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Purpose: The study aimed to investigate the effect of a Western classical symphonic concert on mental wellbeing in war veterans compared to a general audience. Methods: A quasi-experimental pre-post measurement study assessed psychological stress with the Immediate Stress State VAS scale. The Music Experience Questionnaire captured perceived bodily, emotional, and mental changes. Findings: Twenty-one veterans and a general audience of n = 405 participated in the study. Both groups found reduced stress from before to after the concert; in the general audience, it was significant (p < .001). 47% of the veterans experienced a high-stress state before the concert compared to 19% after the concert (versus 15% and 5% in the general audience). The veterans perceived significantly more safety, relaxation, and calm after the concerts and indicated a positive bodily state and presence change. In contrast, the public emphasized the aesthetical impact of the concert. Originality: The unique contribution of this study lies in its collaboration with veterans in the organization of the concerts. This adds significant value to the study, enlightening the audience with new knowledge in an underresearched field: the impact of music experiences on the wellbeing of veterans.

Abstract Background SafeBoosC-III is a pragmatic, multinational clinical trial evaluating cerebral oximetry-guided treatment for extremely preterm infants. In total, 1601 infants were randomised across 70 sites in Asia, Europe, and USA. To enhance data quality and patient care, a web-based training program was implemented for staff. We now report on the processes. Methods All training modules consisted of initial learning material followed by a case-based quiz, with elaborate responses to correct as well as to wrong answers. Modules covered trial introduction, cerebral oximetry monitoring, treatment guidelines, cerebral ultrasound, and Good Clinical Practice. The introduction module was accessible in eight languages on an online platform, while language versions varied for other modules, due to different needs. Certification was earned upon module completion, relevant to the staff category. The training was not mandatory, but for motivational purposes, principal investigators continuously received local certification rate reports. Results A total of 926 out of 2347 staff (39%) obtained certification. Amongst 295 staff who completed the evaluation, 83% rated the program as overall good and 94% found it relevant to clinical practice. Sites exhibited varying certification rates, with 10 at 0%, 43 between 0.1 and 79.9%, and 17 exceeding 80%. There was no correlation between the rate of certification in individual sites and how often the clinical management was changed due to cerebral hypoxia nor a correlation to site-specific estimates of the intervention effect. Conclusion Despite language barriers and a low budget, our web-based training and certification program proved feasible. Only a minority of sites reached 80% certification of staff and an impact on the trial could not be detected. Trial registration The SafeBoosC-III trial is registered at ClinicalTrials.gov NCT03770741. The first participant was randomised in June 2019 and recruitment was completed in December 2021.

Interprofessional teamwork is important for the provision of safe, high value patient care and is recognized as essential by the ACGME. We aimed to assess the impact of an interprofessional continuity clinic teamwork curriculum on perceptions of team development and patient safety. This project was conducted in an IM Resident Continuity Clinic where 96 residents, supported by 28 faculty and 48 interprofessional team members, attended continuity clinic two afternoons per week during alternating months of a 50/50 outpatient-inpatient training model. Teams were configured into two groups of residents, faculty and interprofessional team members. The randomly selected intervention group participated in strategically-timed TeamSTEPPS training. The control group received usual clinic education. Teamwork and safety climate were measured using the Team Development Measure (TDM) and Safety Attitudes Questionnaire (SAQ) collected before and after the intervention. Following the teamwork curriculum, team development improved in the intervention group as compared to control [mean change (95% CI) +13.9 (+9.3, +18.6) versus + 4.8 (+0.4, +9.1), p = 0.007]. Though 30% of the individual items on the SAQ improved significantly in the faculty intervention group as compared to control, the overall improvement in SAQ [intervention mean change + 0.4 (+0.2, +0.5), control mean change + 0.2 (−0.1, +0.5)] was not statistically significant (p = 0.36). It is feasible to implement a TeamSTEPPs-based interprofessional teamwork curriculum among IM residents in a block clinic model and achieve enhanced teamwork and safety attitudes. Additional assessment of clinical and educational outcomes is ongoing.

Klebsiella pneumoniae is a ubiquitous nosocomial pathogen associated with various types of infections in hospitalized patients and different animal species. In the current study, 49 Klebsiella strains isolated from humans, dogs, and cats were investigated using NGS technology. MALDI-TOF failed to identify newly discovered K. variicola and K. quasipneumoniae isolates correctly. MLST analysis revealed different sequence types among K. pneumoniae isolates, and the most frequent STs were ST29, ST219, and ST37. Three ST23 that are generally known as hypervirulent type were identified but they lacked major discriminatory determinants for hypervirulent K. pneumoniae (hvKp). K. pneumoniae isolates showed high diversity, and several isolates from humans and animals were assigned to the same ST and were almost identical. Isolates from humans exhibited more pronounced resistance patterns compared to the animal isolates. High levels of resistance were observed for piperacillin, trimethoprim/sulfamethoxazole, and cephalosporins, and resistance to carbapenem compounds was only found in isolates of human origin. Three strains of human origin were extensively drug-resistant (XDR). A diverse range of resistance genes primarily confer resistance to beta-lactams., phenicol/quinolone, aminoglycoside, macrolide, sulfonamides, and fosfomycin were identified in silico. However, there were inconsistencies between the phenotypic characterization of isolates and the set of resistance genes detected in silico in this set of Klebsiella isolates. Further research using a larger number of isolates from various sources is necessary to fully comprehend the relationship between the presence of antimicrobial resistance determinants and phenotypic data. It is also necessary to monitor the spread of K. pneumoniae from a One Health perspective in Egypt.

Objective: To test and evaluate a sofware dedicated to the follow-up of oncological CT scans for potential use in the Radiology department. Materials and methods: In this retrospective study, 37 oncological patients with baseline and follow-up CT scans were reinterpreted using a dedicated software. Baseline CT scans were chosen from the imaging reports available in our PACS (picture archiving and communicatin systems). Follow-up interpretations were independently assessed with the software. We evaluated the target lesion sums and the tumor response based on RECIST 1.1 (Response Evaluation Criteria in Solid Tumors). Results: There was no significant difference in the target lesion sums and the tumor response assessments between the PACS data and the imaging software. There was no over or underestimation of the disease with the software. There was a sigificant deviation (progression versus stability) in three cases. For two patients, this difference was related to the evaluation of the response of non-target lesions. The difference in the third patient was due to comparison with a previous CT scan than to the baseline exam. There was a miscalculation in 13 % of the reports and in 28 % of the cases the examination was compared to the previous CT scan. Finally, the tumor response was not detailed in 43 % of the follow-up reports. Conclusion: The use of dedicated oncology monitoring software could help in reducing intepretation time and in limiting human errors.

Objective: Examination of the impact of the COVID-19 pandemic on rates of antipsychotic medication use, initiation and discontinuation, among newly admitted long-term care residents. Design: Repeated cross-sectional study. Settings and Participants: Long-term care home residents in Alberta, British Columbia and Ontario, Canada assessed with the Minimum Data Set (MDS) 2.0 assessment. The cohort was segmented according to admission during the pandemic (March 2020/2021) and 2 pre-pandemic (March 2018/2019 and March 2019/2020) periods. Methods: Multivariable logistic regression models were fit to characterize the association between long-term care admission during the COVID-19 pandemic and the use of antipsychotic medications. A second set of logistic regression models were fit among residents with follow-up assessments to characterize the association between long-term care admission and antipsychotic initiation/discontinuation at follow-up. All models were adjusted for resident characteristics including sex, age group, Aggressive Behaviour Scale score, Cognitive Performance Scale score, and diagnoses of Alzheimer’s disease and related dementias, anxiety disorder, depression, and bipolar disorder. Results: 21 612 residents admitted during the pandemic and over 30 000 in each pre-pandemic period were included. Antipsychotic use increased during the pandemic period among newly admitted residents from both community (adjusted odds ratio [aOR] 1.20-1.29) and hospital settings (aOR 1.21-1.23). Residents admitted during the pandemic period were more likely to have antipsychotic medications initiated (aOR 1.25-1.26) and less likely to have had them discontinued (aOR 0.74-0.76) at the time of follow-up assessment. Conclusion and Implications: Multiple factors contributed to the observed increase in antipsychotic medication use among newly admitted long-term care home residents during the COVID-19 pandemic: increased medication use at the time of admission, increased medication initiation at follow-up, and decreased medication discontinuation at follow-up. A whole-systems approach that extends beyond long-term care into hospital and community settings is necessary to address this prevalent issue.

Abstract Synucleinopathies such as Parkinson’s disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We have previously shown that destabilization of α-synuclein tetramers is associated with familial PD due to SNCA mutations and demonstrated brain-region specific alterations of α-synuclein multimers in sporadic PD patients following the classical Braak spreading theory. In this study, we assessed relative levels of disordered and higher-ordered multimeric forms of cytosolic α-synuclein in blood from familial PD with G51D mutations and sporadic PD patients. We used an adapted in vitro-cross-linking protocol for human EDTA-whole blood. The relative levels of higher-ordered α-synuclein tetramers were diminished in blood from familial PD and sporadic PD patients compared to controls. Interestingly, the relative amount of α-synuclein tetramers was already decreased in asymptomatic G51D carriers, supporting the hypothesis that α-synuclein multimer destabilization precedes the development of clinical PD. Our data, therefore suggest that measuring α-synuclein tetramers in blood may have potential as a facile biomarker assay for early detection and quantitative tracking of PD progression.

