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© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.562 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made., Objective: Cerebral venous thrombosis (CVT) caused by vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse effect of adenovirus-based severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines. In March 2021, after autoimmune pathogenesis of VITT was discovered, treatment recommendations were developed. These comprised immunomodulation, non-heparin anticoagulants, and avoidance of platelet transfusion. The aim of this study was to evaluate adherence to these recommendations and its association with mortality. Methods: We used data from an international prospective registry of patients with CVT after the adenovirus-based SARS-CoV-2 vaccination. We analyzed possible, probable, or definite VITT-CVT cases included until January 18, 2022. Immunomodulation entailed administration of intravenous immunoglobulins and/or plasmapheresis. Results: Ninety-nine patients with VITT-CVT from 71 hospitals in 17 countries were analyzed. Five of 38 (13%), 11 of 24 (46%), and 28 of 37 (76%) of the patients diagnosed in March, April, and from May onward, respectively, were treated in-line with VITT recommendations (p < 0.001). Overall, treatment according to recommendations had no statistically significant influence on mortality (14/44 [32%] vs 29/55 [52%], adjusted odds ratio [OR] = 0.43, 95% confidence interval [CI] = 0.16-1.19). However, patients who received immunomodulation had lower mortality (19/65 [29%] vs 24/34 [70%], adjusted OR = 0.19, 95% CI = 0.06-0.58). Treatment with non-heparin anticoagulants instead of heparins was not associated with lower mortality (17/51 [33%] vs 13/35 [37%], adjusted OR = 0.70, 95% CI = 0.24-2.04). Mortality was also not significantly influenced by platelet transfusion (17/27 [63%] vs 26/72 [36%], adjusted OR = 2.19, 95% CI = 0.74-6.54). Conclusions: In patients with VITT-CVT, adherence to VITT treatment recommendations improved over time. Immunomodulation seems crucial for reducing mortality of VITT-CVT. ANN NEUROL 2022;92:562-573., This research was funded by The Netherlands Organisation for Health Research and Development (ZonMw, grant number 10430072110005) and the Dr. C. J. Vaillant Foundation.

Background: Absolute Psoriasis Area and Severity Index (PASI) is a key endpoint in psoriasis management. Petto et al. [Pharm Stat. 2019;18(1):4–21] developed a statistical method to estimate the proportion of patients reaching absolute PASI response given baseline PASI score and proportion of patients achieving relative improvements at predefined time points. Objectives: To test this method on clinical data from two phase 3 tildrakizumab trials (reSURFACE 1/2) comparing estimated absolute PASI ≤1/≤2/≤3/≤5 responses with reference responses from clinical databases. Methods: Reference PASI responses of ≤1/≤2/≤3/≤5 were extracted from clinical databases. Estimation of absolute PASI ≤1/≤2/≤3/≤5 response rates at week (W) 12 and W28 by treatment and trial were performed. Differences between estimated and reference responses were analysed. Bland-Atman limits of agreement and Passing-Bablok regression to assess variations between estimated and reference responses were performed. Results: Differences between estimated and reference absolute PASI ≤1/≤2/≤3/≤5 responses at W12 and W28 by treatment and trial were of little clinical relevance with an overall mean difference in PASI response proportion of −2.2% (e.g., for the tildrakizumab 100-mg arm, original proportions of patients achieving PASI of ≤1/≤2/≤3/≤5 at W28 were 38.5%/52.2%/63.5%/73.9% and 39.8%/54.8%/63.6%/76.9% [reSURFACE 1 and 2, respectively] vs. estimated proportions of 33.2%/49.8%/62.5%/78.3% and 34.3%/51.6%/64.5%/79.9%). Limits of agreement were −7.1% to 1.4% at W12 and –6.8% to 4.3% at W28. Scatterplots revealed linearity that stood the cusum test in Passing-Bablok regression with slope 1.14 (95% confidence intervals: 1.06 to 1.20). Conclusion: Good estimates of absolute PASI response rates were achieved with the application of the statistical method to tildrakizumab data reported in the phase 3 studies, in particular in the verum study arms. Our data support the method provided by Petto et al. [2019] to estimate proportions of psoriasis patients reaching absolute PASI value thresholds using relative PASI improvements.

A Transient Hypertrophic Cardiomyopathy?

Background This study evaluated the use of comprehensive geriatric assessment (CGA) in older patients undergoing pacemaker implantation. Methods In this prospective cohort, CGA was performed in 197 patients ≥75 years at pacemaker implantation and yearly thereafter. CGA embraced the following domains: cognition, mobility, nutrition, activities of daily living (ADLs), and falls (with or without loss of consciousness). Based on comorbidities, the Charlson comorbidity index (CCI) was calculated. For predictive analysis, logistic regression was used. Results During a mean follow-up duration of 2.4 years, the incidence rates of syncope decreased from 0.46 to 0.04 events per year (p p = 0.013), malnutrition (OR 3.26, 95%CI 1.52–7.01, p = 0.002), and a higher CCI (OR per point increase 1.25, 95%CI 1.04–1.50, p = 0.019) at baseline were significant predictors of mortality. Among 169 patients who survived for more than 1 year and thus underwent follow-up CGA, CGA domains did not deteriorate during follow-up, except for ADLs. This decline in ADLs during follow-up was the strongest predictor of later nursing home admission (OR 9.29, 95%CI 1.82–47.49, p = 0.007). Higher baseline age (OR per year increase 1.10, 95%CI 1.02–1.20, p = 0.018) and a higher baseline CCI (OR per point increase 1.32, 95%CI 1.05–1.65, p = 0.017) were associated with a decline in ADLs during follow-up. Conclusions CGA is useful to detect functional deficits, which are associated with mortality or nursing home admission after pacemaker implantation. The present study seems to support the use of CGA in older patients undergoing pacemaker implantation as functional deficits and falls are amenable to geriatric interventions.

Neurexins are presynaptic transmembrane proteins crucial for synapse development and organization. Deletion and missense mutations in all three Neurexin genes have been identified in psychiatric disorders, with mutations in the NRXN1 gene most strongly linked to schizophrenia (SZ) and autism spectrum disorder (ASD). While the consequences of NRXN1 deletion have been extensively studied on the synaptic and behavioral levels, circuit endophenotypes that translate to the human condition have not been characterized yet. Therefore, we investigated the electrophysiology of cortico-striatal-thalamic circuits in Nrxn1α−/− rats and wildtype littermates focusing on a set of translational readouts, including spontaneous oscillatory activity, auditory-evoked oscillations and potentials, as well as mismatch negativity-like (MMN) responses and responses to social stimuli. On the behavioral level Nrxn1α−/− rats showed locomotor hyperactivity. In vivo freely moving electrophysiology revealed pronounced increases of spontaneous oscillatory power within the gamma band in all studied brain areas and elevation of gamma coherence in cortico-striatal and thalamocortical circuits of Nrxn1α−/− rats. In contrast, auditory-evoked oscillations driven by chirp-modulated tones showed reduced power in cortical areas confined to slower oscillations. Finally, Nrxn1α−/− rats exhibited altered auditory evoked-potentials and profound deficits in MMN-like responses, explained by reduced prediction error. Despite deficits for auditory stimuli, responses to social stimuli appeared intact. A central hypothesis for psychiatric and neurodevelopmental disorders is that a disbalance of excitation-to-inhibition is underlying oscillatory and sensory deficits. In a first attempt to explore the impact of inhibitory circuit modulation, we assessed the effects of enhancing tonic inhibition via δ-containing GABAA receptors (using Gaboxadol) on endophenotypes possibly associated with network hyperexcitability. Pharmacological experiments applying Gaboxadol showed genotype-specific differences, but failed to normalize oscillatory or sensory processing abnormalities. In conclusion, our study revealed endophenotypes in Nrxn1α−/− rats that could be used as translational biomarkers for drug development in psychiatric disorders.

