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Background: Cardiogenic shock (CS) is complicated by high mortality rates. Targeted temperature control (TTC) has been proposed as an adjunct therapy in CS. This study aims to examine the safety of TTC in patients presenting with CS., Methods and Results: In this open-label, randomized controlled pilot trial, 20 patients with hemodynamic criteria for CS were assigned to standard of care plus TTC vs standard of care alone. The primary outcome was a composite safety outcome, including well-described complications of TTC. Secondary outcomes included mortality at 90 days, invasive hemodynamic and echocardiographic parameters, electrocardiographic measurements, and inotrope dosing. There were no significant differences in the composite analysis of prespecified safety outcomes (3 events in the TTC group vs 0 events in the control group; P = 0.24). Patients randomized to TTC demonstrated a statistically significant increase in cardiac index and cardiac power index compared to the control group at 48-96 hours after randomization (3.6 [3.1, 3.9] L/min/m 2 vs 2.6 [2.5, 3.15] L/min/m 2 ; P = 0.029 and 0.61 [0.55, 0.7] W/m 2 vs 0.53 [0.435, 0.565] W/m 2 ; P = 0.029, respectively)., Conclusion: TTC may be a safe adjunct therapy for patients presenting with CS and may yield improvement in specific hemodynamic parameters., Competing Interests: Disclosures The authors have no disclosures to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background/purpose: The Upper Extremity Fugl-Meyer Assessment (UEFMA, maximum 66) is widely used in clinics and research studies to examine poststroke upper extremity (UE) impairment. This study aimed to develop and provide pilot data to support the validity of a remote version of the UEFMA to examine UE impairment after stroke through telerehabilitation., Methods: Team members developed a remote version of the UEFMA for telerehabilitation (tUEFMA, maximum 44) using subscales II to IV and VII of the UEFMA. Twenty-two participants with moderate to severe arm impairment (UEFMA, median = 19) and chronic stroke (>1 year post) were evaluated using the UEFMA (face-to-face) and the tUEFMA (remotely). A prediction equation was used to identify the function to predict the UEFMA based on the tUEFMA. Intraclass correlation (ICC) was used to test the absolute agreement between the subscales included in the UEFMA and the tUEFMA, and between their 2 normalized total scores., Results: A strong and significant agreement was found between the total scores of the UEFMA and the projected value based on the tUEFMA (ICC = 0.79, P < 0.05). The ICC test also reported a good agreement in subscales II to IV and a poor agreement in subscale VII between the UEFMA and the tUEFMA using a real-time video link., Discussion and Conclusions: The study findings suggest that the tUEFMA is a promising tool to remotely examine UE impairment in individuals with chronic stroke and moderate to severe arm impairment. Future research should evaluate additional psychometric properties and clinical utility of the tUEFMA across stroke participants with a broad range of arm impairments.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A441 )., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published byWolters Kluwer Health, Inc. on behalf of Academy of Neurologic Physical Therapy, APTA.)

Background: Patients with concomitant anemia and congestive heart failure have poor outcomes. The prevalence and clinical risk of anemia in patients receiving durable left ventricular assist devices (LVAD) remain unknown., Methods: We retrospectively analyzed patients who underwent LVAD implantation between 2014 and 2018. The association between hemoglobin level at the time of index discharge and the one-year composite endpoint of heart failure readmissions or hemocompatibility-related adverse events was investigated., Results: A total of 168 patients (57 [48, 66] years old, 123 males) were included and stratified into a classification of anemia (hemoglobin <9.7 g/dl, N = 99) or non-anemia (N = 69). The anemia group had a higher one-year incidence of the composite endpoint (56% vs 36%, p = .013) with an adjusted hazard ratio of 1.83 (95% confidence interval 1.08-2.82). Patients with anemia also experienced suboptimal bi-ventricular unloading., Conclusions: Anemia was prevalent in LVAD patients and associated with a greater risk of heart failure and hemocompatibility-related adverse events. The optimal threshold for therapeutic intervention in response to post-LVAD anemia needs further investigation., (© 2022 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Background: Catheter ablation strategies for ventricular fibrillation (VF) and polymorphic ventricular tachycardia (PMVT) are not established when spontaneous triggers are rare or absent., Objective: The purpose of this study was to report the feasibility and efficacy of a novel empiric ablation strategy of pacemapping to stored implantable cardioverter-defibrillator (ICD) template electrograms (SITE) of the clinical premature ventricular contraction (PVC) trigger., Methods: Fifteen patients with drug-refractory VF/PMVT receiving defibrillator shocks without identifiable and mappable PVC triggers were prospectively analyzed. The protocol incorporated systematic pacemapping from known arrhythmogenic sites (moderator band/right ventricular [RV] papillary muscles, left conduction system/Purkinje network, outflow tracts) with real-time comparison between the paced ICD electrogram (EGM) morphology and SITE., Results: Regions within the left Purkinje network yielded the best pacemap match for the SITE of the clinical PVC trigger in 55% of ablation targets (left posterior fascicle 6, left septal fascicle 1, left anterior fascicle 5), followed by the RV moderator band region in 14% (n = 3), RV papillary muscles in 13% (n = 3), periaortic region in 14% (n = 3), and left ventricular anterolateral papillary muscle in 4% (n = 1). Freedom from ICD therapies off antiarrhythmic drug (AAD) was 64% at 6 months and 48% at 12 months. Shock burden was reduced from 4 (2-6) to 0 (0-1) (P = .001), and use of AADs was reduced from 2 (1-2) to 0 (0-1) (P = .001)., Conclusion: In the absence of a mappable trigger, an empiric strategy of interrogating the Purkinje network, papillary muscles, and outflow tract regions by pacemap matching with SITE of the clinical PVC is feasible to guide ablation. A significant reduction in VF/PMVT therapy burden and AAD utilization was observed after a single procedure., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The prognostic impact of mitral inflow wave overlap during ivabradine therapy in patients with heart failure with reduced ejection fraction (HFrEF) remains to be unknown. Thus, in this study, we have retrospectively examined consecutive inpatients with HFrEF admitted with decompensated heart failure who continued ivabradine following the index discharge. Ideal heart rate (HR), at which echocardiographic mitral inflow wave overlap is theoretically 0, was retrospectively calculated as follows: 96 - 0.13 × (deceleration time [msec]). HR difference was then calculated as follows: actual HR - ideal HR. The association between the HR difference at index discharge and a composite outcome of cardiovascular death and heart failure readmissions was investigated. In total, 16 patients (68 [47, 75] years old, 11 men, median left ventricular ejection fraction 28% [22%, 35%]) were included in this study for analysis. Baseline actual HR was determined to be 88 (81, 93) bpm, whereas the ideal HR was calculated as 75 (73, 76) bpm. Following the initiation of ivabradine, actual HR at index discharge was 75 (64, 84) bpm. Patients with optimal HR (actual HR - ideal HR < ± 10 bpm; n = 9) were found to have experienced a lower incidence of the composite endpoint (40% versus 100%, P = 0.013) compared with those with sub-optimal HR (n = 7) with a hazard ratio of 0.10 (95% confidence interval 0.01-0.91) adjusted for actual HR at index discharge. In conclusion, HR modulation therapy using ivabradine may improve outcomes in patients with HFrEF if individualized ideal HR was achieved.

