The Structured Delegation of Medical Care Services for Patients With Inflammatory Rheumatic Diseases.

BACKGROUND: In some areas of Germany, there is a shortage of specialist physicians for patients with inflammatory rheumatic diseases. Delegating certain medical care services to qualified, specialized rheumatological assistants (SRAs) might be an effective way to supplement the available capacity for specialized medical care. METHODS: Patients under stable treatment for rheumatoid arthritis (RA) or psoriatic arthritis (PsA) were included in this trial, which was designed to demonstrate, in a first step, the non-inferiority of a form of care involving delegation of physicians' tasks to SRAs (team-based care), in comparison to standard care, with respect to changes in disease activity at one year. "Non-inferiority," in this context, means either superiority or else an irrelevant extent of inferiority. In a second step, in case non-inferiority could be shown, the superiority of team-based care with respect to changes in patients' health-related quality of life would be tested as well. Disease activity was measured with the Disease Activity Score 28, and health-related quality of life with the EQ-5D-5L. This was a randomized, multicenter, rater-blinded trial with two treatment arms (team-based care and standard care). The statistical analysis was performed with mixed linear models (DRKS00015526). RESULTS: From September 2018 to June 2019, 601 patients from 14 rheumatological practices and 3 outpatient rheumatological clinics in the German states of North Rhine-Westphalia and Lower Saxony were randomized to either team-based or standard care. Team-based care was found to be non-inferior to standard care with respect to changes in disease activity (adjusted difference = -0.19; 95% confidence interval [-0.36; -0.02]; p <0.001 for non-inferiority). Superiority with respect to health-related quality of life was not demonstrated (adjusted difference = 0.02 [-0.02; 0.05], p = 0.285). CONCLUSION: Team-based care, with greater integration of SRAs, is just as good as standard care in important respects. Trained SRAs can effectively support rheumatologists in the care of stable patients with RA or PsA.

Efficacy of a Low-threshold, Culturally-Sensitive Group Psychoeducation Programme for Asylum Seekers (LoPe): study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Despite high levels of mental distress, accessing psychological treatment is difficult for asylum seekers in Western host countries due to a lack of knowledge about mental disorders, and the health system, as well as due to cultural and language barriers. This study aims to investigate whether brief culturally sensitive and transdiagnostic psychoeducation is effective in increasing mental health literacy. METHODS AND ANALYSIS: The study is a parallel two-group randomised controlled trial with 1:1 individual allocation to either culturally sensitive, low-threshold psychoeducation ('Tea Garden' (TG)) or a waitlist (WL) control group. It takes place at four study sites in Germany. A total of 166 adult asylum seekers who report at least mild mental distress will be randomly assigned. The TG consists of two 90 min group sessions and provides information about mental distress, resources and mental health services in a culturally sensitive manner. The primary outcome is the percentage of participants in the TG, as compared with the WL, achieving an increase in knowledge concerning symptoms of mental disorders, individual resources and mental healthcare from preintervention to postintervention. The further trajectory will be assessed 2 and 6 months after the end of the intervention. Secondary outcomes include changes in mental distress, openness towards psychotherapy and resilience. Furthermore, healthcare utilisation and economics will be assessed at all assessment points. ETHICS AND DISSEMINATION: The study has been approved by the Ethics Commission of the German Psychological Society (ref: WeiseCornelia2019-10-18VA). Results will be disseminated via presentations, publication in international journals and national outlets for clinicians. Furthermore, intervention materials will be available, and the existing network will be used to disseminate and implement the interventions into routine healthcare. TRIAL REGISTRATION NUMBER: DRKS00020564; Pre-results. PROTOCOL VERSION: 2020-10-06, version number: VO2F.

The janus-kinase inhibitor ruxolitinib in SARS-CoV-2 induced acute respiratory distress syndrome (ARDS).

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 (coronavirus disease 2019), which is associated with high morbidity and mortality, especially in elder patients. Acute respiratory distress syndrome (ARDS) is a life-threatening complication of COVID-19 and has been linked with severe hyperinflammation. Dexamethasone has emerged as standard of care for COVID-19 associated respiratory failure. In a non-randomized prospective phase II multi-center study, we asked whether targeted inhibition of Janus kinase-mediated cytokine signaling using ruxolitinib is feasible and efficacious in SARS-CoV-2- induced ARDS with hyperinflammation. Sixteen SARS-CoV-2 infected patients requiring invasive mechanical ventilation for ARDS were treated with ruxolitinib in addition to standard treatment. Ruxolitinib treatment was well tolerated and 13 patients survived at least the first 28 days on treatment, which was the primary endpoint of the trial. Immediate start of ruxolitinib after deterioration was associated with improved outcome, as was a lymphocyte-to-neutrophils ratio above 0.07. Together, treatment with the janus-kinase inhibitor ruxolitinib is feasible and might be efficacious in COVID-19 induced ARDS patients requiring invasive mechanical ventilation. The trial has been registered under EudraCT-No.: 2020-001732-10 and NCT04359290.

Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double-blind, randomised, placebo-controlled, phase 2b trial.

