 Intensive Care Unit (ICU) survivors. All consecutive COVID19 with moderate to severe ARDS were evaluated for OSA by Level I Polysomnography (PSG) after 4-6 weeks of discharge. Prevalence of OSA and PSG variables {Total sleep time, Sleep efficiency, sleep stage percentage, Apnea Hypopnea Index (AHI), T90, nadir oxygen} was estimated. ResultsOut of 103 patients discharged from ICU during study period (October 2020 to 15 December 2020), 67 underwent Level I PSG. Mean Age was 52.6{+/-}10.9 years and mean Body Mass Index was 27.5 {+/-} 6.2 Kg/m2. Total sleep time was 343.2 {+/-} 86 minutes, sleep efficiency was 75.9{+/-}14.2%. OSA (AHI [≥]5) was seen in 65/67 patients and 49 patients had moderate to severe OSA (i.e. AHI [≥] 15). ConclusionModerate-severe OSA was highly prevalent (73%) in COVID19 moderate to severe ARDS survivors. Role of OSA in pathophysiology of COVID19 ARDS needs further evaluation. HighlightsO_LIThis study was done to find prevalence of OSA in patients with COVID-19 related Acute respiratory distress syndrome C_LIO_LIModerate-severe OSA is highly prevalent (73%) in COVID19 ARDS survivors. C_LIO_LITo the best of our knowledge, it is first study in which level I PSG was done in COVID19 survivors. C_LI

Association of Obstructive Sleep Apnea and severity of COVID-19: A hospital based observational study. (preprint)

IntroductionOSA has been postulated to be associated with mortality in COVID19, but studies are lacking thereof. This study was done to estimate prevalence of OSA in patients with COVID-19 using various screening questionnaires and to assess effect of OSA on outcome of disease. MethodologyIn this prospective observational study, consecutive patients with RTPCR confirmed COVID 19 patients were screened for OSA by different questionnaires (STOPBANG, Berlin Questionnaire, NoSAS and Epworth Scale). Association between OSA and outcome (mortality) and requirement for respiratory support was assessed. ResultsIn study of 213 patients; screening questionnaires for OSA {STOPBANG, Berlin Questionnaire (BQ), NoSAS} were more likely to be positive in patients who died compared to patients who survived. On binary logistic yregression analysis, age[≥]55 and STOPBANG score [≥]5 were found to have small positive but independent effect on mortality even after adjusting for other variables. Proportion of patients who were classified as high risk for OSA by various OSA screening tools significantly increased with increasing respiratory support (p<0.001 for STOPBANG, BQ, ESS and p=0.004 for NoSAS). ConclusionThis is one of the first prospective studies of sequentially hospitalized patients with confirmed COVID 19 status who were screened for possible OSA. This study shows that OSA could be an independent risk factor for poor outcome in patients with COVID19.

Impact of COVID-19 epidemic curtailment strategies in selected Indian states: An analysis by reproduction number and doubling time with incidence modelling.

The Government of India in-network with the state governments has implemented the epidemic curtailment strategies inclusive of case-isolation, quarantine and lockdown in response to ongoing novel coronavirus (COVID-19) outbreak. In this manuscript, we attempt to estimate the impact of these steps across ten selected Indian states using crowd-sourced data. The trajectory of the outbreak was parameterized by the reproduction number (R0), doubling time, and growth rate. These parameters were estimated at two time-periods after the enforcement of the lockdown on 24th March 2020, i.e. 15 days into lockdown and 30 days into lockdown. The authors used a crowd sourced database which is available in the public domain. After preparing the data for analysis, R0 was estimated using maximum likelihood (ML) method which is based on the expectation minimum algorithm where the distribution probability of secondary cases is maximized using the serial interval discretization. The doubling time and growth rate were estimated by the natural log transformation of the exponential growth equation. The overall analysis shows decreasing trends in time-varying reproduction numbers (R(t)) and growth rate (with a few exceptions) and increasing trends in doubling time. The curtailment strategies employed by the Indian government seem to be effective in reducing the transmission parameters of the COVID-19 epidemic. The estimated R(t) are still above the threshold of 1, and the resultant absolute case numbers show an increase with time. Future curtailment and mitigation strategies thus may take into account these findings while formulating further course of action.

Impact of COVID-19 epidemic curtailment strategies in selected Indian states: an analysis by reproduction number and doubling time with incidence modelling (preprint)

The Government of India in networks with its state government has implemented the epidemic curtailment strategies inclusive of case-isolation, quarantine and lockdown in response to ongoing novel coronavirus (COVID-19) outbreak . In this manuscript we attempt to estimate the effect of these steps across ten Indian states using crowd-sourced data. The chosen transmission parameters are -reproduction number (R0), doubling time and growth rate during the early epidemic phase (15 days into lockdown) and 30 days into lockdown (23rd April 2020) through maximum likelihood approach. The overall analysis shows the decreasing trends in reproductive numbers and growth rate (with few exceptions) and incremental doubling time. The curtailment strategies employed by the Indian government seemed to be effective in reducing the transmission parameters of the COVID-19 epidemic. The effective reproductive numbers are still higher above the threshold of 1 and the resultant absolute numbers tend to be exponentiating fundamentally. The curtailment strategy thus may take into account these findings while formulating further course of actions.