Tofacitinib and risk of cardiovascular outcomes: results from the Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) study

ObjectivesRecent results from ‘ORAL Surveillance’ trial have raised concerns regarding the cardiovascular safety of tofacitinib in patients with rheumatoid arthritis (RA). We further examined this safety concern in the real-world setting.MethodsWe created two cohorts of patients with RA initiating treatment with tofacitinib or tumour necrosis factor inhibitors (TNFI) using deidentified data from Optum Clinformatics (2012–2020), IBM MarketScan (2012–2018) and Medicare (parts A, B and D, 2012–2017) claims databases: (1) A ‘real-world evidence (RWE) cohort’ consisting of routine care patients and (2) A ‘randomised controlled trial (RCT)-duplicate cohort’ mimicking inclusion and exclusion criteria of the ORAL surveillance trial to calibrate results against the trial findings. Cox proportional hazards models with propensity score fine stratification weighting were used to estimate HR and 95% CIs for composite outcome of myocardial infarction and stroke and accounting for 76 potential confounders. Database-specific effect estimates were pooled using fixed effects models with inverse-variance weighting.ResultsIn the RWE cohort, 102 263 patients were identified of whom 12 852 (12.6%) initiated tofacitinib. The pooled weighted HR (95% CI) comparing tofacitinib with TNFI was 1.01 (0.83 to 1.23) in RWE cohort and 1.24 (0.90 to 1.69) in RCT-duplicate cohort which aligned closely with ORAL-surveillance results (HR: 1.33, 95% CI 0.91 to 1.94).ConclusionsWe did not find evidence for an increased risk of cardiovascular outcomes with tofacitinib in patients with RA treated in the real-world setting; however, tofacitinib was associated with an increased risk of cardiovascular outcomes, although statistically non-significant, in patients with RA with cardiovascular risk factors.Trial registration numberNCT04772248.

Livestock, pathogens, vectors, and their environment: a causal inference-based approach to estimating the pathway-specific effect of livestock on human African trypanosomiasis risk

Livestock are important reservoirs for many diseases, and investigation of such zoonoses has long been the focus of One Health research. However, the effects of livestock on human and environmental health extend well beyond direct disease transmission. In this retrospective ecological cohort study we use pre-existing data and methods derived from causal inference and spatial epidemiology to estimate three hypothesized mechanisms by which livestock can come to bear on human African trypanosomiasis (HAT) risk: the reservoir effect, by which infected cattle and pigs are a source of infection to humans; the zooprophylactic effect, by which preference for livestock hosts exhibited by the tsetse fly vector of HAT means that their presence protects humans from infection; and the environmental change effect, by which livestock keeping activities modify the environment in such a way that habitat suitability for tsetse flies, and in turn human infection risk, is reduced. We conducted this study in four high burden countries: at the point level in Uganda, Malawi, and Democratic Republic of Congo (DRC), and at the county-level in South Sudan. Our results indicate cattle and pigs play an important reservoir role for the rhodesiense form (rHAT) in Uganda, however zooprophylaxis outweighs this effect for rHAT in Malawi. For the gambiense form (gHAT) we found evidence that pigs may be a competent reservoir, however dominance of the reservoir versus zooprophylactic pathway for cattle varied across countries. We did not find compelling evidence of an environmental change effect.

Caffeine and attentional control: improved and impaired performance in healthy older adults and Parkinson’s disease according to task demands

Introduction Caffeine is frequently consumed to boost goal-directed attention. These procognitive effects may occur due to the adenosine-mediated enhancement of monoamines, such as dopamine, after caffeine administration. As such, caffeine’s beneficial effects may be altered in conditions such as Parkinson’s disease (PD). However, whether caffeine improves cognition, and at what cost, has not been experimentally established in patients with neurodegenerative disease. Methods Single-dose trials to probe cognitive effects of caffeine are often confounded by short-term caffeine abstinence which conflates caffeine’s effects with treatment of withdrawal. Using a placebo controlled, blinded, randomised trial design, we assessed the effect of 100 mg of caffeine across well-established tasks (Choice reaction time, Stroop Task and Rapid Serial Visual Presentation Task; RSVP) that probe different aspects of attention in PD patients (n = 24) and controls (n = 44). Critically, participants withdrew from caffeine for a week prior to testing to eliminate the possibility that withdrawal reversal explained any cognitive benefit. Results Caffeine administration was found to reduce the overall number of errors in patients and controls on the Stroop (p = .018, η2p = .086) and Choice reaction time (p < . 0001, η2p = .588) tasks, but there was no specific effect of caffeine on ignoring irrelevant information in the Stroop task. On the RSVP task, caffeine improved dual item accuracy (p = .037) but impaired single item accuracy (p = .044). Across all tasks, there was little evidence that caffeine has different effects in PD participants and controls. Conclusion When removing withdrawal effects as a factor, we demonstrate caffeine has beneficial effects on selective attention but is a double-edge sword for visual temporal attention and would need careful targeting to be clinically useful.

