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Introduction Precision medicine in psychiatry is still in its infancy. To establish patient-tailored treatment, adequate indicators predicting treatment response are required. Electroconvulsive therapy (ECT) is considered one of the most effective options for pharmacoresistant major depressive disorder (MDD), yet remission rates were reported to be below 50%. Methods Since epigenetics of the stress response system seem to play a role in MDD, we analyzed the DNA methylation (DNAm) of genes encoding the glucocorticoid receptor (NR3C1) and proopiomelanocortin (POMC) through Sanger Sequencing. For analysis, blood was taken before and after the first and last ECT from MDD patients (n=31), unmedicated depressed controls (UDC; n=19, baseline), and healthy controls (HC; n=20, baseline). Results Baseline DNAm in NR3C1 was significantly lower in UDCs compared to both other groups (UDC: 0.014(±0.002), ECT: 0.031(±0.001), HC: 0.024(±0.002); p Discussion Our findings indicate that both genes might play a role in the chronification of depression and NR3C1 may be relevant for ECT response prediction.

The significance of neurological soft signs (NSS) in major depressive disorder (MDD) remains unclear and the stability of NSS in relation to antidepressant treatment has never been investigated. We hypothesized that NSS are relatively stable trait markers of MDD. We thus predicted that patients show more NSS than healthy controls, irrespective of illness duration and antidepressant treatment. To test this hypothesis, NSS were assessed in chronically depressed, medicated MDD patients before (n = 23) and after (n = 18) a series of electroconvulsive therapy (ECT). In addition, NSS were assessed once in acutely depressed, unmedicated MDD patients (n = 16) and healthy controls (n = 20). We found that both chronically depressed, medicated MDD patients and acutely depressed, unmedicated MDD patients showed more NSS than healthy controls. The degree of NSS in both patient groups did not differ. Importantly, we found no change in NSS after on average eleven sessions of ECT. Thus, the manifestation of NSS in MDD seems to be independent of illness duration and pharmacological and electroconvulsive antidepressant treatment. From a clinical perspective, our findings corroborate the neurological safety of ECT.

Neutropenia and agranulocytosis (N&A) are relatively rare, but potentially fatal adverse drug reactions (ADR). This study presents cases of N&A related to one or more antipsychotic drugs (APDs) in psychiatric inpatients. Data on APD utilization and reports of N&A caused by APDs were analyzed by using data from an observational pharmacovigilance program in German-speaking countries—Arzneimittelsicherheit in der Psychiatrie (AMSP)—from 1993 to 2016. 333,175 psychiatric inpatients were treated with APDs for schizophrenia and other indications during the observation period. A total of 124 cases of APD-induced N&A were documented, 48 of which fulfilled the criteria for agranulocytosis, corresponding to a rate of 0.37, respectively, 0.14 in 1000 inpatients treated with APDs. Neutropenia was more often detected in women, whereas there was no difference regarding sex in cases of agranulocytosis. Clozapine had the highest relative risk for inducing N&A and was imputed alone as a probable cause of N&A in 60 cases (1.57‰ of all patients exposed). Perazine showed the second highest relative risk with 8 cases and an incidence 0.52‰, followed by quetiapine (15 cases resp. 0.23‰ of all patients exposed) and olanzapine (7 cases; 0.13‰ of all patients exposed). N&A most often occurred during the first 3 months of treatment. Overall N&A are severe and potentially fatal complications that can occur during treatment with APDs. The results from this study largely agree with the currently available literature, highlighting the positive effects of alertness and established appropriate monitoring.

The adoption of Directive 2010/63/EU on the protection of animals used for scientific purposes has given a major push to the formation of Three Rs initiatives in the form of centres and platforms. These centres and platforms are dedicated to the so-called Three Rs, which are the Replacement, Reduction and Refinement of animal use in experiments. ATLA’s 50th Anniversary year has seen the publication of two articles on European Three Rs centres and platforms. The first of these was about the progressive rise in their numbers and about their founding history; this second part focuses on their current status and activities. This article takes a closer look at their financial and organisational structures, describes their Three Rs focus and core activities (dissemination, education, implementation, scientific quality/translatability, ethics), and presents their areas of responsibility and projects in detail. This overview of the work and diverse structures of the Three Rs centres and platforms is not only intended to bring them closer to the reader, but also to provide role models and show examples of how such Three Rs centres and platforms could be made sustainable. The Three Rs centres and platforms are very important focal points and play an immense role as facilitators of Directive 2010/63/EU ‘on the ground’ in their respective countries. They are also invaluable for the wide dissemination of information and for promoting the implementation of the Three Rs in general.

We demonstrate how sociological theories of discursive opportunity structures illuminate key elements of US and French media coverage of Black Lives Matter (BLM) in France. Fundamental discursive differences between the two countries shape the visibility, resonance, and legitimacy of claims made on behalf of racially identified groups. A textual analysis of thirty-five articles from each country that discuss BLM and France published between 2015 and 2020 reveals that the US journalists commonly identify BLM activists as members of marginalized communities, interpret French circumstances as similar to the racial dynamics found in the United States, critique France's “republican” model of citizenship, and are relatively positively disposed toward BLM activity in France. By comparison, French coverage largely eschews identifying actors by racial identities, avoids or rejects comparisons with the United States, and at times contains implicit or explicit valorization of the French color-blind republican model, with some authors casting BLM as a product of the excesses of the American system. Our findings demonstrate the relevance of discursive opportunity structure theories to comparative media analysis, suggesting that coverage of race-based movements abroad may respond to different dynamics than coverage within the United States.

