Two-Year observational study of autonomic skin function in patients with Parkinson's disease compared to healthy individuals.

BACKGROUND AND PURPOSE: We characterized autonomic pilomotor and sudomotor skin function in early Parkinson's disease (PD) longitudinally. METHODS: We enrolled PD patients (Hoehn and Yahr 1-2) and healthy controls from movement disorder centers in Germany, Hungary, and the United States. We evaluated axon-reflex responses in adrenergic sympathetic pilomotor nerves and in cholinergic sudomotor nerves and assessed sympathetic skin response (SSR), predominantly parasympathetic neurocardiac function via heart rate variability, and disease-related symptoms at baseline, after 2 weeks, and after 1 and 2 years. CLINICALTRIALS: gov: NCT03043768. RESULTS: We included 38 participants: 26 PD (60% females, aged 62.4 ± 7.4 years, mean ± SD) and 12 controls (75% females, aged 59.5 ± 5.8 years). Pilomotor function was reduced in PD compared to controls at baseline when quantified via spatial axon-reflex spread (78 [43-143], median [interquartile range] mm2 vs. 175 [68-200] mm2 , p = 0.01) or erect hair follicle count in the axon-reflex region (8 [6-10] vs. 11 [6-16], p = 0.008) and showed reliability absent any changes from baseline to Week 2 (p = not significant [ns]). Between-group differences increased over the course of 2 years (p < 0.05), although no decline was observed within groups (p = ns). Pilomotor impairment in PD correlated with motor symptoms (rho = -0.59, p = 0.017) and was not lateralized (p = ns). Sudomotor axon-reflex and neurocardiac function did not differ between groups (p = ns), but SSR was reduced in PD (p = 0.0001). CONCLUSIONS: Impairment of adrenergic sympathetic pilomotor function and SSR in evolving PD is not paralleled by changes to cholinergic sudomotor function and parasympathetic neurocardiac function, suggesting a sympathetic pathophysiology. A pilomotor axon-reflex test might be useful to monitor PD-related pathology.

Integration of Heterogeneous Biological Data in Multiscale Mechanistic Model Calibration: Application to Lung Adenocarcinoma.

Mechanistic models are built using knowledge as the primary information source, with well-established biological and physical laws determining the causal relationships within the model. Once the causal structure of the model is determined, parameters must be defined in order to accurately reproduce relevant data. Determining parameters and their values is particularly challenging in the case of models of pathophysiology, for which data for calibration is sparse. Multiple data sources might be required, and data may not be in a uniform or desirable format. We describe a calibration strategy to address the challenges of scarcity and heterogeneity of calibration data. Our strategy focuses on parameters whose initial values cannot be easily derived from the literature, and our goal is to determine the values of these parameters via calibration with constraints set by relevant data. When combined with a covariance matrix adaptation evolution strategy (CMA-ES), this step-by-step approach can be applied to a wide range of biological models. We describe a stepwise, integrative and iterative approach to multiscale mechanistic model calibration, and provide an example of calibrating a pathophysiological lung adenocarcinoma model. Using the approach described here we illustrate the successful calibration of a complex knowledge-based mechanistic model using only the limited heterogeneous datasets publicly available in the literature.

Assessment of cutaneous axon-reflex responses to evaluate functional integrity of autonomic small nerve fibers.

