Category: Nevin Manimala

Horm Mol Biol Clin Investig. 2021 Mar 5. doi: 10.1515/hmbci-2020-0097. Online ahead of print.

ABSTRACT

OBJECTIVES: Prader-Willi syndrome (PWS) is a rare genetic syndrome characterized by hyperphagia and early development of morbid obesity. Cardiovascular disease (CVD) and metabolic syndrome (MetS) are major comorbidities in these patients leading to premature death. Inhibitory factor 1 (IF₁) works as a regulatory protein, inhibiting the ATP hydrolase activity of mitochondrial ATP synthase and likely playing a role in lipid metabolism. We aimed to assay IF₁ in adult patients with PWS evaluating any relationship with clinical, genetic and biochemical parameters.

METHODS: We recruited 35 adult patients with genetically confirmed PWS.

RESULTS: IF₁ serum concentration displayed a normal distribution with an average value of 70.7 ± 22.6 pg/mL, a median value of 66.1 pg/mL. It was above the reference range only in one patient. All parameters were compared from both sides of IF₁ median without displaying any significant differences. Patients with normal or low HDL-cholesterol did not present any difference as regards IF₁ levels, which were not different between patients with and without MetS. Non-esterified fatty acids (NEFA) serum levels (r=0.623; p<0.001) showed a statistically significant correlation with IF₁. Cholesterol and its fractions did not present any correlation with IF_1.

CONCLUSIONS: In this study we do not confirm that HDL-cholesterol and IF₁ are correlated, but we show that in adult PWS patients, NEFA are correlated with serum IF_1. This protein could play a role to some extent in determining the complex metabolic alterations in PWS patients.

PMID:33675216 | DOI:10.1515/hmbci-2020-0097

Diagnosis (Berl). 2021 Mar 5. doi: 10.1515/dx-2020-0139. Online ahead of print.

ABSTRACT

OBJECTIVES: Diagnostic Management Teams (DMTs) are one strategy for reducing diagnostic errors. This study examined errors in serology test selection after a positive antinuclear antibody (ANA) test in patients with suspected systemic autoimmune rheumatic disorder (SARD).

METHODS: This retrospective study included 246 patient cases reviewed by our ANA DMT from March to August 2019. The DMT evaluated the appropriateness of tests beyond ANA screening tests (overutilization, underutilization, or both) based on American College of Rheumatology recommendations and classified cases into diagnostic error or no error groups. Errors were quantified, and patient and provider characteristics associated with diagnostic errors were assessed.

RESULTS: Among 246 cases, 60.6% had at least one diagnostic error in test selection. The number of sub-serology tests ordered was 2.4 times higher in the diagnostic error group than in the no error group. The likelihood of at least one diagnostic error was higher in males and African American/Black patients, although the differences were not statistically significant. Providers from general internal medicine, primary care, and non-rheumatology specialties were approximately two times more likely to make diagnostic errors than rheumatology specialists.

CONCLUSIONS: Diagnostic errors in test selection after a positive ANA for patients with suspected SARD were common, although there were fewer errors when ordered by rheumatology specialists. These findings support the need to develop strategies to reduce diagnostic errors in test selection for autoimmunity evaluation and suggest that implementation of a DMT can be useful for providing guidance to clinicians to reduce overutilization and underutilization of laboratory tests.

PMID:33675217 | DOI:10.1515/dx-2020-0139

Pharm Stat. 2021 Mar 6. doi: 10.1002/pst.2106. Online ahead of print.

ABSTRACT

Regulatory agencies typically evaluate the efficacy and safety of new interventions and grant commercial approval based on randomized controlled trials (RCTs). Other major healthcare stakeholders, such as insurance companies and health technology assessment agencies, while basing initial access and reimbursement decisions on RCT results, are also keenly interested in whether results observed in idealized trial settings will translate into comparable outcomes in real world settings-that is, into so-called “real world” effectiveness. Unfortunately, evidence of real world effectiveness for new interventions is not available at the time of initial approval. To bridge this gap, statistical methods are available to extend the estimated treatment effect observed in a RCT to a target population. The generalization is done by weighting the subjects who participated in a RCT so that the weighted trial population resembles a target population. We evaluate a variety of alternative estimation and weight construction procedures using both simulations and a real world data example using two clinical trials of an investigational intervention for Alzheimer’s disease. Our results suggest an optimal approach to estimation depends on the characteristics of source and target populations, including degree of selection bias and treatment effect heterogeneity.