Aim and Objectives: We aimed to test the predictive value of readily accessible and easily performed post-surgical “bedside tests” on their validity of long-term urinary incontinence (UI) (≥12 months) in patients following robot-assisted laparoscopic radical prostatectomy (RALP). Material and Methods: Patients undergoing RALP between July 2020 and March 2021 were prospectively included and subdivided into two groups based on their pad usage after 12 months (0 vs. ≥1 pad). After catheter removal, patients performed a 1 h pad test, documented the need for pad change in a micturition protocol and received post-voiding residual urine volume ultrasound. Univariate and multivariable analyses were used to demonstrate the predictive value of easily accessible tests applied after catheter removal for UI following RALP. Results: Of 109 patients, 47 (43%) had to use at least one pad (vs. 62 (57%) zero pads) after 12 months. Univariate testing showed a significant difference in urine loss between both groups evaluated by the 1 h pad test performed within 24 h after catheter removal (70% < 10 mL, vs. 30% ≥ 10 mL, p = 0.004) and in the need for pad change within the first 24 h after catheter removal (14% dry pads vs. 86% wet pads, p = 0.003). In multivariable analyses, the combination of both tests (synoptical incontinence score) could be confirmed as an independent predictor for UI after 12 months (p = 0.011). Conclusions: Readily accessible “everyday” diagnostics (pad test/change of pads after catheter removal) following RALP seem to be associated with a higher rate of long-term UI. This finding is crucial since patients with a potentially higher need for patient education and counselling can be identified using these readily accessible tests. This could lead to a higher patient satisfaction and improved outcomes.

Abstract Background The process of obtaining prior informed consent for experimental treatment does not fit well into the clinical reality of acute and intensive care. The therapeutic window of interventions is often short, which may reduce the validity of the consent and the rate of enrolled participants, to delay trial completion and reduce the external validity of the results. Deferred consent and ‘opt-out’ are alternative consent methods. The SafeBoosC-III trial was a randomised clinical trial investigating the benefits and harms of cerebral oximetry monitoring in extremely preterm infants during the first 3 days after birth, starting within the first 6 h after birth. Prior, deferred and opt-out consent were all allowed by protocol. This study aimed to evaluate the use of different consent methods in the SafeBoosC-III trial, Furthermore, we aimed to describe and analyse concerns or complaints that arose during the first 6 months of trial conduct. Methods All 70 principal investigators were invited to join this descriptive ancillary study. Each principal investigator received a questionnaire on the use of consent methods in their centre during the SafeBoosC-III trial, including the possibility to describe any concerns related to the consent methods used during the first 6 months of the trial, as raised by the parents or the clinical staff. Results Data from 61 centres were available. In 43 centres, only prior informed consent was used: in seven, only deferred consent. No centres used the opt-out method only, but five centres used prior and deferred, five used prior, deferred and opt-out (all possibilities) and one used both deferred and opt-out. Six centres applied to use the opt-out method by their local research ethics committee but were denied using it. One centre applied to use deferred consent but was denied. There were only 23 registered concerns during the execution of the trial. Conclusions Consent by opt-out was allowed by the protocol in this multinational trial but only a few investigators opted for it and some research ethics boards did not accept its use. It is likely to need promotion by the clinical research community to unfold its potential.

Summary: Background: Female mice are more resistant to obesogenic effects of a high-fat diet (HFD), compared to male mice. Although the underlying mechanisms are poorly understood, sex hormones seem to play an important role. Interestingly, the activity of the oestrogen receptor-α (ERα) is affected by the calcium-sensing-receptor (CaSR). Therefore, we investigated sex-differences upon diet-induced obesity and the role of adipocyte-specific CaSR herein. Methods: Adipocyte-specific Casr deficient mice (AdipoqCre+Casrflox) and control mice (Casrflox) were injected with AAV8-PCSK9 to make them prone to develop atherosclerosis and fed an obesity-inducing diet for 12 weeks. Findings: Female mice have lower visceral white adipose tissue (vWAT) mass compared to male mice, while this sex-difference is abolished upon adipocyte-specific Casr deficiency. Furthermore, while females showed elevated levels of inflammatory cytokines and CD3+CD8+ T cell accumulation in vWAT, compared to males, adipocyte-specific Casr deficiency abrogated this sex-phenotype and demonstrated an inhibition of inflammatory signalling pathways. The expression of Erα, as well as associated genes involved in adipocyte differentiation, was increased in female mice in a mostly adipocyte-specific Casr dependent manner. Interestingly, circulating lipid levels were reduced in female compared to male mice, which correlated with decreased atherosclerotic plaque formation. These systemic effects were abrogated upon adipocyte-specific Casr deficiency. Interpretation: Our findings indicate that female mice show a more pronounced vWAT dysfunction compared to males upon obesity. This sex effect is abolished upon adipocyte-specific Casr deficiency. In contrast, females show diminished atherosclerotic plaque formation compared to males, an effect that was abrogated by adipocyte-specific Casr deficiency. Funding: This work was supported by a grant from the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University, by the Corona Foundation, by the Deutsche Forschungsgemeinschaft (DFG), the BMBF and Free State of Bavaria and the DZHK.

Summary: Background: Contact tracing was described as a key strategy to contribute to controlling the spread of severe acute respiratory syndrome of Coronavirus 2 (SARS-CoV-2) but implementing it can be a challenge. Digitalisation of contact tracing is among the proposed solutions being explored in sub-Saharan African settings. We assessed the effectiveness of a digital tool to expand SARS-CoV-2 testing in exposed individuals in Cameroon. Methods: We conducted a cluster-randomised (1:1) trial in eight health districts, including 22 facilities and SARS-CoV-2 testing units, randomly assigned to a digital (intervention) or standard (control) contact tracing approach. The intervention consisted of a contact tracing module added to the digital platform “Mamal PRO” used for monitoring and coordination of Coronavirus Disease 2019 pandemic response in Cameroon. The primary outcome was the proportion of contacts declared by SAR-CoV-2 index patients who were successfully traced and tested for SARS-CoV-2 evaluated with a Poisson regression model with cluster adjustment. This study is registered with ClinicalTrials.gov (NCT05684887). Findings: Between October 18, 2022, and March 31, 2023, we enrolled 164 index patients in the intervention arm and 149 in the control arm, who identified 854 and 849 contacts, respectively. In the intervention arm, 93.8% (801/854) of identified contacts were successfully reached by the tracing unit versus 54.5% (463/849) in the control arm. The intervention significantly increased the likelihood of successfully tracing contacts (adjusted relative risks (RR) 1.72 [95% CI: 1.00–2.95], p = 0.049). The median (interquartile range, IQR) time to successfully tracing contacts was 0 days [IQR: 0, 1] in the intervention and 1 day [IQR: 0, 2] in the control arm. In the intervention arm, 21.3% (182/854) of identified contacts received SARS-CoV-2 testing compared to 14.5% (123/849) in the control arm (adjusted RR 1.47 [95% CI: 0.44–4.90], p = 0.530). Interpretation: Digitalising the contact tracing process improved exposure notification and facilitated the tracing of a greater number of contacts of individuals infected with SARS-CoV-2 in resource-limited settings. Funding: The study was funded by FIND, United Kingdom (FCDO 40105983), Switzerland (81066910), Netherlands (SDD 4000004160), Canada (DFATD 7429348), The Kingdom of Saudi Arabia (FIND—ACT-A DX PARTNERSHIP 20.08.2020), The Rockefeller Foundation (2020 HTH 059), Germany (BMZ Covid-19 Diagnostic and Surveillance Response 27.07.2021), Australia (DFAT 76442), Kuwait (M239/2020), The Government of Portugal and Partners (ANF, BCP, CGF, APIFARMA) and The BlackRock Foundation (Grant Agreement as of April 20, 2022).

This study aimed to investigate metabolism modulation and dyslipidemia in genetic dyslipidemic mice through physical exercise. Thirty-four male C57Bl/6 mice aged 15 months were divided into non-transgenic (NTG) and transgenic overexpressing apoCIII (CIII) groups. After treadmill adaptation, the trained groups (NTG Ex and CIII Ex) underwent an effort test to determine running performance and assess oxygen consumption (V̇O2), before and after the training protocol. The exercised groups went through an 8-week moderate-intensity continuous training (MICT) program, consisting of 40 min of treadmill running at 60% of the peak velocity achieved in the test, three times per week. At the end of the training, animals were euthanized, and tissue samples were collected for ex vivo analysis. ApoCIII overexpression led to hypertriglyceridemia (P

The aim of this study was to validate the Neuropathic Pain for Post-Surgical Patients (NeuPPS) scale against clinically verified neuropathic pain (NP) by quantitative sensory testing (QST) as well as evaluation of other psychometric properties. The NeuPPS is a validated 5-item scale designed to evaluate NP in surgical populations.

