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Background: Idiopathic and secondary megacolon (MC) and megarectum (MR) in adults is associated with persistent bowel dilatation and reduced intestinal motility. Little is known about the optimal treatment of this rare disease. Therefore, we retrospectively analysed long-term data from these patients in 5 community and university hospitals, focusing on conservative versus surgical treatment., Methods: Patient records from 7/2004 to 9/2021 were screened for colorectal diseases with severe constipation and persistent megacolon ≥ 9.0 cm and/or megarectum ≥ 6.5 cm. Follow up-data was collected through telephone interviews and written surveys. ClinicalTrialsgov NCT04340856., Results: Sixty-seven patients with idiopathic (n=10) and secondary (n=57) MC or MR were identified with only 20 of 67 patients (29.9%) correctly diagnosed. Mean/median age was 64/69 (range 18-93) years. Thirty-two patients were treated with laxative regimens, and 35 underwent surgery (colostomy: n=12, segmental resection, or hemicolectomy: n=10, (sub)total colectomy: n= 13) after conservative treatment attempts in 32/35 (91.4%). The mean/median follow-up was 4.2/2.7 (range 0.1-17.0) years. The readmission rate for MC-associated symptoms was significantly higher after conservative treatment than after surgical therapy at 12 (0.84 vs. 0.36 per patient, p=0.036), 24 (1.00 vs. 0.52, p=0.048) and 36 (1.13 vs. 0.58, p=0.047) months, as was the number of patients with persistent laxative dependence (28/32 (87.5%) vs. 19/33 (57.6%); p = 0.007). Therapy-associated adverse events (Clavien-Dindo classification) were documented more often in surgically treated patients (11/35, 31.4%) (p=0.025)., Conclusion: Surgical treatment may be considered earlier if idiopathic or secondary MC or MR is correctly diagnosed, and conservative treatment has been attempted., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

The integration of next-generation sequencing into clinical diagnostics and surveillance initiatives is impeded by the lack of data analysis pipelines that align with privacy legislation and laboratory certification protocols. To address these challenges, we developed Jovian, an open-source, virus-focused, metagenomic analysis workflow for Illumina data. Jovian generates scaffolds enriched with pertinent annotations, including taxonomic classification, combined with metrics needed for quality assessment (coverage depth, average GC content, localization of open reading frames, minority single nucleotide polymorphisms), and incorporates host and disease metadata. Interactive web-based reports with an audit trail are generated. Jovian was employed on four systems, hosted by three institutes, utilizing grid-computers, a high-performance compute singular server, and a Windows10 laptop. All systems yielded identical results with matching MD5sums. Comparison with a commercial online reference tool using viral gastroenteritis samples confirmed the identification of the same pathogens. Jovian provides comparable results to a commercially available online reference tool and generates identical results at different institutes with different IT architectures, proving it is portable and reproducible. Jovian addresses bottlenecks in the deployment of metagenomics within public health and clinical laboratories and has the potential to enhance the breadth of surveillance and testing programs, thereby fostering more effective public health interventions., (© 2024. The Author(s).)

Sharp wave-ripple complexes (SPW-Rs) are spontaneous oscillatory events that characterize hippocampal activity during resting periods and slow-wave sleep. SPW-Rs are related to memory consolidation - the process during which newly acquired memories are transformed into long-lasting memory traces. To test the involvement of SPW-Rs in this process, it is crucial to understand how SPW-Rs originate and propagate throughout the hippocampus. SPW-Rs can originate in CA3, and they typically spread from CA3 to CA1, but little is known about their formation within CA3. To investigate the generation and propagation of SPW-Rs in CA3, we recorded from mouse hippocampal slices using multi-electrode arrays and patch-clamp electrodes. We characterized extracellular and intracellular correlates of SPW-Rs and quantified their propagation along the pyramidal cell layer of CA3. We found that a hippocampal slice can be described by a speed and a direction of propagation of SPW-Rs. The preferred propagation direction was from CA3c (the subfield closer to the dentate gyrus) toward CA3a (the subfield at the boundary to CA2). In patch-clamp recordings from CA3 pyramidal neurons, propagation was estimated separately for excitatory and inhibitory currents associated with SPW-Rs. We found that propagation speed and direction of excitatory and inhibitory currents were correlated. The magnitude of the speed of propagation of SPW-Rs within CA3 was consistent with the speed of propagation of action potentials in axons of CA3 principal cells. KEY POINTS: Hippocampal sharp waves are considered important for memory consolidation; therefore, it is of interest to understand the mechanisms of their generation and propagation. Here, we used two different approaches to study the propagation of sharp waves in mouse CA3 in vitro: multi-electrode arrays and multiple single-cell recordings. We find a preferred direction of propagation of sharp waves from CA3c toward CA3a - both in the local field potential and in sharp wave-associated excitatory and inhibitory synaptic activity. The speed of sharp wave propagation is consistent with the speed of action potential propagation along the axons of CA3 pyramidal neurons. These new insights into the dynamics of sharp waves in the CA3 network will inform future experiments and theoretical models of sharp-wave generation mechanisms., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Dysphagia is a common symptom in patients presenting to the gastroenterologist. However, extraluminal causes of dysphagia may be missed by endoluminal diagnosis alone. This case report presents a 72-year-old man with slowly progressive dysphagia that occurred with the ingestion of certain solid foods and was intermittently associated with severe aspiration. Esophagogastroduodenoscopy and barium swallow study were both normal. However, a conventional x-ray and computed tomography (CT) scan of the neck revealed diffuse idiopathic skeletal hyperostosis (Forestier's disease) of the anterior cervical spine (C2-C7). Fiber endoscopic evaluation of swallowing (FEES) revealed functionally incomplete emptying of the oral cavity during swallowing, and the patient reported dysphagia score (EAT-10) was 23 (normal < 3). Surgical removal of the hyperostosis (C3-C6) resulted in immediate and sustained improvement in dysphagia at 3 months., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

The biophysical characterization and engineering of optogenetic tools and photobiological systems has been hampered by the lack of efficient methods for spectral illumination of microplates for high-throughput analysis of action spectra. Current methods to determine action spectra only allow the sequential spectral illumination of individual wells. Here we present the open-source RainbowCap-system, which combines LEDs and optical filters in a standard 96-well microplate format for simultaneous and spectrally defined illumination. The RainbowCap provides equal photon flux for each wavelength, with the output of the LEDs narrowed by optical bandpass filters. We validated the RainbowCap for photoactivatable G protein-coupled receptors (opto-GPCRs) and enzymes for the control of intracellular downstream signaling. The simultaneous, spectrally defined illumination provides minimal interruption during time-series measurements, while resolving 10 nm differences in the action spectra of optogenetic proteins under identical experimental conditions. The RainbowCap is also suitable for studying the spectral dependence of light-regulated gene expression in bacteria, which requires illumination over several hours. In summary, the RainbowCap provides high-throughput spectral illumination of microplates, while its modular, customizable design allows easy adaptation to a wide range of optogenetic and photobiological applications., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