Transgenic overexpression of CTRP3 does not prevent alcohol induced hepatic steatosis in female mice

Alcoholic liver disease (ALD) is one of the leading causes of morbidity and mortality from hepatic complications. C1q/TNF-related protein 3 (CTRP3) is an adiponectin paralog and, in male mice, increased levels of circulating CTRP3 prevents ALD. Therefore, the purpose of this study was to replicate the observed hepatoprotective effect of elevated circulating CTRP3 levels in female mice. Twelve-week-old female wildtype and CTRP3 overexpressing transgenic mice were fed the Lieber-DeCarli alcohol-containing liquid diet (5% vol/vol) for 6 weeks. Unlike the previous study with male mice, CTRP3 overexpression provided no attenuation to alcohol-induced hepatic lipid accumulation, cytokine production, or overall mortality. In conclusion, there appears to be a clear sex-specific effect of CTRP3 in response to alcohol consumption that needs to be explored further.

Tetramic Acids Mutanocyclin and Reutericyclin A, Produced by Streptococcus mutans Strain B04Sm5 Modulate the Ecology of an in vitro Oral Biofilm

The human oral microbiome consists of diverse microbes actively communicating and interacting through a variety of biochemical mechanisms. Dental caries is a major public health issue caused by fermentable carbohydrate consumption that leads to dysbiosis of the oral microbiome. Streptococcus mutans is a known major contributor to caries pathogenesis, due to its exceptional ability to form biofilms in the presence of sucrose, as well as to its acidophilic lifestyle. S. mutans can also kill competing bacteria, which are typically health associated, through the production of bacteriocins and other small molecules. A subset of S. mutans strains encode the muc biosynthetic gene cluster (BGC), which was recently shown to produce the tetramic acids, mutanocyclin and reutericyclins A, B, and C. Reutericyclin A displayed strong antimicrobial activity and mutanocyclin appeared to be anti-inflammatory; however the effect of these compounds, and the carriage of muc by S. mutans, on the ecology of the oral microbiota is not known, and was examined here using a previously developed in vitro biofilm model derived from human saliva. While reutericyclin significantly inhibited in vitro biofilm formation and acid production at sub-nanomolar concentrations, mutanocyclin did not present any activity until the high micromolar range. 16S rRNA gene sequencing revealed that reutericyclin drastically altered the biofilm community composition, while mutanocyclin showed a more specific effect, reducing the relative abundance of cariogenic Limosilactobacillus fermentum. Mutanocyclin or reutericyclin produced by the S. mutans strains amended to the community did not appear to affect the community in the same way as the purified compounds, although the results were somewhat confounded by the differing growth rates of the S. mutans strains. Regardless of the strain added, the addition of S. mutans to the in vitro community significantly increased the abundance of S. mutans and Veillonella infantium, only. Overall, this study illustrates that reutericyclin A and mutanocyclin do impact the ecology of a complex in vitro oral biofilm; however, further research is needed to determine the extent to which the production of these compounds affects the virulence of S. mutans.