Susan D Mathias,1 Laurie Burke,2 Hilary H Colwell,1 George Mensing,3 Will Savage,3 Hetanshi Naik4 1Health Outcomes Solutions, Palm Beach Gardens, FL, USA; 2LORA Group, Normal, IL, USA; 3Disc Medicine, Watertown, MA, USA; 4Department of Genetics, Stanford University School of Medicine, Palo Alto, CA, USACorrespondence: Hetanshi Naik, Department of Genetics, Stanford University School of Medicine, Palo Alto, CA, USA, Email naikh@stanford.eduPurpose: Erythropoietic protoporphyria (EPP), a rare inherited disorder, presents in early childhood with severe, painful phototoxicity, with significant impacts on health-related quality of life (HRQoL). Previous studies have not captured all concepts important to patients. Therefore, this study sought to develop a novel, comprehensive, and content valid patient-reported outcome (PRO) measure to assess the efficacy of new therapies.Patients and Methods: Qualitative interviews were conducted with EPP participants and clinical experts to obtain views on concepts relevant to patients. Results informed the development of novel PROs, which were debriefed during subsequent combined concept elicitation and cognitive debriefing interviews.Results: Twenty-three interviews were conducted with 17 adults and 6 adolescents with EPP. Concept elicitation revealed that participants experienced many symptoms with significant variability. The most common were burning, pain, swelling, and tingling. Tingling was the most common prodromal symptom, while burning was the most bothersome, and pain was the worst full reaction symptom. Participants reported being negatively impacted in their ability to do daily activities, and social and emotional functioning. Many reported impacted ability to work and be productive at their job. Participants reviewed and completed the newly developed PRO measures assessing full reactions and ability to do activities, as well as items to assess severity and change in severity of prodromal symptoms, full reactions, and EPP overall. All measures were found to be comprehensive, clear, and relevant.Conclusion: PRO measures are needed to assess important aspects of HRQoL and evaluate therapeutic response. These PRO measures are unique in assessing overall severity and change in EPP.Plain Language Summary: Erythropoietic protoporphyria (EPP) is a rare but severe condition; people with it experience painful reactions on their skin after exposure to sun and in some cases, artificial light. Measuring how EPP affects individual’s lives is critical to properly understanding the disorder. However, current questionnaires do not capture all the issues important to individuals with EPP. Therefore, we conducted interviews with individuals with EPP and doctors who are experts in EPP to create and evaluate a questionnaire that addresses these gaps. The interviews showed that people with EPP experience many symptoms with lots of variability, and that EPP impacts their ability to work and be productive at their job. This information was used to create a questionnaire that measures individual’s full EPP reactions and ability to do activities (EPP Impact Questionnaire), and how bad early warning symptoms, full reactions, and EPP overall are, as well as how they change (Patient Global Impression of Severity and Change). The questionnaire was found to be clear and relevant. This is important in being able to measure how patients feel and function and whether treatments work for people with EPP.Keywords: erythropoietic protoporphyria, porphyria, patient-reported outcome development, qualitative interviews, rare disease

Background: Atherosclerosis and its sequels, such as coronary artery disease and cerebrovascular stroke, still represent global health burdens. The pathogenesis of atherosclerosis consists of growing calcified plaques in the arterial wall and is accompanied by inflammatory processes, which are not entirely understood. This study aims to evaluate the effect of peptide receptor radionuclide therapy (PRRT) using 90Y- and 177Lu-DOTATATE on atherosclerotic plaque inflammation. Methods: Atherosclerotic plaques in 57 cancer patients receiving PRRT using 90Y- and 177Lu-DOTATATE were longitudinally monitored by 68Ga-DOTATATE PET/CT. The target-to-background ratio (TBR) and overall vessel uptake (OVU) were measured in eight distinct arterial regions (ascending aorta, aortic arch, descending aorta, abdominal aorta, both iliac arteries, and both carotid arteries) to monitor calcified plaques. Results: PET/CT analysis shows a positive correlation between calcified plaque scores and the 68Ga-DOTATATE overall vessel uptake (OVU) in cancer patients. After PRRT, an initially high OVU was observed to decrease in the therapy group compared to the control group. An excellent correlation could be shown for each target-to-background ratio (TBR) to the OVU, especially the ascending aorta. Conclusions: The ascending aorta could present a future reference for estimating generalized atherosclerotic inflammatory processes. PRRT might represent a therapeutic approach to modulating atherosclerotic plaques.

Cell polarity is crucial for gastric mucosal barrier integrity and mainly regulated by polarity-regulating kinase partitioning-defective 1b (Par1b). During infection, the carcinogen Helicobacter pylori hijacks Par1b via the bacterial oncoprotein CagA leading to loss of cell polarity, but the precise molecular mechanism is not fully clear. Here we discovered a novel function of the actin-binding protein cortactin in regulating Par1b, which forms a complex with cortactin and the tight junction protein zona occludens-1 (ZO-1). We found that serine phosphorylation at S405/418 and the SH3 domain of cortactin are important for its interaction with both Par1b and ZO-1. Cortactin knockout cells displayed disturbed Par1b cellular localization and exhibited morphological abnormalities that largely compromised transepithelial electrical resistance, epithelial cell polarity, and apical microvilli. H. pylori infection promoted cortactin/Par1b/ZO-1 abnormal interactions in the tight junctions in a CagA-dependent manner. Infection of human gastric organoid-derived mucosoids supported these observations. We therefore hypothesize that CagA disrupts gastric epithelial cell polarity by hijacking cortactin, and thus Par1b and ZO-1, suggesting a new signaling pathway for the development of gastric cancer by Helicobacter.

The upper respiratory tract (URT) is the entry site for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), from where it further disseminates. Early and effective adaptive immune responses are crucial to restrict viral replication and limit symptom development and transmission. Current vaccines increasingly incorporate strategies to boost mucosal immunity in the respiratory tract. Positron emission tomography (PET) is a non-invasive technology that measures cellular responses at a whole-body level. In this case series, we explored the feasibility of [89Zr]Zr-crefmirlimab berdoxam PET to assess CD8+ T-cell localization during active COVID-19. Our results suggest that CD8+ T-cell distributions assessed by PET imaging reflect their differentiation and functional state in blood. Therefore, PET imaging may represent a novel tool to visualize and quantify cellular immune responses during infections at a whole-body level.

Summary: Background: Neuroimaging studies often quantify tau burden in standardized brain regions to assess Alzheimer disease (AD) progression. However, this method ignores another key biological process in which tau spreads to additional brain regions. We have developed a metric for calculating the extent tau pathology has spread throughout the brain and evaluate the relationship between this metric and tau burden across early stages of AD. Methods: 445 cross-sectional participants (aged ≥ 50) who had MRI, amyloid PET, tau PET, and clinical testing were separated into disease-stage groups based on amyloid positivity and cognitive status (older cognitively normal control, preclinical AD, and symptomatic AD). Tau burden and tau spatial spread were calculated for all participants. Findings: We found both tau metrics significantly elevated across increasing disease stages (p

Summary: Background: The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced. Methods: The EPICOVIDEHA registry (National Clinical Trials Identifier, NCT04733729) gathers COVID-19 data from hematological malignancy patients since the pandemic's start worldwide. It spans various global locations, allowing comprehensive analysis over the first three years (2020–2022). Findings: The EPICOVIDEHA registry collected data from January 2020 to December 2022, involving 8767 COVID-19 cases in hematological malignancy patients from 152 centers across 41 countries, with 42% being female. Over this period, there was a significant reduction in critical infections and an overall decrease in mortality from 29% to 4%. However, hospitalization, particularly in the ICU, remained associated with higher mortality rates. Factors contributing to increased mortality included age, multiple comorbidities, active malignancy at COVID-19 onset, pulmonary symptoms, and hospitalization. On the positive side, vaccination with one to two doses or three or more doses, as well as encountering COVID-19 in 2022, were associated with improved survival. Interpretation: Patients with hematological malignancies still face elevated risks, despite reductions in critical infections and overall mortality rates over time. Hospitalization, especially in ICUs, remains a significant concern. The study underscores the importance of vaccination and the timing of COVID-19 exposure in 2022 for enhanced survival in this patient group. Ongoing monitoring and targeted interventions are essential to support this vulnerable population, emphasizing the critical role of timely diagnosis and prompt treatment in preventing severe COVID-19 cases. Funding: Not applicable.

The relationship between thyroid and testis is well understood, and the association between changes in thyroid function and male infertility has been reported. However, the contribution of thyroid dysfunction to male infertility is not sufficiently addressed in our setting. This study aims to assess the thyroid hormones level among males undergoing investigation for infertility and to establish correlations between thyroid hormones and sperm indices. Thyroid hormones were determined in 150 infertile males and 50 fertile male controls. Semen analysis was done according to the World Health Organization criteria while thyroid hormones were determined using Enzyme linked Immunosorbent assay technique. The measured anthropometric data, sperm indices and thyroid hormone levels were compared using appropriate statistical tools. Serum triiodothyronine, and thyroxine levels were significantly lower (p < 0.001), while thyroid stimulating hormone was higher among infertile males than control subjects. The body mass index of the infertile subjects was significantly higher (p < 0.011) than control subjects. Of the 150 subjects, 41.33% (62/150) were euthyroid, 7.33% (11/150) had subclinical hypothyroidism while 51.34% (77/150) had overt hypothyroidism. Among the 88 altered thyroid function, 6.82% (6/88) had normozoospermia, 44.32% (39/88) had oligozoospermia while 48.86% (43/88) were azoospermia. The area Under the Curve of T3 (0.858), T4 (0.765) and sperm count (0.875) were able to differentiate fertile men from infertile subjects. Thyroid disorders are prevalent among infertile men and should be considered in the laboratory assessment of male infertility cases. Including thyroid function tests in the investigative panel can help identify and manage potential thyroid-related factors contributing to infertility. This comprehensive approach ensures thorough evaluation and targeted treatment for better reproductive outcomes in affected individuals.

