Selection of epigenetically privileged HIV-1 proviruses during treatment with panobinostat and interferon-α2a.

CD4+ T cells with latent HIV-1 infection persist despite treatment with antiretroviral agents and represent the main barrier to a cure of HIV-1 infection. Pharmacological disruption of viral latency may expose HIV-1-infected cells to host immune activity, but the clinical efficacy of latency-reversing agents for reducing HIV-1 persistence remains to be proven. Here, we show in a randomized-controlled human clinical trial that the histone deacetylase inhibitor panobinostat, when administered in combination with pegylated interferon-α2a, induces a structural transformation of the HIV-1 reservoir cell pool, characterized by a disproportionate overrepresentation of HIV-1 proviruses integrated in ZNF genes and in chromatin regions with reduced H3K27ac marks, the molecular target sites for panobinostat. By contrast, proviruses near H3K27ac marks were actively selected against, likely due to increased susceptibility to panobinostat. These data suggest that latency-reversing treatment can increase the immunological vulnerability of HIV-1 reservoir cells and accelerate the selection of epigenetically privileged HIV-1 proviruses.

Daily versus fortnightly oral vitamin D3 in treatment of symptomatic vitamin D deficiency in children aged 1-10 years: An open labelled randomized controlled trial.

OBJECTIVE: Compare the efficacy and safety of daily versus fortnightly oral vitamin D3 in treating symptomatic vitamin D deficiency in children aged 1-10 years. DESIGN: Open labelled randomized controlled trial. PATIENTS: Eighty children with symptomatic vitamin D deficiency were randomized into group daily (D) and group bolus (B) [40 in each group] to receive oral vitamin D3, 4000 IU daily or 60,000 IU fortnightly for 12 weeks respectively. Both groups received daily oral calcium of 500 mg/day. MEASUREMENTS: Serum calcium (Ca), phosphate (P), alkaline phosphatase (ALP), 25-hydroxy cholecalciferol (25(OH)D), parathyroid hormone (PTH) levels, urine calcium: creatinine ratio and radiological score were assessed at baseline, 4 weeks and 12 weeks. At the end of 12 weeks, 74 children were available for evaluation of the efficacy and safety of both regimens. RESULTS: Both regimens led to a significant increase in Ca and P levels and a fall in ALP and PTH levels from baseline to 4 and 12 weeks of therapy, with no intergroup difference. At 4- and 12-week assessments, all children in both treatment arms achieved 25(OH)D level in sufficiency range, with no significant difference in their geometric mean. Both regimens were associated with asymptomatic transient hypercalcemia [group D-51.4% vs. group B-34.3%; p -0.14] and hypercalciuria (5.7%) in group D that resolved spontaneously on follow-up. CONCLUSIONS: Daily and fortnightly oral vitamin D3 in similar cumulative doses are efficacious for treating symptomatic vitamin D deficiency in children (1-10 years). Treated children should be monitored for serum 25(OH)D, Ca and urinary calcium creatinine ratio.

A comparative evaluation of fibreoptic bronchoscopy versus C-MAC® D-BLADE-guided videolaryngoscopy for nasotracheal intubation under general anesthesia in oropharyngeal carcinoma surgery patients.

PURPOSE: Nasotracheal intubation (NTI) is required for surgery in oropharyngeal (OP) carcinoma patients, but it may be challenging because of distorted anatomy, mucosal congestion, and increased risk of bleeding. Flexible bronchoscopy (FB)-guided NTI is preferred in these cases but has limitations. In this randomized controlled study, we sought to compare C-MAC® D-BLADE-guided videolaryngoscopy (VL) (Karl Storz SE & Co. KG, Tuttlingen, Germany) with FB for NTI under general anesthesia in patients with OP carcinomas. METHODS: We randomized a total of 100 patients with OP carcinoma and El-Ganzouri's risk index (EGRI) < 7 to undergo NTI under general anesthesia with FB (n = 50) or C-MAC D-BLADE-guided VL (n = 50). The primary outcome was the total intubation time. We also recorded the time to glottis view, nasal intubation difficulty scale (NIDS) score, best percentage of glottis opening score, and complications. RESULTS: The median [interquartile range (IQR)] total intubation time was shorter with VL than with FB (total intubation time, 38 [26-43] sec vs 60 [52-65] sec; difference, -20 sec [95% confidence interval (CI), -27 to -11]; P < 0.001). Similarly, the median [IQR] time to glottis view was shorter with VL compared to FB (8 [6-9] sec vs 22 [14-25] sec; difference, -13 sec [95% CI, -17 to -10]; P < 0.001). The median NIDS score was higher with VL (difference, 2 [95% CI, 2 to 3]; P < 0.001). The incidences of airway trauma (two cases with FB vs seven with VL; P = 0.30) and postoperative sore throat (ten cases in both groups; P = 0.56) were similar. CONCLUSION: Compared to FB, C-MAC D-BLADE-based VL reduced the total time for nasal intubation oropharyngeal carcinoma patients, potentially representing an acceptable alternative in selected cases. TRIAL REGISTRATION: CTRI.nic.in (2018/11/0162830); first submitted 8 November 2018.

