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Tubulin alpha 8 (Tuba8) is the most divergent member of the highly conserved alpha tubulin family, and uniquely lacks two key post-translational modification sites. It is abundantly expressed in testis and muscle, with lower levels in the brain. We previously identified homozygous hypomorphic TUBA8 mutations in human subjects with a polymicrogyria (PMG) syndrome, suggesting its involvement in development of the cerebral cortex. We have now generated and characterized a Tuba8 knockout mouse model. Homozygous mice were confirmed to lack Tuba8 protein in the testis, but did not display PMG and appeared to be neurologically normal. In response to this finding, we re-analyzed the human PMG subjects using whole exome sequencing. This resulted in identification of an additional homozygous loss-of-function mutation in SNAP29, suggesting that SNAP29 deficiency, rather than TUBA8 deficiency, may underlie most or all of the neurodevelopmental anomalies in these subjects. Nonetheless, in the mouse brain, Tuba8 specifically localised to the cerebellar Purkinje cells, suggesting that the human mutations may affect or modify motor control. In the testis, Tuba8 localisation was cell-type specific. It was restricted to spermiogenesis with a strong acrosomal localization that was gradually replaced by cytoplasmic distribution and was absent from spermatozoa. Although the knockout mice were fertile, the localisation pattern indicated that Tuba8 may have a role in spermatid development during spermatogenesis, rather than as a component of the mature microtubule-rich flagellum itself.

The aim of this study was to investigate the interaction and co-localization of novel interacting proteins with the Leber congenital amaurosis (LCA) associated protein aryl hydrocarbon receptor interacting protein-like 1 (AIPL1).The CytoTrapXR yeast two-hybrid system was used to screen a bovine retinal cDNA library. A novel interaction between AIPL1 and members of the family of EB proteins was confirmed by directed yeast two-hybrid analysis and co-immunoprecipitation assays. The localization of AIPL1 and the EB proteins in cultured cells and in retinal cryosections was examined by immunofluorescence microscopy and cryo-immunogold electron microscopy.Yeast two-hybrid (Y2H) analysis identified the interaction between AIPL1 and the EB proteins, EB1 and EB3. EB1 and EB3 were specifically co-immunoprecipitated with AIPL1 from SK-N-SH neuroblastoma cells. In directed 1:1 Y2H analysis, the interaction of EB1 with AIPL1 harbouring the LCA-causing mutations A197P, C239R and W278X was severely compromised. Immunofluorescent confocal microscopy revealed that AIPL1 did not co-localize with endogenous EB1 at the tips of microtubules, endogenous EB1 at the microtubule organising centre following disruption of the microtubule network, or with endogenous β-tubulin. Moreover, AIPL1 did not localize to primary cilia in ARPE-19 cells, whereas EB1 co-localized with the centrosomal marker pericentrin at the base of primary cilia. However, both AIPL1 and the EB proteins, EB1 and EB3, co-localized with centrin-3 in the connecting cilium of photoreceptor cells. Cryo-immunogold electron microscopy confirmed the co-localization of AIPL1 and EB1 in the connecting cilia in human retinal photoreceptors.AIPL1 and the EB proteins, EB1 and EB3, localize at the connecting cilia of retinal photoreceptor cells, but do not co-localize in the cellular microtubule network or in primary cilia in non-retinal cells. These findings suggest that AIPL1 function in these cells is not related to the role of EB proteins in microtubule dynamics or primary ciliogenesis, but that their association may be related to a specific role in the specialized cilia apparatus of retinal photoreceptors.

