ß-(1→3)-D-glucan- and mannan-guided early termination of antifungal therapy in ICU patients: a randomized controlled study.

Candida spp. are frequently encountered in specimens from ICUs. However, most of these detections represent colonization. Nevertheless, clinical practice shows that a considerable proportion of these patients will receive antifungal therapy (AT). ß-(1→3)-D-glucan (BDG) and mannan are fungal biomarkers with high negative predictive values. We aimed to examine whether biomarker-guided discontinuation of AT can reduce the antifungal consumption. Therefore, we conducted a prospective, randomized intervention study between 1 April 2019 and 31 March 2020. All adult ICU patients with a newly started systemic AT but without fungal infection were eligible for inclusion. Enrolled patients were randomized into an intervention and a control group. In both groups, serum BDG and mannan were determined on days 1 and 2 of AT. If all measurements were negative, AT was discontinued in the intervention group. The primary endpoint was antifungal use. The study was terminated after 12 months. Until this time-point, 41 patients had been included. In the intervention group (n = 19), AT was stopped in only two patients because all others showed either positive BDG and/or mannan levels. One of these two patients developed candidemia and AT had to be restarted. There was no significant difference in the primary and secondary endpoints. In summary, the strategy of using two negative BDG and mannan levels to stop AT failed to reduce antifungal consumption in our cohort. Indeed, there will inevitably be patients with invasive candidiasis in whom necessary AT is discontinued. The optimal patient population, biomarker set, and termination criteria are critical to the success of biomarker-based termination strategies.

[Development of a Return-to-work Intervention for Psychiatric Inpatients]. / Entwicklung einer Intervention zur Unterstützung von stationär-psychiatrisch behandelten Patienten bei der Rückkehr an den Arbeitsplatz im Rahmen der RETURN-Studie.

OBJECTIVE: Patients with mental illnesses often face difficulties when returning to workplace after an episode of inpatient treatment. Available resources intended to support the return-to-work process are often not used. It was the aim of the present study to develop an intervention that facilitates the implementation of patient support at the interface of in- and outpatient care. METHODS: We used a structured development process for the establishment of a return-to-work intervention for psychiatric inpatients. RESULTS: The intervention consisted of the use of return-to-work experts who worked on the basis of a manual. In clearly defined modules, patients were given information on social law basics and details of the return process. Difficult situations (e. g., dealing with the disclosure of the diagnosis, return interview) were discussed and rehearsed. After discharge, further care took place, above all with regard to experiences on the first working day, accompaniment to discussions with the employer and support with any other upcoming difficulties. CONCLUSION: The results of the ongoing study will show whether the chosen approach actually yields the expected results, namely an improvement of the return-to-work process.

Return-to-work-experts for inpatient treatment of patients with mental illnesses- a proof-of-concept-study (RETURN): the study protocol.

BACKGROUND: Patients with mental illnesses often have massive difficulties returning to work after inpatient treatment at a psychiatric clinic and are often at risk of losing their jobs. The psychosocial support for this patient group at the interface of clinic/outpatient care is often insufficient. METHODS/DESIGN: The RETURN-study prospectively assesses and surveys 200 patients with mental disorders in a cluster randomized intervention study, i.e. treatment teams and patients from intervention wards receive a return-to-work (RTW) intervention. Patients in control wards obtain treatment as usual (TAU). Pairs of comparable wards (similar patient population, similar staff density) have been identified and then randomized for control and intervention (n = 14 for each condition). On intervention wards return-to-work experts (RTW experts) who focus treatment on the workplace-related needs of patients with mental illnesses have been established. These RTW experts ensure the use of available resources within the framework of work-related discharge management and should lead to a more successful return to the workplace. The days at work in the year after release will be evaluated in a mixed methods approach as well as the return rate in the year after release, disability days in the year after return, relapse rate after 12 months, cost-benefit ratio of the intervention, analysis of the predictors / barriers for a successful return to the workplace (e.g. psychopathology, cognition, stigma, social-psychiatric support, company support, etc.), possibilities to implement the concept of RTW experts in standard psychiatric care (TAU - treatment as usual), the impact of the RTW experts' approach on the treatment process in standard psychiatric care. DISCUSSION: This approach is already internationally established in the field of somatic rehabilitation and supported employment [Am J Psychiatry 171:1183-90, 2014; Lancet 370:1146-52, 2007; Cochrane Database Syst Rev, doi:10.1002/14651858.CD006237.pub3, 2014]; the innovative aspect of this project is to implement and evaluate it in standard psychiatric care in Germany. This project requires no new interventions to be developed and tested, as the techniques of the case manager/job coach is applied to the field of return to work. TRIAL REGISTRATION: The study was registered in Deutsches Register Klinische Studien searchable via its Meta-registry (http://apps.who.int/trialsearch/), Trial registration number: DRKS00016037, Date of registration: 21/12/2018, URL of trial registry record.

