Search

Elongation by RNA polymerase is dynamically modulated by accessory factors. The transcription-repair coupling factor (TRCF) recognizes paused/stalled RNAPs and either rescues transcription or initiates transcription termination. Precisely how TRCFs choose to execute either outcome remains unclear. With Escherichia coli as a model, we used single-molecule assays to study dynamic modulation of elongation by Mfd, the bacterial TRCF. We found that nucleotide-bound Mfd converts the elongation complex (EC) into a catalytically poised state, presenting the EC with an opportunity to restart transcription. After long-lived residence in this catalytically poised state, ATP hydrolysis by Mfd remodels the EC through an irreversible process leading to loss of the RNA transcript. Further, biophysical studies revealed that the motor domain of Mfd binds and partially melts DNA containing a template strand overhang. The results explain pathway choice determining the fate of the EC and provide a molecular mechanism for transcription modulation by TRCF., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

How to cite this article: Aggarwal A, Arora U, Mittal A, Aggarwal A, Singh K, Ray A, et al. Outcomes of HFNC Use in COVID-19 Patients inNon-ICU Settings: A Single-center Experience. Indian J Crit Care Med 2022;26(4):528-530., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2022; Jaypee Brothers Medical Publishers (P) Ltd.)

The genome sequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been evolving via genomic drifts resulting in "emerging/drifting variants" circulating worldwide. The construction of polymerase chain reaction (PCR) assays for the reliable, efficient, and specific diagnosis of the drifting variants of SARS-CoV-2 is specifically governed by the selection and construction of primers and probes. The efficiency of molecular diagnosis is impacted by the identity/homology of the genome sequence of SARS-CoV-2 with other coronaviruses, drifting variants or variants of concern (VOCs) circulating in communities, inherent capacity of mutation(s) of various target genes of SARS-CoV-2, and concentration of genes of interest in host cells. The precise amplicon selection and construction of primers and probes for PCR-based assays can efficiently discriminate specific SARS-CoV-2 drifting variants. The construction of single nucleotide polymorphism (SNP)-specific primers and probes for PCR assays is pivotal to specifically distinguish SARS-CoV-2 variants present in the communities and contributes to better diagnosis and prevention of the ongoing COVID-19 pandemic. In this study, we have utilized in silico -based bioinformatic tools where the alignment for genes, the positions and types of SNPs/mutations of VOCs, and the relative number of SNPs per nucleotide in different genomic regions were investigated. Optimal and specific genome region (amplicon) selection with comparatively lower mutability in the SARS-CoV-2 genome should be prioritized to design/construct PCR assays for reliable and consistent diagnosis in various regions of the world for a longer duration of time. Further, the rational selection of target genes that is at an optimal detectable concentration in biological samples can bolster PCR assays of high analytical sensitivity. Hence, the construction of primers and probes with the rational selection of targeting specific E gene, genomic regions with highly conserved sequences, multiple target genes with relatively lower mutability and detectable level of concentration, SNP-specific binding regions of spike (S gene) protein, and shorter amplicon size (100-150 bp) are vital for the PCR assays to achieve optimal efficiency in the point-of-care laboratory diagnosis of circulating drifting variants of SARS-CoV-2 with optimal accuracy., Competing Interests: The authors declare they have no conflicts of interest., (Copyright © 2022 Divya RSJB Rana et al.)

The Angiotensin Converting Enzyme 2 (ACE2) assists the regulation of blood pressure and is the main target of the coronaviruses responsible for SARS and COVID19. The catalytic function of ACE2 relies on the opening and closing motion of its peptidase domain (PD). In this study, we investigated the possibility of allosterically controlling the ACE2 PD functional dynamics. After confirming that ACE2 PD binding site opening-closing motion is dominant in characterizing its conformational landscape, we observed that few mutations in the viral receptor binding domain fragments were able to impart different effects on the binding site opening of ACE2 PD. This showed that binding to the solvent exposed area of ACE2 PD can effectively alter the conformational profile of the protein, and thus likely its catalytic function. Using a targeted machine learning model and relative entropy-based statistical analysis, we proposed the mechanism for the allosteric perturbation that regulates the ACE2 PD binding site dynamics at atomistic level. The key residues and the source of the allosteric regulation of ACE PD dynamics are also presented.

Background: Surgical treatment of scoliosis includes long and invasive multi-level instrumentation and correction which may result in high rates of postoperative complications, especially in elderly patients with osteopenia or multiple comorbidities. Minimally invasive surgical options may benefit these patients., Case Description: A 73-year-old female patient with a history of degenerative lumbar scoliosis, L4-5 pseudarthrosis, and resulting L5-S1 adjacent segment following prior unsuccessful lateral L4-5 interbody fusion presented to the clinic with severe lower back pain and lower extremity radiculopathy. The decision was made to proceed with surgical correction via a robotic-guided prone transpsoas (PTP) approach, which is a novel approach similar to lateral lumbar interbody fusion (LLIF) with the patient in a prone decubitus position. Excellent spinal alignment was achieved with no complications. On two-month follow-up, imaging revealed pedicle screws at the L3, L4, L5 levels and at the sacrum without change and continued interbody cages position with no signs or symptoms of infection., Discussion: Minimally invasive procedures have demonstrated benefit in spine surgery especially for at risk populations. The LLIF procedure has been well established for use in a wide range of spinal pathologies given its noted benefits in increasing spinal column stability through posterior fixation and indirect decompression. However, only marginal improvements in segmental lordosis are expected and there are reports of neurological complications. The PTP procedure has emerged as an alternative to LLIF for the treatment of spinopelvic pathologies. This approach enables greater improvements to spinal lordosis through single-position surgery while simultaneously reducing intraoperative repositioning and providing the known benefits of lateral interbody surgery., Conclusion: Our experience suggests that the PTP approach is safe and effective because it does not require patient repositioning, easily interfaces with robotic guidance, and achieves increased lordosis gains via the prone positional effect compared to LLIF and comparable approaches., (Copyright © 2022. Published by Elsevier Ltd.)

Introduction: Lung cancer is the leading cause of cancer deaths all over the world and adenocarcinoma is the most common type. Diagnosis is made usually at an advanced stage of lung cancer in patients, making it nearly impossible to cure. The aim of this study is to find out prevalence of adenocarcinoma among patients diagnosed with lung cancer in a tertiary care centre., Methods: A descriptive cross-sectional study was carried out in the Department of Pulmonary Medicine of a tertiary care centre among 69 patients from October, 2018 to September, 2019. Ethical approval was taken from the Institutional Review Committee of a tertiary care hospital (Reference number: 54/2018). A convenience sampling technique was used. Data were entered and analysed using the Statistical Package for the Social Sciences version 21.0. Point estimate at 90% Confidence Interval and descriptive statistics were interpreted as frequency, percentage, or as mean and standard deviations., Results: Among 69 lung cancer patients, adenocarcinoma was seen in 27 (39.13%) (29.47-48.79 at 90% Confidence Interval). Out of 27, 10 (37.04%) were male and 17 (62.96%) were female. Chronic obstructive pulmonary disease was the major comorbidity seen among 17 (62.96%) patients., Conclusions: The prevalence of adenocarcinoma was similar to other studies done in similar settings., Keywords: adenocarcinoma; lung cancer; Nepal; smoking.