Social play is pervasive in juvenile mammals, yet it is poorly understood in terms of its underlying brain mechanisms. Specifically, we do not know why young animals are most playful and why most adults cease to social play. Here, we analyze the synaptic mechanisms underlying social play. We found that blocking the rat periaqueductal gray (PAG) interfered with social play. Furthermore, an age-related decrease of neural firing in the PAG is associated with a decrease in synaptic release of glycine. Most importantly, modulation of glycine concentration-apparently acting on the glycinergic binding site of the N-methyl-D-aspartate (NMDA) receptor-not only strongly modulates social play but can also reverse the age-related decline in social play. In conclusion, we demonstrate that social play critically depends on the neurotransmitter glycine within the PAG., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Synapsins are highly abundant presynaptic proteins that play a crucial role in neurotransmission and plasticity via the clustering of synaptic vesicles. The synapsin III isoform is usually downregulated after development, but in hippocampal mossy fiber boutons, it persists in adulthood. Mossy fiber boutons express presynaptic forms of short- and long-term plasticity, which are thought to underlie different forms of learning. Previous research on synapsins at this synapse focused on synapsin isoforms I and II. Thus, a complete picture regarding the role of synapsins in mossy fiber plasticity is still missing. Here, we investigated presynaptic plasticity at hippocampal mossy fiber boutons by combining electrophysiological field recordings and transmission electron microscopy in a mouse model lacking all synapsin isoforms. We found decreased short-term plasticity, i.e., decreased facilitation and post-tetanic potentiation, but increased long-term potentiation in male synapsin triple knock-out (KO) mice. At the ultrastructural level, we observed more dispersed vesicles and a higher density of active zones in mossy fiber boutons from KO animals. Our results indicate that all synapsin isoforms are required for fine regulation of short- and long-term presynaptic plasticity at the mossy fiber synapse., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Bruentgens et al.)

Information is transmitted between brain regions through the release of neurotransmitters from long-range projecting axons. Understanding how the activity of such long-range connections contributes to behavior requires efficient methods for reversibly manipulating their function. Chemogenetic and optogenetic tools, acting through endogenous G-protein-coupled receptor pathways, can be used to modulate synaptic transmission, but existing tools are limited in sensitivity, spatiotemporal precision or spectral multiplexing capabilities. Here we systematically evaluated multiple bistable opsins for optogenetic applications and found that the Platynereis dumerilii ciliary opsin (PdCO) is an efficient, versatile, light-activated bistable G-protein-coupled receptor that can suppress synaptic transmission in mammalian neurons with high temporal precision in vivo. PdCO has useful biophysical properties that enable spectral multiplexing with other optogenetic actuators and reporters. We demonstrate that PdCO can be used to conduct reversible loss-of-function experiments in long-range projections of behaving animals, thereby enabling detailed synapse-specific functional circuit mapping., (© 2024. The Author(s).)

Mutations in the transcription factors encoded by PHOX2B or LBX1 correlate with congenital central hypoventilation disorders. These conditions are typically characterized by pronounced hypoventilation, central apnea, and diminished chemoreflexes, particularly to abnormally high levels of arterial PCO 2 . The dysfunctional neurons causing these respiratory disorders are largely unknown. Here, we show that distinct, and previously undescribed, sets of medullary neurons coexpressing both transcription factors (dB2 neurons) account for specific respiratory functions and phenotypes seen in congenital hypoventilation. By combining intersectional chemogenetics, intersectional labeling, lineage tracing, and conditional mutagenesis, we uncovered subgroups of dB2 neurons with key functions in (i) respiratory tidal volumes, (ii) the hypercarbic reflex, (iii) neonatal respiratory stability, and (iv) neonatal survival. These data provide functional evidence for the critical role of distinct medullary dB2 neurons in neonatal respiratory physiology. In summary, our work identifies distinct subgroups of dB2 neurons regulating breathing homeostasis, dysfunction of which causes respiratory phenotypes associated with congenital hypoventilation.

Aim: This study aimed to explore what changes rural placement had on the perceptions of nursing students and the impact of placement frequency and duration on student considerations for rural practice., Background: A strong rural healthcare workforce is a global concern and has led countries to look for creative ways to address this challenge. One approach is to train more health professionals, however, nursing students who grew up or lived in metropolitan or urbanised areas are suggested to be less inclined to pursue a rural career. As such it is posited that recurrent exposure to rural settings may exert a positive impact on future intention for rural practice. However, there is a need to explore the specific thresholds related to both the frequency and duration of rural placement exposure, as well as the cumulative impact multiple rural placements may have on the intention to engage in rural practice., Design: A repeated cross-sectional design., Methods: All nursing students from an Australian regional university were invited to complete an online questionnaire between 2019 and 2023. Demographic and placement specific questions were included. A modified version of the Nursing Community Apgar tool also measured the importance of key variables in rural career decision-making. Data were analysed using independent sample t-tests and one-way ANOVAs. Significance was determined at two-tailed p≤.05., Results: Among the 835 respondents (response rate 15.4%), the average number and duration of rural placements was 2.45 placements and 3.01 weeks respectively. Rural placements did not have an impact on students who resided rurally or regionally. However, among metropolitan students who had experienced more than three rural placements, or more than sixteen cumulative weeks of placement, were significantly more likely to consider rural employment. Greater number of rural placements and longer cumulative duration had the greatest impact., Conclusion: Issues related to the nursing rural workforce are dynamic and complex. Understanding the unique drivers that improve the rural experiences among students, particularly metropolitan students, can have an impact on decision-making to pursue employment in rural environments. Importantly, whilst professional and clinical motivation and experiences are influential factors, the socialisation, environment and community features are essential elements that influence students' decisions to pursue a career in rural practice. Undertaking a nuanced approach that facilitates rural practice understanding among students may help shape future employment decision-making., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Exposure to radon gas at home is the second largest cause of lung cancer after smoking and dramatically increases smokers' risk of lung cancer. State tobacco quitlines are uniquely positioned to inform smokers about radon, yet, to our knowledge, none does so. We explored the feasibility of introducing free radon tests via the tobacco quitline in North Dakota, a state with one of the highest radon levels in the U.S., Methods: Five hundred consecutive callers to the ND Quits Tobacco quitline from February 2021 to February 2023 were invited to complete a brief radon questionnaire and receive a free radon test kit. Radon tests were bar-coded so that the return rate of the tests and the radon levels could be determined., Results: Two hundred fifty-one (51 %) callers completed the questionnaire and seventy-five radon tests were successfully returned to the laboratory. More than one third of the test results were ≥ 4.0 pCi/L, the action level recommended by the EPA. Only 1 in 5 participants reported knowing that radon caused lung cancer., Conclusion: Radon knowledge among ND smokers is poor. Radon test distribution via quitlines is feasible and may be a valuable addition to quitline services, particularly in states with high radon levels., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

The computational capabilities of neuronal networks are fundamentally constrained by their specific connectivity. Previous studies of cortical connectivity have mostly been carried out in rodents; whether the principles established therein also apply to the evolutionarily expanded human cortex is unclear. We studied network properties within the human temporal cortex using samples obtained from brain surgery. We analyzed multineuron patch-clamp recordings in layer 2-3 pyramidal neurons and identified substantial differences compared with rodents. Reciprocity showed random distribution, synaptic strength was independent from connection probability, and connectivity of the supragranular temporal cortex followed a directed and mostly acyclic graph topology. Application of these principles in neuronal models increased dimensionality of network dynamics, suggesting a critical role for cortical computation.

