Contextualising adverse events of special interest to characterise the baseline incidence rates in 24 million patients with COVID-19 across 26 databases: a multinational retrospective cohort study.

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.

Statin Intake and All-Cause Mortality among Older Nursing Home Residents.

BACKGROUND: Statins are progressively accepted as being associated with reduced mortality. However, few real-world statin studies have been conducted on statin use in older people and especially the most frail, that is, the nursing home residents. OBJECTIVE: The aim of this study was to evaluate the impact of statin intake in nursing home residents on all-cause mortality. METHOD: This is a cross-sectional study of 1,094 older people residing in 6 nursing homes in Flanders (Belgium) between March 1, 2020 and May 30, 2020. We considered all residents who were taking statins for at least 5 days as statin users. All-cause mortality during the 3 months of data collection was the primary outcome. Propensity score overlap-weighted logistic regression models were applied with age, sex, functional status, diabetes, and cardiac failure/ischemia as potential confounders. RESULTS: 185 out of 1,094 residents were on statin therapy (17%). The statin intake was associated with decreased all-cause mortality: 4% absolute risk reduction; adjusted odds ratio 0.50; CI 0.31-0.81, p = 0.005. CONCLUSIONS: The statin intake was associated with decreased all-cause mortality in older people residing in nursing homes. More in-depth studies investigating the potential geroprotector effect of statins in this population are needed.

Hospital mortality in COVID-19 patients in Belgium treated with statins, ACE inhibitors and/or ARBs.

The COVID-19 pandemic has disrupted life throughout the world. Newly developed vaccines promise relief to people who live in high-income countries, although vaccines and expensive new treatments are unlikely to arrive in time to help people who live in low-and middle-income countries. The pathogenesis of COVID-19 is characterized by endothelial dysfunction. Several widely available drugs like statins, ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have immunometabolic activities that (among other things) maintain or restore endothelial cell function. For this reason, we undertook an observational study in four Belgian hospitals to determine whether in-hospital treatment with these drugs could improve survival in 959 COVID-19 patients. We found that treatment with statins and ACEIs/ARBs reduced 28-day mortality in hospitalized COVID-19 patients. Moreover, combination treatment with these drugs resulted in a 3-fold reduction in the odds of hospital mortality (OR = 0.33; 95% CI 0.17-0.69). These findings were in general agreement with other published studies. Additional observational studies and clinical trials are needed to convincingly show that in-hospital treatment with statins, ACEIs/ARBs, and especially their combination saves lives.

Adjunctive Use of Statins for COVID-19.

The interaction between obesity, cardiometabolic disorders and COVID-19 represents a syndemic that requires both social intervention and a multipharmacological approach [...].

Accurate prediction of clinical stroke scales and improved biomarkers of motor impairment from robotic measurements.

OBJECTIVE: One of the greatest challenges in clinical trial design is dealing with the subjectivity and variability introduced by human raters when measuring clinical end-points. We hypothesized that robotic measures that capture the kinematics of human movements collected longitudinally in patients after stroke would bear a significant relationship to the ordinal clinical scales and potentially lead to the development of more sensitive motor biomarkers that could improve the efficiency and cost of clinical trials. MATERIALS AND METHODS: We used clinical scales and a robotic assay to measure arm movement in 208 patients 7, 14, 21, 30 and 90 days after acute ischemic stroke at two separate clinical sites. The robots are low impedance and low friction interactive devices that precisely measure speed, position and force, so that even a hemiparetic patient can generate a complete measurement profile. These profiles were used to develop predictive models of the clinical assessments employing a combination of artificial ant colonies and neural network ensembles. RESULTS: The resulting models replicated commonly used clinical scales to a cross-validated R2 of 0.73, 0.75, 0.63 and 0.60 for the Fugl-Meyer, Motor Power, NIH stroke and modified Rankin scales, respectively. Moreover, when suitably scaled and combined, the robotic measures demonstrated a significant increase in effect size from day 7 to 90 over historical data (1.47 versus 0.67). DISCUSSION AND CONCLUSION: These results suggest that it is possible to derive surrogate biomarkers that can significantly reduce the sample size required to power future stroke clinical trials.

The Effects of ARBs, ACEis, and Statins on Clinical Outcomes of COVID-19 Infection Among Nursing Home Residents.

