Search

Introduction: During Covid-19 pandemics, healthcare workers are on the front lines putting themselves and their families at risk this could result in mental health problems .stress is a major obstacle for health care personnel that makes them less satisfied, less capable of making the best choices and could have difficulties when confronted with their patients which affects patient's care. Mindfulness – Based stress reduction (MBSR) is a program aimed to improve awareness of one’s mental processes, become flexible and act with the principal of compassion. (2). Many researches proposed MBSR for helping practitioners of becoming less vulnerable to stressors. However, results were inconclusive. Objective: To evaluate the effectiveness of MBSR intervention in stress reduction and enhancing level of satisfaction among health care professionals. Method and design: Meta-analysis of Randomized Controlled Trials (RCTs). Data Source: Medline, Psych info, PubMed, Web science and Cochrane Library Database from 2009 till 2019 for related RCTs. Selection Criteria: Published RCTs Comparing Mindfulness- Based Stress Reduction with other modalities for stress reduction and improving level of satisfaction among health care workers and stressed personnel were eligible for inclusion. Data Collection and analysis: Data entered organized in Microsoft excel 2010 then exported to comprehensive meta-analysis software version 3. Pooled: for analysis of multiple studies, and found adjusted accumulative outcome Z score method: to test difference in mean. Test for heterogeneity: Cochran’s Q test and I2. Results: In the ALL 6 included studies, 2896 subjects. There is significant improvement in perceived stress score significantly more among intervention (MBSR) group with pooled significant difference (Mean change-3.47 & SE 1.01, Z score 8.11) with no significant heterogeneity among studies. There is significant job satisfaction improvement in MBSR group significantly more than other group with pooled significant difference (mean change 5.18, SE 1.23, Z score 13.2) with no significant heterogeneity. Conclusion: these finding support that MBSR program is effective in reducing stress and increases job satisfaction among health care professionals. KEYWORDS: Mindfulness, Health workers, Stress, COVID-19 Pandemic, Systematic review, RCTs.

Context Hyponatremia has been associated with excess long-term morbidity and mortality. However, effects during hospitalization are poorly studied. Objective The objective of this work is to examine the association of hyponatremia with the risk of in-hospital mortality, 30-day readmission, and other short-term adverse events among medical inpatients. Design and Setting A population-based cohort study was conducted using a Swiss claims database of medical inpatients from January 2012 to December 2017 Patients Hyponatremic patients were 1:1 propensity-score matched with normonatremic medical inpatients. Main Outcome Measure The primary outcome was a composite of all-cause in-hospital mortality and 30-day hospital readmission. Secondary outcomes were intensive care unit (ICU) admission, intubation rate, length-of-hospital stay (LOS), and patient disposition after discharge. Results After matching, 94 352 patients were included in the cohort. Among 47 176 patients with hyponatremia, 8383 (17.8%) reached the primary outcome compared with 7994 (17.0%) in the matched control group (odds ratio [OR] 1.06 [95% CI, 1.02-1.10], P = .001). Hyponatremic patients were more likely to be admitted to the ICU (OR 1.43 [95% CI, 1.37-1.50], P Conclusion In this study, hyponatremia was associated with increased risk of short-term adverse events, primarily driven by higher readmission rates, which was consistent among all outcomes except for decreased in-hospital mortality in SIAD patients.

Context Patients with hypopituitarism face excess mortality in the long-term outpatient setting. However, associations of pituitary dysfunction with outcomes in acutely hospitalized patients are lacking. Objective The objective of this work is to assess clinical outcomes of hospitalized patients with hypopituitarism with or without diabetes insipidus (DI). Design, Setting, and Patients In this population-based, matched-cohort study from 2012 to 2017, hospitalized adult patients with a history of hypopituitarism were 1:1 propensity score–matched with a general medical inpatient cohort. Main Outcome Measures The primary outcome was in-hospital mortality. Secondary outcomes included all-cause readmission rates within 30 days and 1 year, intensive care unit (ICU) admission rates, and length of hospital stay. Results After matching, 6764 cases were included in the study. In total, 3382 patients had hypopituitarism and of those 807 (24%) suffered from DI. All-cause in-hospital mortality occurred in 198 (5.9%) of patients with hypopituitarism and in 164 (4.9%) of matched controls (odds ratio [OR] 1.32, [95% CI, 1.06-1.65], P = .013). Increased mortality was primarily observed in patients with DI (OR 3.69 [95% CI, 2.44-5.58], P Conclusions Patients with hypopituitarism are highly vulnerable once hospitalized for acute medical conditions with increased risk of mortality and adverse clinical outcomes. This was most pronounced among those with DI.