Cutaneous autonomic small nerve fibers encompass unmyelinated C-fibers and thinly myelinated Aδ-fibers, which innervate dermal vessels (vasomotor fibers), sweat glands (sudomotor fibers), and hair follicles (pilomotor fibers). Analysis of their integrity can capture early pathology in autonomic neuropathies such as diabetic autonomic neuropathy or peripheral nerve inflammation due to infectious and autoimmune diseases. Furthermore, intraneural deposition of alpha-synuclein in synucleinopathies such as Parkinson's disease can lead to small fiber damage. Research indicated that detection and quantitative analysis of small fiber pathology might facilitate early diagnosis and initiation of treatment. While autonomic neuropathies show substantial etiopathogenetic heterogeneity, they have in common impaired functional integrity of small nerve fibers. This impairment can be evaluated by quantitative analysis of axonal responses to iontophoretic application of adrenergic or cholinergic agonists to the skin. The axon-reflex can be elicited in cholinergic sudomotor fibers to induce sweating and in cholinergic vasomotor fibers to induce vasodilation. Currently, only few techniques are available to quantify axon-reflex responses, the majority of which is limited by technical demands or lack of validated analysis protocols. Function of vasomotor small fibers can be analyzed using laser Doppler flowmetry, laser Doppler imaging, and laser speckle contrast imaging. Sudomotor function can be assessed using quantitative sudomotor axon-reflex test, silicone imprints, and quantitative direct and indirect testing of sudomotor function. More recent advancements include analysis of piloerection (goose bumps) following stimulation of adrenergic small fibers using pilomotor axon-reflex test. We provide a review of the current literature on axon-reflex tests in cutaneous autonomic small fibers.

Evidence for cephalic phase insulin release in humans: A systematic review and meta-analysis.

The initial release of insulin in response to food stimuli acting on receptors in the head and oropharynx is called the cephalic phase of insulin secretion. Insulin has been shown to act centrally to regulate food intake and glucose metabolism and the cephalic phase of insulin secretion may contribute to these functions. Though well documented in laboratory animals, the existence of cephalic phase insulin release in humans has recently come into question. We therefore performed a systematic review and meta-analysis of studies of cephalic phase insulin release in humans. Efficacy outcomes included any change in circulating insulin levels in healthy human volunteers post any food stimulus as compared to baseline or control in a time period of no longer than 10 min. Primary outcome: The overall pooled effect size estimate for cephalic phase insulin release was 0.47 [0.36, 0.58] p-value <0.0001. Secondary outcomes: A random effects meta-analysis with an added moderator for type of stimulus presentation (one, two, four or five sensory qualities) and type of stimulus offered (liquid, solid formulation) also significantly influenced results p = 0.0116 and p = 0.0024 respectively, while sex had no significant effect. Sensitivity Analysis: More restrictive analyses only including studies that used non-ingestive stimuli (p = 0.0001), or studies that reported insulin values within 5 min post stimulus presentation (p < 0.0001) still showed significant positive overall effect size estimates. In summary, our analysis shows that there is evidence for the presence of cephalic phase insulin secretion in humans. Secondary analyses suggest that the type and presentation of stimulus may significantly influence cephalic phase insulin secretion, while sex had no significant effect on cephalic phase insulin secretion.

Sex-specific efficacy and safety of cryoballoon versus radiofrequency ablation for atrial fibrillation: A systematic review and meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is a growing healthcare burden, for which pulmonary vein isolation (PVI) using cryoballoon (CB) or radiofrequency (RF) represent attractive therapies. Women are at higher risk of recurrence after AF ablation and present a specific complications profile. Therefore, a systematic catheter-specific assessment of pulmonary vein isolation is urgently needed in women. OBJECTIVE: Systematically assessing the sex-specific efficacy/safety of CB vs RF ablation. METHODS: We performed a structured database search of the scientific literature for randomized controlled trials (RCTs) and observational prospective studies (OPS) comparing CB and RF ablation efficacy at 1 year. We investigated the reporting of sex-specific analyses and assessed the comparative sex-specific efficacy, safety and procedural characteristics of CB vs RF using random-effect meta-regression accounting for the proportion of enrolled women. RESULTS: Twenty-three studies were included (18 OPS and 5 RCTs) for a total of 13 509 patients. Sex-specific outcomes by ablation device were reported in two and sex-specific regression in four studies, none of which took the ablation device into account. Meta-regression accounting for the proportion of enrolled women showed no significant difference in outcomes between RF or CB. CONCLUSION: The sex-specific reporting in trials comparing CB to RF is extremely low. A quantitative meta-regression using the percentage of enrolled women as sex-specific indicator did not show any difference between CB and RF but acknowledging the low percentage of enrolled women and the lack of sex-specific data, further research including patient-level data is urgently needed to draw more definitive conclusions.

Assessment of sudomotor function.

