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Aging coincides with the progressive loss of muscle mass and strength, increased adiposity, and diminished physical function. Accordingly, interventions aimed at improving muscle, metabolic, and/or physical health are of interest to mitigate the adverse effects of aging. In this study, we tested a stem cell secretome product, which contains extracellular vesicles and growth, cytoskeletal remodeling, and immunomodulatory factors. We examined the effects of 4 weeks of 2×/week unilateral intramuscular secretome injections (quadriceps) in ambulatory aged male C57BL/6 mice (22-24 months) compared to saline-injected aged-matched controls. Secretome delivery substantially increased whole-body lean mass and decreased fat mass, corresponding to higher myofiber cross-sectional area and smaller adipocyte size, respectively. Secretome-treated mice also had greater whole-body physical function (grip strength and rotarod performance) and had higher energy expenditure and physical activity levels compared to control mice. Furthermore, secretome-treated mice had greater skeletal muscle Pax7+ cell abundance, capillary density, collagen IV turnover, reduced intramuscular lipids, and greater Akt and hormone sensitive lipase phosphorylation in adipose tissue. Finally, secretome treatment in vitro directly enhanced muscle cell growth and IL-6 production, and in adipocytes, it reduced lipid content and improved insulin sensitivity. Moreover, indirect treatment with secretome-treated myotube culture media also enhanced muscle cell growth and adipocyte size reduction. Together, these data suggest that intramuscular treatment with a stem cell secretome improves whole-body metabolism, physical function, and remodels skeletal muscle and adipose tissue in aged mice.

Exercise has beneficial effects on cognition throughout the lifespan. Here, we demonstrate that specific exercise patterns transform insufficient, subthreshold training into long-term memory in mice. Our findings reveal a potential molecular memory window such that subthreshold training within this window enables long-term memory formation. We performed RNA-seq on dorsal hippocampus and identify genes whose expression correlate with conditions in which exercise enables long-term memory formation. Among these genes we found Acvr1c, a member of the TGF ß family. We find that exercise, in any amount, alleviates epigenetic repression at the Acvr1c promoter during consolidation. Additionally, we find that ACVR1C can bidirectionally regulate synaptic plasticity and long-term memory in mice. Furthermore, Acvr1c expression is impaired in the aging human and mouse brain, as well as in the 5xFAD mouse model, and over-expression of Acvr1c enables learning and facilitates plasticity in mice. These data suggest that promoting ACVR1C may protect against cognitive impairment.

DNA damage is a central contributor to the aging process. In the brain, a major threat to the DNA is the considerable amount of reactive oxygen species produced, which can inflict oxidative DNA damage. This type of damage is removed by the base excision repair (BER) pathway, an essential DNA repair mechanism, which contributes to genome stability in the brain. Despite the crucial role of the BER pathway, insights into how this pathway is affected by aging in the human brain and the underlying regulatory mechanisms are very limited. By microarray analysis of four cortical brain regions from humans aged 20-99 years (n = 57), we show that the expression of core BER genes is largely downregulated during aging across brain regions. Moreover, we find that expression of many BER genes correlates positively with the expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in the human brain. In line with this, we identify binding sites for the BDNF-activated transcription factor, cyclic-AMP response element-binding protein (CREB), in the promoter of most BER genes and confirm the ability of BDNF to regulate several BER genes by BDNF treatment of mouse primary hippocampal neurons. Together, these findings uncover the transcriptional landscape of BER genes during aging of the brain and suggest BDNF as an important regulator of BER in the human brain.

Abstract Exercise has beneficial effects on cognition throughout the lifespan. Here, we demonstrate that specific exercise patterns transform insufficient, subthreshold training into long-term memory in mice. Our findings reveal a potential molecular memory window such that subthreshold training within this window enables long-term memory formation. We performed RNA-seq on dorsal hippocampus and identify genes whose expression correlate with conditions in which exercise enables long-term memory formation. Among these genes we found Acvr1c, a member of the TGF ß family. We find that exercise, in any amount, alleviates epigenetic repression at the Acvr1c promoter during consolidation. Additionally, we find that ACVR1C can bidirectionally regulate synaptic plasticity and long-term memory in mice. Furthermore, Acvr1c expression is impaired in the aging human and mouse brain, as well as in the 5xFAD mouse model, and over-expression of Acvr1c enables learning and facilitates plasticity in mice. These data suggest that promoting ACVR1C may protect against cognitive impairment.

Using secondary data has many advantages, but there are also many limitations, including the lack of relevant information. This article draws on a previous study that used secondary data to investigate substance use in young, elite athletes. Three types of missing data appeared: missing data, lack of information about the data collection process, and unavailable data. Other concerns were also highlighted, such as coverage and sampling errors. The impacts of secondary data on scientific research results can be divided into unavoidable changes and researchers' choices. The research question should guide the option to use secondary data, and it is essential to assess the level of constraint that will result from it early on. Additionally, along with the quality of information available, consistency in questionnaires is vital for broadening the scope and ensuring research progress.