Introduction: Pharmacists serve an important role in rural communities, and in some cases they may be the only health professional available. Their recruitment and retention is a major concern for rural communities and health services; however, a deeper understanding regarding the advantages and challenges of sustaining a rural pharmacy workforce is somewhat limited. The aim of this study was to develop a deeper understanding of pharmacists' perspectives about factors influencing pharmacist recruitment and retention to rural and remote communities., Methods: The exploratory study, carried out in rural Tasmania and rural Western Victoria, used a qualitative descriptive design. Structured interviews, lasting between 30-60 minutes, were conducted by a single researcher using the Pharmacist Community Apgar Questionnaire via face-to-face, telephone or videoconferencing technology. Data were analysed thematically using verbatim transcription, extraction of significant statements and identification of similarities in formulated meanings, grouping the similar meanings and significant statements that pertained to the phenomena of interest. Specifically, qualitative data were used to provide a deeper understanding of factors identified as key assets, capabilities, or those most challenging for pharmacist recruitment and retention., Results: The advantages and disadvantages rural communities face in recruiting and retaining pharmacists are presented. These insights are linked to the advantages of financial income, incentives and moving allowance. Further advantages include the degree of practice autonomy, breadth of tasks, the perception of the community, loyalty to the pharmacy and its pharmacists, along with community recognition. Challenges associated with the recruitment and retention of pharmacists centred on the need for spousal or partner employment opportunities, having greater proximity to schools, access to social or cultural opportunities, along with good transport connections. Further challenges included housing, the cost of schooling for children, having adequate locum or peer coverage and opportunities to host interns., Discussion: The study provides a deeper exploration of the meaning and experiences of factors that previous research has shown are considered advantageous or challenging to the recruitment and retention of pharmacists in rural areas. Through the voices of pharmacists living and working in a rural area, the findings further enlighten our understanding regarding how the multifaceted and complex nature of health workforce planning may be addressed. As such, greater pharmacist recruitment and retention is enabled through adequate financial compensation and incentives, along with additional tax incentives for business and health services. Further, innovation is required to enhance economic sustainability. Locum coverage and intern opportunities also require innovative approaches to address concerns among potential candidates. Lastly, efforts to enable and support social connections such as schooling and spousal employment, while building community connection and a sense of rural community belonging, remain essential to recruit and retain pharmacists., Conclusion: Rural pharmacist recruitment and retention is complex, requiring a multi-pronged approach to implement practical solutions. Given this complexity and the unique features of each rural community, solutions require whole-of-community ownership to create innovative solutions. Recognition of specific advantages and challenges can address key driving factors for pharmacist recruitment and retention in rural communities.

Introduction: In addition to medication, the standard clinical treatment for vestibular vertigo primarily includes physical therapy in the form of regular exercises. Vertidisan is a future digital health application (DiGA) for structured dizziness therapy. Its content is multimodal and consists of Adaptive Balance and Eye Movements and Visual Stimulation (ABEV) exercises, which are expected to have an anti-vertigo effect through neural learning., Methods: A cohort study with 104 patients with intra-individual control was conducted to examine the clinical efficacy of solely 16 ABEV exercises for the treatment of peripheral vestibulopathies which are also used digitally in the future DiGA Vertidisan. Using the short version vertigo symptom scale short form1 vertigo and related symptoms (VSS-sf1-VER) of the vertigo-specific and validated VSS rating scale (Vertigo Symptom Scale) as the primary outcome variable, the vertigo scores before therapy (time T0) were compared with the corresponding data at the end of a period of 12-16 weeks (time T1)., Results: Complete datasets on T0 and T1 were available for N=104 patients. The mean VSS-sf1-V score decreased from 3.80 (median 4, SD 0.47) to 0.92 (median 1, SD 1.19) from T0 to T1 (weeks 12-16). The result is statistically significant (p=0.001) and shows a high clinical effect size., Conclusion: In summary, the analysis of the dizziness score shows a statistically and clinically significant reduction in dizziness through the use of the 16 ABEV exercises., Competing Interests: BPZ und HPZ sind am Vertidisan-Hersteller Digitineers GmbH & CO KG beteiligt., (Thieme. All rights reserved.)

Drought and water shortage are serious problems in many arid and semi-arid regions. This problem is getting worse and even continues in temperate climatic regions due to climate change. To address this problem, the use of biodegradable hydrogels is increasingly important for the application as water-retaining additives in soil. Furthermore, efficient (micro-)nutrient supply can be provided by the use of tailored hydrogels. Biodegradable polyaspartic acid (PASP) hydrogels with different available (1,6-hexamethylene diamine (HMD) and L-lysine (LYS)) and newly developed crosslinkers based on diesters of glycine (GLY) and (di-)ethylene glycol (DEG and EG, respectively) were synthesized and characterized using Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM) and regarding their swelling properties (kinetic, absorbency under load (AUL)) as well as biodegradability of PASP hydrogel. Copper (II) and zinc (II), respectively, were loaded as micronutrients in two different approaches: in situ with crosslinking and subsequent loading of prepared hydrogels. The results showed successful syntheses of di-glycine-ester-based crosslinkers. Hydrogels with good water-absorbing properties were formed. Moreover, the developed crosslinking agents in combination with the specific reaction conditions resulted in higher water absorbency with increased crosslinker content used in synthesis (10% vs. 20%). The prepared hydrogels are candidates for water-storing soil additives due to the biodegradability of PASP, which is shown in an exemple. The incorporation of Cu(II) and Zn(II) ions can provide these micronutrients for plant growth.

The hippocampal formation is crucial for learning and memory, with submodule CA3 thought to be the substrate of pattern completion. However, the underlying synaptic and computational mechanisms of this network are not well understood. Here, we perform circuit reconstruction of a CA3 module using three dimensional (3D) electron microscopy data and combine this with functional connectivity recordings and computational simulations to determine possible CA3 network mechanisms. Direct measurements of connectivity schemes with both physiological measurements and structural 3D EM revealed a high connectivity rate, multi-fold higher than previously assumed. Mathematical modelling indicated that such CA3 networks can robustly generate pattern completion and replay memory sequences. In conclusion, our data demonstrate that the connectivity scheme of the hippocampal submodule is well suited for efficient memory storage and retrieval., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: While most countries that allow abortion on women's request also grant physicians a right to conscientious objection (CO), this has proven to constitute a potential barrier to abortion access. Conscientious objection is regarded as an understudied phenomenon the effects of which have not yet been examined in Germany. Based on expert interviews, this study aims to exemplarily reconstruct the processes of abortion in a mid-sized city in Germany, and to identify potential effects of conscientious objection., Methods: Five semi-structured interviews with experts from all instances involved have been conducted in April 2020. The experts gave an insight into the medical care structures with regard to abortion procedures, the application and manifestations of conscientious objection in medical practice, and its impact on the care of pregnant women. A content analysis of the transcribed interviews was performed., Results: Both the procedural processes and the effects of conscientious objection are reported to differ significantly between early abortions performed before the 12th week of pregnancy and late abortions performed at the second and third trimester. Conscientious objection shows structural consequences as it is experienced to further reduce the number of possible providers, especially for early abortions. On the individual level of the doctor-patient relationship, the experts confirmed the neutrality and patient-orientation of the vast majority of doctors. Still, it is especially late abortions that seem to be vulnerable to barriers imposed by conscientious objection in individual medical encounters., Conclusion: Our findings indicate that conscientious objection possibly imposes barriers to both early and late abortion provision and especially in the last procedural steps, which from an ethical point of view is especially problematic. To oblige hospitals to partake in abortion provision in Germany has the potential to prevent negative impacts of conscientious objection on women's rights on an individual as well as on a structural level., (© 2024. The Author(s).)