GENCODE produces comprehensive reference gene annotation for human and mouse. Entering its twentieth year, the project remains highly active as new technologies and methodologies allow us to catalog the genome at ever-increasing granularity. In particular, long-read transcriptome sequencing enables us to identify large numbers of missing transcripts and to substantially improve existing models, and our long non-coding RNA catalogs have undergone a dramatic expansion and reconfiguration as a result. Meanwhile, we are incorporating data from state-of-the-art proteomics and Ribo-seq experiments to fine-tune our annotation of translated sequences, while further insights into function can be gained from multi-genome alignments that grow richer as more species' genomes are sequenced. Such methodologies are combined into a fully integrated annotation workflow. However, the increasing complexity of our resources can present usability challenges, and we are resolving these with the creation of filtered genesets such as MANE Select and GENCODE Primary. The next challenge is to propagate annotations throughout multiple human and mouse genomes, as we enter the pangenome era. Our resources are freely available at our web portal www.gencodegenes.org, and via the Ensembl and UCSC genome browsers., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Introduction: Various techniques have been described for restoring leg length and offset during total hip arthroplasty (THA). We herein describe a novel "Quartered Head Technique" (QHT) involving a series of femoral osteotomies., Methods: 124 hips were included in the analysis. An anterolateral approach was used in all cases. Leg length, and offset were assessed intraoperatively and reproduced using the QHT. A leg-length discrepancy (LLD) of <6 mm was chosen as acceptable based on previously published literature. Postoperative pelvic radiographs were assessed by two independent observers to ensure inter-observer reliability., Results: The mean absolute postoperative difference in leg length from the contralateral leg was +3.58 mm. 84% of patients had LLD within ±6 mm of the contralateral limb. Mean absolute postoperative difference in offset from the contralateral leg was +3.88 mm. 90% of patients were within ±6 mm offset of the contralateral limb. There was no statistical difference noted between observer measurement., Conclusions: The QHT provides a simple, inexpensive, yet effective method of maintaining femoral leg length and offset during total hip arthroplasty., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Knowledge of the spatial distribution of many polar seabird species is incomplete due to the remoteness of their breeding locations. Here, we compiled a new database of published and unpublished records of all known snow petrel Pagodroma nivea breeding sites. We quantified local environmental conditions at sites by appending indices of climate and substrate, and regional-scale conditions by appending 30 year mean (1992-2021) sea-ice conditions within accessible foraging areas. Breeding snow petrels are reported at 456 sites across Antarctica and subantarctic islands. Although many counts are old or have large margins of error, population estimates available for 222 known sites totalled a minimum of ~ 77400 breeding pairs. However with so many missing data, the true breeding population will be much higher. Most sites are close to the coast (median = 1.15 km) and research stations (median = 26 km). Median distance to the November sea-ice edge (breeding season sea-ice maximum) is 430 km. Locally, most nests occur in cavities in high-grade metamorphic rocks. Minimum air temperatures occur at inland sites, and maxima at their northern breeding limit. Breeding location and cavity selection is likely determined by availability of suitable breeding substrate within sustainable distance of suitable foraging habitat. Within this range, nest sites may then be selected based on local conditions such as cavity size and aspect. Our database will allow formal analyses of habitat selection and provides a baseline against which to monitor future snow petrel distribution changes in response to climate change., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2024.)

For two decades the ASCO CAP HER2 testing criteria have included 0 and 1+ scores, but this distinction was inconsequential. Now, based on the DESTINY Breast-04 Trial (DB-04) results, for patients with metastatic breast cancer it underpins eligibility for T-DXd treatment. Discerning 0 from 1+ IHC staining is challenging, as HER2 low is not a biologically distinct cancer subset, there are no reference standards or controls and second-tier tests do not apply. Prior reports cast doubt on the reliability of pathologists' IHC scoring, with resulting treatment misalignments. With IRB approval, our group of 9 breast pathologists from 8 Australian laboratories had previously established HER2-low focused scoring conventions, based on the ASCO CAP 2018 HER2 guidelines, and specifying common staining pitfalls. We reported the results of a first set of 60 breast cancers evaluated with these methods 1 . After a five-month washout, for the present validation study, we have compiled a second set of 64 HER2 negative invasive breast cancer core biopsies, all assessed with the Ventana 4B5 HER2 assay. We have each scored digitized images of HER2 IHC slides of the cases. Using the majority opinion as the target score, we have calculated our performance metrics. We have compared the results of our performance in set 1 and set 2 to assess the effectiveness of our approach and learning retention. The cases in this validation set included 40 (62.5%) HER2-low, 10 (17.2%) ultralow (UL) and 13 (18.8%) null cancers. Concordance was not achieved in one case. For distinguishing HER2 low from other cancers (UL and null combined) the mean values of our performance metrics were: accuracy 89.58%, sensitivity 90.83%, specificity 87.50%, positive predictive value: 95.63%, negative predictive value 83.59% and Cohen's kappa score 0.81. Comparing these results with our initial study, we have maintained our high level of performance across these parameters. Our mean kappa score is now in the excellent range for concordance. Maintaining high performance across a range of measures in two separate datasets validates the effectiveness of our HER2 low-focused scoring conventions. Having validated our approach, we will use these reference case sets with expert level consensus scores for peer training and updating our national HER2 IHC external quality assurance program. In our ongoing studies, we are also assessing the performance of software algorithms to determine their suitability for pre-screening of HER2 IHC slides., (Copyright © 2024. Published by Elsevier Inc.)