[When does StäB (not) Work? A Qualitative, Multi-Perspective Survey on Factors that can Affect the Outcome of Inpatient-Equivalent Home Treatment (IEHT)]. / Wann funktioniert StäB (nicht)? Eine qualitative, multiperspektivische Erhebung zu Faktoren, die den Erfolg einer stationsäquivalenten Behandlung (StäB) beeinträchtigen können.

OBJECTIVE: There are always cases in which an already started inpatient equivalent home treatment is terminated. Aim of our study was to reach a better understanding of the circumstances leading to a termination of IEHT that has already begun. METHODS: 17 qualitative interviews were conducted with patients, relatives as well as practitioners and therapists. Data analysis was performed by means of qualitative content analysis. RESULTS: Our data shows, that there are further factors, besides the formal exclusion criteria for IEHT, that can complicate or prevent an inpatient equivalent home treatment or lead to its termination. CONCLUSION: IEHT offers many patients the possibility of an intensive treatment in their own home. However, there our various constellations that can lead to a complication or termination of an inpatient equivalent home treatment.

[Return-to-Work - The Transition after Psychiatric Inpatient Treatment]. / Return-to-Work ­ Übergangsprozesse nach Behandlung in einem psychiatrischen Akutkrankenhaus.

OBJECTIVES: Workers on sick-leave due to a mental illness have enormous problems to return to work. The main objective of the present study is to examine, how individuals experience the transition from the mental health system to their workplace. METHODS: A qualitative research design guided by a grounded theory approach was used. Narrative interviews with ten workers on sick leave and four semi-structured interviews with return-to-work-experts were conducted. RESULTS: Relevant for returning to work is the interplay between the involved persons. Essential is the interpretation of the transition and as a result, which calls for action are made to the participants. CONCLUSION: Clinical interventions for returning to work should focus the support on the expectations of the participants and stimulate a common interpretation.

Ethical conflicts associated with COVID-19 pandemic, triage and frailty-unexpected positive disease progression in a 90-year-old patient: A case report.

During the COVID 19 pandemic, advanced age, scoring systems, and a shortage of ICU beds were used as cut-offs for ICU admission. This case report describes the epicrisis of an elderly patient who was almost mistakenly not treated in an ICU.

The cost-utility of a return-to-work intervention in comparison to routine care for patients with mental disorders in Germany: Results from the RETURN project.

BACKGROUND: Only two-thirds of patients admitted to psychiatric wards return to their previous jobs. Return-to-work interventions in Germany are investigated for their effectiveness, but information regarding cost-effectiveness is lacking. This study investigates the cost-utility of a return-to-work intervention for patients with mental disorders compared to treatment as usual (TAU). METHODS: We used data from a cluster-randomised controlled trial including 166 patients from 28 inpatient psychiatric wards providing data at 6- and 12-month follow-ups. Health and social care service use was measured with the Client Sociodemographic and Service Receipt Inventory. Quality of life was measured with the EQ-5D-3L questionnaire. Cost-utility analysis was performed by calculating additional costs per one additional QALY (Quality-Adjusted Life Years) gained by receiving the support of return-to-work experts, in comparison to TAU. RESULTS: No significant cost or QALY difference between the intervention and control groups has been detected. The return-to-work intervention cannot be identified as cost-effective in comparison to TAU. CONCLUSIONS: The employment of return-to-work experts could not reach the threshold of providing good value for money. TAU, therefore, seems to be sufficient support for the target group.

How do employees currently admitted to acute psychiatric inpatient units rate their psychosocial working conditions with the COPSOQ (Copenhagen Psychosocial Questionnaire).