Scalp psoriasis is common in psoriasis patients, difficult to treat and manifests a significant burden on quality of life.Efficacy assessment of biologics and small molecules in scalp psoriasis with reported safety and quality of life.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).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.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.

Background: The main symptoms of fibromyalgia comprise diffuse pain, disability, depressive symptoms, catastrophizing, sleep disruption and fatigue, associated with dysfunction of the descending pain-modulating system (DPMS). Objectives: We aimed to identify patterns of main symptoms of fibromyalgia and neuroplasticity biomarkers (i.e. brain-derived neurotrophic factor (BDNF) and S100B protein) in non-responders to the conditioned pain modulation task (CPM-task) induced by immersion of hand in cold water (0–1°C). Furthermore, we evaluated if these patterns predict responsiveness to CPM-task. Methods: This cross-sectional study included 117 women with fibromyalgia (( n = 60) non-responders and ( n = 57) responders), with age ranging from 30 to 65 years old. We analysed changes in numerical pain scale (NPS-10) during the CPM-task using a standardized protocol. Results: A hierarchical multivariate logistic regression analysis was used to construct a propensity score-adjusted index to identify non-responders compared to responders to CPM-task. The following variables were retained in the models: analgesic use four or more times per week, heat pain threshold (HPT), poor sleep quality, pain catastrophizing, serum levels of BDNF, number of psychiatric diagnoses and the impact of symptoms of fibromyalgia on quality of life. Receiver operator characteristics (ROC) analysis showed non-responders can be discriminated from responders by a composite index of more frequent symptoms of fibromyalgia and neuroplasticity markers (area under the curve (AUC) = 0.83, sensitivity = 100% and specificity = 98%). Conclusion: Patterns of fibromyalgia symptoms and neuroplasticity markers may be helpful to predict responsiveness to the CPM-task which might help personalize treatment and thereby contribute to the care of patients with fibromyalgia.

Clinical research in infectious respiratory diseases has been profoundly affected by non-pharmaceutical interventions (NPIs) against COVID-19. On top of trial delays or even discontinuation which have been observed in all disease areas, NPIs altered transmission pattern of many seasonal respiratory viruses which followed regular patterns for decades before the pandemic. Clinical trial design based on pre-pandemic historical data therefore needs to be put in question. In this article, we show how knowledge-based mathematical modeling can be used to address this issue. We set up an epidemiological model of respiratory tract infection (RTI) sensitive to a time dependent between-host transmission rate and coupled this model to a mechanistic description of viral RTI episodes in an individual patient. By reducing the transmission rate when the lockdown was introduced in the United Kingdom in March 2020, we were able to reproduce the perturbed 2020 RTI disease burden data. Using this setup, we simulated several NPIs scenarios of various strength (none, mild, medium, strong) and conducted placebo-controlled in silico clinical trials in pediatric patients with recurrent RTIs (RRTI) quantifying annual RTI rate distributions. In interventional arms, virtual patients aged 1-5 years received the bacterial lysate OM-85 (approved in several countries for the prevention of pediatric RRTIs) through a pro-type I immunomodulation mechanism of action described by a physiologically based pharmacokinetics and pharmacodynamics approach (PBPK/PD). Our predictions showed that sample size estimates based on the ratio of RTI rates (or the post-hoc power of fixed sample size trials) are not majorly impacted under NPIs which are less severe (none, mild and medium NPIs) than a strict lockdown (strong NPI). However, NPIs show a stronger impact on metrics more relevant for assessing the clinical relevance of the effect such as absolute benefit. This dichotomy shows the risk that successful trials (even with their primary endpoints being met) still get challenged in risk benefit assessment during the review of market authorization. Furthermore, we found that a mild NPI scenario already affected the time to recruit significantly when sticking to eligibility criteria complying with historical data. In summary, our model predictions can help rationalize and forecast post-COVID-19 trial feasibility. They advocate for gauging absolute and relative benefit metrics as well as clinical relevance for assessing efficacy hypotheses in trial design and they question eligibility criteria misaligned with the actual disease burden.

The common pathological features of synucleinopathies are abnormal aggregates of the synaptic protein alpha-synuclein (αSN) in the cytoplasm of neurons or glia. These abnormal aggregates appear several years before the onset of clinical manifestations, and so the early detection of αSN in body fluids or peripheral tissues (e.g., cerebrospinal fluid, colonic mucosa, salivary glands, and skin) is considered a potential tool for identifying synucleinopathies. Performing a skin biopsy is a practical option because it is a relatively noninvasive, safe, and reliable method to measure αSN deposition in the peripheral nervous system. Moreover, there is growing research interest in the use of cutaneous synuclein deposition as a biomarker for synucleinopathies. The aim of this study was to interpret the current data on cutaneous αSN deposition and present the current perspectives and future prospects.