BACKGROUND: Pirfenidone has been shown to slow disease progression in patients with idiopathic pulmonary fibrosis (IPF). However, there are few treatment options for progressive fibrotic interstitial lung diseases (ILDs)) other than IPF. In view of the pathomechanistic and clinical similarities between IPF and other progressive fibrotic ILDs, we aimed to assess the efficacy and safety of pirfenidone in patients with four non-IPF progressive fibrotic ILDs. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18-80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40-90% predicted, a diffusing capacity of the lung for carbon monoxide of 10-90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6-24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebo-controlled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32; DRKS00009822 and is no longer recruiting. FINDINGS: Between April 5, 2016, and Oct 4, 2018, we randomly assigned 127 patients to treatment: 64 to pirfenidone, 63 to placebo. After 127 patients had been randomised, the study was prematurely terminated on the basis of an interim analysis for futility triggered by slow recruitment. After 48 weeks and in the overall population of 127 patients, rank ANCOVA with diagnostic group included as a factor showed a significantly lower decline in FVC % predicted in the pirfenidone group compared with placebo (p=0·043); the result was similar when the model was stratified by diagnostic group (p=0·042). A significant treatment effect was also observed when applying the LOCF and multiple imputation methods to analyses of the primary endpoint. The median difference (Hodges-Lehmann estimate) between pirfenidone and placebo groups for the primary endpoint was 1·69 FVC % predicted (95% CI -0·65 to 4·03). In the linear mixed-model repeated measures slope analysis of FVC % predicted, the estimated difference between treatment and placebo groups from baseline to week 48 was 3·53 FVC % predicted (95% CI 0·21 to 6·86) with imputation of deaths as prespecified, or 2·79 FVC % predicted (95% CI 0·03 to 5·54) without imputation. One death (non-respiratory) occurred in the pirfenidone group (2%) and five deaths (three of which were respiratory) occurred in the placebo group (8%). The most frequent serious adverse events in both groups were infections and infestations (five [8%] in the pirfenidone group, ten [16%] in the placebo group); general disorders including disease worsening (two [3%] in the pirfenidone group, seven [11%] in the placebo group); and cardiac disorders (one ([2%] in the pirfenidone group, 5 [8%] in the placebo group). Adverse events (grade 3-4) of nausea (two patients on pirfenidone, two on placebo), dyspnoea (one patient on pirfenidone, one on placebo), and diarrhoea (one patient on pirfenidone) were also observed. INTERPRETATION: In view of the premature study termination, results should be interpreted with care. Nevertheless, our data suggest that in patients with fibrotic ILDs other than IPF who deteriorate despite conventional therapy, adding pirfenidone to existing treatment might attenuate disease progression as measured by decline in FVC. FUNDING: German Center for Lung Research, Roche Pharma.

Brief imagery rescripting vs. usual care and treatment advice in refugees with posttraumatic stress disorder: study protocol for a multi-center randomized-controlled trial.

Background: Many refugees have experienced multiple traumatic events in their country of origin and/or during flight. Trauma-related disorders such as posttraumatic stress disorder (PTSD) or complex PTSD (CPTSD) are prevalent in this population, which highlights the need for accessible and effective treatment. Imagery Rescripting (ImRs), an imagery-based treatment that does not use formal exposure and that has received growing interest as an innovative treatment for PTSD, appears to be a promising approach. Objective: This randomized-controlled trial aims to investigate the efficacy of ImRs for refugees compared to Usual Care and Treatment Advice (UC+TA) on (C)PTSD remission and reduction in other related symptoms. Method: Subjects are 90 refugees to Germany with a diagnosis of PTSD according to DSM-5. They will be randomly allocated to receive either UC+TA (n = 45) or 10 sessions of ImRs (n = 45). Assessments will be conducted at baseline, post-intervention, three-month follow-up, and 12-month follow-up. Primary outcome is the (C)PTSD remission rate. Secondary outcomes are severity of PTSD and CPTSD symptoms, psychiatric symptoms, dissociative symptoms, quality of sleep, and treatment satisfaction. Economic analyses will investigate health-related quality of life and costs. Additional measures will assess migration and stress-related factors, predictors of dropout, therapeutic alliance and session-by-session changes in trauma-related symptoms. Results and Conclusions: Emerging evidence suggests the suitability of ImRs in the treatment of refugees with PTSD. After positive evaluation, this short and culturally adaptable treatment can contribute to close the treatment gap for refugees in high-income countries such as Germany. Trial registration: German Clinical Trials Register under trial number DRKS00019876, registered prospectively on 28 April 2020.