Understanding the plasticity of neuronal networks is an emerging field of (patho-) physiological research, yet the underlying cellular mechanisms remain poorly understood. Gamma oscillations (30 to 80 hertz), a biomarker of cognitive performance, require and potentiate glutamatergic transmission onto parvalbumin-positive interneurons (PVIs), suggesting an interface for cell-to-network plasticity. In ex vivo local field potential recordings, we demonstrate long-term potentiation of hippocampal gamma power. Gamma potentiation obeys established rules of PVI plasticity, requiring calcium-permeable AMPA receptors (CP-AMPARs) and metabotropic glutamate receptors (mGluRs). A microcircuit computational model of CA3 gamma oscillations predicts CP-AMPAR plasticity onto PVIs critically outperforms pyramidal cell plasticity in increasing gamma power and completely accounts for gamma potentiation. We reaffirm this ex vivo in three PVI-targeting animal models, demonstrating that gamma potentiation requires PVI-specific signaling via a Gq/PKC pathway comprising mGluR5 and a Gi-sensitive, PKA-dependent pathway. Gamma activity-dependent, metabotropically mediated CP-AMPAR plasticity on PVIs may serve as a guiding principle in understanding network plasticity in health and disease.

Psychedelic agents, such as LSD and psilocybin, induce marked alterations in consciousness via activation of the 5-HT 2A receptor (5-HT 2A Rs). We hypothesize that psychedelics enforce a state of synthetic surprise through the biased activation of the 5-HTRs system. This idea is informed by recent insights into the role of 5-HT in signaling surprise. The effects on consciousness, explained by the cognitive penetrability of perception, can be described within the predictive coding framework where surprise corresponds to prediction error, the mismatch between predictions and actual sensory input. Crucially, the precision afforded to the prediction error determines its effect on priors, enabling a dynamic interaction between top-down expectations and incoming sensory data. By integrating recent findings on predictive coding circuitry and 5-HT 2A Rs transcriptomic data, we propose a biological implementation with emphasis on the role of inhibitory interneurons. Implications arise for the clinical use of psychedelics, which may rely primarily on their inherent capacity to induce surprise in order to disrupt maladaptive patterns., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To determine the distinct influences of rural background and rural residency training on rural practice choice among family physicians., Data Sources and Study Setting: We used a subset of The RTT Collaborative rural residency list and longitudinal data on family physicians from the American Board of Family Medicine National Graduate Survey (NGS; three cohorts, 2016-2018) and American Medical College Application Service (AMCAS)., Study Design: We conducted a logistic regression, computing predictive marginals to assess associations of background and residency location with physician practice location 3 years post-residency., Data Collection/extraction Methods: We merged NGS data with residency type-rural or urban-and practice location with AMCAS data on rural background., Principal Findings: Family physicians from a rural background were more likely to choose rural practice (39.2%, 95% CI = 35.8, 42.5) than those from an urban background (13.8%, 95% CI = 12.5, 15.0); 50.9% (95% CI = 43.0, 58.8) of trainees in rural residencies chose rural practice, compared with 18.0% (95% CI = 16.8, 19.2) of urban trainees., Conclusions: Increasing rural programs for training residents from both rural and urban backgrounds, as well as recruiting more rural students to medical education, could increase the number of rural family physicians., (© 2023 Health Research and Educational Trust.)

Neurodevelopmental disorders, such as intellectual disability (ID), epilepsy, and autism, involve altered synaptic transmission and plasticity. Functional characterization of their associated genes is vital for understanding physio-pathological brain functions. LGI3 is a recently recognized ID-associated gene encoding a secretory protein related to an epilepsy-gene product, LGI1. Here, we find that LGI3 is uniquely secreted from oligodendrocytes in the brain and enriched at juxtaparanodes of myelinated axons, forming nanoscale subclusters. Proteomic analysis using epitope-tagged Lgi3 knockin mice shows that LGI3 uses ADAM23 as a receptor and selectively co-assembles with Kv1 channels. A lack of Lgi3 in mice disrupts juxtaparanodal clustering of ADAM23 and Kv1 channels and suppresses Kv1-channel-mediated short-term synaptic plasticity. Collectively, this study identifies an extracellular organizer of juxtaparanodal Kv1 channel clustering for finely tuned synaptic transmission. Given the defective secretion of the LGI3 missense variant, we propose a molecular pathway, the juxtaparanodal LGI3-ADAM23-Kv1 channel, for understanding neurodevelopmental disorders., Competing Interests: Declaration of interests T.E. is the founder and researcher at Phenovance, LLC, Japan., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Global nursing workforce shortage represents an impediment to the delivery of safe, evidence-based healthcare. Despite collective efforts, a consistent stream of nurses leaving the profession remains, particularly within the first five years of practice, which is exacerbated in rural communities. The aim of the study was to compare self-efficacy, grit, and rural career aspirations among nursing graduates between their second and fourth year of their nursing profession., Methods: As part of a longitudinal investigation, a repeated cross-sectional design was utilised. Participants included, 117 (response rate 52.2%) who completed an online questionnaire 18-24 months after graduating, and 32 participants (response rate of 21.0%) who agree to repeat the questionnaire 36-48 months after graduating. The questionnaire included demographic, employment, and measures examining general and occupational self-efficacy, grit, and rural career aspirations., Results: No differences between general and occupational self-efficacy or grit were identified between second- and fourth-year nurses. In addition, the importance placed on undertaking rural career also remains unchanged. However, a higher proportion of fourth year nurses were more likely to be in management or were considering leaving the profession., Conclusions: This examination of early career nurses, now in their second and fourth-year post-graduation highlights self-efficacy, grit, and rural career aspirations remains stable between two- and four-years following graduation, while nursing in their fourth year were more likely to consider leaving the profession. Nursing retention is a 'Wicked Problem' that is unavoidably a complex amalgam of macro, meso and micro factors that we are yet to fully appreciate., (© 2024. The Author(s).)

Purpose: Supporting family caregivers is a major challenge for the healthcare system. The first points of contact are physicians, nurses and social services, which are not easily accessible. For this reason, an information platform has been developed to provide information for family caregivers caring for people with dementia at home. The aim of this article is to provide an insight into the didactic design of this platform., Sample and Methods: A didactic concept was developed based on didactic target group analysis and interviews with caring relatives (n=6)., Results: The didactic concept of the digital platform takes into account the characteristics of family caregivers as learners, such as time constraints and reciprocity. Therefore two different learning paths, a long and a short version, are offered. Reciprocity is supported by information which are related to individual characteristics of the caring relation. This is made possible by an adaptation of the didactic method "anchored instructions": Family caregivers experience a problematic caring situation. They use the platform and central concepts related to this situation are offered as anchors. In chatbot mediated learning, these concepts are identified and, ideally, relevant information is provided in a short version. These concepts are displayed as a learning map and must be proactively selected. Chatbot mediated learning has the advantage that matching concepts are offered as a pre-selection. Especially for inexperienced carers who are not familiar with the concepts, this learning path seems to be suitable., Conclusion: The combination of learning through the "Information for Relatives" website and CML seems to meet all needs. In order to promote learner motivation, the chatbot should not only offer the identified concept, but also those related to this concept, in order to link new knowledge in one's own knowledge network., Competing Interests: The study was funded by the German Federal Ministry of Education and Research. The authors report no conflicts of interest in this work., (© 2024 Schmitz and Becker.)