PURPOSE: To review the currently available literature on clinical autonomic tests of sudomotor function. METHODS: We searched PubMED/MEDLINE for articles on technical principles and clinical applications of sudomotor tests with a focus on their drawbacks and perspectives in order to provide a narrative review. RESULTS: The quantitative sudomotor axon reflex sweat test (QSART) is the most widely used test of sudomotor function. The technique captures pathology with low intra- and inter-subject variability but is limited by technical demands. The thermoregulatory sweat test comprises topographic sweat pattern analysis of the ventral skin surface and allows differentiating preganglionic from postganglionic sudomotor damage when combined with a small fiber test such as QSART. The sympathetic skin response also belongs to the more established techniques and is used in lie detection systems due to its high sensitivity for sudomotor responses to emotional stimuli. However, its clinical utility is limited by high variability of measurements, both within and between subjects. Newer and, therefore, less widely established techniques include silicone impressions, quantitative direct and indirect axon reflex testing, sensitive sweat test, and measurement of electrochemical skin conductance. The spoon test does not allow a quantitative assessment of the sweat response but can be used as bedside-screening tool of sudomotor dysfunction. CONCLUSION: While new autonomic sudomotor function testings have been developed and studied over the past decades, the most were well-studied and established techniques QSART and TST remain the gold standard of sudomotor assessment. Combining these techniques allows for sophisticated analysis of neurally mediated sudomotor impairment. However, newer techniques display potential to complement gold standard techniques to further improve their precision and diagnostic value.

Effect of short-term heart rate variability biofeedback on long-term abstinence in alcohol dependent patients - a one-year follow-up.

BACKGROUND: A randomized controlled study (RCT) recently showed that short-term heart rate variability (HRV) biofeedback in addition to standard rehabilitation care for alcohol dependence can reduce craving, anxiety and improve cardiovascular autonomic function. In this one-year follow-up study we aimed to explore whether completion of 2-week HRV-Biofeedback training is associated with long-term abstinence. Furthermore, we sought to identify potential predictors of post-treatment abstinence. METHODS: We conducted a survey on abstinence in patients with alcohol dependence 1 year after completion of an RCT comparing HRV-biofeedback in addition to inpatient rehabilitation treatment alone (controls). Abstinence rates were compared and analysed for association with demographic data as well as psychometric and autonomic cardiac assessment before and after completion of the biofeedback training using bivariate and multivariate regression analyses. RESULTS: Out of 48 patients who participated in the RCT, 27 patients (9 females, ages 42.9 ± 8.6, mean ± SD) completed our one-year follow-up. When including in the analysis only patients who completed follow-up, the rate of abstinence tended to be higher in patients who underwent HRV-biofeedback 1 year earlier compared to those who received rehabilitative treatment alone (66.7% vs 50%, p = ns). This non-significant trend was also observed in the intention-to-treat analysis where patients who did not participate in the follow-up were assumed to have relapsed (46,7% biofeedback vs. 33.3% controls, p = ns). Neither cardiac autonomic function nor psychometric variables were associated with abstinence 1 year after HRV-biofeedback. CONCLUSION: Our follow-up study provide a first indication of possible increase in long-term abstinence after HRV-biofeedback for alcohol dependence in addition to rehabilitation. TRIAL REGISTRATION: The original randomized controlled trial was registered in the German Clinical Trials Register ( DRKS00004618 ). This one-year follow-up survey has not been registered.

Intraoperative biomarkers in renal transplantation.

The emerging need for biomarkers in the management of renal transplantation is highlighted by the severity of related complications such as acute renal failure and ischaemia/reperfusion injury (IRI) and by the increasing efforts to identify novel markers of these events to predict and monitor delayed graft function (DGF) and long-term outcome. In clinical studies candidate markers such as kidney injury molecule-1, neutrophil gelatinase-associated lipocalin and interleukin-18 have been demonstrated to be valid biomarkers with high predictive value for DFG in a post-transplant setting. However, studies investigating biomarkers for early diagnosis of IRI and assumable DGF as well as identification of potential graft recipients at increased risk at the time point of transplantation lack further confirmation and translation into clinical practice. This review summarizes the current literature on the value of IRI biomarkers in outcome prediction following renal transplantation as well their capacity as surrogate end points from an intraoperative perspective.