BACKGROUND: In recent years it could be shown that psychosocial working conditions and mental health of employees are closely correlated. One well-established instrument to measure psychosocial stress at work is the COPSOQ (Copenhagen Psychosocial Questionnaire, German Standard Version). It is an 84 item self-rating instrument addressing several domains of psychosocial working conditions and is generally used for risk assessments in companies. AIMS: To examine associations between COPSOQ ratings with clinical features and symptoms of employees who currently suffer from an episode of a mental illness requiring inpatient treatment. METHOD: For 265 inpatients with mental disorders who participated in a cluster randomized trial (RETURN-study) COPSOQ-data were available as part of the baseline data acquisition. These data were compared with the German COPSOQ validation sample of the Freiburg research center for occupational sciences (FFAW; approximately 250,000 participants). For subdomains of the COPSOQ that showed major and significant differences between the two samples regression analyses were done to predict COPSOQ scores within the RETURN-sample. RESULTS: Psychiatric inpatients did not assess their working conditions significantly different compared to the population based FFAW sample. However, with regard to the effects of working conditions (general health, burnout, presenteeism, and intention to leave the job) there were major differences between the two samples with the clinical sample expressing more negative views. In the RETURN sample these were predicted by a greater expression of depressive symptoms. CONCLUSIONS: The linkage between work and mental wellbeing is complex. Mental illness is not necessarily a result of poor working conditions, while good working conditions may not in every case prevent symptoms of bad health, even if such associations exist.

Supporting return to work after psychiatric hospitalization-A cluster randomized study (RETURN-study).

BACKGROUND: If people with episodic mental-health conditions lose their job due to an episode of their mental illness, they often experience personal negative consequences. Therefore, reintegration after sick leave is critical to avoid unfavorable courses of disease, longer inability to work, long payment of sickness benefits, and unemployment. Existing return-to-work (RTW) programs have mainly focused on "common mental disorders" and often used very elaborate and costly interventions without yielding convincing effects. It was the aim of the RETURN study to evaluate an easy-to-implement RTW intervention specifically addressing persons with mental illnesses being so severe that they require inpatient treatment. METHODS: The RETURN study was a multi-center, cluster-randomized controlled trial in acute psychiatric wards addressing inpatients suffering from a psychiatric disorder. In intervention wards, case managers (RTW experts) were introduced who supported patients in their RTW process, while in control wards treatment, as usual, was continued. RESULTS: A total of 268 patients were recruited for the trial. Patients in the intervention group had more often returned to their workplace at 6 and 12 months, which was also mirrored in more days at work. These group differences were statistically significant at 6 months. However, for the main outcome (days at work at 12 months), differences were no longer statistically significant (p = 0.14). Intervention patients returned to their workplace earlier than patients in the control group (p = 0.040). CONCLUSIONS: The RETURN intervention has shown the potential of case-management interventions when addressing RTW. Further analyses, especially the qualitative ones, may help to better understand limitations and potential areas for improvement.

Is there a link between shell morphology and parasites of zebra mussels?

The shell morphology of zebra mussels, Dreissena polymorpha, was analyzed to determine if alterations in shell shape and asymmetry between valves were related to its infection status, i.e. infected or not by microparasites like ciliates Ophryoglena spp. or intracellular bacteria Rickettsiales-like organisms (RLOs), and by macroparasites like trematodes Phyllodistomum folium and Bucephalus polymorphus. For microparasites, two groups of mussels were observed depending on shell measurements. Mussels with the more concave shells were the most parasitized by ciliates. This could be more a consequence than a cause and we hypothesized that a modification of the water flow through the mantle cavity could promote the infection with a ciliate. There were more RLOs present in the most symmetrical individuals. A potential explanation involved a canalization of the left-right asymmetry as a by-product of the parasite infection. Trematode infections were associated with different responses in valve width. Females infected by P. folium displayed significantly higher symmetry in valve width compared with non-infected congeners, whereas the infection involved an opposite pattern in males. B. polymorphus was also linked to a decrease in valve width asymmetry. This study suggested that a relationship exists between parasitism and shell morphology through the physiological condition of host zebra mussels.

Return-to-work interventions for persons/employees with mental illnesses.