The complex neuromuscular network that controls body movements is the target of severe diseases that result in paralysis and death. Here, we report the development of a robust and efficient self-organizing neuromuscular junction (soNMJ) model from human pluripotent stem cells that can be maintained long-term in simple adherent conditions. The timely application of specific patterning signals instructs the simultaneous development and differentiation of position-specific brachial spinal neurons, skeletal muscles, and terminal Schwann cells. High-content imaging reveals self-organized bundles of aligned muscle fibers surrounded by innervating motor neurons that form functional neuromuscular junctions. Optogenetic activation and pharmacological interventions show that the spinal neurons actively instruct the synchronous skeletal muscle contraction. The generation of a soNMJ model from spinal muscular atrophy patient-specific iPSCs reveals that the number of NMJs and muscle contraction is severely affected, resembling the patient's pathology. In the future, the soNMJ model could be used for high-throughput studies in disease modeling and drug development. Thus, this model will allow us to address unmet needs in the neuromuscular disease field., (© 2023. The Author(s).)

Areas of high concentration of seal carcasses have been observed in localized areas of James Ross Island, Antarctica. Such carcasses show an unusual vegetation development, in a semi-arid area with bare soils under intense winds, high salinity and sandy texture. We investigated carcasses of seals around a lake in James Ross Island, with four different stages of decomposition, with three replicates: Seal (S01), with recently mummified carcasses; S02, with partially degraded carcasses; S03, with broken carcasses with partially degraded exposed bones, and S04, with completely broken, scattered skeletons. The vegetation showed a maximum degree of development in carcasses at stages S02 and S03, with the environment between the skin and the skeleton as the preferred place for vegetation establishment. The chemical alteration was greater with increasing carcass decomposition but reduced with the spreading and final decomposition of the bones, with anomalous values observed only in the vicinity of the carcasses. It is concluded that the presence of carcasses of seals, concentrated in wet places, even in a semi-desert climate, represent important oases of nutrients, with a combination of physical and chemical effects throughout the decomposition process that favor plant establishment and succession.

Structural variations, including copy number variations (CNVs), affect around 20 million bases in the human genome and are common causes of rare conditions. CNVs are rarely investigated in complex disease research because most CNVs are not targeted on the genotyping arrays or the reference panels for genetic imputation. In this study, we characterize CNVs in a Swedish cohort (N = 1,021) using short-read whole-genome sequencing (WGS) and use long-read WGS for validation in a subcohort (N = 15), and explore their effect on 438 plasma proteins. We detected 184,182 polymorphic CNVs and identified 15 CNVs to be associated with 16 proteins (P < 8.22×10-10). Of these, 5 CNVs could be perfectly validated using long-read sequencing, including a CNV which was associated with measurements of the osteoclast-associated immunoglobulin-like receptor (OSCAR) and located upstream of OSCAR, a gene important for bone health. Two other CNVs were identified to be clusters of many short repetitive elements and another represented a complex rearrangement including an inversion. Our findings provide insights into the structure of common CNVs and their effects on the plasma proteome, and highlights the importance of investigating common CNVs, also in relation to complex diseases., Competing Interests: Conflict of interest M.R.A. has performed remunerated consulting services for Olink Proteomics, Uppsala, Sweden. D.S., Z.L., V.L.F., A.A., N.R., and Å.J. declare no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

Anti-NMDA receptor (NMDAR) autoantibodies cause NMDAR encephalitis, the most common autoimmune encephalitis, leading to psychosis, seizures, and autonomic dysfunction. Current treatments comprise broad immunosuppression or non-selective antibody removal. We developed NMDAR-specific chimeric autoantibody receptor (NMDAR-CAAR) T cells to selectively eliminate anti-NMDAR B cells and disease-causing autoantibodies. NMDAR-CAARs consist of an extracellular multi-subunit NMDAR autoantigen fused to intracellular 4-1BB/CD3ζ domains. NMDAR-CAAR T cells recognize a large panel of human patient-derived autoantibodies, release effector molecules, proliferate, and selectively kill antigen-specific target cell lines even in the presence of high autoantibody concentrations. In a passive transfer mouse model, NMDAR-CAAR T cells led to depletion of an anti-NMDAR B cell line and sustained reduction of autoantibody levels without notable off-target toxicity. Treatment of patients may reduce side effects, prevent relapses, and improve long-term prognosis. Our preclinical work paves the way for CAAR T cell phase I/II trials in NMDAR encephalitis and further autoantibody-mediated diseases., Competing Interests: Declaration of interests Related to this work, the German Center for Neurodegenerative Diseases (DZNE) and Max-Delbrück-Centrum Berlin have filed a patent application describing NMDAR-CAAR T cells for treatment of NMDAR encephalitis on which S.M.R., I.E., and H.P. are named as inventors (WO/2020/245343). In addition, the DZNE has filed a patent application on constructs for detection and isolation of NMDAR autoantibodies on which H.-C.K. and H.P. are named as inventors (WO/2021/008890)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: To evaluate awareness and knowledge of diabetic ketoacidosis (DKA), a common and potentially life-threatening complication in people living with type 1 diabetes (T1D)., Research Design and Methods: A survey was developed to assess individuals' current knowledge, management, and unmet needs regarding DKA. The study was conducted in six Swiss and three German endocrine outpatient clinics specialized in the treatment of diabetes., Results: A total of 333 participants completed the questionnaire (45.7% female, mean age of 47 years, average duration of T1D at 22 years). Surprisingly, 32% of individuals were not familiar with the term 'diabetic ketoacidosis'. Participants rated their own knowledge of DKA significantly lower than their physicians (p<0.0001). 46% of participants were unable to name a symptom of DKA, and 45% were unaware of its potential causes. 64% of participants did not test for ketones at all. A significant majority (67%) of individuals expressed the need for more information about DKA., Conclusions: In patients treated in specialized centers, knowledge of DKA was found to be inadequate, with a lack of understanding regarding symptoms and causes. Healthcare professionals tended to overestimate individuals' knowledge. Future efforts should focus on addressing these knowledge gaps and incorporating protective factors into the treatment of T1D., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