Background: Inconsistent findings about the impact of the COVID-19 pandemic on cardiovascular disease diagnosis and consultations have been reported internationally. The objective of this study was to analyse the impact of the pandemic period (2020-2021) on the incidence rate of coronary heart disease (CHD) compared with the pre-pandemic period (2012-2019) in Bavaria, Germany., Methods: We used health claims data of around 9 million statutorily insured residents (≥20 years) of Bavaria, Germany. We calculated quarterly age-standardised incidence rates for men and women diagnosed with CHD using the European Standard Population 2013. Interrupted time series regression models were used to analyse possible pandemic effects on the CHD incidence rates., Results: Overall, 797 074 new CHD cases (47% women) were diagnosed from 2012 to 2021. Both pre-pandemic and pandemic incidence rates for women were lower than for men. Regression models showed decreasing incidence rates in the pre-pandemic period in men (-5.2% per year (p.a.), 95% CI: -5.7% to -4.7%) and in women (-6.6% p.a., 95% CI: -7.3% to -6.0%) and seasonal effects (higher in quarter 4 compared with Q1-Q3). During the pandemic period, there was no clear evidence of a level change in the incidence rates both in women and men. However, there are indications of a smaller decline in the incidence during the pandemic compared with the pre-pandemic period, in particular in women (-0.7% p.a., 95% CI: -6.0% to 4.8%) and less prominent in men (-1.7% p.a., 95% CI: -6.0% to 2.8%)., Conclusions: An overall decreasing CHD incidence rate was observed in men and women in the past decade but no clear impact of the pandemic was seen. These results show the importance of incidence monitoring beyond the pandemics to maintain chronic disease care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Objectives: To audit prospectively the accuracy, time saving and utility of a commercial artificial intelligence auto-contouring tool (AIAC). To assess the reallocation of time released by AIAC., Methods: We audited the perceived usefulness (PU), clinical acceptability and reallocation of time during the introduction of a commercial AIAC. The time from CT to plan completion (PPTT) was audited for several pathways., Results: 248 patients and 32 staff were included in this audit. PU increased with exposure to AIAC (p < 0.05). For 80% of sites AIAC was timesaving and AI contours were clinically acceptable after minor edits. Edits had little impact on doses for the majority of cases. Median PPTT reduced by 5.5 (breast) and 9 (prostate) working days (p < 0.01). Radiographers spent more time on other tasks within planning. Oncologists improved their work-life balance and increased time spent on professional development and research by up to 2 hours per week., Conclusions: All users of AIAC found it a useful tool and it improved their productivity. The contours were high quality and needed little editing. It reduced contouring time and reduced PPTT by several days in some cases. The reallocated time was staff group dependent., Advances in Knowledge: The time released by the use of AIAC can lead to a reduction in the PPTT by up to 9 days. It also improves the work-life balance of oncologists by reducing the time spent out of hours contouring., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This pilot study evaluated the design, usability, and practicality of the dPDT@home kit for treating actinic keratoses (AKs) on the face and scalp. The kit allowed patients to manage their treatment at home, reducing hospital visits and utilizing natural sunlight. While patients were very willing to use the kit again, further studies are required to evaluate outcomes and ascertain the need for additional improvements and support. Background/Objectives : Daylight photodynamic therapy (dPDT) is an established effective therapy for superficial mild-to-moderate actinic keratoses (AKs) on the face and scalp. In this project, we redesigned the delivery of dPDT using design principles and the concept of Realistic Medicine to create the dPDT@home kit. This user-friendly and environmentally conscious kit allows patients to manage their AKs at home, reducing the need for hospital visits and ensuring timely treatment to coincide with appropriate weather conditions and to prevent disease progression due to delays in diagnosis and treatment. The initial pilot phase of the study was to evaluate the usability and convenience of the practicalities of the dPDT@home kit. Methods : Patients were instructed to conduct two dPDT@home kit treatments approximately three weeks apart on suitable weather days. After a follow-up telephone consultation from the specialist PDT nurse following the first treatment, patients then completed an initial questionnaire (Questionnaire 1, Q1) to share their experience. A second questionnaire (Q2) was completed 3-6 months after their final treatment to assess treatment outcomes. Results : A total of 16 patients with AK on the face and/or scalp used the dPDT@home kit. Five patients formed an initial pilot group in 2020/21, whose feedback and involvement informed the final product for the larger group of eleven patients (2021/22). All patients reported no issues with receiving the kit or the pro-drug used in the treatment (Q1). Q2 had an 81.25% return rate, with an average willingness score of 8.9/10 to use dPDT@home again. However, patients expressed doubts about their confidence in the treatment's efficacy, giving an average score of 6.9/10, with preferences leaning towards other treatments, such as hospital-based PDT or cryotherapy. Conclusions : The pilot deployment of the dPDT@home kit identified suitable patients and highlighted the need for comprehensive training and support for both patients and clinicians to deliver dPDT through this novel approach. The kit can reduce the number of hospital visits, but patients still require supervision, which can be provided remotely. The questionnaire outcomes emphasize the importance of setting patient expectations and taking a holistic approach to managing chronic field-change AK. Additionally, the kit's recyclable components and reliance on natural sunlight promote sustainability and reduce patient travel. Further evaluation is required to determine cost-efficacy, safety, and the potential place of the dPDT@home kit in the therapeutic management of patients with this common and challenging condition.