Management of constrictive pericarditis is often clinically challenging. Heart rate (HR) modulation using ivabradine is associated with improved clinical outcomes in patients with systolic heart failure, although it remains uninvestigated for other clinical purposes. We aimed to assess the impact of HR control in patients with constrictive pericarditis. In this retrospective study, consecutive patients who were diagnosed with constrictive pericarditis were included. Transthoracic echocardiography was performed at index discharge (day 0). The impact of HR difference between actual HR and ideal HR, which was calculated using a formula consisting of deceleration time, on heart failure readmission rates was investigated. A total of 15 patients (73 years old on median, 11 men) with constrictive pericarditis were included. On median, actual HR was 71 bpm and ideal HR was 81 bpm. Heart failure readmission rates were stratified into three groups by the HR difference: (1) optimal HR group satisfying "-10 bpm ≤ HR difference ≤ 10 bpm" (n = 4, 0.067 events per year); (2) lower HR group satisfying "HR difference < -10 bpm" (n = 7, 0.118 events per year, incidence rate ratio 1.98, 95% confidence interval 0.06-61.6); (3) higher HR group satisfying "HR difference > 10 bpm" (n = 4, 0.231 events per year, incidence rate ratio 9.22, 95% confidence interval 0.36-237.8). In conclusion, non-optimized HR was associated with an increased risk of heart failure recurrence in patients with constrictive pericarditis. Prospective assessment of deceleration time-guided HR optimization in patients with constrictive pericarditis is needed.

Objectives: To assess the safety, efficacy, and durability of the Absorb bioresorbable vascular scaffold in predominantly complex, infra-popliteal lesions for the management of chronic limb ischemia at two-year clinical follow-up. Bioresorbable vascular scaffold are biodegradable scaffolds that provide short-term vascular support before undergoing intravascular degradation. A recent trial reported excellent 36-month vessel patency rates in simple infrapopliteal arterial lesions treated with Absorb bioresorbable vascular scaffold., Methods: This single-center, retrospective study evaluated the use of the Absorb bioresorbable vascular scaffold (everolimus impregnated poly-L-lactic scaffold) in patients with infra-popliteal peripheral arterial disease (PAD) with respect to safety (thrombosis and TIMI bleeding), technical success, and freedom from clinically driven target vessel failure at 24 months., Results: 31 patients (51.6% male) with a median age of 67 years with predominantly advanced infra-popliteal disease were treated with 49 bioresorbable vascular scaffold in 41 vessels. The mean stenosis was 94% (80-100), with 49% of lesions being chronic thrombotic occlusions. No scaffold thrombosis or peri-procedural bleeding was observed. Procedural success was achieved in all patients; 93.5% of patients experienced freedom from clinically driven target vessel failure at 24 months, driven by one revascularization and one amputation. Primary patency was 96.7% at 12 months and 87.1% at 24 months. All patients were alive at 12 and 24 months., Conclusions: At 24 months, our study found that patients with predominantly advanced infra-popliteal PAD who were treated with Absorb bioresorbable vascular scaffold reported improved clinical status and a low and durable rate of clinically driven target vessel failure extending out to 24 months.

Heart rate reduction therapy using ivabradine has demonstrated its prognostic implication in patients with heart failure with reduced ejection fraction. However, the target heart rate with optimal clinical outcomes, particularly for those with systolic dysfunction following a transcatheter aortic valve replacement (TAVR), remains unknown. Consecutive patients with left ventricular ejection fraction (LVEF) < 50% and sinus rhythm following TAVR received transthoracic echocardiography at index discharge. The ideal heart rate was calculated using a formula: 93 - 0.13 × (deceleration time [ms]). Those whose actual heart rates at discharge were within 10 bpm of the calculated ideal heart rate were assigned to the optimal heart rate group, and their prognosis was compared with those without. Twenty-four patients (83 [78, 85] years old, LVEF 41% [35%, 44%], 16 males) were included. The median difference between actual heart rate and ideal heart rate was 12 (0, 16) bpm and 11 patients were assigned to the optimal heart rate group. One year later, the optimal heart rate group achieved more improvement in LVEF (24% [15%, 28%] vs. 7% [7%, 12%], p = .003) and had lower heart failure readmission rates (0.059 vs. 0.116 events/year; p = .49). In conclusion, an optimal heart rate might be associated with cardiac reverse remodeling and prevention of heart failure recurrences in patients with systolic dysfunction following TAVR. The implication of deceleration time-guided heart rate optimization therapy for such cohorts remains the next concern., (© 2021 Wiley Periodicals LLC.)