RéSUMé: OBJECTIF: L'intubation nasotrachéale est nécessaire pour la chirurgie chez la patientèle atteinte de carcinome oropharyngé, mais elle peut être difficile en raison d'une anatomie déformée, d'une congestion des muqueuses et d'un risque accru de saignement. Dans ces cas, il est préférable d'utiliser une intubation nasotrachéale guidée par bronchoscopie flexible (BF), mais cette modalité a ses limites. Dans cette étude randomisée contrôlée, nous avons cherché à comparer la vidéolaryngoscopie guidée par lame D-BLADE C-MAC® (VL) (Karl Storz SE & Co. KG, Tuttlingen, Allemagne) à la BF pour réaliser l'intubation nasotrachéale sous anesthésie générale chez les patient·es ayant un carcinome oropharyngé. MéTHODE: Au total, nous avons randomisé 100 personnes atteintes d'un carcinome oropharyngé et présentant un indice de risque d'El-Ganzouri (EGRI) < 7 à bénéficier d'une intubation nasotrachéale sous anesthésie générale par BF (n = 50) ou par VL guidée par lame D-BLADE C-MAC (n = 50). Le critère d'évaluation principal était le temps d'intubation total. Nous avons également enregistré le temps écoulé jusqu'à la visualisation de la glotte, le score sur l'échelle de difficulté de l'intubation nasale (NIDS), le meilleur pourcentage de score d'ouverture de la glotte et les complications. RéSULTATS: La durée totale d'intubation médiane [écart interquartile (ÉIQ)] était plus courte avec la VL qu'avec la BF (durée totale d'intubation, 38 [26­43] sec vs 60 [52 à 65] secondes; différence, −20 sec [intervalle de confiance (IC) à 95 %, −27 à −11]; P < 0,001). De même, le temps médian [ÉIQ] jusqu'à la visualisation de la glotte était plus court avec la VL qu'avec la BF (8 [6­9] sec vs 22 [14 à 25] secondes; différence, −13 sec [IC 95 %, −17 à −10]; P < 0,001). Le score médian sur l'échelle NIDS était plus élevé avec la VL (différence, 2 [IC 95 %, 2 à 3]; P < 0,001). L'incidence des traumatismes des voies aériennes (deux cas avec la BF vs sept avec la VL; P = 0,30) et le mal de gorge postopératoire (dix cas dans les deux groupes; P = 0,56) étaient similaires. CONCLUSION: Par rapport à la BF, la VL guidée par lame D-BLADE C-MAC a réduit le temps total d'intubation nasale pour les personnes atteintes d'un carcinome oropharyngé, ce qui représente potentiellement une alternative acceptable dans certains cas. ENREGISTREMENT DE L'éTUDE: CTRI.nic.in (2018/11/0162830); première soumission le 8 novembre 2018.

Despite treatment, HbA1c ≥ 37 mmol/mol in the first trimester is associated with premature delivery among South Asian women with gestational diabetes mellitus: a retrospective cohort study.