This article summarizes the methodology for the identification of practitioners’ challenges, in the context of the H2020 funded project FIRE-IN (Fire and Rescue Innovation Network) activities. The project consisted of five thematic areas or “Thematic Working Groups”, as they are called, i.e., Search and Rescue Emergency Response, Structure Fires, Landscape Fires Crisis Mitigation, Natural Hazard Mitigation and Chemical Biological Radiological Nuclear and Explosives, and three iterations, each one including the identification of capability challenges, the screening for solutions, that can potentially address these challenges, and the request for ideas regarding future innovations that will complement already existing ones and will assist in covering capability gaps. This article focuses on the natural hazard mitigation working group and tsunamis in the Mediterranean region as a case study for the 3rd and last iteration of the project. The scenario of a tsunami occurrence in the Mediterranean is the basis for the FIRE-IN 3rd cycle workshop, as an indicative example of a high impact – low probability event, which aims to identify practitioners’ Future Common Capability Challenges in Europe. The current status of the tsunami hazard in Europe, national and international tsunami risk mitigation measures and procedures and operational experience from recent events are also discussed. Focus is provided on the natural hazard mitigation and tsunami related practitioners’ challenges, while results from the FIRE-IN request for ideas process and the interaction between practitioners, researchers and industry are also discussed. The aim is to present practitioners’ current and future capability challenges , one of the main outcomes of the FIRE-IN project, and to provide further guidelines to stakeholders of disaster management towards a safer Europe, mainly, through preparedness and adaptation for stronger and resilient societies.

IgG4 subclass antibodies represent the rarest subclass of IgG antibodies, comprising only 3-5% of antibodies circulating in the bloodstream. These antibodies possess unique structural features, notably their ability to undergo a process known as fragment-antigen binding (Fab)-arm exchange, wherein they exchange half-molecules with other IgG4 antibodies. Functionally, IgG4 antibodies primarily block and exert immunomodulatory effects, particularly in the context of IgE isotype-mediated hypersensitivity reactions. In the context of disease, IgG4 antibodies are prominently observed in various autoimmune diseases combined under the term IgG4 autoimmune diseases (IgG4-AID). These diseases include myasthenia gravis (MG) with autoantibodies against muscle-specific tyrosine kinase (MuSK), nodo-paranodopathies with autoantibodies against paranodal and nodal proteins, pemphigus vulgaris and foliaceus with antibodies against desmoglein and encephalitis with antibodies against LGI1/CASPR2. Additionally, IgG4 antibodies are a prominent feature in the rare entity of IgG4 related disease (IgG4-RD). Intriguingly, both IgG4-AID and IgG4-RD demonstrate a remarkable responsiveness to anti-CD20-mediated B cell depletion therapy (BCDT), suggesting shared underlying immunopathologies. This review aims to provide a comprehensive exploration of B cells, antibody subclasses, and their general properties before examining the distinctive characteristics of IgG4 subclass antibodies in the context of health, IgG4-AID and IgG4-RD. Furthermore, we will examine potential therapeutic strategies for these conditions, with a special focus on leveraging insights gained from anti-CD20-mediated BCDT. Through this analysis, we aim to enhance our understanding of the pathogenesis of IgG4-mediated diseases and identify promising possibilities for targeted therapeutic intervention.

Abstract Intraoperative radiation therapy (IORT) is a radiation technique applying a single fraction with a high dose during surgery. We report the first abdomino-pelvic application of an image-guided intraoperative electron radiation therapy with intraoperative real time dose calculation based on the individual intraoperative patient anatomy. A patient suffering from locoregionally recurrent rectal cancer after treatment with neoadjuvant re-chemoradiation was chosen for this approach. After surgical removal of the recurrence, an adequate IORT applicator was placed as usual. A novel mobile imaging device (ImagingRing, MedPhoton) was positioned around the patient covering the region to be treated with the IORT-applicator in place. It allowed the acquisition of three-dimensional intraoperative cone-beam computed tomography images suitable for dose calculation using an automated scaling (heuristic object and head scatter as well as hardening corrections) of Hounsfield units. After image acquisition confirmed the correct applicator position, the images were transferred to our treatment planning system for intraoperative dose calculation. Treatment could be accomplished using the calculated dose distribution. We herein describe the details of the procedure including necessary adjustments in the typically used IORT equipment and work flow. We further discuss the pros and cons of this new approach generally overcoming a decade long limitation of IORT procedures as well as future perspectives regarding IORT treatments.

Histone modifications are key contributors to the cognitive decline that occurs in aging and Alzheimer's disease. Our lab has previously shown that elevated H3K9me3 in aged mice is correlated with synaptic loss, cognitive impairment and a reduction in brain derived neurotrophic factor (BDNF). However, the mechanism of H3K9me3 regulation remains poorly understood. In this study, we investigated the role of age-associated stressors on H3K9me3 regulation and examined if changes in H3K9me3 were age dependent. We used cultured hippocampal neurons at 6, 12, and 21 days in vitro (DIV) to examine the effect of different stressors on H3K9me3 across neuron ages. We found that the oxidative stressor hydrogen peroxide (H2O2) does not induce H3K9me3 in 12 DIV neurons. Inhibiting BDNF signaling via TrkB-Fc elevated H3K9me3 in 12 and 21 DIV neurons compared to 6 DIV neurons. Antioxidant treatment prevented H3K9me3 elevation in 12 DIV neurons treated with TrkB-Fc and H2O2. H2O2 elevated the epigenetic regulator SIRT1 in 6 DIV neurons but did not increase H3K9me3 levels. Our findings demonstrate that inhibiting BDNF signaling elevates hippocampal H3K9me3 in a manner dependent on in vitro age and oxidative stress.