Zusammenfassung Ziel der Studie Neben der Vermittlung von theoretischen und klinisch-praktischen Fähigkeiten sollte die Weiterentwicklung der individuellen moralischen Kompetenz ein weiteres Kernanliegen im Studium der Humanmedizin sein. Untersuchungen zeigen allerdings, dass die moralische Kompetenz bei Medizinstudierenden im Verlauf des Studiums stagniert oder sogar abnimmt. Die vorliegende Querschnittstudie untersuchte daher die moralische Kompetenz von Medizinstudierenden zu Beginn des Studiums (d. h. im ersten Fachsemester) sowie im Praktischen Jahr (PJ) sowie die Auswirkungen von Testosteron als Neurohormon auf die moralische Urteilsfähigkeit. Methodik Im Rahmen einer Querschnittstudie wurden mittels des Moralischen Kompetenz Tests (MKT) nach Lind die moralische Urteilsfähigkeit von 24 Erstsemesterstudierenden und 16 PJ-Studierenden der Medizinischen Hochschule Hannover erfasst und ausgewertet. Der Testosteron-Serumspiegel der Studienteilnehmenden wurde statistisch in Beziehung zu den MKT-Ergebnissen gesetzt. Ergebnisse Es zeigten sich keine signifikanten Unterschiede zwischen Erstsemester- (Mittelwert (M)±Standardabweichung (SD): 13,16±8,21) und PJ-Studierenden (M±SD: 11,24±8,07) im Hinblick auf die mittels des MKT gemessene moralische Kompetenz (p=0,36). Ein höherer Testosteron-Serumspiegel zeigte keine statistisch signifikante Korrelation mit der moralischen Kompetenz (r=–0,09, p=0,58). Schlussfolgerung Unsere Ergebnisse zeigen keinen klaren Trend, ob die moralische Kompetenz bei Medizinstudierenden in fortgeschrittenen Studiensemestern geringer ist als zu Beginn des Studiums und ob die moralische Kompetenz durch das Neurohormon Testosteron beeinflusst wird. Dennoch erscheint es sinnvoll, moralische Kompetenztrainings für Medizinstudierende frühzeitig, kontinuierlich und möglichst individuell gestaltet während des Medizinstudiums zu implementieren (und in weiterführenden Untersuchungen zu evaluieren), um einer Stagnation bzw. Rückentwicklung der moralischen Urteilsfähigkeit präventiv zu begegnen.

In the current study, a smart speakers–based system (Amazon ® Echo Dot device, a safety pendant, and facility tailored functionalities) for supporting aging in place was implemented in one low-income senior housing property. We aimed to explore perceived benefits, concerns, and expectations about this system among three stakeholder groups (older adults, housing staff, and technology developers) to identify facilitators of and barriers to system implementation. A qualitative analysis of individual interviews using inductive coding methods was performed to identify emerging themes. All stakeholder groups perceived smart speakers as valuable for convenience in daily living and safety. Older adults and system developers identified user difficulty with setting up functions they wanted to use, suggesting the need for user-centered technology support. There were differences in priorities for smart speaker use among three stakeholder groups. This work contributes to the identification of factors affecting smart speaker adoption and use among low-income older adults who often have limited technology experience and support. [ Journal of Gerontological Nursing, 48 (10), 33–39.]

Patient safety is a priority in health care systems. Nurses' safety competence along with environmental and personal factors plays a role in patient safety.The purpose of this study was to explore the relationships among safety competency, structural empowerment, systems thinking, level of education, and certification.A cross-sectional exploratory design was used to collect data from nurses (n = 163) practicing in a large Midwestern hospital system.There were significant positive correlations between safety competency and ( a ) structural empowerment, ( b ) systems thinking, and ( c ) certification. Systems thinking explained 12.9% of the variance in the knowledge component of safety competency and 6.8% of the variance in the skill component of safety competency. Certification explained 2.4% of the variance in the skill component of safety competency.Understanding factors that affect safety competency supports the development of effective interventions that may improve safety.

PurposePatient-reported outcomes have not been sufficiently implemented into the routine care of cancer patients because the existing instruments are often too long and complex or not cancer-specific. The aim of this study is the determination of psychometric properties and item reduction of a newly developed health-related quality of life (HrQoL) questionnaire for use in oncological clinical routines.MethodsThis observational study with a repeated measurements design included oncological inpatients and outpatients. A total of 630 patients participated at the first point of measurement and 404 at the second point of measurement. To evaluate the instrument, we conducted hierarchical confirmative factor analyses and for further validation correlated the resulting factors with standardized and validated HrQoL measurements. Test–retest reliability and responsiveness to change were tested.ResultsThe developed questionnaire “HELP-6” (“Hamburg Inventory for Measuring Quality of Life in Oncological Patients”) has a six-factor structure and has moderate-to-good convergent validity (r= −0.25 –−0.68). Test–retest reliability was moderate-to-good (r =0.56−0.81, p < 0.001). Indications for responsiveness to change were found for three dimensions. The final version of the questionnaire HELP-6 has six dimensions with one item each.ConclusionWith the HELP-6 instrument for measuring HrQoL in cancer patients, we provide a short and practical patient-reported outcome instrument. Though responsiveness to change could not be confirmed for all dimensions in this study, the HELP-6 includes time-efficient completion and evaluation and is informative in relevant HrQoL dimensions of cancer patients. Therefore, the HELP-6 poses an important addition to inpatient and outpatient routine cancer care.Trial registrationThis study was registered at Open Science Framework (https://osf.io/y7xce/), on 9 June 2018.

This study presents a novel concept for a smart cage designed to monitor the physiological parameters of mice and rats in animal-based experiments. The system focuses on monitoring key clinical parameters, including heart rate, respiratory rate, body temperature, activity, and circadian rhythm. To create the smart home cage system, an in-depth analysis of the requirements was performed, including camera positioning, imaging system types, resolution, frame rates, external illumination, video acquisition, data storage, and synchronization. Two different camera perspectives were considered, and specific camera models, including two near-infrared and two thermal cameras, were selected to meet the requirements. During the first testing phase, the system demonstrated the potential of extracting vital parameters such as respiratory and heart rate. This technology has the potential to reduce the need for implantable sensors while providing reliable and accurate physiological data, leading to refinement and improvement in laboratory animal care.