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.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.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).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.

To identify the most important factors that impact brain volume, while accounting for potential collinearity, we used a data-driven machine-learning approach. Gray Matter Volume (GMV) was derived from magnetic resonance imaging (3T, FLAIR) and adjusted for intracranial volume (ICV). 93 potential determinants of GMV from the categories sociodemographics, anthropometric measurements, cardio-metabolic variables, lifestyle factors, medication, sleep, and nutrition were obtained from 293 participants from a population-based cohort from Southern Germany. Elastic net regression was used to identify the most important determinants of ICV-adjusted GMV. The four variables age (selected in each of the 1000 splits), glomerular filtration rate (794 splits), diabetes (323 splits) and diabetes duration (122 splits) were identified to be most relevant predictors of GMV adjusted for intracranial volume. The elastic net model showed better performance compared to a constant linear regression (mean squared error = 1.10 vs. 1.59, p

Failure to recognize symptoms of orthostatic hypotension (OH) may result in falls, syncope, and injuries. The relationship between orthostatic changes in blood pressure and symptom occurrence and severity is not known. The goal of the present study was to define the relationship between the occurrence and severity of the symptoms of orthostatic hypotension (OH) and (1) the upright systolic blood pressure (SBP) and (2) the fall in SBP after tilting in patients with OH. We prospectively studied 89 patients with OH. Reported BP values include the lowest BP in the first 3 minutes of tilt and the change in blood pressure during tilt. Subjects were queried about symptoms of orthostatic intolerance while supine and during the first 3 minutes of tilt testing using Question 1 of the Orthostatic Hypotension Questionnaire. Mean tilted SBP was 101.6±26.1 mm Hg and mean SBP fall 47.9±18.1 mm Hg. Mean symptom scores when upright were: light-headedness (2.3/10±2.7), dizziness (1.6/10±2.5), and impending blackout (0.8/10±1.9). The majority of patients were asymptomatic or mildly symptomatic and no discrete cutoff for symptoms was observed. The magnitude of the SBP fall ( r =−0.07, P =NS) and the lowest upright SBP ( r =0.08, P =NS) did not correlate with any reported symptom. These results suggest a poor relationship between the magnitude of the orthostatic BP fall, the upright orthostatic BP, and symptoms. Many patients are asymptomatic despite substantial SBP falls and low orthostatic blood pressures. These findings have implications for clinical care of patients with OH and clinical trials to treat patients with OH.

Neuropsychiatric and cognitive symptoms are common in Parkinson’s disease (PD) and may precede and exceed motor symptoms as major factors impacting disease course and quality of life. Neuropsychiatric symptoms (NPS) in PD are various and are attributed to pathologic changes within multiple brain regions, to psychological stress, and to adverse effects of dopamine replacement therapy. Sleep disorders and mood symptoms such as apathy, depression, and anxiety may antedate the development of motor symptoms by years, while other NPS such as impulse control disorders, psychosis, and cognitive impairment are more common in later stages of the disease. Few studies report on NPS in the early, untreated phase of PD. We reviewed the current literature on NPS in PD with a focus on the early, drug-naive stages of PD. Among these early disease stages, premotor and early motor phases were separately addressed in our review, highlighting the underlying pathophysiological mechanisms as well as epidemiological characteristics, clinical features, risk factors, and available techniques of clinical assessment.

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.

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.

The α-synucleinopathies are a group of neurodegenerative diseases characterized by abnormal accumulation of insoluble α-synuclein in neurons and glial cells, comprising Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Although varying in prevalence, symptom patterns, and severity among disorders, all α-synucleinopathies have in common autonomic nervous system dysfunctions, which reduce quality of life. Frequent symptoms among α-synucleinopathies include constipation, urinary and sexual dysfunction, and cardiovascular autonomic symptoms such as orthostatic hypotension, supine hypertension, and reduced heart rate variability. Symptoms due to autonomic dysfunction can appear before motor symptom onset, particularly in MSA and PD, hence, detection and quantitative analysis of these symptoms can enable early diagnosis and initiation of treatment, as well as identification of at-risk populations. While patients with PD, DLB, and MSA show both central and peripheral nervous system involvement of α-synuclein pathology, pure autonomic failure (PAF) is a condition characterized by generalized dysregulation of the autonomic nervous system with neuronal cytoplasmic α-synuclein inclusions in the peripheral autonomic small nerve fibers. Patients with PAF often present with orthostatic hypotension, reduced heart rate variability, anhydrosis, erectile dysfunction, and constipation, without motor or cognitive impairment. These patients also have an increased risk of developing an α-synucleinopathy with central involvement, such as PD, DLB, or MSA in later life, possibly indicating a pathophysiological disease continuum. Pathophysiological aspects, as well as developments in diagnosing and treating dysautonomic symptoms in patients with α-synucleinopathies are discussed in this review.

