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.

Continuous, but not intermittent, regimens of hypoxia prevent and reverse ataxia in a murine model of Friedreich's ataxia.

Friedreich's ataxia (FA) is a devastating, multi-systemic neurodegenerative disease affecting thousands of people worldwide. We previously reported that oxygen is a key environmental variable that can modify FA pathogenesis. In particular, we showed that chronic, continuous normobaric hypoxia (11% FIO2) prevents ataxia and neurological disease in a murine model of FA, although it did not improve cardiovascular pathology or lifespan. Here, we report the pre-clinical evaluation of seven 'hypoxia-inspired' regimens in the shFxn mouse model of FA, with the long-term goal of designing a safe, practical and effective regimen for clinical translation. We report three chief results. First, a daily, intermittent hypoxia regimen (16 h 11% O2/8 h 21% O2) conferred no benefit and was in fact harmful, resulting in elevated cardiac stress and accelerated mortality. The detrimental effect of this regimen is likely owing to transient tissue hyperoxia that results when daily exposure to 21% O2 combines with chronic polycythemia, as we could blunt this toxicity by pharmacologically inhibiting polycythemia. Second, we report that more mild regimens of chronic hypoxia (17% O2) confer a modest benefit by delaying the onset of ataxia. Third, excitingly, we show that initiating chronic, continuous 11% O2 breathing once advanced neurological disease has already started can rapidly reverse ataxia. Our studies showcase both the promise and limitations of candidate hypoxia-inspired regimens for FA and underscore the need for additional pre-clinical optimization before future translation into humans.

FHL5 Controls Vascular Disease-Associated Gene Programs in Smooth Muscle Cells.

BACKGROUND: Genome-wide association studies have identified hundreds of loci associated with common vascular diseases, such as coronary artery disease, myocardial infarction, and hypertension. However, the lack of mechanistic insights for many GWAS loci limits their translation into the clinic. Among these loci with unknown functions is UFL1-four-and-a-half LIM (LIN-11, Isl-1, MEC-3) domain 5 (FHL5; chr6q16.1), which reached genome-wide significance in a recent coronary artery disease/ myocardial infarction GWAS meta-analysis. UFL1-FHL5 is also associated with several vascular diseases, consistent with the widespread pleiotropy observed for GWAS loci. METHODS: We apply a multimodal approach leveraging statistical fine-mapping, epigenomic profiling, and ex vivo analysis of human coronary artery tissues to implicate FHL5 as the top candidate causal gene. We unravel the molecular mechanisms of the cross-phenotype genetic associations through in vitro functional analyses and epigenomic profiling experiments in coronary artery smooth muscle cells. RESULTS: We prioritized FHL5 as the top candidate causal gene at the UFL1-FHL5 locus through expression quantitative trait locus colocalization methods. FHL5 gene expression was enriched in the smooth muscle cells and pericyte population in human artery tissues with coexpression network analyses supporting a functional role in regulating smooth muscle cell contraction. Unexpectedly, under procalcifying conditions, FHL5 overexpression promoted vascular calcification and dysregulated processes related to extracellular matrix organization and calcium handling. Lastly, by mapping FHL5 binding sites and inferring FHL5 target gene function using artery tissue gene regulatory network analyses, we highlight regulatory interactions between FHL5 and downstream coronary artery disease/myocardial infarction loci, such as FOXL1 and FN1 that have roles in vascular remodeling. CONCLUSIONS: Taken together, these studies provide mechanistic insights into the pleiotropic genetic associations of UFL1-FHL5. We show that FHL5 mediates vascular disease risk through transcriptional regulation of downstream vascular remodeling gene programs. These transacting mechanisms may explain a portion of the heritable risk for complex vascular diseases.

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.

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.

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.

Molecular Mechanisms of Vascular Health: Insights From Vascular Aging and Calcification.

