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.

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.

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.

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.

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.

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.

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.

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.

Systemic Arterial Oxygen Levels Differentiate Pre- and Post-capillary Predominant Hemodynamic Abnormalities During Exercise in Undifferentiated Dyspnea on Exertion.

BACKGROUND: Whether systemic oxygen levels (SaO2) during exercise can provide a window into invasively derived exercise hemodynamic profiles in patients with undifferentiated dyspnea on exertion is unknown. METHODS: We performed cardiopulmonary exercise testing with invasive hemodynamic monitoring and arterial blood gas sampling in individuals referred for dyspnea on exertion. Receiver operator analysis was performed to distinguish heart failure with preserved ejection fraction from pulmonary arterial hypertension. RESULTS: Among 253 patients (mean ± SD, age 63 ± 14 years, 55% female, arterial O2 [PaO2] 87 ± 14 mmHg, SaO2 96% ± 4%, resting pulmonary capillary wedge pressure [PCWP] 18 ± 4mmHg, and pulmonary vascular resistance [PVR] 2.7 ± 1.2 Wood units), there was no exercise PCWP threshold, measured up to 49 mmHg, above which hypoxemia was consistently observed. Exercise PaO2 was not correlated with exercise PCWP (rho = 0.04; P = 0.51) but did relate to exercise PVR (rho = -0.46; P < 0.001). Exercise PaO2 and SaO2 levels distinguished left-heart-predominant dysfunction from pulmonary-vascular-predominant dysfunction with an area under the curve of 0.89 and 0.89, respectively. CONCLUSION: Systemic O2 levels during exercise distinguish relative pre- and post-capillary pulmonary hemodynamic abnormalities in patients with undifferentiated dyspnea. Hypoxemia during upright exercise should not be attributed to isolated elevation in left heart filling pressures and should prompt consideration of pulmonary vascular dysfunction.

Clinical Utility of Infrapopliteal Calcium Score for the Evaluation of Severity of Peripheral Artery Disease.

PURPOSE: To identify associations between computed tomography (CT)-based lower-extremity calcium score (LECS) across different anatomic segments and the presence, severity, and clinical outcomes of peripheral artery disease (PAD). MATERIALS AND METHODS: In a mixed retrospective and prospective cohort study, 139 patients without prior lower-extremity intervention who underwent CT angiography of the aorta and lower extremities were identified. Subjects were classified as asymptomatic, claudicants, or having chronic limb-threatening ischemia (CLTI). LECS was measured using the Agatston method. Univariate and multivariate analyses were performed across categories of PAD severity. Receiver operating characteristic (ROC) analysis was performed, and an optimal cutoff point for LECS was identified. Claudicants were followed prospectively for CLTI and mortality. RESULTS: Higher infrapopliteal calcium score (CS) was independently associated with CLTI versus claudication (odds ratio [OR], 3.24 per unit increase in log10-transformed CS; P < .001) in addition to hemodialysis dependence and poor functional status. One hundred eighty-eight Agatston units was identified as the optimal cutoff for infrapopliteal CS in assessing the risk of CLTI versus claudication (area under the ROC curve, 0.84 [SD ± 0.049]). This cutoff was validated in an independent cohort to be associated with progression to CLTI (OR, 12.8; P = .0039). In the claudicant group followed prospectively, infrapopliteal CS ≥188 predicted increased risk of CLTI or death after adjusting for functional status and hemodialysis dependence (Cox hazard ratio, 4.92; P = .0202). CONCLUSIONS: Higher infrapopliteal CS was associated with CLTI among those with symptomatic PAD. An infrapopliteal CS cutoff of 188 Agatston units may serve as a useful tool to identify patients with increased risk of CLTI and mortality.

Treatment of calcific arterial disease via enhancement of autophagy using GSK343.

Vascular calcification is a hallmark of atherosclerotic disease and serves as a strong predictor and risk factor for cardiovascular events. Growing evidence suggests that autophagy may play a protective role in early atherosclerosis. The precise effects of autophagy on VSMC-mediated calcification remain unknown. In this study, we utilized multi-omic profiling to investigate impaired autophagy at the transcriptional level as a key driver of VSMC calcification. Our findings revealed that impaired autophagy is an essential determinant of VSMC calcification. We observed that an osteogenic environment affects the open chromatin status of VSMCs, compromising the transcriptional activation of autophagy initiation genes. In vivo experiments involve pharmacological and genetic activation of autophagy using mouse models of spontaneous large (Mgp-/-) and small (Abcc6-/-) artery calcification. Taken together, these data advance our mechanistic understanding of vascular calcification and provide important insights for a broad range of cardiovascular diseases involving VSMC phenotype switch.

Integrative single-cell meta-analysis reveals disease-relevant vascular cell states and markers in human atherosclerosis.