NUT (nuclear-protein-in-testis) carcinoma (NC) is a highly aggressive tumor disease. Given that current treatment regimens offer a median survival of six months only, it is likely that this type of tumor requires an extended multimodal treatment approach to improve prognosis. In an earlier case report, we could show that an oncolytic herpes simplex virus (T-VEC) is functional in NC patients. To identify further combination partners for T-VEC, we have investigated the anti-tumoral effects of T-VEC and five different small molecule inhibitors (SMIs) alone and in combination in human NC cell lines. Dual combinations were found to result in higher rates of tumor cell reductions when compared to the respective monotherapy as demonstrated by viability assays and real-time tumor cell growth monitoring. Interestingly, we found that the combination of T-VEC with SMIs resulted in both stronger and earlier reductions in the expression of c-Myc, a main driver of NC cell proliferation, when compared to T-VEC monotherapy. These results indicate the great potential of combinatorial therapies using oncolytic viruses and SMIs to control the highly aggressive behavior of NC cancers and probably will pave the way for innovative multimodal clinical studies in the near future.

Background: There is a gap in the literature regarding data on sexting among youth under the age of 16 whereas the problems related to this practice could affect them more because of their ongoing development. This study aims to determine the prevalence rate and characteristics of sending one's own sexually related image among middle-school teens. Methods: Data were obtained from a web-based in-school survey conducted between October 2019 and February 2020. The sample comprised 3006 (mean age 13.7; 50.2% males) 10th-grade pupils in the canton of Vaud (Switzerland). Participants were asked "Have you ever sent a sexually related/sexy image of yourself?". Analysis of variance/chi-square tests and multinomial regression analyses were used to compare the groups. Results: Overall, 93.0% reported never, 3.7% once and 3.3% several times. No gender differences were found. Sending was associated with older age, low academic performance, cyberbullying victimization and reception of unsolicited sexually related images. Conclusions: Education and health professionals should be aware that it is necessary to discuss the theme, perhaps with a more global approach including pressure, consent, exchange of nonsexual images, and so on from an early age. The context and reasons for sending remain to be explored, particularly to determine if the pressure is greater at this age.

Surgery plays a central role in the treatment of benign and malignant pancreatic diseases. Artificial intelligence (AI) is an important upcoming technology to support surgeons in pre-, intra-, and postoperative diagnosis, decision-making and training toward an optimized patient care. Current AI applications show a promising role in the evaluation of preoperative images for prediction of malignancy and resectability, intraoperative decision support, surgical training as well as a postoperative risk stratification to personalize the management of complications. This scoping review summarizes the most up to date developments of AI in pancreatic surgery with the highest available level of evidence.

Exercise improves cognition in the aging brain and is a key regulator of neuronal plasticity genes such as BDNF. However, the mechanism by which exercise modifies gene expression continues to be explored. The repressive histone modification H3K9me3 has been shown to impair cognition, reduce synaptic density and decrease BDNF in aged but not young mice. Treatment with ETP69, a selective inhibitor of H3K9me3's catalyzing enzyme (SUV39H1), restores synapses, BDNF and cognitive performance. GABA receptor expression, which modulates BDNF secretion, is also modulated by exercise and H3K9me3. In this study, we examined if exercise and ETP69 regulated neuronal plasticity genes by reducing H3K9me3 at their promoter regions. We further determined the effect of age on H3K9me3 promoter binding and neuronal plasticity gene expression. Exercise and ETP69 decreased H3K9me3 at BDNF promoter VI in aged mice, corresponding with an increase in BDNF VI expression with ETP69. Exercise increased GABRA2 in aged mice while increasing BDNF 1 in young mice, and both exercise and ETP69 reduced GABRA2 in young mice. Overall, H3K9me3 repression at BDNF and GABA receptor promoters decreased with age. Our findings suggest that exercise and SUV39H1 inhibition differentially modulate BDNF and GABRA2 expression in an age dependent manner.