Cardiovascular disease is the most common cause of death worldwide, especially beyond the age of 65 years, with the vast majority of morbidity and mortality due to myocardial infarction and stroke. Vascular pathology stems from a combination of genetic risk, environmental factors, and the biologic changes associated with aging. The pathogenesis underlying the development of vascular aging, and vascular calcification with aging, in particular, is still not fully understood. Accumulating data suggests that genetic risk, likely compounded by epigenetic modifications, environmental factors, including diabetes and chronic kidney disease, and the plasticity of vascular smooth muscle cells to acquire an osteogenic phenotype are major determinants of age-associated vascular calcification. Understanding the molecular mechanisms underlying genetic and modifiable risk factors in regulating age-associated vascular pathology may inspire strategies to promote healthy vascular aging. This article summarizes current knowledge of concepts and mechanisms of age-associated vascular disease, with an emphasis on vascular calcification.

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.

Gestational diabetes mellitus in early pregnancy amongst Asian Indian women: Evidence for poor pregnancy outcomes despite treatment.

AIM: To compare the pregnancy outcomes in women with gestational diabetes (GDM) based on the timing of diagnosis. METHODS: This retrospective cohort study was conducted between January 2011 and September 2017 amongst 2638 Asian Indian pregnant women. The inclusion criteria included; singleton pregnancies having HbA1c <48 mmols/mol (6.5%) in the first trimester, GDM screening by 75 g OGTT using IADPSG criteria and delivery at our centre. The cohort was divided into 3 groups: Early GDM (E-GDM)-diagnosis <24 gestational weeks (Gw), Standard GDM (S-GDM)-diagnosis ≥24Gw, Non-GDM- No GDM ≥24 Gw. Multivariable logistic regression models compared the pregnancy outcomes between Non-GDM, S-GDM and E-GDM groups. A sub-group multivariable analysis was done amongst GDM women using gestational age at diagnosis both as a categorical and continuous variable. RESULTS: Compared to Non-GDM women, the odds were higher for premature birth, large for gestational age (LGA) babies, macrosomia, Neonatal ICU(NICU) admission and lower for normal vaginal delivery in the E-GDM group, but for the S-GDM group, the risk was higher for premature birth, LGA babies, NICU admission and induction of labour. Compared to GDM women in the 24-28 Gw category significantly higher odds for premature birth and LGA babies were observed in the <14 Gw category. A continuous increase of 19% odds for premature birth with every 4 weeks decrease in gestational age at GDM diagnosis was observed. CONCLUSIONS: Asian Indian women having a GDM diagnosis before 24Gw are at higher risk for adverse pregnancy events than those having diagnosis ≥24Gw or not having GDM.

Intravenous sodium thiosulphate for vascular calcification of hemodialysis patients-a systematic review and meta-analysis.

BACKGROUND: Vascular calcification (VC) is a common comorbidity among patients with chronic kidney disease (CKD), indicating major cardiovascular events. This study aimed to evaluate the effects and safety of intravenous sodium thiosulphate (STS) for VC in CKD patients. METHODS: Electronic databases were searched for clinical trials that provided data comparing outcomes among patients treated with and without STS. The PRISMA guidelines were followed. Efficacy was assessed using calcification scores and arterial stiffness. Safety was examined by analyzing adverse symptoms, electrolytes and bone mineral density (BMD). Random-effects models were performed. Meta-regression and sensitivity analysis were done. The risk of bias was assessed using the Cochrane tools. RESULTS: Among the 5601 publications, 6 studies involving 305 participants (mean age: 56 years, male: 56.6%) with all participants on maintenance hemodialysis met eligibility criteria. For efficacy, the progression in Agatston scores in the coronary arteries [107 patients, mean difference (MD): -241.27, 95% confidence interval (95% CI): -421.50 to -61.03] and iliac arteries (55 patients, MD: -382.00, 95% CI: -751.07 to -12.93) was lower in the STS treated group compared with controls. The increase in pulse wave velocity was lower in the STS group (104 patients, MD: -1.29 m/s, 95% CI: -2.24 to -0.34 m/s). No association was found between the change in calcification scores and STS regimen. For safety, gastrointestinal symptoms (e.g. nausea) and increased anion gap acidosis were noted. No reduction in BMD by STS was observed. CONCLUSIONS: Intravenous STS may attenuate the progression of VC and arterial stiffness in hemodialysis patients. Large and well-designed randomized controlled trials are warranted.

Matrix Gla Protein Levels Are Associated With Arterial Stiffness and Incident Heart Failure With Preserved Ejection Fraction.