BACKGROUND/OBJECTIVES To assess the course and prediction of basic activities of daily living (ADL) function in patients after transcatheter aortic valve implantation (TAVI). DESIGN This was a prospective cohort study. SETTING The setting was a single academic center in Switzerland. PARTICIPANTS Participants included individuals aged ≥70 years (n = 330) undergoing TAVI. MEASUREMENTS A frailty index (based on geriatric assessment) and cardiac risk scores (EuroSCORE, Society of Thoracic Surgeons [STS] score) were determined in patients before TAVI. Basic ADL function was measured with patient or proxy interviews at baseline and 1-year follow up. We used logistic regression models to investigate the association between baseline factors and functional decline. RESULTS At 1-year follow up, 229 (69.4%) of the 330 patients had stable or improved basic ADL function, 49 (14.8%) experienced a decline in basic ADL function, and 52 (15.8%) died. The frailty index, but not cardiac risk scores, significantly predicted decline in basic ADL function. Among the 34 surviving very frail patients, 12 (35.3%) experienced a functional status decline, and the remaining 22 (64.7%) had stable or improved functional status at 1-year follow up. CONCLUSION This study confirms that a frailty index, and not cardiac risk scores, identifies patients at an increased risk of functional status decline after TAVI. Identifying patients with a high frailty index before TAVI is clinically relevant as these patients might benefit from targeted geriatric management and rehabilitation after TAVI. However, based on current data, it is not justified to use information on frailty status as the criterion for identifying patients in whom TAVI might be futile. Although the probability of poor outcome is high, very frail patients also have a high probability of favorable long-term functional outcome.

Purpose Patients with pelvic floor disorders are growing in number. The aim of this study is to outline the main activities of a urotherapist, an advanced nurse practitioner, in the care of patients with pelvic floor disorders and to evaluate patient satisfaction with the service urotherapists provide. Methods The prospective single-center observational study was carried out from July 2016 to June 2018. Parameters used to assess the urotherapist activities included the number of consultations, type of counselling, time frame of consultations and therapy and patient satisfaction. In a subgroup of 38 patients, satisfaction with the urotherapy sessions was evaluated by a questionnaire. Results Totally, 1709 patients were examined by urogynecologists. Five hundred and fourteen (30%) with chronic pelvic floor disorders were subsequently referred to a urotherapist. Of these patients, 60% were at least 65 years old. The most common pelvic floor disorders (221 patients; 43%) were an overactive bladder, recurrent urinary tract infections, chronic cystitis and pelvic pain syndrome; the second most common pelvic floor disorder was pelvic organ prolapsed (151 patients; 29%). Of the study subgroup comprising 38 patients, 32 (84%) returned the patient satisfaction questionnaire. All 32 patients specified their level of agreement with the urotherapist’s professional competence, empathy, temporal availability and quality of advice as “agree to strongly agree.” Conclusions Management by a urotherapist was highly appreciated. The role of the urotherapist as a care coordinator, their level of autonomy and barriers to the implementation in primary care requires further exploration.

In older patients, sarcopenia is a prevalent disease associated with negative outcomes. Sarcopenia has been investigated in patients undergoing transcatheter aortic valve implantation (TAVI), but the criteria for diagnosis of the disease are heterogeneous. This systematic review of the current literature aims to evaluate the prevalence of sarcopenia in patients undergoing TAVI and to analyse the impact of sarcopenia on clinical outcomes. A comprehensive search of the literature has been performed in electronic databases from the date of initiation until March 2020. Using a pre-defined search strategy, we identified studies assessing skeletal muscle mass, muscle quality and muscle function as measures for sarcopenia in patients undergoing TAVI. We evaluated how sarcopenia affects the outcomes mortality at ≥1 year, prolonged length of hospital stay, and functional decline. We identified 18 observational studies, enrolling a total number of 9’513 patients. For assessment of skeletal muscle mass, all included studies used data from computed tomography. Cutoff points for definition of low muscle mass were heterogeneous, and prevalence of sarcopenia varied between 21.0% and 70.2%. In uni- or multivariate regression analysis of different studies, low muscle mass was found to be a significant predictor of mortality, prolonged length of hospital stay, and functional decline. No interventional study was identified measuring the effect of nutritional or physiotherapy interventions on sarcopenia in TAVI patients. Sarcopenia is highly prevalent among patients undergoing TAVI, and negatively affects important outcomes. Early diagnosis of this condition might allow a timely start of nutritional and physiotherapy interventions to prevent negative outcomes in TAVI patients.

Purpose To prospectively compare the diagnostic accuracy of radial breast ultrasound (r-US) to that of conventional meander-like breast ultrasound (m-US), patients of a consecutive, unselected, mixed collective were examined by both scanning methods. Methods Out of 1948 dual examinations, 150 revealed suspicious lesions resulting in 168 biopsies taken from 148 patients. Histology confirmed breast cancers in 36 cases. Sensitivity, specificity, accuracy, PPV, and NPV were calculated for r-US and m-US. The examination times were recorded. Results For m-US and r-US, sensitivity (both 88.9%), specificity (86.4% versus 89.4%), accuracy (86.9% versus 89.3%), PPV (64.0% versus 69.6%), NPV (both 98.3%), false-negative rate (both 5.6%), and rate of cancer missed by one method (both 5.6%) were similar. The mean examination time for r-US (14.8 min) was significantly (p Conclusion Because the diagnostic accuracy of r-US and m-US are comparable, r-US can be considered an alternative to m-US in routine breast US with the added benefit of a significantly shorter examination time.

The design of non-viral vectors that efficiently deliver genetic materials into cells, in particular to the nucleus, remains a major challenge in gene therapy and vaccine development. To tackle the problems associated with cellular uptake and nuclear targeting, here we introduce a delivery platform based on the self-assembly of an amphiphilic peptide carrying an N-terminal KRKR sequence that functions as a nuclear localization signal (NLS). By means of a single-step self-assembly process, the amphiphilic peptides afford the generation of NLS-functionalized multicompartment micellar nanostructures that can embed various oligonucleotides between their individual compartments. Detailed physicochemical, cellular and ultrastructural analyses demonstrated that integrating an NLS in the hydrophilic domain of the peptide along with tuning its hydrophobic domain led to self-assembled DNA-loaded multicompartment micelles (MCMs) with enhanced cellular uptake and nuclear translocation. We showed that the nuclear targeting ensued via the NLS interaction with the nuclear transport receptors of the karyopherin family. Importantly, we observed that the treatment of MCF-7 cells with NLS-MCMs loaded with anti-BCL2 antisense oligonucleotides resulted in up to 86% knockdown of BCL2, an inhibitor of apoptosis that is overexpressed in more than half of all human cancers. We envision that this platform can be used to efficiently entrap and deliver diverse genetic payloads to the nucleus and find applications in basic research and biomedicine., Biomaterials Science, 10 (15), ISSN:2047-4830, ISSN:2047-4849

The Descemet's membrane (DM) and the lens capsule (LC) are two ocular basement membranes (BMs) that are essential in maintaining stability and structure of the cornea and lens. In this study, we investigated the proteomes and biomechanical properties of these two materials to uncover common and unique properties. We also screened for possible protein changes during diabetes. LC-MS/MS was used to determine the proteomes of both BMs. Biomechanical measurements were conducted by atomic force microscopy (AFM) in force spectroscopy mode, and complemented with immunofluorescence microscopy. Proteome analysis showed that all six existing collagen IV chains represent 70% of all LC-protein, and are thus the dominant components of the LC. The DM on the other hand is predominantly composed of a single protein, TGF-induced protein, which accounted for around 50% of all DM-protein. Four collagen IV-family members in DM accounted for only 10% of the DM protein. Unlike the retinal vascular BMs, the LC and DM do not undergo significant changes in their protein compositions during diabetes. Nanomechanical measurements showed that the endothelial/epithelial sides of both BMs are stiffer than their respective stromal/anterior-chamber sides, and both endothelial and stromal sides of the DM were stiffer than the epithelial and anterior-chamber sides of the LC. Long-term diabetes did not change the stiffness of the DM and LC. In summary, our analyses show that the protein composition and biomechanical properties of the DM and LC are different, i.e., the LC is softer than DM despite a significantly higher concentration of collagen IV family members. This finding is unexpected, as collagen IV members are presumed to be responsible for BM stiffness. Diabetes had no significant effect on the protein composition and the biomechanical properties of both the DM and LC.

Objective To compare countries' health care needs by segmenting populations into a set of needs-based health states. Data sources We used seven waves of the Survey of Health, Aging and Retirement in Europe (SHARE) panel survey data. Study design We developed the Cross-Country Simple Segmentation Tool (CCSST), a validated clinician-administered instrument for categorizing older individuals by distinct, homogeneous health and related social service needs. Using clinical indicators, self-reported physician diagnosis of chronic disease, and performance-based tests conducted during the survey interview, individuals were assigned to 1-5 global impressions (GI) segments and assessed for having any of the four identifiable complicating factors (CFs). We used Cox proportional hazard models to estimate the risk of mortality by segment. First, we show the segmentation cross-sectionally to assess cross-country differences in the fraction of individuals with different levels of medical needs. Second, we compare the differences in the rate at which individuals transition between those levels and death. Data collection/extraction methods We segmented 270,208 observations (from Austria, Belgium, Czech Republic, Denmark, France, Germany, Greece, Israel, Italy, the Netherlands, Poland, Spain, Sweden, and Switzerland) from 96,396 individuals into GI and CF categories. Principal findings The CCSST is a valid tool for segmenting populations into needs-based states, showing Switzerland with the lowest fraction of individuals in high medical needs segments, followed by Denmark and Sweden, and Poland with the highest fraction, followed by Italy and Israel. Comparing hazard ratios of transitioning between health states may help identify country-specific areas for analysis of ecological and cultural risk factors. Conclusions The CCSST is an innovative tool for aggregate cross-country comparisons of both health needs and transitions between them. A cross-country comparison gives policy makers an effective means of comparing national health system performance and provides targeted guidance on how to identify strategies for curbing the rise of high-need, high-cost patients.

