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Male infertility (MI) and male sexual dysfunction (MSD) can often coexist together due to various interplay factors such as psychosexual, sociocultural and relationship dynamics. The presence of each form of MSD can adversely impact male reproduction and treatment strategies will need to be individualized based on patients’ factors, local expertise, and geographical socioeconomic status. The Asia Pacific Society of Sexual Medicine (APSSM) and the Asian Society of Men’s Health and Aging (ASMHA) aim to provide a consensus statement and practical set of clinical recommendations based on current evidence to guide clinicians in the management of MI and MSD within the Asia-Pacific (AP) region. A comprehensive, narrative review of the literature was performed to identify the various forms of MSD and their association with MI. MEDLINE and EMBASE databases were searched for the following English language articles under the following terms: “low libido”, “erectile dysfunction”, “ejaculatory dysfunction”, “premature ejaculation”, “retrograde ejaculation”, “delayed ejaculation”, “anejaculation”, and “orgasmic dysfunction” between January 2001 to June 2022 with emphasis on published guidelines endorsed by various organizations. This APSSM consensus committee panel evaluated and provided evidence-based recommendations on MI and clinically relevant MSD areas using a modified Delphi method by the panel and specific emphasis on locoregional socioeconomic- cultural issues relevant to the AP region. While variations exist in treatment strategies for managing MI and MSD due to geographical expertise, locoregional resources, and sociocultural factors, the panel agreed that comprehensive fertility evaluation with a multidisciplinary management approach to each MSD domain is recommended. It is important to address individual MI issues with an emphasis on improving spermatogenesis and facilitating reproductive avenues while at the same time, managing various MSD conditions with evidence-based treatments. All therapeutic options should be discussed and implemented based on the patient’s individual needs, beliefs and preferences while incorporating locoregional expertise and available resources.

Background Nutrition education is one the essential components of any paediatric residency training. However, many paediatricians world-wide have suboptimal knowledge in core clinical nutritional topics. The purpose of our study is to assess the perceived effectiveness of nutrition training among physicians, including paediatric residents, paediatric trainees and paediatricians; identify areas of need for additional education resources and the preferred method of teaching for nutritional topics for medical education. Material and Methods A survey-questionnaire was sent to our physicians in our centre to assess general nutrition education via self-assessment of current nutritional knowledge across 12 distinct topics; importance of teaching amongst these topics and the preferred method of teaching. Results A total of 64 physicians completed the survey with an overall response rate of 88%. Most responders reported having average or above-average knowledge base in all nutritional topics except for nutritional aspects of special diets. Poorest knowledge base (either below average or poor) was reported in special diet ( n = 38, 59.4%), inflammatory bowel disease ( n = 17, 26.6%) and gastrointestinal allergy ( n = 16, 25.0%). There was strong interest in additional teaching needs for the topics of failure to thrive ( n = 38, 59.4%), nutritional assessment ( n = 34, 53.1%) and infant feeding ( n = 31, 48.4%). Most popular teaching methods were clinical case review (31.7%) followed by didactic lectures (29.8%) for overall clinical nutritional education. Conclusions Physicians identified gaps in their nutrition knowledge base and multiple topics were identified for additional nutrition education. Preferred methods of teaching for nutritional education were clinical case reviews and didactic lectures.

Summary: Background: Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD. Methods: We did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005. Findings: 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9·5 months) from nine different countries while 18 did not provide IPD data. Risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0·4%] of 1621) than placebo (12 [0·8%] of 1537) without significant differences between groups (odds ratio [OR] 0·46 [95% CI 0·17–1·24]; p=0·13). Cardiovascular risk was similar during testosterone treatment (120 [7·5%] of 1601 events) and placebo treatment (110 [7·2%] of 1519 events; OR 1·07 [95% CI 0·81–1·42]; p=0·62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0·97 [99% CI 0·92–1·03]; p=0·17), baseline testosterone (interaction 0·97 [0·82–1·15]; p=0·69), smoking status (interaction 1·68 [0·41–6·88]; p=0.35), or diabetes status (interaction 2·08 [0·89–4·82; p=0·025) were not associated with cardiovascular risk. Interpretation: We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone. Funding: National Institute for Health Research Health Technology Assessment Programme.

In this paper, an advanced partitioned-stator switched-flux dual-excitation (PS-SFDE) machine, which is highly suitable for hybrid electric vehicles (HEVs), is proposed. By artfully implementing two excitation sources, namely the high-power-density permanent-magnet (PM) source and the DC-field excitation source, the proposed machine can take benefits from both sides. Unlike the existing PS-SFDE machines that sacrifice the PM materials for DC-field winding accommodation, the proposed machine instead shares the space of the armature winding with the DC-field winding. Hence, comparable power and torque levels can be potentially achieved.

Sclerosing lipogranuloma (SLG) of the male external genitalia is a rare benign condition presenting as subcutaneous masses. The underlying pathological process is a granulomatous reaction of fatty tissue in this area. The cause of this is unclear but hypothesis stems around the pathogenesis of exogenous lipid degeneration from injection of foreign bodies such as paraffin for penile augmentation. However, endogenous lipid degeneration from other various causes such as infection, trauma, and allergic mechanisms has also been reported. We present the case of a 40-year-old man with primary SLG of the external genitalia. Literature review on the treatment strategies are addressed and discussed.