Coronary artery disease (CAD) is characterized by atherosclerotic plaque formation in the arterial wall. CAD progression involves complex interactions and phenotypic plasticity among vascular and immune cell lineages. Single-cell RNA-seq (scRNA-seq) studies have highlighted lineage-specific transcriptomic signatures, but human cell phenotypes remain controversial. Here, we perform an integrated meta-analysis of 22 scRNA-seq libraries to generate a comprehensive map of human atherosclerosis with 118,578 cells. Besides characterizing granular cell-type diversity and communication, we leverage this atlas to provide insights into smooth muscle cell (SMC) modulation. We integrate genome-wide association study data and uncover a critical role for modulated SMC phenotypes in CAD, myocardial infarction, and coronary calcification. Finally, we identify fibromyocyte/fibrochondrogenic SMC markers (LTBP1 and CRTAC1) as proxies of atherosclerosis progression and validate these through omics and spatial imaging analyses. Altogether, we create a unified atlas of human atherosclerosis informing cell state-specific mechanistic and translational studies of cardiovascular diseases.

Quality of Life of Developmentally Normal Children With Epilepsy and Their Siblings.

BACKGROUND: Quality of life (QOL) is a fundamental and multidimensional concept that should be considered with health problems, specifically chronic diseases, such as epilepsy. There have been limited studies on how pediatric epilepsy impacts the QOL of siblings of affected individuals. Hence, we studied the impact of epilepsy on the QOL of affected children and their siblings. OBJECTIVE: This study aimed to assess the QOL of developmentally normal children with epilepsy and their siblings and the association of QOL scores with the clinicodemographic profile. METHODS: This study was conducted at the University College of Medical Sciences and Guru Tegh Bahadur Hospital, New Delhi, India, a tertiary care hospital. The QOL of children (4-12 years) with epilepsy was assessed using epilepsy-specific questionnaires, i.e., Quality of Life in Childhood Epilepsy Questionnaire-55 (QOLCE-55), which covers the cognitive, emotional, social, and physical domains, and Pediatric Quality of Life Epilepsy Module (Peds QL EM), which covers the impact, cognitive, sleep, executive, and mood/ behavior domains. QOL in siblings was assessed using the Peds QL Inventory, which covers the following domains: physical, emotional, social, and school. The principal investigator administered these questionnaires to parents in Hindi/ English. Scoring was done as per standard instructions of the questionnaire. Clinical and demographic data were recorded in a pro forma. RESULT: The median QOLCE-55 score was 81.12, with a range of 74.65-86.34, and the median Peds QL EM score was 89.31, with a range of 75.58-94.48. Overall, Cronbach's alpha of QOLCE-55 and Peds QL EM was >0.8. Breakthrough seizures (≥10) affected the overall QOL (p=0.001) and all domains of QOLCE-55 (except emotional function (p=0.44)) and Peds QL EM (except sleep/fatigue domain (p=0.59)). Age, sex, parental education, socioeconomic status, and type of epilepsy did not affect the overall QOL (p>0.05). The QOL of siblings was not affected as per the Peds QL Inventory score (median score 100) and self-made questionnaire. CONCLUSION: Our results suggest that the QOL of children with epilepsy was compromised, whereas the QOL of their siblings was not affected.

Tumour-infiltrating lymphocyte subsets and their individual prognostic impact in oral squamous cell carcinoma.

AIMS: Current understanding of oral squamous cell carcinoma (OSCC) is incomplete with regard to prognostic factors that lead to the considerable heterogeneity in treatment response and patient outcomes. We aimed to evaluate the impact of individual tumour-infiltrating lymphocyte (TIL) subsets on prognosis as a possible rationale for this, in a retrospective observational study. METHODS: Immunohistochemistry was performed to quantitatively assess cell densities of CD3+, CD20+, CD4+, CD8+ and FOXP3+TIL subsets in 50 surgically treated OSCC cases. Results were correlated with disease-free survival (DFS) and overall survival (OS). Receiver operating characteristic curve analysis and Youden index were applied to determine prognostically significant cut-off values. RESULTS: Mean counts for CD3+, CD4+, CD8+, CD20+ and FOXP3+TILs were 243, 52, 132, 53 and 116 cells per high power field, respectively. High CD8+ and low FOXP3+TIL counts, and high ratio of CD8:FOXP3 were significantly associated with longer DFS and OS, as well as with improved tumour-host interface parameters. CONCLUSIONS: Host immune response and its interaction with cancer cells have a significant impact on OSCC outcomes, with some TIL subsets being more clinically relevant than others. High cytotoxic T-cell (CD8) and low Treg (FOXP3) counts, and high cytotoxic T-cell to Treg (CD8:FOXP3) ratio are significantly associated with favourable prognosis. These results may serve as a leading point in identifying novel therapeutic agents that can redesign the tumour immune microenvironment by reducing infiltrating FOXP3-lymphocytes, and modifying their signalling pathways.

Development and Validation of Total Pain Scale for Evaluation of Total Pain in Cancer Patients.