Concerns associated with nanocarriers' therapeutic efficacy and side effects have led to the development of strategies to advance them into targeted and responsive delivery systems. Owing to their bioactivity and biocompatibility, peptides play a key role in these strategies and, thus, have been extensively studied in nanomedicine. Peptide-based nanocarriers, in particular, have burgeoned with advances in purely peptidic structures and in combinations of peptides, both native and modified, with polymers, lipids, and inorganic nanoparticles. In this review, we summarize advances on peptides promoting gene delivery systems. The efficacy of nucleic acid therapies largely depends on cell internalization and the delivery to subcellular organelles. Hence, the review focuses on nanocarriers where peptides are pivotal in ferrying nucleic acids to their site of action, with a special emphasis on peptides that assist anionic, water-soluble nucleic acids in crossing the membrane barriers they encounter on their way to efficient function. In a second part, we address how peptides advance nanoassembly delivery tools, such that they navigate delivery barriers and release their nucleic acid cargo at specific sites in a controlled fashion., International Journal of Molecular Sciences, 22 (16), ISSN:1422-0067

Self-organized nano- and microscale polymer compartments such as polymersomes, giant unilamellar vesicles (GUVs), polyion complex vesicles (PICsomes) and layer-by-layer (LbL) capsules have increasing potential in many sensing applications. Besides modifying the physicochemical properties of the corresponding polymer building blocks, the versatility of these compartments can be markedly expanded by biomolecules that endow the nanomaterials with specific molecular and cellular functions. In this review, we focus on polymer-based compartments that preserve their structure, and highlight the key role they play in the field of medical diagnostics: first, the self-assembling abilities that result in preferred architectures are presented for a broad range of polymers. In the following, we describe different strategies for sensing disease-related signals (pH-change, reductive conditions, and presence of ions or biomolecules) by polymer compartments that exhibit stimuli-responsiveness. In particular, we distinguish between the stimulus-sensitivity contributed by the polymer itself or by additional compounds embedded in the compartments in different sensing systems. We then address necessary properties of sensing polymeric compartments, such as the enhancement of their stability and biocompatibility, or the targeting ability, that open up new perspectives for diagnostic applications.

Circulating oxidized phospholipids are increasingly recognized as biomarkers of atherosclerosis. Clinical association studies have been mainly performed using an immune assay based on monoclonal antibody E06, which recognizes a variety of molecular species of oxidized phosphatidylcholine (OxPC) in lipoproteins, cell membranes or covalently bound to plasma proteins. Accumulating evidence shows that individual molecular species of OxPC demonstrate different biological activities and have different half-life times. Therefore, it is likely that certain molecular species can be associated with pathology more strongly than others. This hypothesis can only be tested using LC-MS/MS allowing quantification of individual molecular species of OxPCs. In order to ensure that laborious LC-MS/MS methods do not simply replicate the results of a technically simpler E06-OxPCs assay, we have performed relative quantification of 8 truncated molecular species of OxPCs in plasma of 132 probands and compared the data with the results of the E06-OxPCs and OxLDL assays. We have found a strong correlation between individual molecular species of OxPCs but only a weak correlation of LC-MS/MS-OxPCs data with the E06-OxPCs assay and no correlation with the OxLDL assay. Furthermore, in contrast to the results of E06-OxPCs or OxLDL assays, 7 out of 8 OxPC species were associated with hypertension. The data suggest that the results of the LC-MS/MS-OxPCs assay do not replicate the results of two ELISA-based lipid oxidation tests and therefore may produce additional diagnostic information. These findings necessitate development of simplified mass spectrometric procedures for high-throughput and affordable analysis of selected molecular species of OxPCs.

Background This study prospectively investigates the agreement between radial (r-US) and meander-like (m-US) breast ultrasound with regard to lesion location, lesion size, morphological characteristics and final BI-RADS classification of individual breast lesions. Methods Each patient of a consecutive, unselected, mixed collective received a dual ultrasound examination. Results The agreement between r-US and m-US for lesion location ranged from good (lesion to mammilla distance ICC 0.64; lesion to skin distance ICC 0.72) to substantial (clock-face localization κ 0.70). For lesion size the agreement was good (diameter ICC 0.72; volume ICC 0.69), for lesion margin and architectural distortion it was substantial (κ 0.68 and 0.70, respectively). Most importantly, there was a substantial agreement (κ 0.76) in the final BI-RADS classification between r-US and m-US. Conclusions Our recent comparison of radial and meander-like breast US revealed that the diagnostic accuracy of the two scanning methods was comparable. In this study, we observe a high degree of agreement between m-US and r-US for the lesion description (location, size, morphology) and final BI-RADS classification. These findings corroborate that r-US is a suitable alternative to m-US in daily clinical practice. Trial registration NCT02358837. Registered January 2015, retrospectively registered https://clinicaltrials.gov/ct2/results?cond=&term=NCT02358837&cntry=&state=&city=&dist=

Aims This study aims at understanding left ventricular (LV) mechanics of non-compaction (LVNC) phenotype using echocardiographic strain analysis and at assessing the association of functional parameters with cardiovascular (CV) outcomes. Methods and results Longitudinal (GLS) and circumferential strain (GCS) as well as rotation of the LV were analyzed in 55 LVNC patients and 55 matched controls. Cardiovascular outcomes were documented for a median follow-up duration of 6 years. GLS and GCS were impaired in LVNC. Similary, regional longitudinal and circumferential strain as well as twist were reduced. CV events occurred in 28 LVNC patients. Apical peak circumferential strain (APCS), peak systolic rotation of apical segments (APSR), and twist were strongly associated with events. This was independent of and incremental to LVEF and non-compacted to compacted myocardial thickness ratio (NC:C ratio). The association of twist with events was also independent of and slightly superior to GLS. Conclusions GLS, GCS, regional strain, and twist were impaired in LVNC. APCS, APSR, and twist exhibited strong association with CV events independent of and incremental to LVEF and NC:C ratio, and in case of twist even GLS. Thus, STE-derived parameters may complement the echocardiographic assessment of LVNC patients in clinical routine.

Introduction Neurocritical care focuses on the care of critically ill patients with an acute neurologic disorder and has grown significantly in the past few years. However, there is a lack of data that describe the scope of practice of neurointensivists and epidemiological data on the types of patients and treatments used in neurocritical care units worldwide. To address these issues, we designed a multicenter, international, point-prevalence, cross-sectional, prospective, observational, non-interventional study in the setting of neurocritical care (PRINCE Study). Methods In this manuscript, we analyzed data from the initial phase of the study that included registration, hospital, and intensive care unit (ICU) organizations. We present here descriptive statistics to summarize data from the registration case report form. We performed the Kruskal–Wallis test followed by the Dunn procedure to test for differences in practices among world regions. Results We analyzed information submitted by 257 participating sites from 47 countries. The majority of those sites, 119 (46.3%), were in North America, 44 (17.2%) in Europe, 34 (13.3%) in Asia, 9 (3.5%) in the Middle East, 34 (13.3%) in Latin America, and 14 (5.5%) in Oceania. Most ICUs are from academic institutions (73.4%) located in large urban centers (44% > 1 million inhabitants). We found significant differences in hospital and ICU organization, resource allocation, and use of patient management protocols. The highest nursing/patient ratio was in Oceania (100% 1:1). Dedicated Advanced Practiced Providers are mostly present in North America (73.7%) and are uncommon in Oceania (7.7%) and the Middle East (0%). The presence of dedicated respiratory therapist is common in North America (85%), Middle East (85%), and Latin America (84%) but less common in Europe (26%) and Oceania (7.7%). The presence of dedicated pharmacist is highest in North America (89%) and Oceania (85%) and least common in Latin America (38%). The majority of respondents reported having a dedicated neuro-ICU (67% overall; highest in North America: 82%; and lowest in Oceania: 14%). Conclusion The PRINCE Study results suggest that there is significant variability in the delivery of neurocritical care. The study also shows it is feasible to undertake international collaborations to gather global data about the practice of neurocritical care. Electronic supplementary material The online version of this article (10.1007/s12028-019-00750-3) contains supplementary material, which is available to authorized users.