OBJECTIVE: Arterial stiffness is a risk factor for cardiovascular disease, including heart failure with preserved ejection fraction (HFpEF). MGP (matrix Gla protein) is implicated in vascular calcification in animal models, and circulating levels of the uncarboxylated, inactive form of MGP (ucMGP) are associated with cardiovascular disease-related and all-cause mortality in human studies. However, the role of MGP in arterial stiffness is uncertain. Approach and Results: We examined the association of ucMGP levels with vascular calcification, arterial stiffness including carotid-femoral pulse wave velocity (PWV), and incident heart failure in community-dwelling adults from the Framingham Heart Study. To further investigate the link between MGP and arterial stiffness, we compared aortic PWV in age- and sex-matched young (4-month-old) and aged (10-month-old) wild-type and Mgp+/- mice. Among 7066 adults, we observed significant associations between higher levels of ucMGP and measures of arterial stiffness, including higher PWV and pulse pressure. Longitudinal analyses demonstrated an association between higher ucMGP levels and future increases in systolic blood pressure and incident HFpEF. Aortic PWV was increased in older, but not young, female Mgp+/- mice compared with wild-type mice, and this augmentation in PWV was associated with increased aortic elastin fiber fragmentation and collagen accumulation. CONCLUSIONS: This translational study demonstrates an association between ucMGP levels and arterial stiffness and future HFpEF in a large observational study, findings that are substantiated by experimental studies showing that mice with Mgp heterozygosity develop arterial stiffness. Taken together, these complementary study designs suggest a potential role of therapeutically targeting MGP in HFpEF.

Comparative evaluation of King Vision videolaryngoscope channeled and non-channeled blades with direct laryngoscope for intubation performance and skill retention by medical students: a randomized cross over two period study.

PURPOSE: A videolaryngoscope(VL) with an intubation conduit like KingVision channeled(KVC) blade may provide an added advantage over a non-channeled VL like a KingVision non-channeled (KVNC) blade and direct laryngoscope (DL) for acquiring and retention of intubation skills, especially in novices. METHODS: In this prospective two-period randomized crossover trial, one hundred medical students used three laryngoscopes KVC, KVNC and DL for intubation following standardized training with the study devices using a Laerdal Airway Management Trainer. After one month, all participants attempted intubation, in the same manner, using all devices. The duration of intubation, modified Cormack-Lehane (CL) grade, percentage of glottic opening (POGO) score, first-attempt success, number of attempts, ease of intubation and dental trauma was recorded. The retention of intubation skills after 1 month was also assessed on the same parameters. RESULTS: Median intubation times of KVC and DL were comparable and significantly better than KVNC (P < 0.001). The median POGO score was better with both videolaryngoscopes when compared with DL. The ease of intubation (P < 0.0012) and first-attempt success rate (P = 0.001) at the time '0' was significantly better with KVC compared to KVNC and DL. KVC fared better with respect to these intubation parameters during intubation after one month as well. CONCLUSION: KVC performed better in terms of time to intubation, success rate and ease of procedure as compared to KVNC and DL, both for acquisition and retention of skill. Hence, we advocate that KVC should be the preferred device over KVNC and DL for teaching intubation skills to novices.

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.

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.

Arterial Stiffness and Vascular Load in HFpEF: Differences Among Women and Men.

BACKGROUND: Mechanisms underlying sex differences in heart failure with preserved ejection fraction (HFpEF) are poorly understood. We sought to examine sex differences in measures of arterial stiffness and the association of arterial stiffness measures with left ventricular hemodynamic responses to exercise in men and women. METHODS: We studied 83 men (mean age 62 years) and 107 women (mean age 59 years) with HFpEF who underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring and arterial stiffness measurement (augmentation pressure [AP], augmentation index [AIx], and aortic pulse pressure [AoPP]). Sex differences were compared using multivariable linear regression. We examined the association of arterial stiffness with abnormal left ventricular diastolic response to exercise, defined as a rise in pulmonary capillary wedge pressure relative to cardiac output (∆PCWP/∆CO) ≥ 2 mmHg/L/min by using logistic regression models. RESULTS: Women with HFpEF had increased arterial stiffness compared with men. AP was nearly 10 mmHg higher, and AIx was more than 10% higher in women compared with men (P < 0.0001 for both). Arterial stiffness measures were associated with a greater pulmonary capillary wedge pressure response to exercise, particularly among women. A 1-standard deviation higher AP was associated with > 3-fold increased odds of abnormal diastolic exercise response (AP: OR 3.16, 95% CI 1.34-7.42; P = 0.008 [women] vs OR 2.07, 95% CI 0.95-5.49; P = 0.15 [men]) with similar findings for AIx and AoPP. CONCLUSIONS: Arterial stiffness measures are significantly higher in women with HFpEF than in men and are associated with abnormally steep increases in pulmonary capillary wedge pressure with exercise, particularly in women. Arterial stiffness may preferentially contribute to abnormal diastolic function during exercise in women with HFpEF compared with men.