Abstract Brain-machine interface performance can be affected by neuroinflammatory responses due to blood-brain barrier (BBB) damage following intracortical microelectrode implantation. Recent findings suggest that certain gut bacterial constituents might enter the brain through damaged BBB. Therefore, we hypothesized that damage to the BBB caused by microelectrode implantation could facilitate microbiome entry into the brain. In our study, we found bacterial sequences, including gut-related ones, in the brains of mice with implanted microelectrodes. These sequences changed over time. Mice treated with antibiotics showed a reduced presence of these bacteria and had a different inflammatory response, which temporarily improved microelectrode recording performance. However, long-term antibiotic use worsened performance and disrupted neurodegenerative pathways. Many bacterial sequences found were not present in the gut or in unimplanted brains. Together, the current study established a paradigm-shifting mechanism that may contribute to chronic intracortical microelectrode recording performance and affect overall brain health following intracortical microelectrode implantation.

Abstract Before medical professionals are permitted to use a medical device, they first must be instructed in its use. However, it is well known that this method is hazardous for both the staff and the patients due to its inadequate quality. In order to address this problem, we investigated the potential of digital technologies for enhancing medical device training. For this, we designed and implemented several diverse training methods: (1) conventional training by a medical instructor, (2) video-based training, (3) mobile application training on a tablet, (4) virtual reality training, and (5) augmented reality training. Since each method provides identical training content to the user, we compared the resulting learning outcomes between the methods. The findings indicate that virtual and augmented reality training is superior to conventional training. These digital technologies offer the opportunity to reduce the burden on healthcare professionals and increase patient safety.

Abstract Purpose For the first time, three currently available 360° CZT-SPECT/CT cameras were compared under clinical conditions using phantom-based measurements. Methods A 99mTc- and a 177Lu-customized NEMA IEC body phantom were imaged with three different cameras, StarGuide (GE Healthcare), VERITON-CT versions 200 (V200) and 400 (V400) (Spectrum Dynamics Medical) under the same clinical conditions. Energy resolution and volumetric sensitivity were evaluated from energy spectra. Vendors provided the best reconstruction parameters dedicated to visualization and/or quantification, based on their respective software developments. For both 99mTc- and 177Lu-phantoms, noise level, quantification accuracy, and recovery coefficient (RC) were performed with 3DSlicer. Image quality metrics from an approach called “task-based” were computed with iQMetrix-CT on 99mTc visual reconstructions to assess, through spatial frequencies, noise texture in the background (NPS) and contrast restitution of a hot insert (TTF). Spatial resolution indices were calculated from frequencies corresponding to TTF10% and TTF50%. Results Despite the higher sensitivity of VERITON cameras and the enhanced energy resolution of the V400 (3.2% at 140 keV, 5.2% at 113 keV, and 3.6% at 208 keV), StarGuide presents comparable image quality. This highlights the need to differentiate sensitivity from count quality, which is influenced by hardware design (collimator, detector block) and conditions image quality as well as the reconstruction process (algorithms, scatter correction, noise regulation). For 99mTc imaging, the quantitative image optimization approach based on RCmean for StarGuide versus RCmax for V200 and V400 systems (RCmean/RCmax: 0.9/1.8; 0.5/0.9; 0.5/0.9 respectively—Ø37 mm). SRTB10/50 showed nearly equivalent spatial resolution performances across the different reconstructed images. For 177Lu imaging, the 113 keV imaging of the V200 and V400 systems demonstrated strong performances in both image quality and quantification, while StarGuide and V400 systems offer even better potential due to their ability to exploit signals from both the 113 and 208 keV peaks. 177Lu quantification was optimized according to RCmax for all cameras and reconstructions (1.07 ± 0.09—Ø37 mm). Conclusions The three cameras have equivalent potential for 99mTc imaging, while StarGuide and V400 have demonstrated higher potential for 177Lu. Dedicated visual or quantitative reconstructions offer better specific performances compared to the unified visual/quantitative reconstruction. The task-based approach appears to be promising for in-depth comparison of images in the context of system characterization/comparison and protocol optimization.

Abstract Background The utilization of genomic information to improve health outcomes is progressively becoming more common in clinical practice. Nonetheless, disparities persist in accessing genetic services among ethnic minorities, individuals with low socioeconomic status, and other vulnerable populations. The Rio Grande Valley (RGV) at the Texas-Mexico border is predominantly Hispanic/Latino with a high poverty rate and very limited access to genetic services. Funded by the National Center for Advancing Translational Sciences, Project GIVE (Genetic Inclusion by Virtual Evaluation) was launched in 2022 to reduce the time to diagnosis and increase provider knowledge of genomics in this region, with the goal of improving pediatric health outcomes. We describe our experience of establishing a virtual pediatric genomic service in this region to expeditiously identify, recruit, and evaluate pediatric patients with undiagnosed diseases. Methods We have utilized an innovative electronic health record (EHR) agnostic virtual telehealth and educational platform called Consultagene to receive referrals from healthcare providers in the RGV. Using this portal, genetic services, including virtual evaluation and genome sequencing (GS), are being delivered to children with rare diseases. The study has also integrated effective methods to involve and educate community providers through in-person meetings and Continuing Professional Education (CPE) events. Results The recruitment efforts have proven highly successful with the utilization of Consultagene in this medically underserved region. The project’s ongoing engagement efforts with local healthcare providers have resulted in progressively more referrals to the study over time, thus improving inclusion and access to genomic care in the RGV. Additionally, the curated CPE content has been well received by healthcare providers in the region. Conclusions Project GIVE study has allowed advanced genetic evaluation and delivery of GS through the virtual Consultagene portal, effectively circumventing the recognized socioeconomic and logistical barriers to accessing genetic services within this border community.