Antecedentes: Muchos refugiados han experimentado múltiples eventos traumáticos en su país de origen y/o durante la huida. Los trastornos relacionados con el trauma, como el trastorno de estrés postraumático (TEPT) o el trastorno de estrés postraumático complejo (TEPTC), son frecuentes en esta población, lo que pone de relieve la necesidad de un tratamiento accesible y eficaz. La reescritura de imágenes (ImRs, en sus siglas en inglés), un tratamiento basado en imágenes que no utiliza la exposición formal y que ha recibido un creciente interés como tratamiento innovador para el TEPT, parece ser un enfoque prometedor.Objetivo: Este ensayo controlado aleatorizado tiene como objetivo investigar la eficacia de la ImRs para los refugiados en comparación con cuidado habitual y consejería de tratamiento (UC+TA) en la remisión del TEPT(C) y la reducción de otros síntomas relacionados.Método: Los sujetos son 90 refugiados en Alemania con un diagnóstico de TEPT según el DSM-5. Serán asignados aleatoriamente para recibir UC+TA (n = 45) o diez sesiones de ImRs (n = 45). Las evaluaciones se llevarán a cabo al inicio, post-intervención, con un seguimiento de tres meses y un seguimiento de 12 meses. El resultado primario es la tasa de remisión del TEPT(C). Los resultados secundarios son la gravedad de los síntomas del TEPT y del TEPTC, los síntomas psiquiátricos, los síntomas disociativos, la calidad del sueño y la satisfacción del tratamiento. Los análisis económicos investigarán la calidad de vida y los costos relacionados con la salud. Medidas adicionales evaluarán los factores relacionados con la migración y el estrés, los predictores de la deserción, la alianza terapéutica y los cambios sesión por sesión en los síntomas relacionados con el trauma.Resultados y conclusiones: Las evidencias emergentes sugieren la idoneidad de la ImRs en el tratamiento de los refugiados con TEPT. Después de una evaluación positiva, este tratamiento corto y culturalmente adaptable puede contribuir a reducir la brecha de tratamiento para los refugiados en países de altos ingresos como Alemania.

When the mother-in-law is just as good-Differential mortality of reproductive females by family network composition.

Motivated by the cooperative breeding hypothesis, we investigate the effect of having kin on the mortality of reproductive women based on family reconstitutions for the Krummhörn region (East Frisia, Germany, 1720-1874). We rely on a combination of Cox clustered hazard models and hazard models stratified at the family level. In order to study behavior-related effects, we run a series of models in which only kin who lived in the same parish are considered. To investigate structural, non-behavior-related effects, we run a different model series that include all living kin, regardless their spatial proximity. We find that women of reproductive age who had a living mother had a reduced mortality risk. It appears that having living sisters had an ambivalent impact on women's mortality: i.e., depending on the socioeconomic status of the family, the effect of having living sisters ranged between representing a source of competition and representing a source of support. Models which are clustered at the family level suggest that the presence of a living mother-in-law was associated with reduced mortality among her daughters-in-law especially among larger-scale farm families. We interpret this finding as a consequence of augmented consanguineous marriages among individuals of higher social strata. For instance, in first cousin marriages, the mother-in-law could also be a biological aunt. Thus, it appears that among the wealthy elite, the genetic in-law conflict was neutralized to some extent by family solidarity. This result further suggests that the tipping point of the female trade-off between staying with the natal family and leaving the natal family to join an economically well-established in-law family might have been reached very quickly among women living under the socioeconomic conditions of the Krummhörn region.

Conditional grandmother effects on age at marriage, age at first birth, and completed fertility of daughters and daughters-in-law in historical Krummhörn.

Based on historical data pertaining to the Krummhörn population (eighteenth and nineteenth centuries, Germany), we compared reproductive histories of mothers according to whether the maternal grandmother (MGM) or the paternal grandmother (PGM) or neither of them was resident in the parents' parish at the time of the mother's first birth. In contrast to effects of PGMs, we discovered conditional differences in the MGM's effects between landless people and wealthier, commercial farmers. Our data indicate that the presence of the MGM only lowers the woman's age at marriage (AAM) and her age at the birth of her first child (AFB) in the case of landless families. However, among commercial farmers, who can generally be characterized by a lower AAM and AFB, we found opposite tendencies for the MGM's effect leading to a relatively small delay in AAM and AFB. Moreover, we also analyzed differences in the completed fertility (i.e., children ever born: CEB). Results indicate that landless families in general do have fewer CEB compared with commercial farmers except for those families in which the MGM has been present. Emphasizing that the adaptiveness of investment decisions should depend on the interaction of genetic, lineage-specific (intrinsic) and ecologically imposed (extrinsic) constraints, we conclude that kin strategies consequently address different fitness components under different conditions.

The selfish grandma gene: the roles of the x-chromosome and paternity uncertainty in the evolution of grandmothering behavior and longevity.

When considering inclusive fitness, it is expected that individuals will provide more care towards those with whom they are more closely related. Thus, if a selfish X-linked genetic element influenced care giving, we would expect care giving to vary with X-relatedness. Recent studies have shown that X-chromosome inheritance patterns may influence selection of traits affecting behavior and life-history. Sexually antagonistic (SA) zygotic drive could encourage individuals to help those with whom they are more likely to share genetic material at the expense of other relatives. We reanalyze previously reported data in light of this new idea. We also evaluate the effects of paternity uncertainty on SA-zygotic drive. Our evidence suggests that human paternal discrepancy is relatively low. Using published models, we find the effects of paternal discrepancy do not override opportunity for selection based on X-relatedness. Based on these results, longevity and grandmothering behaviors, including favoritism, may be more heavily influenced by selection on the X-chromosome than by paternity uncertainty.