The effects of dimethyl fumarate and fingolimod on T-cell lymphocyte proliferation in patients with multiple sclerosis

Objective The disease-modifying therapies (DMT), dimethyl fumarate (DMF) and fingolimod (FTY) improve the outcomes in multiple sclerosis (MS) by reducing relapses and numbers and volume of lesions. They mediate their effects through reduction of immune reactivation, which may potentially lead to lymphopaenia and increased risk of infections. Previous studies have examined the effects of these therapies on lymphocyte subsets; however, the in vivo effects on circulating lymphocyte proliferation require further elucidation. The aim of this study was to determine the effects of DMF and FTY on T-cell proliferation in patients with MS. Method We examined T-cell lymphocyte proliferation and lymphocyte subsets in ten patients (five on DMF, five on FTY) before starting DMT and again 4 to 11 months after being maintained on DMT. Results In the FTY-treated group, the mean percentage proliferation was significantly lower using both assays (PHA assay mean percentage change − 51.2 ± 25.97, p < 0.05; anti-CD3/CD28 assay mean percentage change − 39.74 ± 27.85, p < 0.05). There was no statistical difference in T-cell lymphocyte proliferation in the DMF-treated group for either assay (PHA, p = 0.316; anti-CD3/CD28, p = 0.373). Conclusions This pilot study suggests that the T-lymphocytes of patients on FTY have an abnormal proliferation response as well as being reduced in the circulation.

Efficacy of Yigu® versus Aclasta® in Chinese postmenopausal women with osteoporosis: a multicenter prospective study

Summary Zoledronic acid (ZOL) is a therapy inhibiting bone resorption. In this study, generic ZOL (Yigu®) showed its clinical efficacy consistency with original ZOL (Aclasta®) in Chinese postmenopausal women with osteoporosis. This study provides a practical basis for the application of Yigu® in Chinese population. Introduction Yigu® has been approved its bioequivalence to Aclasta®. However, the clinical efficacy and safety of Yigu® have not been evaluated yet. Here, we compared the effectiveness and safety between Yigu® and Aclasta® in Chinese postmenopausal women with osteoporosis and assessed the efficacy of intravenous infusion of ZOL. Methods This was a randomized open-label, active-controlled study in postmenopausal women with osteoporosis of 14 clinical centers in China. Postmenopausal women with osteoporosis were recruited and randomized to receive a single infusion of 5 mg Yigu® or Aclasta®. The primary endpoint was the percentage change in bone mineral density (BMD) at lumbar spine after 12 months of treatment and was assessed for equivalence. The secondary endpoint was the percentage change in BMD at proximal femur after 12 months. Additional secondary endpoints were percentage changes in BMD at the above sites after 6 months of treatment and changes in bone turnover biomarkers during ZOL treatment. Safety was also evaluated and compared between two groups. Results A total of 458 postmenopausal women with osteoporosis were enrolled (n = 227, Yigu®; n = 231, Aclasta®). The mean percentage change in the BMD had no statistical difference at the lumbar spine (5.32% vs 5.18%), total hip (2.72% vs 2.83%), and femoral neck (2.37% vs 2.81%) between Yigu® and Aclasta® groups after 12 months of treatment. The mean difference of BMD change at the lumbar spine after 12 months between two groups was 0.15% (95% CI: − 0.71 to 1.00, equivalence margin: − 1.5%, 1.5%), demonstrating the treatments were equivalent. Meanwhile, the decreases in the P1NP and β-CTX showed no difference between two groups after 14 days and 6 and 12 months of treatment. As regards the whole sample, BMD significantly increased after 12 months of treatment. Also, serum C-terminal telopeptide of type 1 collagen (β-CTX) and procollagen 1 N-terminal peptide (P1NP) significantly decreased at each visit period. The overall adverse events were comparable and quite well between two groups. Conclusion Intravenous infusion of zoledronic acid achieved the potent anti-resorptive effects which led to significant increase in BMD of Chinese postmenopausal women with osteoporosis. Yigu® was equivalent to Aclasta® with respect to efficacy and safety.