Abstract The nodal-line semiconductor Mn3Si2Te6 is generating enormous excitment due to the recent discovery of a field-driven insulator-to-metal transition and associated colossal magnetoresistance as well as evidence for a new type of quantum state involving chiral orbital currents. Strikingly, these qualities persist even in the absence of traditional Jahn-Teller distortions and double-exchange mechanisms, raising questions about exactly how and why magnetoresistance occurs along with conjecture as to the likely signatures of loop currents. Here, we measured the infrared response of Mn3Si2Te6 across the magnetic ordering and field-induced insulator-to-metal transitions in order to explore colossal magnetoresistance in the absence of Jahn-Teller and double-exchange interactions. Rather than a traditional metal with screened phonons, the field-driven insulator-to-metal transition leads to a weakly metallic state with localized carriers. Our spectral data are fit by a percolation model, providing evidence for electronic inhomogeneity and phase separation. Modeling also reveals a frequency-dependent threshold field for carriers contributing to colossal magnetoresistance which we discuss in terms of polaron formation, chiral orbital currents, and short-range spin fluctuations. These findings enhance the understanding of insulator-to-metal transitions in new settings and open the door to the design of unconventional colossal magnetoresistant materials.

A doctoral-level internship program was developed at the University of North Carolina at Chapel Hill with the intent to create customizable experiential learning opportunities for biomedical trainees to support career exploration, preparation, and transition into their postgraduate professional roles. We report the outcomes of this program over a 5-year period. During that 5-year period, 123 internships took place at over 70 partner sites, representing at least 20 academic, for-profit, and non-profit career paths in the life sciences. A major goal of the program was to enhance trainees’ skill development and expertise in careers of interest. The benefits of the internship program for interns, host/employer, and supervisor/principal investigator were assessed using a mixed-methods approach, including surveys with closed- and open-ended responses as well as focus group interviews. Balancing stakeholder interests is key to creating a sustainable program with widespread support; hence, the level of support from internship hosts and faculty members were the key metrics analyzed throughout. We hypothesized that once a successful internship program was implemented, faculty culture might shift to be more accepting of internships; indeed, the data quantifying faculty attitudes support this. Furthermore, host motivation and performance expectations of interns were compared with results achieved, and this data revealed both expected and surprising benefits to hosts. Data suggests a myriad of benefits for each stakeholder group, and themes are cataloged and discussed. Program outcomes, evaluation data, policies, resources, and best practices developed through the implementation of this program are shared to provide resources that facilitate the creation of similar internship programs at other institutions. Program development was initially spurred by National Institutes of Health pilot funding, thereafter, successfully transitioning from a grant-supported model, to an institutionally supported funding model to achieve long-term programmatic sustainability.

Background Mitral valve transcatheter edge‐to‐edge repair (M‐TEER) has emerged as a viable therapy option in patients with severe mitral regurgitation and high surgical risk. Although atrial fibrillation is common among patients undergoing M‐TEER, the optimal anticoagulatory treatment after the intervention is unknown. Methods A single‐center retrospective observational analysis was conducted using data from the M‐TEER registry at the University Hospital Cologne collected from 2019 untill 2021 including patients undergoing M‐TEER between November 2012 and April 2019. Patients with atrial fibrillation receiving consistent anticoagulation following M‐TEER were categorized into a direct oral anticoagulant or a vitamin K antagonist (VKA) group. The primary end point was a composite of ischemic cerebrovascular and bleeding events. Additionally, overall survival was assessed. Results Among 613 patients undergoing M‐TEER, 206 met the inclusion criteria, with 61 receiving direct oral anticoagulants and 145 receiving VKAs. After a median follow‐up of 833 (interquartile range, 355–1271) days, the incidence of the composite primary end point did not differ between direct oral anticoagulant and VKA groups (hazard ratio [HR], 0.51 [95% CI, 0.23–1.12]; P=0.07). Similarly, rates of ischemic cerebrovascular events and bleeding events were similar between groups. However, the overall mortality rate was higher in the VKA group (HR, 2.56 [95% CI, 1.54–4.26]; P=0.002). In the multivariable analysis, oral anticoagulation with a VKA was an independent predictor for death (adjusted HR, 2.23 [95% CI, 1.08–5.06]; P=0.03). Conclusions Our findings suggest that direct oral anticoagulants may offer comparable efficacy and safety to VKAs in preventing thromboembolic events following M‐TEER in patients with atrial fibrillation. Further randomized trials are needed to confirm these results and establish optimal anticoagulation strategies in this patient population.

Background Understanding the place of death for individuals with mental and behavioural disorders (MBDs) is essential for identifying disparities in healthcare access and outcomes, as well as addressing broader health inequities within this population. Aims To examine the place of death among individuals in Sweden with the underlying cause of death reported as a MBD and compare variations between diagnostic groups, as well as explore associations between place of death and individual, sociodemographic and clinical factors. Method This population-level analysis used death certificate data (gender, age, underlying cause of death and place of death) recorded between 2013 and 2019 and other national register data. MBD group differences were compared using chi-square tests (χ2) and multinominal logistic regressions explored variations in place of death. Results The final sample consisted of 2875 individuals. Our regression model revealed that individuals with MBDs other than intellectual disabilities were less likely to die in hospitals (odds ratio 0.60–0.134 [95% CI = 0.014–0.651]) or care homes (odds ratio 0.11–0.97 [95% CI = 0.003–0.355]) than at home. Substance use disorders were the most common underlying cause of death (61.3%). This group consisted predominantly of men (78.8%, χ2, P < 0.001), and tended to be younger (χ2, P < 0.001). Conclusions Individuals with intellectual and developmental disabilities are more likely to die in hospitals or care homes than at home. Those with MBDs, particularly substance use disorders, face a high risk of premature death, highlighting gaps in healthcare and palliative care provision for these populations.