Abstract Background Extremely preterm infants have a high mortality and morbidity. Here, we present a statistical analysis plan for secondary Bayesian analyses of the pragmatic, sufficiently powered multinational, trial—SafeBoosC III—evaluating the benefits and harms of cerebral oximetry monitoring plus a treatment guideline versus usual care for such infants. Methods The SafeBoosC-III trial is an investigator-initiated, open-label, randomised, multinational, pragmatic, phase III clinical trial with a parallel-group design. The trial randomised 1601 infants, and the frequentist analyses were published in April 2023. The primary outcome is a dichotomous composite outcome of death or severe brain injury. The exploratory outcomes are major neonatal morbidities associated with neurodevelopmental impairment later in life: (1) bronchopulmonary dysplasia; (2) retinopathy of prematurity; (3) late-onset sepsis; (4) necrotising enterocolitis; and (5) number of major neonatal morbidities (count of bronchopulmonary dysplasia, retinopathy of prematurity, and severe brain injury). The primary Bayesian analyses will use non-informed priors including all plausible effects. The models will use a Hamiltonian Monte Carlo sampler with 1 chain, a sampling of 10,000, and at least 25,000 iterations for the burn-in period. In Bayesian statistics, such analyses are referred to as ‘posteriors’ and will be presented as point estimates with 95% credibility intervals (CrIs), encompassing the most probable results based on the data, model, and priors selected. The results will be presented as probability of any benefit or any harm, Bayes factor, and the probability of clinical important benefit or harm. Two statisticians will analyse the blinded data independently following this protocol. Discussion This statistical analysis plan presents a secondary Bayesian analysis of the SafeBoosC-III trial. The analysis and the final manuscript will be carried out and written after we publicise the primary frequentist trial report. Thus, we can interpret the findings from both the frequentists and Bayesian perspective. This approach should provide a better foundation for interpreting of our findings. Trial registration ClinicalTrials.org, NCT03770741. Registered on 10 December 2018.

Abstract Background The SafeBoosC project aims to test the clinical value of non-invasive cerebral oximetry by near-infrared spectroscopy in newborn infants. The purpose is to establish whether cerebral oximetry can be used to save newborn infants’ lives and brains or not. Newborns contribute heavily to total childhood mortality and neonatal brain damage is the cause of a large part of handicaps such as cerebral palsy. The objective of the SafeBoosC-IIIv trial is to evaluate the benefits and harms of cerebral oximetry added to usual care versus usual care in mechanically ventilated newborns. Methods/design SafeBoosC-IIIv is an investigator-initiated, multinational, randomised, pragmatic phase-III clinical trial. The inclusion criteria will be newborns with a gestational age more than 28 + 0 weeks, postnatal age less than 28 days, predicted to require mechanical ventilation for at least 24 h, and prior informed consent from the parents or deferred consent or absence of opt-out. The exclusion criteria will be no available cerebral oximeter, suspicion of or confirmed brain injury or disorder, or congenital heart disease likely to require surgery. A total of 3000 participants will be randomised in 60 neonatal intensive care units from 16 countries, in a 1:1 allocation ratio to cerebral oximetry versus usual care. Participants in the cerebral oximetry group will undergo cerebral oximetry monitoring during mechanical ventilation in the neonatal intensive care unit for as long as deemed useful by the treating physician or until 28 days of life. The participants in the cerebral oximetry group will be treated according to the SafeBoosC treatment guideline. Participants in the usual care group will not receive cerebral oximetry and will receive usual care. We use two co-primary outcomes: (1) a composite of death from any cause or moderate to severe neurodevelopmental disability at 2 years of corrected age and (2) the non-verbal cognitive score of the Parent Report of Children’s Abilities-Revised (PARCA-R) at 2 years of corrected age. Discussion There is need for a randomised clinical trial to evaluate cerebral oximetry added to usual care versus usual care in mechanically ventilated newborns. Trial registration The protocol is registered at www.clinicaltrials.gov (NCT05907317; registered 18 June 2023).

Abstract Background In the SafeBoosC-III trial, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth did not reduce the incidence of death or severe brain injury in extremely preterm infants at 36 weeks’ postmenstrual age, as compared with usual care. Despite an association between severe brain injury diagnosed in the neonatal period and later neurodevelopmental disability, this relationship is not always strong. The objective of the SafeBoosC-III follow-up study is to assess mortality, neurodevelopmental disability, or any harm in trial participants at 2 years of corrected age. One important challenge is the lack of funding for local costs for a trial-specific assessment. Methods Of the 1601 infants randomised in the SafeBoosC-III trial, 1276 infants were alive at 36 weeks’ postmenstrual age and will potentially be available for the 2-year follow-up. Inclusion criteria will be enrollment in a neonatal intensive care unit taking part in the follow-up study and parental consent if required by local regulations. We aim to collect data from routine follow-up programmes between the ages of 18 and 30 months of corrected age. If no routine follow-up has been conducted, we will collect informal assessments from other health care records from the age of at least 12 months. A local co-investigator blinded to group allocation will classify outcomes based on these records. We will supplement this with parental questionnaires including the Parent Report of Children’s Abilities—Revised. There will be two co-primary outcomes: the composite of death or moderate or severe neurodevelopmental disability and mean Bayley-III/IV cognitive score. We will use a 3-tier model for prioritisation, based on the quality of data. This approach has been chosen to minimise loss to follow-up assuming that little data is better than no data at all. Discussion Follow-up at the age of 2 years is important for intervention trials in the newborn period as only time can show real benefits and harms later in childhood. To decrease the risk of generalisation and data-driven biased conclusions, we present a detailed description of the methodology for the SafeBoosC-III follow-up study. As funding is limited, a pragmatic approach is necessary. Trial registration ClinicalTrials.gov NCT05134116 . Registered on 24 November 2021.

The diagnostic accuracy of handheld ultrasound (HHUS) devices operated by newly certified operators for pneumonia is unknown. This multicenter diagnostic accuracy study included patients prospectively suspected of pneumonia from February 2021 to February 2022 in four emergency departments. The index test was a 14-zone focused lung ultrasound (FLUS) examination, with consolidation with air bronchograms as diagnostic criteria for pneumonia. FLUS examinations were performed by newly certified operators using HHUS. The reference standard was computed tomography (CT) and expert diagnosis using all medical records. The sensitivity and specificity of FLUS and chest X-ray (CXR) were compared using McNemar’s test. Of the 324 scanned patients, 212 (65%) had pneumonia, according to the expert diagnosis. FLUS had a sensitivity of 31% (95% CI 26–36) and a specificity of 82% (95% CI 78–86) compared with the experts’ diagnosis. Compared with CT, FLUS had a sensitivity of 32% (95% CI 27–37) and specificity of 81% (95% CI 77–85). CXR had a sensitivity of 66% (95% CI 61–72) and a specificity of 76% (95% CI 71–81) compared with the experts’ diagnosis. Compared with CT, CXR had a sensitivity of 69% (95% CI 63–74) and a specificity of 68% (95% CI 62–72). Compared with the experts’ diagnosis and CT diagnosis, FLUS performed by newly certified operators using HHUS devices had a significantly lower sensitivity for pneumonia when compared to CXR (p < 0.001). FLUS had a significantly higher specificity than CXR using CT diagnosis as a reference standard (p = 0.02). HHUS exhibited low sensitivity for pneumonia when used by newly certified operators.

Background: To retrospectively investigate scatter radiation (SCR) exposure among staff in the endourology operating theatre. Methods: During surgeries under fluoroscopic guidance, five professional groups (urological surgeon [US], surgical nurse [SN], assistant surgical nurse [ASN], anaesthetist [A], and anaesthesia care [AC]) wore real-time dosimeters (Philips DoseAware System) on their head and chest over lead aprons between July 2023 and February 2024. The SCR data were analysed and correlated with procedural and patient factors. Results: In total, 249 procedures were performed, including 86 retrograde intrarenal surgeries and 10 percutaneous nephrolithotomies. Median SCR exposure was 38.81, 17.20, 7.71, 11.58, 0.63, 0.23, 0.12, and 0.15 Microsievert (µSv) for US chest (USC), US head (USH), SN chest (SNC), SN head (SNH), A chest (AC), AC chest (ACC), ASN chest (ASNC), and ASN head (ASNH), respectively. There was a significant correlation between DAP and SCR doses detected by USC, USH, SNC, SNH, AC, and ACC dosimeters (p < 0.05). The median chest-to-eye conversion factor (CECF) was 2.11 for the US and 0.71 for the SN. Conclusions: This study, using real-time dosimetry, is among the first to assess staff occupational SCR exposure in endourology. It highlights a substantial SCR exposure, indicating an occupational health hazard that warrants further investigation.