Individual-based Creatine Kinase Reference Values in Response to Soccer Match-play

The aim of the present study was to determine the creatine kinase reference limits for professional soccer players based on their own normal post-match response. The creatine kinase concentration was analyzed in response to official matches in 25 players throughout a 3-year period. Samples were obtained between 36–43 hours following 70 professional soccer matches and corresponded to 19.1±12.1 [range: 6–49] samples per player. Absolute reference limits were calculated as 2.5th and 97.5th percentile of the samples collected. Creatine kinase values were also represented as a percentage change from the individual’s season mean and represented by 90th, 95th and 97.5th percentiles. The absolute reference limits for creatine kinase concentration calculated as 97.5th and 2.5th percentiles were 1480 U.L−1 and 115.8 U.L−1, respectively. The percentage change from the individual’s season mean was 97.45±35.92% and players were in the 90th, 95th and 97.5th percentiles when the percentages of these differences were 50.01, 66.7, and 71.34% higher than player’s season mean response, respectively. The data allowed us to determine whether the creatine kinase response is typical or if it is indicative of a higher than normal creatine kinase elevation and could be used as a practical guide for detection of muscle overload, following professional soccer match-play.

Long-Term Combined Effects of Citrulline and Nitrate-Rich Beetroot Extract Supplementation on Recovery Status in Trained Male Triathletes: A Randomized, Double-Blind, Placebo-Controlled Trial

Citrulline (CIT) and nitrate-rich beetroot extract (BR) are widely studied ergogenic aids. Nevertheless, both supplements have been studied in short-term trials and separately. To the best of the authors’ knowledge, the effects of combining CIT and BR supplementation on recovery status observed by distance covered in the Cooper test, exercise-induced muscle damage (EIMD) and anabolic/catabolic hormone status have not been investigated to date. Therefore, the main purpose of this research was to assess the effect of the long-term (9 weeks) mixture of 3 g/day of CIT plus 2.1 g/day of BR (300 mg/day of nitrates (NO3−)) supplementation on recovery by distance covered in the Cooper test, EIMD markers (urea, creatinine, AST, ALT, GGT, LDH and CK) and anabolic/catabolic hormones (testosterone, cortisol and testosterone/cortisol ratio (T/C)) in male trained triathletes. Thirty-two triathletes were randomized into four different groups of eight triathletes in this double-blind, placebo-controlled trial: placebo group (PLG), CIT group (CITG; 3 g/day of CIT), BR group (BRG; 2.1 g/day of BR (300 mg/day of NO3−)) and CIT-BR group (CIT-BRG; 3 g/day of CIT plus 2.1 g/day of BR (300 mg/day of NO3−)). Distance covered in the Cooper test and blood samples were collected from all participants at baseline (T1) and after 9 weeks of supplementation (T2). There were no significant differences in the interaction between group and time in EIMD markers (urea, creatinine, AST, ALT, GGT, LDH and CK) (p > 0.05). However, significant differences were observed in the group-by-time interaction in distance covered in the Cooper test (p = 0.002; η2p = 0.418), cortisol (p = 0.044; η2p = 0.247) and T/C (p = 0.005; η²p = 0.359). Concretely, significant differences were observed in distance covered in the Cooper test percentage of change (p = 0.002; η²p = 0.418) between CIT-BRG and PLG and CITG, in cortisol percentage change (p = 0.049; η2p = 0.257) and in T/C percentage change (p = 0.018; η2p = 0.297) between CIT-BRG and PLG. In conclusion, the combination of 3 g/day of CIT plus 2.1 g/day of BR (300 mg/day of NO3−) supplementation for 9 weeks did not present any benefit for EIMD. However, CIT + BR improved recovery status by preventing an increase in cortisol and showing an increase in distance covered in the Cooper test and T/C.