PURPOSE: To examine the effects of first-trimester HbA1c (HbA1c-FT) ≥ 37 mmol/mol on preterm birth (PTB) and large-for-gestational-age (LGA) babies in a retrospective cohort of South Asian pregnant women with gestational diabetes (GDM). METHODS: The cohort (n = 686) was separated into two groups based on HbA1c-FT values: Group A (n = 97) and Group B (n = 589), with values of 37-46 mmol/mol (5.5-6.4%) and < 37 mmol/mol (5.5%), respectively. HbA1c-FT's independent influence on PTB and LGA babies was examined using multivariable logistic regression in groups A and B women. The reference group (Group C) included 2031 non-GDM women with HbA1c-FT < 37 mmol/mol (< 5.5%). The effects of HbA1c-FT on PTB and LGA babies in obese women in Groups A, B, and C (designated as A-ob, B-ob, and C-ob, respectively) were re-analyzed using multivariable logistic regression. RESULTS: Group A GDM women with greater HbA1c-FT had a higher risk for PTB (aOR:1.86, 95% CI:1.10-3.14) but not LGA babies (aOR:1.13, 95%: 0.70-1.83). The risk of PTB was higher for obese women in Group A-ob: aOR 3.28 [95% CI 1.68-6.39]. However, GDM women with normal HbA1c-FT exhibited no elevated risk for PTB: Groups B and B-ob had aORs of 1.30 (95% CI 0.86-1.98) and 1.28 (95% CI 0.88-1.85) respectively. CONCLUSIONS: South Asian GDM women with prediabetic HbA1c FT; 37-46 mmol/mol (5.5-6.4%) are more likely to deliver preterm babies despite treatment, while the risk for LGA babies was the same as non-GDM women.

Use of Pearson and Spearman correlation testing in Indian anesthesia journals: An audit.

Background and Aims: Correct usage and interpretation of biostatistical tests is imperative. Aim of the present article was to evaluate the use of "correlation test" for biostatistical analysis in two leading Indian journals of anesthesia and sensitize the readers regarding its correct usage. Material and Methods: A prospective analysis was done for all original articles using the correlation test (Pearson or Spearman) that were published in "Indian Journal of Anaesthesia" (IJA) or "Journal of Anaesthesiology and Clinical Pharmacology" (JOACP) in the years 2019 and 2020. Results: Amongst all included original studies, correlation test were used in 6% (JOACP) and 6.5% (IJA) respectively (averaged for the years 2019 and 2020). Correlation test was usedinappropriately) for evaluating an aim of prediction/agreement/comparison, rather than association, in 25% and 10% instances each (JOACP and IJA). In both JOACP and IJA, there were high rates of using and interpreting results without citing 95% confidence intervals (CIs) of correlation coefficient (88% and 90%, respectively), P value for significance of the association (50% and 90%, respectively), or coefficient of discrimination (88% and 70%, respectively). In majority of the instances, test to ascertain presence of mandatory prerequisites such as normal distribution of data could not be found (62% and 90%, respectively). Conclusion: The complete potential of correlation test in exploring research questions is probably underappreciated. Further, even when used, its application and interpretation are prone to errors. We hope that the present analysis and narrative is a well-timed appropriate step in bridging the gaps in existing knowledge regarding use of correlation test in national anesthesia literature.

Demographical and Epidemiological Contribution to Cancer Incidence in Delhi and Its Trends from 1991-2015.

INTRODUCTION: Cancer incidences are rising worldwide, and India ranked third globally in cancer incidence as of 2020, according to estimates from GLOBOCAN. The three components that contributed to changes in cancer incidence include cancer-related risk factors, population size, and population structure. The present study aim is to derive the contribution of these factors to cancer incidence and to evaluate their trend from 1991 to 2015. METHODS: The Data were extracted from the Delhi population-based cancer registry published reports. This longstanding registry covers nearly 100% of the Delhi population. The secular trends of cancer incidence from 1991-2015 were assessed for all sites combined as well as top-five cancer sites among males and females. Joinpoint regression and Riskdiff software were performed to assess the trend among the components of cancer incidence change. RESULTS: Both males and females exhibited nearly equal age-standardised incidence rates over 25 years. Albeit, an overall trend in age-standardised rate was not significant for both sexes (0.68% for males and -0.16% for females) when considering all cancer sites combined. Lung, prostate, oral, and gallbladder cancer exhibits a significant rising trend in the age-standardised rates in males while in females only breast and endometrial cancer showed a rising trend. The cancer counts surged by 252% in males and 208.5% in females from 1991 to 2015. The population size component contributed a 180% increase in males and a 170% increase in females, respectively. The site-specific risk changes were more than 100% for the prostate, oral, and gallbladder cancers in males and endometrial cancer in females. The population structure (aging) contributed to rising cancer incidence varying from 35% to 60% in both genders. CONCLUSION: A significant contribution to new cancer cases was observed due to a demographical shift in both population size and structure, in addition to plausible cancer-specific risk factors. This transformation could surge a potential burden on the Delhi healthcare system. Persistent endeavours are essential to expand and enhance the existing cancer care infrastructure to meet the rising demand driven by aging and population growth. Implementing a stringent population policy can help to mitigate the impact of population growth on cancer incidence.

