Changes in patient characteristics in anti-tumour necrosis factor clinical trials for rheumatoid arthritis: results of an analysis of the literature over the past 16 years

Objective To evaluate changes in baseline patient characteristics and entry criteria of randomised, controlled studies of tumour necrosis factor alpha (TNF alpha) inhibitors in rheumatoid arthritis (RA) patients. Methods A systematic literature review was performed using predefined inclusion criteria to identify randomised, double-blind, controlled trials that evaluated TNF alpha inhibitors in adult RA patients. Entry criteria and baseline clinical characteristics were evaluated over time for methotrexate-experienced and methotrexate-naive study populations. Enrolment start date for each trial was the time metric. The anchor time was the study with the earliest identifiable enrolment start date. Results 44 primary publications (reporting the primary study endpoint) from 1993 to 2008 met the inclusion criteria. Enrolment start dates of August 1993 and May 1997 were identified as time anchors for the 37 methotrexate-experienced studies and the seven methotrexate-naive studies, respectively. In methotrexate-experienced trials, no significant change was observed over the years included in this study in any inclusion criteria (including swollen joint counts and C-reactive protein (CRP)), but a significant decrease over time was observed in the baseline swollen joint count, CRP and total Sharp or van der Heijde modified Sharp score, but not in baseline tender joint counts. In the methotrexate-naive studies, significant decreases over the years were observed in swollen joint and tender joint inclusion criteria, but not in baseline tender joint count, baseline CRP, CRP inclusion criteria or baseline total Sharp or van der Heijde modified Sharp score. Conclusion Inclusion criteria and baseline characteristics of RA patients enrolled in studies of TNF alpha inhibitors have changed, with more recent trials enrolling cohorts with lower disease activity, especially in methotrexate-experienced trials.Pathophysiology and treatment of rheumatic disease

Validation of an integrated pedal desk and electronic behavior tracking platform

Background This study tested the validity of revolutions per minute (RPM) measurements from the Pennington Pedal Desk™. Forty-four participants (73 % female; 39 ± 11.4 years-old; BMI 25.8 ± 5.5 kg/m2 [mean ± SD]) completed a standardized trial consisting of guided computer tasks while using a pedal desk for approximately 20 min. Measures of RPM were concurrently collected by the pedal desk and the Garmin Vector power meter. After establishing the validity of RPM measurements with the Garmin Vector, we performed equivalence tests, quantified mean absolute percent error (MAPE), and constructed Bland–Altman plots to assess agreement between RPM measures from the pedal desk and the Garmin Vector (criterion) at the minute-by-minute and trial level (i.e., over the approximate 20 min trial period). Results The average (mean ± SD) duration of the pedal desk trial was 20.5 ± 2.5 min. Measures of RPM (mean ± SE) at the minute-by-minute (Garmin Vector: 54.8 ± 0.4 RPM; pedal desk: 55.8 ± 0.4 RPM) and trial level (Garmin Vector: 55.0 ± 1.7 RPM; pedal desk: 56.0 ± 1.7 RPM) were deemed equivalent. MAPE values for RPM measured by the pedal desk were small (minute-by-minute: 2.1 ± 0.1 %; trial: 1.8 ± 0.1 %) and no systematic relationships in error variance were evident by Bland–Altman plots. Conclusion The Pennington Pedal Desk™ provides a valid count of RPM, providing an accurate metric to promote usage

Exercise-induced changes in central adiposity during a RCT: effect of exercise dose and associations with compensation

