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BackgroundAdverse events of special interest (AESIs) were pre-specified to be monitored for the COVID-19 vaccines. Some AESIs are not only associated with the vaccines, but with COVID-19. Our aim was to characterise the incidence rates of AESIs following SARS-CoV-2 infection in patients and compare these to historical rates in the general population.MethodsA multi-national cohort study with data from primary care, electronic health records, and insurance claims mapped to a common data model. This study's evidence was collected between Jan 1, 2017 and the conclusion of each database (which ranged from Jul 2020 to May 2022). The 16 pre-specified prevalent AESIs were: acute myocardial infarction, anaphylaxis, appendicitis, Bell's palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, Guillain- Barré syndrome, haemorrhagic stroke, non-haemorrhagic stroke, immune thrombocytopenia, myocarditis/pericarditis, narcolepsy, pulmonary embolism, transverse myelitis, and thrombosis with thrombocytopenia. Age-sex standardised incidence rate ratios (SIR) were estimated to compare post-COVID-19 to pre-pandemic rates in each of the databases.FindingsSubstantial heterogeneity by age was seen for AESI rates, with some clearly increasing with age but others following the opposite trend. Similarly, differences were also observed across databases for same health outcome and age-sex strata. All studied AESIs appeared consistently more common in the post-COVID-19 compared to the historical cohorts, with related meta-analytic SIRs ranging from 1.32 (1.05 to 1.66) for narcolepsy to 11.70 (10.10 to 13.70) for pulmonary embolism.InterpretationOur findings suggest all AESIs are more common after COVID-19 than in the general population. Thromboembolic events were particularly common, and over 10-fold more so. More research is needed to contextualise post-COVID-19 complications in the longer term.FundingNone.

Background: Adverse events of special interest (AESIs) were pre-specified to be monitored for the COVID-19 vaccines. Some AESIs are not only associated with the vaccines, but with COVID-19. Our aim was to characterise the incidence rates of AESIs following SARS-CoV-2 infection in patients and compare these to historical rates in the general population. Methods: A multi-national cohort study with data from primary care, electronic health records, and insurance claims mapped to a common data model. This study's evidence was collected between Jan 1, 2017 and the conclusion of each database (which ranged from Jul 2020 to May 2022). The 16 pre-specified prevalent AESIs were: acute myocardial infarction, anaphylaxis, appendicitis, Bell's palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, Guillain- Barré syndrome, haemorrhagic stroke, non-haemorrhagic stroke, immune thrombocytopenia, myocarditis/pericarditis, narcolepsy, pulmonary embolism, transverse myelitis, and thrombosis with thrombocytopenia. Age-sex standardised incidence rate ratios (SIR) were estimated to compare post-COVID-19 to pre-pandemic rates in each of the databases. Findings: Substantial heterogeneity by age was seen for AESI rates, with some clearly increasing with age but others following the opposite trend. Similarly, differences were also observed across databases for same health outcome and age-sex strata. All studied AESIs appeared consistently more common in the post-COVID-19 compared to the historical cohorts, with related meta-analytic SIRs ranging from 1.32 (1.05 to 1.66) for narcolepsy to 11.70 (10.10 to 13.70) for pulmonary embolism. Interpretation: Our findings suggest all AESIs are more common after COVID-19 than in the general population. Thromboembolic events were particularly common, and over 10-fold more so. More research is needed to contextualise post-COVID-19 complications in the longer term. Funding: None.

Liver enzyme concentrations are measured as safety endpoints in clinical trials to detect drug-related hepatotoxicity, but little is known about the epidemiology of these biomarkers in subjects without hepatic dysfunction who are enrolled in drug trials. We studied alanine and aspartate aminotransferase (ALT, AST) in subjects randomized to placebo who completed assessments over 36 months in a cardiovascular outcome trial (the 'STABILITY' trial; n=4264; mean age: 64.2 yr) or over 12 months in 3 trials that enrolled only subjects with type 2 diabetes (T2D) (the 'DIA' trials; n=308; mean age: 62.4 yr) to investigate time-dependent relationships and the factors that might affect ALT and AST, including body mass index (BMI), T2D and renal function. Multivariate linear mixed models examined time-dependent relationships between liver enzyme concentrations as response variables, and BMI, baseline T2D status, hemoglobin A1c levels and renal function, as explanatory variables. At baseline, ALT was higher in individuals who were males, < 65 years old, obese and who had GFR > 60 mL/min/1.73m2. ALT was not significantly associated with T2D at baseline, although it was positively associated with HbA1c. GFR had a greater impact on ALT than T2D. ALT concentrations decreased over time in subjects who lost weight, but remained stable in individuals with increasing BMI. Weight change did not alter AST concentrations. We provide new insights on the influence of time, GFR and HbA1c on ALT and AST concentrations and confirm the effect of gender, age, T2D, BMI and BMI change in subjects receiving placebo in clinical trials.

The in vivo cutaneous nerve regeneration model using capsaicin is applied extensively to study the regenerative mechanisms and therapeutic efficacy of disease modifying mole- cules for small fiber neuropathy (SFN). Since mismatches between functional and morpho- logical nerve fiber recovery are described for this model, we aimed at determining the capability of the capsaicin model to truly mimic the morphological manifestations of SFN in diabetes. As nerve and blood vessel growth and regenerative capacities are defective in diabetes, we focused on studying the key regulator of these processes, the neuropilin-1 (NRP-1)/semaphorin pathway. This led us to the evaluation of NRP-1 receptor expression in epidermis and dermis of subjects presenting experimentally induced small fiber neuropa- thy, diabetic polyneuropathy and of diabetic subjects without clinical signs of small fiber neuropathy. The NRP-1 receptor was co-stained with CD31 vessel-marker using immuno- fluorescence and analyzed with Definiens1 technology. This study indicates that capsaicin application results in significant loss of epidermal NRP-1 receptor expression, whereas dia- betic subjects presenting small fiber neuropathy show full epidermal NRP-1 expression in contrast to the basal expression pattern seen in healthy controls. Capsaicin induced a decrease in dermal non-vascular NRP-1 receptor expression which did not appear in dia- betic polyneuropathy. We can conclude that the capsaicin model does not mimic diabetic neuropathy related changes for cutaneous NRP-1 receptor expression. In addition, our data suggest that NRP-1 might play an important role in epidermal nerve fiber loss and/or defec- tive regeneration and that NRP-1 receptor could change the epidermal environment to a nerve fiber repellant bed possibly through Sem3A in diabetes.

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

We have investigated the pharmacokinetics and pharmacodynamics of propofol in 11 patients with end-stage renal disease (ESRD) compared with nine healthy patients during and after a manually controlled three-stage infusion of propofol 21, 12 and 6 mg kg-1 h-1 lasting a minimum of 2 h. Mean total body clearance was not reduced significantly in the ESRD group (30.66 (SD 8.47) ml kg-1 min-1) compared with the control group (33.75 (7.8) ml kg-1 min-1). ESRD patients exhibited a greater, but not statistically significant, volume of distribution at steady state compared with patients in the control group (11.25 (8.86) vs 5.79 (2.14) litre kg-1, respectively). Elimination half-life values were unchanged by renal failure. Mean times to induction of anaesthesia were similar in both groups: 177 (SD 57) and 167 (58) s for the ESRD and control groups, respectively. Waking time after cessation of propofol infusion was significantly shorter in the ESRD group (474 (156) s) compared with the control group (714 (240) s) (P < 0.05). Mean plasma concentrations on waking were similar. We conclude that the pharmacokinetic and pharmacodynamic profiles of propofol after infusion were not markedly affected by renal failure., SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published