PMID:33675139 | DOI:10.1002/pst.2106

Eur J Neurosci. 2021 Mar 6. doi: 10.1111/ejn.15174. Online ahead of print.

ABSTRACT

Affective-motivational disturbances are highly inconsistent in animal pain models. The reproducibility of the open-field test in assessing anxiety, malaise, or disability remains controversial despite its popularity. While traumatic, persistent, or multi-regional pain models are commonly considered more effective in inducing negative affect or functional impairment, the early psychobehavioral changes before pain chronification are often underexplored. Here, we aimed to clarify the fundamental relationship between hypernociception and passive distress-like behavior using a model of transient inflammatory pain. To minimize latent confounders and increase data consistency, male C57BL/6N mice were habituated to the open-field arena 6 times before receiving the unilateral intraplantar injection of prostaglandin E2 (PGE2) or vehicle. Open-field (40-minute exploration) and nociceptive behavior were evaluated repeatedly along the course of hypernociception in both wild-type and transgenic mice with a known pronociceptive phenotype. To reduce subjectivity, multivariate open-field behavioral outcomes were analyzed by statistical modeling based on exploratory factor analyses, which yielded a 2-factor solution. Within 3 hours after PGE2 injection, mice developed significantly reduced center exploration (factor 1) and a marginally significant increase in their habituation tendency (factor 2), which were not apparent in vehicle-injected mice. The behavioral passivity generally improved as hypernociception subsided. Therefore, transient inflammatory irritation is sufficient to suppress mouse open-field exploratory activity. The apparent absence of late affective-motivational changes in some rodents with prolonged hypernociception may not imply a lack of preceding or underlying neuropsychological alterations. Procedural pain after invasive animal experiments, however small, should be assessed and adequately controlled as a potential research confounder.

PMID:33675141 | DOI:10.1111/ejn.15174

Pharm Stat. 2021 Mar 5. doi: 10.1002/pst.2109. Online ahead of print.

ABSTRACT

The purpose of assessing adverse events (AEs) in clinical studies is to evaluate what AE patterns are likely to occur during treatment. In contrast, it is difficult to specify which of these patterns occurs in each patient. To tackle this challenging issue, we constructed a new statistical model including nonnegative matrix factorization by incorporating background knowledge of AE-specific structures such as severity and drug mechanism of action. The model uses a meta-analysis framework for integrating data from multiple clinical studies because insufficient information is derived from a single trial. We demonstrated the proposed method by applying it to real data consisting of three Phase III studies, two mechanisms of action, five anticancer treatments, 3317 patients, 848 AE types, and 99,546 AEs. The extracted typical treatment-specific AE patterns coincided with medical knowledge. We also demonstrated patient-level safety profiles using the data of AEs that were observed by the end of the second cycle.

PMID:33675157 | DOI:10.1002/pst.2109

J Cachexia Sarcopenia Muscle. 2021 Mar 5. doi: 10.1002/jcsm.12693. Online ahead of print.

ABSTRACT

BACKGROUND: Muscle atrophy is a common pathology associated with disuse, such as prolonged bed rest or spaceflight, and is associated with detrimental health outcomes. There is emerging evidence that disuse atrophy may differentially affect males and females. Cellular mechanisms contributing to the development and progression of disuse remain elusive, particularly protein turnover cascades. The purpose of this study was to investigate the initial development and progression of disuse muscle atrophy in male and female mice using the well-established model of hindlimb unloading (HU).

METHODS: One hundred C57BL/6J mice (50 male and 50 female) were hindlimb suspended for 0 (control), 24, 48, 72, or 168 h to induce disuse atrophy (10 animals per group). At designated time points, animals were euthanized, and tissues (extensor digitorum longus, gastrocnemius, and soleus for mRNA analysis, gastrocnemius and extensor digitorum longus for protein synthesis rates, and tibialis anterior for histology) were collected for analysis of protein turnover mechanisms (protein anabolism and catabolism).