Purpose: The most common anomaly is an anomalous left coronary artery originating from the pulmonary artery. These variants can be different and depend on the location as well as how they present themselves in their anatomical distribution and their symptomatological relationship. For these reasons, this review aims to identify the variants of the coronary artery and how they are associated with different clinical conditions. Methods: The databases Medline, Scopus, Web of Science, Google Scholar, CINAHL, and LILACS were researched until January 2024. Two authors independently performed the search, study selection, and data extraction. Methodological quality was evaluated using an assurance tool for anatomical studies (AQUA). Pooled prevalence was estimated using a random effects model. Results: A total of 39 studies met the established selection criteria. In this study, 21 articles with a total of 578,868 subjects were included in the meta-analysis. The coronary artery origin variant was 1% (CI = 0.8–1.2%). For this third sample, the funnel plot graph showed an important asymmetry, with a p-value of 0.162, which is directly associated with this asymmetry. Conclusions: It is recommended that patients whose diagnosis was made incidentally and in the absence of symptoms undergo periodic controls to prevent future complications, including death. Finally, we believe that further studies could improve the anatomical, embryological, and physiological understanding of this variant in the heart.

Abstract Background About 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high-dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3-ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at 2 years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and has an acceptable toxicity profile. Methods In this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m2 bidaily day one to day three, mitoxantrone 10mg/m2 days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR, complete remission with incomplete hematologic recovery (CRi), or complete remission with partial recovery of peripheral blood counts (CRh) as primary endpoint. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization. The matched threshold crossing approach is a novel study-design to enhance the classic single-arm trial design by including matched historical controls from previous clinical studies. It overcomes common disadvantages of single-armed and small randomized studies, since the expected outcome of the observed study population can be adjusted based on the matched controls with a comparable distribution of known prognostic and predictive factors. Furthermore, balanced treatment groups lead to stable statistical models. However, one of the limitations of our study is the inability to adjust for unobserved or unknown confounders. Addressing the primary endpoint, CR/CRi/CRh after salvage therapy, the maximal sample size of 80 patients is assessed generating a desirable power of the used adaptive design, assuming a logistic regression is performed at a one-sided significance level α=0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 20 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument. Conclusion Currently, there is no commonly accepted standard for salvage chemotherapy treatment. The objective of the salvage therapy is to reduce leukemic burden, achieve the best possible remission, and perform a hemopoietic stem-cell transplantation. Thus, in patients with FLT3-ITD mutation, the comparison of quizartinib with intensive salvage therapy versus chemotherapy alone appears as a logical consequence in terms of efficacy and safety. Ethics and dissemination Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. Trial registration ClinicalTrials.gov NCT03989713; EudraCT Number: 2018-002675-17.

Abstract Background Increased levels of physical activity are associated with beneficial health effects for people with type 2 diabetes, cardiovascular disease and/or severe obesity; however, transforming knowledge about these effects into action is challenging. The aim of this paper is to explore lessons learnt from a co-creation process in a partnership project involving local stakeholders, including citizens, and researchers. The purpose of the process was to link a public health care institution with civil society organisations in the local community to make it possible for citizens to continue to be physically active after ending their public rehabilitation. Secondarily, this paper aims to develop a conceptual model of the above process. Methods The study constitutes the first part of Project Active Communities and was based on a partnership between three research institutions and a Danish rural municipality, involving municipal and civil society stakeholders and citizens with type 2 diabetes, cardiovascular disease and/or severe obesity in co-creation of concrete interventions for implementation. The co-creation process was divided into two tracks, one involving citizens (two workshops) and one involving municipal and civil society stakeholders (two workshops). The two tracks were concluded with a final workshop involving all stakeholders, including local politicians. Data sources are focus groups and bilateral meetings, workshop observations, and questionnaires. Results Lessons learnt include the importance of having a flexible timeframe for the co-creation process; giving room for disagreements and matching of mutual expectations between stakeholders; the value of a coordinator in the municipality to achieve acceptance of the project; and the significance of engaging local politicians in the co-creation process to accommodate internal political agendas. We have developed a conceptual model for a co-creation process, where we outline and explain three distinct phases: stakeholder identification and description, co-creation, and prototyping. The model can be adapted and applied to other sectors and settings. Conclusions This study documents lessons learnt in a co-creation process aiming to link a public health care institution with civil society organisations in the local community. Further, this study has specified productive co-creative processes and documented the various phases in a conceptual model.

Abstract Background Considered one of the highest levels of evidence, results of randomized controlled trials (RCTs) remain an essential building block in mental health research. They are frequently used to confirm that an intervention “works” and to guide treatment decisions. Given their importance in the field, it is concerning that the quality of many RCT evaluations in mental health research remains poor. Common errors range from inadequate missing data handling and inappropriate analyses (e.g., baseline randomization tests or analyses of within-group changes) to unduly interpretations of trial results and insufficient reporting. These deficiencies pose a threat to the robustness of mental health research and its impact on patient care. Many of these issues may be avoided in the future if mental health researchers are provided with a better understanding of what constitutes a high-quality RCT evaluation. Methods In this primer article, we give an introduction to core concepts and caveats of clinical trial evaluations in mental health research. We also show how to implement current best practices using open-source statistical software. Results Drawing on Rubin’s potential outcome framework, we describe that RCTs put us in a privileged position to study causality by ensuring that the potential outcomes of the randomized groups become exchangeable. We discuss how missing data can threaten the validity of our results if dropouts systematically differ from non-dropouts, introduce trial estimands as a way to co-align analyses with the goals of the evaluation, and explain how to set up an appropriate analysis model to test the treatment effect at one or several assessment points. A novice-friendly tutorial is provided alongside this primer. It lays out concepts in greater detail and showcases how to implement techniques using the statistical software R, based on a real-world RCT dataset. Discussion Many problems of RCTs already arise at the design stage, and we examine some avoidable and unavoidable “weak spots” of this design in mental health research. For instance, we discuss how lack of prospective registration can give way to issues like outcome switching and selective reporting, how allegiance biases can inflate effect estimates, review recommendations and challenges in blinding patients in mental health RCTs, and describe problems arising from underpowered trials. Lastly, we discuss why not all randomized trials necessarily have a limited external validity and examine how RCTs relate to ongoing efforts to personalize mental health care.

Umbilical nodes and cords play a crucial role in fetal development and are essential for the transfer of nutrients and oxygen between the mother and the fetus. Sonographic diagnosis of umbilical nodes and cords has become an integral part of prenatal care, allowing for the early detection of abnormalities and potential complications. The umbilical cord is a vital structure connecting the fetus to the placenta, providing essential nutrients and oxygen for fetal growth and development. Sonographic examination of the umbilical cord and its associated nodes has become an indispensable tool in prenatal care, enabling the early detection of abnormalities and potential complications. This review aims to analyze the current literature on sonographic diagnosis of umbilical nodes and cords, highlighting the key points and advancements in this field. A 37-year-old booked G 4 P 2 +1 A 2 Nigerian woman was registered for prenatal tertiary health care at 12 weeks of gestation. The booking investigations were normal and the booking packed cell volume was 37%. She was compliant with scheduled clinic visits and routine drugs. Pregnancy was carried to term uneventfully. Elective cesarean section was successfully performed at 38 weeks of gestation owing to the patient’s prior history of third-degree perineal tear. The intraoperative findings included a loose cord around the neck of the baby and double true knots along the length of the 65 cm umbilical cord. The baby was delivered with appearance, pulse, grimace, activity and respiration (APGAR) scores of 7 in the first minute, 9 in the fifth minute, and the birth weight was 3.0 kg. Mother and baby were discharged 48 h postpartum in stable clinical condition. Although the presence of true double umbilical knots is rare, its coexistence with the nuchal cord is even rarer. There are risk factors associated with true umbilical knots. The possible risk factor implicated in this index case is the gender of the fetus and maternal multiparity. True umbilical knots are usually associated with certain fetal negative outcomes of pregnancy. There are currently no evidence-based treatment options available.

Patients, life science industry and regulatory authorities are united in their goal to reduce the disease burden of patients by closing remaining unmet needs. Patients have, however, not always been systematically and consistently involved in the drug development process. Recognizing this gap, regulatory bodies worldwide have initiated patient-focused drug development (PFDD) initiatives to foster a more systematic involvement of patients in the drug development process and to ensure that outcomes measured in clinical trials are truly relevant to patients and represent significant improvements to their quality of life. As a source of real-world evidence (RWE), social media has been consistently shown to capture the first-hand, spontaneous and unfiltered disease and treatment experience of patients and is acknowledged as a valid method for generating patient experience data by the Food and Drug Administration (FDA). While social media listening (SML) methods are increasingly applied to many diseases and use cases, a significant piece of uncertainty remains on how evidence derived from social media can be used in the drug development process and how it can impact regulatory decision making, including legal and ethical aspects. In this policy paper, we review the perspectives of three key stakeholder groups on the role of SML in drug development, namely patients, life science companies and regulators. We also carry out a systematic review of current practices and use cases for SML and, in particular, highlight benefits and drawbacks for the use of SML as a way to identify unmet needs of patients. While we find that the stakeholders are strongly aligned regarding the potential of social media for PFDD, we identify key areas in which regulatory guidance is needed to reduce uncertainty regarding the impact of SML as a source of patient experience data that has impact on regulatory decision making.