The background to this study was that factors associated with carcinoid heart disease (CHD) and its impacts on overall survival (OS) are scantly investigated in patients (pts) with neuroendocrine tumors (NETs). In terms of materials and methods, a retrospective multicenter cohort study was conducted of factors associated with CHD in advanced NET pts with carcinoid syndrome (CS) and/or elevated urinary 5-hidroxyindole acetic acid (u5HIAA). CHD was defined as at least moderate right valve alterations. The results were the following: Among the 139 subjects included, the majority had a midgut NET (54.2%), 81.3% had CS, and 93% received somatostatin analogues. In a median follow-up of 39 months, 48 (34.5%) pts developed CHD, with a higher frequency in pts treated in public (77.2%) versus private settings (22.9%). In a multivariate logistic regression, unknown primary or colorectal NETs (Odds Ratio (OR) 4.35, p = 0.002), at least 50% liver involvement (OR 3.45, p = 0.005), and being treated in public settings (OR 4.76, p = 0.001) were associated with CHD. In a Cox multivariate regression, bone metastases (Hazard Ratio {HR} 2.8, p = 0.031), CHD (HR 2.63, p = 0.038), and a resection of the primary tumor (HR 0.33, p = 0.026) influenced the risk of death. The conclusions were the following: The incidence of CHD was higher in pts with a high hepatic tumor burden and in those treated in a public system. Delayed diagnosis and limited access to effective therapies negatively affected the lives of NET patients.

The evaluation of autonomic function requires indirect assessment of neurophysiologic function using specialized equipment that is often available only at tertiary care centers, with few specialists available. However, the evaluation of autonomic function is rooted in basic physiology, and the results can be interpreted by careful consideration of the context of the problem. Many automated devices have become widely available to test autonomic function, but they tend to gather inadequate data leading to frequent misdiagnosis and clinical confusion. We review the details necessary for the neurophysiologist to properly perform, and interpret, autonomic function testing.

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-value0.0001. 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.

Autonomic nervous system disturbances including sweating abnormalities and cardiovascular symptoms are frequent in Parkinson's disease (PD) and often precede motor involvement. Cholinergic vasomotor and sudomotor skin nerves are impaired in patients with PD even at early disease stages. We hypothesized that adrenergic pilomotor nerve function is similarly impaired in early PD and might constitute a novel diagnostic target.We conducted a study in 12 PD patients (HoehnYahr 1-2) and 12 healthy control subjects. Pilomotor function was evaluated after iontophoresis of phenylephrine on the dorsal forearm to elicit axon-reflex mediated pilomotor erection (goose bumps). Silicone impressions were obtained, scanned and quantified for pilomotor muscle impressions by number, area and axon-reflex spread. Vasomotor function was evaluated using laser Doppler flowmetry and sudomotor function via sympathetic skin response. Cardiac autonomic function was assessed via heart rate variability. Severity of autonomic symptoms was evaluated using the Scales for Outcomes in Parkinson's disease-Autonomic questionnaire.Pilomotor response was reduced in PD patients compared to control subjects (impression number: 12.2 ± 8.2 vs. 16.5 ± 5.9, p 0.05; impression area: 10.8 ± 2.2 mmPilomotor function is impaired in early stages of PD. Pilomotor axon-reflex assessment might be useful in the investigation of disease related pathology and supplement other clinical markers of autonomic neuropathy in PD.

Timo Siepmann,1 Ben Min-Woo Illigens,2 Kristian Barlinn1 1Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; 2Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Abstract: Despite progression in the development of pharmacological therapy, treatment of alpha synucleinopathies, such as Parkinson’s disease (PD) and some atypical parkinsonism syndromes, is still challenging. To date, our knowledge of the mechanisms whereby the pathological form of alpha-synuclein causes structural and functional damage to the nervous system is limited and, consequently, there is a lack of specific diagnostic tools to evaluate pathology in these patients and differentiate PD from other neurodegenerative proteinopathies. Recent studies indicated that alpha-synuclein deposition in cutaneous small nerve fibers assessed by skin biopsies might be a valid disease marker of PD and facilitate early differentiation of PD from atypical parkinsonism syndromes. This observation is relevant since early diagnosis may enable timely treatment and improve quality of life. However, challenges include the necessity of standardizing immunohistochemical analysis techniques and the identification of potential distinct patterns of intraneural alpha-synuclein deposition among synucleinopathies. In this perspective, we explore the scientific and clinical opportunities arising from alpha-synuclein assessment using skin biopsies. These include elucidation of the peripheral nervous system pathology of PD and other synucleinopathies, identification of novel targets to study response to neuroprotective treatment, and improvement of clinical management. Furthermore, we discuss future challenges in exploring the diagnostic value of skin biopsy assessment for alpha-synuclein deposition and implementing the technique in clinical practice. Keywords: Parkinson’s disease, diagnosis, skin, immunohistochemistry, biopsy

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.