RESULTS: Both males and females lost ~30% of tibialis anterior cross-sectional area after 168 h of disuse. Males had no statistical difference in MHCIIB fibre area, whereas unloaded females had ~33% lower MHCIIB cross-sectional area by 168 h of unloading. Both males and females had lower fractional protein synthesis rates (FSRs) within 24-48 h of HU, and females appeared to have a greater reduction compared with males within 24 h of HU (~23% lower FSRs in males vs. 40% lower FSRs in females). Males and females exhibited differential patterns and responses in multiple markers of protein anabolism, catabolism, and myogenic capacity during the development and progression of disuse atrophy. Specifically, females had greater mRNA inductions of catabolic factors Ubc and Gadd45a (~4-fold greater content in females compared with ~2-fold greater content in males) and greater inductions of anabolic inhibitors Redd1 and Deptor with disuse across multiple muscle tissues exhibiting different fibre phenotypes.

CONCLUSIONS: These results suggest that the aetiology of disuse muscle atrophy is more complicated and nuanced than previously thought, with different responses based on muscle phenotypes and between males and females, with females having greater inductions of atrophic markers early in the development of disuse atrophy.

PMID:33675163 | DOI:10.1002/jcsm.12693

Exp Physiol. 2021 Mar 6. doi: 10.1113/EP089431. Online ahead of print.

ABSTRACT

NEW FINDINGS: What is the central question of this study? To explore the relationship between proteins in skeletal muscle and adipose tissue determined at rest and peak rates of fat oxidation in men and women. What is the main finding and its importance? Resting content of proteins in skeletal muscle involved in triglyceride hydrolysis and mitochondrial lipid transport are more strongly associated with peak fat oxidation rates than proteins related to lipid transport, or hydrolysis in adipose tissue. Whilst females display higher relative rates of fat oxidation than males, this was unexplained by the proteins measured in this study, suggesting other factors determine sex-differences in fat metabolism.

ABSTRACT: This study explored key proteins involved in fat metabolism that may associate with peak fat oxidation (PFO) and account for sexual dimorphism in exercise fuel metabolism. Thirty-six healthy adults [15 females; age 40 (11); V̇O₂ peak 42.5 (9.5) mL⋅kg BM^-1 ⋅min^-1 ; means±SD] completed two exercise tests to determine PFO via indirect calorimetry. Resting adipose tissue and/or skeletal muscle biopsies were obtained to determine the protein content of adipose tissue PLIN1, CGI-58, HSL, ATGL, ACSL1, CPT1b and oestrogen receptor α (ERα), and skeletal muscle FABPpm, ATGL, ACSL1, CTP1b and ERα. Moderate strength correlations were found between PFO (mg⋅kg FFM^-1 ⋅min^-1 ) and the protein content of ATGL [r_s = 0.41 (0.03-0.68), P<0.05] and CPT1b [r_s = 0.45 (0.09-0.71), P<0.05] in skeletal muscle. No other statistically significant bivariate correlations were consistently found. Females had a greater relative PFO compared to males: 7.1±1.9 vs 4.5±1.3 and 7.3±1.7 vs 4.8±1.2 mg⋅kg FFM^-1 ⋅min^-1 )] in the adipose tissue (n = 14) and skeletal muscle (n = 12) sub-groups, respectively (p<0.05). No statistically significant sex differences were found in the content of these proteins. The regulation of PFO may involve processes relating to intramyocellular triglyceride hydrolysis and mitochondrial fatty acid transport, and adipose tissue is likely to play a more minor role than muscle. Sex differences in fat metabolism are likely to be due to factors other than the resting content of proteins in skeletal muscle and adipose tissue relating to triglyceride hydrolysis and fatty acid transport. This article is protected by copyright. All rights reserved.

PMID:33675111 | DOI:10.1113/EP089431

J Clin Pharm Ther. 2021 Mar 6. doi: 10.1111/jcpt.13398. Online ahead of print.

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: One of the effective and consistent ways to achieve glycaemic control for patients with type 2 diabetes mellitus (T2DM) is once-daily basal insulin. But it is also associated with adverse outcomes such as hypoglycaemia. Dulaglutide, a novel long-acting GLP-1 receptor agonist, may be a more suitable therapy. The present meta-analysis aims to assess the efficacy and safety of once-weekly glucagon-like peptide-1 receptor agonist dulaglutide compared with insulin glargine for the treatment of T2DM.

METHODS: We searched PubMed, Embase and Cochrane Library from inception to December 2020. Randomized clinical trials comparing dulaglutide with insulin glargine in adults with T2DM were included. Revman5.2 software was used for meta-analysis.