ObjectivesTo investigate, whether inflammatory rheumatic diseases (IRD) inpatients are at higher risk to develop a severe course of SARS-CoV-2 infections compared to the general population, data from the German COVID-19 registry for IRD patients and data from the Lean European Survey on SARS-CoV-2 (LEOSS) infected patients covering inpatients from the general population with SARS-CoV-2 infections were compared.Methods4310 (LEOSS registry) and 1139 cases (IRD registry) were collected in general. Data were matched for age and gender. From both registries, 732 matched inpatients (LEOSS registry: n = 366 and IRD registry: n = 366) were included for analyses in total.ResultsRegarding the COVID-19 associated lethality, no significant difference between both registries was observed. Age > 65°years, chronic obstructive pulmonary disease, diabetes mellitus, rheumatoid arthritis, spondyloarthritis and the use of rituximab were associated with more severe courses of COVID-19. Female gender and the use of tumor necrosis factor-alpha inhibitors (TNF-I) were associated with a better outcome of COVID-19.ConclusionInflammatory rheumatic diseases (IRD) patients have the same risk factors for severe COVID-19 regarding comorbidities compared to the general population without any immune-mediated disease or immunomodulation. The use of rituximab was associated with an increased risk for severe COVID-19. On the other hand, the use of TNF-I was associated with less severe COVID-19 compared to the general population, which might indicate a protective effect of TNF-I against severe COVID-19 disease.

Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

Objetivo principal: Conocer la epidemiologia de las fracturas del cuarto distal del radio en el esqueleto en crecimiento y el tratamiento realizado en el CHPR en los años 2017 y 2018. Objetivos específicos: Valorar re-desplazamiento, necesidad de re manipulación, complicaciones, re-fractura. Metodología: Estudio observacional descriptivo retrospectivo. Criterios de inclusión: pacientes de 0 a 14 años con fractura de radio distal (fisaria, metafisaria y suprametafisaria) valorados en el CHPR entre 1 enero del 2017 y 31 diciembre del 2018. Criterios de exclusión: pacientes con radiografía normal, fracturas en miembros con malformaciones, infecciones óseas, patología tumoral maligna o benigna. Obtención de datos: Valoración de radiografías de puño y antebrazo realizadas en el CHPR en 2017 y 18, iniciales y evolutivas. Se analizaron: edad, sexo, fecha fractura, topografía de la fractura, desplazamiento inicial, tratamiento, evolución radiográfica y complicaciones. Resultados: se incluyeron 662 pacientes. Siendo en su mayoría de género masculino (65%), con una media de 9 años, miembro derecho (61%), en los meses de verano (36%). En cuanto a la topografía se evidenció una frecuencia mayor en fracturas tipo rodete y metafisarias (31.72% y 31.57%), seguido por suprametafisaria (18.43%) y fisaria (18.28%). El tratamiento realizado fue ortopédico en el 86.56% de los casos, mientras que quirúrgico fue el 12.84%, en su gran mayoría con alambres de Kirschner (11,2%). El tiempo de inmovilización promedio fue de 6 semanas, con un porcentaje de complicaciones del 14.05% del total de las fracturas. Conclusiones: Se valoraron las características de los pacientes y fracturas de radio distal en el CHPR en los años 2017 y 18, siendo un total de 662 fracturas, en las que su mayoría se realizó tratamiento ortopédico con un índice de complicaciones que ronda el 14%, siendo mayor cuanto mayor es el desplazamiento inicial de la fractura.

Abstract Background Muscle tension dysphonia (MTD) results from inefficient or ineffective voice production and is the cause of voice and throat complaints in up to 40% of patients presenting with hoarseness. Standard treatment is voice therapy (SLT-VT) delivered by specialist speech therapists in voice disorders (SLT-V). The Complete Vocal Technique (CVT) is a structured, pedagogic method which helps healthy singers and other performers optimise their vocal function enabling them to produce any sound required. The aim of this feasibility study is to investigate whether CVT administered by a trained, non-clinical CVT practitioner (CVT-P) can be applied to patients with MTD before progressing to a pilot randomised control study of CVT voice therapy (CVT-VT) versus SLT-VT. Methods/design In this feasibility study, we use a mixed-method, single-arm, prospective cohort design. The primary aim is to demonstrate whether CVT-VT can improve the voice and vocal function in patients with MTD in a pilot study using multidimensional assessment methods. Secondary aims are to assess whether (1) a CVT-VT study is feasible to perform; (2) is acceptable to patients, the CVT-P and SLT-VTs; and (3) whether CVT-VT differs from existing SLT-VT techniques. A minimum of 10 consecutive patients with a clinical diagnosis of primary MTD (types I–III) will be recruited over a 6-month period. Up to 6 video sessions of CVT-VT will be delivered by a CVT-P using a video link. The primary outcome will be a change in pre-/post-therapy scores of a self-reported patient questionnaire (Voice Handicap Index (VHI)). Secondary outcomes include changes in throat symptoms (Vocal Tract Discomfort Scale), acoustic/electroglottographic and auditory-perceptual measures of voice. Acceptability of the CVT-VT will be assessed prospectively, concurrently and retrospectively both quantitatively and qualitatively. Differences from SLT-VT will be assessed by performing a deductive thematic analysis of CVT-P transcripts of therapy sessions. Conclusion This feasibility study will provide important data to support whether to proceed with a randomised controlled pilot study focusing on the effectiveness of the intervention compared to standard SLT-VT. Progression criteria will be based on demonstrating a positive outcome in treatment, successful delivery of the pilot study protocol, acceptability to all stakeholders and satisfactory recruitment rates. Trial registration ClinicalTrials.gov website ( NCT05365126 Unique Protocol ID: 19ET004). Registered on 06 May 2022.

Abstract Background Efficacy and quality of life (QoL) are key criteria for therapy selection in metastatic breast cancer (MBC). In hormone receptor positive (HR +) human epidermal growth factor receptor 2 negative (HER2 −) MBC, addition of targeted oral agents such as everolimus or a cycline-dependent kinase 4/6 (CDK 4/6) inhibitor (e.g., palbociclib, ribociclib, abemaciclib) to endocrine therapy substantially prolongs progression-free survival and in the case of a CDK 4/6i also overall survival. However, the prerequisite is adherence to therapy over the entire course of treatment. However, particularly with new oral drugs, adherence presents a challenge to disease management. In this context, factors influencing adherence include maintaining patients’ satisfaction and early detection/management of side effects. New strategies for continuous support of oncological patients are needed. An eHealth-based platform can help to support therapy management and physician–patient interaction. Methods PreCycle is a multicenter, randomized, phase IV trial in HR + HER2 − MBC. All patients (n = 960) receive the CDK 4/6 inhibitor palbociclib either in first (62.5%) or later line (37.5%) together with endocrine therapy (AI, fulvestrant) according to national guidelines. PreCycle evaluates and compares the time to deterioration (TTD) of QoL in patients supported by eHealth systems with substantially different functionality: CANKADO active vs. inform. CANKADO active is the fully functional CANKADO-based eHealth treatment support system. CANKADO inform is a CANKADO-based eHealth service with a personal login, documentation of daily drug intake, but no further functions. To evaluate QoL, the FACT-B questionnaire is completed at every visit. As little is known about relationships between behavior (e.g., adherence), genetic background, and drug efficacy, the trial includes both patient-reported outcome and biomarker screening for discovery of forecast models for adherence, symptoms, QoL, progression free survival (PFS), and overall survival (OS). Discussion The primary objective of PreCycle is to test the hypothesis of superiority for time to deterioration (TTD) in terms of DQoL = “Deterioration of quality of life” (FACT-G scale) in patients supported by an eHealth therapy management system (CANKADO active) versus in patients merely receiving eHealth-based information (CANKADO inform). EudraCT Number: 2016–004191-22

Abstract Background Acute and chronic pancreatitis constitute a continuum of inflammatory disease of the pancreas with an increasing incidence in most high-income countries. A subset of patients with a history of pancreatitis suffer from recurrence of acute pancreatitis attacks, which accelerate disease progression towards end-stage chronic pancreatitis with loss of exocrine and endocrine function. There is currently no available prophylactic treatment for recurrent acute pancreatitis apart from removing risk factors, which is not always possible. Pain is the primary symptom of acute pancreatitis, which induces the endogenous release of opioids. This may further be potentiated by opioid administration for pain management. Increased exposure to opioids leads to potentially harmful effects on the gastrointestinal tract, including, e.g. increased sphincter tones and decreased fluid secretion, which may impair pancreatic ductal clearance and elevate the risk for new pancreatitis attacks and accelerate disease progression. Peripherally acting µ-opioid receptor antagonists (PAMORAs) have been developed to counteract the adverse effects of opioids on the gastrointestinal tract. We hypothesize that the PAMORA naldemedine will reduce the risk of new pancreatitis attacks in patients with recurrent acute pancreatitis and hence decelerate disease progression. Methods The study is a double-blind, randomized controlled trial with allocation of patients to either 0.2 mg naldemedine daily or matching placebo for 12 months. A total of 120 outpatients will be enrolled from five specialist centres in Denmark and Sweden. The main inclusion criteria is a history of recurrent acute pancreatitis (minimum of two confirmed pancreatitis attacks). The primary endpoint is time to acute pancreatitis recurrence after randomization. Secondary outcomes include changes in quality of life, gastrointestinal symptom scores, new-onset diabetes, exocrine pancreatic insufficiency, disease severity, health care utilization, adherence to treatment, and frequency of adverse events. Exploratory outcomes are included for mechanistic linkage and include the progression of chronic pancreatitis-related findings on magnetic resonance imaging (MRI) and changes in circulating blood markers of inflammation and fibrosis. Discussion This study investigates if naldemedine can change the natural course of pancreatitis in patients with recurrent acute pancreatitis and improve patient outcomes. Trial registration EudraCT no. 2021–000069-34. ClinicalTrials.gov NCT04966559. Registered on July 8, 2021.