Background Inflammatory bowel disease (IBD) patients experience recurrent episodes of intestinal inflammation and often follow an unpredictable disease course. Mucosal colonization with adherent-invasive Escherichia coli (AIEC) are believed to perpetuate intestinal inflammation. However, it remains unclear if the 24-year-old AIEC in-vitro definition fully predicts mucosal colonization in-vivo. To fill this gap, we have developed a novel molecular barcoding approach to distinguish strain variants in the gut and have integrated this approach to explore mucosal colonization of distinct patient-derived E. coli isolates in gnotobiotic mouse models of colitis.Results Germ-free inflammation-susceptible interleukin-10-deficient (Il10−/−) and inflammation-resistant WT mice were colonized with a consortia of AIEC and non-AIEC strains, then given a murine fecal transplant to provide niche competition. E. coli strains isolated from human intestinal tissue were each marked with a unique molecular barcode that permits identification and quantification by barcode-targeted sequencing. 16S rRNA sequencing was used to evaluate the microbiome response to E. coli colonization. Our data reveal that specific AIEC and non-AIEC strains reproducibly colonize the intestinal mucosa of WT and Il10−/− mice. These E. coli expand in Il10−/− mice during inflammation and induce compositional dysbiosis to the microbiome in an inflammation-dependent manner. In turn, specific microbes co-evolve in inflamed mice, potentially diversifying E. coli colonization patterns. We observed no selectivity in E. coli colonization patterns in the fecal contents, indicating minimal selective pressure in this niche from host-microbe and interbacterial interactions. Because select AIEC and non-AIEC strains colonize the mucosa, this suggests the in vitro AIEC definition may not fully predict in vivo colonization potential. Further comparison of seven E. coli genomes pinpointed unique genomic features contained only in highly colonizing strains (two AIEC and two non-AIEC). Those colonization-associated features may convey metabolic advantages (e.g., iron acquisition and carbohydrate consumption) to promote efficient mucosal colonization.Conclusions Our findings establish the in-vivo mucosal colonizer, not necessarily AIEC, as a principal dysbiosis driver through crosstalk with host and associated microbes. Furthermore, we highlight the utility of high-throughput screens to decode the in-vivo colonization dynamics of patient-derived bacteria in murine models.

Experimental craniotomies are a common surgical procedure in neuroscience. Because inadequate analgesia appears to be a problem in animal-based research, we conducted this review and collected information on management of craniotomy-associated pain in laboratory mice and rats. A comprehensive search and screening resulted in the identification of 2235 studies, published in 2009 and 2019, describing craniotomy in mice and/or rats. While key features were extracted from all studies, detailed information was extracted from a random subset of 100 studies/year. Reporting of perioperative analgesia increased from 2009 to 2019. However, the majority of studies from both years did not report pharmacologic pain management. Moreover, reporting of multimodal treatments remained at a low level, and monotherapeutic approaches were more common. Among drug groups, reporting of pre- and postoperative administration of non-steroidal anti-inflammatory drugs, opioids, and local anesthetics in 2019 exceeded that of 2009. In summary, these results suggest that inadequate analgesia and oligoanalgesia are persistent issues associated with experimental intracranial surgery. This underscores the need for intensified training of those working with laboratory rodents subjected to craniotomies.Systematic review registrationhttps://osf.io/7d4qe.

Aim: Impaired calcium homeostasis limits life expectancy and quality in familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC). This rare disease is caused by loss-of-function mutations in CLDN16 or CLDN19 genes leading to impaired paracellular reabsorption of divalent cations along the cortical thick ascending limb (cTAL). The ensuing late distal nephron and collecting duct system partially compensate for the defect in cTAL by increased transcellular Ca2+ reabsorption via the luminal transient receptor potential channel V5 (TRPV5), as well as basolateral plasma membrane calcium ATPase (PMCA) and sodium-potassium exchanger (NCX1). The loop diuretic furosemide induces compensatory activation in these distal segments due to blockade of NaCl and divalent cation reabsorption in the preceeding TAL. Although furosemide enhances urinary calcium excretion via inhibition of the aforementioned cTAL in general population, this effect is not expected in FHHNC patients with already severely impaired Ca2+ transport in the cTAL. The present study follows the hypothesis that furosemide may alleviate hypercalciuria in this disease by activation of the distal transcellular Ca2+ transport proteins. Methods: Cldn16-deficient mice (Cldn16-/- ) served as a FHHNC model. Wild-type (WT) and Cldn16-/- mice were treated with furosemide (7 days of 40 mg/kg bw) or vehicle. We assessed renal electrolyte handling (metabolic cages) and key divalent transport proteins. Results: Cldn16-/- mice show increased Ca2+ excretion than WT and compensatory stimulation of Cldn2 in the proximal tubule, as well as of TRPV5, and NCX1 in the distal nephron at baseline. Furosemide reduced hypercalciuria in Cldn16-/- mice and enhanced TRPV5 and PMCA levels in Cldn16-/- but not in WT mice. Conclusions: Furosemide alleviated hypercalciuria in a mouse FHHNC model, likely via stimulation of transcellular luminal and basolateral Ca2+ transport systems in the distal nephron and collecting duct. These results may have a clinical implication in FHHNC patients. No conflict of interests This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background Differentiating depression and dementia in elderly patients represents a major clinical challenge for psychiatrists. Pharmacological and non-pharmacological treatment options for both conditions are often used cautiously due to fear of adverse effects. If a clinically indicated therapy is not initiated due to fear of adverse effects, the quality of life of affected patients may significantly be reduced. Case presentation Here, we describe the case of a 65-year-old woman who presented to the department of psychiatry of a university hospital with depressed mood, pronounced anxiety, and nihilistic thoughts. While several pharmacological treatments remained without clinical response, further behavioral observation in conjunction with 18F-fluoro‐2‐deoxy‐D‐glucose positron emission tomography/computed tomography (18F-FDG PET/CT) revealed the diagnosis of frontotemporal dementia (FTD). To counter the pharmacological treatment resistance of psychotic depression, we decided to perform electroconvulsive therapy (ECT). Remarkably, ten sessions of ECT yielded an almost complete remission of depressive symptoms. In addition, the patient’s delusional ideas disappeared. A follow-up 18F-FDG PET/CT after the ECT series still showed a frontally and parieto-temporally accentuated hypometabolism, albeit with a clear regression compared to the previous image. The follow-up 18F-FDG PET/CT thus corroborated the diagnosis of FTD, while on the other hand it demonstrated the success of ECT. Conclusions In this case, ECT was a beneficial treatment option for depressive symptoms in FTD. Also, 18F-FDG PET/CT should be discussed as a valuable tool in differentiating depression and dementia and as an indicator of treatment response.

