Progressive myoclonus epilepsies due to SEMA6B mutations. New variants and appraisal of published phenotypes

Variants of SEMA6B have been identified in an increasing number of patients, often presenting with progressive myoclonus epilepsy (PME), and to lesser extent developmental encephalopathy, with or without epilepsy. The exon 17 is mainly involved, with truncating mutations causing the production of aberrant proteins with toxic gain of function. Herein, we describe three adjunctive patients carrying de novo truncating SEMA6B variants in this exon (c.1976delC and c.2086C > T novel; c.1978delC previously reported). These subjects presented with PME preceded by developmental delay, motor and cognitive impairment, worsening myoclonus, and epilepsy with polymorphic features, including focal to bilateral seizures in two, and non-convulsive status epilepticus in one. The evidence of developmental delay in these cases suggests their inclusion in the “PME plus developmental delay” nosological group. This work further expands our knowledge of SEMA6B variants causing PMEs. However, the data to date available confirms that phenotypic features do not correlate with the type or location of variants, aspects that need to be further clarified by future studie

The mechanism of action of a novel neuroprotective low molecular weight dextran sulphate : new platform therapy for neurodegenerative diseases like Amyotrophic Lateral Sclerosis

Background: Acute and chronic neurodegenerative diseases represent an immense socioeconomic burden that drives the need for new disease modifying drugs. Common pathogenic mechanisms in these diseases are evident, suggesting that a platform neuroprotective therapy may offer effective treatments. Here we present evidence for the mode of pharmacological action of a novel neuroprotective low molecular weight dextran sulphate drug called ILB®. The working hypothesis was that ILB® acts via the activation of heparin-binding growth factors (HBGF). Methods: Pre-clinical and clinical (healthy people and patients with ALS) in vitro and in vivo studies evaluated the mode of action of ILB®. In vitro binding studies, functional assays and gene expression analyses were followed by the assessment of the drug effects in an animal model of severe traumatic brain injury (sTBI) using gene expression studies followed by functional analysis. Clinical data, to assess the hypothesized mode of action, are also presented from early phase clinical trials. Results: ILB® lengthened APTT time, acted as a competitive inhibitor for HGF-Glypican-3 binding, effected pulse release of heparin-binding growth factors (HBGF) into the circulation and modulated growth factor signaling pathways. Gene expression analysis demonstrated substantial similarities in the functional dysregulation induced by sTBI and various human neurodegenerative conditions and supported a cascading effect of ILB® on growth factor activation, followed by gene expression changes with profound beneficial effect on molecular and cellular functions affected by these diseases. The transcriptional signature of ILB® relevant to cell survival, inflammation, glutamate signaling, metabolism and synaptogenesis, are consistent with the activation of neuroprotective growth factors as was the ability of ILB® to elevate circulating levels of HGF in animal models and humans. Conclusion: ILB® releases, redistributes and modulates the bioactivity of HBGF that target disease compromised nervous tissues to initiate a cascade of transcriptional, metabolic and immunological effects that control glutamate toxicity, normalize tissue bioenergetics, and resolve inflammation to improve tissue function. This unique mechanism of action mobilizes and modulates naturally occurring tissue repair mechanisms to restore cellular homeostasis and function. The identified pharmacological impact of ILB® supports the potential to treat various acute and chronic neurodegenerative disease, including sTBI and ALS

Regional differences in the quality of maternal and neonatal care during the COVID-19 pandemic in Portugal: results from the IMAgiNE EURO study

