Immune effector cell-associated hematotoxicity: EHA/EBMT consensus grading and best practice recommendations.

Hematological toxicity is the most common adverse event after chimeric antigen receptor (CAR) T-cell therapy. Cytopenias can be profound and long-lasting and can predispose for severe infectious complications. In a recent worldwide survey, we demonstrated that there remains considerable heterogeneity in regard to current practice patterns. Here, we sought to build consensus on the grading and management of immune effector cell-associated hematotoxicity (ICAHT) after CAR T-cell therapy. For this purpose, a joint effort between the European Society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA) involved an international panel of 36 CAR T-cell experts who met in a series of virtual conferences, culminating in a 2-day meeting in Lille, France. On the basis of these deliberations, best practice recommendations were developed. For the grading of ICAHT, a classification system based on depth and duration of neutropenia was developed for early (day 0-30) and late (after day +30) cytopenia. Detailed recommendations on risk factors, available preinfusion scoring systems (eg, CAR-HEMATOTOX score), and diagnostic workup are provided. A further section focuses on identifying hemophagocytosis in the context of severe hematotoxicity. Finally, we review current evidence and provide consensus recommendations for the management of ICAHT, including growth factor support, anti-infectious prophylaxis, transfusions, autologous hematopoietic stem cell boost, and allogeneic hematopoietic cell transplantation. In conclusion, we propose ICAHT as a novel toxicity category after immune effector cell therapy, provide a framework for its grading, review literature on risk factors, and outline expert recommendations for the diagnostic workup and short- and long-term management.

Oncogenic MTOR signaling axis compensates BTK inhibition in a Chronic Lymphocytic Leukemia patient with Richter Transformation: A Case Report and Review of the Literature.

INTRODUCTION: Targeting the B cell receptor (BCR) pathway via ibrutinib, a specific inhibitor of Bruton's tyrosine kinase, has shown marked clinical efficacy in treatment of patients with chronic lymphocytic leukemia (CLL), thus becoming a preferred first line option independent of risk factors. However, acquired resistance to ibrutinib poses a major clinical problem and requires the development of novel treatment combinations to increase efficacy and counteract resistance development and clinical relapse rates. CASE PRESENTATION: In this study, we performed exome and transcriptome analyses of an ibrutinib resistant CLL patient in order to investigate genes and expression patterns associated with ibrutinib resistance. Here we provide evidence that ibrutinib resistance can be attributed to aberrant mammalian target of rapamycin (MTOR) signaling. CONCLUSION: Thus, our study proposes that combined use of MTOR inhibitors with ibrutinib could be a possible option to overcome therapy resistance in ibrutinib treated patients.

Defects in the cytoplasmic assembly of axonemal dynein arms cause morphological abnormalities and dysmotility in sperm cells leading to male infertility.

Axonemal protein complexes, such as outer (ODA) and inner (IDA) dynein arms, are responsible for the generation and regulation of flagellar and ciliary beating. Studies in various ciliated model organisms have shown that axonemal dynein arms are first assembled in the cell cytoplasm and then delivered into axonemes during ciliogenesis. In humans, mutations in genes encoding for factors involved in this process cause structural and functional defects of motile cilia in various organs such as the airways and result in the hereditary disorder primary ciliary dyskinesia (PCD). Despite extensive knowledge about the cytoplasmic assembly of axonemal dynein arms in respiratory cilia, this process is still poorly understood in sperm flagella. To better define its clinical relevance on sperm structure and function, and thus male fertility, further investigations are required. Here we report the fertility status in different axonemal dynein preassembly mutant males (DNAAF2/ KTU, DNAAF4/ DYX1C1, DNAAF6/ PIH1D3, DNAAF7/ZMYND10, CFAP300/C11orf70 and LRRC6). Besides andrological examinations, we functionally and structurally analyzed sperm flagella of affected individuals by high-speed video- and transmission electron microscopy as well as systematically compared the composition of dynein arms in sperm flagella and respiratory cilia by immunofluorescence microscopy. Furthermore, we analyzed the flagellar length in dynein preassembly mutant sperm. We found that the process of axonemal dynein preassembly is also critical in sperm, by identifying defects of ODAs and IDAs in dysmotile sperm of these individuals. Interestingly, these mutant sperm consistently show a complete loss of ODAs, while some respiratory cilia from the same individual can retain ODAs in the proximal ciliary compartment. This agrees with reports of solely one distinct ODA type in sperm, compared to two different ODA types in proximal and distal respiratory ciliary axonemes. Consistent with observations in model organisms, we also determined a significant reduction of sperm flagellar length in these individuals. These findings are relevant to subsequent studies on the function and composition of sperm flagella in PCD patients and non-syndromic infertile males. Our study contributes to a better understanding of the fertility status in PCD-affected males and should help guide genetic and andrological counselling for affected males and their families.