Purpose: Poor adherence to drug therapy and inadequate drug regimens are two frequent factors responsible for the poor blood pressure (BP) control observed in patients with apparent resistant hypertension. We evaluated the efficacy of an antihypertensive management strategy combining a standardised therapy with three long acting drugs and electronic monitoring of drug adherence in patients with apparent resistant hypertension.Materials and methods: In this multicentric observational study, adult patients with residual hypertension on 24 h ambulatory BP monitoring (ABMP) despite the use of three or more antihypertensive drugs could be included. Olmesartan/amlodipine (40/10 mg, single pill fixed-dose combination) and chlorthalidone (25 mg) were prescribed for 3 months in two separated electronic pills boxes (EPB). The primary outcome was 24 h ambulatory systolic BP (SBP) control at 3 months, defined as mean SBP Results: We enrolled 48 patients (36.0% women) of whom 35 had complete EPB data. After 3 months, 52.1% of patients had 24 h SBP Conclusions: A simplified standardised antihypertensive therapy combined with electronic monitoring of adherence normalises SBP in about half of patients with apparent resistant hypertension. Such combined management strategy enables identifying patients who need complementary investigations and those who rather need a long-term support of their adherence.

Emergency Departments (EDs) worldwide are confronted with rising patient volumes causing significant strains on both Emergency Medicine and entire healthcare systems. Consequently, many EDs are in a situation where the number of patients in the ED is temporarily beyond the capacity for which the ED is designed and resourced to manage-a phenomenon called Emergency Department (ED) crowding. ED crowding can impair the quality of care delivered to patients and lead to longer patient waiting times for ED doctor's consult (time to provider) and admission to the hospital ward. In Singapore, total ED attendance at public hospitals has grown significantly, that is, roughly 5.57% per year between 2005 and 2016 and, therefore, emergency physicians have to cope with patient volumes above the safe workload. The purpose of this study is to create a virtual ED that closely maps the processes of a hospital-based ED in Singapore using system dynamics, that is, a computer simulation method, in order to visualize, simulate, and improve patient flows within the ED. Based on the simulation model (virtual ED), we analyze four policies: (i) co-location of primary care services within the ED, (ii) increase in the capacity of doctors, (iii) a more efficient patient transfer to inpatient hospital wards, and (iv) a combination of policies (i) to (iii). Among the tested policies, the co-location of primary care services has the largest impact on patients' average length of stay (ALOS) in the ED. This implies that decanting non-emergency lower acuity patients from the ED to an adjacent primary care clinic significantly relieves the burden on ED operations. Generally, in Singapore, there is a tendency to strengthen primary care and to educate patients to see their general practitioners first in case of non-life threatening, acute illness.

Aims The objective of this study was to examine baseline frailty status (including cognitive deficits) and important clinical outcomes, to inform shared decision-making in older adults receiving transcatheter aortic valve implantation (TAVI). Methods and results We conducted a prospective, observational study of 82 TAVI patients, recruited 2013 to 2015, with 2-year follow-up. Mean age was 83 years (standard deviation (SD) 4.7). Eighteen percent of the patients were frail, as assessed with an 8-item frailty scale. Fifteen patients (18%) had a Mini-Mental Status Examination (MMSE) score below 24 points at baseline, indicating cognitive impairment or dementia and five patients had an MMSE below 20 points. Mean New York Heart Association (NYHA) class at baseline and 6 months was 2.5 (SD 0.6) and 1.4 (SD 0.6), (p p = 0.7). At 2 years, six patients (7%) had died, four (5%, n = 79) lived in a nursing home, four (5%) suffered from disabling stroke, and six (7%) contracted infective endocarditis. Conclusions TAVI patients had improvement in symptoms and maintenance of activity of daily living at 6 months. They had low mortality and most patients lived in their own home 2 years after TAVI. Complications like death, stroke, and endocarditis occurred. Some patients had cognitive impairment before the procedure which might influence decision-making. Our findings may be used to develop pre-TAVI decision aids.

Abstract. We investigated the effect of age on cardiometabolic risk and protective factors in females living in a countryside area of Switzerland. For this cross-sectional analysis, data from 268 female adults, who live in two neighboring countryside villages in Italian-speaking Switzerland were retained. 89 study participants were premenopausal, 82 climacteric and 97 postmenopausal. Television viewing time, short duration of sleep, overweight, blood pressure, levels of atherogenic lipids and glycated hemoglobin significantly increased with age. Walking time also significantly increased with age. Tobacco smoking was more common among premenopausal women. It is concluded that in these countryside villages climacteric and postmenopausal women generally have an unfavorable cardiometabolic risk profile. On the other side, low physical activity and smoking are, compared to premenopausal and climacteric women, less prevalent in postmenopausal women.

Background As treatment interruptions occur during psoriasis management in clinical practice, it is important to know the duration of clinical response after treatment withdrawal. Objectives To report time to and predictors of relapse in patients who were tildrakizumab 100 and 200 mg responders (≥75% improvement in Psoriasis Area and Severity Index, PASI 75) at week 28 re‐randomized to placebo from reSURFACE 1 trial. Methods Post hoc analysis of adult patients with moderate‐to‐severe plaque psoriasis from a 64‐week phase 3 trial. Relapse was primarily defined as loss of PASI 75 response. Both relapses defined as loss of PASI 90 and loss of absolute PASI < 2 response were included as sensitivity analyses. PASI 75, PASI 90 and PASI < 2 responders re‐randomized to placebo at week 28 and followed up until week 64 were included. The Kaplan–Meier (KM) estimates of the 64‐week relapse rate were calculated. The log‐rank test to compare KM curves from responders to tildrakizumab 100 and 200 mg was used. Independent predictors of relapse were explored. Results Median time to loss of PASI 75/PASI 90/PASI < 2 response from week 28 was 142/111/112 days with tildrakizumab 100 mg and 172/140/113 days with tildrakizumab 200 mg, respectively (all not significant). Around 20% of patients did not relapse (either maintained a PASI 75 response or were lost to follow‐up) during the 36‐week period. Increase in body mass index (BMI) (hazard ratio, HR [95% confidence interval, CI] for loss of PASI 75 response: 1.0345 [1.0112–1.0582]) and increase in disease duration (HR [95% CI]: 1.0151 [1.0028–1.0275] for loss of PASI 75 response) were associated with an increased risk of relapse, regardless of the relapse definition. Conclusions When treatment is interrupted, tildrakizumab provides durable maintenance of efficacy with a median time to loss of PASI 75 response of 5–6 months, irrespective of the dose. Interventions on modifiable risk factors for relapse, such as BMI, may improve personalized long‐term psoriasis management.

Ulcerative colitis (UC) is an inflammatory bowel disease of autoimmune origin with an estimated prevalence in Spain of 0.39%. Current treatments for UC do not achieve high long-term efficacy. Treatment recommendations in moderate and severe disease involve drugs, but when these options fail, the alternatives are scarce, and surgery is intended to be reserved for the last option. We present the case of a 48-year-old male patient with UC for 23 years, who had failed several lines of treatment. The patient started combined therapy with tofacitinib and vedolizumab. These drugs have different mechanisms of action, achieving an immune response and reducing gastrointestinal inflammation. The patient's disease symptoms improved 11 months after starting this treatment, and he is now entirely asymptomatic. Analytical parameters related to the disease have also shown improvement, and the patient has so far avoided the need for surgical intervention.

Nanotechnology approaches play an important role in developing novel and efficient carriers for biomedical applications. Peptides are particularly appealing to generate such nanocarriers because they can be rationally designed to serve as building blocks for self-assembling nanoscale structures with great potential as therapeutic or diagnostic delivery vehicles. In this review, we describe peptide-based nanoassemblies and highlight features that make them particularly attractive for the delivery of nucleic acids to host cells or improve the specificity and sensitivity of probes in diagnostic imaging. We outline the current state in the design of peptides and peptide-conjugates and the paradigms of their self-assembly into well-defined nanostructures, as well as the co-assembly of nucleic acids to form less structured nanoparticles. Various recent examples of engineered peptides and peptide-conjugates promoting self-assembly and providing the structures with wanted functionalities are presented. The advantages of peptides are not only their biocompatibility and biodegradability, but the possibility of sheer limitless combinations and modifications of amino acid residues to induce the assembly of modular, multiplexed delivery systems. Moreover, functions that nature encoded in peptides, such as their ability to target molecular recognition sites, can be emulated repeatedly in nanoassemblies. Finally, we present recent examples where self-assembled peptide-based assemblies with “smart” activity are used in vivo. Gene delivery and diagnostic imaging in mouse tumor models exemplify the great potential of peptide nanoassemblies for future clinical applications.