UBA6 and NDFIP1 regulate the degradation of ferroportin.

Hepcidin regulates iron homeostasis by controlling the level of ferroportin, the only membrane channel that facilitates export of iron from within cells. Binding of hepcidin to ferroportin induces the ubiquitination of ferroportin at multiple lysine residues and subsequently causes the internalization and degradation of the ligand-channel complex within lysosomes. The objective of this study was to identify components of the ubiquitin system that are involved in ferroportin degradation. A HepG2 cell line, which inducibly expresses ferroportingreen fluorescent protein (FPN-GFP), was established to test the ability of small interfering (siRNA) directed against components of the ubiquitin system to prevent BMP6- and exogenous hepcidin-induced ferroportin degradation. Of the 88 siRNA directed against components of the ubiquitin pathway that were tested, siRNA-mediated depletion of the alternative E1 enzyme UBA6 as well as the adaptor protein NDFIP1 prevented BMP6- and hepcidin-induced degradation of ferroportin in vitro. A third component of the ubiquitin pathway, ARIH1, indirectly inhibited ferroportin degradation by impairing BMP6-mediated induction of hepcidin. In mice, the AAV-mediated silencing of Ndfip1 in the murine liver increased the level of hepatic ferroportin and increased circulating iron. The results suggest that the E1 enzyme UBA6 and the adaptor protein NDFIP1 are involved in iron homeostasis by regulating the degradation of ferroportin. These specific components of the ubiquitin system may be promising targets for the treatment of iron-related diseases, including iron overload and anemia of inflammation.

Nitric oxide: Clinical applications in critically ill patients.

Inhaled nitric oxide (iNO) acts as a selective pulmonary vasodilator and it is currently approved by the FDA for the treatment of persistent pulmonary hypertension of the newborn. iNO has been demonstrated to effectively decrease pulmonary artery pressure and improve oxygenation, while decreasing extracorporeal life support use in hypoxic newborns affected by persistent pulmonary hypertension. Also, iNO seems a safe treatment with limited side effects. Despite the promising beneficial effects of NO in the preclinical literature, there is still a lack of high quality evidence for the use of iNO in clinical settings. A variety of clinical applications have been suggested in and out of the critical care environment, aiming to use iNO in respiratory failure and pulmonary hypertension of adults or as a preventative measure of hemolysis-induced vasoconstriction, ischemia/reperfusion injury and as a potential treatment of renal failure associated with cardiopulmonary bypass. In this narrative review we aim to present a comprehensive summary of the potential use of iNO in several clinical conditions with its suggested benefits, including its recent application in the scenario of the COVID-19 pandemic. Randomized controlled trials, meta-analyses, guidelines, observational studies and case-series were reported and the main findings summarized. Furthermore, we will describe the toxicity profile of NO and discuss an innovative proposed strategy to produce iNO. Overall, iNO exhibits a wide range of potential clinical benefits, that certainly warrants further efforts with randomized clinical trials to determine specific therapeutic roles of iNO.

Post-cardiac arrest Sedation Promotes Electroencephalographic Slow-wave Activity and Improves Survival in a Mouse Model of Cardiac Arrest.