Effect of Antenatal Oral Vitamin D Supplementation on Serum 25(OH)D Concentration in Exclusively Breastfed Infants at 6 Months of age - A Randomized Double-Blind Placebo-Controlled Trial.

OBJECTIVE: To compare the proportion of exclusively breastfed (EBF) infants having severe vitamin D deficiency (25(OH)D concentration <11 ng/mL) at 6 months of age when mothers were supplemented with 300,000 IU vitamin D3 or placebo during the third trimester of pregnancy. METHODS: In this randomized double-blind placebo-controlled trial, we recruited 100 pregnant women (who were willing to exclu-sively breastfeed their babies for 6 months) at 30-32 weeks gestation and the infants born to them. Pregnant women were randomized to receive either oral vitamin D3 60,000 IU or placebo, given weekly for 5 weeks during the third trimester. Serum 25(OH)D, calcium, phosphorus and alkaline phosphatase concentration were measured in all participants at recruitment, in the cord blood at delivery, and in infants at 6 months of age. The proportion of infants developing severe vitamin D deficiency and rickets at 6 months was assessed. RESULTS: A total 72 mother-infant dyads were followed-up till 6 months. At enrollment, the mean (SD) serum 25(OH)D concentration (ng/mL) were comparable in mothers in the intervention and control groups [12.9 (5.8) vs 12.8 (5.9), P = 0.96]. The mean (SD) 25(OH)D concentration (ng/mL) in the cord blood was significantly higher in the intervention group compared to the control group [42.1 (17.1) vs 12.7 (6.3); P = 0.002]. Serum 25(OH)D levels (ng/mL) in the infants at 6 months age were higher in the intervention group compared to the control group [31.8 (10.9) vs 12.5 (5.7); P < 0.001]. No infant in the intervention group had severe vitamin D deficiency at 6 months age compared to 54.3% infants in the control group (P < 0.001). No infant in the intervention group developed rickets. CONCLUSION: Oral supplementation of vitamin D3 to pregnant women in the third trimester prevents severe hypovitaminosis D in the EBF infants at 6 months of age.

Epidemiological profile and clinical outcomes of very young (<35 years) and young (35-50 years) patients with STEMI: Insights from the NORIN STEMI registry.

BACKGROUND: Despite significant progress in primary prevention, rates of myocardial infarction (MI) in South Asian population is alarmingly high. OBJECTIVES: We sought to compare risk factor profiles and outcomes between individuals with ST-Segment Elevation Myocardial Infarction (STEMI) in young (<50 years) and old (≥50 years) age groups. METHODS: North India STEMI Registry (NORIN-STEMI) is a prospective observational registry of patients hospitalised with STEMI. We conducted a study of young patients (<50 years) regarding their risk factors for coronary artery disease (CAD), in-hospital and 30-day mortality and compared with their older counterpart. RESULTS: Among 5335 patients enrolled, 1752 (32.8%) were young and were 19 years younger than the older cohort. Major risk factors in young patients were physical inactivity (75.1%) and alcohol intake (67.8%). Higher prevalence of tobacco use (66.6% vs 52.4%), but lower prevalence of diabetes (16% vs 26.3%) and hypertension (18.5% vs 29.9%) were seen in young STEMI. Young patients were less likely to die both in-hospital (5.9% vs 10.0%) and at 30-days (11.1% vs 16.2%). Left ventricular ejection fraction (LVEF) < 30% at admission [OR: 8.00, 95% confidence interval (CI): 4.60-13.90, P < 0.001 in-hospital, OR: 3.92, 95% CI: 2.69-5.73 at 30-days] and female sex were strongest predictors of mortality. CONCLUSIONS: Young STEMI patients constituted one-third of total cohort. Most of them were tobacco consumers with lesser prevalence of diabetes and hypertension. They were less likely to die both in-hospital and at 30 days because of earlier presentation to a health care facility and hence a relatively preserved LVEF.