Real-time elastography (RTE) is a noninvasive imaging modality where tumor-associated changes in tissue architecture are recognized as increased stiffness of the lesion compared to surrounding normal tissue. In contrast to this macroscopic appraisal, quantifying stiffness properties at the subcellular level by atomic force microscopy (AFM) reveals aggressive cancer cells to be soft. We compared RTE and AFM profiling of the same breast lesion to explore the diagnostic potential of tissue elasticity at different length scales. Patients were recruited from women who were scheduled for a biopsy in the outpatient breast clinic of the University Hospital Basel, Switzerland. RTE was performed as part of a standard breast work-up. Individual elastograms were characterized based on the Tsukuba elasticity score. Additionally, lesion elasticity was semiquantitatively assessed by the strain ratio. Core biopsies were obtained for histologic diagnosis and nanomechanical profiling by AFM under near-physiological conditions. Bulk stiffness evaluation by RTE does not always allow for a clear distinction between benign and malignant lesions and may result in the false assessment of breast lesions. AFM on the other hand enables quantitative stiffness measurements at higher spatial, i.e., subcellular, and force resolution. Consequently, lesions that were false positive or false negative by RTE were correctly identified by their nanomechanical AFM profiles as confirmed by histological diagnosis. Nanomechanical measurements can be used as unique markers of benign and cancerous breast lesions by providing relevant information at the molecular level. This is of particular significance considering the heterogeneity of tumors and may improve diagnostic accuracy compared to RTE.

Background/objectives Molluscum contagiosum is the most common skin infection in children. One topical treatment used for Molluscum contagiosum is potassium hydroxide. The objective of this study was to compare the efficacy of potassium hydroxide topical treatment at different concentrations with that of placebo in terms of complete clearing of Molluscum contagiosum lesions and to assess the safety and tolerance of potassium hydroxide topical treatment. Methods This was a double-blind randomized clinical trial of three treatments (potassium hydroxide 10%, potassium hydroxide 15%, placebo) applied once daily up to complete clearing of lesions (maximum duration 60 days) in 53 children aged 2-6 years in primary health care pediatric offices in Catalonia, Spain. Results In the intention-to-treat analysis, potassium hydroxide 10% (58.8%, P = .03) and potassium hydroxide 15% (64.3%, P = .02) had efficacy superior to that of placebo (18.8%). The number of Molluscum contagiosum lesions was significantly reduced with potassium hydroxide 10% and 15%. The main efficacy outcome was achieved in 58.8% of children in the potassium hydroxide 10% group (P = .03 vs placebo) and in 64.3% of children in the potassium hydroxide 15% group (P = .02 vs placebo). Potassium hydroxide 10% and 15% were not significantly different in efficacy from each other. Potassium hydroxide 10% and placebo were better tolerated than potassium hydroxide 15%. No adverse events were reported during the study period. Conclusions Potassium hydroxide 10% and 15% demonstrated high rates of efficacy in clearing Molluscum contagiosum lesions, with potassium hydroxide 10% being better tolerated.

Introduction Increased longevity and consequent major changes in demographics and population lifestyles necessitate new approaches to reduce the burden of ageing-related diseases (including cardiovascular disease) and maintain an optimal quality of life. This study aims to examine and longitudinally follow health status and disease risk factors in a Swiss rural cohort, evaluating all health-related research and practice disciplines to assure development of new implementable and successful preventive strategies for healthy ageing. Methods and objectives Small Swiss villages with low migration rates will be selected for this study. 2 villages (Cama/Lostallo) have already been selected as initial study sites. All residents (age ≥6 years, no upper age limit) are eligible. The target enrolment number per village is 300. Examinations and measurements encompass medical history, anthropometry, cardiac and vascular health, pulmonary function, physical performance, nutritional, mental and emotional status, biochemical and molecular analyses. Follow-up examinations (identical to baseline) will be performed after 5 and 10 years, and in 10-year intervals thereafter. The major objective is to assess, and observe change in, health status over time in a prospective manner. Secondary objectives are to: (1) identify ‘hidden’ (asymptomatic and/or unrecognised) health problems which enhance risk for chronic diseases; (2) identify barriers to accessing healthcare and adapting health behaviours; (3) evaluate efficacy of present preventive strategies and recommendations; (4) evaluate knowledge and attitude towards ongoing health programmes and public health recommendations; (5) monitor change and progress towards the national health objectives; (6) formulate new preventive strategies and recommendations based on the findings and knowledge base of the past 10 years; (7) formulate models for successful prevention of chronic diseases and for healthy ageing. Ethics and dissemination The Ethics Committee of Nordwest-und Zentralschweiz approved this study (EKNZ 2014-209). It is registered at ClinicalTrials.gov (NCT02282748). Findings will be disseminated through scientific articles/presentations and public events.

Melanin and polydopamine are potent biopolymers for the development of biomedical nanosystems. However, applications of melanin or polydopamine-based nanoparticles are limited by drawbacks related to a compromised colloidal stability over long time periods and associated cytotoxicity. To overcome these hurdles, a novel strategy is proposed that mimics the confinement of natural melanin in melanosomes. Melanosome mimics are developed by co-encapsulating the melanin/polydopamine precursors L-DOPA/dopamine with melanogenic enzyme Tyrosinase within polymersomes. The conditions of polymersome formation are optimized to obtain melanin/polydopamine polymerization within the cavity of the polymersomes. Similar to native melanosomes, polymersomes containing melanin/polydopamine show long-term colloidal stability, cell-compatibility, and potential for cell photoprotection. This novel kind of artificial melanogenesis is expected to inspire new applications of the confined melanin/polydopamine biopolymers.

To overcome the low efficiency and cytotoxicity associated with most non-viral DNA delivery systems we developed a purely peptidic self-assembling system that is able to entrap single- and double-stranded DNA of up to 100 nucleotides in length. (HR)3gT peptide design consists of a hydrophilic domain prone to undergo electrostatic interactions with DNA cargo, and a hydrophobic domain at a ratio that promotes the self-assembly into multi-compartment micellar nanoparticles (MCM-NPs). Self-assembled (HR)3gT MCM-NPs range between 100 to 180 nm which is conducive to a rapid and efficient uptake by cells. (HR)3gT MCM-NPs had no adverse effects on HeLa cell viability. In addition, they exhibit long-term structural stability at 4 °C but at 37 °C, the multi-micellar organization disassembles overtime which demonstrates their thermo-responsiveness. The comparison of (HR)3gT to a shorter, less charged H3gT peptide indicates that the additional arginine residues result in the incorporation of longer DNA segments, an improved DNA entrapment efficiency and an increase cellular uptake. Our unique non-viral system for DNA delivery sets the stage for developing amphiphilic peptide nanoparticles as candidates for future systemic gene delivery., Soft Matter, 16 (6), ISSN:1744-683X, ISSN:1744-6848

Titanium dioxide nanoparticles (TiO2 NPs) are widely incorporated in various consumer products such as cosmetics and food. Despite known human exposure, the potential risks of TiO2 NPs during pregnancy are not fully understood, but several studies in mice elucidated toxic effects on fetal development. It has also been shown that modifying NPs with positive or negative surface charge alters cellular uptake and abolishes fetotoxicity of silicon dioxide (SiO2) NPs in mice. Here, we investigated accumulation and translocation of positively charged TiO2-NH2 and negatively charged TiO2-COOH NPs at the placental barrier, to clarify whether surface charge provides a means to control TiO2 NP distribution at the placental barrier. To ensure outcome relevant for humans, the recently developed in vitro human placental co-culture model and the gold standard amongst placental translocation models – the ex vivo perfusion of human term placental tissue – were employed during this study. Sector field-ICP-MS analysis of maternal and fetal supernatants as well as placental cells/tissues revealed a substantial accumulation of both TiO2 NP types while no considerable placental translocation was apparent in both models. Characterization of agglomeration behavior demonstrated a strong and fast agglomeration of TiO2-NH2 and TiO2-COOH NPs in the different culture media. Overall, our results indicate that surface charge is not a key factor to steer placental uptake and transfer of TiO2. Moreover, the negligible placental transfer but high accumulation of TiO2 NPs in placental tissue suggests that potential effects on fetal health may occur indirectly, which calls for further studies elucidating the impact of TiO2 NPs on placental tissue functionality and signaling.