Objective: To compare women's perspectives on the quality of maternal and newborn care (QMNC) around the time of childbirth across Nomenclature of Territorial Units for Statistics 2 (NUTS-II) regions in Portugal during the COVID-19 pandemic. Methods: Women participating in the cross-sectional IMAgiNE EURO study who gave birth in Portugal from March 1, 2020, to October 28, 2021, completed a structured questionnaire with 40 key WHO standards-based quality measures. Four domains of QMNC were assessed: (1) provision of care; (2) experience of care; (3) availability of human and physical resources; and (4) reorganizational changes due to the COVID-19 pandemic. Frequencies for each quality measure within each QMNC domain were computed overall and by region. Results: Out of 1845 participants, one-third (33.7%) had a cesarean. Examples of high-quality care included: low frequencies of lack of early breastfeeding and rooming-in (8.0% and 7.7%, respectively) and informal payment (0.7%); adequate staff professionalism (94.6%); adequate room comfort and equipment (95.2%). However, substandard practices with large heterogeneity across regions were also reported. Among women who experienced labor, the percentage of instrumental vaginal births ranged from 22.3% in the Algarve to 33.5% in Center; among these, fundal pressure ranged from 34.8% in Lisbon to 66.7% in Center. Episiotomy was performed in 39.3% of noninstrumental vaginal births with variations between 31.8% in the North to 59.8% in Center. One in four women reported inadequate breastfeeding support (26.1%, ranging from 19.4% in Algarve to 31.5% in Lisbon). One in five reported no exclusive breastfeeding at discharge (22.1%; 19.5% in Lisbon to 28.2% in Algarve). Conclusion: Urgent actions are needed to harmonize QMNC and reduce inequities across regions in Portugal.info:eu-repo/semantics/publishedVersio

Quality of health care around the time of childbirth during the COVID-19 pandemic: Results from the IMAgiNE EURO study in Norway and trends over time

Objective: To describe maternal perception of the quality of maternal and newborn care (QMNC) in facilities in Norway during the first year of COVID-19 pandemic. Methods: Women who gave birth in a Norwegian facility from March 1, 2020, to October 28, 2021, filled out a structured online questionnaire based on 40 WHO standards-based quality measures. Quantile regression analysis was performed to assess changes in QMNC index over time. Results: Among 3326 women included, 3085 experienced labor. Of those, 1799 (58.3%) reported that their partner could not be present as much as needed, 918 (29.8%) noted inadequate staff numbers, 183 (43.6%) lacked a consent request for instrumental vaginal birth (IVB), 1067 (34.6%) reported inadequate communication from staff, 78 (18.6%) reported fundal pressure during IVB, 670 (21.7%) reported that they were not treated with dignity, and 249 (8.1%) reported experiencing abuse. The QMNC index increased gradually over time (3.68 points per month, 95% CI, 2.83– 4.53 for the median), with the domains of COVID-19 reorganizational changes and experience of care displaying the greatest increases, while provision of care was stable over time. Conclusion: Although several measures showed high QMNC in Norway during the first year of the COVID-19 pandemic, and a gradual improvement over time, several findings suggest that gaps in QMNC exist. These gaps should be addressed and monitored

Feasibility of the Transport PLUS Intervention to Improve the Transitions of Care for Patients Transported Home by Ambulance: a Non-Randomized Pilot Study

BACKGROUND: The growing population of patients over the age of 65 faces particular vulnerability following discharge after hospitalization or an emergency room visit. Specific areas of concern include a high risk for falls and poor comprehension of discharge instructions. Emergency medical technicians (EMTs), who frequently transport these patients home from the hospital, are uniquely positioned to aid in mitigating transition of care risks and are both trained and utilized to do so using the Transport PLUS intervention. METHODS: Existing literature and focus groups of various stakeholders were utilized to develop two checklists: the fall safety assessment (FSA) and the discharge comprehension assessment (DCA). EMTs were trained to administer the intervention to eligible patients in the geriatric population. Using data from the checklists, follow-up phone calls, and electronic health records, we measured the presence of hazards, removal of hazards, the presence of discharge comprehension issues, and correction or reinforcement of comprehension. These results were validated during home visits by community health workers (CHWs). Feasibility outcomes included patient acceptance of the Transport PLUS intervention and accuracy of the EMT assessment. Qualitative feedback via focus groups was also obtained. Clinical outcomes measured included 3-day and 30-day readmission or ED revisit. RESULTS: One-hundred three EMTs were trained to administer the intervention and participated in 439 patient encounters. The intervention was determined to be feasible, and patients were highly amenable to the intervention, as evidenced by a 92% and 74% acceptance rate of the DCA and FSA, respectively. The majority of patients also reported that they found the intervention helpful (90%) and self-reported removing 40% of fall hazards; 85% of such changes were validated by CHWs. Readmission/revisit rates are also reported. CONCLUSIONS: The Transport PLUS intervention is a feasible, easily implemented tool in preventative community paramedicine with high levels of patient acceptance. Further study is merited to determine the effectiveness of the intervention in reducing rates of readmission or revisit. A randomized control trial has since begun utilizing the knowledge gained within this study