The immune system is critical in defending against infection from pathogenic microorganisms. Individuals with weakened immune systems, such as the elderly, are more susceptible to infections and developing autoimmune and inflammatory diseases. The gut microbiome contains a plethora of bacteria and other microorganisms, which collectively plays a significant role in immune function and homeostasis. Gut microbiota are considered to be highly influential on host health and immune function. Therefore, dysbiosis of the microbiota could be a major contributor to the elevated incidence of multiple age-related pathologies. While there seems to be a general consensus that the composition of gut microbiota changes with age, very little is known about how diet and exercise might influence the aging microbiome. Here, we examine the current state of the literature regarding alterations to the gut microbiome as hosts age, drawing particular attention to the knowledge gaps in addressing how diet and exercise influence the aging microbiome. Further, we will demonstrate the need for more controlled studies to investigate the roles that diet and exercise play driving the composition, diversity, and function of the microbiome in an aging population.

Animals select habitats based on food, water, space, and cover. Each of those components are essential to the ability of an individual to survive and reproduce in a particular habitat. Selection of resources is linked to reproductive fitness and individuals likely vary in how they select resources relative to their reproductive state: during pregnancy, while provisioning young when nutritional needs of the mother are high, but offspring are vulnerable to predation, or if they lose young to mortality. We investigated the effects of reproductive state on selection of resources by maternal female desert bighorn sheep (Ovis canadensis nelsoni) by comparing selection during the last trimester of gestation, following parturition when females were provisioning dependent young, and if the female lost an offspring. We captured, and recaptured each year, 32 female bighorn sheep at Lone Mountain, Nevada, during 2016–2018. Captured females were fit with GPS collars and those that were pregnant received vaginal implant transmitters. We used a Bayesian approach to estimate differences in selection between females provisioning and not provisioning offspring, as well as the length of time it took for females with offspring to return levels of selection similar to that observed prior to parturition. Females that were not provisioning offspring selected areas with higher risk of predation, but greater nutritional resources than those that were provisioning dependent young. When females were provisioning young immediately following parturition, females selected areas that were safe from predators, but had lower nutritional resources. Females displayed varying rates of return to selection strategies associated with access to nutritional resources as young grew and became more agile and less dependent on mothers. We observed clear and substantial shifts in selection of resources associated with reproductive state, and females exhibited tradeoffs in favor of areas that were safer from predators when provisioning dependent young despite loss of nutritional resources to support lactation. As young grew and became less vulnerable to predators, females returned to levels of selection that provided access to nutritional resources to restore somatic reserves lost during lactation.

Purpose: PD-L1 expression in the pretreatment tumor microenvironment enriches for response to anti-PD-1/PD-L1 therapies. The purpose of this study was to quantitatively compare the performance of five monoclonal anti-PD-L1 antibodies used in recent landmark publications.Experimental Design: PD-L1 IHC was performed on 34 formalin-fixed paraffin-embedded archival melanoma samples using the 5H1, SP142, 28-8, 22C3, and SP263 clones. The percentage of total cells (including melanocytes and immune cells) demonstrating cell surface PD-L1 staining, as well as intensity measurements/H-scores, were assessed for each melanoma specimen using a computer-assisted platform. Staining properties were compared between antibodies.Results: Strong correlations were observed between the percentage of PD-L1(+) cells across all clones studied (R2 = 0.81–0.96). When present, discordant results were attributable to geographic heterogeneity of the melanoma tissue section rather than differences in PD-L1 antibody staining characteristics. PD-L1 intensity/H-scores strongly correlated with percentage of PD-L1(+) cells (R2 > 0.78, all clones).Conclusions: The 5H1, SP142, 28-8, 22C3, and SP263 clones all demonstrated similar performance characteristics when used in a standardized IHC assay on melanoma specimens. Reported differences in PD-L1 IHC assays using these antibodies are thus most likely due to assay characteristics beyond the antibody itself. Our findings also argue against the inclusion of an intensity/H-score in chromogenic PD-L1 IHC assays. Clin Cancer Res; 23(16); 4938–44. ©2017 AACR.