Introduction: Intact tympanic membrane acts as a partition between the external ear and middle ear. Tympanic membrane perforation is one of the commonest causes of conductive hearing loss. Perforation size is the most important determination of hearing loss. The aim of this study was to find out the prevalence of tympanic membrane perforation among patients presenting to the otorhinolaryngology department of a tertiary care hospital., Methods: A descriptive cross-sectional study was carried out in the Department of Otorhinolaryngology and Head Neck Surgery of a tertiary care hospital from March 2021 to August 2021. Ethical approval was taken from Institutional Review Committee (Reference number: 57112021). Convenience sampling was done and data was collected from 414 patients presenting to the department. Collected data were entered, analyzed in Statistical Package for the Social Sciences version 21.0 and documented for study. Point estimate at 95% Confidence Interval was calculated along with frequency and percentage for binary data., Results: Among 414 patients, tympanic membrane perforation was seen in 100 (24.15%) (20.02-28.27 at 95% Confidence Interval). Among 100 patients with a total of 153 perforated eardrums, mild hearing loss was seen in the majority of the cases. Posterior perforation had a mean hearing loss of 40.41±5.96 dB, central had 39.09±3.13 dB, and anterior had 35.15±5.88 dB., Conclusions: Our study showed the prevalence of tympanic membrane perforation to be high when compared to other similar studies. Hearing loss was observed in all cases; the majority with mild hearing loss. The degree of hearing loss was more in larger and posterior perforation., Keywords: eardrum perforation; hearing loss; otitis media.

Angiotensin-converting enzyme 2 (ACE2) is a key host protein by which severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) enters and multiplies within cells. The level of ACE2 expression in the lung is hypothesised to correlate with an increased risk of severe infection and complications in COrona VIrus Disease 2019 (COVID-19). To test this hypothesis, we compared the protein expression status of ACE2 by immunohistochemistry (IHC) in post-mortem lung samples of patients who died of severe COVID-19 and lung samples obtained from non-COVID-19 patients for other indications. IHC for CD61 and CD163 was performed for the assessment of platelet-rich microthrombi and macrophages, respectively. IHC for SARS-CoV-2 viral antigen was also performed. In a total of 55, 44 COVID-19 post-mortem lung samples were tested for ACE2, 36 for CD163, and 26 for CD61, compared to 15 non-covid 19 control lung sections. Quantification of immunostaining, random sampling, and correlation analysis were used to substantiate the morphologic findings. Our results show that ACE2 protein expression was significantly higher in COVID-19 post-mortem lung tissues than in controls, regardless of sample size. Histomorphology in COVID-19 lungs showed diffuse alveolar damage (DAD), acute bronchopneumonia, and acute lung injury with SARS-CoV-2 viral protein detected in a subset of cases. ACE2 expression levels were positively correlated with increased expression levels of CD61 and CD163. In conclusion, our results show significantly higher ACE2 protein expression in severe COVID-19 disease, correlating with increased macrophage infiltration and microthrombi, suggesting a pathobiological role in disease severity., (© 2022. The Author(s).)

The role of ionic electrostatics in colloidal processes is well-understood in natural and applied contexts; however, the electrostatic contribution of zwitterions, known to be present in copious amounts in extremophiles, has not been extensively explored. In response, we studied the effects of glycine as a surrogate zwitterion, ion, and osmolyte on the electrostatic forces between negatively charged mica-mica and silica-silica interfaces. Our results reveal that while zwitterions layer at electrified interfaces and contribute to solutions' osmolality, they do not affect at all the surface potentials, the electrostatic surface forces (magnitude and range), and solutions' ionic conductivity across 0.3-30 mM glycine concentration. We infer that the zwitterionic structure imposes an inseparability among positive and negative charges and that this inseparability prevents the buildup of a counter-charge at interfaces. These elemental experimental results pinpoint how zwitterions enable extremophiles to cope with the osmotic stress without affecting finely tuned electrostatic force balance.

Background: Hydroxychloroquine (HCQ) had generated considerable interest for coronavirus disease 2019 (COVID-19) prophylaxis. We conducted a prospective observational study at a tertiary care hospital in India, with dedicated COVID-19 care facilities., Objectives: Primary objective was incidence of adverse effects, secondary objective being efficacy in preventing COVID-19., Methods: Healthcare workers were recruited and grouped based on voluntary HCQ prophylaxis as per national guidelines. Side effects in HCQ group were graded in accordance with national cancer institute-common terminology criteria for adverse events (NCI-CTCAE) version 5.0. At 3-7-week follow-up, groups were compared for COVID-19 exposure, symptoms development and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR results., Results: Among 358 participants recruited, 216 (60.3%) were males and mean age was 31.2 ± 6.6 years. Chemoprophylaxis was initiated by 258 (72%) participants. After loading dose, 7 (2.7%) reported grade 2 and 1 (0.4%) grade 3 adverse effects. Discontinuation of HCQ due to side effects was reported in 11 (4.3%) participants. Electrocardiogram was done by 50 (19.4%) participants on HCQ; no abnormalities were noted. A total of 106 (41%) among those taking and 63 (63%) among those not taking HCQ were tested for SARS-CoV-2 due to influenza-like illness or significant exposure. Among all participants, 25 (6.9%, 95% confidence interval [CI] 4.3-9.6) developed COVID-19 during the study period. In the group taking HCQ, 10 (3.9%) tested positive compared to 15 (15%) in the group not taking HCQ ( P < 0.001). Odds ratio with HCQ intake was 0.34 (95% CI 0.13-0.83, P = 0.01) and the number needed to treat was 12., Conclusion: HCQ is safe at the recommended dose for pre-exposure prophylaxis of COVID-19., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Family Medicine and Primary Care.)

Background: The epidemiology of the Coronavirus-disease associated mucormycosis (CAM) syndemic is poorly elucidated. We aimed to identify risk factors that may explain the burden of cases and help develop preventive strategies., Methods: We performed a case-control study comparing cases diagnosed with CAM and taking controls as recovered COVID 19 patients who did not develop mucormycosis. Information on comorbidities, glycemic control, and practices related to COVID-19 prevention and treatment was recorded. Multivariate regression analysis was used to identify independent predictors., Results: A total of 352 patients (152 cases and 200 controls) diagnosed with COVID-19 during April-May 2021 were included. In the CAM group, symptoms of mucormycosis began a mean of 18.9 (SD 9.1) days after onset of COVID-19, and predominantly rhino-sinus and orbital involvement was present. All, but one, CAM cases had conventional risk factors of diabetes and steroid use. On multivariable regression, increased odds of CAM were associated with the presence of diabetes (adjusted OR 3.5, 95% CI 1.1-11), use of systemic steroids (aOR 7.7, 95% CI 2.4-24.7), prolonged use of cloth and surgical masks (vs. no mask, aOR 6.9, 95%CI 1.5-33.1), and repeated nasopharyngeal swab testing during the COVID-19 illness (aOR 1.6, 95% CI 1.2-2.2). Zinc therapy was found to be protective (aOR 0.05, 95%CI 0.01-0.19). Notably, the requirement of oxygen supplementation or hospitalization did not affect the risk of CAM., Conclusion: Judicious use of steroids and stringent glycemic control are vital to preventing mucormycosis. Use of clean masks, preference for N95 masks if available, and minimizing swab testing after the diagnosis of COVID-19 may further reduce the incidence of CAM., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2021 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Competing Interests: The authors declare no funding or conflicts of interest.