CAPRISA 018: a phase I/II clinical trial study protocol to assess the safety, acceptability, tolerability and pharmacokinetics of a sustained-release tenofovir alafenamide subdermal implant for HIV prevention in women

IntroductionYoung African women bear a disproportionately high risk for HIV acquisition. HIV technologies that empower women to protect themselves are needed. Safe, potent antiretroviral agents such as tenofovir alafenamide (TAF), formulated as long-acting subdermal implants, offer an innovative solution.Methods and analysisCAPRISA 018 is a phase I/II trial to evaluate the safety, acceptability, tolerability and pharmacokinetics (PKs) of a TAF free base subdermal silicone implant containing 110 mg of TAF with an anticipated 0.25 mg/day release rate.The phase I trial (n=60) will assess the safety of one implant inserted in six participants (Group 1), followed by dose escalation components (Groups 2 and 3) assessing the safety, tolerability and PK of one to four TAF 110 mg implants releasing between 0.25 mg and 1 mg daily in 54 healthy women at low risk for HIV infection. Data from this phase I trial will be used to determine the dosing, implant location and implant replacement interval for the phase II trial.The phase II component (Group 4) will assess extended safety, PK, tolerability and acceptability of the implant in 490 at risk women, randomised in a 1:1 ratio to the TAF implant and placebo tablet or to the placebo implant and an oral pre-exposure prophylaxis tablet. Safety will be assessed by calculating the percentage change in creatinine clearance from baseline at weeks 4, 12, 24, 36, 72, 96 and 120, compared with the percentage change in the control group.Ethics and disseminationThe South African Health Products Regulatory Authority and the University of KwaZulu-Natal’s Biomedical Research Ethics Committee have approved the trial. Results will be disseminated through open access peer reviewed publications, conference presentations, public stakeholder engagement and upload of data into the clinical trials registry.Trial registration numberPACTR201809520959443.

COVID-19 Pandemic and Trends in Clinical Trials: A Multi-Region and Global Perspective

To evaluate the effect of the COVID-19 pandemic on clinical development, the number of newly started clinical trials in each geographical region between January 2018 and December 2020 were calculated based on data from the ClinicalTrials.gov database. Data regarding new drug applications were obtained from European Medicines Agency monthly reports, pharmaceutical company press releases, and the archives of the Drugs.com database. The mean percentage change in newly started clinical trials for diseases other than COVID-19 between each month in 2019 and the corresponding month in 2020 was −7.5%, with the maximum of −57.3% observed between April 2019 and April 2020. Similarly, the mean percentage change of reported results for each month in 2019 and 2020 was −5.1%, with the maximum of −27.4% observed in July 2020. The activity of clinical trials was decreased as the number of COVID-19 patients was increased, and a statistically negative correlation was observed between the prevalence of COVID-19 and the percentage decrease in the number of clinical trials stared or reported results. As for new drug submissions, decreases were observed in the latter half of 2020 compared with the same period during the previous year, for each indicator. A considerable decline in non-COVID-19 activity for all indicators regarding clinical developments was suggested during the first wave of the COVID-19 pandemic. It is important to recognize the situation and continue to make efforts to conduct clinical trials for both COVID-19 and no-COVID-19 for new medical developments in the future.

Trends in Premature Mortality From Acute Myocardial Infarction in the United States, 1999 to 2019