Autonomic Dysregulation in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic, progressive central neurological disease characterized by inflammation and demyelination. In patients with MS, dysregulation of the autonomic nervous system may present with various clinical symptoms including sweating abnormalities, urinary dysfunction, orthostatic dysregulation, gastrointestinal symptoms, and sexual dysfunction. These autonomic disturbances reduce the quality of life of affected patients and constitute a clinical challenge to the physician due to variability of clinical presentation and inconsistent data on diagnosis and treatment. Early diagnosis and initiation of individualized interdisciplinary and multimodal strategies is beneficial in the management of autonomic dysfunction in MS. This review summarizes the current literature on the most prevalent aspects of autonomic dysfunction in MS and provides reference to underlying pathophysiological mechanisms as well as means of diagnosis and treatment.

The Effects of Pretreatment versus De Novo Treatment with Selective Serotonin Reuptake Inhibitors on Short-term Outcome after Acute Ischemic Stroke.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) administered in patients following acute ischemic stroke have shown to improve clinical recovery independently of changes in depression. Animal studies have demonstrated that sustained SSRI treatment is superior to short-term SSRI in evoking neurogenesis but how this benefit translates into humans remains to be answered. We hypothesized that in acute ischemic stroke patients, SSRI treatment started before the event leads to improved short-term outcomes compared to de novo SSRI treatment poststroke. METHODS: We performed an exploratory analysis in consecutive acute ischemic stroke patients and compared patients already receiving fluoxetine, citalopram, or escitalopram with those who started treatment de novo. RESULTS: Of 2653 screened patients, 239 were included (age, 69 ± 14 years; 42% men, baseline median National Institutes of Health Stroke Scale score, 7 [IQR, 10]). Of these patients, 51 started treatment with SSRI before stroke and 188 were prescribed newly SSRIs during hospitalization. In the adjusted multivariate logistic regression models, SSRI pretreatment was associated with favorable functional outcome at discharge defined as a modified Rankin Scale score of 2 or less (odds ratio [OR], 4.00; 95% confidence interval [CI], 1.68-9.57; P < .005), improved early clinical recovery (OR, 2.35; 95% CI, 1.15-4.81; P = .02), and a trend toward prediction of superior motor recovery (OR, 1.82; 95% CI, .90-3.68; P < .01). CONCLUSIONS: Our data suggest that SSRI pretreatment may improve clinical outcomes in the early stages of acute ischemic stroke supporting the hypothesis that prolonged SSRI treatment started prestroke is superior to poststroke SSRI.

CR1-mediated ATP release by human red blood cells promotes CR1 clustering and modulates the immune transfer process.

Humans and other higher primates are unique among mammals in using complement receptor 1 (CR1, CD35) on red blood cells (RBC) to ligate complement-tagged inflammatory particles (immune complexes, apoptotic/necrotic debris, and microbes) in the circulation for quiet transport to the sinusoids of spleen and liver where resident macrophages remove the particles, but allow the RBC to return unharmed to the circulation. This process is called immune-adherence clearance. In this study we found using luminometric- and fluorescence-based methods that ligation of CR1 on human RBC promotes ATP release. Our data show that CR1-mediated ATP release does not depend on Ca(2+) or enzymes previously shown to mediate an increase in membrane deformability promoted by CR1 ligation. Furthermore, ATP release following CR1 ligation increases the mobility of the lipid fraction of RBC membranes, which in turn facilitates CR1 clustering, and thereby enhances the binding avidity of complement-opsonized particles to the RBC CR1. Finally, we have found that RBC-derived ATP has a stimulatory effect on phagocytosis of immune-adherent immune complexes.

A systematic review of the clinical characteristics and course of atrioventricular blocks in hyperthyroidism.