Background: BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine that has been deployed in India. The results of the phase 3 trial have shown clinical efficacy of BBV152. We aimed to evaluate the effectiveness of BBV152 against symptomatic RT-PCR-confirmed SARS-CoV-2 infection., Methods: We conducted a test-negative, case-control study among employees of the All India Institute of Medical Sciences (a tertiary care hospital in New Delhi, India), who had symptoms suggestive of COVID-19 and had an RT-PCR test for SARS-CoV-2 during the peak of the second wave of the COVID-19 pandemic in India between April 15 and May 15, 2021. Cases (test-positives) and controls (test-negatives) were matched (1:1) on the basis of age and gender. The odds of vaccination with BBV152 were compared between cases and controls and adjusted for level of occupational exposure (to COVID-19), previous SARS-CoV-2 infection, and calendar time, using conditional logistic regression. The primary outcome was effectiveness of two doses of BBV152 (with the second dose received at least 14 days before testing) in reducing the odds of symptomatic RT-PCR-confirmed SARS-CoV-2 infection, expressed as (1 - odds ratio) × 100%., Findings: Between April 15 and May 15, 2021, 3732 individuals had an RT-PCR test. Of these, 2714 symptomatic employees had data on vaccination status, and 1068 matched case-control pairs were available for analysis. The adjusted effectiveness of BBV152 against symptomatic COVID-19 after two doses administered at least 14 days before testing was 50% (95% CI 33-62; p<0·0001). The adjusted effectiveness of two doses administered at least 28 days before testing was 46% (95% CI 22-62) and administered at least 42 days before testing was 57% (21-76). After excluding participants with previous SARS-CoV-2 infections, the adjusted effectiveness of two doses administered at least 14 days before testing was 47% (95% CI 29-61)., Interpretation: This study shows the effectiveness of two doses of BBV152 against symptomatic COVID-19 in the context of a huge surge in cases, presumably dominated by the potentially immune-evasive delta (B.1.617.2) variant of SARS-CoV-2. Our findings support the ongoing roll-out of this vaccine to help control the spread of SARS-CoV-2, while continuing the emphasis on adherence to non-pharmacological measures., Funding: None., Translation: For the Hindi translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction and Importance: Gallstone ileus is caused by an impaction of one or more gallstones within the gastrointestinal tract, leading to mechanical intestinal obstruction. It is a rare complication of cholelithiasis leading to the formation of a cholecystoenteric fistula and is associated with high mortality rates. We report a case of atypical subacute small bowel obstruction due to gallstone ileus., Presentation of Case: An 82-year-old man, with previously diagnosed cholelithiasis, presented with abdominal pain and vomiting for nine days. The contracted gallbladder with distended bowel loops was visualized on abdominal ultrasound. Computed tomography of the abdomen and pelvis revealed dilated loops of the small intestine with a gallstone in the proximal ileum, causing intestinal obstruction with pneumobilia, suggesting gallstone ileus with cholecystoduodenal fistula. The patient underwent an emergency laparotomy and enterolithotomy to remove the impacting gallstone. The cholecystoduodenal fistula was left undisturbed due to the significant risk of duodenal injury. The patient had an uneventful postoperative recovery., Conclusion: Gallstone ileus almost always requires surgical management. However, performing an interval biliary surgery is based on the clinical judgment of the surgeon. In our case, the patient's clinical status determined the treatment in which an enterotomy with stone extraction alone was largely sufficient, and has supported the literature. Gallstone ileus is an important differential diagnosis in elderly patients with gallstone disease, untreated or undiagnosed, presenting with features of small bowel obstruction., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Ectopia cordis is a rare congenital defect with the prevalence of 5 to 8 per million live births. Here we report a rare case of preterm female live birth with ectopia cordis associated with omphalocele, cleft lip, and palate. In this case, 14+ weeks ultrasound did not show any fetal abnormalities and parents were unaware of the condition until 35+ weeks when ultrasound detected the anomaly a few days before delivery. After delivery, they didn't give consent for further intervention which led to neonatal mortality 3 hours after birth. If the condition was diagnosed in time, an earlier intervention could have been done.

This study aims to evaluate the role of cardiac enzymes N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin-I (CTnI) as predictors of outcomes in patients with sepsis.78 cases with a diagnosis of sepsis were enrolled over a 2-year period. Baseline demographic, Acute Physiology and Chronic Health Evaluation-II (APACHE-II), Simplified Acute Physiology Score-II (SAPS-II), hematologic and biochemical parameters were noted. Serum NT-proBNP and CTnI were evaluated at 24 and 72 hours of admission along with echocardiography. Patients were prospectively followed up until death or discharge.Mean APACHE-II score was 19.8±9.6 and SAPS-II was 44.8±17.2. Survival rate in the study was 47.5% (36 of 78 patients). NT-proBNP was significantly higher in non-survivors with values over 4300 pg/mL at 24 hours and 5229 pg/mL at 72 hours associated with poor outcomes (p<0.05). CTnI was higher among non-survivors than in survivors, but the difference was not significant. APACHE-II score combined with NT-proBNP predicted a poor outcome in 51.2% cases compared with 14.6% cases with APACHE-II alone (p<0.05), while SAPS-II combined with NT-proBNP predicted a poor outcome in 53.6% cases as compared with 9.6% cases with SAPS-II alone (p<0.05). SAPS-II greater than 45 and NT-proBNP values at 72 hours were independent predictors of mortality in patients with sepsis.NT-proBNP is an independent predictor of mortality in patients with sepsis and its combination with APACHE-II and SAPS-II improves the predictive values of the scoring systems., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Study Design: We performed a prospective observational study of 52 patients who were clinically suspected of cervical spondylotic myelopathy (CSM), based on the modified Japanese Orthopaedic Association (mJOA) score, and were referred for magnetic resonance imaging (MRI) of the cervical spine., Purpose: To evaluate the quantitative parameters of the diffusion tensor imaging (DTI) matrix (fractional anisotropy [FA] and apparent diffusion coefficient [ADC] values) and determine the subsequent correlation with the clinical assessment of disease severity in CSM., Overview of Literature: Conventional MRI is the modality of choice for the identification of cervical spondylotic changes and is known to have a low sensitivity for myelopathy changes. DTI is sensitive to disease processes that alter the water movement in the cervical spinal cord at a microscopic level beyond the conventional MRI., Methods: DTI images were processed to produce FA and ADC values of the acquired axial slices with the regions of interest placed within the stenotic and non-stenotic segments. The final quantitative radiological derivations were matched with the clinical scoring system., Results: Total 52 people (24 men and 28 women), mean age 53.16 years with different symptoms of myelopathy, graded as mild (n=11), moderate (n=25), and severe (n=16) as per the mJOA scoring system, underwent MRI of the cervical spine with DTI. In the most stenotic segments, the mean FA value was significantly lower (0.5009±0.087 vs. 0.655.7±0.104, p<0.001), and the mean ADC value was significantly higher (1.196.5±0.311 vs. 0.9370±0.284, p<0.001) than that in the non-stenotic segments. The overall sensitivity in identifying DTI metrics abnormalities was more with FA (87.5%) and ADC (75.0%) than with T2 weighted images (25%)., Conclusions: In addition to the routine MRI sequences, DTI metrics (FA value better than ADC) can detect myelopathy even in patients with a mild grade mJOA score before irreversible changes become apparent on routine T2 weighted imaging and thus enhance the clinical success of decompression surgery.

HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) are commonly encountered blood-borne infectious microorganisms. Infection with these viruses typically requires long-lasting drug therapy. Coinfections, especially with tuberculosis, pose a challenge to the creation of a regimen with adequate efficacy and minimal drug-drug interactions and adverse effects. We present the case of a young man with a history of intravenous drug misuse who was diagnosed with disseminated tuberculosis and with a triple infection with HBV, HCV, and HIV. The treatment for tuberculosis was initiated first, followed 2 months later by antiretrovirals that were effective against both HIV and HBV. After 9 months of antitubercular therapy, HCV was successfully treated with 12 weeks of oral direct-acting antivirals. We describe the challenges faced in formulating a therapeutic plan for such patients and discuss the various drug interactions that can arise between antitubercular drugs, antiretrovirals, anti-HBV drugs, and direct-acting antivirals against HCV., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Use of systemic corticosteroids is well-established in COVID-19 patients with hypoxia; however, there is scant data on its role in patients with mild disease and prolonged symptoms as a measure to prevent disease progression. The aim of this study is to evaluate the role of systemic corticosteroids in preventing hypoxia (SpO 2 ≤ 93% on room-air) among mild COVID-19 patients. An observational study was conducted among symptomatic COVID-19 patients taking oral corticosteroids and attending institute teleconsultation facility between 10th-30th June 2021. Patients who were already on corticosteroids for other indication or required oxygen supplementation before or within 24-hours of initiation of corticosteroids were excluded. A total of 140 consecutive symptomatic COVID-19 patients were included. Higher baseline C-reactive protein (OR: 1.03, 95% CI: 1.02-1.06, p < 0.001) and early systemic corticosteroid (within 7 days) initiation (OR: 6.5, 95% CI: 2.1-20.1, p = 0.001) were independent risk factors for developing hypoxia (SpO 2 ≤ 93%). Progression to hypoxia was significantly higher in patients who received corticosteroids before day 7 of illness (36.7%, 95% CI, 23.4-51.7%) compared to ≥ 7 of illness (14.3%, 95% CI, 7.8-23.2%) for persistent fever. Systemic corticosteroids within 7 days from symptom-onset were harmful and increased the risk of progression to hypoxia, whereas it may decrease the risk of progression when administered on or beyond 7 days in patients with mild COVID-19 and persistent symptoms. A well-designed randomised controlled trial is required to validate the findings.