Sex-specific effect of maternal thyroid hormone trajectories on preschoolers’ behavioral development: a birth cohort study

Context Maternal thyroid hormone trajectories are better predictor of offspring’s neurodevelopment than hormone levels in single trimester of pregnancy. Programming effect of uterine hormonal environment on offspring’s health is usually sex-specific. Objective To examine the sex-specific effect of thyroid hormone trajectories on preschoolers’ behavioral development. Design Based on Ma’ anshan Birth Cohort (MABC) in China, pregnant women were recruited at their first antenatal checkup from May 2013 to September 2014. Setting Ma’ anshan Maternal and Child Health Hospital in China. Patients or Other Participants 1860 mother-child pairs were included in the analysis. Children were followed up at age of 4. Main Outcome Measures Maternal thyroid hormones (TSH, FT4) and TPOAb in the first, second and third trimesters of pregnancy were retrospectively assayed. Preschoolers’ behavioral development was assessed by Achenbach Child Behavior Checklist (CBCL/1.5~5). Results Maternal TSH and FT4 levels were respectively fitted into high, moderate and low trajectories. In boys, maternal high TSH trajectory was related to withdrawn (OR = 2.01, 95% CI: 1.16, 3.50) and externalizing problems (OR = 2.69, 95% CI: 1.22, 5.92), and moderate TSH trajectory was associated with aggressive behavior (OR = 3.76, 95% CI: 1.16, 12.23). Maternal high FT4 trajectory was associated with anxious/depressed (OR = 2.22, 95% CI: 1.08, 4.56) and total problems (OR = 1.74, 95% CI: 1.13, 2.66), and low FT4 trajectory was associated with aggressive behavior (OR = 4.17, 95% CI: 1.22, 14.24). Conclusions Maternal thyroid hormone trajectories impact preschool boys’ behavioral development.

OPA1 Modulates Mitochondrial Ca2+ Uptake Through ER-Mitochondria Coupling

Autosomal Dominant Optic Atrophy (ADOA), a disease that causes blindness and other neurological disorders, is linked to OPA1 mutations. OPA1, dependent on its GTPase and GED domains, governs inner mitochondrial membrane (IMM) fusion and cristae organization, which are central to oxidative metabolism. Mitochondrial dynamics and IMM organization have also been implicated in Ca2+ homeostasis and signaling but the specific involvements of OPA1 in Ca2+ dynamics remain to be established. Here we studied the possible outcomes of OPA1 and its ADOA-linked mutations in Ca2+ homeostasis using rescue and overexpression strategies in Opa1-deficient and wild-type murine embryonic fibroblasts (MEFs), respectively and in human ADOA-derived fibroblasts. MEFs lacking Opa1 required less Ca2+ mobilization from the endoplasmic reticulum (ER) to induce a mitochondrial matrix [Ca2+] rise ([Ca2+]mito). This was associated with closer ER-mitochondria contacts and no significant changes in the mitochondrial calcium uniporter complex. Patient cells carrying OPA1 GTPase or GED domain mutations also exhibited altered Ca2+ homeostasis, and the mutations associated with lower OPA1 levels displayed closer ER-mitochondria gaps. Furthermore, in Opa1−/− MEF background, we found that acute expression of OPA1 GTPase mutants but no GED mutants, partially restored cytosolic [Ca2+] ([Ca2+]cyto) needed for a prompt [Ca2+]mito rise. Finally, OPA1 mutants’ overexpression in WT MEFs disrupted Ca2+ homeostasis, partially recapitulating the observations in ADOA patient cells. Thus, OPA1 modulates functional ER-mitochondria coupling likely through the OPA1 GED domain in Opa1−/− MEFs. However, the co-existence of WT and mutant forms of OPA1 in patients promotes an imbalance of Ca2+ homeostasis without a domain-specific effect, likely contributing to the overall ADOA progress.

Impact of statin treatment on non-invasive tests based predictions of fibrosis in a referral pathway for NAFLD