We present a scalable protocol for measuring full counting statistics (FCS) in experiments or tensor-network simulations. In this method, an ancilla in the middle of the system acts as a turnstile, with its phase keeping track of the time-integrated particle flux. Unlike quantum gas microscopy, the turnstile protocol faithfully captures FCS starting from number-indefinite initial states or in the presence of noisy dynamics. In addition, by mapping the FCS onto a single-body observable, it allows for stable numerical calculations of FCS using approximate tensor-network methods. We demonstrate the wide-ranging utility of this approach by computing the FCS of the transferred magnetization in a Floquet Heisenberg spin chain, as studied in a recent experiment with superconducting qubits, as well as the FCS of charge transfer in random circuits.

Dirac fluids-interacting systems obeying particle-hole symmetry and Lorentz invariance-are among the simplest hydrodynamic systems; they have also been studied as effective descriptions of transport in strongly interacting Dirac semimetals. Direct experimental signatures of the Dirac fluid are elusive, as its charge transport is diffusive as in conventional metals. In this paper, we point out a striking consequence of fluctuating relativistic hydrodynamics: The full counting statistics (FCS) of charge transport is highly non-Gaussian. We predict the exact asymptotic form of the FCS, which generalizes a result previously derived for certain interacting integrable systems. A consequence is that, starting from quasi-one-dimensional nonequilibrium initial conditions, charge noise in the hydrodynamic regime is parametrically enhanced relative to that in conventional diffusive metals., Competing Interests: Competing interests statement:The authors declare no competing interest.

Motivation: Genome-wide association studies (GWAS) have been remarkably successful in identifying associations between genetic variants and imaging-derived phenotypes. To date, the main focus of these analyses has been on established, clinically-used imaging features. We sought to investigate if deep learning approaches can detect more nuanced patterns of image variability., Results: We used an autoencoder to represent retinal optical coherence tomography (OCT) images from 31,135 UK Biobank participants. For each subject, we obtained a 64-dimensional vector representing features of retinal structure. GWAS of these autoencoder-derived imaging parameters identified 118 statistically significant loci; 41 of these associations were also significant in a replication study. These loci encompassed variants previously linked with retinal thickness measurements, ophthalmic disorders and/or neurodegenerative conditions. Notably, the generated retinal phenotypes were found to contribute to predictive models for glaucoma and cardiovascular disorders. Overall, we demonstrate that self-supervised phenotyping of OCT images enhances the discoverability of genetic factors influencing retinal morphology and provides epidemiologically-informative biomarkers., Availability: Code and data links available at https://github.com/tf2/autoencoder-oct., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2024. Published by Oxford University Press.)