Summary: Progranulin (PGRN) deficiency is linked to neurodegenerative diseases, including frontotemporal dementia (FTD), Alzheimer’s disease, and Parkinson’s disease. Proper PGRN levels are critical for brain health; however, the function of PGRN is unclear. PGRN is composed of 7.5 repeat domains, called granulins, and processed into granulins inside the lysosome. PGRN is beneficial for neuronal health, but the role of individual granulins is controversial and unclear. We find that the expression of single granulins broadly rescues disease pathology in Grn−/− mice. Adeno-associated virus (AAV)-mediated expression of human granulin-2/F, granulin-4/A, or PGRN in Grn−/− mouse brain ameliorates dysregulated lysosomal proteins and lipids, microgliosis, and lipofuscinosis. Mechanistically, granulins localize to lysosomes in Grn−/− mouse brains or fibroblasts. These data support the hypothesis that PGRN is a precursor to granulins, which share a beneficial function inside the lysosome to maintain lipid and protein homeostasis to prevent neurodegeneration. Thus, granulins are potential therapeutics to treat FTD-GRN and related diseases.

Purpose To describe how Qualitative Meaning Analysis (QMA), based on a lifeworld theoretical approach, can be made accessible to students and researchers not well-versed in the philosophy of science or qualitative research. Additionally, to demonstrate that it is a more rigorous approach than qualitative content analysis in guiding healthcare inquiries. Method In recent years, qualitative approaches in nurse education and research have increasingly relied on various content analytical procedures. Liberated from clear philosophical underpinnings, they offer a seemingly pragmatic stance to nursing inquiries. However, by prioritizing ‘sorting content’ over the exploration of meaning, there’s a risk of adopting a mechanistic approach to qualitative analysis. This is problematic because we contend that the search for meaning lies at the heart of qualitative inquiry in nursing and healthcare research, dealing with existential phenomena surrounding health, illness, and care. Result This paper explores the search for meaning in health care research, particularly in nursing, and introduces key epistemological aspects. It also discusses practical considerations to further familiarize and encourage the use of QMA in graduate nursing education and research. Conclusion Qualitative inquiry with a focus on meaning is a powerful means when the intention is to develop person-centered care, and the relationship between the professionals and patients is in focus. Such an approach has the potential to illuminate existential suffering as well as innate health capacities in patients.

Purpose Forensic psychiatric inpatient care in Sweden is characterized by strict regulations and adherence to court-mandated rules, with a median care time of 7 years. Comorbity has significant clinical implications, impacting health and well-being, violent behaviour and criminal recidivism, and prolonging inpatient stays. This study investigated the individual experiences and perspectives of Swedish patients in forensic psychiatric care with substance use (SU) disorders, focusing on past, present and future orientations. Methods Ten male forensic psychiatric inpatients were individually interviewed following a semi-structured interview guide. A qualitative content analysis was conducted to inductively analyse the participants’ experiences. The study adhered to the Standards for Reporting Qualitative Research. Results Under the main theme of “embracing harmony in opposition”, three categories emerged: (1) unveiling the beginning of SU and its impact on navigating challenges in care, (2) exploring current confined care and gratitude despite unease and (3) yearning for a somewhat normal life. Conclusions Participants’ subjective perspectives underscored the importance of factors such as forensic nurses/healthcare providers in forensic psychiatry considering the patients’ life narratives, their aspirations for the future, their need for a secure environment and patient—staff relationships. These findings highlight the need for structural interventions that emphasize the importance of tailored and comprehensive health plans within rehabilitation.

Abstract Interleukin-1α is a suggested dual-function cytokine that diverged from interleukin-1β in mammals potentially by acquiring additional biological roles that relate to highly conserved regions in the pro-domain of interleukin-1α, including a nuclear localisation sequence and histone acetyltransferase-binding domains. Why evolution modified pro-interleukin-1α’s subcellular location and protein interactome, and how this shaped interleukin-1α’s intracellular role, is unknown. Here we show that TurboID proximity labelling with pro-interleukin-1α suggests a nuclear role for pro-interleukin-1α that involves interaction with histone acetyltransferases, including EP300. We also identify and validate inactivating mutations in the pro-interleukin-1α nuclear localisation sequence of multiple mammalian species, including toothed whales, castorimorpha and marsupials. However, histone acetyltransferase-binding domains are conserved in those species that have lost pro-interleukin-1α nuclear localisation. Together, these data suggest that histone acetyltransferase binding and nuclear localisation occurred together, and that while some species lost the nuclear localisation sequence in their pro-interleukin-1α, histone acetyltransferase binding ability was maintained. The nuclear localisation sequence was lost from several distinct species at different evolutionary times, suggesting convergent evolution, and that the loss of the nuclear localisation sequence confers some important biological outcome.

Aim: Human epidermal growth factor receptor-2 (HER2) is a well-established prognostic and predictive biomarker. It is an FDA-approved therapeutic target for HER2 positive breast, gastroesophageal, and more recently, lung and colon cancers. It is an emerging biomarker in biliary tract, bladder, cervical, endometrial, ovarian, and pancreatic cancers. The emergence of new indications warrants further characterization of HER2 expression in diverse cancer populations. This study investigated HER2 expression in solid tumour samples and the feasibility of obtaining these results. Methods: Prospective consent was obtained at a Canadian tertiary academic cancer center from adult oncology patients who were referred for molecular genetic testing of malignant tissue samples. Standard HER2-targeted malignancies were considered breast and gastroesophageal, and were excluded from this study. Between July 2020 and November 2023, 499 samples of solid tumors underwent immunohistochemistry (IHC) HER2 staining. A median turnaround time (TAT) of 14 days would be considered feasible for clinical decision making. Results: The mean age (± SD) of participants was 67 ± 12.5 years, with 270 (54%) male and 229 (46%) female. HER2 protein expression was measured in 42 unique cancer types. IHC levels of 0, 1+, 2+, and 3+ were reported and were 43%, 12%, 35%, and 10% of all analyzable samples respectively (tissue inadequate in 3% of samples). The median TAT for HER2 expression results from time of request to result in release was 18 (interquartile range, 11 to 30) days. Conclusions: HER2 protein expression varies widely between different cancer types. TAT for HER2 IHC results was a median of 18 days, which is close to our feasibility cut-off.