Our aim was to prospectively evaluate inter- and intra-observer agreement between Breast Imaging Reporting and Data System (BI-RADS) classifications and Tsukuba elasticity scores (TSs) of breast lesions. The study included 164 breast lesions (63 malignant, 101 benign). The BI-RADS classification and TS of each breast lesion was assessed by the examiner and twice by three reviewers at an interval of 2 months. Weighted κ values for inter-observer agreement ranged from moderate to substantial for BI-RADS classification (κ = 0.585–0.738) and was substantial for TS (κ = 0.608–0.779). Intra-observer agreement was almost perfect for ultrasound (US) BI-RADS (κ = 0.847–0.872) and TS (κ = 0.879–0.914). Overall, individual reviewers are highly self-consistent (almost perfect intra-observer agreement) with respect to BI-RADS classification and TS, whereas inter-observer agreement was moderate to substantial. Comprehensive training is essential for achieving high agreement and minimizing the impact of subjectivity. Our results indicate that breast US and real-time elastography can achieve high diagnostic performance.

Workplace environment is related to the physical and psychological well-being, and quality of work life (QWL) for nurses.The aim of this paper was to perform a comprehensive literature review on nurses' quality of work life to identify a comprehensive set of QWL predictors for nurses employed in the United States and Canada.Using publications from 2004-2014, contributing factors to American and Canadian nurses' QWL were analyzed. The review was structured using the Work Disability Prevention Framework. Sixty-six articles were selected for analysis.Literature indicated that changes are required within the workplace and across the health care system to improve nurses' QWL. Areas for improvement to nurses' quality of work life included treatment of new nursing graduates, opportunities for continuing education, promotion of positive collegial relationships, stress-reduction programs, and increased financial compensation.This review's findings support the importance of QWL as an indicator of nurses' broader work-related experiences. A shift in health care systems across Canada and the United States is warranted where health care delivery and services are improved in conjunction with the health of the nurses working in the system.

Objective To evaluate cognitive trajectories after radical cystectomy and their impact on surgical outcomes, including urinary continence. Materials and Methods Ninety patients received cognitive testing using the Mini Mental State Examination before open radical cystectomy as well as 3 days and 2 weeks after surgery. Based on the Mini Mental State Examination changes ≥3 points between the three time points, five cognitive trajectories emerged (stable cognition, persistent or transient deterioration, or persistent or transient improvement). Surgical outcomes were assessed 90 days, 6 months, and 1 year postoperatively. Results Mean age was 67.9 ± 9.3 years (range 40-88 years). Sixty-six patients (73.3%) had stable cognition, 9 patients (10.0%) had persistent deterioration and 7 patients (7.8%) had transient deterioration, 5 patients (5.6%) had persistent improvement and 3 patients (3.3%) had transient improvement. An impaired preoperative cognition was the only significant risk factor of short-term cognitive deterioration (odds ratio adjusted for age and sex 9.4, 95% confidence interval 1.6-56.5, P = .014). Cognition showed no associations with 1-year mortality, 90-day complication rate, cancer progression, or duration of in-hospital stay. Patients with transient or persistent cognitive deterioration had an increased risk for nighttime incontinence (odds ratio adjusted for age and sex 5.1, 95% confidence interval 1.1-22.4, P = .032). Conclusion In this study, the majority of patients showed stable cognition after major abdominopelvic surgery. Cognitive deterioration occurred in a small subgroup of patients, and an impaired preoperative cognition was the only significant risk factor. Postoperative cognitive deterioration was associated with nighttime incontinence.

BACKGROUND Patients with atrial fibrillation (AF) have an increased risk of cognitive decline, potentially resulting from clinically unrecognized vascular brain lesions. OBJECTIVES This study sought to assess the relationships between cognitive function and vascular brain lesions in patients with AF. METHODS Patients with known AF were enrolled in a multicenter study in Switzerland. Brain magnetic resonance imaging (MRI) and cognitive testing using the Montreal Cognitive Assessment (MoCA) were performed in all participants. Large noncortical or cortical infarcts (LNCCIs), small noncortical infarcts (SNCIs), microbleeds, and white matter lesions were quantified by a central core laboratory. Clinically silent infarcts were defined as infarcts on brain MRI in patients without a clinical history of stroke or transient ischemic attack. RESULTS The study included 1,737 patients with a mean age of 73 ± 8 years (28% women, 90% taking oral anticoagulant agents). On MRI, LNCCIs were found in 387 patients (22%), SNCIs in 368 (21%), microbleeds in 372 (22%), and white matter lesions in 1715 (99%). Clinically silent infarcts among the 1,390 patients without a history of stroke or transient ischemic attack were found in 201 patients with LNCCIs (15%) and 245 patients with SNCIs (18%). The MoCA score was 24.7 ± 3.3 in patients with and 25.8 ± 2.9 in those without LNCCIs on brain MRI (p < 0.001). The difference in MoCA score remained similar when only clinically silent LNCCIs were considered (24.9 ± 3.1 vs. 25.8 ± 2.9; p < 0.001). In a multivariable regression model including all vascular brain lesion parameters, LNCCI volume was the strongest predictor of a reduced MoCA (β = -0.26; 95% confidence interval: -0.40 to -0.13; p < 0.001). CONCLUSIONS Patients with AF have a high burden of LNCCIs and other brain lesions on systematic brain MRI screening, and most of these lesions are clinically silent. LNCCIs were associated with worse cognitive function, even among patients with clinically silent infarcts. Our findings raise the question of MRI screening in patients with AF.

Background Beta-lactam anti-infective levels after standard dosing have been shown to be subtherapeutic when renal clearance is augmented. Objective To determine if piperacillin and meropenem are found to be in their therapeutic range in infected critically ill patients when administered by continuous intravenous infusion (CII) assisted by a therapeutic drug monitoring (TDM) report issued by the pharmacy service. Methods This prospective non-controlled intervention study evaluated septic patients in an intensive care unit. Patients received a loading dose of meropenem or piperacillin-tazobactam and the antibiotics were afterwards administered by CII. Blood concentrations were determined by high-performance liquid chromatography assays. The adequacy of β-lactam therapy in the cohort subjected to intervention was assessed by determining whether plasma levels during CII were >4 times the informed minimum inhibitory concentration during the first 96 hours of treatment. Results A total of 124 patients were subject to TDM during antibiotic treatment but, for the analysis of the fulfilment of pharmacodynamic requirements, data from 31/124 (25%) were excluded. Of the whole cohort of treatment courses, 57/93 (61.3%) reached the target level. Plasma levels were adequate in 41/70 (58.6%) and 16/23 (69.6%) of the patients treated with piperacillin-tazobactam and meropenem, respectively. Globally, recommendations based on TDM results were followed in 35/93 (37.6%) of the treatment courses. Conclusions The results of the study show that, in critically ill patients with sepsis, there is a significant proportion of treatment courses where target levels are not reached even if the antibiotics are administered by CII and TDM support is provided by the pharmacy service. This TDM support should be offered on a real-time basis to be really useful.

Healthy tendon tissue features a highly aligned extracellular matrix that becomes disorganized with disease. Recent evidence suggests that inflammation coexists with early degenerative changes in tendon, and that crosstalk between immune-cells and tendon fibroblasts (TFs) can contribute to poor tissue healing. We hypothesized that a disorganized tissue architecture may predispose tendon cells to degenerative extracellular matrix remodeling pathways, particularly within a pro-inflammatory niche. This hypothesis was tested by analyzing human TFs cultured on electrospun polycaprolactone (PCL) mats with either highly aligned or randomly oriented fiber structures. We confirmed that fibroblast morphology, phenotype, and markers of matrix turnover could be significantly affected by matrix topography. More strikingly, the TF response to paracrine signals from polarized macrophages or by stimulation with pro-inflammatory cytokines featured significant downregulation of signaling related to extracellular synthesis, with significant concomitant upregulation of gene and protein expression of matrix degrading enzymes. Critically, this tendency towards degenerative re-regulation was exacerbated on randomly oriented PCL substrates. These novel findings indicate that highly aligned tendon cell scaffolds not only promote tendon matrix synthesis, but also play a previously unappreciated role in mitigating adverse resident fibroblast response within an inflammatory milieu., Acta Biomaterialia, 71, ISSN:1742-7061, ISSN:1878-7568

Pleurofibrinolysis has been reported to be potentially beneficial in the management of complicated parapneumonic effusions (CPPE) and empyemas in the adult population. Prospective, controlled, randomized, and double-blind study, to evaluate intrapleural alteplase 10 mg (initially 20 mg was considered but bleeding events forced dose reduction) versus 100,000 UI urokinase every 24 h for a maximum of 6 days in patients with CPPE or empyemas. The primary aim was to evaluate the success rate of each fibrinolytic agent at 3 and 6 days. Success of therapy was defined as the presence of both clinical and radiological improvement, making additional fibrinolytic doses unnecessary, and eventually leading to resolution. Secondary outcomes included the safety profile of intrapleural fibrinolytics, referral for surgery, length of hospital stay, and mortality. A total of 99 patients were included, of whom 51 received alteplase and 48 urokinase. Success rates for urokinase and alteplase at 3 and 6 days were not significantly different, but when only the subgroup of CPPE was considered, urokinase resulted in a high proportion of cures. There were no differences in mortality or surgical need (overall, 3 %). Five (28 %) patients receiving 20 mg of alteplase and 4 (12 %) receiving 10 mg presented serious bleeding events. If intrapleural fibrinolytics are intended to be used, urokinase may be more effective than alteplase in patients with non-purulent CPPE and have a lower rate of adverse events.