The traditional treatment approach for complicated diverticulitis with purulent or fecal peritonitis is an open surgery procedure with resection of the perforated colon and colostomy (Hartmann`s surgery). Less invasive, laparoscopic surgery techniques have been established but the decision whether patients should undergo open or laparoscopic treatment remains challenging and has to take into account individual factors such as the surgeon's skillset and available resources. Selection of the adequate procedure is further hampered by heterogeneity of the literature. We conducted a systematic review following PRISMA guidelines of studies of efficacy on open and laparoscopic surgical approaches for complicated diverticulitis using databases SciELO, LILACS and MEDLINE. We included prospective controlled studies published from 2005 to 2015. Out of 896-screened articles, 6 articles met our criteria and were included in the systematic review. Included studies tended to support the laparoscopic treatment over conventional open surgery. In particular, two staged laparoscopic surgery with lavage and subsequent follow up surgery to remove the pathological tissue appears to be superior to open surgery in both short and long term outcomes

Eine Schadigung der kleinkalibrigen peripheren unmyelinisierten C-Fasern und der gering myelinisierten A-delta-Fasern (Small Fibers), z. B. durch Diabetes mellitus oder Gifte bzw. Medikamente, kann zu ganz unterschiedlichen Symptomen fuhren. Neben schmerzhaften Parasthesien beeintrachtigen dyshidrotische, kardiovaskulare, urogenitale oder gastrointestinale Beschwerden die Lebensqualitat nachhaltig. Verschaffen Sie sich einen Uberblick daruber, was Sie fur betroffene Patienten tun konnen.

Chapter 9 provides an introduction to statistical testing,alongside the most common parametric tests. It reviews the basis of hypothesis testing while highlighting important concepts such as chance, bias, and confounding. Additionally, this chapter discusses fundamental topics in basic statistics, including p-value, type I and type II errors, alpha (α‎), beta (β‎), and statistical significance. The reader is taken throughout the basics of the theoretical explanation of t-test, ANOVA and linear regression, together with the indications of appropriate use for each of them. Additionally, the reader will learn how to perform and interpret the output for these tests in statistical softwares (e.g., STATA and SPSS). This chapter also examines the concept of normality and central limit theorem (CLT), and how it applies to the evaluation of data distribution.

To review the currently available literature on clinical autonomic tests of sudomotor function. 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. 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. 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.

Background Tuberculosis is a major cause of morbidity and mortality in the developing world. Drug resistance, which is predicted to rise in many countries worldwide, threatens tuberculosis treatment and control. Objective To identify features associated with treatment failure and to predict which patients are at highest risk of treatment failure. Methods On a multi-country dataset managed by the National Institute of Allergy and Infectious Diseases we applied various machine learning techniques to identify factors statistically associated with treatment failure and to predict treatment failure based on baseline demographic and clinical characteristics alone. Results The complete-case analysis database consisted of 587 patients (68% males) with a median (p25-p75) age of 40 (30–51) years. Treatment failure occurred in approximately one fourth of the patients. The features most associated with treatment failure were patterns of drug sensitivity, imaging findings, findings in the microscopy Ziehl-Nielsen stain, education status, and employment status. The most predictive model was forward stepwise selection (AUC: 0.74), although most models performed at or above AUC 0.7. A sensitivity analysis using the 643 original patients filling the missing values with multiple imputation showed similar predictive features and generally increased predictive performance. Conclusion Machine learning can help to identify patients at higher risk of treatment failure. Closer monitoring of these patients may decrease treatment failure rates and prevent emergence of antibiotic resistance. The use of inexpensive basic demographic and clinical features makes this approach attractive in low and middle-income countries.