During the SARS-CoV-2 pandemic, the Dr. Risch medical group employed the multiplex TaqPathTM COVID-19 CE-IVD RT-PCR Kit for large-scale routine diagnostic testing in Switzerland and the principality of Liechtenstein. The TaqPath Kit is a widely used multiplex assay targeting three genes (i.e., ORF1AB, N, S). With emergence of the B.1.1.7 (Alpha) variant, a diagnostic flaw became apparent as the amplification of the S-gene target was absent in these samples due to a deletion (ΔH69/V70) in the Alpha variant genome. This S-gene target failure (SGTF) was the earliest indication of a new variant emerging and was also observed in subsequent variants such as Omicron BA.1 and BA4/BA.5. The Delta variant and Omicron BA.2 did not present with SGTF. From September 2020 to November 2022, we investigated the applicability of the SGTF as a surrogate marker for emerging variants such as B.1.1.7, B.1.617.2 (Delta), and Omicron BA.1, BA.2, and BA.4/BA.5 in samples with cycle threshold (Ct) values < 30. Next to true SGTF-positive and SGTF-negative samples, there were also samples presenting with delayed-type S-gene amplification (higher Ct value for S-gene than ORF1ab gene). Among these, a difference of 3.8 Ct values between the S- and ORF1ab genes was found to best distinguish between “true” SGTF and the cycle threshold variability of the assay. Samples above the cutoff were subsequently termed partial SGTF (pSGTF). Variant confirmation was performed by whole-genome sequencing (Oxford Nanopore Technology, Oxford, UK) or mutation-specific PCR (TIB MOLBIOL). In total, 17,724 (7.4%) samples among 240,896 positives were variant-confirmed, resulting in an overall sensitivity and specificity of 93.2% [92.7%, 93.7%] and 99.3% [99.2%, 99.5%], respectively. Sensitivity was increased to 98.2% [97.9% to 98.4%] and specificity lowered to 98.9% [98.6% to 99.1%] when samples with pSGTF were included. Furthermore, weekly logistic growth rates (α) and sigmoid’s midpoint (t0) were calculated based on SGTF data and did not significantly differ from calculations based on comprehensive data from GISAID. The SGTF therefore allowed for a valid real-time estimate for the introduction of all dominant variants in Switzerland and Liechtenstein.

Neuroendocrine neoplasms represent a heterogenous group of rare tumors whose current therapeutic options show only limited efficacy. Oncolytic viruses exert their mode of action through (onco-)lysis of infected tumor cells and the induction of a systemic antitumoral immune response in a virus-induced inflammatory micromilieu. Here, we investigated the potential of our well-established second-generation suicide-gene armed oncolytic measles vaccine virus (MeV-SCD) in five human NEN cell lines. First, (i) expression of the MeV receptor CD46 and (ii) its correlation with primary infection rates were analyzed. Next, (iii) promising combination partners for MeV-SCD were tested by employing either the prodrug 5-fluorocytosine, which is converted into the chemotherapeutic compound 5-fluorouracil, or the mTOR-inhibitor everolimus. As a result, MeV-SCD was found to kill all NEN tumor cell lines efficiently in a dose-dependent manner. This oncolytic effect was further enhanced by exploiting the prodrug-converting system, which was found to be highly instrumental in overcoming the partial resistance found in a single NEN cell line. Furthermore, viral replication was unaffected by everolimus, which is a basic requirement for combined use in NEN patients. These data suggest that MeV-SCD has profound potential for patients with NEN, thus paving the way for early clinical trials.

Effective treatment options for peritoneal surface malignancies (PSMs) are scarce. Oncolytic virotherapy with recombinant vaccinia viruses might constitute a novel treatment option for PSM. We aimed to identify the most effective oncolytic vaccinia virus strain in two murine mesothelioma cell lines and the oncolytic potential in a murine model of peritoneal mesothelioma. Cell lines AB12 and AC29 were infected in vitro with vaccinia virus strains Lister (GLV-1h254), Western Reserve (GLV-0b347), and Copenhagen (GLV-4h463). The virus strain GLV-0b347 was shown most effective in vitro and was further investigated by intraperitoneal (i.p.) application to AB12 and AC29 mesothelioma-bearing mice. Feasibility, safety, and effectiveness of virotherapy were assessed by evaluating the peritoneal cancer index (PCI), virus detection in tumor tissues and ascites, virus growth curves, and comparison of overall survival. After i.p. injection of GLV-0b347, virus was detected in both tumor cells and ascites. In comparison to mock-treated mice, overall survival was significantly prolonged, ascites was less frequent and PCI values declined. However, effective treatment was only observed in animals with limited tumor burden at the time point of virus application. Nonetheless, intraperitoneal virotherapy with GLV-0b347 might constitute a novel therapeutic option for the treatment of peritoneal mesothelioma. Additional treatment modifications and combinational regimes will be investigated to further enhance treatment efficacy.

This article summarizes the methodology for the identification of practitioners’ challenges of the H2020 funded project FIRE-IN (Fire and Rescue Innovation Network) activities with a strong focus on the natural hazard mitigation working group and tsunamis in the Mediterranean region as a case study for the 3rd cycle. The scenario of a tsunami occurrence in the Mediterranean is the basis for the FIRE-IN 3rd cycle workshop, as an indicative example of a high impact – low probability event, which aims to identify the Future Common Capability Challenges of practitioners in Europe. The current status of the tsunami hazard in Europe, national and international tsunami risk mitigation measures and procedures and operational experience from recent events are also discussed. Focus is provided on the natural hazard mitigation and tsunami related practitioners’ challenges, while results from the FIRE-IN request for ideas process and the interaction between practitioners, researchers and industry is also discussed. The aim is to present the current and future capability challenges of practitioners, one of the main outcomes of FIRE-IN project, and to provide further guidelines to stakeholders of disaster management towards a safer Europe, mainly, through preparedness for stronger and resilient societies.