Background and Purpose: Abdominal pain is a leading cause of morbidity for people living with gastrointestinal disease. Whereas the transient receptor potential vanilloid 4 (TRPV4) ion channel has been implicated in the pathogenesis of abdominal pain, the relative paucity of TRPV4 expression in colon-projecting sensory neurons suggests that non-neuronal cells may contribute to TRPV4-mediated nociceptor stimulation., Experimental Approach: Changes in murine colonic afferent activity were examined using ex vivo electrophysiology in tissues with the gut mucosa present or removed. ATP and glutamate release were measured by bioluminescence assays from human colon organoid cultures and mouse colon. Dorsal root ganglion sensory neuron activity was evaluated by Ca 2+ imaging when cultured alone or co-cultured with colonic mucosa., Key Results: Bath application of TRPV4 agonist GSK1016790A elicited a robust increase in murine colonic afferent activity, which was abolished by removing the gut mucosa. GSK1016790A promoted ATP and glutamate release from human colon organoid cultures and mouse colon. Inhibition of ATP degradation in mouse colon enhanced the afferent response to GSK1016790A. Pretreatment with purinoceptor or glutamate receptor antagonists attenuated and abolished the response to GSK1016790A when given alone or in combination, respectively. Sensory neurons co-cultured with colonic mucosal cells produced a marked increase in intracellular Ca 2+ to GSK1016790A compared with neurons cultured alone., Conclusion and Implications: Our data indicate that mucosal release of ATP and glutamate is responsible for the stimulation of colonic afferents following TRPV4 activation. These findings highlight an opportunity to target the gut mucosa for the development of new visceral analgesics., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Vaccination is essential, especially in older adults whose immune system function declines with age. The COVID-19 pandemic and its associated lockdowns temporarily disrupted routine vaccination services. We aimed to assess vaccination coverage for Influenza, Pneumococcus, and Herpes zoster among older adults in Bavaria over time and investigate potential pandemic effects on these rates., Methods: Based on health claims data from the Bavarian Association of Statutory Health Insurance Physicians (KVB), we estimated the percentage of adults aged 60 years and older vaccinated following the German Standing Committee on Vaccinations (STIKO) recommendation for Influenza (2012-2021), Pneumococcus (2017-2021) and Herpes zoster (2019-2021), stratified by sex and 10-year age groups. Using time series regression analysis, we estimated the effect of the pandemic period (2020-2021) on quarterly Influenza and Pneumococcal vaccination rates., Results: In the first year of the pandemic (2020), Influenza, Pneumococcus and Herpes zoster coverage in both sexes increased by 9.9, 8.7, and 2.5 percentage points (pp), respectively. In 2021, Influenza coverage decreased by 4.7 pp., while Pneumococcus and Herpes zoster coverage increased by 2.7 and 3.8 pp., respectively. Influenza and Pneumococcal vaccinations showed a seasonal pattern, with vaccinations occurring mainly in the fourth quarter; this pattern was distorted for Pneumococcus during the pandemic. Per the time series regression analysis, Influenza vaccination rates in the fourth quarters of 2020 and 2021 were 7.86 (95 %CI: 5.10-10.62) and 8.87 (95 %CI: 5.80-11.54) pp. higher for males and females, respectively, compared to that of the pre-pandemic period. During the pandemic, the quarterly Pneumococcal vaccination rates increased by 0.68 (95 %CI: 0.19-1.18) pp. in males and 0.80 (95 %CI: 0.30-1.30) pp. in females., Conclusion: The heightened increase in vaccination rates observed in 2020 may have resulted from increased vaccination awareness during the pandemic. As the pandemic effect wanes, more efforts are needed to sustain and increase these vaccination rates., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof. Dr. Stefanie J. Klug reports financial support was provided by German Research Foundation. Marian Eberl reports a relationship with Daiichi Sankyo Europe GmbH that includes: employment. If there are other authors, they 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.)