Iron deficiency (ID) and iron deficiency anemia (IDA) are common findings in patients undergoing lipoprotein apheresis (LA). Different intravenous (iv) formulations are used to treat ID in LA patients, however guidelines and data on ID/IDA management in LA patients are lacking. We therefore performed a prospective observational multi-center cohort study of ID/IDA in LA patients, comparing two approved i.v. iron formulations, ferric gluconate (FG) and ferric carboxymaltose (FCM).Inclusion criteria were a) serum ferritin100 μg/L or b) serum ferritin300 μg/L and transferrin saturation20%. Patients received either FG (62.5 mg weekly) or FCM (500 mg once in ID or up to 1000 mg if IDA was present) i.v. until iron deficiency was resolved. Efficacy and safety were determined by repeated laboratory and clinical assessment. Iron parameters pre and post apheresis were measured to better understand the pathogenesis of ID/IDA in LA patients.80% of LA patients treated at the three participating centers presented with ID/IDA; 129 patients were included in the study. Serum ferritin and transferrin levels were reduced following apheresis (by 18% (p0.0001) and by 13% (p0.0001) respectively). Both FG and FCM were effective and well tolerated in the treatment of ID/IDA in LA patients. FCM led to a quicker repletion of iron stores (p0.05), while improvement of ID/IDA symptoms was not different. Number and severity of adverse events did not differ between FG and FCM, no severe adverse events occurred.Our results suggest that FG and FCM are equally safe, well-tolerated and effective in treating ID/IDA in LA patients. These data form the basis for follow-up randomized controlled trials to establish clinical guidelines.

Axon-Reflex-basierte funktionelle Messverfahren kutaner Nervenfasern werden in der Diagnostik autonomer Neuropathien angewendet. Sie umfassen quantitative Methoden zur Erfassung vasomotorischer und sudomotorischer Antwortreaktionen auf die iontophoretische Applikation von Acetylcholin. Die etablierten Axon-Reflex-Messverfahren „laser Doppler flowmetry“ (LDF) zur vasomotorischen und „quantitative sudomotor axon-reflex test“ (QSART) zur sudomotorischen Funktionsmessung sind durch hohen technischen Aufwand und interindividuelle Variabilitat limitiert. Sie bleiben daher in der Regel spezialisierten klinischen Zentren vorbehalten. Neue Axon-Reflex-basierte Verfahren zeichnen sich durch die Erfassung der axonalen Antwortreaktionen mit zeitlicher und zweidimensionaler Auflosung aus. Diese umfassen den „laser Doppler imaging (LDI) axon-reflex flare area test“ zur vasomotorischen, den „quantitative direct and indirect test of sudomotor function“ (QDIRT) zur sudomotorischen Funktionsmessung sowie den „quantitative pilomotor axon-reflex test“ (QPART), ein Verfahren zur Messung der pilomotorischen Nervenfunktion mithilfe adrenerger Stimulation der Haut durch Phenylephriniontophorese. Die Effektivitat neuer Axon-Reflex-basierter Messverfahren in der Neuropathiediagnostik ist Gegenstand derzeitiger klinischer Prufung.

Small fiber neuropathy is common in a number of systemic diseases and is often challenging to diagnose. Laser Doppler imaging (LDI) is a test of small fiber neurovascular function that can quantify the integrity of the vasomotor C-fiber mediated axon-reflex, but no standardized method of analysis exists. We developed a novel LDI analysis technique and tested it in a human model of small fiber neuropathy. Eighteen healthy subjects (age 24 ± 3 years) underwent LDI testing to assess the axon-mediated flare area in response to 10% acetylcholine iontophoresis. LDI measurements were taken before and longitudinally after a 48-hour application of 0.1% capsaicin (to cause a transient small fiber neuropathy) on the skin of the thigh; placebo cream was placed on the contralateral thigh as a control. We compared our new LDI image analysis technique to two previously published methods. The new LDI analysis technique was the only method to show a consistent difference in axon-reflex area between capsaicin treated and placebo treated skin on all testing days (p

Derzeit zur Verfugung stehende Methoden zur Diagnostik autonomer Neuropathie umfassen Mesverfahren der orthostatischen Funktion und der Herzratenvariabilitat sowie Axon-Reflex basierte sudomotorische (die Schweisdrusenfunktion erfassende) Funktionsuntersuchungen. Zudem wurden in Studien vasomotorische (die neurovaskulare Funktion messende) und pilomotorische (die Haarfollikelmuskelfunktion messende) Mesverfahren gepruft. Aufgrund geringer Sensitivitat und bisher unzureichender Datenlage zur Anwendung vasomotorischer und pilomotorischer Funktionsuntersuchungen bei Patienten mit autonomer Neuropathie werden diese Verfahren klinisch nur in wenigen spezialisierten Zentren angewendet. Im Vordergrund der zu treffenden Masnahmen bei Patienten mit autonomer Neuropathie stehen die fruhzeitige Erkennung und Therapie der zugrundeliegenden Erkrankung. Die symptomatische Behandlung autonomer Neuropathien sollte individuell und multimodal erfolgen und kann neben nicht-medikamentosen Strategien nach sorgfaltiger Risiko-Nutzen Analyse auch die Verabreichung von Pharmaka beinhalten.