Introduction Portal vein obstruction (PVO) consists of anastomotic stenosis and thrombosis, which occurs due to a progression of the former. The aim of this large-scale international study is to assess the prevalence, current management practices and efficacy of treatment in patients with PVO.Methods and analysis The Portal vein Obstruction Revascularisation Therapy After Liver transplantation registry will facilitate an international, retrospective, multicentre, observational study, with 25 centres around the world already actively involved. Paediatric patients (aged

The beneficial effects of exercise on cognition are well established; however specific exercise parameters regarding the frequency and duration of physical activity that provide optimal cognitive health have not been well defined. Here, we explore the effects of the duration of exercise and sedentary periods on long-term object location memory (OLM) in mice. We use a weak object location training paradigm that is subthreshold for long-term memory formation in sedentary controls, and demonstrate that exercise enables long-term memories to form. We show that 14- and 21-d of running wheel access enables mice to discriminate between familiar and novel object locations after a 24 h delay, while 2- or 7-d running wheel access provides insufficient exercise for such memory enhancement using the subthreshold learning paradigm. After 14- and 21-d of wheel running, exercise-induced cognitive enhancement then decays back to baseline performance following 3-d of sedentary activity. However, exercise-induced cognitive enhancement can be reactivated by an additional period of just 2 d exercise, previously shown to be insufficient to induce cognitive enhancement on its own. The reactivating period of exercise is capable of enhancing memory after three- or seven-sedentary days, but not 14-d. These data suggest a type of "molecular memory" for the exercise stimulus, in that once exercise duration reaches a certain threshold, it establishes a temporal window during which subsequent low-level exercise can capitalize on the neurobiological adaptations induced by the initial period of exercise, enabling it to maintain the benefits on cognitive function. These findings provide new information that may help to guide future clinical studies in exercise.

Abstract Background Persistent pain and disability following rib fractures result in a large psycho-socio-economic impact for health-care system. Benefits of rib osteosynthesis are well documented in patients with flail chest that necessitates invasive ventilation. In patients with uncomplicated and simple rib fractures, indication for rib osteosynthesis is not clear. The aim of this trial is to compare pain at 2 months after rib osteosynthesis versus medical therapy. Methods This trial is a pragmatic multicenter, randomized, superiority, controlled, two-arm, not-blinded, trial that compares pain evolution between rib fixation and standard pain medication versus standard pain medication alone in patients with uncomplicated rib fractures. The study takes place in three hospitals of Thoracic Surgery of Western Switzerland. Primary outcome is pain measured by the brief pain inventory (BPI) questionnaire at 2 months post-surgery. The study includes follow-up assessments at 1, 2, 3, 6, and 12 months after discharge. To be able to detect at least 2 point-difference on the BPI between both groups (standard deviation 2) with 90% power and two-sided 5% type I error, 46 patients per group are required. Adjusting for 10% drop-outs leads to 51 patients per group. Discussion Uncomplicated rib fractures have a significant medico-economic impact. Surgical treatment with rib fixation could result in better clinical recovery of patients with uncomplicated rib fractures. These improved outcomes could include less acute and chronic pain, improved pulmonary function and quality of life, and shorter return to work. Finally, surgical treatment could then result in less financial costs. Trial registration ClinicalTrials.gov NCT04745520 . Registered on 8 February 2021.

BACKGROUND: Under-detection and under-reporting of child abuse remains a considerable challenge in paediatric care, with a high number of cases missed each year in Switzerland and abroad. Published data regarding the obstacles and facilitators of detecting and reporting child maltreatment among paediatric nursing and medical staff in the paediatric emergency department (PED) are scarce. Despite the existence of international guidelines, the measures taken to counteract the incomplete detection of harm done to children in paediatric care are insufficient. AIM: We sought to examine up-to-date obstacles and enablers for detecting and reporting child abuse among nursing and medical staff in PED and paediatric surgery departments in Switzerland. METHODS: We surveyed 421 nurses and physicians working in PEDs and on paediatric surgical wards in six large Swiss paediatric hospitals using an online questionnaire between February 1, 2017, and August 31, 2017. RESULTS: The survey was returned by 261/421 (62.0%) respondents (complete n = 200, 76.6%; incomplete n = 61, 23.3%) with a preponderance of nurses (n = 150/261; 57.5%), 106/261 (40.6%) physicians, and 1/261 (0.4%) psychologists (n = 4/261; 1.5% missing profession). The stated obstacles to reporting child abuse were uncertainty about the diagnosis (n = 58/80; 72.5%), feeling unaccountable for notification (n = 28/80; 35%), uncertainty of whether reporting has any consequences (n = 5/80; 6.25%), lack of time (n = 4/80; 5%), forgetting to report (n = 2/80; 2.5%), and parental protection (n = 2/80; 2.5%) (unspecific answer, n = 4/80; 5%, multiple answers were possible, therefore items don not sum up to 100%). Even though most (n = 249/261 95.4%) respondents had previously been confronted with child abuse at/outside work, only 185/245 (75.5%) reported cases; significantly fewer nursing (n = 100/143, 69.9%) than medical staff (n = 83/99, 83.8%) (p = 0.013). Furthermore, significantly more nursing (n = 27/33; 81.8%) than medical staff (n = 6/33; 18.2%) (p = 0.005) reported a discrepancy between the number of suspected and reported cases (total 33/245 (13.5%). An overwhelming amount of participants were strongly interested in mandatory child abuse training (n= 226/242, 93.4%) and in the availability of standardised patient questionnaires and documentation forms (n = 185/243, 76.1%). CONCLUSION: In line with previous studies, insufficient knowledge about and lack of confidence in detecting the signs and symptoms of child abuse were the principal obstacles to reporting maltreatment. To finally address this unacceptable gap in child abuse detection, we recommend the implementation of mandatory child protection education in all countries where no such education has been implemented in addition to the introduction of cognitive aid tools and validated screening tools to increase child abuse detection rates and ultimately prevent further harm to children.