Background: The seasonal variation of incidence and severity of heart failure is well known. However, the impact of seasonal variation on clinical outcomes following left ventricular assist device (LVAD) implantation remains unknown., Methods: We retrospectively reviewed consecutive patients who received LVAD implantation between January 2014 and December 2016 along with their first year of post-implant outcomes. Clinical outcomes were compared between those with winter LVAD implantation (between October and March) and those with non-winter LVAD implantation., Results: 168 patients with a median age of 57 years and 130 males were included. There was no seasonal difference in the number of LVAD implantations. One-year survival free from major adverse events was significantly lower in the winter implant group ( n = 88) compared to the non-winter group ( n = 80) (44% vs 61%) with an adjusted hazard ratio of 1.81 (95% confidence interval 1.11-2.90, p = 0.014), largely due to a higher rate of heart failure readmission in the winter implant patients (incidence rate ratio 2.29, 95% confidence interval 0.89-5.84)., Conclusion: Patients who underwent LVAD implantation during the winter season had a higher heart failure readmission rate. A detailed mechanism and therapeutic strategy given our findings warrant further investigation.

Background: Active smoking is associated with worse clinical outcomes following left ventricular assist device (LVAD) implantation. However, the effect of sex differences in conjunction with smoking status remains uninvestigated., Methods: Consecutive patients who underwent LVAD implantation between January 2013 and September 2018 were included. Clinical outcomes were retrospectively compared between the current smokers and never smokers among male cohorts and female cohorts separately., Results: About 130 patients, with a median age of 56 years, were included. Among the male cohort (N = 85), the current smokers (N = 25/85) had a higher total readmission rate than the never smokers (N = 60/85) with an adjusted incidence rate ratio of 2.38 (95% confidence interval, 1.16-3.85, P = .014), dominantly due to higher rates of gastrointestinal bleeding, stroke, and hemolysis. Among the female cohorts (N = 45), never smokers (N = 36/45) had a statistically comparable total readmission rate (2.80 vs 2.50 events per year; P = .37) compared with current smokers (N = 9/45)., Conclusion: Among male patients with LVAD, active smoking was associated with higher rates of adverse events. Female patients with LVAD had a high rate of adverse events irrespective of smoking status. Gender-specific therapeutic approaches might be required to prevent LVAD-related comorbidities., (© 2020 Wiley Periodicals LLC.)

Objectives: To assess the safety and efficacy of the Absorb bioresorbable vascular scaffold (BVS) in complex, infrapopliteal lesions for the management of chronic limb ischemia., Background: The interventional management of infrapopliteal PAD remains challenging due to high restenosis rates with metallic drug-eluting stents and balloon angioplasty. Metallic stents are associated with impaired vessel vasomotor tone, remodeling, autoregulation, and long-term inflammation. BVSs are biodegradable scaffolds that provide short-term vascular support before degrading to allow restoration of vasomotor tone and endothelial function. A recent trial reported excellent 12-month vessel patency rates in simple infrapopliteal arterial lesions treated with Absorb BVS., Methods: This single-center, retrospective study evaluated the use of the Absorb BVS (everolimus impregnated poly-L-lactic scaffold) in patients with infrapopliteal PAD with respect to safety (thrombosis and TIMI bleeding), technical success, and clinically driven target vessel failure (CD-TVF) at 12 months., Results: Thirty-one patients (51.6% male) with a median age of 67 years with advanced infrapopliteal disease were treated with 49 BVS in 41 vessels. The mean stenosis was 94% (80-100), with 49% of lesions being CTOs. No scaffold thrombosis or periprocedural bleeding was observed. Procedural success was achieved in all patients. Freedom from CD-TVF was 95.1% at 12 months driven by one revascularization and one amputation. Primary patency was 96.7% at 12 months. All patients were alive at 12 months, and 96.8% of patients improved their Rutherford-Becker classification., Conclusions: At 12 months, our study found that patients with advanced infrapopliteal PAD who were treated with Absorb BVS reported improved clinical status and a low rate of CD-TVF., (© 2019 Wiley Periodicals, Inc.)