Update of the European Society of Anaesthesiology and Intensive Care Medicine evidence-based and consensus-based guideline on postoperative delirium in adult patients.

Postoperative delirium (POD) remains a common, dangerous and resource-consuming adverse event but is often preventable. The whole peri-operative team can play a key role in its management. This update to the 2017 ESAIC Guideline on the prevention of POD is evidence-based and consensus-based and considers the literature between 01 April 2015, and 28 February 2022. The search terms of the broad literature search were identical to those used in the first version of the guideline published in 2017. POD was defined in accordance with the DSM-5 criteria. POD had to be measured with a validated POD screening tool, at least once per day for at least 3 days starting in the recovery room or postanaesthesia care unit on the day of surgery or, at latest, on postoperative day 1. Recent literature confirmed the pathogenic role of surgery-induced inflammation, and this concept reinforces the positive role of multicomponent strategies aimed to reduce the surgical stress response. Although some putative precipitating risk factors are not modifiable (length of surgery, surgical site), others (such as depth of anaesthesia, appropriate analgesia and haemodynamic stability) are under the control of the anaesthesiologists. Multicomponent preoperative, intra-operative and postoperative preventive measures showed potential to reduce the incidence and duration of POD, confirming the pivotal role of a comprehensive and team-based approach to improve patients' clinical and functional status.

Setting new priorities for nursing research: The updated Swiss Nursing Research Agenda-a systematic, participative approach.

AIM: To identify current key areas for nursing research in Switzerland, we revised the Swiss Research Agenda for Nursing (SRAN) initially published in 2008. BACKGROUND: By developing a research agenda, nursing researchers internationally prioritize and cluster relevant topics within the research community. The process should be collaborative and systematic to provide credible information for decisionmakers in health care research, policy, and practice. SOURCES OF EVIDENCE: After a participative, systematic, and critical evaluation within and outside of the Swiss Association for Nursing Science, the updated SRAN 2019-2029 defines four research priorities (new models of care, nursing care interventions, work and care environment, and quality of care and patient safety) and four transversal themes (organization of research, research methodologies, research in health care policy and public health perspectives). CONCLUSION: Adding to other national nursing research agendas, the categories are organized in a framework of key research priorities and transversal themes. They relate to the importance of global and local foci of research as well as challenges in health care services and policy systems. The agenda is an important prerequisite for enhancing the influence of nursing research in Switzerland and provides guidance for the next decade. IMPLICATIONS FOR NURSING PRACTICE: The revised agenda ensures that research projects target key knowledge gaps and the discipline's core questions in respective countries. IMPLICATIONS FOR HEALTH POLICY: Nursing research should inform and influence health policy on all institutional and political levels. Therefore, the integration of public health perspectives in research is one of the most important new aspects of SRAN 2019-2029.

[The use of the DOS and Delirium Prevalence: a quantitative longitudinal study at a Swiss-German central hospital]. / Anwendung der DOS und Delirprävalenz.