Abstract Background Shift workers are at an increased risk of developing sleep disorders. The standard therapy recommended for sleep disorders is cognitive behavioural therapy for insomnia (CBT-I). Many of its interventions are based on a regular sleep and wake rhythm, which is difficult to apply for shift workers. We have therefore developed a new therapy manual specifically for shift workers (CBT-I-S), which should be more applicable to their needs. In particular, all interventions that require regularity have been removed, and instead, interventions that address factors that proved to be relevant to sleep in our preliminary study have been integrated. We now want to test this manual for its effectiveness. Methods A randomised controlled trial with N = 142 will be conducted to compare two conditions: the newly developed therapy manual will be carried out in the experimental group, while cognitive behavioural therapy for insomnia will be employed in the standard group. Both treatments will be conducted online via MS Teams in a group setting with seven sessions each. Data will be collected at three measurement points (pre, post, 6-month follow-up) and analysed using linear mixed models. The study will investigate whether the two treatments have led to significant improvements in total sleep time, sleep onset latency, subjective sleep quality and daytime sleepiness in shift workers. It will also examine whether the new therapy manual is superior to standard therapy in shift workers and whether these effects are stable. Discussion We assume that interventions designed to address depressive mood, anxiety, worry, rumination, dysfunctional thought patterns and attitudes towards sleep will also improve sleep. If this is indeed the case, these interventions could replace previous ones that require regularity. This could significantly improve the treatment of insomnia in shift workers. Trial registration German Clinical Trials Registry DRKS DRKS00032086 . Registered on August 16, 2023.

We used boundary layer observations in the Stuttgart area from two summer episodes for model evaluation of the urban climate model PALM-4U. In summer 2017, radiosondes and Doppler lidars were operated, and the lidar virtual tower technique was applied to provide vertical profiles of wind speed and direction at different sites. In summer 2018, two Doppler lidars were operated in vertical stare mode providing vertical wind speeds and their variances. PALM-4U with grid spacings of 10 m in 2018 and 40 m in 2017 was driven by COSMO analysis data. The PALM-4U output data were evaluated with the observations at the corresponding sites.For 14 to 15 August 2017, the normalised root mean square error (NRMSE) between simulated and measured wind speed time series at 100 m agl is about 0.5, except for the last hours of the investigated period. The RMSE for wind direction is 30–35°. At 700 m agl, the NRMSE for wind speed is 0.2–0.3 and the RMSE for wind direction is about 15°. The greater NRMSE differences found in the night and morning of 15 August can be explained by differences between the observed and simulated height of the low-level jet which caused stronger simulated turbulent downward mixing of momentum in the morning.On 20 June 2018, the daytime convective boundary-layer evolution was well represented in the model. However, as the wind speed was low, 1-h integration times turned out to be not suitable for model evaluation because the uncertainty in variances of the vertical wind is considerable (50%). To overcome the poor statistics due to the low number of eddies dominating, 3-h integration times turned out to be necessary. For these time intervals, the simulated profiles lie within the error bars of the observations. Theoretical considerations provide suggestions for experimental set-ups and synoptic conditions to capture vertical profiles allowing model evaluations under convective conditions based on 1-h intervals.

Abstract Global optimization techniques are increasingly preferred over human-driven methods in the design of electromagnetic structures such as metasurfaces, and careful construction and parameterization of the physical structure is critical in ensuring computational efficiency and convergence of the optimization algorithm to a globally optimal solution. While many design variables in physical systems take discrete values, optimization algorithms often benefit from a continuous design space. This work demonstrates the use of level set functions as a continuous basis for designing material distributions for metasurface arrays and introduces an improved parameterization which is termed the periodic level set function. We explore the use of alternate norms in the definition of the level set function and define a new pseudo-inverse technique for upsampling basis coefficients with these norms. The level set method is compared to the fragmented parameterization and shows improved electromagnetic responses for two dissimilar cost functions: a narrowband objective and a broadband objective. Finally, we manufacture an optimized level set metasurface and measure its scattering parameters to demonstrate real-world performance.