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Background Crohn’s disease (CD) is associated with changes in the microbiota, and murine models of CD-like ileo-colonic inflammation depend on the presence of microbial triggers. Increased abundance of unknown Clostridiales and the microscopic detection of filamentous structures close to the epithelium of TnfΔARE mice, a mouse model of CD-like ileitis pointed towards segmented filamentous bacteria (SFB), a commensal mucosal adherent bacterium involved in ileal inflammation. Results We show that the abundance of SFB strongly correlates with the severity of CD-like ileal inflammation in two mouse models of ileal inflammation, including TnfΔARE and SAMP/Yit mice. SFB mono-colonization of germ-free TnfΔARE mice confirmed the causal link and resulted in severe ileo-colonic inflammation, characterized by elevated tissue levels of Tnf and Il-17A, neutrophil infiltration and loss of Paneth and goblet cell function. Co-colonization of SFB in human-microbiota associated TnfΔARE mice confirmed that SFB presence is indispensable for disease development. Screening of 468 ileal and colonic mucosal biopsies from adult and pediatric IBD patients, using previously published and newly designed human SFB-specific primer sets, showed no presence of SFB in human tissue samples, suggesting a species-specific functionality of the pathobiont. Simulating the human relevant therapeutic effect of exclusive enteral nutrition (EEN), EEN-like purified diet antagonized SFB colonization and prevented disease development in TnfΔARE mice, providing functional evidence for the protective mechanism of diet in modulating microbiota-dependent inflammation in IBD. Conclusions We identified a novel pathogenic role of SFB in driving severe CD-like ileo-colonic inflammation characterized by loss of Paneth and goblet cell functions in TnfΔARE mice. A purified diet antagonized SFB colonization and prevented disease development in TnfΔARE mice in contrast to a fiber-containing chow diet, clearly demonstrating the important role of diet in modulating a novel IBD-relevant pathobiont and supporting a direct link between diet and microbial communities in mediating protective functions.

IntroductionThe ubiquitous Epstein–Barr virus (EBV) is an oncogenic herpes virus associated with several human malignancies. EBV is an immune-evasive pathogen that promotes CD8+ T cell exhaustion and dysregulates CD4+ T cell functions. Burkitt lymphoma (BL) is frequently associated with EBV infections. Since BL relapses after conventional therapies are difficult to treat, we evaluated prospective off-the-shelf edited CAR-T cell therapies targeting CD19 or the EBV gp350 cell surface antigen.MethodsWe used CRISPR/Cas9 gene editing methods to knock in (KI) the CD19CAR.CD28z or gp350CAR.CD28z into the T cell receptor (TCR) alpha chain (TRAC) locus.ResultsApplying upscaled methods with the ExPERT ATx® MaxCyte system, KI efficacy was ~20% of the total ~2 × 108 TCR-knocked-out (KO) generated cells. KOTCRKICAR-T cells were co-cultured in vitro with the gp350+CD19+ BL cell lines Daudi (infected with type 1 EBV) or with Jiyoye (harboring a lytic type 2 EBV). Both types of CAR-T cells showed cytotoxic effects against the BL lines in vitro. CD8+ KICAR-T cells showed higher persistency than CD4+ KICAR-T cells after in vitro co-culture with BL and upregulation of the activation/exhaustion markers PD-1, LAG-3, and TIM-3. Two preclinical in vivo xenograft models were set up with Nod.Rag.Gamma mice injected intravenously (i.v.) with 2 × 105 Daudi/fLuc-GFP or with Jiyoye/fLuc-GFP cells. Compared with the non-treated controls, mice challenged with BL and treated with CD19KICAR-T cells showed delayed lymphoma dissemination with lower EBV DNA load. Notably, for the Jiyoye/fLuc-GFP model, almost exclusively CD4+ CD19KICAR-T cells were detectable at the endpoint analyses in the bone marrow, with increased frequencies of regulatory T cells (Tregs) and TIM-3+CD4+ T cells. Administration of gp350KICAR-T cells to mice after Jiyoye/GFP-fLuc challenge did not inhibit BL growth in vivo but reduced the EBV DNA load in the bone marrow and promoted gp350 antigen escape. CD8+PD-1+LAG-3+ gp350KICAR-T cells were predominant in the bone marrow.DiscussionThe two types of KOTCRKICAR-T cells showed different therapeutic effects and in vivo dynamics. These findings reflect the complexities of the immune escape mechanisms of EBV, which may interfere with the CAR-T cell property and potency and should be taken into account for future clinical translation.

IntroductionQTc prolongation carries the risk of ventricular tachyarrhythmia (Torsades de Pointes) and sudden cardiac death. Psychotropic drugs can affect ventricular repolarization and thus prolong the QTc interval. The present study sought to investigate the risk factors (pharmacological and non-pharmacological) of severe QTc prolongation in gerontopsychiatric patients.MethodsElectrocardiograms of patients on a gerontopsychiatric ward were screened for QTc prolongation. Medication lists were examined utilizing the AzCERT classification. Potential drug interactions were identified with the electronic drug interaction program mediQ.ResultsThe overall prevalence of QTc prolongation was 13.6%, with 1.9% displaying severe QTc prolongation (≥ 500 ms). No statistically significant differences between patients with moderate and severe QTc prolongation were identified; however, patients with severe QTc prolongation tended to take more drugs (p = 0.063). 92.7% of patients with QTc prolongation took at least one AzCERT-listed drug, most frequently risperidone and pantoprazole. Risperidone and pantoprazole, along with pipamperone, were also most frequently involved in potential drug interactions. All patients displayed additional risk factors for QTc prolongation, particularly cardiac diseases.ConclusionIn addition to the use of potentially QTc-prolonging drugs, other risk factors, especially cardiac diseases, appear to be relevant for the development of QTc prolongation in gerontopsychiatric patients. Pantoprazole was frequently involved in potential drug interactions and should generally not be used for more than 8 weeks in geriatric populations. As clinical consequences of QTc prolongation were rare, potentially QTc-prolonging drugs should not be used overcautiously; their therapeutic benefit should be considered as well. It is paramount to perform diligent benefit–risk analyses prior to the initiation of potentially QTc-prolonging drugs and to closely monitor their clinical (side) effects.