Autonome Neuropathien umfassen eine atiopathogenetisch heterogene Gruppe von Erkrankungen, die eine selektive Schadigung der dunnen peripheren unmyelinisierten C-Fasern und gering myelinisierten Aδ-Fasern des autonomen Nervensystems gemein haben. Zu den Ursachen autonomer Nervenfaserschadigung zahlen hochpravalente Krankheitsbilder, wie Diabetes mellitus oder Acquired Immune Deficiency Syndrome (AIDS). Die resultierenden Symptome, wie gastrointestinale, urogenitale, orthostatische oder kardiale Funktionsbeeintrachtigungen stellen fur die betroffenen Patienten zumeist eine Verringerung der Lebensqualitat dar. Daruber hinaus konnen autoimmune Erkrankungen, wie die akute inflammatorische Polyneuritis, Amyloidose, erbliche Erkrankungen, wie die lysosomale Speicherkrankheit Morbus Fabry und hereditare sensorisch-autonome Neuropathien, sowie verschiedene Toxine und Medikamente zu autonomer Neuropathie fuhren.

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.

In hypertrophy, progressive loss of function caused by impaired diastolic compliance correlates with advancing cardiac fibrosis. Endothelial cells contribute to this process through endothelial-to-mesenchymal transition (EndMT) resulting from inductive signals such as transforming growth factor (TGF-β). Vascular endothelial growth factor (VEGF) has proven effective in preserving systolic function and delaying the onset of failure. In this study, we hypothesize that VEGF inhibits EndMT and prevents cardiac fibrosis, thereby preserving diastolic function.The descending aorta was banded in newborn rabbits. At 4 and 6 weeks, hypertrophied animals were treated with intrapericardial VEGF protein and compared with controls (n = 7 per group). Weekly transthoracic echocardiography measured peak systolic stress. At 7 weeks, diastolic stiffness was determined through pressure-volume curves, fibrosis by Masson trichrome stain and hydroxyproline assay, EndMT by immunohistochemistry, and activation of TGF-β and SMAD2/3 by quantitative real-time polymerase chain reaction.Peak systolic stress was preserved during the entire observation period, and diastolic compliance was maintained in treated animals (hypertrophied: 20 ± 1 vs treated: 11 ± 3 and controls: 12 ± 2; p0.05). Collagen was significantly higher in the hypertrophied group by Masson trichrome (hypertrophied: 3.1 ± 0.9 vs treated: 1.8 ± 0.6) and by hydroxyproline assay (hypertrophied: 2.8 ± 0.6 vs treated: 1.4 ± 0.4; p0.05). Fluorescent immunostaining showed active EndMT in the hypertrophied group but significantly less in treated hearts, which was directly associated with a significant increase in TGF-β/SMAD-2 messenger RNA expression.EndMT contributes to cardiac fibrosis in hypertrophied hearts. VEGF treatment inhibits EndMT and prevents the deposition of collagen that leads to myocardial stiffness through TGF-β/SMAD-dependent activation. This presents a therapeutic opportunity to prevent diastolic failure and preserve cardiac function in pressure-loaded hearts.

Randomized controlled trials (RCTs) are the hallmark of evidence-based medicine and form the basis for translating research data into clinical practice. This review summarizes commonly applied designs and quality indicators of RCTs to provide guidance in interpreting and critically evaluating clinical research data. It further reflects on the principle of equipoise and its practical applicability to clinical science with an emphasis on critical care and neurological research. We performed a review of educational material, review articles, methodological studies, and published clinical trials using the databases MEDLINE, PubMed, and ClinicalTrials.gov. The most relevant recommendations regarding design, conduction, and reporting of RCTs may include the following: 1) clinically relevant end points should be defined a priori, and an unbiased analysis and report of the study results should be warranted, 2) both significant and nonsignificant results should be objectively reported and published, 3) structured study design and performance as indicated in the Consolidated Standards of Reporting Trials statement should be employed as well as registration in a public trial database, 4) potential conflicts of interest and funding sources should be disclaimed in study report or publication, and 5) in the comparison of experimental treatment with standard care, preplanned interim analyses during an ongoing RCT can aid in maintaining clinical equipoise by assessing benefit, harm, or futility, thus allowing decision on continuation or termination of the trial.