Abstract Aims In pulmonary arterial hypertension (PAH), upfront combination therapy with ERA and PDE5i is associated with a reduction in morbidity and mortality events and improves standard haemodynamics, but data remain limited. Aims of this study were (i) to capture detailed haemodynamic effects of rapid sequential dual combination therapy in patients with newly diagnosed PAH; (ii) to monitor the impact of treatment initiation on clinical variables and patients' risk status, and (iii) to compare the treatment effect in patients with ‘classical PAH’ and ‘PAH with co‐morbidities’. Methods Fifty patients (median age 57 [42–71] years, 66% female) with newly diagnosed PAH (76% idiopathic) were treated with a PD5i/sGC‐S or ERA, followed by addition of the respective other drug class within 4 weeks. All patients underwent repeat right heart catheterization (RHC) during early follow‐up. Results At early repeat RHC (7 ± 2 months), there were substantial reductions in mean pulmonary artery pressure (mPAP: 52.2 ± 13.5 to 39.0 ± 10.6 mmHg; −25.3%), and pulmonary vascular resistance (PVR: 12.1 ± 5.7 to 5.8 ± 3.1 WU; −52.1%), and an increase in cardiac index (2.1 ± 0.4 to 2.7 ± 0.7 mL/min/m2; +32.2%) (all P 30 kg/m2, hypertension, diabetes, coronary artery disease [≥3]; n = 13), albeit baseline PVR in PAH patients with multiple co‐morbidities was lower (9.3 ± 4.4 vs. 13.1 ± 5.9 WU) and PVR reduction less pronounced compared with those with few co‐morbidities (−42.7% vs. −54.7%). However, comprehensive haemodynamic assessment considering further variables of prognostic relevance such as stroke volume index and pulmonary artery compliance showed similar improvements among the two groups (SVI: +50.0% vs. +49.2%; PAC: 91.7% vs. 100.0%). Finally, the 4‐strata risk assessment approach was better able to capture treatment response as compared with other approaches, particularly in patients with co‐morbidities. Conclusions Rapid sequential combination therapy with PDE5i/sGC‐S and ERA substantially ameliorates cardiopulmonary haemodynamics at early follow‐up in patients without, and to a lesser extent, with cardiovascular co‐morbidities. This occurs in line with improvements of clinical parameters and risk status.

Purpose – In 2022, the International Network for Quality Assurance (QA) Agencies in Higher Education (INQAAHE) published the new guidelines by adding three QA modules in response to the changing higher education landscape. The paper aims to investigate the transformative focus of quality assurance in higher education globally as well as Asian response to three new QA modules according to the INQAAHE ISGs. Design/methodology/approach – The research conducted a quantitative approach for data collection. An on-line survey was conducted to perceive QA practices, perceptions toward new emerging QA modules and challenges encountered. In total, there were 26 responses from 18 territories with 22 QA agencies. A total of 13 out of them have a national qualifications framework in place. Findings – Three are three major findings in the study. First, national policy and criteria and standards in distance education have been developed in the majority of Asian nations. Second, non-signatories of the Tokyo Convention had a higher proportion of having related policies, regulations and criteria in CBHE and distance education. Third, national policies and regulations; and lack of professional staff are two common challenges implementing QA in new types of providers. Originality/value – The findings are of value for policymakers, QA agencies and universities to advocate the new QA model as a systematic approach in response to changing higher education landscape in the post pandemic era.

Abstract Thymic stromal lymphopoietin (TSLP) is a key player in atopic diseases, which has sparked great interest in therapeutically targeting TSLP. Yet, no small-molecule TSLP inhibitors exist due to the challenges of disrupting the protein–protein interaction between TSLP and its receptor. Here, we report the development of small-molecule TSLP receptor inhibitors using virtual screening and docking of >1,000,000 compounds followed by iterative chemical synthesis. BP79 emerged as our lead compound that effectively abrogates TSLP-triggered cytokines at low micromolar concentrations. For in-depth analysis, we developed a human atopic disease drug discovery platform using multi-organ chips. Here, topical application of BP79 onto atopic skin models that were co-cultivated with lung models and Th2 cells effectively suppressed immune cell infiltration and IL-13, IL-4, TSLP, and periostin secretion, while upregulating skin barrier proteins. RNA-Seq analysis corroborate these findings and indicate protective downstream effects on the lungs. To the best of our knowledge, this represents the first report of a potent putative small molecule TSLPR inhibitor which has the potential to expand the therapeutic and preventive options in atopic diseases.

Introduction Integrating health and social care to address unmet social needs is an emerging priority for health systems worldwide. Screening and referral interventions for unmet social needs, also known as Health Navigator (HN) interventions, in healthcare settings have shown mixed but promising results, mostly due to a large variability in intervention design and outcomes assessed. Most HN interventions are implemented in primary care, despite evidence that disadvantaged populations face substantial barriers to accessing such care, and these interventions are limited in Australia. To address this gap, we designed a HN intervention to address the unmet social needs of a disadvantaged population living with cancer presenting at an outpatient cancer treatment facility in South Australia. To our knowledge, this paper presents a protocol for one of the first feasibility and acceptability studies of an HN intervention in an Australian healthcare setting.Methods and analysis We will conduct a single-centre study to explore the feasibility and acceptability of screening and referral for unmet social needs for patients attending an outpatient cancer clinic at a major metropolitan hospital serving a disadvantaged population in South Australia. Eligible participants are 18 years of age or older receiving treatment at the Northern Adelaide Cancer Centre, with an expected prognosis of minimum 6 months. During recruitment, a researcher will ask eligible participants to complete unmet social needs screening and baseline assessments. Participants with unmet social needs who request assistance will be connected with an HN. The HN will work with participants to prioritise their needs and provide referrals to community and government services with follow-up of over 6 months from enrolment. Post-HN intervention, all participants will be asked to complete repeat unmet social needs screening and repeat assessments. The primary criteria for determining feasibility success are: (1) recruitment rates, where 80% of eligible participants agree to unmet needs screening; (2) intervention uptake, where 80% of participants who report unmet social needs consent to assistance from a HN; (3) intervention completion, where 80% of participants receive HN assistance complete follow-up; (4) reasons for not completing intervention; and (5) participant and clinician acceptability of the intervention. Secondary outcomes include changes to unmet social needs and coping with cancer ability, quality of life and patient-reported experience measures. Thematic analysis will be applied to focus groups with clinicians and participants to assess intervention acceptability. Secondary clinical outcomes will be reported as effect size estimates for future trials. Based on previous work in this area, we will aim to recruit 350 participants. Study findings will be used to optimise recruitment and intervention components and develop suitable outcome measures for larger, randomised studies.Ethics and dissemination The protocol has ethical approval from the Central Adelaide Local Health Network Human Research Ethics Committee (approval ID: 16448). Findings will be disseminated in research publications and non-academic formats for a variety of audiences.Trial registration number Australian New Zealand Clinical Trial Registry (ACTRN12622000802707p).Protocol date and version: 07 June 2022, V1.