BACKGROUND: Atrioventricular block (AVB) is rare in hyperthyroidism (HTH). Little is known about the true prevalence, clinical course, optimal management, and outcomes of different types of AVBs in patients with HTH. To address these uncertainties, we aimed to conduct a systematic review by combining the available literature to provide more meaningful data regarding AVBs in HTH. METHODS: We systematically searched PubMed, Scopus, Embase, and Google Scholar for articles reporting patients who developed AVB in the context of HTH. Data were analysed in STATA 16. The main outcomes included types of AVB, frequency of pacemaker insertion, and resolution of AVB. The systematic review is registered with the International Prospective Register of Systematic Reviews (PROSPERO) with the identification number CRD42022335598. RESULTS: A total of 56 studies (39 case reports, 12 case series, 3 conference abstracts, 1 retrospective study, and 1 prospective observational study) with 87 patients were included in the analysis, with a mean age of 39.1 ± 17.6 years. Females constituted 65.7% (n = 48) of the cohort. Complete heart block (CHB) was the most commonly reported AVB (N = 45, 51.7%), followed by first-degree AVB (16.1%) and second-degree AVB (14.9%). Overall, 21 patients underwent pacing. A permanent pacemaker was inserted in one patient with second-degree AVB and six patients with CHB. Mortality was reported in one patient with CHB. The clinical course and management of HTH and AVBs did not differ in patients with CHB or lower-degree blocks. Apart from lower rates of goitre and more use of carbimazole in those who underwent pacing, no differences were found when compared to the patients managed without pacing. CONCLUSION: Current data suggest that CHB is the most common type of AVB in patients with HTH. Most patients can be managed with anti-thyroid management alone. Additionally, whether pacemaker insertion alters the clinical outcomes needs further exploration.

An animal model of endocardial fibroelastosis.

BACKGROUND: Hypoplastic left heart syndrome (HLHS) is one of the most common severe congenital cardiac anomalies, characterized by a marked hypoplasia of left-sided structures of the heart, which is commonly accompanied by a thick layer of fibroelastic tissue, termed endocardial fibroelastosis (EFE). Because human EFE develops only in fetal or neonatal hearts, and often in association with reduced blood flow, we sought to mimic these conditions by subjecting neonatal and 2-wk-old rat hearts to variations of the heterotopically transplanted heart model with either no intracavitary or normal flow and compare endocardium with human EFE tissue. MATERIALS AND METHODS: Hearts obtained from neonatal and 2-wk-old rats were heterotopically transplanted in young adult Lewis rats in a working (loaded) or nonworking (unloaded) mode. After 2-wk survival, hearts were explanted for histologic analysis by staining for collagen, elastin, and cellular elements. These sections were compared with human EFE tissue from HLHS. RESULTS: EFE, consisting of collagen and elastin with scarce cellular and vascular components, developed only in neonatal unloaded transplanted hearts and displayed the same histopathologic findings as EFE from patients with HLHS. Loaded hearts and 2-wk-old hearts did not show these alterations. CONCLUSIONS: This animal model for EFE will serve as a tool to study the mechanisms of EFE formation, such as fluid forces, in HLHS in a systematic manner. A better understanding of the underlying cause of the EFE formation in HLHS will help to develop novel treatment strategies to better preserve growth of the hypoplastic left ventricle.

Polymyositis with cytochrome C oxidase negative fibers--a pathological and clinical challenge.

Polymyositis (PM) with cytochrome C oxidase negative fibers also referred to as PM with mitochondrial pathology (PM-Mito) is characterized by the symptoms of inclusion body myositis (IBM) and by the myopathological findings of PM except for an increase of muscle fibers with insufficient mitochondrial cytochrome C oxidase activity. Few PM-Mito cases are published; mitochondrial ultrastructure has not been studied in these patients. We report 2 PM-Mito patients with later onset than usually seen in IBM and poor responsiveness to glucocorticoids. Electron microscopy of muscle fibers showed irregular mitochondrial ultrastructure. Sjögren syndrome related antinuclear antibodies (Anti-Ro and Anti-La) were found in one of the two patients but the typical clinical symptoms of Sjögren syndrome such as xerostomia and keratoconjunctivitis were absent in this patient. Taken together, our observations, viewed in conjunction with the current literature, suggest that PM-Mito is an underdiagnosed disease with a multifactorial pathogenesis that should be elucidated in further studies. We want to encourage clinicians and pathologists to consider the possibility of PM-Mito in patients with atypical PM or sIBM.