Background Evaluating premature (<65 years of age) mortality because of acute myocardial infarction (AMI) by demographic and regional characteristics may inform public health interventions. Methods and Results We used the Centers for Disease Control and Prevention’s WONDER (Wide‐Ranging Online Data for Epidemiologic Research) death certificate database to examine premature (<65 years of age) age‐adjusted AMI mortality rates per 100 000 and average annual percentage change from 1999 to 2019. Overall, the age‐adjusted AMI mortality rate was 13.4 (95% CI, 13.3–13.5). Middle‐aged adults, men, non‐Hispanic Black adults, and rural counties had higher mortality than young adults, women, NH White adults, and urban counties, respectively. Between 1999 and 2019, the age‐adjusted AMI mortality rate decreased at an average annual percentage change of −3.4 per year (95% CI, −3.6 to −3.3), with the average annual percentage change showing higher decline in age‐adjusted AMI mortality rates among large (−4.2 per year [95% CI, −4.4 to −4.0]), and medium/small metros (−3.3 per year [95% CI, −3.5 to −3.1]) than rural counties (−2.4 per year [95% CI, −2.8 to −1.9]). Age‐adjusted AMI mortality rates >90th percentile were distributed in the Southern states, and those with mortality <10th percentile were clustered in the Western and Northeastern states. After an initial decline between 1999 and 2011 (−4.3 per year [95% CI, −4.6 to −4.1]), the average annual percentage change showed deceleration in mortality since 2011 (−2.1 per year [95% CI, −2.4 to −1.8]). These trends were consistent across both sexes, all ethnicities and races, and urban/rural counties. Conclusions During the past 20 years, decline in premature AMI mortality has slowed down in the United States since 2011, with considerable heterogeneity across demographic groups, states, and urbanicity. Systemic efforts are mandated to address cardiovascular health disparities and outcomes among nonelderly adults.

10-Year Trend of Abdominal Magnetic Resonance Imaging Compared With Abdominal Computed Tomography Scans in Inflammatory Bowel Disease

Background Patients with inflammatory bowel disease (IBD) frequently undergo multiple computed tomography (CT) examinations. With the widespread availability of magnetic resonance imaging (MRI), it is unclear whether the use of CTs in IBD has declined. We aimed to analyze the trends of CT and MRI use in a large cohort of IBD patients in a 10-year period. Methods We retrospectively analyzed adults ≥18 years of age using a de-identified database, IBM Explorys. Patients with ≥1 CT of the abdomen (± pelvis) or MRI of the abdomen (± pelvis) at least 30 days after the diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC) were included. We examined the factors associated with patients undergoing multiple CTs (≥5 CTs of the abdomen) and performed a trend analysis from 2010 to 2019. Results Among 176 110 CD and 143 460 UC patients, those with ≥1 CT of the abdomen annually increased from 2010 to 2019 with mean annual percentage change of +3.6% for CD and +4.9% for UC. Similarly, annual percentage change for patients with ≥1 MRI (CD: +15.6%; UC: +22.8%) showed a rising trend. There was a 3.8% increase in CD patients receiving ≥5 CTs of the abdomen annually compared with a 2.4% increase among UC patients in the 10-year period. Age ≥50 years, men, African Americans, public insurance payors, body mass index ≥30kg/m2, and smoking history were associated with ≥5 CTs. Conclusions There is a considerable increase in the number of CT scans performed in IBD patients. Further studies can explore factors influencing the use of CT and MRI of the abdomen in IBD patients.

Retinal Microvascular Reactivity in Chronic Cigarette Smokers and Non-smokers: An Observational Cross-Sectional Study

Purpose: To evaluate the changes in the retinal microvasculature and its reactivity in chronic cigarette smokers.Methods: Thirty-four male chronic cigarette smokers and 18 male non-smokers were enrolled. Optical coherence tomography angiography was used to measure the perfused retinal vessel densities (PVDs) of the peripapillary and parafoveal areas at baseline and during phase IV of the Valsalva maneuver (VM-IV). Systemic blood pressure and intraocular pressure were also measured.Results: The baseline PVD in the peripapillary area of the smokers was significantly lower than the non-smokers (59.56 ± 2.26% vs. 61.67 ± 3.58%, respectively; P = 0.005). However, there was no significant difference in the foveal avascular zone or parafoveal PVD between the two groups. During VM-IV, the peripapillary PVD of the smokers decreased by 1.13 ± 3.50%, which was significantly less than that of the non-smokers (−3.83 ± 4.26%, P &lt; 0.05). Similarly, the parafoveal PVD of the smokers decreased by 5.49 ± 9.70%, which was significantly less than the percentage change of the non-smokers (−13.01 ± 8.39%, P &lt; 0.05). There was no significant difference in the percentage change in systemic blood pressure parameters between the two groups.Conclusion: The retinal microvasculature and its reactivity were impaired in chronic smokers compared with non-smokers. The extent of impairment differed among different regions of the fundus.