Seclusion as a coercive measure in suicidality – daily routine or exception?

Background: Coercive measures continue to be an important topic in psychiatry. However, there is no proof of the effectiveness of the use of coercive measures, especially with suicidal people. For many years, attempts have been made to replace such measures with alternative noncoercive intervention options. This paper aims to clarify the situation of coercive measures, more precisely seclusions, in a general psychiatric hospital in Switzerland. It focuses on compulsory measures in patients with suicidal tendencies. Method: In this single-centre retrospective cohort study, we used routinely collected medical data and performed qualitative analyses of medical histories to examine whether alternative measures to seclusion had been offered and/or provided to patients who had been secluded solely because of suicidality. Patients were aged 18-65 years and had received inpatient treatment at one of five adult acute care units at a general psychiatric hospital in Switzerland between September 2016 and December 2019. Results: There were 5,935 inpatient treatment cases during the study period. Suicidality was rated as "acute" or "very high" at least once during the hospitalization in 219 (3.7%) cases. Of these, 60 were excluded from further analyses as they involved seclusion, but suicidality was not the exclusive indication for this measure. Coercive seclusion was imposed exclusively due to suicidality in 53 (33.3%) of the remaining 159 cases, whereas 106 (66.7%) cases were not secluded. The rates of seclusion among suicidal patients varied considerably between the hospital wards (13.0% to 55.3%). Suicidal patients with non-Swiss residence status and/or lacking language skills were particularly prone to be secluded. Additionally, alternative interventions were offered and provided significantly more frequently in the nonsecluded patients. Conclusions: To avoid seclusion due to suicidal tendencies, it is necessary to have a general attitude of avoiding coercive measures at all costs. It is also important for qualified staff to be able to deal with challenging sociodemographic characteristics of patients such as foreign-language, which may require translators and intercultural interpreters. Keywords: Coercive measures; Seclusion; Suicidality

Growth hormone prevents steroid-induced growth depression in health and uremia

Growth hormone prevents steroid-induced growth depression in health and uremia. Treatment with supraphysiological doses of corticosteroids results in protein wasting and impairment of growth, whereas exogenous growth hormone (GH) causes anabolism and improvement of growth. We wanted to know whether the growth depressing effects of methylprednisolone (MP) are more expressed in an organism which is chronically diseased and whether these effects can be counterbalanced by concomitant treatment with recombinant human growth hormone (rhGH). MP in doses from 1 to 9 mg/kg/day caused a dose dependent reduction of length gain, weight gain and weight gain/food intake ratio in 140 g healthy female Sprague-Dawley rats. Food intake was not affected by MP. This points to a change in food metabolism as a mechanism for growth impairment. In addition, treatment with MP inhibited endogenous GH secretion, documented by serum GH concentration profiles over seven hours, decreased IGF-1 serum concentration and disturbed growth cartilage plate architecture. Concomitant treatment with 2.5 to 20 IU/rhGH/kg/day prevented the negative effects of MP on growth in a dose dependent manner and normallized growth plate architecture. In uremic rats in which food efficiency and growth was already reduced, 6 mg MP/kg/day further decreased length gain and prevented weight gain completely by bringing the weight gain/food conversion ratio to the nadir. All effects of MP including reduction of muscle mass could be prevented by concomitant treatment with 10 IU rhGH/kg/day. The effects of MP and rhGH on food efficiency and growth in uremic animals were numerically nearly identical to those in pair fed and ad libitum fed controls, but this may be more relevant in the diseased organism in which basal growth is already suppressed

Scanning electrochemical microscopy as a local probe of oxygen permeability in cartilage

The use of scanning electrochemical microscopy, a high-resolution chemical imaging technique, to probe the distribution and mobility of solutes in articular cartilage is described. In this application, a mobile ultramicroelectrode is positioned close (not, vert, similar1 μm) to the cartilage sample surface, which has been equilibrated in a bathing solution containing the solute of interest. The solute is electrolyzed at a diffusion-limited rate, and the current response measured as the ultramicroelectrode is scanned across the sample surface. The topography of the samples was determined using Ru(CN)64−, a solute to which the cartilage matrix was impermeable. This revealed a number of pit-like depressions corresponding to the distribution of chondrocytes, which were also observed by atomic force and light microscopy. Subsequent imaging of the same area of the cartilage sample for the diffusion-limited reduction of oxygen indicated enhanced, but heterogeneous, permeability of oxygen across the cartilage surface. In particular, areas of high permeability were observed in the cellular and pericellular regions. This is the first time that inhomogeneities in the permeability of cartilage toward simple solutes, such as oxygen, have been observed on a micrometer scale

Activation of Dendritic Cells through the Interleukin 1 Receptor 1 Is Critical for the Induction of Autoimmune Myocarditis