One of the most captivating questions in neuroscience revolves around the brain's ability to efficiently and durably capture and store information. It must process continuous input from sensory organs while also encoding memories that can persist throughout a lifetime. What are the cellular-, subcellular-, and network-level mechanisms that underlie this remarkable capacity for long-term information storage? Furthermore, what contributions do distinct types of GABAergic interneurons make to this process? As the hippocampus plays a pivotal role in memory, our review focuses on three aspects: (1) delineation of hippocampal interneuron types and their connectivity, (2) interneuron plasticity, and (3) activity patterns of interneurons during memory-related rhythms, including the role of long-range interneurons and disinhibition. We explore how these three elements, together showcasing the remarkable diversity of inhibitory circuits, shape the processing of memories in the hippocampus., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The persistence of play after decortication points to a subcortical mechanism of play control. We found that global blockade of the rat periaqueductal gray with either muscimol or lidocaine interfered with ticklishness and play. We recorded vocalizations and neural activity from the periaqueductal gray of young, playful rats during interspecific touch, play, and tickling. Rats vocalized weakly to touch and more strongly to play and tickling. Periaqueductal gray units showed diverse but strong modulation to tickling and play. Hierarchical clustering based on neuronal responses to play and tickling revealed functional clusters mapping to different periaqueductal gray columns. Specifically, we observed play-neutral/tickling-inhibited and tickling/play-neutral units in dorsolateral and dorsomedial periaqueductal gray columns. In contrast, strongly play/tickling-excited units mapped to the lateral columns and were suppressed by anxiogenic conditions. Optogenetic inactivation of lateral periaqueductal columns disrupted ticklishness and play. We conclude that the lateral periaqueductal gray columns are decisive for play and laughter., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Norovirus is the primary cause of viral gastroenteritis (GE). To investigate norovirus epidemiology, there is a need for whole-genome sequencing and reference sets consisting of complete genomes. To investigate the potential of shotgun metagenomic sequencing on the Illumina platform for whole-genome sequencing, 71 reverse transcriptase quantitative PCR (RT-qPCR) norovirus positive-feces (threshold cycle [ C T ], <30) samples from norovirus surveillance within The Netherlands were subjected to metagenomic sequencing. Data were analyzed through an in-house next-generation sequencing (NGS) analysis workflow. Additionally, we assessed the potential of metagenomic sequencing for the surveillance of off-target viruses that are of importance for public health, e.g., sapovirus, rotavirus A, enterovirus, parechovirus, aichivirus, adenovirus, and bocaparvovirus. A total of 60 complete and 10 partial norovirus genomes were generated, representing 7 genogroup I capsid genotypes and 12 genogroup II capsid genotypes. In addition to the norovirus genomes, the metagenomic approach yielded partial or complete genomes of other viruses for 39% of samples from children and 6.7% of samples from adults, including adenovirus 41 ( N  = 1); aichivirus 1 ( N  = 1); coxsackievirus A2 ( N  = 2), A4 ( N  = 2), A5 ( N  = 1), and A16 ( N  = 1); bocaparvovirus 1 ( N  = 1) and 3 ( N  = 1); human parechovirus 1 ( N  = 2) and 3 ( N  = 1); Rotavirus A ( N  = 1); and a sapovirus GI.7 ( N  = 1). The sapovirus GI.7 was initially not detected through RT-qPCR and warranted an update of the primer and probe set. Metagenomic sequencing on the Illumina platform robustly determines complete norovirus genomes and may be used to broaden gastroenteritis surveillance by capturing off-target enteric viruses. IMPORTANCE Viral gastroenteritis results in significant morbidity and mortality in vulnerable individuals and is primarily caused by norovirus. To investigate norovirus epidemiology, there is a need for whole-genome sequencing and reference sets consisting of full genomes. Using surveillance samples sent to the Dutch National Institute for Public Health and the Environment (RIVM), we compared metagenomics against conventional techniques, such as RT-qPCR and Sanger-sequencing, with norovirus as the target pathogen. We determined that metagenomics is a robust method to generate complete norovirus genomes, in parallel to many off-target pathogenic enteric virus genomes, thereby broadening our surveillance efforts. Moreover, we detected a sapovirus that was not detected by our validated gastroenteritis RT-qPCR panel, which exemplifies the strength of metagenomics. Our study shows that metagenomics can be used for public health gastroenteritis surveillance, the generation of reference-sets for molecular epidemiology, and how it compares to current surveillance strategies., Competing Interests: The authors declare no conflict of interest.

Active layer and permafrost are important indicators of climate changes in periglacial areas of Antarctica, and the soil thermal regime of Maritime Antarctica is sensitive to the current warming trend. This research aimed to characterize the active layer thermal regime of a patterned ground located at an upper marine terrace in Half Moon Island, during 2015-2018. Temperature and moisture sensors were installed at different soil depths, combined with air temperature, collecting hourly data. Statistical analysis was applied to describe the soil thermal regime and estimate active layer thickness. The thermal regime of the studied soil was typical of periglacial environment, with high variability in temperature and water content in the summer, resulting in frequent freeze-thaw cycles. We detected dominant freezing conditions, whereas soil temperatures increased, and the period of high soil moisture content lasted longer over the years. Active layer thickness varied between the years, reaching a maximum depth in 2018. Permafrost degradation affects soil drainage and triggers erosion in the upper marine terrace, where permafrost occurrence is unlikely. Longer monitoring periods are necessary for a detailed understanding on how current climatic and geomorphic conditions affect the unstable permafrost of low-lying areas of Antarctica (marine terraces).

Autoantibodies against the NR1 subunit of NMDA receptors (NMDARs) have been shown to promote crosslinking and internalization of bound receptors in NMDAR encephalitis (NMDARE). This internalization-mediated loss of NMDARs is thought to be the major mechanism leading to pathogenic outcomes in patients. However, the role of bound autoantibody in engaging the resident immune cells, microglia, remains poorly understood. Here, using a patient-derived monoclonal NR1 autoantibody (hNR1-mAb) and a co-culture system of microglia and neurons, we could show that hNR1-mAb bound to hippocampal neurons led to microglia-mediated removal of hNR1-mAb bound NMDARs. These complexes were found to accumulate inside endo-lysosomal compartments of microglia. Utilizing another patient isolated monoclonal autoantibody, against the α1-subunit of GABA A receptors (α1-GABA A -mAb), such removal of receptors was found to be specific to the antibody-bound receptor targets. Interestingly, along with receptor removal, we also observed a reduction in synapse number, more specifically in the numbers of post-synaptic proteins like PSD95 and Homer 1, when microglia were present in the culture. Importantly, mutations in the Fc region of hNR1-mAb, blocking its Fcγ receptor (FcγR) and complement binding, attenuated hNR1-mAb driven loss of NMDARs and synapses, indicating that microglia engagement by bound hNR1-mAb is critical for receptor and synapse loss. Our data argues for an active involvement of microglia in removal of NMDARs and other receptors in individuals with autoimmune encephalitis, thereby contributing to the etiology of these diseases., (© 2023 The Authors. GLIA published by Wiley Periodicals LLC.)

Background: Patients with active nonvariceal upper gastrointestinal bleeding (NVUGIB) usually require urgent endoscopic treatment. Standard therapy (ST) using haemoclip + / - epinephrine injection is not always successful. Bipolar haemostatic forceps (HemoStat/Pentax®) are an approved medical device for the treatment of gastrointestinal bleeding. However, their use as a primary endoscopic treatment for active NVUGIB has not yet been proven in a randomized prospective study., Methods: This is a prospective, randomized, multicentre superiority trial (n ≥ 5). Patients with active NVUGIB will be randomized (1:1) to ST and to experimental therapy (ET) by application of bipolar haemostatic forceps. In the case of failed initial treatment within 15 min, crossover treatment will be attempted first. Rescue treatment (e.g. via over-the-scope-clip) will then be allowed after 30 min. All patients will also receive standard therapy with proton pump inhibitors. Forty-five patients per treatment arm are required to demonstrate an absolute difference of 25.4% with a power of 80% and a significance level of 0.05., Discussion: The hypothesis of the study is that bipolar haemostatic forceps are superior to ST in terms of successful primary haemostasis and the absence of recurrent bleeding within 30 days (combined endpoint). The 1:1 randomization is also ethically justifiable for this study, as both procedures are approved for the intervention in question. To further increase the safety of the patients in the study, crossover treatment and rescue treatment are planned. The prospective design seems feasible in a reasonable time frame (recruitment period of 12 months), as nonvariceal upper gastrointestinal bleeding is common. Anticoagulants and/or antiplatelet drugs could be an important confounding factor in the statistical analysis that needs to be taken into account and calculated if necessary. In conclusion, this randomized, prospective, multicentre study could make an important contribution to answering the question of whether bipolar haemostatic forceps could be the first-line therapy in the endoscopic treatment of stage Forrest I a + b NVUGIB., Trial Registration: ClinicalTrials.gov NCT05353062. Registered on April 30 2022., (© 2023. The Author(s).)