The use of the DOS and Delirium Prevalence: a quantitative longitudinal study at a Swiss-German central hospital Abstract: Background: With a prevalence of 12-64%, delirium is a common complication in acute care, associated with negative outcomes such as increased mortality and prolonged length of stay. Many hospitals have guidelines to improve the delirium management. The Delirium Observation Screening Scale (DOS) Score is collected in the study hospital from all patients ≥ 70 years at each shift for at least 3 days. Delirium is diagnosed by a physician and coded according to ICD-10. Purpose: Evaluation of the delirium screening with the DOS according to internal guideline in terms of number of DOS assessments performed, prevalence of delirium (DOS score ≥ 3 points, CD-10 code delirium). Method: This retrospective quantitative single-centre longitudinal study used 2017 and 2018 data of 10046 cases. Statistical analysis methods were used to analyse prevalence of delirium and subgroup comparisons. Results: At least one DOS score was documented in 92% of cases aged ≥ 70-years (n = 5038). DOS implementation varied between 60% in the early, 49% in the late and 38% in the night shift. The prevalence of delirium was 12% according to DOS score ≥ 3 and 4% according to physician diagnosis of a delirium. Cases with a DOS score ≥ 3 were significantly older, more often female, had more comorbidities and were depressed. Conclusions: DOS is performed in most patients when indicated. The DOS implementation frequency varied depending on the shift.

Validation of genetic variants from NGS data using deep convolutional neural networks.

Accurate somatic variant calling from next-generation sequencing data is one most important tasks in personalised cancer therapy. The sophistication of the available technologies is ever-increasing, yet, manual candidate refinement is still a necessary step in state-of-the-art processing pipelines. This limits reproducibility and introduces a bottleneck with respect to scalability. We demonstrate that the validation of genetic variants can be improved using a machine learning approach resting on a Convolutional Neural Network, trained using existing human annotation. In contrast to existing approaches, we introduce a way in which contextual data from sequencing tracks can be included into the automated assessment. A rigorous evaluation shows that the resulting model is robust and performs on par with trained researchers following published standard operating procedure.

SAMHD1 restrains aberrant nucleotide insertions at repair junctions generated by DNA end joining.

Aberrant end joining of DNA double strand breaks leads to chromosomal rearrangements and to insertion of nuclear or mitochondrial DNA into breakpoints, which is commonly observed in cancer cells and constitutes a major threat to genome integrity. However, the mechanisms that are causative for these insertions are largely unknown. By monitoring end joining of different linear DNA substrates introduced into HEK293 cells, as well as by examining end joining of CRISPR/Cas9 induced DNA breaks in HEK293 and HeLa cells, we provide evidence that the dNTPase activity of SAMHD1 impedes aberrant DNA resynthesis at DNA breaks during DNA end joining. Hence, SAMHD1 expression or low intracellular dNTP levels lead to shorter repair joints and impede insertion of distant DNA regions prior end repair. Our results reveal a novel role for SAMHD1 in DNA end joining and provide new insights into how loss of SAMHD1 may contribute to genome instability and cancer development.

[Prevention of Post-operative Delirium]. / Prävention des postoperativen Delirs.

Postoperative delirium (POD) is an adverse but often preventable complication of surgery and surgery-related anaesthesia, and increasingly prevalent. This article provides an overview on non-pharmacological preventive measures, divided into individualized and non-individualized measures. Non-individualized measures, such as the most minimally invasive surgical procedure, avoidance of unnecessary fasting before surgery, and the most tolerable anaesthesia are used to minimize the risk of POD in all patients. Based on the results of preoperative screenings for risk factors such as frailty or cognitive impairment, individualized measures may encompass prehabilitation, treatment of specific risk factors, operation room companionship or cognitive, motor, and sensory stimulation as well as social support. This article additionally lists several examples of best practice approaches already implemented in German-speaking countries and websites for further readings.

[Evaluation of the implementation of non-pharmacological measures for the prevention and treatment of delirium: A retrospective cohort study]. / Evaluation der Umsetzung nicht-pharmakologischer Massnahmen zur Delirprävention und -behandlung.