Dilated cardiomyopathy, resulting from myocarditis, is the most common cause of heart failure in young patients. We here show that interleukin (IL)-1 receptor type 1–deficient (IL-1R1−/−) mice are protected from development of autoimmune myocarditis after immunization with α-myosin-peptide(614–629). CD4+ T cells from immunized IL-1R1−/− mice proliferated poorly and failed to transfer disease after injection into naive severe combined immunodeficiency (SCID) mice. In vitro stimulation experiments suggested that the function of IL-1R1−/−CD4+ T cells was not intrinsically defect, but their activation by dendritic cells was impaired in IL-1R1−/− mice. Accordingly, production of tumor necrosis factor (TNF)-α, IL-1, IL-6, and IL-12p70 was reduced in dendritic cells lacking the IL-1 receptor type 1. In fact, injection of immature, antigen-loaded IL-1R1+/+ but not IL-1R1−/− dendritic cells into IL-1R1−/− mice fully restored disease susceptibility by rendering IL-1R1−/− CD4+ T cells pathogenic. Thus, IL-1R1 triggering is required for efficient activation of dendritic cells, which is in turn a prerequisite for induction of autoreactive CD4+ T cells and autoimmunity

Prevalence, outcomes and costs of a contemporary, multinational population with heart failure.

OBJECTIVE Digital healthcare systems could provide insights into the global prevalence of heart failure (HF). We designed the CardioRenal and Metabolic disease (CaReMe) HF study to estimate the prevalence, key clinical adverse outcomes and costs of HF across 11 countries. METHODS Individual level data from a contemporary cohort of 6 29 624 patients with diagnosed HF was obtained from digital healthcare systems in participating countries using a prespecified, common study plan, and summarised using a random effects meta-analysis. A broad definition of HF (any registered HF diagnosis) and a strict definition (history of hospitalisation for HF) were used. Event rates were reported per 100 patient years. Cumulative hospital care costs per patient were calculated for a period of up to 5 years. RESULTS The prevalence of HF was 2.01% (95% CI 1.65 to 2.36) and 1.05% (0.85 to 1.25) according to the broad and strict definitions, respectively. In patients with HF (broad definition), mean age was 75.2 years (95% CI 74.0 to 76.4), 48.8% (40.9-56.8%) had ischaemic heart disease and 34.5% (29.4-39.6%) had diabetes. In 51 442 patients with a recorded ejection fraction (EF), 39.1% (30.3-47.8%) had a reduced, 18.8% (13.5-24.0%) had a mildly reduced and 42.1% (31.5-52.8%) had a preserved left ventricular EF. In 1 69 518 patients with recorded estimated glomerular filtration rate, 49% had chronic kidney disease (CKD) stages III-V. Event rates were highest for cardiorenal disease (HF or CKD) and all cause mortality (19.3 (95% CI 11.3 to 27.1) and 13.1 (11.1 to 15.1), respectively), and lower for myocardial infarction, stroke and peripheral artery disease. Hospital care costs were highest for cardiorenal diseases. CONCLUSIONS We estimate that 1-2% of the contemporary adult population has HF. These individuals are at significant risk of adverse outcomes and associated costs, predominantly driven by hospitalisations for HF or CKD. There is considerable public health potential in understanding the contemporary burden of HF and the importance of optimising its management

Transurethral injection of autologous muscle precursor cells for treatment of female stress urinary incontinence: a prospective phase I clinical trial

INTRODUCTION AND HYPOTHESIS The purpose was to investigate the safety and feasibility of transurethral injections of autologous muscle precursor cells (MPCs) into the external urinary sphincter (EUS) to treat stress urinary incontinence (SUI) in female patients. METHODS Prospective and randomised phase I clinical trial. Standardised 1-h pad test, International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI-SF), urodynamic study, and MRI of the pelvis were performed at baseline and 6 months after treatment. MPCs gained through open muscle biopsy were transported to a GMP facility for processing and cell expansion. The final product was injected into the EUS via a transurethral ultrasound-guided route. Primary outcomes were defined as any adverse events (AEs) during follow-up. Secondary outcomes were functional, questionnaire, and radiological results. RESULTS Ten female patients with SUI grades I-II were included in the study and 9 received treatment. Out of 8 AEs, 3 (37.5%) were potentially related to treatment and treated conservatively: 1 urinary tract infection healed with antibiotics treatment, 1 dysuria and 1 discomfort at biopsy site. Functional urethral length under stress was 25 mm at baseline compared with 30 mm at 6 months' follow-up (p=0.009). ICIQ-UI-SF scores improved from 7 points at baseline to 4 points at follow-up (p=0.035). MRI of the pelvis revealed no evidence of tumour or necrosis, whereas the diameter of the EUS muscle increased from 1.8 mm at baseline to 1.9 mm at follow-up (p=0.009). CONCLUSION Transurethral injections of autologous MPCs into the EUS for treatment of SUI in female patients can be regarded as safe and feasible. Only a minimal number of expected and easily treatable AEs were documented