Mammals are imperiled worldwide, primarily from habitat loss or modification, and exhibit downward trends in their populations and distributions. Likewise, large-bodied herbivores have undergone a collapse in numbers and are at the highest extinction risk of all mammals. Bighorn sheep (Ovis canadensis) are among those large-bodied herbivores that possess a slow-paced life history, suffer from debilitating diseases, and have experienced range contractions across their historical distribution since the late 1800s. Translocations and reintroductions of these mountain ungulates are key aspects of restoration and often are used to re-establish populations in historical habitat or to supplement declining herds. Millions of US dollars and much effort by state and federal natural resource agencies, as well as public and private organizations, have been expended to restore bighorn sheep. Despite those efforts, translocated populations of bighorn sheep have not always been successful. We assessed restoration of bighorn sheep to provide insights in the context of conservation of populations of bighorn sheep, because this management tool is a frequently used to re-establish populations. We focused briefly on past efforts to restore bighorn sheep populations and followed with updates on the value of habitat enhancements, genetic issues, the importance of ecotypic or phenotypic adaptations when restoring populations, predation, and disease transmission. We also raised issues and posed questions that have potential to affect future decisions regarding the restoration of bighorn sheep. This information will help conservationists improve the success of conserving these iconic large mammals.

The International Classification of Diseases (10th Version) categorizes major depressive disorder (MDD) according to severity. Guidelines provide recommendations for the treatment of MDD according to severity. Aim of this study was to assess real-life utilization of psychotropic drugs based on severity of MDD in psychiatric inpatients. Drug utilization data from the program “Drug Safety in Psychiatry” (German: Arzneimittelsicherheit in der Psychiatrie, AMSP) were analyzed according to the severity of MDD. From 2001 to 2017, 43,868 psychiatric inpatients with MDD were treated in participating hospitals. Most patients were treated with ≥ 1 antidepressant drug (ADD; 85.8% of patients with moderate MDD, 89.8% of patients with severe MDD, and 87.9% of patients with psychotic MDD). More severely depressed patients were more often treated with selective serotonin–norepinephrine reuptake inhibitors and mirtazapine and less often with selective serotonin reuptake inhibitors (p p p

Evidence suggests that sweetened beverage taxes reduce taxed beverage purchases, but few studies have used individual-level data to assess whether these taxes affect purchases of nontaxed foods, beverages, and alcohol. Additionally, research has not examined whether sweetened beverage taxes influence restaurant purchases.We assessed changes in individuals' purchases of taxed beverage types; low-calorie/low-added-sugar nontaxed beverages; high-calorie/high-added-sugar nontaxed beverages, foods, and alcohol; and beverages from restaurants following implementation of the 1.5 cent-per-ounce Philadelphia sweetened beverage tax.A longitudinal cohort of adult sugar-sweetened beverage consumers in Philadelphia (n = 306; 67% female; mean age: 43.9 years) and Baltimore (n = 297; comparison city without a beverage tax; 58% female; mean age: 41.7 years) submitted all food and beverage receipts during 2-week periods at baseline and at 3, 6, and 12 months posttax. Difference-in-differences analyses compared changes in purchases from pre- to posttax in Philadelphia to changes in Baltimore.Purchases of taxed juice drinks [ratio of incidence rate ratios (RIRR) = 0.62; 95% CI, 0.42-0.91], but not other taxed beverage types, decreased in Philadelphia compared to Baltimore following the tax. Analyses did not find changes in purchases of low-calorie/low-added-sugar nontaxed beverages, such as water or milk. Additionally, analyses did not find increases in purchases of most high-calorie/high-added-sugar nontaxed products, including alcohol, juice, candy, sweet snacks, salty snacks, and desserts. Purchases of beverage concentrates increased in Philadelphia (RIRR = 2.22; 95% CI, 1.39-3.54).In this difference-in-differences analysis, the Philadelphia beverage tax was associated with reduced purchases of taxed juice drinks. Purchases of beverage concentrates increased after the tax, but no increases were observed for other high-calorie/high-added-sugar nontaxed foods, beverages, or alcohol.

To describe policies and practices of online grocery retailers that may affect healthy food access, including retailers participating in the US Department of Agriculture's Supplemental Nutrition Assistance Program Online Purchasing Pilot.Cross-sectional, quantitative content analysis of 21 online grocery retail websites from November 2019 to January 2020.Data collected using a coding instrument capturing the presence of policies and practices related to (1) online purchasing and delivery access; (2) availability of features that allow price comparisons and provide nutrition information; and (3) data privacy.Descriptive statistics for features, practices, and policies across online grocery retail websites.Most retailers (95%) added fees to online orders. Among pilot retailers, 38% added ≥ 3 fees, and 50% required a minimum order$15. Few retailers (29%) displayed Nutrition Facts Labels on all products, including 50% of pilot retailers. All retailers collected personal information from shoppers and automatically shared data with affiliated companies.High fees, limited access to nutrition information on retailer sites, and lack of data privacy are prevalent in online grocery retail settings, including among Online Purchasing Pilot retailers. Online retail practices may perpetuate disparities in healthy food access by discouraging use through fees and making nutritious food choices difficult.

Dear Doctor Letters (DDLs, Direct Healthcare Professional Communications) from 2011 provided guidance regarding QTc-prolonging effects with risk of torsade de pointes during treatment with citalopram and escitalopram. This study examines the DDLs’ effects on prescription behavior. Data from 8842 inpatients treated with citalopram or escitalopram with a primary diagnosis of major depressive disorder (MDD) were derived from a European pharmacovigilance study (Arzneimittelsicherheit in der Psychiatrie, AMSP) from 2001 to 2017. It was examined to what extent new maximum doses were adhered to and newly contraindicated combinations with QTc-prolonging drugs were avoided. In addition, the prescriptions of psychotropic drugs before and after DDLs were compared in all 43,480 inpatients with MDD in the data set. The proportion of patients dosed above the new limit decreased from 8 to 1% in patients ≤ 65 years and from 46 to 23% in patients > 65 years old for citalopram versus 14–5% and 47–31% for escitalopram. Combinations of es-/citalopram with other QTc-prolonging psychotropic drugs reduced only insignificantly (from 35.9 to 30.9%). However, the proportion of patients with doses of quetiapine > 150 mg/day substantially decreased within the combinations of quetiapine and es-/citalopram (from 53 to 35%). After the DDLs, prescription of citalopram decreased and of sertraline increased. The DDLs’ recommendations were not entirely adhered to, particularly in the elderly and concerning combination treatments. This might partly be due to therapeutic requirements of the included population. Official warnings should consider clinical needs.