Anti-Inflammatory Treatment Efficacy in Major Depressive Disorder: A Systematic Review of Meta-Analyses.

Purpose: Immune imbalances in major depressive disorder (MDD) have been targeted by anti-inflammatory treatment approaches in clinical trials to increase responsiveness to therapy. However, even after several meta-analyses, no translation of evidence into clinical practice has taken place. We performed a systematic review to evaluate meta-analytic evidence of randomized controlled trials on the use of anti-inflammatory agents for MDD to summarize efficacy estimates and elucidate shortcomings. Methods: Pooled effect estimates and heterogeneity indices were primary outcomes. Characteristics of the included meta-analyses were extracted. Scientific quality of meta-analyses was assessed using the Revised Assessment of Multiple Systematic Reviews (R-AMSTAR). Results: N=20 meta-analyses met the eligibility criteria. Study characteristics like outcome scales, composition of patient populations, and add-on or monotherapy regimen varied very little for celecoxib studies, varied little for minocycline studies, and were rather variable for omega 3 fatty acids studies. R-AMSTAR scores ranged from 26 to 39 out of 44 points indicating variable quality, where a comprehensive literature search was the strongest and the consideration of scientific quality in the conclusions was the weakest domain across all meta-analyses. For minocycline and celecoxib, superiority was demonstrated with medium to large effect size with substantial heterogeneity and with large to very large effect size with negligible heterogeneity, respectively. For omega 3 fatty acids, superiority was also demonstrated with mainly small and medium effect sizes with substantial heterogeneity. However, for minocycline and omega 3 fatty acids, non-significant meta-analyses were found also. Conclusion: Even in our synthesized approach, no clear recommendations could be derived on the use of anti-inflammatory treatment for MDD due to several critical aspects like heterogeneity, diversity of patient populations, treatment regimen, and outcomes, and limited scientific quality. However, we observed clear inter-substance differences with meta-analytic evidence being strongest for celecoxib and weakest for omega 3 fatty acids.

Canal wall up versus canal wall down mastoidectomy techniques in the pediatric population with cholesteatoma: A systematic review and meta-analysis of comparative studies.

IMPORTANCE: The optimal surgical management of cholesteatoma remains controversial. Within pediatric otolaryngology, one of the most vital points of contention is the selection of canal wall-up (CWU) versus canal wall-down (CWD) procedures. Pediatric cholesteatoma has high rates of recurrence (16%-54%). In adults, there is evidence that the selection of surgical techniques affects recurrence rates. This has not been shown in children. OBJECTIVES: 1. To systematically review the literature on recurrent and residual cholesteatoma after CWU and CWD in children and perform a meta-analysis of the data. 2. To assess the rates of recurrent and residual cholesteatoma between CWU and CWD techniques in pediatric patients. 3. To assess hearing outcomes by evaluating postoperative differences in the air-bone gap (ABG) between CWU and CWD techniques. DATA SOURCES: A systematic search of PubMed, Embase, Scopus, and Cochrane Collaboration was performed from inception to May 1st, 2020, to identify studies that compared CWU and CWD procedures for acquired cholesteatoma in children. STUDY SELECTION: Search records were screened in duplicate by four reviewers. Inclusion criteria consisted of comparative randomized clinical trials and observational studies assessing outcomes of CWU and CWD techniques in the pediatric population. Studies involving patients with congenital cholesteatoma were excluded. DATA EXTRACTION AND SYNTHESIS: Four reviewers working independently and in duplicate systematically reviewed and extracted study data. Dichotomous variables were analyzed as risk ratios (RR), while continuous variables were compared using weighted mean differences (MD). The risk of bias was assessed using the CLARITY Scale. PRIMARY OUTCOMES AND MEASURES: The outcomes were recurrence, residual disease, air-bone gap (ABG), and air conductive (AC) thresholds. RESULTS: After screening 1036 publications, 17 retrospective cohort studies were selected. 1333 children were included; the overall mean age was ten years (SD 7.9), and the overall mean follow-up time was 5.9 years (SD 6.6). CWU and CWD techniques were performed in 60% (796) and 40% (537) cases. We did not find differences in cholesteatoma recurrence (RR: 1.50, 95% CI 0.94; 2.40; n = 544; I2 0%; Tau [2]: 0.00), or rates of residual cholesteatoma (RR 1.51, 95% CI 0.96; 2.38, n = 506; I2: 0%; Tau [2]: 0.00) in patients who underwent CWU and CWD mastoidectomy. The mean air-bone gap was lower with CWU than CWD (mean difference: 7.60, 95% CI -10.65; -4.54; n = 242; I2: 71%; Tau [2]: 5.98). CONCLUSION: and relevance: We show similar rates of recurrence and residual disease after either CWU or CWD tympanoplasty. Our results challenge the fundamental principle of CWD surgery as a standard technique, as there is no difference in rates of recurrence and residual disease in CWU and CWD. Moreover, audiometric results support CWU with improved hearing outcomes. TRIAL REGISTRATION: PROSPERO identifier: CRD42020184029.