OBJECTIVES: Angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), and HMG-CoA reductase inhibitors ("statins") have been hypothesized to affect COVID-19 severity. However, up to now, no studies investigating this association have been conducted in the most vulnerable and affected population groups (ie, older adults residing in nursing homes). The objective of this study was to explore the association of ACEi/ARB and/or statins with clinical manifestations in COVID-19-infected older adults residing in nursing homes. DESIGN: We undertook a retrospective multicenter cohort study to analyze the association between ACEi/ARB and/or statin use with clinical outcome of COVID-19. The outcomes were (1) serious COVID-19 defined as long-stay hospital admission or death within 14 days of disease onset, and (2) asymptomatic (ie, no disease symptoms in the whole study period while still being diagnosed by polymerase chain reaction). SETTING AND PARTICIPANTS: A total of 154 COVID-19-positive subjects were identified, residing in 1 of 2 Belgian nursing homes that experienced similar COVID-19 outbreaks. MEASURES: Logistic regression models were applied with age, sex, functional status, diabetes, and hypertension as covariates. RESULTS: We found a statistically significant association between statin intake and the absence of symptoms during COVID-19 (odds ratio [OR] 2.91; confidence interval [CI] 1.27-6.71), which remained statistically significant after adjusting for covariates (OR 2.65; CI 1.13-6.68). Although the effects of statin intake on serious clinical outcome were in the same beneficial direction, these were not statistically significant (OR 0.75; CI 0.24-1.87). There was also no statistically significant association between ACEi/ARB and asymptomatic status (OR 2.72; CI 0.59-25.1) or serious clinical outcome (OR 0.48; CI 0.10-1.97). CONCLUSIONS AND IMPLICATIONS: Our data indicate that statin intake in older, frail adults could be associated with a considerable beneficial effect on COVID-19 clinical symptoms. The role of statins and renin-angiotensin system drugs needs to be further explored in larger observational studies as well as randomized clinical trials.

Relating the Diers formetric measurements with the subjective severity of acute and chronic low back pain.

BACKGROUND CONTEXT: Nonspecific low back pain (LBP) is a common disorder with a high economic, social and psychological burden. Many systems have been developed for evaluating the severity of LBP, though these are mainly based on scoring questionnaires for the functional status of the patients. Objective quantifiable methods relating LBP with anthropometric factors are scarce. PURPOSE: To find the correlates of nonspecific LBP with spine shape variables and demographic characteristics. To investigate the possible relationship between the latter and the result of a questionnaire subjectively quantifying the severity of LBP. STUDY DESIGN/SETTING: This is a pragmatic observational prospective cohort study. PATIENT SAMPLE: 218 subjects participated in this study. A first group of participants were 160 patients consulting at an osteopathic outpatient clinic for back pain complaints. The second group consisted of 58 healthy pain-free volunteers. OUTCOME MEASURES: The Oswestry Disability Index (ODI) was used to quantify the degree of functional impairment due to low back pain. The surface topography of the back was registered statically with the Diers-4D formetric® system. METHODS: Multivariate analyses of the DIERS 4D formetric system recordings in the subjects with or without nonspecific, acute or chronic LBP. RESULTS: Different patterns between female and male subjects were found. Age, coronal and sagittal imbalance correlated with LBP in female subjects, whereas pelvic inclination, the trunk torsion and apical deviation correlated with LBP in male. Multivariate analyses allowed creating an algorithm to predict the functional disability (predicted LBP-score, PLBP), based on the above variables for females and males. Logistic stepwise regression analysis indicated the probability of a patient having a LBP-score above or below ODI 20 (P= <0.0001), which is considered the clinically relevant threshold value for justifying absence from work. CONCLUSIONS: In this study LBP was correlated with spine shape variables leading to an algorithm predicting the functional disability of a patient due to LBP. Discrepancies between the model and the ODI result may suggest elements that are clinically relevant.

Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials.

Liver enzyme concentrations are measured as safety end points 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 and AST) in subjects randomized to placebo who completed assessments over 36 mo in a cardiovascular outcome trial [the Stabilisation of Atherosclerotic Plaque by Initiation of Darapladib Therapy ("STABILITY") trial; n = 4,264; mean age: 64.2 yr] or over 12 mo in three 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 men, <65 yr old, and obese and who had glomerular filtration rate (GFR) >60 ml·min-1·1.73 m-2. 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 sex, age, T2D, BMI, and BMI change in subjects receiving placebo in clinical trials. NEW & NOTEWORTHY Clinical trials provide high-quality data on liver enzyme concentrations from subjects randomized to placebo that can be used to investigate the epidemiology of these biomarkers. The adjusted models show the influence of sex, age, time, renal function, type 2 diabetes, HbA1c, and body mass index on alanine aminotransferase and aspartate aminotransferase concentrations and their relative importance. These factors need to be considered when assessing potential signals of hepatotoxicity in trials of new drugs and in clinical trials investigating subjects with nonalcoholic fatty liver disease.

NRP-1 Receptor Expression Mismatch in Skin of Subjects with Experimental and Diabetic Small Fiber Neuropathy.