Members of the Regulator of G-protein signaling (Rgs) family regulate the extent and timing of G protein signaling by increasing the GTPase activity of Gα protein subunits. The Rgs family member Rgs1 is one of the most up-regulated genes in tissue-resident memory (TRM) T cells when compared to their circulating T cell counterparts. Functionally, Rgs1 preferentially deactivates Gαq, and Gαi protein subunits and can therefore also attenuate chemokine receptor-mediated immune cell trafficking. The impact of Rgs1 expression on tissue-resident T cell generation, their maintenance, and the immunosurveillance of barrier tissues, however, is only incompletely understood. Here we report that Rgs1 expression is readily induced in naïve OT-I T cells in vivo following intestinal infection with Listeria monocytogenes-OVA. In bone marrow chimeras, Rgs1-/- and Rgs1+/+ T cells were generally present in comparable frequencies in distinct T cell subsets of the intestinal mucosa, mesenteric lymph nodes, and spleen. After intestinal infection with Listeria monocytogenes-OVA, however, OT-I Rgs1+/+ T cells outnumbered the co-transferred OT-I Rgs1-/- T cells in the small intestinal mucosa already early after infection. The underrepresentation of the OT-I Rgs1-/- T cells persisted to become even more pronounced during the memory phase (d30 post-infection). Remarkably, upon intestinal reinfection, mice with intestinal OT-I Rgs1+/+ TRM cells were able to prevent the systemic dissemination of the pathogen more efficiently than those with OT-I Rgs1-/- TRM cells. While the underlying mechanisms are not fully elucidated yet, these data thus identify Rgs1 as a critical regulator for the generation and maintenance of tissue-resident CD8+ T cells as a prerequisite for efficient local immunosurveillance in barrier tissues in case of reinfections with potential pathogens.

T cell-based immunotherapy has significantly improved treatment options for many malignancies. However, despite these and other therapeutic improvements over the last decades, gastrointestinal cancers, in particular pancreatic, hepatic and gastric cancer, are still characterized by high relapse rates and dismal prognosis, with an accordingly high unmet medical need for novel treatment strategies. We here report on the preclinical characterization of a novel bispecific antibody in an IgG-based format termed CC-3 with B7-H3xCD3 specificity. In many cancer entities including pancreatic, hepatic and gastric cancers, B7-H3 (CD276) is overexpressed on tumor cells and also on the tumor vasculature, the latter allowing for improved access of immune effector cells into the tumor site upon therapeutic targeting. We demonstrate that CC-3 induces profound T cell reactivity against various pancreatic, hepatic and gastric cancer cell lines as revealed by analysis of activation, degranulation and secretion of IL2, IFNγ as well as perforin, resulting in potent target cell lysis. Moreover, CC-3 induced efficient T cell proliferation and formation of T cell memory subsets. Together, our results emphasize the potential of CC-3, which is presently being GMP-produced to enable clinical evaluation for treatment of pancreatic, hepatic and gastric cancer.

BackgroundThe Heartmate 3 (HM 3) is a left ventricular assist device featuring less shear stress, milder acquired von Willebrand syndrome, and fewer bleeding incidences than its predecessor the Heartmate II (HM II). The novel surface coating of the HM 3 suggests less contact activation of plasmatic coagulation. We hypothesized that patients with HM 3 exhibit fewer aberrations in their thrombin potential than patients with HM II. We compared these results with the thrombin potential of patients with heart transplantation (HTX).MethodsThrombin generation in plasma samples of patients with HM II (n = 16), HM 3 (n = 20), and HTX (n = 13) was analyzed 3 days after implantation/transplantation and after long-term support (3–24 months) with HM II (n = 16) or HM 3 (n = 12) using calibrated automated thrombography. Heparin in postoperative samples was antagonized with polybrene.ResultsThree days postoperatively HM II patients exhibited a lower endogenous thrombin potential (ETP) than HM 3 and HTX patients (HM II: 947 ± 291 nM*min; HM 3: 1231 ± 176 nM*min; HTX: 1376 ± 162 nM*min, p