Evaluation of the implementation of non-pharmacological measures for the prevention and treatment of delirium: A retrospective cohort study Abstract. Background: Delirium is burdensome for the affected patients, their relatives, hospital staff and the health care system. Preventing delirium with targeted multicomponent interventions is therefore essential. Aim: To investigate the implementation of defined non-pharmacological, preventive, and supportive measures in patients with an increased risk of delirium and/or delirium by the hospital's directions. Methods: In this observational study, routine data from 175 hospitalized patients were included. Data on delirium prevention, treatment and presence of delirium were extracted from the patient records and analyzed using appropriate statistical methods. Group comparisons were made between the medical/surgical clinic and the delirium/no delirium group. Results: Of the 175 patients, 31 had delirium. For delirium prevention, measures to improve oxygen supply, excretion, pain and mobility were most frequently implemented and measures such as improving cognition and communication were least frequently implemented. In the case of delirium, measures to modify risk factors, ensure safety, as well as prophylaxis were applied most frequently. Between the two clinics and between the delirium/no delirium group significant differences in the frequency of these measures were shown. Conclusion: The differences in frequency of implementation provide preliminary evidence that clinic-specific delirium prevention, early detection, and treatment may be needed.

CD33-directed immunotherapy with third-generation chimeric antigen receptor T cells and gemtuzumab ozogamicin in intact and CD33-edited acute myeloid leukemia and hematopoietic stem and progenitor cells.

Immunotherapies, such as chimeric antigen receptor (CAR) modified T cells and antibody-drug conjugates (ADCs), have revolutionized the treatment of cancer, especially of lymphoid malignancies. The application of targeted immunotherapy to patients with acute myeloid leukemia (AML) has been limited in particular by the lack of a tumor-specific target antigen. Gemtuzumab ozogamicin (GO), an ADC targeting CD33, is the only approved immunotherapeutic agent in AML. In our study, we introduce a CD33-directed third-generation CAR T-cell product (3G.CAR33-T) for the treatment of patients with AML. 3G.CAR33-T cells could be expanded up to the end-of-culture, that is, 17 days after transduction, and displayed significant cytokine secretion and robust cytotoxic activity when incubated with CD33-positive cells including cell lines, drug-resistant cells, primary blasts as well as normal hematopoietic stem and progenitor cells (HSPCs). When compared to second-generation CAR33-T cells, 3G.CAR33-T cells exhibited higher viability, increased proliferation and stronger cytotoxicity. Also, GO exerted strong antileukemia activity against CD33-positive AML cells. Upon genomic deletion of CD33 in HSPCs, 3G.CAR33-T cells and GO preferentially killed wildtype leukemia cells, while sparing CD33-deficient HSPCs. Our data provide evidence for the applicability of CD33-targeted immunotherapies in AML and its potential implementation in CD33 genome-edited stem cell transplantation approaches.

Response to extracorporeal photopheresis therapy of patients with steroid-refractory/-resistant GvHD is associated with up-regulation of Th22 cells and Tfh cells.

Extracorporeal photopheresis (ECP), a personalized cellular immunotherapy, constitutes a promising treatment for steroid-refractory/-resistant graft-versus-host disease (SR-GvHD), with encouraging clinical response rates. To further investigate its mechanism of action, ECP's effects on T helper (Th) cells as well as on expression of immune checkpoint (PD-1 and Tim-3) and apoptotic (Fas receptor [FasR]) molecules were investigated in 27 patients with SR-GvHD. Our data show that GvHD patients had significantly higher levels of Th2, Th17, Th22 and granulocyte-macrophage colony-stimulating factor (GM-CSF)-positive Th (ThG) cells and clearly lower levels of T follicular helper (Tfh) cells, including Th1- and Th2-like cells, compared with healthy donors. ECP therapy for GvHD was effective through the modulation of different Th subsets: increases of Th22 (1.52-fold) and Tfh cells (1.48-fold) in acute GvHD (aGvHD) and increases of Th2-like Tfh cells (1.74-fold) in chronic GvHD (cGvHD) patients were associated with clinical response. Expression of FasR was further upregulated in CD4+CD8+ T cells. Additionally, Tim-3-expressing effector T cells associated with the severity of GvHD were reduced. Taken together, these data show that ECP therapy exerts immunomodulatory effects by promoting a balanced immune reconstitution and inducing immune tolerance. Therefore it represents an attractive option for the treatment of GvHD.