PURPOSE OF REVIEW: Mental illnesses are among the most common diseases worldwide. Cases of inability to work caused by mental illness are frequent and the related economic burden is immense. A successful reintegration into their work environment of those patients who were on sick leave due to a mental illness is an important prognostic factor for the further course of the disease and helps reducing financial consequences. It was the aim of the present review to give an overview of the status quo of return-to-work interventions in the international literature. RECENT FINDINGS: Main themes of interventions addressing return to work of persons with mental illnesses are the provision of psychotherapeutic support with or without combining these approaches with work directed interventions. Personal contact of employees, mental healthcare staff and supervisors may be helpful with regard to facilitating return to work. SUMMARY: Current return to work interventions are mostly elaborate, extensive and expensive without convincing results regarding work related outcome parameters. A variety of reasons might be responsible for this finding, including heterogeneity of outcomes, a poor definition of return-to-work-interventions and the complexity of the issue (involving multiple stakeholders).

Chronic intake of red wine polyphenols by young rats prevents aging-induced endothelial dysfunction and decline in physical performance: role of NADPH oxidase.

Aging is associated with oxidative stress-mediated endothelial dysfunction and decline in physical performance, which promote cardiovascular diseases. This study examined whether chronic intake of red wine polyphenols (RWPs), a rich source of natural antioxidants, prevents aging-related impairment of vascular function and physical exercise capacity. Vascular reactivity from 12, 20 and 40 week-old rats was assessed in organ chambers. Rats received from week 16 to 40 either solvent, RWPs or the antioxidant and NADPH oxidase inhibitor, apocynin. Aging was associated with blunted endothelium-dependent relaxations, oxidative stress (dihydroethidine staining), and an upregulation of eNOS, arginase I, NADPH oxidase p22phox and nox1 subunits, and AT1 and AT2 receptors (assessed by immunohistochemistry) in the mesenteric artery. RWPs and apocynin improved the endothelial dysfunction, normalized oxidative stress and the expression of the different proteins. RWPs also improved aging-related decline in physical exercise. Thus, intake of RWPs protects against aging-induced endothelial dysfunction and decline in physical performance. These effects likely involve the ability of RWPs to normalize oxidative stress and the expression of proteins involved in the formation of NO and the angiotensin II pathway.

Differences between suicide note leavers and other suicides: A German psychological autopsy study.

INTRODUCTION: Suicide notes are not only the last personal message from the suicide victim to the bereaved, but are also a valuable source for research in preventing suicides. However, not all suicide victims leave a suicide note and it is unclear whether note leavers are representative of the general population of suicide victims. METHODS: The aim of our study was to compare suicide victims who leave a suicide note compared to those who do not. Therefore, data from the Allgäu Suicide Study, which comprised detailed information on N = 626 suicides, were analysed using multiple regression analyses. RESULTS: Of N = 612 cases with complete data, n = 255(42%) left a suicide note and n = 357 (58%) did not. Persons who wrote suicide notes before they killed themselves were more often female, less often married, found themselves more often in a financial or partnership crisis, and were more likely to suffer from a medical illness. They tended to poison themselves more often and were less likely to have a history of alcohol abuse disorder. CONCLUSION: Suicide notes are one source to better understand the motives, which lie behind suicides and therefore may help to further develop and improve suicide prevention programs. Keeping in mind that suicide has heterogeneous reasons, the group of "note writers" might be one, which might especially have benefitted from psychosocial and psychotherapeutic interventions, as interpersonal relationships obviously played an important role even shortly before suicide.

Immunomonitoring of Stage IV Relapsed Neuroblastoma Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation and Subsequent GD2 (ch14.18/CHO) Antibody Treatment.