Introduction: Chronic cough is considered a disorder of neuronal hypersensitivity in which patients frequently report abnormal laryngeal and chest sensations, and excessive triggers. To facilitate clinical assessment, we developed the Cough Hypersensitivity Questionnaire (CHQ)., Methods: Candidate questionnaire items were developed following interviews with patients with refractory chronic cough (n=10, United Kingdom), and review by a multidisciplinary team. The CHQ was evaluated in individuals with chronic cough (n=535, UK/South Korea), for unidimensionality and differential item functioning (with Rasch analysis), internal consistency, concurrent validity (against cough severity visual analogue scale (VAS) and Leicester Cough Questionnaire (LCQ) scores), and content validity (cognitive debriefing interviews, n=13)., Results: Concept elicitation created a pool of 34 items. Eleven items were removed following multidisciplinary team review of patient interviews. Rasch analysis confirmed the CHQ total score to be a unidimensional scale; one item was removed due to differential item functioning. The final 22 binary-item CHQ comprises 6 sensation-related and 16 trigger-related items. Median (interquartile range) total CHQ scores were 9 (6-12); sensations 4 (2-5) and triggers 5 (3-8). Internal consistency was good (person separation index 0.74). The CHQ total score was moderately associated with cough severity VAS (0.42, p=0.005) and LCQ total score (ρ=-0.52, p<0.001). In cognitive debriefing, patients found that the CHQ was relevant to their condition and simple to complete., Conclusion: The CHQ is simple to use and has validity for assessing cough triggers and sensations in patients with chronic cough. Further studies are needed to assess its repeatability, responsiveness and clinical utility., Competing Interests: Conflict of interest: R. Turner is an associate editor and W.-J. Song is the current Chief Editor of ERJ Open Research. The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)

Background: The movement of the barbell has been detected as success factor for the snatch and the clean and jerk events. As the barbell's movement has been shown to be related to the athlete's body movement, we hypothesized that the latter could be a success factor also for the back squat (BS) event. Hence, this study aimed to investigate postural control during the execution of the BS at different load intensities in powerlifters and weightlifters., Methods: Seventeen powerlifters and weightlifters were enrolled and the one-repetition maximum (1-RM) of the BS of each participant was measured. Afterwards, the assessment of postural control during the execution of the BS at different load intensities (i.e. 60%, 70%, 80%, 90%, 100%) of the 1-RM of each participant was carried out through a posturographic platform to measure the displacement of the centre of pressure (CoP). The following parameters were considered: sway path length (SPL), sway ellipse surface (SES), length/surface (LFS ratio), sway mean speed (SMS), CoP coordinates along X and Y planes., Results: We found a significant increase in SPL and LFS ratio, and a significant decrease in SMS as the load intensity increased. In detail, we detected a significant difference in: (a) SPL between the BS at 60% and 80%, 60% and 90%, 60% and 100%; between the BS at 70% and 90%, 70% and 100%; between the BS at 80% and 100%; and between the BS at 90% and 100%; (b) SMS between the BS at 60% and 80%, 60% and 90%; (c) LFS ratio between the BS at 60% and 90%, 60% and 100%., Conclusions: These results suggest that powerlifters and weightlifters adopt different postural control strategies depending on the load intensity when performing the BS. Our findings showed that higher effort could affect postural control during the BS. Thus, postural control could be considered a success factor for the BS.