Background: The His-SYNC pilot trial was the first randomized comparison between His bundle pacing in lieu of a left ventricular lead for cardiac resynchronization therapy (His-CRT) and biventricular pacing (BiV-CRT), but was limited by high rates of crossover., Objective: To evaluate the results of the His-SYNC pilot trial utilizing treatment-received (TR) and per-protocol (PP) analyses., Methods: The His-SYNC pilot was a multicenter, prospective, single-blinded, randomized, controlled trial comparing His-CRT vs BiV-CRT in patients meeting standard indications for CRT (eg, NYHA II-IV patients with QRS >120 ms). Crossovers were required based on prespecified criteria. The primary endpoints analyzed included improvement in QRS duration, left ventricular ejection fraction (LVEF), and freedom from cardiovascular (CV) hospitalization and mortality., Results: Among 41 patients enrolled (aged 64 ± 13 years, 38% female, LVEF 28%, QRS 168 ± 18 ms), 21 were randomized to His-CRT and 20 to BiV-CRT. Crossover occurred in 48% of His-CRT and 26% of BiV-CRT. The most common reason for crossover from His-CRT was inability to correct QRS owing to nonspecific intraventricular conduction delay (n = 5). Patients treated with His-CRT demonstrated greater QRS narrowing compared to BiV (125 ± 22 ms vs 164 ± 25 ms [TR], P < .001;124 ± 19 ms vs 162 ± 24 ms [PP], P < .001). A trend toward higher echocardiographic response was also observed (80 vs 57% [TR], P = .14; 91% vs 54% [PP], P = .078). No significant differences in CV hospitalization or mortality were observed., Conclusions: Patients receiving His-CRT on-treatment demonstrated superior electrical resynchronization and a trend toward higher echocardiographic response than BiV-CRT. Larger prospective studies may be justifiable with refinements in patient selection and implantation techniques to minimize crossovers., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Inhibitory neurons crucially contribute to shaping the breathing rhythm in the brain stem. These neurons use GABA or glycine as neurotransmitter; or co-release GABA and glycine. However, the developmental relationship between GABAergic, glycinergic and cotransmitting neurons, and the functional relevance of cotransmitting neurons has remained enigmatic. Transgenic mice expressing fluorescent markers or the split-Cre system in inhibitory neurons were developed to track the three different interneuron phenotypes. During late embryonic development, the majority of inhibitory neurons in the ventrolateral medulla are cotransmitting cells, most of which differentiate into GABAergic and glycinergic neurons around birth and around postnatal day 4, respectively. Functional inactivation of cotransmitting neurons revealed an increase of the number of respiratory pauses, the cycle-by-cycle variability, and the overall variability of breathing. In summary, the majority of cotransmitting neurons differentiate into GABAergic or glycinergic neurons within the first 2 weeks after birth and these neurons contribute to fine-tuning of the breathing pattern., (Copyright © 2019 Hirrlinger, Marx, Besser, Sicker, Köhler, Hirrlinger, Wojcik, Eulenburg, Winkler and Hülsmann.)

Background Metabolic impairment is common in heart failure patients. Continuous-flow left ventricular assist devices (CF-LVADs) improve hemodynamics and outcomes in patients with advanced heart failure; however, the effect of CF-LVADs on metabolic status is unknown. This study aims to evaluate the changes in metabolic status following CF-LVAD implantation and measure the correlation of metabolic status with outcomes. Methods and Results Prospective data on CF-LVAD patients were obtained. Metabolic evaluation, including hemoglobin A1C, free and total testosterone, thyroid-stimulating hormone (TSH), and free T4, was obtained before and at multiple time points following implantation. Patients with nonelevated thyroid-stimulating hormone and normal hemoglobin A1C and testosterone levels were defined as having normal metabolic status. Baseline characteristics, hemodynamics, and outcomes were collected. One hundred six patients were studied, of which 56 had paired data at baseline and 1- to 3-month follow-up. Before implantation, 75% of patients had insulin resistance, 86% of men and 39% of women had low free testosterone, and 44% of patients had abnormal thyroid function. There was a significant improvement in hemoglobin A1C, free testosterone, and thyroid-stimulating hormone following implantation ( P <0.001 for all). Patients with normal hemoglobin A1C (<5.7%) following implantation had higher 1-year survival free of heart failure readmissions (78% versus 23%; P <0.001). Patients with normal metabolic status following implantation also had higher 1-year survival free of heart failure readmissions (92% versus 54%; P =0.04). Conclusions Metabolic dysfunction is highly prevalent in advanced heart failure patients and improves after CF-LVAD implantation. Normal metabolic status is associated with a significantly higher rate of 1-year survival free of heart failure readmissions.

Background: Left ventricular assist device (LVAD) therapy improves the hemodynamics of advanced heart failure patients. However, it is unknown whether hemodynamic optimization improves clinical outcomes. The aim of this study was to investigate whether hemodynamic optimization reduces hospital readmission rate in LVAD patients., Methods and Results: LVAD patients undergoing an invasive hemodynamic ramp test were prospectively enrolled and followed for 1 year. LVAD speed was optimized using a ramp test, targeting the following goals: central venous pressure <12 mm Hg, pulmonary capillary wedge pressure <18 mm Hg, and cardiac index >2.2 L/(min·m 2 ). The frequency and cause of hospital readmissions were compared between patients who achieved (optimized group) or did not achieve (nonoptimized group) these goals. Eighty-eight outpatients (median 61 years old, 53 male) underwent ramp testing 236 days after LVAD implantation, and 54 (61%) had optimized hemodynamics after LVAD speed adjustment. One-year survival after the ramp study was comparable in both groups (89% versus 88%). The total hospital readmission rate was lower in the optimized group compared with the nonoptimized group (1.15 versus 2.86 events/y, P<0.001). This result was predominantly because of a reduction in the heart failure readmission rate in the optimized group (0.08 versus 0.71 events/y, P=0.016)., Conclusions: LVAD patients, in whom hemodynamics were optimized, had a significantly lower rate of hospital readmissions, primarily because of fewer heart failure admissions. These findings highlight the importance of achieving hemodynamic optimization in LVAD patients.