Exercise has emerged as a powerful variable that can improve cognitive function and delay age-associated cognitive decline and Alzheimer's disease (AD); however, the underlying mechanisms are poorly understood. To determine if protective mechanisms may occur at the transcriptional level, we used microarrays to investigate the relationship between physical activity levels and gene expression patterns in the cognitively intact aged human hippocampus. In parallel, hippocampal gene expression patterns associated with aging and AD were assessed using publicly available microarray data profiling hippocampus from young (20-59 years), cognitively intact aging (73-95 years) and age-matched AD cases. To identify "anti-aging/AD" transcription patterns associated with physical activity, probesets significantly associated with both physical activity and aging/AD were identified and their directions of expression change in each condition were compared. Remarkably, of the 2210 probesets significant in both data sets, nearly 95% showed opposite transcription patterns with physical activity compared with aging/AD. The majority (>70%) of these anti-aging/AD genes showed increased expression with physical activity and decreased expression in aging/AD. Enrichment analysis of the anti-aging/AD genes showing increased expression in association with physical activity revealed strong overrepresentation of mitochondrial energy production and synaptic function, along with axonal function and myelin integrity. Synaptic genes were notably enriched for synaptic vesicle priming, release and recycling, glutamate and GABA signaling, and spine plasticity. Anti-aging/AD genes showing decreased expression in association with physical activity were enriched for transcription-related function (notably negative regulation of transcription). These data reveal that physical activity is associated with a more youthful profile in the hippocampus across multiple biological processes, providing a potential molecular foundation for how physical activity can delay age- and AD-related decline of hippocampal function.

Here, Tan et al. find that the rapid spread of SARS-CoV-2 in mink and deer required minimal adaptation, has only caused moderate changes to the evolutionary trajectory of the virus, and has not led to viral mutations that greatly improve human transmission thus far.

Abstract Introduction Increasingly, literature has focused on community participation in places visited by persons living with and without dementia. Earlier research indicates that multiple factors, including socio-demographic aspects and risk perception may influence community participation. Aim and methods This cross-sectional, explorative study aims to inquire into how places visited, socio-demographic aspects and risks perception are associated with self-rated community participation for persons living with and without dementia (n = 70) in Switzerland. Data was collected through face-to-face interviews with questionnaires (ACT-OUT, MoCA, sociodemographic). First, we investigated whether the number of places visited was correlated with self-rated participation; then we added socio-demographic and risks perception factors with a bivariate analysis; and searched for a model using multinomial logistic regressions. Results For the group of participants living with dementia, risks of falling (p = .014) and of getting lost (p = .037) were significantly associated with self-rated participation. For the group of participants living without dementia, visiting places outside the home was significantly associated with self-rated participation, especially visiting places in domain D/places for recreational and physical activities (p = .005). Discussion and conclusions The results of exploring multiple factors and searching for a model highlights the complexity of community participation as a construct. Risks and visiting places for recreational and physical activities seem to play a role in self-rated participation. Mobile interviews might be better suited to gain in-depth understanding on community participation for persons living with dementia.

BackgroundSince 2003, the government of Ethiopia has trained and deployed more than 42,000 Health Extension Workers across the country to provide primary healthcare services. However, no research has assessed the return on investments into human resources for health in this setting. This study aims to fill this gap by analyzing the return on investment within the context of the Ethiopian Health Extension Program.MethodsWe collected data on associated costs and benefits attributed to the Health Extension Program from primary and secondary sources. Primary sources included patient exit interviews, surveys with Health Extension Workers and other health professionals, key informant interviews, and focus groups conducted in the following regions: Amhara, Oromia, Tigray, and the Southern Nations Nationalities and Peoples' Region. Secondary sources consisted of financial and administrative reports gathered from the Ministry of Health and its subsidiaries, as well as data accessed through the Lives Saved Tool. A long-run return on investment analysis was conducted considering program costs (personnel, recurrent, and capital investments) in comparison to benefits gained through improved productivity, equity, empowerment, and employment.FindingsBetween 2008-2017, Health Extension Workers saved 50,700 maternal and child lives. Much of the benefits were accrued by low income, less educated, and rural women who had limited access to services at higher level health centers and hospitals. Regional return ranged from $1.27 to $6.64, with an overall return on investment in the range of $1.59 to $3.71.ConclusionWhile evidence of return on investments are limited, results from the Health Extension Program in Ethiopia show promise for similar large, sustainable system redesigns. However, this evidence needs to be contextualized and adapted in different settings to inform policy and practice. The Ethiopian Health Extension Program can serve as a model for other nations of a large-scale human resources for health program containing strong economic benefits and long-term sustainability through successful government integration.