Media coverage of Muslims has been repeatedly shown to be negative, and attitudes toward Muslims in American society are typically more negative than attitudes toward other social groups. Does the tone of media coverage directly affect public attitudes? This relationship is not well established with respect to Muslims, nor as a proposition about social groups in general. We use an online between-subjects experiment to examine whether exposure to articles of quantifiably different valences about Muslims or Catholics affects reported attitudes toward each of those groups. We find clear support for this proposition. Our additional tests demonstrate that this effect persists but is attenuated when money is at stake. We also identify anxiety as a key mediator between exposure to articles of different valences and attitudes about each group. Our findings suggest that articles of a particular tone can influence views of social groups.

Health monitoring of laboratory rodents not only improves animal health but also enhances the validity of animal experiments. In particular, infections of laboratory animals with murine parvoviruses influence biomedical research data. Despite strict barrier housing, prevalence remains high in animal facilities, leading to increased risk of parvovirus introduction after the import of contaminated mice. Unfortunately, hygienic rederivation can be challenging, since gametes often contain residual virus material. Consequently, the process has to be closely monitored with highly sensitive diagnostic methods to verify parvovirus decontamination of the rederived progeny. However, diagnostic sensitivity of traditional methods is often low and requires testing of large animal cohorts. Therefore, we aimed to develop a powerful quantitative real-time polymerase chain reaction (qPCR) assay for the fast and reliable detection of murine parvoviruses in different sample materials. We validated the assay within an infection experiment and systematically analysed various animal-derived and environmental sample materials. We further developed a strategic risk assessment procedure for parvovirus monitoring after embryo transfer. Our novel qPCR assay reliably detected parvovirus DNA in a broad variety of sample materials, with environmental samples dominating in the acute phase of infection, whereas animal-derived samples were more suitable to detect low virus loads in the chronic phase. Here, the assay served as a highly sensitive screening method for parvovirus contamination in mouse colonies, requiring significantly lower sample sizes than traditional methods like conventional PCR and serology. Thus, the use of our novel qPCR assay substantially improves parvovirus diagnostics, enhancing research validity according to the 6Rs.

Das vorrangige Ziel der Europäischen Zentralbank (EZB) ist die Gewährleistung der Preisniveaustabilität im Euro-Raum. Mit ihren Anleihekäufen seit März 2015 gibt die EZB über lange Zeiträume auch Impulse zur Unterstützung der Wirtschaftspolitik im Euro-Raum und gerät dadurch zunehmend in die öffentliche Diskussion. Dementsprechend hat die EZB ihre Strategie überprüft und ihr geldpolitisches Ziel neu formuliert. In diesem Aufsatz wird die neue geldpolitische Strategie der EZB unter Einbeziehung grundsätzlicher geldpolitischer Konzepte dargestellt.

Contains fulltext : 251266.pdf (Publisher’s version ) (Open Access) Systematic reviews are important tools in animal research, but the ever-increasing number of studies makes retrieval of all relevant publications challenging. Search filters aid in retrieving as many animal studies as possible. In this paper we provide updated and expanded versions of the SYRCLE animal filters for PubMed and Embase. We provide the Embase filter for both Embase.com and via Ovid. Furthermore, we provide new animal search filters for Web of Science (WoS) and APA PsycINFO via psycnet.apa.org and via Ovid. Compared with previous versions, the new filters retrieved 0.5-47.1% (19 references for PubMed, 837 for WoS) more references in a real-life example. All filters retrieved additional references, comprising multiple relevant reviews. A random sample from WoS found at least one potentially relevant primary study. These animal search filters facilitate identifying as many animal studies as possible while minimising the number of non-animal studies.

Objective To investigate the frequency and characteristics of adverse drug reactions (ADRs) that occurred on the gerontopsychiatric ward of Hannover Medical School over a 6-year period. Design Retrospective monocentric cohort study. Results Six hundred thirty-four patient cases (mean age 76.6 ± 7.1 years; 67.2% female) were analysed. In total, 92 ADRs in 56 patient cases were registered in the study population. The overall ADR prevalence, the ADR prevalence upon hospital admission, and the ADR prevalence during hospitalisation were 8.8%, 6.3%, and 4.9%, respectively. The most frequent ADRs were extrapyramidal symptoms, alterations in blood pressure or heart rate, and electrolyte disturbances. Of note, two cases of asystole and one case of obstructive airway symptoms related to general anaesthesia in the context of electroconvulsive therapy (ECT) were detected. The presence of coronary heart disease was associated with an increased risk of ADR occurrence (odds ratio (OR) 2.92, 95% confidence interval (CI) 1.37–6.22), while the presence of dementia was associated with a decreased risk of ADR development (OR 0.45, 95% CI 0.23–0.89). Conclusions Type and prevalence of ADRs in the present study were largely in accordance with previous reports. By contrast, we did not observe a relationship between advanced age or female sex and ADR occurrence. We detected a risk signal for cardiopulmonary ADRs related to general anaesthesia in the context of ECT that warrants further investigation. Elderly psychiatric patients should be carefully screened for cardiopulmonary comorbidities before initiation of ECT.