Background: With more hospital consolidations as an inevitable part of our future health care ecosystem, we investigated the relationship between hospital consolidations and operative outcomes., Methods: Using the Health Care Cost and Utilization Project State Inpatient Database (Florida and California), the American Hospital Association Annual Survey Database, and Medicare's Case Mix Index data, we identified 19 hospitals that consolidated between 2007 and 2013 and propensity matched them with 19 independent hospitals, using patient and hospital characteristics. One year before consolidation and again 1 year after, we used difference-in-differences analysis to compare changes in the risk-adjusted complication rate of 7 elective operations performed in the consolidated hospitals and in the matched control group., Results: Of the 7 procedures studied, 2 procedures saw a decrease in complication rate (lumbar and lumbosacral fusion of the posterior column posterior technique, difference-in-differences = -0.6%, P < .01; total hip replacement, difference-in-differences = -0.6%, P < .01); 3 procedures saw an increase in complication rate (transurethral prostatectomy, difference-in-differences = 4.1%, P < .01; cervical fusion of the anterior column anterior technique, difference-in-differences = 1.5%, P < .01; total knee replacement, difference-in-differences = 0.3%, P < .01); and 2 procedures saw no change in complication rate (laparoscopic cholecystectomy, lumbar and lumbosacral fusion of the anterior column posterior technique, both P > .05) after hospital consolidation., Conclusion: Arguments have been made that consolidated health care systems can share high-performing clinical services and infrastructure resources, such as electronic medical records, to improve quality. Our results indicate that hospital consolidation does not uniformly improve postoperative complication rates., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Recent evidence suggests transient postoperative atrial fibrillation leads to future cardiovascular events, even in noncardiac surgery. The long-term effects of postoperative atrial fibrillation in gastrectomy patients are unknown., Methods: The Healthcare Cost and Utilization Project State Inpatient Databases identified patients undergoing gastrectomy for malignancy between 2007 and 2010. Patients were matched by propensity scores based on various factors. Adjusted Kaplan-Meier and Cox proportional hazards models assessed the effect of postoperative atrial fibrillation on cardiovascular events., Results: A higher incidence of cardiovascular events occurred over the 1st year in patients who developed postoperative atrial fibrillation. Cox proportional hazards regression confirmed an increased risk of cardiovascular events in postoperative atrial fibrillation patients., Conclusions: Our results demonstrate that patients undergoing gastrectomy for malignancy who develop postoperative atrial fibrillation are at increased risk of cardiovascular events within 1 year. Physicians should be vigilant in assessing postoperative atrial fibrillation, given the increased risk of cardiovascular morbidity., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Both glycinergic and GABAergic neurons require the vesicular inhibitory amino acid transporter (VIAAT) for synaptic vesicle filling. Presynaptic GABA concentrations are determined by the GABA-synthesizing enzymes glutamate decarboxylase (GAD)65 and GAD67, whereas the presynaptic glycine content depends on the plasma membrane glycine transporter 2 (GlyT2). Although severely impaired, glycinergic transmission is not completely absent in GlyT2-knockout mice, suggesting that other routes of glycine uptake or de novo synthesis of glycine exist in presynaptic terminals. To investigate the consequences of a complete loss of glycinergic transmission, we generated a mouse line with a conditional ablation of VIAAT in glycinergic neurons by crossing mice with loxP-flanked VIAAT alleles with a GlyT2-Cre transgenic mouse line. Interestingly, conditional VIAAT knockout (VIAAT cKO) mice were not viable at birth. In addition to the dominant respiratory failure, VIAAT cKO showed an umbilical hernia and a cleft palate. Immunohistochemistry revealed an almost complete depletion of VIAAT in the brainstem. Electrophysiology revealed the absence of both spontaneous glycinergic and GABAergic inhibitory postsynaptic currents from hypoglossal motoneurons. Our results demonstrate that the deletion of VIAAT in GlyT2-Cre expressing neurons also strongly affects GABAergic transmission and suggest a large overlap of the glycinergic and the GABAergic neuron population during early development in the caudal parts of the brain.

GABAergic inhibitory neurons are a large population of neurons in the central nervous system (CNS) of mammals and crucially contribute to the function of the circuitry of the brain. To identify specific cell types and investigate their functions labelling of cell populations by transgenic expression of fluorescent proteins is a powerful approach. While a number of mouse lines expressing the green fluorescent protein (GFP) in different subpopulations of GABAergic cells are available, GFP expressing mouse lines are not suitable for either crossbreeding to other mouse lines expressing GFP in other cell types or for Ca2+-imaging using the superior green Ca2+-indicator dyes. Therefore, we have generated a novel transgenic mouse line expressing the red fluorescent protein tdTomato in GABAergic neurons using a bacterial artificial chromosome based strategy and inserting the tdTomato open reading frame at the start codon within exon 1 of the GAD2 gene encoding glutamic acid decarboxylase 65 (GAD65). TdTomato expression was observed in all expected brain regions; however, the fluorescence intensity was highest in the olfactory bulb and the striatum. Robust expression was also observed in cortical and hippocampal neurons, Purkinje cells in the cerebellum, amacrine cells in the retina as well as in cells migrating along the rostral migratory stream. In cortex, hippocampus, olfactory bulb and brainstem, 80% to 90% of neurons expressing endogenous GAD65 also expressed the fluorescent protein. Moreover, almost all tdTomato-expressing cells coexpressed GAD65, indicating that indeed only GABAergic neurons are labelled by tdTomato expression. This mouse line with its unique spectral properties for labelling GABAergic neurons will therefore be a valuable new tool for research addressing this fascinating cell type.

Background: Insufficient use of behavioral theory to understand health care workers' (HCWs) hand hygiene compliance may result in suboptimal design of hand hygiene interventions and limit effectiveness. Previous studies examined HCWs' intended, rather than directly observed, compliance and/or focused on just 1 behavioral model. This study examined HCWs' explanations of noncompliance in "real time" (immediately after observation), using a behavioral theory framework, to inform future intervention design., Methods: HCWs were directly observed and asked to explain episodes of noncompliance in "real-time." Explanations were recorded, coded into 12 behavioral domains, using the Theory Domains Framework, and subdivided into themes., Results: Over two-thirds of 207 recorded explanations were explained by 2 domains. These were "Memory/Attention/Decision Making" (87, 44%), subdivided into 3 themes (memory, loss of concentration, and distraction by interruptions), and "Knowledge" (55, 26%), with 2 themes relating to specific hand hygiene indications. No other domain accounted for more than 18 (9%) explanations., Conclusion: An explanation of HCW's "real-time" explanations for noncompliance identified "Memory/Attention/Decision Making" and "Knowledge" as the 2 behavioral domains commonly linked to noncompliance. This suggests that hand hygiene interventions should target both automatic associative learning processes and conscious decision making, in addition to ensuring good knowledge. A theoretical framework to investigate HCW's "real-time" explanations of noncompliance provides a coherent way to design hand hygiene interventions., (Copyright © 2014 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Mosby, Inc. All rights reserved.)