Haploidentical stem cell transplantation (haplo SCT) in Stage IV neuroblastoma relapsed patients has been proven efficacious, while immunotherapy utilizing the anti-GD2 antibody dinutuximab beta has become a standard treatment for neuroblastoma. The combinatorial therapy of haplo SCT and dinutuximab may potentiate the efficacy of the immunotherapy. To gain further understanding of the synergistic effects, functional immunomonitoring was assessed during the clinical trial CH14.18 1021 Antibody and IL2 After haplo SCT in Children with Relapsed Neuroblastoma (NCT02258815). Rapid immune reconstitution of the lymphoid compartment was confirmed, with clinically relevant dinutuximab serum levels found in all patients over the course of treatment. Only one patient developed human anti-chimeric antibodies (HACAs). In-patient monitoring revealed highly functional NK cell posttransplant capable of antibody-dependent cellular cytotoxicity (ADCC). Degranulation of NK cell subsets revealed a significant response increased by dinutuximab. This was irrespective of the KIR receptor-ligand constellation within the NK subsets, defined by the major KIR receptors CD158a, CD158b, and CD158e. Moreover, complement-dependent cytotoxicity (CDC) was shown to be an extremely potent effector-cell independent mechanism of tumor cell lysis, with a clear positive correlation to GD2 expression on the cancer cells as well as to the dinutuximab concentrations. The ex vivo testing of patient-derived effector cells and the sera collected during dinutuximab therapy demonstrated both high functionality of the newly established lymphoid immune compartment and provided confidence that the antibody dosing regimen was sufficient over the duration of the dinutuximab therapy (up to nine cycles in a 9-month period). During the course of the dinutuximab therapy, proinflammatory cytokines and markers (sIL2R, TNFa, IL6, and C reactive protein) were significantly elevated indicating a strong anti-GD2 immune response. No impact of FcGR polymorphism on event-free and overall survival was found. Collectively, this study has shown that in-patient functional immunomonitoring is feasible and valuable in contributing to the understanding of anti-cancer combinatorial treatments such as haplo SCT and antibody immunotherapy.

Disclosure Management When Returning to Work After a Leave of Absence Due to Mental Illness.

People with mental illness must often decide the extent to which they want to disclose their mental illness publicly. Especially in the context of work, this is a complex and individual decision. This Open Forum discusses the importance of well-reasoned disclosure management to increase the chances of successful workplace reintegration after a leave of absence due to a mental illness. The authors posit that despite the risks of stigma and discrimination, disclosing a mental illness to an employer can benefit employees. However, proper support is often essential in establishing how to best manage disclosure or nondisclosure.

Hyperscanning: A Valid Method to Study Neural Inter-brain Underpinnings of Social Interaction.

Social interactions are a crucial part of human life. Understanding the neural underpinnings of social interactions is a challenging task that the hyperscanning method has been trying to tackle over the last two decades. Here, we review the existing literature and evaluate the current state of the hyperscanning method. We review the type of methods (fMRI, M/EEG, and fNIRS) that are used to measure brain activity from more than one participant simultaneously and weigh their pros and cons for hyperscanning. Further, we discuss different types of analyses that are used to estimate brain networks and synchronization. Lastly, we present results of hyperscanning studies in the context of different cognitive functions and their relations to social interactions. All in all, we aim to comprehensively present methods, analyses, and results from the last 20 years of hyperscanning research.

Study of Small Intestinal Bacterial Overgrowth in a Cohort of Patients with Abdominal Symptoms Who Underwent Bariatric Surgery.

INTRODUCTION: Small intestinal bacterial overgrowth (SIBO) is a common complication of bariatric surgery. Digestive decontamination treatments with oral antibiotic therapy vary and are not codified. This retrospective study was conducted to analyse the characteristics of bariatric surgery patients who underwent a glucose breath test (GBT) and to analyse the effectiveness of the antibiotic decontamination therapy. MATERIALS AND METHODS: A total of 101 operated patients (Roux-en-Y bypass (RYB), omega bypass (ΩB) and sleeve gastrectomy (SG)) who underwent a GBT (75 g/250 mL) were included. Anthropometric data, symptoms of SIBO, type of surgery, use of proton pump inhibitors (PPIs) and antibiotic therapy were analysed. The effectiveness of the antibiotic treatment, defined by improvement of the symptoms, was evaluated during the follow-up. RESULTS: Of the 85 women and 16 men included (48.5 ± 3.6 years old), 63 underwent RYB, 31 underwent ΩB and 7 underwent SG. The GBT was positive in 83% of the patients. A positive test was associated with age (p < 0.001), female sex (p < 0.01) and PPI use (p < 0.01), but there was no significant difference according to the type of surgery. Sixty-one percent of patients treated with gentamicin/metronidazole sequential antibiotic therapy and 58% of patients treated with metronidazole alone achieved treatment efficacy (with no significant difference in efficacy between these treatments). CONCLUSION: SIBO should be systematically considered in the context of abdominal symptoms in bariatric surgery patients, regardless the type of surgery, particularly in patients who are older or female and after PPI treatment. Digestive decontamination appears to be similar between gentamycin/metronidazole and metronidazole treatments.