Increased Frequency of Severe Hypoglycemia with the Modified-Release Gliclazide Compared to Glimepiride in Diabetic Older Adults; Propensity Score-Adjusted Analysis.

Objective: The main aim is to compare the risk of severe hypoglycemia associated with the modified-release (MR) gliclazide against glimepiride in diabetic older adults. Methods: All older adult diabetic patients who attended the emergency department (ED) between the 1st of Aug. 2017 and the end of Mar 2020 on gliclazide MR or glimepiride are included in two cohorts. We compared baseline differences between cohorts in demographics, lab results, diabetes complications, comorbidities, and drugs using the chi-squared test for categorical variables and unpaired t-test for continuous variables. All the baseline variables are used in a logistic regression to produce the propensity scores for receiving gliclazide MR. The primary outcome was Severe Hypoglycemia requiring Emergency Admission (SHEA). We used documented hypoglycemia, falls, fractures, Cardiovascular ED Admission (CVEA), and recurrent ED admissions as secondary outcomes. We used a univariate logistic regression followed by a propensity score-adjusted logistic regression to identify the adjusted odds ratio. We did a subgroup analysis for low and moderate-high doses users. Results: We included 2320 patients, 1786 were on gliclazide MR while 534 were on glimepiride. The risk of SHEA (Adjusted Odds Ratio AOR 6.74, p=0.002), falls (AOR 1.43, p=0.003), fractures (AOR 1.43, p=0.01), CVEA (AOR 1.66, p<0.001), recurrent ED admission (AOR 1.39, p=0.002) were significantly higher. At the same time, documented hypoglycemia was insignificantly higher (AOR 1.17, p= 0.444) with gliclazide MR compared to glimepiride. The low doses of both treatments did not show any SHEA cases, while the results with higher doses showed the same pattern of increased risk with gliclazide MR as the principle analysis. Conclusion: Using gliclazide MR for older patients may not be a relatively safer alternative to avoid severe hypoglycemia and its possible consequences compared to glimepiride. It may be added to glimepiride in the Beers list of medications to be avoided in older adults.

Perceptions and attitudes toward participation in clinical research in the Eastern Mediterranean Region: A systematic review.