The mental foramen (MF) is an opening found bilaterally on the anterolateral aspect of the mandible; it can be round or oval and have different diameters. One of the anatomical variants of the jaw is the presence of an accessory mental foramen (AMF). These are usually smaller than the MF and can be located above, below, or to the sides of the main MF. The objective of this study was to recognize the presence of AMF in dry jaws of the Chilean population and collect information about its clinical relevance reported in the literature. In this descriptive observational study, we have collected dried jaws obtained from three higher education institutions in Santiago de Chile, from the Department of Morphology of the Andrés Bello University, the Normal Human Anatomy Unit of the University of Santiago, and the Human Anatomy pavilion from the Faculty of Medicine of the Finis Terrae University. The samples for this research were obtained by convenience, and the observation of the jaws was carried out in the human anatomy laboratories of each institution by three evaluators independently, and a fourth evaluator was included to validate that each evaluation was correct. The sample for this research came from 260 dry jaws, showing the following findings from the total jaws studied, and to classify as an accessory MF, it will be examined and measured so that it complies with what is declared in the literature as the presence of AMF, which is between 0.74 mm. and 0.89 mm. There were 17 studies included with a sample that fluctuated between 1 and 4000, with a cumulative total of 7946 and an average number of jaws analyzed from the studies of 467.4, showing statistically significant differences between the means with the sample analyzed in this study; p = 0.095. For the cumulative prevalence of the presence of AMF, this was 3.07 in this study, and in the compared studies, the average of AMF was 8.01%, which did not present a statistically significant difference; p = 0.158. Regarding the presence of variants of unilateral AMF, this occurred in five jaws, which is equivalent to 1.84% in the sample of this study, while in previous studies, it was 7.5%, being higher on the left side than on the right. The presence of AMF is a variant with high prevalence if we compare it with other variants of the jaw. Knowledge of the anatomy and position of the AMF is crucial to analyze different scenarios in the face of surgical procedures or conservative treatments of the lower anterior dental region.

Community-acquired pneumonia is a common cause of acute hospitalisation. Identifying patients with community-acquired pneumonia among patients suspected of having the disease can be a challenge, which causes unnecessary antibiotic treatment. We investigated whether the circulatory pulmonary injury markers surfactant protein D (SP-D), Krebs von den Lungen-6 (KL-6), and Club cell protein 16 (CC16) could help identify patients with community-acquired pneumonia upon acute admission. In this multi-centre diagnostic accuracy study, SP-D, KL-6, and CC16 were quantified in plasma samples from acutely hospitalised patients with provisional diagnoses of community-acquired pneumonia. The area under the receiver operator characteristics curve (AUC) was calculated for each marker against the following outcomes: patients’ final diagnoses regarding community-acquired pneumonia assigned by an expert panel, and pneumonic findings on chest CTs. Plasma samples from 339 patients were analysed. The prevalence of community-acquired pneumonia was 63%. AUCs for each marker against both final diagnoses and chest CT diagnoses ranged between 0.50 and 0.56. Thus, SP-D, KL-6, and CC16 demonstrated poor diagnostic performance for community-acquired pneumonia in acutely hospitalised patients. Our findings indicate that the markers cannot readily assist physicians in confirming or ruling out community-acquired pneumonia.

We report a [18F]fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) scan of a 17-year-old male presenting increased focal glucose metabolism of a histologically proven solitary nodular fasciitis mimicking an extranodal manifestation of Hodgkin lymphoma. This interesting image should draw attention to considering nodular fasciitis as a possible pitfall in the staging of malignant diseases.

Summary: Background: We aimed to assess whether exposure to risk factors in early life from conception to puberty continue to contribute to lung function decline later in life by using a pooled cohort comprising approx. 11,000 adults followed for more than 20 years and with up to three lung function measurements. Methods: Participants (20–68 years) in the ECRHS and NFBC1966 cohort studies followed in the periods 1991–2013 and 1997–2013, respectively, were included. Mean annual decline in maximum forced expired volume in 1 s (FEV1) and forced vital capacity (FVC) were main outcomes. Associations between early life risk factors and change in lung function were estimated using mixed effects linear models adjusted for sex, age, FEV1, FVC and height at baseline, accounting for personal smoking. Findings: Decline in lung function was accelerated in participants with mothers that smoked during pregnancy (FEV1 2.3 ml/year; 95% CI: 0.7, 3.8) (FVC 2.2 ml/year; 0.2, 4.2), with asthmatic mothers (FEV1 2.6 ml/year; 0.9, 4.4) (FEV1/FVC 0.04 per year; 0.04, 0.7) and asthmatic fathers (FVC 2.7 ml/year; 0.5, 5.0), and in women with early menarche (FVC 2.4 ml/year; 0.4, 4.4). Personal smoking of 10 pack-years contributed to a decline of 2.1 ml/year for FEV1 (1.8, 2.4) and 1.7 ml/year for FVC (1.3, 2.1). Severe respiratory infections in early childhood were associated with accelerated decline among ever-smokers. No effect-modification by personal smoking, asthma symptoms, sex or cohort was found. Interpretation: Mothers’ smoking during pregnancy, parental asthma and early menarche may contribute to a decline of FEV1 and FVC later in life comparable to smoking 10 pack-years. Funding: European Union's Horizon 2020; Research Council of Norway; Academy of Finland; University Hospital Oulu; European Regional Development Fund; Spanish Ministry of Science and Innovation; Generalitat de Catalunya.

Summary: Background: Clinical manifestations and severity of SARS-CoV-2 infection in individuals with sickle cell disease (SCD) and sickle cell trait (SCT) are not well understood yet. Methods: We performed a systematic review and meta-analysis to assess COVID-19 outcomes in individuals with SCD or SCT compared to individuals without sickle cell disease or trait. An electronic search on PubMed, Embase, and Cochrane Library was performed on August 3, 2023. Two authors (IFM and ISP) independently screened (IFM and ISP) and extracted data (IFM and ILC) from included studies. Main exclusion criterion was the absence of the non-SCD/SCT group. Exposure effects for binary endpoints were compared using pooled odds ratio (OR) with 95% confidence intervals (CI). I2 statistics was used to assess the heterogeneity and DerSimonian and Laird random-effects models were applied for all analyses to minimize the impact of differences in methods and outcomes definitions between studies. The overall quality of evidence was assessed using the GRADE system. Review Manager 5.4 and R software (v4.2.2) were used for statistical analyses. Registered with PROSPERO, CRD42022366015. Findings: Overall, 22 studies were included, with a total of 1892 individuals with SCD, 8677 individuals with SCT, and 1,653,369 individuals without SCD/SCT. No difference in all-cause mortality was seen between SCD/SCT and non-SCD/SCT (OR 1.18; 95% CI 0.78–1.77; p = 0.429; I2 = 82%). When considering only studies adjusted for confounders (8 studies), patients with SCD/SCT were shown to be at increased risk of death (OR 1.86; 95% CI 1.30–2.66; p = 0.0007; I2 = 34%). No significant difference was seen between individuals with SCD and SCT (p = 0.863). The adjusted for confounders analysis for hospitalisation revealed higher rates for the SCD (OR 5.44; 95% CI 1.55–19.13; p = 0.008; I2 = 97%) and the SCT groups (OR 1.31; 95% CI 1.10–1.55; p = 0.002; I2 = 0) compared to the non-SCD/SCT population. Moreover, it was significantly higher for the SCD group (test for subgroup difference; p = 0.028). Interpretation: Our findings suggest that patients with SCD or SCT may present with a higher mortality and hospitalisation rates due to COVID-19 infection. Funding: None.