MRI T1-mapping is an important non-invasive tool for renal diagnosis. Previous work shows that ΔT1 (cortex-medullary difference in T1) has significant correlation with interstitial fibrosis in chronic kidney disease (CKD) allograft patients. However, measuring cortico-medullary values by manually drawing ROIs over cortex and medulla (a gold standard method) is challenging, time-consuming, subjective and requires human training. Moreover, such subjective ROI placement may also affect the work reproducibility. This work proposes a deep learning-based 2D U-Net (RCM U-Net) to auto-segment the renal cortex and medulla of CKD allograft kidney T1 maps. Furthermore, this study presents a correlation of automatically measured ΔT1 values with eGFR and percentage fibrosis in allograft kidneys. Also, the RCM U-Net correlation results are compared with the manual ROI correlation analysis. The RCM U-Net has been trained and validated on T1 maps from 40 patients (n = 2400 augmented images) and tested on 10 patients (n = 600 augmented images). The RCM U-Net segmentation results are compared with the standard VGG16, VGG19, ResNet34 and ResNet50 networks with U-Net as backbone. For clinical validation of the RCM U-Net segmentation, another set of 114 allograft kidneys patient’s cortex and medulla were automatically segmented to measure the ΔT1 values and correlated with eGFR and fibrosis. Overall, the RCM U-Net showed 50% less Mean Absolute Error (MAE), 16% better Dice Coefficient (DC) score and 12% improved results in terms of Sensitivity (SE) over conventional CNNs (i.e. VGG16, VGG19, ResNet34 and ResNet50) while the Specificity (SP) and Accuracy (ACC) did not show significant improvement (i.e. 0.5% improvement) for both cortex and medulla segmentation. For eGFR and fibrosis assessment, the proposed RCM U-Net correlation coefficient (r) and R-square (R2) was better correlated (r = -0.2, R2 = 0.041 with p = 0.039) to eGFR than manual ROI values (r = -0.19, R2 = 0.037 with p = 0.051). Similarly, the proposed RCM U-Net had noticeably better r and R2 values (r = 0.25, R2 = 0.065 with p = 0.007) for the correlation with the renal percentage fibrosis than the Manual ROI results (r = 0.3, R2 = 0.091 and p = 0.0013). Using a linear mixed model, T1 was significantly higher in the medulla than in the cortex (p

The presence of abundant tumor stroma is a prominent characteristic of pancreatic ductal adenocarcinomas (PDAC) that potentially influences disease progression and therapy response. This study aims to investigate immune cell infiltration and epigenetic profiles in tumor cell enriched ("Tumor") and stroma cell enriched ("Stroma") regions within human PDAC tissue samples. By comparing those regions, we identified 25,410 differentially methylated positions (DMPs) distributed across 6,963 unique genes. Pathway enrichment analysis using the top 2,000 DMPs that were either hyper- or hypomethylated indicated that immune response pathways and the estrogen receptor pathway are epigenetically dysregulated in Tumor and Stroma regions, respectively. In terms of immune cell infiltration, we observed overall low levels of T cells in both regions. In Tumor regions however, occurrence of tumor-associated macrophages (TAMs) was higher than in Stroma regions (p = 0.02) concomitant with a dualistic distribution that stratifies PDAC patients into those with high and low TAM infiltration. By categorizing TAM levels into quartiles, our analysis revealed that PDAC patients with more than 1,515 TAMs per mm² exhibited significantly shorter overall survival (p = 0.036). Our data suggest that variations in inflammatory characteristics between the Tumor and Stroma defined compartments of PDAC may primarily stem from the presence of macrophages rather than lymphocytes. The abundance of TAMs within regions enriched with tumor cells correlates with patient survival, underscoring the potential significance of exploring therapeutic interventions targeting TAMs. Furthermore, directing attention towards the estrogen receptor pathway may represent a promising strategy to address the stroma cell component within the PDAC tumor microenvironment. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to assess indications for and report outcomes of pancreatic surgery in pediatric patients. Background: Indications for pancreatic surgery in children are rare and data on surgical outcomes after pediatric pancreatic surgery are scarce. Methods: All children who underwent pancreatic surgery at a tertiary hospital specializing in pancreatic surgery between 2003 and 2022 were identified from a prospectively maintained database. Indications, surgical procedures, and perioperative as well as long-termoutcomes were analyzed. Results: In total, 73 childrenwith a mean age of 12.8 years (range: 4 mo to 18 y) underwent pancreatic surgery during the observation period. Indications included chronic pancreatitis (n=35), pancreatic tumors (n=27), and pancreatic trauma (n=11). Distal pancreatectomy was the most frequently performed procedure (n=23), followed by pancreatoduodenectomy (n=19), duodenum-preserving pancreatic head resection (n=10), segmental pancreatic resection (n=7), total pancreatectomy (n=3), and others (n=11). Postoperative morbidity occurred in 25 patients (34.2%), including 7 cases (9.6%) with major complications (Clavien-Dindo=III). There was no postoperative (90-d) mortality. The 5-year overall survival was 90.5%. The 5-year event-free survival of patients with chronic pancreatitis was 85.7%, and 69.0% for patients with pancreatic tumors. Conclusion: This is the largest single-center study on pediatric pancreatic surgery in a Western population. Pediatric pancreatic surgery can be performed safely. Centralization in pancreatic centers with high expertise in surgery of adult and pediatric patients is important as it both affords the benefits of pancreatic surgery experience and ensures that surgical management is adapted to the specific needs of children. [ABSTRACT FROM AUTHOR]

A set of visualizations developed for the purpose of explaining solid state lattice structures is presented in this paper. The visualizations provide students with the option to view stacking patterns, extended structures, and individual unit cells for simple, body-centered and face-centered cubic, and hexagonal close-packed structures. Additionally, the visualizations include lattice structures for NaCl and CaF[subscript 2], providing a visual perspective of empirical formulas and ionic lattice arrangements.