Post COVID-19 sequelae are a constellation of symptoms often reported after recovering from COVID-19. There is a need to better understand the clinical spectrum and long-term course of this clinical entity. The aim of this study is to describe the clinical features and risk factors of post COVID-19 sequelae in the North Indian population. This prospective observational study was conducted at a tertiary healthcare centre in Northern India between October 2020 and February 2021. Patients aged >18 years with laboratory-confirmed COVID-19 were recruited after at least two weeks of diagnosis, and details were captured. A total of 1234 patients were recruited and followed up for a median duration of 91 days (IQR: 45-181 days). Among them, 495 (40.1%) had persistent symptoms post-discharge or recovery. In 223 (18.1%) patients, the symptoms resolved within four weeks; 150 (12.1%) patients had symptoms till 12 weeks, and 122 (9.9%) patients had symptoms beyond 12 weeks of diagnosis/symptom-onset of COVID-19. Most common symptoms included myalgia (10.9%), fatigue (5.5%), shortness of breath (6.1%), cough (2.1%), insomnia (1.4%), mood disturbances (0.48%) and anxiety (0.6%). Patients who were hospitalized were more likely to report fatigue as a feature of long COVID. Hypothyroidism (OR: 4.13, 95% CI: 2.2-7.6, p-value < 0.001) and hypoxia (SpO 2 ≤ 93%) (OR: 1.7, 95% CI: 1.1-2.4, p-value 0.012) were identified as risk factors for long COVID sequelae. In conclusion, long COVID symptoms were common (22%), and 9.9% had the post COVID-19 syndrome. Myalgias, fatigue and dyspnoea were common symptoms. Patients with hypothyroidism and hypoxia during acute illness were at higher risk of long COVID.

Currently, there is no single technology capable of assessing all the multitude of factors associated with peripheral complications of diabetic neuropathy. In this work, a multimodal wound detection system is proposed to help facilitate in-home examinations, utilizing a combination of thermal, multi-spectral 3D imaging modalities. The proposed system is capable of the 3D surface rendering of the foot and would overlay thermal, blood oxygenation, besides other skin health information to aid with foot health monitoring. Examples of biomarkers include pre-ulcer formation, blood circulation, temperature change, oxygenation, swelling, blisters/ulcer formation and healing, and toe health.

Objectives: To study the histopathology of patients dying of COVID-19 using post-mortem minimally invasive sampling techniques., Methods: This was a single-center observational study conducted at JPNATC, AIIMS. Thirty-seven patients who died of COVID-19 were enrolled. Post-mortem percutaneous biopsies were taken from lung, heart, liver, kidney and stained with hematoxylin and eosin. Immunohistochemistry was performed using CD61 and CD163. SARS-CoV-2 virus was detected using IHC with primary antibodies., Results: The mean age was 48.7 years and 59.5% were males. Lung histopathology showed diffuse alveolar damage in 78% patients. Associated bronchopneumonia was seen in 37.5% and scattered microthrombi in 21% patients. Immunopositivity for SARS-CoV-2 was observed in Type II pneumocytes. Acute tubular injury with epithelial vacuolization was seen in 46% of renal biopsies. Seventy-one percent of liver biopsies showed Kupffer cell hyperplasia and 27.5% showed submassive hepatic necrosis., Conclusions: Predominant finding was diffuse alveolar damage with demonstration of SARS-CoV-2 protein in the acute phase. Microvascular thrombi were rarely identified in any organ. Substantial hepatocyte necrosis, Kupffer cell hypertrophy, microvesicular, and macrovesicular steatosis unrelated to microvascular thrombi suggested that liver might be a primary target of COVID-19.

Blood flow rate in dialysis (vascular) access is the key parameter to examine patency and to evaluate the outcomes of various endovascular interve7ntions. While angiography is extensively used for dialysis access-salvage procedures, to date, there is no image-based blood flow measurement application commercially available in the angiography suite. We aim to calculate the blood flow rate in the dialysis access based on cine-angiographic and fluoroscopic image sequences. In this study, we discuss image-based methods to quantify access blood flow in a flow phantom model. Digital subtraction angiography (DSA) and fluoroscopy were used to acquire images at various sampling rates (DSA-3 and 6 frames/s, fluoroscopy-4 and 10 pulses/s). Flow rates were computed based on two bolus tracking algorithms, peak-to-peak and cross-correlation, and modeled with three curve-fitting functions, gamma variate, lagged normal, and polynomial, to correct errors with transit time measurement. Dye propagation distance and the cross-sectional area were calculated by analyzing the contrast enhancement in the vessel. The calculated flow rates were correlated versus an in-line flow sensor measurement. The cross-correlation algorithm with gamma-variate curve fitting had the best accuracy and least variability in both imaging modes. The absolute percent error (mean ± SEM) of flow quantification in the DSA mode at 6 frames/s was 21.4 ± 1.9%, and in the fluoroscopic mode at 10 pulses/s was 37.4 ± 3.6%. The radiation dose varied linearly with the sampling rate in both imaging modes and was substantially low to invoke any tissue reactions or stochastic effects. The cross-correlation algorithm and gamma-variate curve fitting for DSA acquisition at 6 frames/s had the best correlation with the flow sensor measurements. These findings will be helpful to develop a software-based vascular access flow measurement tool for the angiography suite and to optimize the imaging protocol amenable for computational flow applications.

Background: The prevalence of anti-retroviral therapy (ART) failure is not uniform in India. In this study we attempted to determine the prevalence and risk factors of treatment failure among patients who were on ART for >1 y., Methods: We conducted an ambispective study from 2017 to 2019 in the All India Institute of Medical Sciences, New Delhi, India. Patients and their past medical records were examined to determine clinical, immunological and virological failure., Results: Among 301 enrolled patients, the majority was male (61.8%), with a mean age of 36.98±10.84 y. The prevalence of ART failure in our study was 10.63% (32/301). Clinical, immunological and virological failure rates were 1.66%, 10.63% and 5.65%, respectively. The maximum chance of failure was the tenofovir-lamivudine-nevirapine (33.3%) regimen followed by the stavudine-lamivudine-nevirapine (30.4%) regimen. Among the nucleoside reverse transcriptase inhibitors, a stavudine-based regimen had a significantly greater chance of failure (25.8%) compared with tenofovir (9.6%) and zidovudine (7.9%) regimens (p<0.005). Low baseline CD4 count and development of tuberculosis after ART initiation were significantly (p<0.05) associated with treatment failure in univariate analysis. Patients with a low peak CD4 count (adjusted odds ratio [AOR 4.26 {95% confidence interval 1.83 to 9.88}]) and who developed symptoms after ART initiation (AOR 3.77 [95% CI 1.47 to 9.69]) had significantly higher odds of treatment failure in the multivariate analysis (p<0.001)., Conclusions: Early identification of risk factors by regular follow-up and selection of the proper ART regimen can reduce the rate of treatment failure., (© The Author(s) 2021. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