The fundament of an evidence-based severity assessment in laboratory animal science is reliable distress parameters. Many readouts are used to evaluate and determine animal distress and the severity of experimental procedures. Therefore, we analyzed four distinct parameters like the body weight, burrowing behavior, nesting, and distress score in the four gastrointestinal animal models (pancreatic ductal adenocarcinoma (PDA), pancreatitis, CCl4 intoxication, and bile duct ligation (BDL)). Further, we determined the parameters’ robustness in various experimental subgroups due to slight variations like drug treatment or telemeter implantations. We used non-parametric bootstrapping to get robust estimates and 95% confidence intervals for the experimental groups. It was found that the performance of the readout parameters is model-dependent and that the distress score is prone to experimental variation. On the other hand, we also found that burrowing and nesting can be more robust than, e.g., the body weight when evaluating PDA. However, the body weight still was highly robust in BDL, pancreatitis, and CCl4 intoxication. To address the complex nature of the multi-dimensional severity space, we used the Relative Severity Assessment (RELSA) procedure to combine multiple distress parameters into a score and mapped the subgroups and models against a defined reference set obtained by telemeter implantation. This approach allowed us to compare the severity of individual animals in the experimental subgroups using the maximum achieved severity (RELSAmax). With this, the following order of severity was found for the animal models: CCl4 within and between models, it can be deemed a valuable tool for laboratory animal severity assessment.

Rodent behavior is affected by different environmental conditions. These do not only comprise experimental and housing conditions but also familiarization with the experimenter. However, specific effects on pain-related behavior and chronic pain conditions have not been examined. Therefore, we aimed to investigate the impact of different housing conditions, using individually ventilated and standard open top cages, inverted day-night cycles, and experimenter familiarization on male mice following peripheral neuropathy using the spared nerve injury (SNI) model. Using a multimodal approach, we evaluated evoked pain-related- using von Frey hair filaments, measured gait pattern with the CatWalk system, assessed anxiety- and depression-like behavior with the Elevated plus maze and tail suspension test, measured corticosterone metabolite levels in feces and utilized an integrative approach for relative-severity-assessment. Mechanical sensitivity differed between the cage systems and experimenter familiarization and was affected in both sham and SNI mice. Experimenter familiarization and an inverted day-night cycle reduced mechanical hypersensitivity in SNI and sham mice. SNI mice of the inverted day-night group displayed the slightest pronounced alterations in gait pattern in the Catwalk test. Anxiety-related behavior was only found in SNI mice of experimenter-familiarized mice compared to the sham controls. In addition, familiarization reduced the stress level measured by fecal corticosteroid metabolites caused by the pain and the behavioral tests. Although no environmental condition significantly modulated the severity in SNI mice, it influenced pain-affected phenotypes and is, therefore, crucial for designing and interpreting preclinical pain studies. Moreover, environmental conditions should be considered more in the reporting guidelines, described in more detail, and discussed as a potential influence on pain phenotypes.

Selection of forage and habitats is driven by nutritional needs of individuals. Some species may sacrifice nutritional quality of forage for the mother in favor of safety of offspring (risk-averse strategy), immediately following parturition. We studied diet quality and forage selection by bighorn sheep before and following parturition to determine how nutritional demands associated with rearing offspring influenced forage acquisition. We used desert bighorn sheep, Ovis canadensis nelsoni, to investigate that potential tradeoff. We captured and radio-collared female bighorn sheep from 2016 to 2018. We used vaginal implant transmitters (VIT)s in pregnant females to identify parturition and to capture and radio-collar neonates to monitor survival of young. We collected fecal samples throughout the breeding season and throughout the year to understand diet quality and composition throughout those temporal periods. We determined diet quality and composition for pre-parturient females, females provisioning offspring, females that lost offspring, and non-pregnant individuals using fecal nitrogen and DNA metabarcoding analyses. Additionally, we compared the diet quality and composition of offspring and adult females during the spring, as well as summer and winter months. Our results indicated differences in diet quality between individuals provisioning offspring and those whose offspring had died. Females that were provisioning dependent young had lower quality diets than those that lost their offspring. Diet composition among those groups was also markedly different; females that had lost an offspring had a more diverse diet than did females with dependent young. Diet quality differed among seasons, wherein offspring and adult females had higher quality diets during the spring months, with decreasing quality as the year progressed. Diet diversity was similar across seasons, although spring months tended to be most diverse. Our results support tradeoffs associated with risk-averse strategies made by adult females associated with parturition. Nutritional quality of forage was linked to provisioning status, indicating that females were trading diet quality for safety of offspring, but those females whose offspring had died selected high quality forages. Those results help explain habitat selection observed in mountain ungulates around parturition and provide further insight into the evolutionary processes and adaptive significance exhibited by those specialized artiodactyls.

Objective Geriatric patients account for a significant proportion of the collective treated by psychiatric consultation service in hospitals. In the Emergency Department (ED), psychotropic drugs are frequently recommended, notwithstanding their extensive side-effect profiles. This study sought to investigate medication safety of geriatric patients referred to psychiatric consultation service in the ED. Methods Medication lists of 60 patients from the general internal medicine and trauma surgery EDs referred to psychiatric consultation service were analyzed. Utilizing PRISCUS list and Fit fOR The Aged (FORTA) classification, prescriptions of potentially inappropriate medications (PIMs) were assessed. Results 84 drugs were newly prescribed following psychiatric consultations. The total number of drugs per patient was 5.4 ± 4.2 before psychiatric consultation and 6.5 ± 4.2 thereafter ( p < .001). 22.6 % of the newly recommended drugs were PIMs according to the PRISCUS list, while 54.8 % were designated as therapeutic alternatives to PIMs. 54.8 % and 20.2 % of the newly recommended drugs were FORTA category C and D drugs, respectively. An average of 1.2 ± 1.7 drug–drug interactions (DDIs) existed before psychiatric consultation and 1.3 ± 1.9 DDIs thereafter ( p = .08). Conclusion The majority of newly recommended drugs by psychiatric consultation service in the ED were designated as suitable therapeutic alternatives to PIMs according to the PRISCUS list, but had comparatively unfavorable ratings according to the FORTA classification, demonstrating discrepancies between these two PIM classification systems. Physicians delivering psychiatric consultation services in the ED should not solely rely on one PIM classification system.