BACKGROUND: Patients resuscitated from cardiac arrest are routinely sedated during targeted temperature management, while the effects of sedation on cerebral physiology and outcomes after cardiac arrest remain to be determined. The authors hypothesized that sedation would improve survival and neurologic outcomes in mice after cardiac arrest. METHODS: Adult C57BL/6J mice of both sexes were subjected to potassium chloride-induced cardiac arrest and cardiopulmonary resuscitation. Starting at the return of spontaneous circulation or at 60 min after return of spontaneous circulation, mice received intravenous infusion of propofol at 40 mg · kg-1 · h-1, dexmedetomidine at 1 µg · kg-1 · h-1, or normal saline for 2 h. Body temperature was lowered and maintained at 33°C during sedation. Cerebral blood flow was measured for 4 h postresuscitation. Telemetric electroencephalogram (EEG) was recorded in freely moving mice from 3 days before up to 7 days after cardiac arrest. RESULTS: Sedation with propofol or dexmedetomidine starting at return of spontaneous circulation improved survival in hypothermia-treated mice (propofol [13 of 16, 81%] vs. no sedation [4 of 16, 25%], P = 0.008; dexmedetomidine [14 of 16, 88%] vs. no sedation [4 of 16, 25%], P = 0.002). Mice receiving no sedation exhibited cerebral hyperemia immediately after resuscitation and EEG power remained less than 30% of the baseline in the first 6 h postresuscitation. Administration of propofol or dexmedetomidine starting at return of spontaneous circulation attenuated cerebral hyperemia and increased EEG slow oscillation power during and early after sedation (40 to 80% of the baseline). In contrast, delayed sedation failed to improve outcomes, without attenuating cerebral hyperemia and inducing slow-wave activity. CONCLUSIONS: Early administration of sedation with propofol or dexmedetomidine improved survival and neurologic outcomes in mice resuscitated from cardiac arrest and treated with hypothermia. The beneficial effects of sedation were accompanied by attenuation of the cerebral hyperemic response and enhancement of electroencephalographic slow-wave activity.

Effective Dose of Prophylactic Oxytocin Infusion During Cesarean Delivery in 90% Population of Nonlaboring Patients With Preeclampsia Receiving Magnesium Sulfate Therapy and Normotensives: An Up-Down Sequential Allocation Dose-Response Study.

BACKGROUND: Oxytocin administration during cesarean delivery is the first-line therapy for the prevention of uterine atony. Patients with preeclampsia may receive magnesium sulfate, a drug with known tocolytic effects, for seizure prophylaxis. However, no study has evaluated the minimum effective dose of oxytocin during cesarean delivery in women with preeclampsia. METHODS: This study compared the effective dose in 90% population (ED90) of oxytocin infusion for achieving satisfactory uterine tone during cesarean delivery in nonlaboring patients with preeclampsia who were receiving magnesium sulfate treatment with a control group of normotensives who were not receiving magnesium sulfate. This prospective dual-arm dose-finding study was based on a 9:1 biased sequential allocation design. Oxytocin infusion was initiated at 13 IU/h, on clamping of the umbilical cord, in the first patient of each group. Uterine tone was graded as satisfactory or unsatisfactory by the obstetrician at 4 minutes after initiation of oxytocin infusion. The dose of oxytocin infusion for subsequent patients was decided according to the response exhibited by the previous patient in the group; it was increased by 2 IU/h after unsatisfactory response or decreased by 2 IU/h or maintained at the same level after satisfactory response, in a ratio of 1:9. Oxytocin-associated side effects were also evaluated. Dose-response data for the groups were evaluated using a log-logistic function and ED90 estimates were derived from fitted equations using the delta method. RESULTS: The ED90 of oxytocin was significantly greater for the preeclampsia group (n = 27) than for the normotensive group (n = 40) (24.9 IU/h [95% confidence interval {CI}, 22.4-27.5] and 13.9 IU/h [95% CI, 12.4-15.5], respectively); the difference in dose requirement was 10.9 IU/h (95% CI, 7.9-14.0; P < .001). The number of patients with oxytocin-related hypotension, defined as a decrease in systolic blood pressure >20% from baseline or to <90 mm Hg, was significantly greater in the preeclampsia group (92.6% vs 62.5%; P = .030), while other side effects such as ST-T depression, nausea/vomiting, headache, and flushing, were not significantly different. There was no significant difference in the need for additional uterotonic or uterine massage, estimated blood loss, and need for re-exploration for uncontrolled bleeding. CONCLUSIONS: Patients with preeclampsia receiving preoperative magnesium therapy need a greater intraoperative dose of oxytocin to achieve satisfactory contraction of the uterus after fetal delivery, as compared to normotensives.