Percent Predicted Peak Exercise Oxygen Pulse Provides Insights Into Ventricular-Vascular Response and Prognosticates HFpEF.

Background: Peak oxygen consumption and oxygen pulse along with their respective percent predicted measures are gold standards of exercise capacity. To date, no studies have investigated the relationship between percent predicted peak oxygen pulse (%PredO2P) and ventricular-vascular response (VVR) and the association of %PredO2P with all-cause mortality in heart failure with preserved ejection fraction (HFpEF) patients. Objectives: The authors investigated the association between: 1) CPET measures of %PredO2P and VVR; and 2) %PredO2P and all-cause mortality in HFpEF patients. Methods: Our cohort of 154 HFpEF patients underwent invasive CPET and were grouped into %PredO2P tertiles. The association between percent predicted Fick components and markers of VVR (ie, proportionate pulse pressure, effective arterial elastance) was determined with correlation analysis. The Cox proportional hazards model was used to identify predictors of mortality. Results: The participants' mean age was 57 ± 15 years. Higher %PredO2P correlated with higher exercise capacity. In terms of VVR, higher %PredO2P correlated with a lower pressure for a given preload (effective arterial elastance r = -0.45, P < 0.001 and proportionate pulse pressure r = -0.22, P = 0.008). %PredO2P distinguished normal and abnormal percent predicted peak stroke volume and correlated positively with %PredVO2 (r = 0.61, P < 0.001). Participants had a median follow-up time of 5.6 years and 15% death. Adjusted for age and body mass index, there was a 5% relative reduction in mortality (HR: 0.95, 95% CI: 0.92-0.98, P = 0.003) for every percent increase in %PredO2P. Conclusions: In HFpEF, %PredO2P is a VVR marker that can stratify invasive parameters such as percent predicted peak stroke volume. %PredO2P is an independent prognostic marker for all-cause mortality and those with higher %PredO2P exhibited longer survival.

Adenosine kinase inhibition protects mice from abdominal aortic aneurysm via epigenetic modulation of VSMC inflammation.

AIM: Abdominal aortic aneurysm (AAA) is a common, serious vascular disease with no effective pharmacological treatment. The nucleoside adenosine plays an important role in modulating vascular homeostasis, which prompted us to determine whether adenosine kinase (ADK), an adenosine metabolizing enzyme, modulates AAA formation via control of intracellular adenosine level, and to investigate the underlying mechanisms. METHODS AND RESULTS: We used a combination of genetic and pharmacological approaches in murine models of AAA induced by calcium chloride (CaCl2) application or angiotensin II (Ang II) infusion to study the role of ADK in the development of AAA. In vitro functional assays were performed by knocking down ADK with adenovirus-short hairpin RNA in human vascular smooth muscle cells (VSMCs), and the molecular mechanisms underlying ADK function were investigated using RNA-sequencing, isotope tracing and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). Heterozygous deficiency of Adk protected mice from CaCl2- and Ang II-induced AAA formation. Moreover, specific knockout of Adk in VSMCs prevented Ang II-induced AAA formation, as evidenced by reduced aortic extracellular elastin fragmentation, neovascularization and aortic inflammation. Mechanistically, ADK knockdown in VSMCs markedly suppressed the expression of inflammatory genes associated with AAA formation, and these effects were independent of adenosine receptors. Metabolic flux and ChIP-qPCR results showed that ADK knockdown in VSMCs decreased S-adenosylmethionine (SAM)-dependent transmethylation, thereby reducing H3K4me3 binding to the promoter regions of the genes that are associated with inflammation, angiogenesis and extracellular elastin fragmentation. Furthermore, the ADK inhibitor ABT702 protected mice from CaCl2-induced aortic inflammation, extracellular elastin fragmentation and AAA formation. CONCLUSION: Our findings reveal a novel role for ADK inhibition in attenuating AAA via epigenetic modulation of key inflammatory genes linked to AAA pathogenesis.

Uncovering Unrecognized Heart Failure With Preserved Ejection Fraction Among Individuals With Obesity and Dyspnea.