Canakinumab in patients with COVID-19 and type 2 diabetes - A multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND: Patients with type 2 diabetes and obesity have chronic activation of the innate immune system possibly contributing to the higher risk of hyperinflammatory response to SARS-CoV2 and severe COVID-19 observed in this population. We tested whether interleukin-1β (IL-1β) blockade using canakinumab improves clinical outcome. METHODS: CanCovDia was a multicenter, randomised, double-blind, placebo-controlled trial to assess the efficacy of canakinumab plus standard-of-care compared with placebo plus standard-of-care in patients with type 2 diabetes and a BMI > 25 kg/m$^{2}$ hospitalised with SARS-CoV2 infection in seven tertiary-hospitals in Switzerland. Patients were randomly assigned 1:1 to a single intravenous dose of canakinumab (body weight adapted dose of 450-750 mg) or placebo. Canakinumab and placebo were compared based on an unmatched win-ratio approach based on length of survival, ventilation, ICU stay and hospitalization at day 29. This study is registered with ClinicalTrials.gov, NCT04510493. FINDINGS: Between October 17, 2020, and May 12, 2021, 116 patients were randomly assigned with 58 in each group. One participant dropped out in each group for the primary analysis. At the time of randomization, 85 patients (74·6 %) were treated with dexamethasone. The win-ratio of canakinumab vs placebo was 1·08 (95 % CI 0·69-1·69; p = 0·72). During four weeks, in the canakinumab vs placebo group 4 (7·0%) vs 7 (12·3%) participants died, 11 (20·0 %) vs 16 (28·1%) patients were on ICU, 12 (23·5 %) vs 11 (21·6%) were hospitalised for more than 3 weeks, respectively. Median ventilation time at four weeks in the canakinumab vs placebo group was 10 [IQR 6.0, 16.5] and 16 days [IQR 14.0, 23.0], respectively. There was no statistically significant difference in HbA1c after four weeks despite a lower number of anti-diabetes drug administered in patients treated with canakinumab. Finally, high-sensitive CRP and IL-6 was lowered by canakinumab. Serious adverse events were reported in 13 patients (11·4%) in each group. INTERPRETATION: In patients with type 2 diabetes who were hospitalised with COVID-19, treatment with canakinumab in addition to standard-of-care did not result in a statistically significant improvement of the primary composite outcome. Patients treated with canakinumab required significantly less anti-diabetes drugs to achieve similar glycaemic control. Canakinumab was associated with a prolonged reduction of systemic inflammation. FUNDING: Swiss National Science Foundation grant #198415 and University of Basel. Novartis supplied study medication

GWAS Hits for Bilateral Convergent Strabismus with Exophthalmos in Holstein Cattle Using Imputed Sequence Level Genotypes

Bilateral convergent strabismus with exophthalmos (BCSE) is a malformation of the eyes and is recognized as a mild but progressive disorder that affects cattle in the first two years of life. This most likely inherited disorder is rarely described in cattle resembling autosomal dominantly inherited forms of human progressive external ophthalmoplegia (PEO). In German Braunvieh cattle, two linked genome regions were found that could be responsible for the development and/or progression of BCSE. The goal of this study was to phenotypically characterize BCSE in Holstein cattle from Germany and Switzerland as well as to identify associated genome regions by GWAS. The clinicopathological phenotype of 52 BCSE-affected Holstein cattle was in accordance with the phenotype described in German Braunvieh cattle, but in addition, signs of degeneration and cellular infiltration in the eye muscles were found. By using imputed sequence level genotype data, three genome-wide significant GWAS hits were revealed on different chromosomes that were not detected by initial GWAS based on high density SNP array data highlighting the usefulness of this approach for mapping studies. The associated genome regions include the ABCC4 gene as well as markers adjacent to the NCOR2 and DNAJC3 genes all illustrating possible functional candidate genes. Our results challenge a monogenic mode of inheritance and indicate a more complex inheritance of BCSE in Holstein cattle. Furthermore, in comparison to previous results from German Braunvieh cattle, it illustrates an obvious genetic heterogeneity causing BSCE in cattle. Subsequent whole genome sequencing (WGS)-based analyses might elucidate pathogenic variants in the future

Structural basis of siRNA recognition by TRBP double-stranded RNA binding domains

The accurate cleavage of pre-micro(mi)RNAs by Dicer and mi/siRNA guide strand selection are important steps in forming the RNA-induced silencing complex (RISC). The role of Dicer binding partner TRBP in these processes remains poorly understood. Here, we solved the solution structure of the two N-terminal dsRNA binding domains (dsRBDs) of TRBP in complex with a functionally asymmetric siRNA using NMR, EPR, and single-molecule spectroscopy. We find that siRNA recognition by the dsRBDs is not sequence-specific but rather depends on the RNA shape. The two dsRBDs can swap their binding sites, giving rise to two equally populated, pseudo-symmetrical complexes, showing that TRBP is not a primary sensor of siRNA asymmetry. Using our structure to model a Dicer-TRBP-siRNA ternary complex, we show that TRBP's dsRBDs and Dicer's RNase III domains bind a canonical 19 base pair siRNA on opposite sides, supporting a mechanism whereby TRBP influences Dicer-mediated cleavage accuracy by binding the dsRNA region of the pre-miRNA during Dicer cleavage