PRMT5 is an essential arginine methyltransferase and a therapeutic target in MTAP-null cancers. PRMT5 uses adaptor proteins for substrate recruitment through a previously undefined mechanism. Here, we identify an evolutionarily conserved peptide sequence shared among the three known substrate adaptors (CLNS1A, RIOK1, and COPR5) and show that it is necessary and sufficient for interaction with PRMT5. We demonstrate that PRMT5 uses modular adaptor proteins containing a common binding motif for substrate recruitment, comparable with other enzyme classes such as kinases and E3 ligases. We structurally resolve the interface with PRMT5 and show via genetic perturbation that it is required for methylation of adaptor-recruited substrates including the spliceosome, histones, and ribosomal complexes. Furthermore, disruption of this site affects Sm spliceosome activity, leading to intron retention. Genetic disruption of the PRMT5-substrate adaptor interface impairs growth of MTAP-null tumor cells and is thus a site for development of therapeutic inhibitors of PRMT5., Competing Interests: Declaration of interests Materials related to this article are in a provisional patent application by the Broad Institute. W.R.S. is a board or scientific advisory board (SAB) member and holds equity in Peloton Therapeutics, Ideaya Biosciences, Civetta Therapeutics, and Bluebird bio; has consulted for Array, Astex, Dynamo Therapeutics, Ipsen, Merck Pharmaceuticals, PearlRiver Therapeutics, Sanofi, Scorpion Therapeutics, and Servier; and receives research funding from Pfizer Pharmaceuticals, Merck Pharmaceuticals, Ideaya Biosciences, and Deerfield Management. B.J.M. is an employee and equity holder of Tango Therapeutics. D. Porter is an employee and equity holder of Cedilla Therapeutics. A.J.A. has consulted for Oncorus Inc., Arrakis Therapeutics, and Merck & Company and has research funding from Mirati Therapeutics and Deerfield Management., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Case: A 24-year-old active duty soldier with a chronic pectoralis major tendon rupture presented a year later with a bony lesion consistent with an enthesophyte at the humeral insertion. The patient continued to have pain that was affecting his activities of daily living and underwent surgical intervention., Conclusion: Operative management with enthesophyte excision and pectoralis major tendon repair provided relief to the patient's symptoms and return to preinjury levels of function as evaluated with Tegner, single assessment numeric evaluation, and visual analog scale scores at the 2-year follow-up., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/B681)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Objectives: To study whether a trained convolutional neural network (CNN) can be of assistance to radiologists in differentiating Coronavirus disease (COVID)-positive from COVID-negative patients using chest X-ray (CXR) through an ambispective clinical study. To identify subgroups of patients where artificial intelligence (AI) can be of particular value and analyse what imaging features may have contributed to the performance of AI by means of visualisation techniques., Methods: CXR of 487 patients were classified into [4] categories-normal, classical COVID, indeterminate, and non-COVID by consensus opinion of 2 radiologists. CXR which were classified as "normal" and "indeterminate" were then subjected to analysis by AI, and final categorisation provided as guided by prediction of the network. Precision and recall of the radiologist alone and radiologist assisted by AI were calculated in comparison to reverse transcriptase-polymerase chain reaction (RT-PCR) as the gold standard. Attention maps of the CNN were analysed to understand regions in the CXR important to the AI algorithm in making a prediction., Results: The precision of radiologists improved from 65.9 to 81.9% and recall improved from 17.5 to 71.75 when assistance with AI was provided. AI showed 92% accuracy in classifying "normal" CXR into COVID or non-COVID. Analysis of attention maps revealed attention on the cardiac shadow in these "normal" radiographs., Conclusion: This study shows how deployment of an AI algorithm can complement a human expert in the determination of COVID status. Analysis of the detected features suggests possible subtle cardiac changes, laying ground for further investigative studies into possible cardiac changes., Key Points: • Through an ambispective clinical study, we show how assistance with an AI algorithm can improve recall (sensitivity) and precision (positive predictive value) of radiologists in assessing CXR for possible COVID in comparison to RT-PCR. • We show that AI achieves the best results in images classified as "normal" by radiologists. We conjecture that possible subtle cardiac in the CXR, imperceptible to the human eye, may have contributed to this prediction. • The reported results may pave the way for a human computer collaboration whereby the expert with some help from the AI algorithm achieves higher accuracy in predicting COVID status on CXR than previously thought possible when considering either alone., (© 2021. European Society of Radiology.)

Objective: VAP prevention bundle includes daily sedation free interval, DVT prophylaxis, raising head end of bed, use of orogastric rather than nasogastric tube. This study aims to study the practices regarding VAP prevention bundle and its compliance, educating about the practices and effects on patients outcome., Design: Quasi-experimental study, conducted in 3 phases., Setting: Hospital based., Participants: Invasive Mechanically ventilated patients in the Department of Medicine of a tertiary care hospital. 50 patients included in phase 1 and 3., Intervention: Phase 1 and Phase 3 were pre and post intervention phases respectively when compliance to VAP prevention bundle was assessed with intermediate Phase 2, the intervention phase where the residents and nurses were educated about VAP bundle through various means. A checklist was attached to patient records., Outcome Measures: Incidence of VAP, total hospital and ICU stay, duration of mechanical ventilation and mortality., Results: On comparing the 2 phases, it was found that there was increase in the compliance to VAP bundle(p&lt;0.001), use of orogastric tube (p&lt;0.001) and use of daily sedation free interval (p&lt;0.001). Statistically insignificant increase in the use of DVT prophylaxis (p= 0.996) and raising the head end of the bed (p=0.513), and decline in the number of days of ICU(p=0.804) and hospital stay(p=0.907), the duration of mechanical ventilation(p=0.909), mortality(p=0.315) and incidence of VAP(p=0.715) was noted. Among those who developed VAP, there was lower compliance to bundle., Conclusions: Practices like use of VAP prevention bundle improve on teaching efforts and use of checklist which improves patient care., (© Journal of the Association of Physicians of India 2011.)

Cryptochromes (CRYs) function as blue light photoreceptors in diverse physiological processes in nearly all kingdoms of life. Over the past several decades, they have emerged as the most likely candidates for light-dependent magnetoreception in animals, however, a long history of conflicts between in vitro photochemistry and in vivo behavioral data complicate validation of CRYs as a magnetosensor. In this review, we highlight the origins of conflicts regarding CRY photochemistry and signal transduction, and identify recent data that provides clarity on potential mechanisms of signal transduction in magnetoreception. The review primarily focuses on examining differences in photochemistry and signal transduction in plant and animal CRYs, and identifies potential modes of convergent evolution within these independent lineages that may identify conserved signaling pathways., (© 2021 The Protein Society.)

Background: Brain abscess is a common complication in children with cyanotic congenital heart disease. The presence of an underlying acyanotic congenital heart disease is usually not suspected in an adult patient presenting with brain abscess., Case Summary: A 51-year-old male patient with no known co-morbidities came with complaints of recent onset right lower limb weakness needing support while walking and on evaluation was found to have brain abscess. He underwent robotic endoscope assisted endoport excision of the brain abscess. Two-dimensional transthoracic echocardiography showed right atrial and right ventricular dilatation with mild low-pressure tricuspid regurgitation. Transoesophageal echocardiography (TOE) revealed sinus venosus atrial septal defect (ASD) with left-to-right shunt with the right upper pulmonary vein draining into superior vena cava. Contrast echocardiography revealed a small transient right-to-left shunt. He has been advised to undergo elective surgical closure of ASD with partial anomalous pulmonary venous connection repair., Discussion: Right-to-left shunting in ASDs can occur in the early systole even in the absence of raised pressures in the right side of the heart, even when the predominant shunt is left to right, but the magnitude of such a shunt is small and transient and is easily missed. Contrast echocardiography and TOE should be done as a part of evaluation of patients presenting with brain abscess., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Prostate-specific antigen (PSA) screening for prostate cancer (PCa) is limited by the lack of specificity but is further complicated in the benign prostatic hyperplasia (BPH) population which also exhibit elevated PSA, representing a clear unmet need to distinguish BPH from PCa. Herein, we evaluated the utility of FLNA IP-MRM, age, and prostate volume to stratify men with BPH from those with PCa. Diagnostic performance of the biomarker panel was better than PSA alone in discriminating patients with negative biopsy from those with PCa, as well as those who have had multiple prior biopsies (AUC 0.75 and 0.87 compared to AUC of PSA alone 0.55 and 0.57 for patients who have had single compared to multiple negative biopsies, respectively). Of interest, in patients with PCa, the panel demonstrated improved performance than PSA alone in those with Gleason scores of 5-7 (AUC 0.76 vs. 0.56) and Gleason scores of 8-10 (AUC 0.74 vs. 0.47). With Gleason scores (8-10), the negative predictive value of the panel is 0.97, indicating potential to limit false negatives in aggressive cancers. Together, these data demonstrate the ability of the biomarker panel to perform better than PSA alone in men with BPH, thus preventing unnecessary biopsies., (© 2021. The Author(s).)