Are nurse`s needs assessment methods robust enough to recognise palliative care needs in people with dementia? A scoping review.

BACKGROUND: People with dementia are most at risk of experiencing serious health related suffering, if they do not have a palliative care approach introduced early enough in the illness. It can be challenging for nurses to assess experienced needs of people, who are thought no longer able to self-report such as people with dementia. Assessment help to understand the care the patient and their family need promptly. It is unknown how nurses recognise holistic palliative care needs in people with dementia during routine care. METHODS: Scoping review where EMBASE, MEDLINE, CINAHL, PsycInfo databases, and references were searched with an advanced search strategy, which was built on three concepts (nurses, dementia, and nursing assessment) using corresponding Medical Subject Headings. Data were charted in a piloted extraction form, based on the assessment domains within the nursing process followed by summarise and synthesise results narratively. RESULTS: 37 out of 2,028 qualitative and quantitative articles published between 2000 and 2021, and relating to 2600 + nurses, were identified. Pain was sole focus of assessment in 29 articles, leaving 8 articles to describe assessment of additional needs (e.g., discomfort). Nurses working in a nursing home assess pain and other needs by observing the persons with dementia behaviour during routine care. Nurses in the acute care setting are more likely to assess symptoms with standard assessment tools at admission and evaluate symptoms by observational methods. Across settings, about one third of pain assessments are supported by person-centred pain assessment tools. Assessments were mostly triggered when the person with dementia vocalised discomfort or a change in usual behaviour was observed. Nurses rely on family members and colleagues to gain more information about needs experienced by people with dementia. CONCLUSION: There is a scarcity of evidence about techniques and methods used by nurses to assess needs other than pain experienced by people with dementia. A holistic, person-centred screening tool to aid real-time observations at the bedside and used in conversations with health care professionals and families/friends, may improve need recognition other than pain, to ensure holistic needs could then be addressed timely to improve care in people with dementia.

Antecedents of unfinished nursing care: a systematic review of the literature.

BACKGROUND: Unfinished Nursing Care (UNC) concept, that express the condition when nurses are forced to delay or omit required nursing care, has been largely investigated as tasks left undone, missed care, and implicit rationing of nursing care. However, no summary of the available evidence regarding UNC antecedents has been published. The aim of this study is to identify and summarise antecedents of UNC as documented in primary studies to date. METHODS: A systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted. MEDLINE, CINAHL, SCOPUS, and PROSPERO databases were searched for quantitative studies reporting the relationships between antecedents and UNC published after 2004 up to 21 January 2020. The reference lists of secondary studies have been scrutinised to identify additional studies. Two reviewers independently identified studies and evaluated them for their eligibility and disagreements were resolved by the research team. The quality appraisal was based on the Joanna Briggs Institute Critical Appraisal tools, according to the study designs. A data extraction grid was piloted and then used to extract data. The antecedents that emerged were thematically categorised with an inductive approach. RESULTS: Fifty-eight studies were included; among them, 54 were cross-sectional, three were cohort studies, and one was a quasi-experimental study. They were conducted mainly in the United States and in hospital settings. The UNC antecedents have been investigated to date at the (a) unit (e.g., workloads, non-nursing tasks), (b) nurse (e.g., age, gender), and (c) patient levels (clinical instability). CONCLUSIONS: At the unit level, it is highly recommended to provide an adequate staff level, strategies to deal with unpredictable workloads, and to promote good practice environments to reduce or minimise UNC. By contrast, at the nurse and patient levels, there were no clear trends regarding modifiable factors that could decrease the occurrence of UNC. The map of antecedents that emerged can be used to design interventional studies aimed at changing research from merely descriptive to that which evaluates the effectiveness of interventions.