Background There are no specific national guidelines in England to guide healthcare professionals in how to assess or treat young people with tic disorders. Access to evidence-based treatment, including behavioural therapy, is of limited availability.Objectives This study examined the economic impact on services arising from a lack of access to appropriate healthcare services for young people with tic disorders, alongside the impact on school attendance.Methods This study used data from the randomised controlled trial ‘ORBIT’ (Online Remote Behavioural Intervention for Tics). ORBIT compared online exposure and response prevention behavioural therapy for tics with online psychoeducation and recruited 224 young people aged 9–17 years in England. Here, we explore costs of health service use and school absenteeism from children who participated in the ORBIT trial and present these alongside the economic impact of including ORBIT within a tic service. We supplement ORBIT data with findings from two case studies.Findings The data showed that patients have care from several healthcare professionals and miss school due to accessing care for tics. The case studies suggest that most of these contacts with specialist services are unlikely to be supportive. However, adding ORBIT could save the National Health Service £1 million.Conclusions Young people with tic disorders are likely to engage in substantial use of healthcare resources because of inadequate care pathways. The availability of an evidence-based online therapy such as ORBIT could save money to the healthcare system.Clinical implications There is a need to improve service provision and develop national guidelines for tic disorders.Trial registration number ISRCTN70758207, NCT03483493.

Shrimp allergy, the most common food allergy in the United States, affects up to 2% of the population. Its etiology is multi-factorial with the combination of genetic predisposition and environmental exposures. This review summarizes the latest diagnosis and management strategies for shrimp allergy. Currently, the double-blind, placebo-controlled food challenge is the gold standard for diagnosis. Moreover, mainstream and experimental management strategies include food allergen avoidance, the FDA-approved omalizumab, and oral immunotherapy. Herein, we emphasize the urgent need to develop more effective diagnostic tools and therapies for shrimp allergy.

Background:. Closed-incision negative pressure therapy (ciNPT) decreases the rate of wound complications in oncoplastic breast surgery (OBS) but at a fiscal cost. Our aim was to examine the cost-utility of ciNPT in OBS. Methods:. A literature review was performed to obtain the probabilities and outcomes for the treatment of unilateral breast cancer with OBS with ciNPT versus without. Reported utility scores in the literature were used to calculate quality-adjusted life years (QALYs) for each health state. A decision analysis tree was constructed with rollback analysis to determine the more cost-effective strategy. An incremental cost–utility ratio was calculated. Sensitivity analyses were performed. Results:. OBS with ciNPT is associated with a higher clinical effectiveness (QALY) of 33.43 compared to without (33.42), and relative cost increase of $667.89. The resulting incremental cost-utility ratio of $57432.93/QALY favored ciNPT. In one-way sensitivity analysis, ciNPT was the more cost-effective strategy if the cost of ciNPT was less than $1347.02 or if the probability of wound dehiscence without was greater than 8.2%. Monte Carlo analysis showed a confidence of 75.39% that surgery with ciNPT is more cost effective. Conclusion:. Despite the added cost, surgery with ciNPT is cost-effective. This finding is a direct result of decreased overall wound complications with ciNPT.

OBJECTIVES: This article aims to expand the literature on myoepitheliomas by describing several cases with an emphasis on histological presentation, clinical appearance, and demographics. To the best of our knowledge, this article is the largest single-center case series of myoepitheliomas. METHODS: A retrospective search for myoepithelioma salivary gland tumors in the oral and maxillofacial pathology archive at The Dental College of Georgia was performed. Patient demographics and the clinicopathologic features were collected and analyzed. Additionally, a comprehensive literature review of benign myoepithelioma of the salivary glands was conducted. The database PubMed was searched from (1/1/2008-to-9/1/2023) using the search terms: “salivary gland”, “myoepithelioma.” Demographic and clinicopathologic data were extracted and analyzed. Descriptive analysis was performed using SPSS Statistics Version 26 (IBM Corporation, NY). Categorical data was analyzed through the Fisher exact test. Results were considered statistically significant at (P < .05). RESULTS: Institutional Case Series: The retrospective search revealed 13 cases of myoepithelial salivary gland tumors—9 benign myoepitheliomas & 4 malignant myoepithelial tumors (included for comparison). Tumor morphology was analyzed—epithelioid pattern, 6 cases (4 benign, 2 malignant); spindle cell pattern, 6 cases (4 benign, 2 malignant); plasmacytoid pattern, 7 cases (6 benign, 1 malignant). The characteristics of connective tissue trauma were also analyzed. The stroma was myxoid in 2 cases (1 benign, 1 malignant), fibrinous in 5 cases (4 benign, 1 malignant), and necrotic in 2 cases (2 malignant). The difference in reported clinicopathologic characteristics was not statistically significant, except for the presence of mitosis (p=.001). CONCLUSIONS: Rare salivary gland tumors, especially those arising in atypical locations with ambiguous morphological patterns, present a unique diagnostic challenge. Due to myoepithelioma's ability to manifest in the various glandular structures of the head and neck, dental professionals and physicians who encounter head and neck pathology must recognize this entity as part of their differential diagnosis when clinically appropriate. IMPLICATIONS: This project is targeted at clinicians and pathologists who encounter and manage head and neck pathology. Due to the rarity of this tumor class, there are many case reports, but no case series or reviews of this magnitude providing a clear profile of this neoplasm. The value of this article lies in the scope of our data set and the clinicopathologic overview it provides. It will contribute to improved differential diagnoses and, therefore, improved management of this condition.