The Phospholipid Phosphatase Related 4 gene (PLPPR4,  *607813) encodes the Plasticity-Related-Gene-1 (PRG-1) protein. This cerebral synaptic transmembrane-protein modulates cortical excitatory transmission on glutamatergic neurons. In mice, homozygous Prg-1 deficiency causes juvenile epilepsy. Its epileptogenic potential in humans was unknown. Thus, we screened 18 patients with infantile epileptic spasms syndrome (IESS) and 98 patients with benign familial neonatal/infantile seizures (BFNS/BFIS) for the presence of PLPPR4 variants. A girl with IESS had inherited a PLPPR4-mutation (c.896C > G, NM&#95;014839; p.T299S) from her father and an SCN1A-mutation from her mother (c.1622A > G, NM&#95;006920; p.N541S). The PLPPR4-mutation was located in the third extracellular lysophosphatidic acid-interacting domain and in-utero electroporation (IUE) of the Prg-1p.T300S construct into neurons of Prg-1 knockout embryos demonstrated its inability to rescue the electrophysiological knockout phenotype. Electrophysiology on the recombinant SCN1Ap.N541S channel revealed partial loss-of-function. Another PLPPR4 variant (c.1034C > G, NM&#95;014839; p.R345T) that was shown to result in a loss-of-function aggravated a BFNS/BFIS phenotype and also failed to suppress glutamatergic neurotransmission after IUE. The aggravating effect of Plppr4-haploinsufficiency on epileptogenesis was further verified using the kainate-model of epilepsy: double heterozygous Plppr4-/+|Scn1awt|p.R1648H mice exhibited higher seizure susceptibility than either wild-type, Plppr4-/+, or Scn1awt|p.R1648H littermates. Our study shows that a heterozygous PLPPR4 loss-of-function mutation may have a modifying effect on BFNS/BFIS and on SCN1A-related epilepsy in mice and humans., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The aim of this study was to assess associations between socio-demographic characteristics and dental costs of children living in Amsterdam. Having incurred dental costs was an indicator for having visited the dentist. Having incurred low or high dental costs may indicate the type of dental care provided (periodic examination, preventive care or restorative treatment)., Methods: This study followed a cross-sectional, observational design. The research population contained all children up until 17 years living in Amsterdam in 2016. Dental costs from all Dutch healthcare insurance companies were obtained via Vektis, and socio-demographic data were obtained from Statistics Netherlands (CBS). The study population was stratified into age groups: 0-4 and 5-17 years. Dental costs were classified as no dental costs (0 euros), low dental costs (>0 to <100 euros) or high dental costs (≥100 euros). Univariable and multivariable logistic regression analyses were performed to study the distribution of dental costs and associations with socio-demographic child and parent variables., Results: In the population of 142 289 children, 44 887 (31.5%) incurred no dental costs, 32 463 (22.8%) incurred low dental costs and 64 939 (45.6%) incurred high dental costs. Among children of 0-4 years, a much larger proportion (70.2%) incurred no dental costs, compared to those of 5-17 years (15.8%). In both age groups, migration background (adjusted Odds Ratio (aOR) range 1.23-1.98), low(er) household income (aOR range 0.45-0.93), low(er) parental educational level (aOR range 0.51-0.87) and living in a single-parent household (aOR range 0.89-0.91) were strongly associated with incurring high (vs. low) dental costs. Furthermore, in 5-17-year-old children, a lower level of secondary or vocational education (aOR range 1.12-1.17) and living in households receiving social benefits (aOR 1.23) were associated with incurring high dental costs., Conclusions: Among children living in Amsterdam in 2016, one in three children did not visit a dentist. For children that did visit a dentist, those with a migration background, low parental educational level and from a low household income were more likely to incur high dental costs, which could be indicative for additional restorative treatment. Hence, patterns of oral healthcare consumption, specified by type of dental care over time, and their association with oral health status, are targets for future research., (© 2023 The Authors. Community Dentistry and Oral Epidemiology published by John Wiley & Sons Ltd.)

This study developed an easy-to-use mortality prediction tool, which showed an acceptable discrimination and no significant lack of fit. The GeRi-Score was able to predict mortality and could distinguish between mild, moderate and high risk groups. Therefore, the GeRi-Score might have the potential to distribute the intensity of medical care., Purpose: Several mortality-predicting tools for hip fracture patients are available, but all consist of a high number of variables, require a time-consuming evaluation and/or are difficult to calculate. The aim of this study was to develop and validate an easy-to-use score, which depends mostly on routine data., Methods: Patients from the Registry for Geriatric Trauma were divided into a development and a validation group. Logistic regression models were used to build a model for in-house mortality and to obtain a score. Candidate models were compared using Akaike information criteria (AIC) and likelihood ratio tests. The quality of the model was tested using the area under the curve (AUC) and the Hosmer-Lemeshow test., Results: 38,570 patients were included, almost equal distributed to the development and to the validation dataset. The AUC was 0.727 (95% CI 0.711 - 0.742) for the final model, AIC resulted in a significant reduction in deviance compared to the basic model, and the Hosmer-Lemeshow test showed no significant lack of fit (p = 0.07). The GeRi-Score predicted an in-house mortality of 5.3% vs. 5.3% observed mortality in the development dataset and 5.4% vs. 5.7% in the validation dataset. The GeRi-Score was able to distinguish between mild, moderate and high risk groups., Conclusions: The GeRi-Score is an easy-to-use mortality-predicting tool with an acceptable discrimination and no significant lack of fit. The GeRi-Score might have the potential to distribute the intensity of perioperative medical care in hip fracture surgery and can be used in quality management programs as benchmark tool., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

The recurrent emerging of novel viral variants of concern (VOCs) with evasion of preexisting antibody immunity upholds severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case numbers and maintains a persistent demand for updated therapies. We selected the patient-derived antibody CV38-142 based on its potency and breadth against the VOCs Alpha, Beta, Gamma, and Delta for preclinical development into a therapeutic. CV38-142 showed in vivo efficacy in a Syrian hamster VOC infection model after post-exposure and therapeutic application and revealed a favorable safety profile in a human protein library screen and tissue cross-reactivity study. Although CV38-142 targets the same viral surface as sotrovimab, which maintains activity against Omicron, CV38-142 did not neutralize the Omicron lineages BA.1 and BA.2. These results highlight the contingencies of developing antibody therapeutics in the context of antigenic drift and reinforce the need to develop broadly neutralizing variant-proof antibodies against SARS-CoV-2., Competing Interests: The German Center for Neurodegenerative Diseases (DZNE) and Charité-Universitätsmedizin Berlin have filed a patent application (application number: PCT/EP2021/064,352) on antibodies for the treatment of SARS-CoV-2 infection on which J.K., S.M.R., H.-C.K., E.S.-S., L.E.S., V.M.C., and H.P. are named as inventors. V.M.C. is named together with Euroimmun GmbH on a patent application filed recently regarding the diagnostic of SARS-CoV-2 by antibody testing. S.E., V.N., M.M., S.K., S.H., P.H., and U.J. are employees of Miltenyi Biotec B.V. & Co. KG., (© 2023 The Author(s).)

Hippocampal ripples are highly synchronous neural events critical for memory consolidation and retrieval. A minority of strong ripples has been shown to be of particular importance in situations of increased memory demands. The propagation dynamics of strong ripples inside the hippocampal formation are, however, still opaque. We analyzed ripple propagation within the hippocampal formation in a large open-access dataset comprising 267 Neuropixel recordings in 49 awake, head-fixed mice. Surprisingly, strong ripples (top 10% in ripple strength) propagate differentially depending on their generation point along the hippocampal longitudinal axis. The septal hippocampal pole is able to generate longer ripples that engage more neurons and elicit spiking activity for an extended time even at considerable distances. Accordingly, a substantial portion of the variance in strong ripple duration ( R ² = 0.463) is explained by the ripple generation location on the longitudinal axis, in agreement with a possible distinctive role of the hippocampal septal pole in conditions of high-memory demand. Moreover, we observed that the location of the ripple generation has a significant impact on the spiking rate modulation of different hippocampal subfields, even before the onset of the ripple. This finding suggests that ripple generation location plays a crucial role in shaping the neural activity across the hippocampus., Competing Interests: RD, DS No competing interests declared, (© 2023, De Filippo and Schmitz.)