ObjectiveIn non-alcoholic fatty liver disease (NAFLD), fibrosis determines the risk of liver complications. Non-invasive tests (NITs) such as FIB-4, NAFLD Fibrosis Score (NFS) and Hepamet, have been proposed as a tool to triage NAFLD patients in primary care (PC). These NITs include AST±ALT in their calculations. Many patients with NAFLD take statins, which can affect AST/ALT, but it is unknown if statin affects NITs fibrosis prediction.MethodsWe included 856 patients referred through a standardised pathway from PC with a final diagnosis of NAFLD. 832 had reliable vibration controlled transient elastography (VCTE) measurements. We assessed the effects of statins on the association between NITs and VCTE at different fibrosis thresholds.Results129 out of 832 patients were taking a statin and 138 additional patients had indication for a statin. For any given FIB-4 value, patients on a statin had higher probabilities of high VCTE than patients not on a statin. Adjusting for body mass index, diabetes and age almost completely abrogated these differences, suggesting that these were related to patient’s profile rather to a specific effect of statins. Negative predictive values (NPVs) of FIB-4 <1.3 for VCTE >8, 10, 12 and 16 were, respectively, 89, 94, 96% and 100% in patients on a statin and 92, 95, 98% and 99% in patients not on a statin. Statins had similar impact on Hepamet predictions but did not modify NFS predictions.ConclusionIn patients with NAFLD referred from PC, those on statins had higher chances of a high VCTE for a given FIB-4 value, but this had a negligible impact on the NPV of the commonly used FIB-4 threshold (<1.3).

Sex-specific effect of blood O2 carrying capacity on orthostatic tolerance in older individuals

Blood oxygen (O2) carrying capacity is reduced with ageing and has been previously linked with the capacity to withstand the upright posture, i.e., orthostatic tolerance (OT). This study experimentally tested the hypothesis that a definite reduction in blood O2 carrying capacity via hemoglobin (Hb) manipulation differently affects the OT of older women and men as assessed by lower body negative pressure (LBNP). Secondary hemodynamic parameters were determined with transthoracic echocardiography throughout incremental LBNP levels for 1 hour or until presyncope in healthy older women and men (total n=26) matched by age (64±7 vs. 65±8 yr, P&lt;0.618) and physical activity levels. Measurements were repeated within a week period after a 10 % reduction of blood O2 carrying capacity via carbon monoxide rebreathing and analyzed via two-way ANCOVA. In the assessment session, OT time was similar between women and men (53.5±6.1 vs. 56.4±6.0 min, P=0.238). Following a 10 % reduction of blood O2 carrying capacity, OT time was reduced in women compared with men (51.3±7.0 vs. 58.2±2.8 min, P=0.003). The effect of reduced O2 carrying capacity on OT time differed between sexes (mean difference (MD)=-5.30 min, P=0.010). Prior to presyncope. reduced O2 carrying capacity resulted in lower left ventricular end-diastolic volume (MD=-8.11 ml∙m -2, P=0.043) and stroke volume (MD=-8.04 ml∙m -2, 95 % CI=-14.36, -1.71, P=0.018) in women relative to men, even after adjusting for baseline variables. In conclusion, present results suggest that reduced blood O2 carrying capacity specifically impairs OT and its circulatory determinants in older women.

The Evaluation of Temporal and Spatial Trends of Global Warming and Extreme Ocean Surface Temperatures: A Case Study of Canada

In recent years, extreme weather has frequently occurred worldwide and caused significant disasters, including large-scale forest fires, rare heat waves, heavy rains, floods, and tornadoes. Those have caused unprecedented losses of human lives and property in some countries, affecting the livelihoods of many people. Climate change and natural disasters are the two hotspots of scientific research today, and there is a certain degree of correlation between the two. Although countries worldwide have long known about climate change and its threats to human existence and have been discussing countermeasures, they have still not been able to carry out concerted and practical actions. The study takes Canada as an example, and selects six representative provinces to evaluate the temporal change characteristics of extreme temperature at different sites. We use MATLAB software to perform multiple linear regression, linear fitting methods, and Pearson correlation analysis to analyze spatial changes and time-space trends. The method studies the relationship between the emergence of extreme weather and climate change and uses the evolutionary game theory to explore whether there is any contradiction between global warming and extreme local cold. The study found: (i) The maximum temperature of most provinces in Canada will be constantly higher, and the minimum temperature will be lower. Generally speaking, the average temperature of each year is slowly decreasing. (ii) The average temperature data of British Columbia (Eastern Pacific) and Quebec (West Atlantic) show that ocean temperature has a specific effect on land temperature in surrounding areas. (iii) Pearson correlation analysis shows that the emergence of extreme weather is closely related to climate change. (iv) The evolution path of the two-party game shows that global warming and the occurrence of extreme local cold are not contradictory. Under the conditions, there is a certain degree of synchronization between the two, interacting and influencing each other.