Quality control and degradation of misfolded proteins are essential processes of all cells. The endoplasmic reticulum (ER) is the entry site of proteins into the secretory pathway in which protein folding occurs and terminally misfolded proteins are recognized and retrotranslocated across the ER membrane into the cytosol. Here, proteins undergo polyubiquitination by one of the membrane-embedded ubiquitin ligases, in yeast Hrd1/Der3 (HMG-CoA reductase degradation/degradation of the ER) and Doa10 (degradation of alpha), and are degraded by the proteasome. In this study, we identify cytosolic Ubr1 (E3 ubiquitin ligase, N-recognin) as an additional ubiquitin ligase that can participate in ER-associated protein degradation (ERAD) in yeast. We show that two polytopic ERAD substrates, mutated transporter of the mating type a pheromone, Ste6* (sterile), and cystic fibrosis transmembrane conductance regulator, undergo Ubr1-dependent degradation in the presence and absence of the canonical ER ubiquitin ligases. Whereas in the case of Ste6* Ubr1 is specifically required under stress conditions such as heat or ethanol or in the absence of the canonical ER ligases, efficient degradation of human cystic fibrosis transmembrane conductance regulator requires function of Ubr1 already in wild-type cells under standard growth conditions. Together with the Hsp70 (heat shock protein) chaperone Ssa1 (stress-seventy subfamily A) and the AAA-type ATPase Cdc48 (cell division cycle), Ubr1 directs the substrate to proteasomal degradation. These data unravel another layer of complexity in ERAD.

Astrocytes operate in close spatial relationship to other cells including neurons. Structural interaction is controlled by a dynamic interplay between actin-based cell motility and contact formation via cell-cell and cell-extracellular matrix adhesions. A central player in the control of cell adhesion is the cytoskeletal adaptor protein Vinculin. Incorporation of Vinculin affects mechanical properties and turnover of cell adhesion sites. To study the in vivo function of Vinculin in astrocytes, a mouse line with astrocyte specific and inducible deletion of vinculin was generated. Deletion of vinculin decreased the expression of the glial acidic fibrillary protein (GFAP) in Bergmann glial cells in the cerebellum. In addition, localization of GFAP to Bergmann glial endfeet was disturbed, indicating a role for vinculin in controlling its expression and localization. In contrast, vimentin expression, morphology, activation state and polarity of the targeted cells as well as the localization of the extracellular matrix protein laminin was not compromised. Furthermore, stab wound lesions were performed in the cerebellar cortex. In both wildtype and vinculin knockout mice GFAP expression was upregulated in Bergmann glial cells of the lesioned area with no differences observed between genotypes in expression and localization of GFAP. These results propose a selective requirement for vinculin in cellular events related to cell adhesion in vivo. As in vitro data suggested a major role for vinculin in the control of the cytoskeletal connection affecting mechanical stability and cell motility, our data add a note of caution to the extrapolation of in vitro data to in vivo function., (Copyright © 2013 Wiley Periodicals, Inc.)

Inhibitory neurons are involved in the generation and patterning of the respiratory rhythm in the adult animal. However, the role of glycinergic neurons in the respiratory rhythm in the developing network is still not understood. Although the complete loss of glycinergic transmission in vivo is lethal, the blockade of glycinergic transmission in slices of the medulla has little effect on pre-Bötzinger complex network activity. As 50% of the respiratory rhythmic neurons in this slice preparation are glycinergic, they have to be considered as integrated parts of the network. We aimed to investigate whether glycinergic neurons receive mixed miniature inhibitory postsynaptic currents (mIPSCs) that result from co-release of GABA and glycine. Quantification of mixed mIPSCs by the use of different objective detection methods resulted in a wide range of results. Therefore, we generated traces of mIPSCs with a known distribution of mixed mIPSCs and mono-transmitter-induced mIPSCs, and tested the detection methods on the simulated data. We found that analysis paradigms, which are based on fitting the sum of two mIPSC templates, to be most acceptable. On the basis of these protocols, 20-40% of all mIPSCs recorded from respiratory glycinergic neurons are mixed mIPSCs that result from co-release of GABA and glycine. Furthermore, single-cell reverse transcriptase polymerase chain reaction revealed that 46% of glycinergic neurons co-express mRNA of glycine transporter 2 together with at least one marker protein of GABAergic neurons. Our data suggest that significant co-transmission occurs in the pre-Bötzinger complex that might be involved in the shaping of synaptic inhibition of respiratory glycinergic neurons., (© 2013 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Astrocytes are important glial cells in the brain providing metabolic support to neurons as well as contributing to brain signaling. These different functional levels have to be highly coordinated to allow for proper cell and brain function. In this study, we show that in astrocytes the NAD(+) /NADH redox state modulates dopamine-induced Ca(2+) signals thereby connecting metabolism and Ca(2+) signaling. Application of dopamine induced a dose-dependent increase in Ca(2+) signal frequency in these cells, which was dependent on D(1) -receptor signaling, glycolytic activity, an increase in cytosolic NADH and inositol 1,4,5-triphosphate receptor operated intracellular Ca(2+) stores. Application of dopamine at a low concentration (1 μM) did not induce an increase in Ca(2+) signal frequency by itself. However, simultaneously increasing cytosolic NADH content either by direct application of NADH or by application of lactate resulted in a pronounced increase in Ca(2+) signal frequency. This increase could be blocked by co-application of pyruvate, suggesting that indeed the NAD(+) /NADH redox state is regulating Ca(2+) signals. We conclude that at the NAD(+) /NADH redox state metabolic and signaling information is integrated in astrocytes, thereby most likely contributing to precisely coordinate these different tasks of astrocytes., (© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.)