Objectives: Cancer pain has all the components of total pain such as physical, social, psychological, and spiritual. These components contribute to the overall pain experience in cancer patients. Many instruments have been developed till date to assess the effect of pain in cancer patients but none of the instruments include all components of total pain. In this article, we describe the development and validation of the total pain scale (TPS) for the evaluation of total pain in cancer patients with pain. This study aimed to develop and validate a questionnaire for the evaluation of total pain in cancer patients with pain. Material and Methods: This study included a review of existing pain questionnaires for cancer pain for item pool generation. Items were generated in the Hindi language by six stakeholders to create 23 items to develop TPS. TPS was applied to 300 Hindi-speaking cancer patients. Bivariate correlation was used to reduce the number of items as well as construction of the domain followed by factor analysis to finalise TPS. Confirmatory factor analysis (CFA) was performed for testing the validity and reliability of TPS. Results: TPS is an 18-item scale composed of four domains (physical, social, spiritual and psychological domain). The internal consistency of TPS and its subscales was found to be very good (a = 0.84-0.88). CFA and structural equation modeling Goodness of fit has confirmed that model 4 is the best fit as it yielded a lesser root-mean-squared error of approximation value of 0.062 and a greater comparative fit index, Tucker-Lewis index value of 0.944. The convergent and divergent validity of TPS and its domain was good. Conclusion: This study reports TPS to be a brief (18-item), valid, and reliable questionnaire in the Hindi language for assessment of all components of total pain in cancer patients with pain.

Obesity-Related Biomarkers Are Associated With Exercise Intolerance and HFpEF.

BACKGROUND: Obesity and adiposity are associated with an increased risk of heart failure with preserved ejection fraction (HFpEF); yet, specific underlying mechanisms remain unclear. We sought to examine the association of obesity-related biomarkers including adipokines (leptin, resistin, adiponectin), inflammatory markers (CRP [C-reactive protein], IL-6 [interleukin-6]), and insulin resistance (HOMA-IR) with HFpEF status, exercise capacity, and cardiovascular outcomes. METHODS: We studied 509 consecutive patients with left ventricular ejection fraction ≥50% and chronic dyspnea, who underwent clinically indicated cardiopulmonary exercise test with invasive hemodynamic monitoring between 2006 and 2017. We defined HFpEF based on the presence of elevated left ventricular filling pressures at rest or during exercise. Fasting blood samples collected at the time of the cardiopulmonary exercise test were used to assay obesity-related biomarkers. We examined the association of log-transformed biomarkers with HFpEF status and exercise traits using multivariable-adjusted logistic regression models. RESULTS: We observed associations of obesity-related biomarkers with measures of impaired exercise capacity including peak VO2 (P≤0.002 for all biomarkers). The largest effect size was seen with leptin, where a 1-SD higher leptin was associated with a 2.35 mL/kg per min lower peak VO2 (ß, -2.35±0.19; P<0.001). In addition, specific biomarkers were associated with distinct measures of exercise reserve including blood pressure (homeostatic model assessment of insulin resistance, leptin, adiponectin; P≤0.002 for all), and chronotropic response (CRP, IL-6, homeostatic model assessment of insulin resistance, leptin, and resistin; P<0.05 for all). Our findings suggest that among the obesity-related biomarkers studied, higher levels of leptin and CRP are independently associated with increased odds of HFpEF, with odds ratios of 1.36 (95% CI, 1.09-1.70) and 1.25 (95% CI, 1.03-1.52), respectively. CONCLUSIONS: Specific obesity-related pathways including inflammation, adipokine signaling, and insulin resistance may underlie the association of obesity with HFpEF and exercise intolerance.

Minimum effective dose of oxytocin bolus during the caesarean section for patients at high vs low risk of uterine atony: A non-randomized, dual-arm, dose-finding prospective trial.

Background and Aims: There are scanty data for oxytocin dose in patients at high risk of uterine atony. We aimed to compare the effective dose (ED) 90 of oxytocin for adequate uterine tone during the caesarean section in patients at high-risk vs low-risk uterine atony. Methods: This dose-finding study was undertaken after ethical approval in non-labouring women aged >18 years with pre-defined risk factors for uterine atony (high-risk group) vs those without such factors (low-risk group) (n = 39 each). Starting dose of oxytocin in the first patient of low-risk and high-risk groups was 1 and 3 IU, respectively. Achieving adequate uterine tone at 3 min of oxytocin bolus was designated 'success', while inadequate tone constituted 'failure'. If the response was 'failure', the dose of oxytocin was increased for the next patient by 0.5 or 0.2 IU (high- and low-risk groups, respectively). In case of a successful response, the dose for the next patient was decreased with a probability of 1/9 using the same dosing intervals or otherwise kept unchanged. Results: The ED90 (95% CI) of oxytocin bolus was 4.7 (3.3-6.0) IU for the high-risk group and 2.2 (1.3-3.2) IU for the low-risk group (P = 0.044). Oxytocin-associated tachycardia (P = 0.247) and hypotension (P = 0.675) were clinically greater for the high-risk vs low-risk group but statistically similar. Conclusion: Non-labouring patients with high-risk factors for uterine atony require a greater dose of initial oxytocin bolus to achieve adequate uterine tone during the caesarean section compared to those without risk factors.