Economic Impact of Poststroke Delirium and Associated Risk Factors: Findings From a Prospective Cohort Study.

Background and Purpose: Delirium is a common severe complication of stroke. We aimed to determine the cost-of-illness and risk factors of poststroke delirium (PSD). Methods: This prospective single-center study included n=567 patients with acute stroke from a hospital-wide delirium cohort study and the Swiss Stroke Registry in 2014. Delirium was determined by Delirium Observation Screening Scale or Intensive Care Delirium Screening Checklist 3 times daily during the first 3 days of admission. Costs reflected the case-mix index and diagnosis-related groups from 2014 and were divided into nursing, physician, and total costs. Factors associated with PSD were assessed with multiple regression analysis. Partial correlations and quantile regression were performed to assess costs and other factors associated with PSD. Results: The incidence of PSD was 39.0% (221/567). Patients with delirium were older than non-PSD (median 76 versus 70 years; P<0.001), 52% male (115/221) versus 62% non-PSD (214/346) and hospitalized longer (mean 11.5 versus 9.3 days; P<0.001). Dementia was the most relevant predisposing factor for PSD (odds ratio, 16.02 [2.83­90.69], P=0.002). Moderate to severe stroke (National Institutes of Health Stroke Scale score 16­20) was the most relevant precipitating factor (odds ratio, 36.10 [8.15­159.79], P<0.001). PSD was a strong predictor for 3-month mortality (odds ratio, 15.11 [3.33­68.53], P<0.001). Nursing and total costs were nearly twice as high in PSD (P<0.001). There was a positive correlation between total costs and admission National Institutes of Health Stroke Scale (correlation coefficient, 0.491; P<0.001) and length of stay (correlation coefficient, 0.787; P<0.001) in all patients. Quantile regression revealed rising nursing and total costs associated with PSD, higher National Institutes of Health Stroke Scale, and longer hospital stay (all P<0.05). Conclusions: PSD was associated with greater stroke severity, prolonged hospitalization, and increased nursing and total costs. In patients with severe stroke, dementia, or seizures, PSD is anticipated, and additional costs are associated with hospitalization.

Ibrutinib for improved chimeric antigen receptor T-cell production for chronic lymphocytic leukemia patients.

Chimeric antigen receptor T (CART) cells targeting CD19 have shown promising results in the treatment of chronic lymphocytic leukemia (CLL). However, efficacy seems to be inferior compared to diffuse large B-cell lymphoma or acute lymphoblastic leukemia. Impaired T-cell fitness of CLL patients may be involved in treatment failure. Less-differentiated naïve-like T cells play an important role in CART expansion and long-term persistence in vivo. These cells are sparse in CLL patients. Therefore, optimization of CART cell production protocols enriching less differentiated T cell subsets may overcome treatment resistance. The B-cell receptor inhibitor ibrutinib targeting Bruton's tyrosine kinase (BTK) is approved for the treatment of CLL. Besides BTK, ibrutinib additionally inhibits interleukin-2-inducible T-cell kinase (ITK) which is involved in T-cell differentiation. To evaluate the effect of ibrutinib on CART cell production, peripheral blood mononuclear cells from nine healthy donors and eight CLL patients were used to generate CART cells. T-cell expansion and phenotype, expression of homing and exhaustion makers as well as functionality of CART cells were evaluated. CART cell generation in the presence of ibrutinib resulted in increased cell viability and expansion of CLL patient-derived CART cells. Furthermore, ibrutinib enriched CART cells with less-differentiated naïve-like phenotype and decreased expression of exhaustion markers including PD-1, TIM-3 and LAG-3. In addition, ibrutinib increased the cytokine release capacity of CLL patient-derived CART cells. In summary, BTK/ITK inhibition with ibrutinib during CART cell culture can improve yield and function of CLL patient-derived CART cell products.