Background: One year after persistent peripheral facial paresis (PFP), prescriptions of conventional rehabilitation are often downgraded into maintenance rehabilitation or discontinued, the patient entering what is seen as a chronic stage. This therapeutic choice is not consistent with current knowledge about behavior-induced plasticity, which is available all life long and may allow intense sensorimotor rehabilitation to remain effective. This prospective, randomized, multicenter single-blind study in subjects with chronic unilateral PFP evaluates changes in facial motor function with a Guided Self-rehabilitation Contract (GSC) vs. conventional therapy alone, carried out for six months., Methods: Eighty-two adult subjects with chronic unilateral PFP (> 1 year since facial nerve injury) will be included in four tertiary, maxillofacial surgery (2), otolaryngology (1) and rehabilitation (1) centers to be randomized into two rehabilitation groups. In the experimental group, the PM&R specialist will implement the GSC method, which for PFP involves intensive series of motor strengthening performed daily on three facial key muscle groups, i.e. Frontalis, Orbicularis oculi and Zygomatici. The GSC strategy involves: i) prescription of a daily self-rehabilitation program, ii) teaching of the techniques involved in the program, iii) encouragement and guidance of the patient over time, in particular by requesting a quantified diary of the work achieved to be returned by the patient at each visit. In the control group, participants will benefit from community-based conventional therapy only, according to their physician's prescription. The primary outcome measure is the composite score of Sunnybrook Facial Grading System. Secondary outcome measures include clinical and biomechanical facial motor function quantifications (Créteil Scale and 3D facial motion analysis through the Cara system), quality of life (Facial Clinimetric Evaluation and Short-Form 12), aesthetic considerations (FACE-Q scale) and mood representations (Hospital Anxiety and Depression scale). Participants will be evaluated every three months by a blinded investigator, in addition to four phone calls (D30/D60/D120/D150) to monitor compliance and tolerance to treatment., Discussion: This study will increase the level of knowledge on the effects of intense facial motor streng-          Facial paralysisthening prescribed through a GSC in patients with chronic peripheral facial paresis., Trial Registration: ClinicalTrials.gov, NCT04074018 . Registered 29 August 2019., Protocol Version: Version N°4.0-04/02/2021., (© 2023. The Author(s).)

Objective: To pilot the Pharmacist Community Apgar Questionnaire (PharmCAQ) and evaluate its usability and capacity to develop a greater understanding of the unique factors that impact the rural recruitment and retention of pharmacists., Design: Cross-sectional design involving face-to-face, telephone or video conferencing interviews., Setting: Twelve rural communities across Tasmania and Western Victoria, Australia., Participants: Participants (n = 24) included pharmacists, a Director of Clinical Services, pharmacy practice managers and senior pharmacy assistants., Main Outcome Measures: Interviews enabled the completion of the PharmCAQ, which assigns quantitative values to 50 key factors to ascertain a community's strengths and challenges associated with recruitment and retention and their relative importance to the pharmacist workforce., Results: The cumulative PharmCAQ scores indicated the tool was sensitive enough to differentiate high- and low-performing communities. Overall, the highest-rated factors considered most vital to pharmacist recruitment and retention were the reputation of the pharmacy, the ability of the pharmacist to be independent and autonomous, the loyalty of the community to the pharmacy, the level and stability of monetary compensation and the breadth of tasks available to a pharmacist., Conclusions: This study identified the strengths and challenges of participating communities and provided an insight into the shared factors to consider in recruiting and retaining pharmacists. Further, each community has unique strengths that can further be promoted in recruitment, flagging where limited resources are best used to address site specific challenges. This is more likely to ensure the matching of the right candidate with the right community., (© 2022 The Authors. Australian Journal of Rural Health published by John Wiley & Sons Australia, Ltd on behalf of National Rural Health Alliance Ltd.)

Background and Objectives: The quality of training in rural family medicine (FM) residencies has been questioned. Our objective was to assess differences in academic performance between rural and urban FM residencies., Methods: We used American Board of Family Medicine (ABFM) data from 2016-2018 residency graduates. Medical knowledge was measured by the ABFM in-training examination (ITE) and Family Medicine Certification Examination (FMCE). The milestones included 22 items across six core competencies. We measured whether residents met expectations on each milestone at each assessment. Multilevel regression models determined associations between resident and residency characteristics milestones met at graduation, FMCE score, and failure., Results: Our final sample was 11,790 graduates. First-year ITE scores were similar between rural and urban residents. Rural residents passed their initial FMCE at a lower rate than urban residents (96.2% vs 98.9%) with the gap closing upon later attempts (98.8% vs 99.8%). Being in a rural program was not associated with a difference in FMCE score but was associated with higher odds of failure. Interactions between program type and year were not significant, indicating equal growth in knowledge. The proportions of rural vs urban residents who met all milestones and each of six core competencies were similar early in residency but diverged over time with fewer rural residents meeting all expectations., Conclusions: We found small, but persistent differences in measures of academic performance between rural- and urban-trained FM residents. The implications of these findings in judging the quality of rural programs are much less clear and warrant further study, including their impact on rural patient outcomes and community health.

Background and Objectives: Little is known about how rural and urban family medicine residencies compare in preparing physicians for practice. This study compared the perceptions of preparation for practice and actual postgraduation scope of practice (SOP) between rural and urban residency program graduates., Methods: We analyzed data on 6,483 early-career, board-certified physicians surveyed 2016-2018, 3 years after residency graduation, and 44,325 later-career board-certified physicians surveyed 2014-2018, every 7 to 10 years after initial certification. Bivariate comparisons and multivariate regressions of rural and urban residency graduates examined perceived preparedness and current practice in 30 areas and overall SOP using a validated scale, with separate models for early-career and later-career physicians., Results: In bivariate analyses, rural program graduates were more likely than urban program graduates to report being prepared for hospital-based care, casting, cardiac stress tests, and other skills, but less likely to be prepared in some gynecologic care and pharmacologic HIV/AIDS management. Both early- and later-career rural program graduates reported broader overall SOPs than their urban-program counterparts in bivariate analyses; in adjusted analyses this difference remained significant only for later-career physicians., Conclusions: Compared with urban program graduates, rural graduates more often rated themselves prepared in several hospital care measures and less often in certain women's health measures. Controlling for multiple characteristics, only rurally trained, later-career physicians reported a broader SOP than their urban program counterparts. This study demonstrates the value of rural training and provides a baseline for research exploring longitudinal benefits of this training to rural communities and population health.

The extent to which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) break through infection- or vaccine-induced immunity is not well understood. We analyzed 28,578 sequenced SARS-CoV-2 samples from individuals with known immune status obtained through national community testing in the Netherlands from March to August 2021. We found evidence of an increased risk of infection by the Beta (B.1.351), Gamma (P.1), or Delta (B.1.617.2) variants compared with the Alpha (B.1.1.7) variant after vaccination. No clear differences were found between vaccines. However, the effect was larger in the first 14 to 59 days after complete vaccination compared with ≥60 days. In contrast to vaccine-induced immunity, there was no increased risk for reinfection with Beta, Gamma, or Delta variants relative to the Alpha variant in individuals with infection-induced immunity.