Introduction: Elevated arterial blood pressure (BP) increases the risk of intracerebral hemorrhage after intravenous (IV) thrombolysis with tPA in acute ischemic stroke (AIS). While arterial BP is usually monitored using intermittent oscillometric measurements with an upper arm cuff, the vascular unloading technique (VUT) provides non-invasive continuous BP monitoring with a finger cuff. Hypothesis: We hypothesized that VUT monitoring is feasible in AIS patients receiving IV tPA, is comparable to the standard technique, and allows detection of BP peaks that might be missed in oscillometric BP monitoring. Methods: We performed an interim analysis of an ongoing prospective method comparison study. AIS patients were simultaneously monitored over 24 h following IV tPA bolus using VUT and contralateral oscillometric BP assessment every 30 min. Results: We present interim data from 15 out of 24 AIS (4 m, 11 f; aged 72.5±14.9 y, mean±SD) receiving IV tPA. Nominal significance level was set to 0.029 in accordance with Pocock’s rule. Missing data were less than 5% for both techniques. There was a positive correlation between VUT and oscillometric BP assessment (Pearson’s correlation coefficient r=0.91, p180 or diastolic BP>110 mmHg) were detected by VUT monitoring (at least one episode≥5 min) in 12 patients, and by oscillometric BP assessment (≥one time point of measurement) in 7 patients (p Conclusions: Our interim data suggest that VUT-based BP monitoring is feasible in AIS patients receiving IV tPA, and might be more sensitive than intermittent oscillometric BP assessment in detecting potentially harmful blood pressure peaks. Figure 1: Bland Altman plot

Cortical lesions in status epilepticus have been reported but the underlying mechanisms are poorly elucidated.We report on afemale patient (75 years) with a history of alcohol abuse who presented with complex partial status epilepticus and lateralized epileptiform discharges in the left frontal and temporal regions in EEG. While cranial magnetic resonance imaging (MRI) showed left hippocampal T2-hyperintensity and diffusion restriction, cerebrospinal fluid was normal and revealed no limbic encephalitis-related antibodies. Following treatment with levitiracetam, seizures ceased and the patient was dismissed. Nine months later, she was readmitted with generalized status epilepticus. Cranial MI now showed hippocampal diffusion restriction and T2 hyperintensity, but in the right hemisphere, as well as atrophy and partial gliotic transformation of the initially affected left hippocampus.Although hippocampal damage due to antibody-negative limbic encephalitis cannot be ruled out, our observation of subsequent bilateral hippocampal diffusion restriction with gliotic transformation may demonstrate permanent seizure-induced structural brain damage and underlines the importance of further research to elucidate the effects of prolonged epileptic discharges on cerebral structural integrity.

Peripheral sudomotor dysfunction is present in many peripheral neuropathies, but structural assessments of sudomotor fibers rarely occur. We evaluated 36 diabetic and 72 healthy control subjects who underwent detailed neurologic examinations and punch skin biopsies. Physical exam findings were quantified by neuropathy impairment score in the lower limb. Skin biopsies quantified intraepidermal nerve fiber density (IENFD) and sweat gland nerve fiber density (SGNFD) by a manual, automated, and semiquantitative method. The automated and manual SGNFD correlated with the IENFD at the same site (r = 0.62, P < 0.05 automated method, r = 0.67, P < 0.05 manual method). As neuropathy worsened, the SGNFD at the distal leg declined (automated counting r = -0.81, P < 0.001; manual counting r = -0.88, P < 0.001). The semiquantitative method displayed poor inter- and intrareviewer reliability and correlated poorly with standard neuropathy evaluation scores. Our results suggest that sudomotor fibers can be rapidly and reproducibly quantified, and results correlate well with physical exam findings.

Cell-based therapy is a possible avenue for the treatment of Duchenne muscular dystrophy (DMD), an X-linked skeletal muscle-wasting disease. We have demonstrated that cultured myogenic progenitors derived from the adult skeletal muscle side population can engraft into dystrophic fibers of non-irradiated, non-chemically injured mouse models of DMD (mdx(5cv)) after intravenous and intraarterial transplantation, with engraftment rates approaching 10%. In an effort to elucidate the cell-surface markers that promote progenitor cell extravasation and engraftment after systemic transplantation, we found that expression of the chemokine receptor CXCR4, whose ligand SDF-1 is overexpressed in dystrophic muscle, enhances the extravasation of these cultured progenitor cells into skeletal muscle after intraarterial transplantation. At 1 day post-transplantation, mice that received CXCR4-positive enhanced green fluorescent protein (eGFP)-positive cultured cells derived from the skeletal muscle side population displayed significantly higher amounts of eGFP-positive mononuclear cells in quadriceps and tibialis anterior than mice that received CXCR4-negative eGFP-positive cells derived from the same cultured population. At 30 days posttransplantation, significantly higher engraftment rates of donor cells were observed in mice that received CXCR4-positive cells compared with mice transplanted with CXCR4-negative fractions. Our data suggest that CXCR4 expression by muscle progenitor cells increases their extravasation into skeletal muscle shortly after transplantation. Furthermore, this enhanced extravasation likely promotes higher donor cell engraftment rates over time.