Context: Exercise can decrease central adiposity, but the effect of exercise dose and the relationship between central adiposity and exercise-induced compensation is unclear. Objective: Test the effect of exercise dose on central adiposity change and the association between central adiposity and exercise-induced weight compensation. Methods: In this ancillary analysis of a 6-month randomized controlled trial, 170 participants with overweight or obesity (mean±SD BMI: 31.5±4.7 kg/m2) were randomized to a control group or exercise groups that reflected exercise recommendations for health (8 kcal/kg/week [KKW]) or weight loss and weight maintenance (20 KKW). Waist circumference was measured, and dual-energy X-ray absorptiometry assessed central adiposity. Predicted weight change was estimated and weight compensation (weight change minus predicted weight change) was calculated. Results: Between-group change in waist circumference (control: 0.0 cm [95% CI: -1.0,1.0], 8 KKW: -0.7 cm [95% CI: -1.7,0.4], 20 KKW: -1.3 cm [95% CI: -2.4, -0.2]) and visceral adipose tissue (VAT; control: -0.02 kg [95% CI: -0.07,0.04], 8 KKW: -0.01 kg [95% CI: -0.07,0.04], 20 KKW: -0.04 kg [95% CI: -0.10,0.02]) was similar (P≥0.23). Most exercisers (82.6%) compensated (predicted weight change lower than actual weight change). Exercisers who compensated exhibited a 2.5 cm (95% CI: 0.8,4.2) and 0.23 kg (95% CI: 0.14,0.31) increase in waist circumference and VAT, respectively, versus those who did not (P<0.01). Desire to eat predicted VAT change during exercise (β=0.21; P=0.03). Conclusions: In the presence of significant weight compensation, exercise at doses recommended for health and weight loss and weight maintenance leads to negligible changes in central adiposity

Racial variations in appetite-related hormones, appetite, and laboratory-based energy intake from the E-MECHANIC randomized clinical trial

African Americans (AAs) have a higher obesity risk than Whites; however, it is unclear if appetite-related hormones and food intake are implicated. We examined differences in appetite-related hormones, appetite, and food intake between AAs (n = 53) and Whites (n = 111) with overweight or obesity. Participants were randomized into a control group or into supervised, controlled exercise groups at 8 kcal/kg of body weight/week (KKW) or 20 KKW. Participants consumed lunch and dinner at baseline and follow-up, with appetite and hormones measured before and after meals (except leptin). At baseline, AAs had lower peptide YY (PYY; p < 0.01) and a blunted elevation in PYY after lunch (p = 0.01), as well as lower ghrelin (p = 0.02) and higher leptin (p < 0.01) compared to Whites. Despite desire to eat being lower and satisfaction being higher in AAs relative to Whites (p ≤ 0.03), no racial differences in food intake were observed. Compared to Whites, leptin increased in the 8 KKW group in AAs (p = 0.01), yet no other race-by-group interactions were evident. Differences in appetite-related hormones between AAs and Whites exist; however, their influence on racial disparities in appetite, food intake, and obesity within this trial was limited

A Feedback Quenched Oscillator Produces Turing Patterning with One Diffuser

Efforts to engineer synthetic gene networks that spontaneously produce patterning in multicellular ensembles have focused on Turing's original model and the “activator-inhibitor” models of Meinhardt and Gierer. Systems based on this model are notoriously difficult to engineer. We present the first demonstration that Turing pattern formation can arise in a new family of oscillator-driven gene network topologies, specifically when a second feedback loop is introduced which quenches oscillations and incorporates a diffusible molecule. We provide an analysis of the system that predicts the range of kinetic parameters over which patterning should emerge and demonstrate the system's viability using stochastic simulations of a field of cells using realistic parameters. The primary goal of this paper is to provide a circuit architecture which can be implemented with relative ease by practitioners and which could serve as a model system for pattern generation in synthetic multicellular systems. Given the wide range of oscillatory circuits in natural systems, our system supports the tantalizing possibility that Turing pattern formation in natural multicellular systems can arise from oscillator-driven mechanisms

Vitamin D Supplementation and Prevention of Type 2 Diabetes

BACKGROUND Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.

Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization

The emergence of Omicron (Pango lineage B.1.1.529), first identified in Botswana and South Africa, may compromise vaccine effectiveness and lead to re-infections1. We investigated whether Omicron escapes antibody neutralization in South Africans vaccinated with Pfizer BNT162b2. We also investigated if Omicron requires the ACE2 receptor to infect cells. We isolated and sequence confirmed live Omicron virus from an infected person in South Africa and compared plasma neutralization of Omicron relative to an ancestral SARS-CoV-2 strain, observing that Omicron still required ACE2 to infect. For neutralization, blood samples were taken soon after vaccination from participants who were vaccinated and previously infected or vaccinated with no evidence of previous infection. Neutralization of ancestral virus was much higher in infected and vaccinated versus vaccinated only participants but both groups showed a 22-fold escape from vaccine elicited neutralization by the Omicron variant. However, in the previously infected and vaccinated group, the level of residual neutralization of Omicron was similar to the level of neutralization of ancestral virus observed in the vaccination only group. These data support the notion that, provided high neutralization capacity is elicited by vaccination/boosting approaches, reasonable effectiveness against Omicron may be maintained

Who uses outpatient healthcare services under Ghana’s health protection scheme and why?

Background: The National Health Insurance Scheme (NHIS) was launched in Ghana in 2003 with the main objective of increasing utilisation to healthcare by making healthcare more affordable. Previous studies on the NHIS have repeatedly highlighted that cost of premiums is one of the major barriers for enrollment. However, despite introducing premium exemptions for pregnant women, older people, children and indigents, many Ghanaians are still not active members of the NHIS. In this paper we investigate why there is limited success of the NHIS in improving access to healthcare in Ghana and whether social exclusion could be one of the limiting barriers. The study explores this by looking at the Social, Political, Economic and Cultural (SPEC) dimensions of social exclusion. Methods: Using logistic regression, the study investigates the determinants of health service utilisation using SPEC variables including other variables. Data was collected from 4050 representative households in five districts in Ghana covering the 3 ecological zones (coastal, forest and savannah) in Ghana. Results: Among 16,200 individuals who responded to the survey, 54 % were insured. Out of the 1349 who sought health care, 64 % were insured and 65 % of them had basic education and 60 % were women. The results from the logistic regressions show health insurance status, education and gender to be the three main determinants of health care utilisation. Overall, a large proportion of the insured who reported ill, sought care from formal health care providers compared to those who had never insured in the scheme. Conclusion: The paper demonstrates that the NHIS presents a workable policy tool for increasing access to healthcare through an emphasis on social health protection. However, affordability is not the only barrier for access to health services. Geographical, social, cultural, informational, political, and other barriers also come into play

Vitamin D Supplementation and Prevention of Type 2 Diabetes

BACKGROUND Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.

A common missense variant of <i>LILRB₅</i> is associated with statin intolerance and myalgia

Aims A genetic variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B) (rs12975366: T > C: Asp247Gly) has been reported to be associated with lower creatine phosphokinase (CK) and lactate dehydrogenase (LDH) levels. Both biomarkers are released from injured muscle tissue, making this variant a potential candidate for susceptibility to muscle-related symptoms. We examined the association of this variant with statin intolerance ascertained from electronic medical records in the GoDARTS study. Methods and results In the GoDARTS cohort, the LILRB5 Asp247 variant was associated with statin intolerance (SI) phenotypes; one defined as having raised CK and being non-adherent to therapy [odds ratio (OR) 1.81; 95% confidence interval (CI): 1.34–2.45] and the other as being intolerant to the lowest approved dose of a statin before being switched to two or more other statins (OR 1.36; 95% CI: 1.07–1.73). Those homozygous for Asp247 had increased odds of developing both definitions of intolerance. Importantly the second definition did not rely on CK elevations. These results were replicated in adjudicated cases of statin-induced myopathy in the PREDICTION-ADR consortium (OR1.48; 95% CI: 1.05–2.10) and for the development of myalgia in the JUPITER randomized clinical trial of rosuvastatin (OR1.35, 95% CI: 1.10–1.68). A meta-analysis across the studies showed a consistent association between Asp247Gly and outcomes associated with SI (OR1.34; 95% CI: 1.16–1.54). Conclusion This study presents a novel immunogenetic factor associated with statin intolerance, an important risk factor for cardiovascular outcomes. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a potential role for the immune system in their development. We identify a genetic group that is more likely to be intolerant to their statins