Introduction: Achieving a sustained improvement in hand-hygiene compliance is the WHO's first global patient safety challenge. There is no RCT evidence showing how to do this. Systematic reviews suggest feedback is most effective and call for long term well designed RCTs, applying behavioural theory to intervention design to optimise effectiveness., Methods: Three year stepped wedge cluster RCT of a feedback intervention testing hypothesis that the intervention was more effective than routine practice in 16 English/Welsh Hospitals (16 Intensive Therapy Units [ITU]; 44 Acute Care of the Elderly [ACE] wards) routinely implementing a national cleanyourhands campaign). Intervention-based on Goal & Control theories. Repeating 4 week cycle (20 mins/week) of observation, feedback and personalised action planning, recorded on forms. Computer-generated stepwise entry of all hospitals to intervention. Hospitals aware only of own allocation., Primary Outcome: direct blinded hand hygiene compliance (%)., Results: All 16 trusts (60 wards) randomised, 33 wards implemented intervention (11 ITU, 22 ACE). Mixed effects regression analysis (all wards) accounting for confounders, temporal trends, ward type and fidelity to intervention (forms/month used). INTENTION TO TREAT ANALYSIS: Estimated odds ratio (OR) for hand hygiene compliance rose post randomisation (1.44; 95% CI 1.18, 1.76;p<0.001) in ITUs but not ACE wards, equivalent to 7-9% absolute increase in compliance. PER-PROTOCOL ANALYSIS FOR IMPLEMENTING WARDS: OR for compliance rose for both ACE (1.67 [1.28-2.22]; p<0.001) & ITUs (2.09 [1.55-2.81]; p<0.001) equating to absolute increases of 10-13% and 13-18% respectively. Fidelity to intervention closely related to compliance on ITUs (OR 1.12 [1.04, 1.20]; p = 0.003 per completed form) but not ACE wards., Conclusion: Despite difficulties in implementation, intention-to-treat, per-protocol and fidelity to intervention, analyses showed an intervention coupling feedback to personalised action planning produced moderate but significant sustained improvements in hand-hygiene compliance, in wards implementing a national hand-hygiene campaign. Further implementation studies are needed to maximise the intervention's effect in different settings., Trial Registration: Controlled-Trials.com ISRCTN65246961.

Background and Objective: Wearing of gloves reduces transmission of organisms by healthcare workers' hands but is not a substitute for hand hygiene. Results of previous studies have varied as to whether hand hygiene is worse when gloves are worn. Most studies have been small and used nonstandardized assessments of glove use and hand hygiene. We sought to observe whether gloves were worn when appropriate and whether hand hygiene compliance differed when gloves were worn., Design: Observational study., Participants and Setting: Healthcare workers in 56 medical or care of the elderly wards and intensive care units in 15 hospitals across England and Wales., Methods: We observed hand hygiene and glove usage (7,578 moments for hand hygiene) during 249 one-hour sessions. Observers also recorded whether gloves were or were not worn for individual contacts., Results: Gloves were used in 1,983 (26.2%) of the 7,578 moments for hand hygiene and in 551 (16.7%) of 3,292 low-risk contacts; gloves were not used in 141 (21.1%) of 669 high-risk contacts. The rate of hand hygiene compliance with glove use was 41.4% (415 of 1,002 moments), and the rate without glove use was 50.0% (1,344 of 2,686 moments). After adjusting for ward, healthcare worker type, contact risk level, and whether the hand hygiene opportunity occurred before or after a patient contact, glove use was strongly associated with lower levels of hand hygiene (adjusted odds ratio, 0.65 [95% confidence interval, 0.54-0.79]; P < .0001)., Conclusion: The rate of glove usage is lower than previously reported. Gloves are often worn when not indicated and vice versa. The rate of compliance with hand hygiene was significantly lower when gloves were worn. Hand hygiene campaigns should consider placing greater emphasis on the World Health Organization indications for gloving and associated hand hygiene., Trial Registration: National Research Register N0256159318.

Trials evaluating interventions to improve health care workers' hand hygiene compliance use directly observed compliance as a primary outcome measure. Observers should be blinded to the intervention and the effectiveness of blinding assessed to prevent systematic bias. The literature has not addressed this issue, and this study describes a robust and pragmatic method for assessing the adequacy of blinding in hand hygiene intervention trials., (Copyright (c) 2010 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Mosby, Inc. All rights reserved.)