INTRODUCTION: Successful recruitment of participants into clinical research has always been challenging and is affected by many factors. This systematic review aimed to explore the perceptions and attitudes as well as identify the factors affecting the participation in clinical research among the Eastern Mediterranean Regional Office countries' population. METHODS: A systematic search of the literature was conducted to explore attitudes or perceptions of the general public or patients towards participation in clinical research. PubMed, Pro-Quest Central, World Health Organizations Index Medicus for the Eastern Mediterranean Region, and Google Scholar were searched. Studies were considered eligible for inclusion if they presented primary data and were conducted in one of the Eastern Mediterranean Regional Office countries. A data extraction sheet was used to record the following: year, country, aim, population, sample size, study design, data collection, and setting. The identified factors from the included studies were categorized into motivators and barriers. RESULTS: In total, 23 original research articles were identified that addressed perceptions or attitudes towards clinical research participation. Six main motivators and barriers of research participation among patients, the general public, and patient family members were identified. The most common cited motivators included personal benefits to the individual, altruism and the desire to help others, the research process, the influence of the physician, family encouragement, and religion. Concerns regarding safety, confidentiality, and other factors in addition to the research process, lack of trust in healthcare providers or healthcare system, lack of interest in research and no perceived personal benefit, religious concerns, and family/cultural concerns were the most cited barriers to participation. CONCLUSION: The identified motivators and barriers are essential to tackle during clinical research planning among the population of Eastern Mediterranean Regional Office countries. Further research is needed to assess the attitudes and perceptions of individuals approached to participate in trials.

Etiology, pathological characteristics, and clinical management of black pleural effusion: A systematic review.

BACKGROUND: Pleural effusion is characterized by excessive fluid collection in the pleural cavity. Black pleural effusion (BPE) is a rare entity with only limited scientific data. We aimed to review the current literature on black pleural effusion to characterize demographics, etiology, clinical presentation, pathological findings, available treatment strategies, and prognosis of this rare condition. METHODS: We performed a systematic review of case reports and series and synthesized data on demographics, manifestations, management, and outcomes of patients with BPE. We searched Cochrane Library, PubMed, SCOPUS, and Google Scholar for any date until January 10, 2021. All studies (n = 31) that reported black pleural effusion in patients were added to the review. Prospective Register of Systematic Reviews registration number: CRD42020213839. Summary and descriptive analysis was performed on Jamovi version 1.2. RESULTS: The mean age of 32 patients with BPE was 53 years, with male predominance (69%). The commonest risk factor was smoking (n = 9) followed by alcohol intake (n = 8). Dyspnea was the commonest symptom (n = 24, 75%). Pleural fluid was mostly exudative (n = 21). The commonest associated diagnosis was malignancy (n = 14), with 50% secondary to metastatic melanoma. The commonest intervention was therapeutic thoracocentesis (n = 25, 78%), and the effusion recurred in half of the cases where recurrence was reported (n = 13). In our review, we found the mortality rate to be at 20.8% (n = 20.8%). 58.3% of the patients were successfully treated and discharged home (n = 14). CONCLUSION: Although rare, BPE appears to be a relevant symptom as it seems to be frequently associated with modifiable risk factors and underlying malignancy. Our systematic review substantiates a vital research gap as observational research is imperative to characterize BPE further and form a basis for designing tailored diagnostic, preventive, and therapeutic strategies for BPE.

Biologics and small molecules in patients with scalp psoriasis: a systematic review.

BACKGROUND: Scalp psoriasis is common in psoriasis patients, difficult to treat and manifests a significant burden on quality of life. OBJECTIVE: Efficacy assessment of biologics and small molecules in scalp psoriasis with reported safety and quality of life. METHODS: Biological therapies and small molecules licensed for treatment of plaque psoriasis are assessed. Fourteen studies reporting results from RCTs are included. Efficacy assessment is measured through improvement of Psoriasis Scalp Severity Index (PSSI), Scalp Physician Global Assessment (ScPGA) and/or Scalp-Specific Investigator's Global Assessment (ss-IGA). RESULTS: Among biologics measured by PSSI, brodalumab, secukinumab and in a subgroup ixekizumab showed high efficacy in moderate to severe scalp psoriasis. Both brodalumab and ixekizumab demonstrated rapid response within 2 weeks. Guselkumab was superior to adalimumab and ixekizumab was superior to etanercept. Apremilast showed long-term efficacy. Only few studies reported quality of life in treatment of scalp involvement which showed improvement. All treatments demonstrated acceptable safety profile. CONCLUSION: Effective treatment of scalp psoriasis is essential for improving the quality of life of psoriasis patients. Both Biologics and small molecules proved efficacy. This review may help choosing the appropriate treatment in cases where scalp psoriasis is the main complaint. A unified measurement tool for scalp psoriasis severity is needed to facilitate comparisons.