BACKGROUND The early diagnosis of acute myocardial infarction (AMI) very soon after symptom onset remains a major clinical challenge, even when using high-sensitivity cardiac troponin (hs-cTnT). METHODS AND RESULTS We investigated the incremental value of heart-type fatty acid-binding protein (hFABP) in a pre-specified subgroup analysis of patients presenting with suspected AMI within 1 h of symptom onset to the emergency department (ED) in a multicentre study. HFABP was measured in a blinded fashion. Two independent cardiologists using all available clinical information, including hs-cTnT, adjudicated the final diagnosis. Overall, 1411 patients were enrolled, of whom 105 patients presented within 1 h of symptom onset. Of these, 34 patients (32.4%) had AMI. The diagnostic accuracy as quantified by the area under the receiver-operating characteristics curve (AUC) of hFABP was high (0.84 (95% CI 0.74-0.94)). However, the additional use of hFABP only marginally increased the diagnostic accuracy of hs-cTnT (AUC 0.88 (95% CI 0.81-0.94) for hs-cTnT alone to 0.90 (95% CI 0.83-0.98) for the combination; p=ns). After the exclusion of 18 AMI patients with ST-segment elevation, similar results were obtained. Among the 16 AMI patients without ST-segment elevation, six had normal hs-cTnT at presentation. Of these, hFABP was elevated in two (33.3%) patients. CONCLUSIONS hFABP does not seem to significantly improve the early diagnostic accuracy of hs-cTnT in the important subgroup of patients with suspected AMI presenting to the ED very early after symptom onset.

Objectives This study evaluated Multidimensional Geriatric Assessment (MGA) as predictor of mortality and major adverse cardiovascular and cerebral events (MACCE) after transcatheter aortic valve implantation (TAVI). Background Currently used global risk scores do not reliably estimate mortality and MACCE in these patients. Methods This prospective cohort comprised 100 consecutive patients ≥70 years undergoing TAVI. Global risk scores (Society of Thoracic Surgeons [STS] score, EuroSCORE) and MGA-based scores (cognition, nutrition, mobility, activities of daily living [ADL], and frailty index) were evaluated as predictors of all-cause mortality and MACCE 30 days and 1 year after TAVI in regression models. Results In univariable analyses, all predictors were significantly associated with mortality and MACCE at 30 days and 1 year, except for the EuroSCORE at 30 days and instrumental ADL at 30 days and 1 year. Associations of cognitive impairment (odds ratio [OR]: 2.98, 95% confidence interval [CI]: 1.07 to 8.31), malnutrition (OR: 6.72, 95% CI: 2.04 to 22.17), mobility impairment (OR: 6.65, 95% CI: 2.15 to 20.52), limitations in basic ADL (OR: 3.63, 95% CI: 1.29 to 10.23), and frailty index (OR: 3.68, 95% CI: 1.21 to 11.19) with 1-year mortality were similar compared with STS score (OR: 5.47, 95% CI: 1.48 to 20.22) and EuroSCORE (OR: 4.02, 95% CI: 0.86 to 18.70). Similar results were found for 30-day mortality and MACCE. Bivariable analyses, including STS score or EuroSCORE suggested independent associations of MGA-based scores (e.g., OR of frailty index: 3.29, 95% CI: 1.06 to 10.15, for 1-year mortality in a model including EuroSCORE). Conclusions This study provides evidence that risk prediction can be improved by adding MGA-based information to global risk scores. Larger studies are needed for the development and validation of improved risk prediction models.

Diuretic treatment for heart failure may lead to an increased urinary thiamine excretion and in long-term thiamine deficiency, which may further compromise cardiac function. This study evaluated the effect of high dose thiamine supplementation in heart failure patients. Nine patients with diuretic treatment for symptomatic chronic heart failure and a left ventricular ejection fraction (LVEF)

Background: Functional intestinal disorders (FIDs) are frequently observed in patients with anorexia nervosa (AN). Relationship between FIDs and a potential gut microbiota dysbiosis has been poorly explored.Objective: We aimed to determine an association between FIDs severity and dysbiosis of the intestinal microbiota in a severely malnourished patient population with AN undergoing enteral nutrition.Design: Faecal microbiota of AN (DSM IVr criteria) female inpatients were collected and compared to healthy controls based on 16S rRNA profiling. The severity of FIDs was evaluated in patients and healthy controls using Francis Score.Results: Thirty-three patients (BMI: 11,7 +/- 1,5; Age: 32 +/- 12) and 22 healthy controls (BMI: 21 +/- 2; age: 36 +/- 12) were included. A marked dysbiosis was identified in AN patients compared to healthy controls (p = 0.03). Some potentially pathogenic bacterial genera (Klebsiella, Salmonella) were more abundant in AN patients whereas, other bacterial symbionts (Eubacterium and Roseburia) involved in immune balance were significantly less abundant in patients than controls. Severity of FIDs was strongly correlated with several microbial genera (r = -0.581 for an unknown genus belonging to Peptostreptococcaceae family; r = 0.392 for Dialister, r = 0.444 for Robinsoniella and r = 0.488 for Enterococcus). Other associations between dysbiosis, clinical and biological characteristics were identified including severity of undernutrition (BMI).Conclusion: Observed gut microbiota dysbiosis in malnourished patients with anorexia nervosa is correlated with the severity of FIDs and other metabolic disturbances, which strongly suggests an altered host-microbe symbiosis. (C) 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism.

Aims Established surgical scores have limitations in delineating risk among candidates for transcatheter aortic valve implantation (TAVI). Assessment of frailty might help to estimate the mortality risk and identify patients likely to benefit from treatment. The aim of the study was to develop a frailty score to guide the decision for TAVI. Methods and results We conducted a prospective observational study in patients ≥70 years referred for TAVI during 2011–15. A Heart Team had declined the patients for open heart surgery due to high risk but accepted them for TAVI. Prior to the procedure, a geriatric assessment (GA) was performed. Based on this, an 8-element frailty score with a 0–9 (least frail–most frail) scale was developed. A total of 142 patients, 54% women, mean age 83 (standard deviation 4) years, with severe and symptomatic aortic stenosis were assessed. All-cause 2 year mortality was 11%. The novel GA frailty score predicted 2-year mortality in Cox analyses, also when adjusted for age, gender, and logistic EuroSCORE [hazard ratio (HR) 1.75, 95% confidence interval (CI): 1.28–2.42, P < 0.001]. A receiver operating characteristic (ROC) curve analysis indicated that a GA frailty score cut-off at ≥4 predicted 2-year mortality with a specificity of 80% (95% CI: 73–86%) and a sensitivity of 60% (95% CI: 36–80%). The area under the curve was 0.81 (95% CI 0.71–0.90). Conclusion A novel 8-element GA frailty score identified gradations in survival in patients declined for open heart surgery. Patients with higher GA frailty scores had significantly higher 2-year mortality after TAVI.