Pituitary response to GnRH stimulation tests in different FSHB-211 G/T genotypes.

STUDY QUESTION: Does pituitary response to a GnRH stimulation test differ according to the different FSHB-211 G/T genotypes? SUMMARY ANSWER: The promoter polymorphism FSHB-211 G > T affects the pituitary response to exogenous GnRH stimulation by reducing FSH and increasing LH outputs. WHAT IS KNOWN ALREADY: The FSHB-211 G > T single nucleotide polymorphism (SNP) is known to affect pituitary FSH output by impairing the transcriptional activity of FSHB. STUDY DESIGN, SIZE, DURATION: This was a cross-sectional, retrospective study on 67 male subjects (mean age: 24.6 ± 10.3 years) undergoing a GnRH stimulation test for diagnostic purposes in cases of secondary hypogonadism. PARTICIPANTS/MATERIALS, SETTING, METHODS: A GnRH stimulation test was performed by administering an i.v. bolus of 100 µg of the GnRH-analogue gonadorelin acetate to all patients, with blood samples drawn from the cubital vein immediately prior to injection (T0) and 30 (T1) and 45 minutes (T2) after. Clinical and genetic data were retrieved from a computerized database. Linear longitudinal mixed-effect models were used to assess the effects of SNP genotype on FSH and LH levels over time via additive and recessive models. MAIN RESULTS AND THE ROLE OF CHANCE: An overall marked increase in serum FSH and LH following administration i.v. of 100 µg of an LHRH-analogue was found (P < 0.0001 for linear trend, both models). Peak levels of LH were significantly higher in TT carriers than in GT and GG carriers (P = 0.012); no significant between-groups difference was found concerning stimulated FSH levels. In both the additive and recessive model, the main effect of T allele(s) did not reach statistical significance concerning FSH levels (P = 0.9502 and P = 0.8576, respectively), yet interaction effects over time demonstrated an attenuated response in T-allele carriers compared to the GG-allele carriers (P = 0.0219 and P = 0.0276). Main and interaction effects for LH were significant in both the additive (P = 0.0022 and P = 0.0013, respectively) and recessive model (P = 0.0025 and P = 0.0016, respectively). LIMITATIONS, REASONS FOR CAUTION: Given the retrospective nature of the study and the small number of TT carriers, results should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: The FSHB c.-211G>T polymorphism might result in an impaired response to endogenous, as well as exogenous, GnRH stimulation. This finding might contribute to the clinical phenotype of reduced testicular volume and sperm count for patients carrying one or two T alleles. STUDY FUNDING/COMPETING INTEREST(S): Parts of the study were supported by the German Research Foundation (CRU326 Male Germ Cells). On behalf of all authors, the corresponding author states that there is no conflict of interest. TRIAL REGISTRATION NUMBER: NA.

Letermovir prophylaxis is effective in preventing cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation: single-center real-world data.

Morbidity and mortality after allogeneic hematopoietic cell transplantation (alloHCT) are still essentially affected by reactivation of cytomegalovirus (CMV). We evaluated 80 seropositive patients transplanted consecutively between March 2018 and March 2019 who received letermovir (LET) prophylaxis from engraftment until day +100 and retrospectively compared them with 80 patients without LET allografted between January 2017 and March 2018. The primary endpoint of this study was the cumulative incidence (CI) of clinically significant CMV infection (CS-CMVi) defined as CMV reactivation demanding preemptive treatment or CMV disease. With 14% CI of CS-CMVi at day +100 (11 events) was significantly lower in the LET cohort when compared to the control group (33 events, 41%; HR 0.29; p < 0.001). Whereas therapy with foscarnet could be completely avoided in the LET group, 7 out of 80 patients in the control cohort received foscarnet, resulting in 151 extra in-patient days for foscarnet administration (p = 0.002). One-year overall survival was 72% in the control arm vs 84% in the LET arm (HR 0.75 [95%CI 0.43-1.30]; p < 0.306). This study confirms efficacy and safety of LET for prophylaxis of CS-CMVi after alloHCT in a real-world setting, resulting in a significant patient benefit by reducing hospitalization needs and exposure to potentially toxic antiviral drugs for treatment of CMV reactivation.