Wellens syndrome is a pre-infarction stage due to the critical stenosis of the proximal left anterior descending artery. It is characterized by intermittent chest pain with classical ECG changes. The cardiac biomarker is within the normal limit or only slightly elevated in this condition. Early recognition and cardiac intervention are important to prevent adverse cardiac outcomes. We report this rare case of Wellens syndrome in a 70-year-old male with intermittent chest and epigastric pain associated with belching for five days. The patient presented characteristic T-wave changes, symmetric deeply inverted T-waves, in precordial leads (V2-V4). Cardiac biomarkers, including troponin, were negative. He underwent cardiac catheterization and found a clot in the proximal left anterior descending coronary artery, which required a catheter-directed thrombectomy and drug-eluting stent placement. It is important to recognize this condition early and referred on time from primary health centers to higher centers, especially in developing countries like the Maldives, since delays in transfer may lead to a serious outcome., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Shah et al.)

Objective: With the advent of minimally invasive techniques, minimally invasive spine surgery (MISS) has become a realistic option for many spine cases. This study aims to evaluate the operative and clinical outcomes of MISS for total versus subtotal tumor resection from current evidence., Methods: A literature search was performed using the search term (Minimally invasive surgery OR MIS) AND (spine tumor OR spinal tumor). Studies including both minimally invasive total and subtotal resection cases with operative or clinical data were included., Results: Seven studies describing 159 spinal tumor cases were included. Compared with total resection, subtotal resection showed no significant differences in surgical time (mean difference (MD), 9.44 minutes; 95% confidence interval [CI], -47.66 to 66.55 minutes; P = 0.37), surgical blood loss (MD, -84.72 mL; 95% CI, -342.82 to 173.39 mL; P = 0.34), length of stay (MD, 1.38 days; 95% CI, -0.95 to 3.71 days; P = 0.17), and complication rate (odds ratio, 9.47; 95% CI, 0.34-263.56; P = 0.12). Pooled analyses with the random-effects model showed that neurologic function improved in 89% of patients undergoing total resection, whereas neurologic function improved in 61% of patients undergoing subtotal resection., Conclusions: Our analyses show that there is no significant difference in operative outcomes between total and subtotal resection. Patients undergoing total resection showed slightly better improvement in neurologic outcomes compared with patients undergoing subtotal resection. Overall, this study suggests that both total and subtotal resection may result in comparable outcomes for patients with spinal tumors. However, maximal safe resection remains the ideal treatment because it provides the greatest chance of long-term benefit., (Copyright © 2021. Published by Elsevier Inc.)

Kawasaki disease (KD) is an acute rheumatological illness usually affecting children between six months and five years of age. It is a vasculitis syndrome of medium-sized vessels that has typical clinical characteristics such as fever, rash, cervical lymphadenopathy, conjunctivitis, and mucosal changes. However, sometimes, it may present with the features of shock when it is known as Kawasaki disease shock syndrome (KDSS). The actual etiology of this disease is still unknown. The primary treatment of this disease is aspirin and intravenous immunoglobulin (IVIG). The most common and serious complication of KD is cardiac complications which can be avoided by IVIG if given on time. KDSS is the other rare but serious early complication that can be presented to the ED as an initial presenting feature. Early diagnosis of KDSS in the ED and its treatment is very important to prevent early and late complications, including cardiac complications of this disease. Although the usual age group for this disease is under five years, here we have presented a rare case of KDSS in a nine-year-old female child., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Shah et al.)

The use of unique cell surface markers to target and eradicate HIV-infected cells has been a longstanding objective of HIV-1 cure research. This approach, however, overlooks the possibility that intracellular changes present within HIV-infected cells may serve as valuable therapeutic targets. For example, the identification of dysregulated antiviral signaling in cancer has led to the characterization of oncolytic viruses capable of preferentially killing cancer cells. Since impairment of cellular antiviral machinery has been proposed as a mechanism by which HIV-1 evades immune clearance, we hypothesized that HIV-infected macrophages (an important viral reservoir in vivo ) would be preferentially killed by the interferon-sensitive oncolytic Maraba virus MG1. We first showed that HIV-infected monocyte-derived macrophages (MDM) were more susceptible to MG1 infection and killing than HIV-uninfected cells. As MG1 is highly sensitive to type I interferons (IFN-I), we then investigated whether we could identify IFN-I signaling differences between HIV-infected and uninfected MDM and found evidence of impaired IFN-α responsiveness within HIV-infected cells. Finally, to assess whether MG1 could target a relevant, primary cell reservoir of HIV-1, we investigated its effects in alveolar macrophages (AM) obtained from effectively treated individuals living with HIV-1. As observed with in vitro -infected MDM, we found that HIV-infected AM were preferentially eliminated by MG1. In summary, the oncolytic rhabdovirus MG1 appears to preferentially target and kill HIV-infected cells via impairment of antiviral signaling pathways and may therefore provide a novel approach to an HIV-1 cure. IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) remains a treatable, but incurable, viral infection. The establishment of viral reservoirs containing latently infected cells remains the main obstacle in the search for a cure. Cure research has also focused on only one cellular target of HIV-1 (the CD4 + T cell) while largely overlooking others (such as macrophages) that contribute to HIV-1 persistence. In this study, we address these challenges by describing a potential strategy for the eradication of HIV-infected macrophages. Specifically, we show that an engineered rhabdovirus - initially developed as a cancer therapy - is capable of preferential infection and killing of HIV-infected macrophages, possibly via the same altered antiviral signaling seen in cancer cells. As this rhabdovirus is currently being explored in phase I/II clinical trials, there is potential for this approach to be readily adapted for use within the HIV-1 cure field., (Copyright © 2021 Sandstrom et al.)

Background: Ependymomas are rare tumors originating from neuroepithelial cells lining the wall of the ventricles or central canal of the spinal cord. While these tumors mainly occur within the central nervous system (CNS), there are occasional reports in children and young adult patients with a primary tumor occurrence outside of the CNS. Ependymomas of the sacrococcygeal region have been infrequently described in the literature with no standard of care established. We present a case report and review of the literature regarding this rare entity., Case Description: A 24-year-old woman presented with right gluteal pain worsened by sitting and a palpable soft tissue mass of the sacrococcygeal region. Magnetic resonance imaging revealed a 3.7 cm cystic mass centered in the right gluteal region. She underwent a biopsy at an outside institution, with histology revealing myxopapillary ependymoma. The patient was referred to our hospital and underwent an interdisciplinary neurosurgical and orthopedic oncology en bloc resection of the ependymoma, which intraoperatively appeared to originate from the coccygeal nerve., Conclusion: In the present report, the authors demonstrate that a myxopapillary ependymoma may present as an isolated gluteal mass attached to the coccygeal nerve, without frank CNS involvement. Furthermore, an interdisciplinary approach to surgical resection of this lesion appears to represent an effective treatment modality., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Surgical Neurology International.)