BACKGROUND In older patients with aortic stenosis (AS) undergoing TAVI, the potential role of prior CGA is not well established. To explore the value of comprehensive geriatric assessment (CGA) for predicting mortality and/or hospitalisation within the first 3 months after transcatheter aortic valve implantation (TAVI). METHODS An international, multi-centre, prospective registry (CGA-TAVI) was established to gather data on CGA results and medium-term outcomes in geriatric patients undergoing TAVI. Logistic regression was used to evaluate the predictive value of a multidimensional prognostic index (MPI); a short physical performance battery (SPPB); and the Silver Code, which was based on administrative data, for predicting death and/or hospitalisation in the first 3 months after TAVI (primary endpoint). RESULTS A total of 71 TAVI patients (mean age 85.4 years; mean log EuroSCORE I 22.5%) were enrolled. Device success according to VARC criteria was 100%. After adjustment for selected baseline characteristics, a higher (poorer) MPI score (OR: 3.34; 95% CI: 1.39-8.02; p = 0.0068) and a lower (poorer) SPPB score (OR: 1.15; 95% CI: 1.01-1.54; p = 0.0380) were found to be associated with an increased likelihood of the primary endpoint. The Silver Code did not show any predictive ability in this population. CONCLUSIONS Several aspects of the CGA have shown promise for being of use to physicians when predicting TAVI outcomes. While the MPI may be useful in clinical practice, the SPPB may be of particular value, being simple and quick to perform. Validation of these findings in a larger sample is warranted. TRIAL REGISTRATION The trial was registered in ClinicalTrials.gov on November 7, 2013 ( NCT01991444 ).

Dual PEGylated interferon-α (PEG-IFN) and ribavirin therapy has been the main hepatitis C virus (HCV) treatment of the last decade. Current direct-acting antiviral agents have improved the outcome of therapy but also have increased the cost and management complexity of treatment. The current study analyzes host genetics, viral and clinical predictors of sustained viral response (SVR) to dual PEG-IFN and ribavirin therapy in a representative Spanish population.Observational prospective multicentre pharmacogenetic cohort study conducted in 12 different hospitals of 12 different Spanish regions. A total of 98 patients with SVR and 106 with non-SVR in response to PEG-IFN and ribavirin therapy were included. 33 single nucleotide polymorphisms located in 24 different genes related with inflammatory, immune and virus response were selected. Clinical and viral data were also analyzed as candidate of SVR predictors.IL-28B (rs12979860, rs7248668, rs8105790, rs8099917) and TNFRSF1B (rs1061622) genotypes, as well as TNFRSF1B/IL-10/TNFα (-308) non-TTG and TNFRSF1B/IL- 10/IL-4 non-TTC haplotypes together with lower age, lower basal HCV RNA load, higher basal serum LDL cholesterol values, VHC genotypes 2 and 3 and basal low grade fibrosis 0-2 were associated with a SVR in the univariate analysis. Independent predictors of SVR in the multivariate analysis were IL-28B rs12979860 CC, TNFRSF1B/IL-10/IL-4 non-TTC along with low baseline HCV RNA load and HCV genotypes 2 and 3.IL-28B rs12979860 CC, TNFRSF1B/ IL-10/ IL-4 non-TTC haplotype, low baseline HCV RNA load and HCV genotypes 2 and 3 may help to predict successful outcome to PEG-IFN/ribavirin therapy in Spanish population.Objetivo: El interferon-pegilado (IFN-PEG) junto a ribavirina ha sido el principal tratamiento de la infeccion por el virus de la hepatitis C (VHC) de la ultima decada. Los agentes antivirales de accion directa actuales han mejorado los resultados de la terapia, pero tambien han aumentado el costo y la gestion de la complejidad del tratamiento. El presente estudio analiza factores geneticos de los pacientes, asi como predictores virales y clinicos de respuesta sostenida viral (RSV) al tratamiento con IFN-PEG y ribavirina en poblacion Espanola. Métodos: Estudio farmacogenetico, multicentrico, prospectivo, observacional de cohortes realizado en 12 hospitales diferentes de 12 comunidades autonomas diferentes. Se incluyeron un total de 98 pacientes con RVS y 106 sin SVR al tratamiento con IFNPEG y ribavirina. Se seleccionaron 33 polimorfismos de nucleotido unico ubicados en 24 genes diferentes relacionados con la respuesta inflamatoria, inmunologica y viral. Los datos clinicos y virales tambien se analizaron como candidatos predictores de RVS. Resultados: Los genotipos IL-28B (rs12979860, rs7248668, rs8105790, rs8099917) y TNFRSF1B (rs1061622), asi como los haplotipos TNFRSF1B / IL-10 / TNF(-308) no-TTG y TNFRSF1B / IL-10 / IL-4 no-TTC junto con la menor edad, menor carga de ARN-VHC basal, valores elevados de colesterol LDL en suero basal, genotipos VHC2 y 3 y bajo grado de fibrosis basal (0-2) se asociaron con una RVS en el analisis univariante. Los predictores independientes de RVS en el analisis multivariante fueron el genotipo IL-28B rs12979860 CC, el haplotipo TNFRSF1B / IL-10 / IL-4 no-TTC junto con los bajos niveles basales de VHCARN y los genotipos virales VHC2 y 3. Conclusiones: El genotipo IL-28B rs12979860 CC, el haplotipo TNFRSF1B / IL-10 / IL-4 haplotipos no-TTC, la carga viral basal baja y los genotipos del VHC2 y 3 pueden ayudar a predecir una buena respuesta a la terapia con IFN-PEG y ribavirina en poblacion espanola.

AIMS: To determine the effect of anti-ischaemic drug therapy on long-term outcomes of asymptomatic patients without coronary artery disease (CAD) history but silent exercise ST-depression. METHODS AND RESULTS: In a randomized multicentre trial, 263 of 522 asymptomatic subjects without CAD but at least one CAD risk factor in whom silent ischaemia by exercise ECG was confirmed by stress imaging were asked to participate. The 54 (21%) consenting patients were randomized to anti-anginal drug therapy in addition to risk factor control (MED, n = 26) or risk factor control-only (RFC, n = 28). They were followed yearly for 11.2 +/- 2.2 years. During 483 patient-years, cardiac death, non-fatal myocardial infarction, or acute coronary syndrome requiring hospitalization or revascularization occurred in 3 (12%) of MED vs. 17 (61%) of RFC patients (P < 0.001). In addition, MED patients had consistently lower rates of exercise-induced ischaemia during follow-up, and left ventricular ejection fraction remained unchanged (-0.7%, P = 0.597) in contrast to RFC patients in whom it decreased over time (-6.0%, P = 0.006). CONCLUSION: Anti-ischaemic drug therapy and aspirin seem to reduce cardiac events in subjects with asymptomatic ischaemia type I. In such patients, exercise-induced ST-segment depression should be verified by stress imaging; if silent ischaemia is documented, anti-ischaemic drug therapy and aspirin should be considered.

AIMS This study evaluated associations between plasma T cadherin levels and severity of atherosclerotic disease. METHODS AND RESULTS Three hundred and ninety patients undergoing coronary angiography were divided into three groups based on clinical and angiographic presentation: a group (n=40) with normal coronary arteries a group (n=250) with chronic coronary artery disease and a group (n=100) with acute coronary syndrome. Plasma T cadherin levels were measured by double sandwich ELISA. Intravascular ultrasound data of the left anterior descending artery were acquired in a subgroup of 284 patients. T cadherin levels were lower in patients with acute coronary syndrome than in normal patients (p=0.007) and patients with chronic coronary artery disease (p=0.002). Levels were lower in males (p=0.002) in patients with hypertension (p=0.002) and inpatients with diabetes (p=0.008) and negatively correlated with systolic blood pressure (p=0.014) body mass index (p=0.001) and total number of risk factors (p=0.001). T cadherin negatively associated with angiographic severity of disease (p=0.001) and with quantitative intravascular ultrasound measures of lesion severity (p

Background: Existing prediction models for mortality in chronic obstructive pulmonary disease (COPD) patients have not yet been validated in primary care, which is where the majority of patients receive care. Objectives: Our aim was to validate the ADO (age, dyspnoea, airflow obstruction) index as a predictor of 2-year mortality in 2 general practice-based COPD cohorts. Methods: Six hundred and forty-six patients with COPD with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages I-IV were enrolled by their general practitioners and followed for 2 years. The ADO regression equation was used to predict a 2-year risk of all-cause mortality in each patient and this risk was compared with the observed 2-year mortality. Discrimination and calibration were assessed as well as the strength of association between the 15-point ADO score and the observed 2-year all-cause mortality. Results: Fifty-two (8.1%) patients died during the 2-year follow-up period. Discrimination with the ADO index was excellent with an area under the curve of 0.78 [95% confidence interval (CI) 0.71-0.84]. Overall, the predicted and observed risks matched well and visual inspection revealed no important differences between them across 10 risk classes (p = 0.68). The odds ratio for death per point increase according to the ADO index was 1.50 (95% CI 1.31-1.71). Conclusions: The ADO index showed excellent prediction properties in an out-of-population validation carried out in COPD patients from primary care settings.