The in vivo cutaneous nerve regeneration model using capsaicin is applied extensively to study the regenerative mechanisms and therapeutic efficacy of disease modifying molecules for small fiber neuropathy (SFN). Since mismatches between functional and morphological 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 neuropathy, 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 immunofluorescence and analyzed with Definiens® technology. This study indicates that capsaicin application results in significant loss of epidermal NRP-1 receptor expression, whereas diabetic 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 diabetic 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 defective regeneration and that NRP-1 receptor could change the epidermal environment to a nerve fiber repellant bed possibly through Sem3A in diabetes.

Robotic measurement of arm movements after stroke establishes biomarkers of motor recovery.

BACKGROUND AND PURPOSE: Because robotic devices record the kinematics and kinetics of human movements with high resolution, we hypothesized that robotic measures collected longitudinally in patients after stroke would bear a significant relationship to standard clinical outcome measures and, therefore, might provide superior biomarkers. METHODS: In patients with moderate-to-severe acute ischemic stroke, we used clinical scales and robotic devices to measure arm movement 7, 14, 21, 30, and 90 days after the event at 2 clinical sites. The robots are interactive devices that measure speed, position, and force so that calculated kinematic and kinetic parameters could be compared with clinical assessments. RESULTS: Among 208 patients, robotic measures predicted well the clinical measures (cross-validated R(2) of modified Rankin scale=0.60; National Institutes of Health Stroke Scale=0.63; Fugl-Meyer=0.73; Motor Power=0.75). When suitably scaled and combined by an artificial neural network, the robotic measures demonstrated greater sensitivity in measuring the recovery of patients from day 7 to day 90 (increased standardized effect=1.47). CONCLUSIONS: These results demonstrate that robotic measures of motor performance will more than adequately capture outcome, and the altered effect size will reduce the required sample size. Reducing sample size will likely improve study efficiency.

Individualized decreasing-dose maintenance fluconazole regimen for recurrent vulvovaginal candidiasis (ReCiDiF trial).

OBJECTIVE: Although many women with recurrent vulvovaginal candidiasis initially benefit from prophylactic intermittent treatment with antimycotics, most of them experience relapse after cessation of therapy, and often they return to the pretreatment recurrence rate. The purpose of this study was to demonstrate the efficacy and safety of an individualized, degressive, prophylactic regimen in 136 women with recurrent vulvovaginal candidiasis. STUDY DESIGN: After an induction dose of 600 mg fluconazole during the first week, 117 women started maintenance therapy: 200 mg fluconazole weekly for 2 months, followed by 200 mg biweekly for 4 months, and 200 mg monthly for 6 months, according to their individual response to therapy. All women were tested for recurrences monthly with wet mount microscopy and vaginal culture during the first 6 months and bimonthly during the next 6 months. Patients were allowed to move on to the next level of maintenance therapy only if they were symptom free and microscopy and culture negative. RESULTS: Of the women who were cured successfully after the induction phase, 101 women (90%) were disease-free after 6 months of maintenance therapy with this degressive regimen, and 80 women (77%) were disease-free after 1 year. The weekly incidence of the first clinical relapse was 0.5% during any period of the maintenance phase, and the rate of all new relapses, which included evidence of mycologic or microscopic colonization, was 1% per week. Women who experienced several relapses (poor responders) had experienced more relapses before entering the study compared with the optimal responders (odds ratio, 4.9; 95% CI,1.8-13.7; P = .002), experienced the disease for a longer period of time (6.5 vs 3.7 years; P = .06), and harbored significantly more Candida non-albicans during maintenance therapy (P = .001). No serious side-effects were noted. CONCLUSION: Individualized, degressive, prophylactic maintenance therapy with oral fluconazole is an efficient treatment regimen to prevent clinical relapses in women with recurrent vulvovaginal candidiasis.

Postoperative residual paralysis in outpatients versus inpatients.

Postoperative residual paralysis is an important complication of the use of neuromuscular blocking drugs. In this prospective study, the incidence of residual paralysis detected as a train-of-four response <90% was less frequent in surgical outpatients (38%) than inpatients (47%) (P = 0.001). This might have been the result of the more frequent use of mivacurium for outpatients. Before undertaking tracheal extubation, the anesthesiologists had applied clinical criteria (outpatients, 49%; inpatients, 45%), pharmacological reversal (26%, 25%), neuromuscular transmission monitoring (12%, 11%), or a combination of these. None of these measures seemed to reduce the incidence of residual paralysis except for quantitative train-of-four monitoring. Postoperatively, eight individual clinical tests or a sum of these tests were also unable to predict residual paralysis by train-of-four. Although the incidence of residual paralysis was less frequent in surgical outpatients, predictive criteria were not evident.