Background: Recent clinical trials and guideline updates have highlighted the efficacy and safety of sodium-glucose cotransporter-2 inhibitor (SGLT2i) use in patients with type 2 diabetes (T2D) and comorbidities including atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or heart failure (HF). Objective: This study assesses the rates of guideline-based prescribing of SGLT2i in patients with T2D and one or more of the following comorbidities: ASCVD, CKD, or HF, prior to and after the 2022 American Diabetes Association (ADA) guideline publication within the Atrius Health clinical pharmacy, internal medicine, and specialty medicine departments. Methods: This is a retrospective chart review of data from the electronic medical record. Patients with the aforementioned criteria were included if they were managed by either the clinical pharmacy department, internal medicine, or specialty medicine departments. Patients were excluded if they did not have any of the comorbidities listed or a form of diabetes other than T2D. Results: Of the 10,631 patients enrolled, 354 (3.3%) were initiated on an SGLT2i during the study. The average number of SGLT2i initiations prior to the 2022 ADA guideline publication was five prescription starts per week. After the guideline publication initiation increased to seven prescription starts per week. Secondary outcomes showed the majority of SGLT2i prescriptions were started in the internal medicine department, followed by cardiology and nephrology. Conclusion: Overall utilization rates of SGLT2i are low but increased after the 2022 ADA guidelines were published. These results suggest opportunities to optimize the use of SGLT2i in this patient population., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: The peripheral stress response, consisting of the autonomic nervous system (ANS) and hypothalamic pituitary adrenal-axis (HPA-axis), functions to maintain homeostasis in response to stressors. Cervical spine manual therapy has been shown to differentially modulate the stress response in healthy populations. No study has investigated whether cervical spine mobilizations can differentially modulate the stress response in individuals with persistent post-concussion symptoms (PPCS), a population characterized by a dysfunctional stress response., Methods: A randomized, controlled, parallel design trial was performed to investigate whether upper or lower cervical spine mobilization can differentially modulate components of the stress response in individuals with PPCS. The outcomes were salivary cortisol (sCOR) concentration (primary) and the HRV metric, rMSSD, measured with a smartphone application (secondary). Nineteen males diagnosed with PPCS, aged 19-35, were included. Participants were randomly assigned into either intervention group, upper ( n  = 10) or lower ( n  = 9) cervical spine mobilization. Each outcome was collected at different time points, pre- and post-intervention. Statistical analyses were performed using the Friedman's Two-Way ANOVA, Mann-Whitney U test, and Wilcoxon Signed Rank Test., Results: There was a statistically significant within-group reduction in sCOR concentration 30 minutes following lower cervical spine mobilizations and statistically significant within-group increase in rMSSD 30 minutes following upper cervical spine mobilizations., Conclusion: The results of this trial provide preliminary evidence for cervical spine mobilizations to differentially modulate components of the stress response at specific time points. Understanding the mechanisms of the effect of cervical spine mobilizations on the stress response provides a novel rationale for selecting cervical spine mobilizations to rehabilitate individuals with PPCS.

Background: Although the number of places at medical schools and physicians in Germany has increased continuously over the past 25 years, there is a threat of a shortage of physicians. Based on data from the Bavarian Medical Association (BLÄK) and the Association of Statutory Health Insurance Physicians of Bavaria (KVB), an analysis of the number of physicians in Bavaria over a longer period of time was carried out in order to understand current developments and possible starting points for the future organization of medical care. The figures were analyzed with regard to the distribution of physicians by outpatient and inpatient sector as well as with regard to the development of the number of employees, the scope of employment and the gender distribution in the outpatient sector., Methods: Data were taken from the annually published and systematically compiled numbers of physicians from the BLÄK (2000 to 2022) as well as the outpatient billing data of practicing and employed physicians in Bavaria (2010 to 2022), processed by the KVB. Descriptive analyses were performed., Results: Since 2000, the number of physicians in Bavaria has risen by 83% in the inpatient setting and by 35% in the outpatient setting. As a result, more physicians have been working in hospitals than in outpatient care since 2010. In the outpatient setting the trend is moving away from establishing one's own practice and full-time work towards salaried and part-time employment. Employed physicians have lower average working hours than self-employed physicians. The proportion of women among physicians has steadily increased, with female physicians more likely to be employed and working part-time compared with male physicians. Nevertheless, part-time employment is also prominent among male physicians in some specialties today., Conclusion: The trend towards practicing in salaried and part-time positions continues unabated and is represented across all specialties, suggesting that more physicians are needed to maintain the number of working hours over time. In addition to incentives and subsidies, this reality must be taken into account when planning care. At the same time, it is questionable whether increasing medical school places without managing them according to need is the right way to address the shortage of physicians in outpatient care when an ever-increasing proportion of physicians is working in inpatient care., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

