Weaknesses in Experimental Design and Reporting Decrease the Likelihood of Reproducibility and Generalization of Recent Cardiovascular Research.

Recent evidence indicates that many clinical and preclinical studies are not reproducible. Prominent causes include design and implementation issues, low statistical power, unintentional bias, and incomplete reporting in the published literature. The primary goal of this study was to assess the quality of published research in three prominent cardiovascular research journals by examining statistical power and assessing the adherence to augmented ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments). For unpaired t-tests, the average median power for a 20% and 50% change was 0.27 ± 0.06 and 0.88 ± 0.08, respectively. For analysis of guidelines, 40 categories were assessed with a 0-2 scale. Although many strengths were observed, several key elements that were needed for reproducibility were inadequate, including differentiation of primary and secondary outcomes, power calculations for group size, allocation methods, use of randomization and blinding, checks for normality, reports of attrition, and adverse events of subjects, and assessment of bias. A secondary goal was to examine whether a required checklist improved the quality of reporting; those results indicated that a checklist improved compliance and quality of reporting, but adequacy levels in key categories were still too low. Overall, the findings of this study indicated that the probability for reproducibility of many clinical and preclinical cardiovascular research studies was low because of incomplete reporting, low statistical power, and lack of research practices that decrease experimental bias. Expansion of group sizes to increase power, use of detailed checklists, and closer monitoring for checklist adherence by editors and journals should remediate many of these deficits and increase the likelihood of reproducibility.

Validation of the STOP questionnaire as a screening tool for OSA among different populations: a systematic review and meta-regression analysis.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is a sleep breathing disorder associated with adverse health outcomes, but it remains largely underdiagnosed. The STOP questionnaire is a simple tool for screening OSA and is widely used in various populations. The objective of this study was to determine the predictive parameters of the STOP questionnaire to detect OSA in sleep clinics, medical population, surgical population, commercial drivers, and the general population. METHODS: Electronic databases were searched from January 2008 to April 2021. Pooled predictive parameters were recalculated using 2 × 2 contingency tables and random-effects meta-analyses were performed. The combined test characteristics at different OSA severities (any OSA [apnea-hypopnea index ≥ 5 events/h], moderate-to-severe OSA [apnea-hypopnea index ≥ 15 events/h], severe OSA [apnea-hypopnea index ≥ 30 events/h]) were used to compare the accuracy of the STOP questionnaire with polysomnography. The quality of the studies was evaluated using Cochrane Methods criteria. RESULTS: Twenty-four studies met the inclusion criteria: 16 were in the sleep clinic population (n = 8,132), 4 in the medical population (n = 1,023), 2 in the surgical population (n = 258), and 1 study each on commercial drivers (n = 85) and the general population (n = 4,770). A STOP score ≥ 2 showed excellent sensitivity to the different OSA severities for the sleep clinic population (> 89%) and to severe OSA for the medical population (85.6%). In both populations, the STOP questionnaire also had excellent discriminative power to exclude severe OSA (negative predictive values > 84%). The pooled sensitivity and negative predictive values for the surgical population with moderate-to-severe OSA was 81% and 75%. CONCLUSIONS: This meta-analysis suggests that the STOP questionnaire is a valid and effective screening tool for OSA among these populations. CITATION: Patel D, Tsang J, Saripella A, et al. Validation of the STOP questionnaire as a screening tool for OSA among different populations: a systematic review and meta-regression analysis. J Clin Sleep Med. 2022;18(5):1441-1453.

Employing Broadly Neutralizing Antibodies as a Human Immunodeficiency Virus Prophylactic & Therapeutic Application.

Despite the discovery that the human immunodeficiency virus 1 (HIV-1) is the pathogen of acquired immunodeficiency syndrome (AIDS) in 1983, there is still no effective anti-HIV-1 vaccine. The major obstacle to the development of HIV-1 vaccine is the extreme diversity of viral genome sequences. Nonetheless, a number of broadly neutralizing antibodies (bNAbs) against HIV-1 have been made and identified in this area. Novel strategies based on using these bNAbs as an efficacious preventive and/or therapeutic intervention have been applied in clinical. In this review, we summarize the recent development of bNAbs and its application in HIV-1 acquisition prevention as well as discuss the innovative approaches being used to try to convey protection within individuals at risk and being treated for HIV-1 infection.

Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria.

Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV via binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound 25, which has potent activity against Gram-positive bacteria, a favorable in vitro safety profile, and excellent in vivo pharmacokinetic properties. Compound 25 was found to be efficacious against fluoroquinolone-sensitive Staphylococcus aureus infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by topoisomerase IV from Klebsiella pneumoniae, compound 25, and cleaved DNA indicates that this compound does not engage in a water-metal ion bridge interaction and forms no direct contacts with residues in the quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on antibacterial activity of 25 compared to fluoroquinolones.

Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria.

Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1H)-ones, exemplified by 34, that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens. X-ray crystallography reveals that 34 occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex but does not form significant contacts with residues in the quinolone resistance determining region.

Estimation of critical end-test torque using neuromuscular electrical stimulation of the quadriceps in humans.

Characterization of critical power/torque (CP/CT) during voluntary exercise requires maximal effort, making difficult for those with neuromuscular impairments. To address this issue we sought to determine if electrically stimulated intermittent isometric exercise resulted in a critical end-test torque (ETT) that behaved similar to voluntary CT. In the first experiment participants (n = 9) completed four bouts of stimulated exercise at a 3:2 duty cycle, at frequencies of 100, 50, 25 Hz, and a low frequency below ETT (Sub-ETT; ≤ 15 Hz). The second experiment (n = 20) consisted of four bouts at a 2:2 duty cycle-two bouts at 100 Hz, one at an intermediate frequency (15-30 Hz), and one at Sub-ETT. The third experiment (n = 12) consisted of two bouts at 50 Hz at a 3:2 duty* cycle with proximal blood flow occlusion during one of the bouts. ETT torque was similar (p ≥ 0.43) within and among stimulation frequencies in experiment 1. No fatigue was observed during the Sub-ETT bouts (p > 0.05). For experiment 2, ETT was similar at 100 Hz and at the intermediate frequency (p ≥ 0.29). Again, Sub-ETT stimulation did not result in fatigue (p > 0.05). Altering oxygen delivery by altering the duty cycle (3:2 vs. 2:2; p = 0.02) and by occlusion (p < 0.001) resulted in lower ETT values. Stimulated exercise resulted in an ETT that was consistent from day-to-day and similar regardless of initial torque, as long as that torque exceeded ETT, and was sensitive to oxygen delivery. As such we propose it represents a parameter similar to voluntary CT.

Effect of structurally constrained oxime-ether linker on PPAR subtype selectivity: Discovery of a novel and potent series of PPAR-pan agonists.

A novel series of thaizole and oxazole containing phenoxy acetic acid derivatives is reported as PPAR-pan agonists. Incorporation of structurally constrained oxime-ether based linker in the chemotype of a potent PPARδ selective agonist GW-501516 was adapted as designing strategy. In vitro, selected test compounds 12a, 12c, 17a and 18a showed PPAR-pan agonists activities and among these four compounds tested, 12a emerged as highly potent and efficacious compound, while 17a exhibited moderate and balanced PPAR-pan agonistic activity. In vivo, selected test compounds 12a and 17a exhibited significant anti-hyperglycemic and anti-hyperlipidemic activities in relevant animal models. These results support our hypothesis that the introduction of structurally constrained oxime-ether linker between lipophilic tail and acidic head plays an important role in modulating subtype selectivity and subsequently led to the discovery of potent PPAR-pan agonists.

Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/γ dual agonist into α selective PPAR agonist through bioisosteric modification.

A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders.

Design and synthesis of novel bis-oximinoalkanoic acids as potent PPAR alpha agonists.

Bis-oximinoalkanoic acid derivatives were designed and synthesized to aid in the characterization of selective PPARalpha agonists by replacing the oxazole ring with flexible oximino group in the lipophilic tail part of a previously reported compound 3. Selected compounds 9d and 9m showed excellent potency and high selectivity towards PPARalpha in vitro. These compounds found effective in reducing serum triglycerides (TG) in vivo.