Interventions to prevent or reduce rationing or missed nursing care: A scoping review.

AIMS: To collate and synthesize published research on interventions developed and tested to prevent or reduce the rates of rationed or missed nursing care in healthcare institutions. BACKGROUND: Rationed and missed nursing care has been widely studied, including its predictors and associations with patient and nurse outcomes. DESIGN: Scoping review. DATA SOURCES: We searched for eligible studies, published between 1980-2019, in six electronic databases. REVIEW METHODS: Researchers independently screened the abstracts of the retrieved studies using the inclusion and exclusion criteria. The decision of whether or not to include any given study was consensus-based. RESULTS: The search yielded 1,815 records, of which 13 were included. Three studies reported structural interventions, namely increased nurse staffing and improved nursing teamwork, both resulted in significant reductions in the rates of rationed or missed nursing care. The remaining 10 studies reported on process interventions: four concerned reminders (via technology or designated persons) and seven described interventions to change or optimize the relevant care processes. All 10 process interventions contributed to significant reductions in the rates of missed nursing care. CONCLUSIONS: The results of the scoping review indicate that specific interventions can positively influence the performance of a selected nursing care activity, for example fall prevention. There is no evidence of a global reduction of rationed and missed nursing care through these interventions. IMPACT: Clinicians, managers and researchers can use the results for adapting and implementing interventions to reduce rationed and missed nursing care.

Interleukin-1ß Induced Matrix Metalloproteinase Expression in Human Periodontal Ligament-Derived Mesenchymal Stromal Cells under In Vitro Simulated Static Orthodontic Forces.

The periodontal ligament (PDL) responds to applied orthodontic forces by extracellular matrix (ECM) remodeling, in which human periodontal ligament-derived mesenchymal stromal cells (hPDL-MSCs) are largely involved by producing matrix metalloproteinases (MMPs) and their local inhibitors (TIMPs). Apart from orthodontic forces, the synthesis of MMPs and TIMPs is influenced by the aseptic inflammation occurring during orthodontic treatment. Interleukin (IL)-1ß is one of the most abundant inflammatory mediators in this process and crucially affects the expression of MMPs and TIMPs in the presence of cyclic low-magnitude orthodontic tensile forces. In this study we aimed to investigate, for the first time, how IL-1ß induced expression of MMPs, TIMPs and how IL-1ß in hPDL-MSCs was changed after applying in vitro low-magnitude orthodontic tensile strains in a static application mode. Hence, primary hPDL-MSCs were stimulated with IL-1ß in combination with static tensile strains (STS) with 6% elongation. After 6- and 24 h, MMP-1, MMP-2, TIMP-1 and IL-1ß expression levels were measured. STS alone had no influence on the basal expression of investigated target genes, whereas IL-1ß caused increased expression of these genes. In combination, they increased the gene and protein expression of MMP-1 and the gene expression of MMP-2 after 24 h. After 6 h, STS reduced IL-1ß-induced MMP-1 synthesis and MMP-2 gene expression. IL-1ß-induced TIMP-1 gene expression was decreased by STS after 6- and 24-h. At both time points, the IL-1ß-induced gene expression of IL-1ß was increased. Additionally, this study showed that fetal bovine serum (FBS) caused an overall suppression of IL-1ß-induced expression of MMP-1, MMP-2 and TIMP-1. Further, it caused lower or opposite effects of STS on IL-1ß-induced expression. These observations suggest that low-magnitude orthodontic tensile strains may favor a more inflammatory and destructive response of hPDL-MSCs when using a static application form and that this response is highly influenced by the presence of FBS in vitro.