Defibrotide for the Treatment of Pediatric Inflammatory Multisystem Syndrome Temporally Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Infection in 2 Pediatric Patients.

The pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 infection is a severe complication of coronavirus disease 2019. Since impaired coagulation and thrombosis/endotheliitis are suspected pathomechanisms, we treated 2 patients with defibrotide, a profibrinolytic, antithrombotic, antiinflammatory oligonucleotide. Symptoms resolved during treatment. Moreover, coagulation parameters indicating hypofibrinolysis and complement activation normalized. The pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 infection is a severe complication of coronavirus disease 2019. Since impaired coagulation and thrombosis/endotheliitis are suspected pathomechanisms, 2 patients received defibrotide, a profibrinolytic, antithrombotic, antiinflammatory oligonucleotide. Symptoms resolved and hypofibrinolysis/complement activation normalized during treatment.

Ex vivo expansion of autologous, donor-derived NK-, γδT-, and cytokine induced killer (CIK) cells post haploidentical hematopoietic stem cell transplantation results in increased antitumor activity.

Posttransplant treatment strategies are narrowed by the vulnerability of bone marrow. Building on immune cells with antitumor activity is a growing field in cancer therapy. Thus, transfer of expanded and preactivated immune cells is a promising intensification of treatment in high-risk tumor patients. We tested ex vivo expanded NK-, γδT-, and CIK cells that were generated by coincubation with irradiated K562-mb15-41BBL and Il2 and compared the expansion conditions of PBMCs versus CD3-depleted PBMCs as well as static versus semi-automated expansion. The median fold expansion was significantly higher using PBMCs and static expansion conditions. Expanded cells were preactivated with a CD56brightCD69high immunophenotype exerting excellent direct cellular cytotoxicity as well as ADCC in various tumor entities. We established a large-scale clinical-grade ex vivo expansion and activation protocol of NK-, γδT-, and CIK cells from donor-derived PBMCs of patients after haploidentical HSCT. In a patient with AML, NK/γδT/CIK cell transfer was associated with MRD response. A significant increase of direct antitumor activity and ADCC post cell transfer was documented. The results that we report here provide the rationale for clinical testing of expanded, preactivated NK/γδT/CIK cells for cancer therapy.

ADCC can improve graft vs leukemia effect after T- and B-cell depleted haploidentical stem cell transplantation in pediatric B-lineage ALL.

Posttransplant relapsed B-cell precursor ALL can be cured by 2nd hematopoietic stem cell transplantation (HSCT) in 20% of patients. The major cause of death after second HSCT is leukemic relapse. One reliable predictor for survival after 2nd-HSCT are posttransplant MRD levels. Patients with detectable or increase of MRD are likely to relapse. Patients in complete molecular remission show the best leukemia-free survival and lowest cumulative incidence (CI) of relapse. As patients who undergo second or subsequent HSCT are high-risk patients, we evaluated the prophylactic use of the chimeric Fc-optimized CD19-4G7SDIE-mAb. Posttransplant relapsed CD19+ BCP-ALL patients, who underwent a second or subsequent haplo-HSCT from a T- and B-cell depleted graft received posttransplant prophylactic CD19-4G7SDIE-mAb treatment on compassionate use in complete molecular remission, to increase the antileukemic activity of the new reconstituting immune system by recruiting Fc-expressing effector cells. NK cells recovered early and robust. The 3 year overall survival in 15 evaluable patients was 56%, the 3 year event-free survival was 55% and the CI of relapse 38%. Compared to a historical control group, the CI of relapse was markedly lower and consecutively the EFS higher. Posttransplant-targeted therapy may overcome the need for unspecific GvL effect of undesired GvHD, that can cause severe morbidity and mortality. Due to a low adverse event profile the CD19-4G7SDIE-mAb may be suitable for broad administration to consolidate posttransplant MRD negativity.