Lymph node tuberculosis is one of the most common forms of extrapulmonary tuberculosis worldwide. The study aimed to evaluate the role of positron emission tomography-computed tomography (PET-CT) in determining post-treatment response in lymph node tuberculosis. A PET-CT was done in all treatment naïve tubercular lymphadenitis adults at baseline and after six months of therapy. The post-treatment clinical response was compared with the metabolic response on PET-CT. Of the 25 patients with tubercular lymphadenitis, 9/25 patients showed a complete metabolic response (CMR) at six months, while 16 patients had a partial metabolic response (PMR). All patients with CMR had a good clinical response. However, discordance between clinical and PET findings was noticed in those with PMR. The role of PET-CT in evaluating post-treatment response in patients with tubercular lymphadenitis needs further evaluation with a larger sample size.

The aim of this integrative review was to examine the impact of past viral epidemics on mental health, with a specific focus on changes in numbers of acute mental health presentations and mental health service recommendations in response to this, in the context of the COVID-19 pandemic. Following PRISMA methodology, databases were searched for relevant publications. A total of 83 articles with a range of methodologies were included to ensure broad coverage of this rapidly emerging research area. The literature supports an initial increase in mental health concerns which generally do not reach the threshold for diagnosis with a mental illness, but present to frontline telephone services. There is a potential delay before community and hospital-based mental health services see an increase in new or relapsing mental illness presentations. However vulnerable populations, such as people with pre-existing mental illness, are at increased risk of mental health issues during such public health crises. Many of the general recommendations distilled from the literature are closely aligned with existing strategic frameworks for mental health service provision. However, in review of these frameworks, gaps in the literature become more apparent, such as a failure to include people with lived experience, peer workers, and First Nations People in the COVID-19 mental health response.

Severe Acute Respiratory Syndrome Corona Virus 2 has altered life on a global scale. A concerted effort from research labs around the world resulted in the identification of potential pharmaceutical treatments for CoVID-19 using existing drugs, as well as the discovery of multiple vaccines. During an urgent crisis, rapidly identifying potential new treatments requires global and cross-discipline cooperation, together with an enhanced open-access research model to distribute new ideas and leads. Herein, we introduce an application of a deep neural network based drug screening method, validating it using a docking algorithm on approved drugs for drug repurposing efforts, and extending the screen to a large library of 750,000 compounds for de novo drug discovery effort. The results of large library screens are incorporated into an open-access web interface to allow researchers from diverse fields to target molecules of interest. Our combined approach allows for both the identification of existing drugs that may be able to be repurposed and de novo design of ACE2-regulatory compounds. Through these efforts we demonstrate the utility of a new machine learning algorithm for drug discovery, SSnet, that can function as a tool to triage large molecular libraries to identify classes of molecules with possible efficacy.

Computational prediction of Protein-Ligand Interaction (PLI) is an important step in the modern drug discovery pipeline as it mitigates the cost, time, and resources required to screen novel therapeutics. Deep Neural Networks (DNN) have recently shown excellent performance in PLI prediction. However, the performance is highly dependent on protein and ligand features utilized for the DNN model. Moreover, in current models, the deciphering of how protein features determine the underlying principles that govern PLI is not trivial. In this work, we developed a DNN framework named SSnet that utilizes secondary structure information of proteins extracted as the curvature and torsion of the protein backbone to predict PLI. We demonstrate the performance of SSnet by comparing against a variety of currently popular machine and non-Machine Learning (ML) models using various metrics. We visualize the intermediate layers of SSnet to show a potential latent space for proteins, in particular to extract structural elements in a protein that the model finds influential for ligand binding, which is one of the key features of SSnet. We observed in our study that SSnet learns information about locations in a protein where a ligand can bind, including binding sites, allosteric sites and cryptic sites, regardless of the conformation used. We further observed that SSnet is not biased to any specific molecular interaction and extracts the protein fold information critical for PLI prediction. Our work forms an important gateway to the general exploration of secondary structure-based Deep Learning (DL), which is not just confined to protein-ligand interactions, and as such will have a large impact on protein research, while being readily accessible for de novo drug designers as a standalone package.

Plants measure light quality, intensity, and duration to coordinate growth and development with daily and seasonal changes in environmental conditions; however, the molecular details linking photochemistry to signal transduction remain incomplete. Two closely related light, oxygen, or voltage (LOV) domain-containing photoreceptor proteins, ZEITLUPE (ZTL) and FLAVIN-BINDING, KELCH REPEAT, F-BOX 1 (FKF1), divergently regulate the protein stability of circadian clock and photoperiodic flowering components to mediate daily and seasonal development. Using structural approaches, we identified that mutations at the Gly46 position led to global rearrangements of the ZTL dimer interface in the isolated ZTL-LOV domain. Specifically, G46S and G46A variants induce a 180° rotation about the ZTL-LOV dimer interface that is coupled to ordering of N- and C-terminal signaling elements. These conformational changes hinge upon rotation of a C-terminal Gln residue (Gln154) analogous to that present in light-state structures of ZTL. In contrast to other LOV proteins, a Q154L variant retains light-state interactions with GIGANTEA (GI), thereby indicating N5 protonation is not required for ZTL signaling. The results presented herein confirm a divergent signaling mechanism within ZTL, whereby steric and electronic effects following adduct formation can be sufficient for signal propagation in LOV proteins containing a Gly residue at position 46. Examination of bacterial LOV structures with Gly residues at the equivalent position suggests that mechanisms of signal transduction in LOV proteins may be fluid across the LOV protein family.

Background  High-resolution ultrasound (HRUS) and magnetic resonance neurography (MRN) are considered complementary to clinical and neurophysiological assessment for neuropathies. Aims  The aim of our study was to compare the accuracy of HRUS and MRN for detecting various peripheral nerve pathologies, to choose the correct investigation to facilitate prompt patient management. Materials and Methods  This prospective study was done using HRUS with 14 MHz linear-transducer and 3 or 1.5T MR in cases referred for the assessment of peripheral nerve pathologies. Image interpretation was done using a scoring system (score 0-3 confidence level) to assess for nerve continuity/discontinuity, increased nerve signal/edema, fascicular change, caliber change, and neuroma/mass lesion. We determined the accuracy, sensitivity, and specificity of these modalities compared with the diagnostic standard determined by surgical and/or histopathological, if not performed then clinical and/or electrodiagnostic evaluation. Results  The overall accuracy of MRN was 89.3% (specificity: 66.6%, sensitivity: 92.6%, negative predictive value [NPV]: 57.1%, positive predictive value [PPV]: 95%) and that of HRUS was 82.9% (specificity: 100%, sensitivity: 80.4%, NPV: 42.8, PPV: 100). The confidence level for detecting nerve discontinuity and change in nerve caliber was found to be higher on ultrasonography than magnetic resonance imaging (MRI) (100 vs. 70% and 100 vs. 50%, respectively). Pathology of submillimeter caliber nerves was accurately detected by HRUS and these could not be well-visualized on MRI. Conclusion  HRUS is a powerful tool that may be used as the first-line imaging modality for the evaluation of peripheral nerve pathologies, and a better means of evaluation of peripheral nerves with submillimeter caliber., Competing Interests: Conflict of InterestNoteSource(s) of SupportFinancial Support and Sponsorship There are no conflicts of interest. Work primarily performed at Department of Radiology, Medanta-The Medicity, Gurugram, Haryana, India. Nil. Nil., (Indian Radiological Association. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Anesthesiologists are frequently responsible for placement of transesophageal echocardiography probes prior to cardiac surgery in children. A number of potential complications are possible, including placement failure. This report documents one such failed attempt at probe placement in a 3-month-old patient with a history of ventricular septal defect, and the utilization of video laryngoscopy by the anesthesiologist to diagnose a previously unknown extrinsic esophageal compression likely caused by an aberrant right subclavian artery. This case highlights the multiple vascular anomalies that may act as a source of esophageal obstruction in children undergoing transesophageal echocardiography for cardiac surgery.