Cardiomyopathy Associated with Diabetes: The Central Role of the Cardiomyocyte

The term diabetic cardiomyopathy (DCM) labels an abnormal cardiac structure and performance due to intrinsic heart muscle malfunction, independently of other vascular co-morbidity. DCM, accounting for 50%–80% of deaths in diabetic patients, represents a worldwide problem for human health and related economics. Optimal glycemic control is not sufficient to prevent DCM, which derives from heart remodeling and geometrical changes, with both consequences of critical events initially occurring at the cardiomyocyte level. Cardiac cells, under hyperglycemia, very early undergo metabolic abnormalities and contribute to T helper (Th)-driven inflammatory perturbation, behaving as immunoactive units capable of releasing critical biomediators, such as cytokines and chemokines. This paper aims to focus onto the role of cardiomyocytes, no longer considered as “passive” targets but as “active” units participating in the inflammatory dialogue between local and systemic counterparts underlying DCM development and maintenance. Some of the main biomolecular/metabolic/inflammatory processes triggered within cardiac cells by high glucose are overviewed; particular attention is addressed to early inflammatory cytokines and chemokines, representing potential therapeutic targets for a prompt early intervention when no signs or symptoms of DCM are manifesting yet. DCM clinical management still represents a challenge and further translational investigations, including studies at female/male cell level, are warranted

Atorvastatin Downregulates Monocyte CD36 Expression, Nuclear NF kappa B and TNF alpha Levels in Type 2 Diabetes

Aim: Type 2 diabetes increases the risk for cardiovascular disease, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) reduce cardiovascular events in these patients. The benefits of statin therapy cannot be explained only by the lipid-lowering effect. The aim of this study was to test the effect of atorvastatin therapy on CD36 scavenger receptor expression, nuclear factor-kappaB (NF kappa B) levels and markers of inflammation (C-reactive protein, CRP, Tumor Necrosis Factor-alpha, TNF-alpha) in circulating monocytes from diabetic patients. Methods: Twenty-two type 2 diabetic patients were treated for 8 weeks with atorvastatin (20 mg/day). At baseline and after treatment a blood sample was collected for measurement of glucose, lipid profile (total cholesterol, HDL, LDL cholesterol, triglycerides), glycated hemoglobin (HbA1c), CRP and for isolation of monocytes. Results: Atorvastatin decreased total (p<0.0001) and LDL (p<0.01), and incresased HDL cholesterol (p<0.02). CD36 surface protein expression (anti-CD36 fluorescein isothiocyanate-FITC) was reduced in circulating monocytes after atorvastatin therapy (p<0.02) while immunoblot analysis showed reduced nuclear and increased cytoplasm NF alpha B levels (p<0.05). Finally, TNF alpha production in lipopolysaccharide-activated monocytes from patients treated with atorvastatin was reduced (p<0.05). Conclusion: These results suggest that atorvastatin therapy, beside lowering serum cholesterol levels, could exert anti-atherogenic and anti-inflammatory effects in type 2 diabetic patients