RESULTS AND DISCUSSION: We included 5 studies with 3383 randomized participants. Compared with insulin glargine, dulaglutide 1.5 mg led to greater mean HbA1c reduction (MD = -0.33%, 95% CI = -0.52, -0.15) whereas dulaglutide 0.75 mg did not (MD = -0.21%, 95% CI = -0.43, 0.01). Body weight loss was seen with dulaglutide whereas weight gain was seen with insulin glargine. The risk of hypoglycaemia was lower in dulaglutide 0.75 mg and 1.5 mg groups than in insulin glargine group,whereas dulaglutide had a statistically higher gastrointestinal adverse events incidence than insulin glargine.

WHAT IS NEW AND CONCLUSIONS: Compared with insulin glargine, dulaglutide may serve as an effective alternative to provide improvement in glycaemic control with weight loss and less hypoglycaemia in patients with T2DM. It may be a more suitable therapy instead of basal insulin.

PMID:33675117 | DOI:10.1111/jcpt.13398

J Vet Intern Med. 2021 Mar 6. doi: 10.1111/jvim.16089. Online ahead of print.

ABSTRACT

BACKGROUND: Echocardiographic measurements play an important role in detecting cardiac enlargement and assessing cardiac function. In human cardiology, M-mode measurements have been widely replaced by volumetric measurements of the left ventricle (LV) using Simpson’s method of disc (SMOD). In veterinary cardiology, more large-scale studies are necessary to generate reference intervals (RIs) for SMOD LV volume measurements.

OBJECTIVE: To generate body size independent RIs for LV volume measurements in dogs.

ANIMALS: Healthy adult dogs (n = 1331) of variable size and somatotype.

METHODS: Prospective study. The SMOD was measured from the right parasternal long axis and the left apical 4-chamber view in clinically healthy dogs. The SMOD measurements were normalized to various allometric scales (kg, kg^2/3 , or kg^1/3 ). RIs for LV end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV) using SMOD were estimated as prediction intervals of both a linear and an additive regression model. Additionally, after normalization to body weight, 95% RIs were determined using nonparametric methods with 2.5 and 97.5 percentiles serving as the lower and upper limits. Separate analyses were performed for 120 sighthound breeds and 1211 other breeds.

RESULTS: Echocardiographic LV volumes correlated best with weight in kilograms. The additive model proved to be more flexible and accurate than the other 2 methods to generate RIs. Separate RIs for sighthound and all other breeds are provided.

CONCLUSIONS AND CLINICAL IMPORTANCE: Body size and breed-independent RIs for LV volume measurements using SMOD were generated prospectively from a large and diverse population of dogs and are available for clinical use.

PMID:33675121 | DOI:10.1111/jvim.16089

J Am Geriatr Soc. 2021 Mar 5. doi: 10.1111/jgs.17088. Online ahead of print.

ABSTRACT

BACKGROUND: Community health centers (CHCs) are federally funded safety-net clinics that provide care to low income and medically underserved persons. The proportion of CHC patients aged ≥65 doubled in the last ten years, yet little is known about this population. We aim to describe the demographic and clinical characteristics of the older adult CHC population.

DESIGN: Cross sectional analysis.

SETTING: The nationally representative 2014 Health Center Patient Survey.

PARTICIPANTS: CHC patients ≥55 years.

MEASURES: We used descriptive statistics to characterize older adults across demographic and clinical variables. To determine differences by age, we stratified into three groups (55-64, 65-74, 75+ years). We used t-tests and chi-squared to calculate p values and survey weights to make national estimates.

RESULTS: We included 1875 older adults ≥55 years, representing over 4.2 million people. Older adults were mostly aged 55-64 (60%), female (51%), and white (60%). The majority (73%) had Medicare or Medicaid and 47% reported fair or poor health. Regardless of age, older adults had an average of three chronic conditions and 0.6 impairments in activities of daily living (ADL). Healthcare utilization was not significantly different across age groups with most taking ≥5 prescription medications (54%) and one in five reporting ≥2 emergency department visits or ≥1 hospitalization in the last year.

CONCLUSIONS: Adults 55-64 who attend CHCs have similar disease burden as adults ≥65. As the population of older adults who access CHCs grow, our findings highlight the opportunity to enhance focus on key principles of geriatric medicine, such as measurement of functional impairment for those who are <65 while also addressing underlying health disparities.

PMID:33675077 | DOI:10.1111/jgs.17088