This study evaluated the association between pediatric multiple sclerosis and vaccinations within 5 years before diagnosis using German ambulatory claims data. Children with multiple sclerosis ( n  = 346) aged 9-17 were analyzed with logistic and Poisson regression. Control groups included children with Crohn's disease, psoriasis, and no autoimmune diseases. The results indicated a negative association between vaccinations and pediatric multiple sclerosis, with no significant risk identified. This negative relationship was consistent in sensitivity and clinically isolated syndrome analyses. Overall, the study's findings do not support the hypothesis that vaccination is a risk factor for pediatric multiple sclerosis., Competing Interests: Data AvailabilityFor data protection reasons, the authors cannot distribute the underlying data. Interested researchers may contact the corresponding author or the BASHIP to request access. Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: B.H. has served on scientific advisory boards for Novartis; he has received research grants from Hoffmann La Roche for multiple sclerosis research. He has received honoraria for counseling (Gerson Lehrmann Group). He holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of served as a DMSC member for AllergyCare, Sandoz, Polpharma, Biocon, and TG therapeutics; his institution patients with multiple sclerosis and one for genetic determinants of neutralizing antibodies to interferon. None of the conflicts are relevant to the topic of the study.

Background: With hospital electronic prescribing and medicines administration (HEPMA) systems now in widespread use across hospital inpatient clinical services, work is underway to measure the benefits of HEPMA on healthcare systems and patient care. HEPMA functionality enables users to prescribe medicines by 'bundle' or 'protocol'. Although it is assumed that this is a significant system benefit, there are few qualitative studies supporting this conclusion., Aim: To explore the impact of an electronic anticipatory care medicines protocol on junior doctor perceptions of their confidence and competence to prescribe opioids and midazolam for patients at the end of life., Method: Between May and August 2022, one-to-one semi-structured interviews were conducted at a 570-bed District General Hospital with junior doctors who had experience of prescribing on both HEPMA and paper-based systems. Audio recordings of the interviews were transcribed verbatim and underwent thematic analysis., Results: Ten junior doctors participated (median age 23 years). Analysis generated five main themes that described perceptions and attitudes towards confidence and competence. These were prescribing safety benefits; information technology infrastructure, interoperability and system design concerns; clinical knowledge and training needs; cultural and social factors and risks of automation in prescribing., Conclusion: This study suggests that junior doctors experienced an overall increase in their confidence and perceived competence to prescribe anticipatory medicines post-implementation of a HEPMA protocol. Further studies are required to detail the impact of HEPMA/CPOE protocols on clinical practice., Competing Interests: Conflicts of interest The authors declared that they have no conflict of interest., (© 2024. The Author(s).)

We used a spatially explicit agent-based model of SARS-CoV-2 transmission combined with spatially fine-grained COVID-19 observation data from Public Health Scotland to investigate the initial rise of the Omicron (BA.1) variant of concern. We evaluated plausible scenarios for transmission rate advantage and vaccine immune escape relative to the Delta variant based on the data that would have been available at that time. We also explored possible outcomes of different levels of imposed non-pharmaceutical intervention. The initial results of these scenarios were used to inform the Scottish Government in the early outbreak stages of the Omicron variant. Using the model with parameters fit over the Delta variant epidemic, some initial assumptions about Omicron transmission rate advantage and vaccine escape, and a simple growth rate fitting procedure, we were able to capture the initial outbreak dynamics for Omicron. We found that the modelled dynamics hold up to retrospective scrutiny. The modelled imposition of extra non-pharmaceutical interventions planned by the Scottish Government at the time would likely have little effect in light of the transmission rate advantage held by the Omicron variant and the fact that the planned interventions would have occurred too late in the outbreak's trajectory. Finally, we found that any assumptions made about the projected distribution of vaccines in the model population had little bearing on the outcome, in terms of outbreak size and timing. Instead, it was the landscape of prior immunity that was most important., Competing Interests: Declaration of competing interest No financial, personal, or professional competing interests for any of the authors are declared., (Copyright © 2024. Published by Elsevier B.V.)