OBJECTIVES: Localized Juvenile Spongiotic Gingival Hyperplasia (LJSGH) is a condition characterized by localized, red, and raised gingival lesions with distinct histological findings. The exact etiology of LJSGH has not been established, but trauma and orthodontic treatment have been proposed as possible causes. The aim of this review article is to identify etiologies of this condition and report evidence of which factors are most closely associated with LJSGH. METHODS: A systematic literature search of the databases Pubmed, EMBASE, and Google Scholar through December 2023 was conducted. 215 subjects across 30 case series/studies were included and a descriptive analysis of data concerning patient demographics, clinical presentation, and treatment was conducted. Prevalence of potential etiologic contributors was also noted. RESULTS: The review yielded 215 subjects, 110 males (51.2%) and 105 females (48.8%). The age was reported in 135 participants, with a mean age of 14.9 (Median= 12, SD= 11.14). Lesions were solitary in 94.0% of the cases (n= 202) and 86% of the cases (n=197) occurred on the maxilla, with 93.4% (n= 214) of lesions affecting the anterior portions of the gingiva. The facial surface of the gingiva was involved in 90.8% of the cases (n=208). The most common treatment for LJSGH was surgical excision (71%, n=87) followed by biofilm control and observation (13.9%, n= 17). Most lesions were not concurrent with orthodontic treatment (86.3%, n=107). In addition, other types of traumas preceding the lesions, such as dental extractions, were reported in only two patients. CONCLUSIONS: Despite growing interest over the last couple of decades regarding LJSGH, it is still a poorly understood and underreported condition. Further research is required to better understand the disease process and how to treat it. IMPLICATIONS: By highlighting the most prevalent etiological factors, clinical patterns, and treatment modalities associated with LJSGH throughout the current literature, this review may serve as a comprehensive resource for the disease process.

Background. Preformed donor-specific HLA antibodies (DSA) are a well-known risk factor in kidney transplantation. There is still considerable debate, however, about the optimal risk stratification among patients with preformed DSA. Additionally, data on the prognostic value of different crossmatch assays in DSA-positive patients are scarce. Methods. DSA-positive living kidney transplant recipients were selected from a multicenter study examining 4233 consecutive renal transplants. An additional 7 patients from 2 further centers were included. Flow cytometric crossmatches (FXM), Luminex-based crossmatches, and virtual crossmatches based on C1q- and C3d-binding antibodies (C1qXM and C3dXM) were performed retrospectively using pretransplant sera and lymphocytes isolated from fresh samples. These samples were obtained from 44 donor and recipient pairs from 12 centers. Clinical outcome data and the control group without DSA were compiled from the previous study and were supplemented by data on 10-y death-censored graft survival (10yGS). Results. Between 19% (C3dXM) and 46% (FXM) of crossmatches were positive. Crossmatch-positive patients showed high incidences of antibody-mediated rejection (AMR) within 6 mo (up to 60% in B-cell FXM+ patients). The incidence of AMR in crossmatch-negative patients ranged between 5% (FXM−) and 13% (C1qXM−). 10yGS was significantly impaired in patients with positive T-cell FXM and total FXM compared with both patients without DSA and those with DSA with negative FXM. Conclusions. Especially FXM are useful for risk stratification, as the outcome of DSA-positive, FXM-negative patients is similar to that of DSA-negative patients, whereas FXM-positive patients have both more AMR and decreased 10yGS. Because of their lower sensitivity, the significance of Luminex-based crossmatches, C1qXM, and C3dXM would have to be examined in patients with stronger DSA.

Background Higher cardiac troponin is associated with worse outcomes in patients with acute heart failure. The significance of repeat measurements over hours remains unclear. We assessed whether a repeat measurement and the Δ between measurements of high‐sensitivity cardiac troponin I (hs‐cTnI) were associated with outcomes in hypervolemic patients with acute heart failure without acute coronary syndrome. Methods and Results We analyzed 582 individuals from AKINESIS (Acute Kidney Injury Neutrophil Gelatinase‐Associated Lipocalin Evaluation of Symptomatic Heart Failure Study) with hs‐cTnI measured ≤12 hours from admission and repeated ≤6 hours thereafter. Associations between hs‐cTnI levels and their Δ with short‐term (death, intensive care unit admission, receipt of inotropes, or positive pressure ventilation during hospitalization) and long‐term (death or heart failure readmission within 1 year) outcomes were assessed. The average age was 69±13 years, 62% were men, 65% were White, 46% had coronary artery disease, and 22% had chest pain. Median hs‐cTnI levels were 27 (interquartile range [IQR], 13–62) ng/L initially and 28 (IQR, 14–68) ng/L subsequently, with a Δ of 0 [IQR, −2 to 4] ng/L over 3.4±1 hours. Only the second measurement was associated with short‐term outcomes (odds ratio, 1.14 per 2‐fold higher [95% CI, 1.02–1.28]). Both individual measurements and the Δ were associated with long‐term outcomes (hazard ratios, 1.09, 1.12, and 1.16 for first, second, and Δ, respectively). Associated risk for the first and second measurements were not constant over the year but highest early after being measured and decreased over 1 year. Conclusions Repeat measurements of hs‐cTnI over hours can identify individuals with acute heart failure without acute coronary syndrome at risk for short‐ and long‐term outcomes.