Calcyphylaxis consists in vascular calcium deposition and skin necrosis, which appears in the final stage of renal failure. Advanced forms of systemic connective tissue disease such as lupus erythematosus, especially with concomitant vasculitis, leading to renal failure and uremia may be conducive to calcyphylaxis. We are presenting a case of a 50-year-old male requiring chronic peritoneal dialysis since the age of 43, due to end-stage renal disease resulting from chronic glomeluronephritis. The patient presented to our Dermatology Department with large and painful coalescent cutaneous lesions on both lower extremities, fingertips and lips. Both clinical picture and disease history indicated systemic vasculitis that was previously unrecognized. Additional examinations revealed the following markers of inflammation: leukocytosis (11 G/I) with normal level of eosinophils, CRP > 0.6 mg/I, ESR 120 mm/h, and IgG 20 g/l, without any source of infection. Indirect immunofluorescence showed the absence of antineutrophil cytoplasmic antibodies (ANCA) on polynuclear leucocytes. A distinct fluorescence pattern observed in liver sinusoids was suggestive of the presence of some form of anti-granulocyte antibodies. Anti-nuclear antibodies (ANA) were detected in serum (1:1000) with homogenous and microgranular fluorescence pattern. Anti-extractable nuclear antigen panel (ENA), C3/C4 levels, anti-smooth muscle, anti-dsDNA and anti-glomerular basement membrane (GBM) antibodies were within normal limits. Lupus band test revealed IgA and IgG deposits at the dermis-epidermis junction. Histopathological examination of the skin showed calcification complicated by small vessel thrombosis, however, it was non-specific for vasculitis. Our case represents an example of calcyphylaxis associated with a widespread medial vascular calcification in a patient with end stage renal disease secondary to systemic lupus erythematosus. Although renal dialysis itself is known to trigger calcyphylaxis, there have been few reports in literature suggesting that collagen vascular disease may also contribute to this process.

The Grueneberg ganglion (GG) is a cluster of neurones present in the vestibule of the anterior nasal cavity. Although its function is still elusive, recent studies have shown that cells of the GG transcribe the gene encoding the olfactory marker protein (OMP) and project their axons to glomeruli of the olfactory bulb, suggesting that they may have a chemosensory function. Chemosensory responsiveness of olfactory neurones in the main olfactory epithelium (MOE) and the vomeronasal organ (VNO) is based on the expression of either odorant receptors or vomeronasal putative pheromone receptors. To scrutinize its presumptive olfactory nature, the GG was assessed for receptor expression by extensive RT-PCR analyses, leading to the identification of a distinct vomeronasal receptor which was expressed in the majority of OMP-positive GG neurones. Along with this receptor, these cells expressed the G proteins Go and Gi, both of which are also present in sensory neurones of the vomeronasal organ. Odorant receptors were expressed by very few cells during prenatal and perinatal stages; a similar number of cells expressed adenylyl cyclase type III and G(olf/s), characteristic signalling elements of the main olfactory system. The findings of the study support the notion that the GG is in fact a subunit of the complex olfactory system, comprising cells with either a VNO-like or a MOE-like phenotype. Moreover, expression of a vomeronasal receptor indicates that the GG might serve to detect pheromones.

The olfactory marker protein (OMP) is expressed in mature chemosensory neurons in the nasal neuroepithelium. Here, we report the identification of a novel population of OMP-expressing neurons located bilaterally in the anterior/dorsal region of each nasal cavity at the septum. These cells are clearly separated from the regio olfactoria, harboring the olfactory sensory neurons. During mouse development, the arrangement of the anterior OMP-cells undergoes considerable change. They appear at about stage E13 and are localized in the nasal epithelium during early stages; by epithelial budding, ganglion-shaped clusters are formed in the mesenchyme during the perinatal phase, and a filiform layer directly underneath the nasal epithelium is established in adults. The anterior OMP-cells extend long axonal processes which form bundles and project towards the brain. The data suggest that the newly discovered group of OMP-cells in the anterior region of the nasal cavity may serve a distinct sensory function.

Unlabelled: Bronchial asthma in the elderly is the significant medical problem because it is often underdiagnosed and insufficiently treated. The aim of the study was the assessment of natural course of bronchial asthma and its diagnostic procedures and treatment in patients after 65 yrs. The study group consisted of 181 patients suffering from asthma, at mean age 69 +/- 2.1 yrs. Apart from retrospective analysis, spirometry, skin tests and serum IgE concentration were performed., Results: The mean duration of asthma was 23 +/- 7.2 yrs and in most cases time of proper diagnosis was prolonged. 49% of elderly patients bad a positive history to atopy. In spirometry the mean value of FEV1 was 2.78 +/- 1.3 l/s. House dust mites were the most common allergen confirmed by skin prick tests and specific serum IgE level., Conclusion: The observations proved underdiagnosis and insufficient treatment of asthma in the elderly. Positive skin test and specific IgE observed in a large group of elderly objects can indicate atopic mechanism in these cases.

Purpose/objectives: To describe institutional practices related to dietary restrictions for patients with neutropenia to determine whether restrictions are used and when they are implemented and discontinued., Design: Descriptive survey., Sample: 156 institutions belonging to the Association of Community Cancer Centers., Methods: Mailed survey., Findings: Of the institutions surveyed, 78% (n = 120) placed patients with neutropenia on restricted diets. Participating institutions responded that patients were placed on restricted diets at a variety of different white blood cell and neutrophil counts, including neutrophils < 1,000 (43%) and < 500 (46%). The majority of institutions (92%) placed patients on restricted diets once neutropenia was documented, while only 9% of institutions restricted diets when cancer treatment was initiated. Of the participating institutions, 83% (n = 96) restricted diets only when patients were neutropenic rather than throughout the duration of the chemotherapy regimen. The most commonly restricted foods were fresh fruits and juices (92%), fresh vegetables (95%), and raw eggs (74%). Few institutions restricted tap water (12%). Wine was restricted at 39% of institutions, and beer was restricted at 40% of institutions., Conclusions: The role of diet in the development of infection in patients with neutropenia is unclear. This unclear role contributes to the variation in dietary restrictions among institutions., Implications for Nursing Practice: Additional research should focus on dietary factors contributing to neutropenic infections and establishing criteria for implementation of specific dietary modifications. Nursing assessment should include nutritional status and risk factors for neutropenia and bacterial translocation. Nursing protocols for neutropenic dietary restrictions should be based on research findings.