The effect of adapting Hospital at Home to facilitate implementation and sustainment on program drift or voltage drop

Abstract Background Translating evidence-based interventions from study conditions to actual practice necessarily requires adaptation. We implemented an evidence-based Hospital at Home (HaH) intervention and evaluated whether adaptations could avoid diminished benefit from “voltage drop” (decreased benefit when interventions are applied under more heterogeneous conditions than existing in studies) or “program drift.” (decreased benefit arising from deviations from study protocols). Methods Patients were enrolled in HaH over a 6-month pilot period followed by nine quarters of implementation activity. The program retained core components of the original evidence-based HaH model, but adaptations were made at inception and throughout the implementation. These adaptations were coded as to who made them, what was modified, for whom the adaptations were made, and the nature of the adaptations. We collected information on length of stay (LOS), 30-day readmissions and emergency department (ED) visits, escalations to the hospital, and patient ratings of care. Outcomes were assessed by quarter of admission. Selected outcomes were tracked and fed back to the program leadership. We used logistic or linear regression with an independent variable included for the numerical quarter of enrollment after the initial 6-month pilot phase. Models controlled for season and for patient characteristics. Results Adaptations were made throughout the implementation period. The nature of adaptations was most commonly to add or to substitute new program elements. HaH services substituting for a hospital stay were received by 295 patients (a mean of 33, range 11–44, per quarter). A small effect of quarter from program inception was seen for escalations (OR 1.09, 95% CI 1.01 to 1.18, p = 0.03), but no effect was observed for LOS (− 0.007 days/quarter; SE 0.02, p = 0.75), 30 day ED visit (OR 0.93, 95% CI 0.86 to 1.01, p = 0.09), 30-day readmission (OR 1.00, 95% CI 0.93 to 1.08, p = 0.99), or patient rating of overall hospital care (OR for highest overall rating 0.99, 95% CI 0.93 to 1.05, p = 0.66). Conclusions We made adaptations to HaH at inception and over the course of implementation. Our findings indicate that adaptations to evidence-based programs may avoid diminished benefits due to potential ‘program drift’ or ‘voltage drop.’ Trial registration Not applicable. This study is not a clinical trial by the International Committee of Medical Journal Editors (ICMJE) definition because it is an observational study “in which the assignment of the medical intervention is not at the discretion of the investigator.

Circulating monocyte oxidative activity is increased in patients with type 2 diabetes and erectile dysfunction

Purpose: We investigated the relationship between oxidative stress and diabetic erectile dysfunction. Materials and Methods: A total of 23 patients with a mean SD age of 56.7 +/- 5.6 years, a history of type 2 diabetes for 10.0 +/- 8.3 years and erectile dysfunction, as tested by the International Index of Erectile Function questionnaire, but without vascular and neurological complications, and 15 age matched patients with diabetes without erectile dysfunction were recruited. Circulating monocyte oxidative activity by cytofluorometry, and endothelin-1, intercellular adhesion molecule-1, plasminogen activator inhibitor-1 by enzyme linked immunosorbent assay were evaluated in all patients in the study. Results: Monocyte free radical production, and total and low density lipoprotein cholesterol were higher in patients with than in those without erectile dysfunction (p < 0.03, < 0.02 and < 0.05, respectively). In all patients the International Index of Erectile Function score inversely correlated with low density lipoprotein (p < 0.05), while in patients with erectile dysfunction it negatively correlated with age (p < 0.03), body mass index (p < 0.02), endothelin-1 (p < 0.02) and intercellular adhesion molecule-1 (p < 0.05). Endothelin-1, intercellular adhesion molecule-1 and plasminogen activator inhibitor-1 were not different in patients with diabetes with and without erectile dysfunction. Conclusions: In men with type 2 diabetes who have erectile dysfunction but are asymptomatic for cardiovascular disease oxidative activation of monocytes is increased and it is related to other risk factors of endothelial dysfunction