Microbiological diagnosis of extra-pulmonary tuberculosis (EPTB) has been one of the most difficult aspects of tuberculosis (TB) management. Availability of better imaging and diagnostic modalities has led to an increase in the number of diagnosed cases. The current upsurge in multidrug-resistant tuberculosis warrants routine testing of EPTB samples for resistance at baseline with shorter turn-around time. A total of 369 EPTB specimens were subjected to Ziehl-Neelsen (ZN) stain, liquid culture (LC) with phenotypic drug susceptibility testing, MTBDRplus V.2 and MTBDRsl V.2. The molecular categorisation of resistant specimens was further reconfirmed with sequencing. The sensitivity and specificity of MTBDRplus V.2 to detect Mycobacterium tuberculosis (MTB) when compared to ZN stain was 97.9% and 89.2%, respectively while it was 73.4% and 83.8%, respectively when compared to LC. Similarly, for MTBDRsl V.2, the sensitivity and specificity for detection of MTB when compared with ZN was 95.6% and 91.9%, respectively and 75% and 89.2%, respectively when compared to LC. In smear-positive specimens, 94% (141/150) and 86% (129/150) valid results were observed in MTBDRplus V.2 and MTBDRsl V.2, respectively. The utilisation of both MTBDRplus V.2 and MTBDRsl V.2 for the diagnosis of smear-positive EPTB specimens would be useful in programmatic management of TB in high-burden settings., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Pseudoaneurysm of the femoral artery is the most common complication among IV drug abusers who inject drugs in groin. These are usually infective and potentially fatal so it requires astute clinical recognition and prompt treatment, possessing a significant challenge to vascular surgeons., Methods: We present a retrospective descriptive study and the prevalent practice of their management covering the period from 2013 July- December 2019 at our center. Data regarding demography, presentation, surgical management, and the outcome was analyzed., Results: Among 368 femoral pseudoaneurysm operated during the period, groin swelling with pulsatile mass was the most frequent presentation accounting 304 (82.61%) patients. About 67.12% (247 patients) of the pseudoaneurysm has purulent discharge and 60.07% (221 patients) had bleeding at presentation out of which 211patients had hepatitis C (HCV), hepatitis B (HBsAg) and/or Human Immunodeficiency virus (HIV) status positive.  Thirty six patients (9.78%) presented with femoral pseudoaneurysm in both groins. Ligation and excision of the pseudoaneurysm were done in all cases while delayed revascularization was done in eight patients with expanded Polytetrafluoroethylene (ePTFE) graft in one patient and venous bypass grafts in other 7 cases. All patients after bypass had no major limb loss and two patients had a patent graft at five years follow up. There were nine mortalities and thirty two patients underwent amputation.  Conclusions: Infected femoral pseudoaneurysm can be managed by ligation of the involved artery with delayed revascularization if required without major limb and life loss.

Purpose: To compare cellular uptake and cytotoxicity of fluorescein (FL)-labeled polyethylene glycols (PEGs) carrying 2 folate groups (targeted delivery vehicles [TDVs]) to non-PEGylated molecules with 1 or 2 folate groups., Materials and Methods: Three PEGylated TDVs and 2 non-PEGylated folic acid (FA)-fluorescein (FL) conjugates (FA-FL and FA-FL-FA) were synthesized. Two triple-negative breast cancer cell lines (MDA-MB-231and MDA-MB-468) were cultured to 70% confluency and incubated for 2 h in a folate-depleted medium. Folate receptor (FR) expression was confirmed by immunocytochemistry. Cellular uptake and cytotoxicity of compounds were measured by flow cytometry. Intracellular localization was confirmed using confocal microscopy., Results: MDA-MB-231 demonstrated 40% more FR staining than MD-MB-468. Intracellular localization of the 2 non-PEGylated molecules (FA-FL and FA-FL-FA) and the 3 PEGylated TDVs was confirmed with confocal microscopy. Cellular uptake was independent of concentration for FA-FL, but there was 26.8% more cytotoxicity at 30 μg/mL compared with no treatment (P ≤ .05). Uptake was > 90% for FA-FL-FA at 10 μg/mL and 30 μg/mL without significant cytotoxicity (P ≤ .005). Cellular uptake was > 80% for all TDVs. The molecule containing monodispersed PEG with M n  = 1,000 g/mol had the highest uptake in both cell lines without cytotoxicity. Maximum toxicity was demonstrated by the molecule containing PEG 2,000 only at the highest dose of 30 μg/mL (8.66% ± 3.94% cytotoxicity; cut-off was 20%)., Conclusions: The molecule containing monodispersed PEG with M n  = 1,000 g/mol and 2 FA targeting groups demonstrated better targetability and cellular uptake as a TDV., (Copyright © 2020 SIR. Published by Elsevier Inc. All rights reserved.)

Background: There is no effective therapy for COVID-19. Hydroxychloroquine (HCQ) and chloroquine (CQ) have been used for its treatment but their safety and efficacy remain uncertain., Objective: We performed a systematic review to synthesize the available data on the efficacy and safety of CQ and HCQ for the treatment of COVID-19., Methods: Two reviewers searched for published and pre-published relevant articles between December 2019 and 8 June 2020. The data from the selected studies were abstracted and analyzed for efficacy and safety outcomes. Critical appraisal of the evidence was done by Cochrane risk of bias tool and Newcastle Ottawa Scale. The quality of evidence was graded as per the GRADE approach., Results: We reviewed 12 observational and 3 randomized trials which included 10,659 patients of whom 5713 received CQ/HCQ and 4966 received only standard of care. The efficacy of CQ/HCQ for COVID-19 was inconsistent across the studies. Meta-analysis of included studies revealed no significant reduction in mortality with HCQ use [RR 0.98 95% CI 0.66-1.46], time to fever resolution (mean difference - 0.54 days (- 1.19-011)) or clinical deterioration/development of ARDS with HCQ [RR 0.90 95% CI 0.47-1.71]. There was a higher risk of ECG abnormalities/arrhythmia with HCQ/CQ [RR 1.46 95% CI 1.04 to 2.06]. The quality of evidence was graded as very low for these outcomes., Authors' Conclusion: The available evidence suggests that CQ or HCQ does not improve clinical outcomes in COVID-19. Well-designed randomized trials are required for assessing the efficacy and safety of HCQ and CQ for COVID-19.

Context: Nontuberculous mycobacteria (NTM) are ubiquitous mycobacteria present in environment and generally affect patients with either structural lung disease or immunosuppression and commonly involve lungs, lymph node, or skin., Materials and Methods: Between July 2016 and February 2019, 18 cases of NTM were diagnosed and their relevant clinical, diagnostic, and treatment details were recorded after taking informed consent., Results: We report 18 cases of NTM involving lungs (n = 11), skin and soft tissue (n = 3), joint (n = 2), genitourinary (n = 1), and central nervous system (n = 1). History of immunosuppression was present in two patients, whereas history of some form of intervention was seen in six patients. Mycobacterium fortuitum group (n = 5) was the most commonly isolated organism, followed by Mycobacterium avium complex (n = 4), Mycobacterium abscessus (n = 3), Mycobacterium kansasii (n = 2), and Mycobacterium chelonae (n = 1). In two patients, M. chelonae and M. abscessus were isolated in succession. Of these 18 patients, clinical response was present in 15 of the patients. Diagnosis and treatment of NTM in resource limited settings is extremely challenging., Conclusion: Most of the patients with NTM are misdiagnosed and are treated as tuberculosis in India, sometimes with a multidrug resistance regimen, which results in significant morbidity and mortality. We present these cases to shed some light on the epidemiology of NTM in this part of India., Competing Interests: None

•Most of the COVID-19 cases in Nepal are in the Southern districts of Nepal bordering India with travel histories to India.•Very few positive cases of COVID-19 are detected in Nepal which could either be due to early national lockdown.•Low PCR positivity rates could also be due to inefficiency of the PCR methods.•Whole genomes of 93 clinical samples from COVID-19 patients were analyzed to find the primer and probe binding sites.•Mutations in probe binding sites were found which could impact PCR efficiency resulting in false negative results., Competing Interests: None., (© 2020 Elsevier Ltd. All rights reserved.)