BACKGROUND: Although heart failure with preserved ejection fraction (HFpEF) has become the predominant heart failure subtype, it remains clinically under-recognized. HFpEF diagnosis is particularly challenging in the setting of obesity given the limitations of natriuretic peptides and resting echocardiography. We examined invasive and noninvasive HFpEF diagnostic criteria among individuals with obesity and dyspnea without known cardiovascular disease to determine the prevalence of hemodynamic HFpEF in the community. METHODS: Research volunteers with dyspnea and obesity underwent resting echocardiography; participants with possible pulmonary hypertension qualified for invasive cardiopulmonary exercise testing. HFpEF was defined using rest or exercise pulmonary capillary wedge pressure criteria (≥15 mm Hg or Δpulmonary capillary wedge pressure/Δcardiac output slope, >2.0 mm Hg·L-1·min-1). RESULTS: Among n=78 participants (age, 53±13 years; 65% women; body mass index, 37.3±6.8 kg/m2), 40 (51%) met echocardiographic criteria to undergo invasive cardiopulmonary exercise testing. In total, 24 participants (60% among the cardiopulmonary exercise testing group, 31% among the total sample) were diagnosed with HFpEF by rest or exercise pulmonary capillary wedge pressure (n=12) or exercise criteria (n=12). There were no differences in NT-proBNP (N-terminal pro-B-type natriuretic peptide; 79 [62-104] versus 73 [57-121] pg/mL) or resting echocardiography (mitral E/e' ratio, 9.1±3.1 versus 8.0±2.7) among those with versus without HFpEF (P>0.05 for all). Distributions of HFpEF diagnostic scores were similar, with the majority classified as intermediate risk (100% versus 93.75% [H2FPEF] and 87.5% versus 68.75% [HFA-PEFF (Heart Failure Association Pretest assessment, echocardiography and natriuretic peptide, functional testing, and final etiology)] in those with versus without HFpEF). CONCLUSIONS: Among adults with obesity and dyspnea without known cardiovascular disease, at least a third had clinically unrecognized HFpEF uncovered on invasive cardiopulmonary exercise testing. Clinical, biomarker, resting echocardiography, and diagnostic scores were similar among those with and without HFpEF. These results suggest clinical underdiagnosis of HFpEF among individuals with obesity and dyspnea and highlight limitations of noninvasive testing in the identification of HFpEF.

Comparison of KingVision videolaryngoscope channelled blade with Tuoren videolaryngoscope non-channelled blade in a simulated COVID-19 intubation scenario by non-anaesthesiologists and experienced anaesthesiologists: A prospective randomised crossover mannequin study.

Purpose: A videolaryngoscope has been recommended for intubation in the COVID-19 scenario but the videolaryngoscope providing optimal intubation conditions is not ascertained. We compared KingVision channelled blade with a non-Channelled videolaryngoscope for intubation times in a simulated COVID-19 intubation scenario by both anaesthesiologists and non-anaesthesiologists. Methods: This prospective randomised cross over mannequin study was conducted in a skill training lab. 25 anaesthesiologists and 25 non-anaesthesiologists donned in standard personal protective equipment performed 100 intubations with KingVision and Tuoren videolaryngoscopes in a mannequin covered with a transparent plastic sheet. The total intubation time, percentage of glottic opening scores, first attempt success rates were assessed. Results: The mean difference in intubation times in anaesthesiologists and non-anaesthesiologist less with KingVision videolaryngoscope (21.1s; 95% CI 9.6-32.6s vs. 35.9s; 95% CI 24.4-47.4 s; P = 0.001). Percentage of glottic opening score was significantly better with KingVision by non-anaesthesiologists (60; IQR 42.5 to 75 vs. 70; IQR 50 to 100; P = 0.019). KingVision provided superior first attempt success rate in non-anaesthesiologists (84% vs. 61.9%; P = 0.02) and anaesthesiologists (96% vs. 76%; P = 0.12). Conclusion: KingVision channelled videolaryngoscope provided faster intubation times, glottic views and first attempt success rates in a simulated COVID-19 scenario in manikins and might be preferred over videolaryngoscopes with non-channelled blade. The findings need to be further verified in humans. Trial registration: ctri.nic.in identifier: REF/2020/05/033338.