Summary: Background: The DynamX™ bioadaptor is the first coronary implant technology with a unique mechanism of unlocking the bioadaptor frame after polymer resorption over 6 months, uncaging the vessel while maintaining a dynamic support to the vessel. It aims to achieve the acute performance of drug-eluting stents (DES) with the advantages of restoration of vessel function. Methods: This international, single blinded, randomised controlled (1:1) trial compared a sirolimus-eluting bioadaptor with a contemporary zotarolimus-eluting stent (DES) in 34 hospitals in Europe, Japan and New Zealand. Patients with de novo coronary lesions and absence of acute myocardial infarction were enrolled from January 2021 to Feburary 2022. The implantation of the bioadaptor followed the standards of DES. An imaging subset of 100 patients had angiographic and intravascular ultrasound assessments, and 20 patients additionally optical coherence tomography. Data collection will continue through 5 years, we herein report 12-month data based on an intention-to-treat population. This trial is registered at ClinicalTrials.gov (NCT04192747). Findings: 445 patients were randomised between January 2021 and February 2022. Device, lesion and procedural success rates, and acute gain were similar amongst the groups. The primary endpoint, 12-month target lesion failure, was 1.8% [95% CI: 0.5; 4.6] (n = 4) versus 2.8% [95% CI: 1.0; 6.0] (n = 6), pnon-inferiority < 0.001 for the bioadaptor and the DES, respectively (Δ-1.0% [95% CI: −3.3; 1.4]). One definite or probable device thrombosis occurred in each group. The 12-month imaging endpoints showed superior effectiveness of the bioadaptor such as in-device late lumen loss (0.09 mm [SD 0.34] versus 0.25 mm [SD 0.39], p = 0.04), and restored compliance and cyclic pulsatility (%mid in-device lumen area change of 7.5% versus 2.7%, p

PurposeTo compare the risk of transient vision loss (TVL) probably attributable to a severe intraocular pressure spike after intravitreal aflibercept application using the novel prefilled syringe (PFS) vs. the established vial system (VS).MethodsDatasets of the intravitreal injection service of the Ludwig Maximilians-University Munich and the Technical University Munich, Germany, were screened for documentation of TVL after intravitreal injection of aflibercept. The observation period included two full months prior to the introduction of the novel PFS and two months afterwards. TVL was defined as loss of perception of hand motion for a duration of >30 s.ResultsOver a period of four months, 1720 intravitreal injections of aflibercept were administered in 672 patients. There were 842 injections with the old VS, and 878 injections using the novel PFS. Using the VS, TVL was noted during two injections (0.24%) in two patients, as compared to 11 cases of TVL (1.25%) in 10 patients with the PFS (p = 0.015). Using the PFS, patients had a 5.3-fold risk of TVL as compared to the VS (OR: 5.33; 95% CI: 1.2–24.1; p = 0.0298).ConclusionThere was a more than five-fold risk of TVL using the novel pre-filled aflibercept syringe as compared to the established vial system. During informed consent, this risk should be discussed.

BackgroundReproducible approaches are needed to bring AI/ML for medical image analysis closer to the bedside. Investigators wishing to shadow test cross-sectional medical imaging segmentation algorithms on new studies in real-time will benefit from simple tools that integrate PACS with on-premises image processing, allowing visualization of DICOM-compatible segmentation results and volumetric data at the radiology workstation.PurposeIn this work, we develop and release a simple containerized and easily deployable pipeline for shadow testing of segmentation algorithms within the clinical workflow.MethodsOur end-to-end automated pipeline has two major components- 1. A router/listener and anonymizer and an OHIF web viewer backstopped by a DCM4CHEE DICOM query/retrieve archive deployed in the virtual infrastructure of our secure hospital intranet, and 2. An on-premises single GPU workstation host for DICOM/NIfTI conversion steps, and image processing. DICOM images are visualized in OHIF along with their segmentation masks and associated volumetry measurements (in mL) using DICOM SEG and structured report (SR) elements. Since nnU-net has emerged as a widely-used out-of-the-box method for training segmentation models with state-of-the-art performance, feasibility of our pipleine is demonstrated by recording clock times for a traumatic pelvic hematoma nnU-net model.ResultsMean total clock time from PACS send by user to completion of transfer to the DCM4CHEE query/retrieve archive was 5 min 32 s (± SD of 1 min 26 s). This compares favorably to the report turnaround times for whole-body CT exams, which often exceed 30 min, and illustrates feasibility in the clinical setting where quantitative results would be expected prior to report sign-off. Inference times accounted for most of the total clock time, ranging from 2 min 41 s to 8 min 27 s. All other virtual and on-premises host steps combined ranged from a minimum of 34 s to a maximum of 48 s.ConclusionThe software worked seamlessly with an existing PACS and could be used for deployment of DL models within the radiology workflow for prospective testing on newly scanned patients. Once configured, the pipeline is executed through one command using a single shell script. The code is made publicly available through an open-source license at “https://github.com/vastc/,” and includes a readme file providing pipeline config instructions for host names, series filter, other parameters, and citation instructions for this work.

Abstract Background The HOPPSA trial is a multi-center national registry-based randomized controlled trial to test the safety and effectiveness of performing opportunistic salpingectomy at hysterectomy to reduce the risk of epithelial ovarian cancer (EOC). The study protocol was first published in January 2019 and is available at https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-018-3083-8 . Here, we report amendments made to the study protocol since commencement of the trial. Changes in methods and analysis The primary outcomes analyses have been changed. (1) Complications will be analyzed using binomial generalized estimating equation (GEE) with log link function, while the unadjusted analyses according to Miettinen and Nurminen will be performed as a sensitivity analysis. (2) Absolute change in Menopause Rating Scale (MRS) will primarily be analyzed using a mixed effects model, adjusted for baseline MRS and center as a random effect. (3) Time to EOC will be analyzed using the mixed effects Cox regression model with center as random effect, while the unadjusted log-rank test will be performed as a sensitivity analysis. The primary outcome Complications will be based solely on the specific assessment in the GynOp quality registry. The Clavien-Dindo classification will be evaluated as a secondary outcome. Furthermore, MRS is also measured three years postoperatively to better pinpoint the onset of menopausal symptoms. Discussion The changes to the protocol mainly concern the analyses of data. No changes to recruitment, randomization, intervention, or follow-up of primary outcomes have been made. An interim analysis during 2021 concluded that the study should continue until the target sample size is reached. Trial registration ClinicalTrials.gov, NCT03045965 . Registered 8 February 2017.

Abstract Background Substance use among youth is a longstanding global health concern that has dramatically risen in the era of highly toxic and unregulated drugs, including opioids. It is crucial to ensure that youth using unregulated opioids have access to evidence-based interventions, and yet, youth encounter critical gaps in the quality of such interventions. This study aims to address these gaps by identifying opportunities to improve the quality of opioid use services from the perspective of service providers, a perspective that has received scant attention. Methods This community-based participatory study was conducted in four communities in British Columbia (Canada), a province that declared a public health overdose emergency in 2016. Human-centered co-design workshops were held to understand service providers’ (n = 41) experiences, needs, and ideas for improving the quality of youth opioid use services/treatments in their community. Multi-site qualitative analysis was used to develop overarching experiences and needs themes that were further contextualized in each local community. A blended deductive and inductive thematic analysis was used to analyze the ideas data. Results Three overarching themes were identified, reflecting service providers’ goals to respond to youth in a timely and developmentally appropriate manner. However, this was significantly limited by organizational and systems-level barriers, revealing service providers’ priorities for intra- and inter-organizational support and collaboration and systems-level innovation. Across communities, service providers identified 209 individual ideas to address these prioritized needs and improve the quality of youth opioid use services/treatments. Conclusion These themes demonstrate a multi-level tension between macro-level systems and the meso-level organization of youth opioid use services, which undermine the quality of individual-level care service providers can deliver. These findings underscore the need for a coordinated multi-level response, such as developing youth-specific standards (macro-level), increasing inter-organizational activities and collaboration (meso-level), and creating programs that are specific to youths’ needs (micro-level).

Abstract Background Coronary artery disease (CAD) remains a severe socio-economic burden in the Western world. Coronary obstruction and subsequent myocardial ischemia result in the progressive replacement of contractile myocardium with dysfunctional, fibrotic scar tissue. Post-infarctional remodelling is causal for the concomitant decline of left-ventricular function and the fatal syndrome of heart failure. Available neurohumoral treatment strategies aim at the improvement of symptoms. Despite extensive research, therapeutic options for myocardial regeneration, including (stem)-cell therapy, gene therapy, cellular reprogramming or tissue engineering, remain purely experimental. Thus, there is an urgent clinical need for novel treatment options for inducing myocardial regeneration and improving left-ventricular function in ischemic cardiomyopathy. Shockwave therapy (SWT) is a well-established regenerative tool that is effective for the treatment of chronic tendonitis, long-bone non-union and wound-healing disorders. In preclinical trials, SWT regenerated ischemic myocardium via the induction of angiogenesis and the reduction of fibrotic scar tissue, resulting in improved left-ventricular function. Methods In this prospective, randomized controlled, single-blind, monocentric study, 80 patients with reduced left-ventricular ejection fraction (LVEF≤ 40%) are subjected to coronary-artery bypass-graft surgery (CABG) surgery and randomized in a 1:1 ratio to receive additional cardiac SWT (intervention group; 40 patients) or CABG surgery with sham treatment (control group; 40 patients). This study aims to evaluate (1) the safety and (2) the efficacy of cardiac SWT as adjunctive treatment during CABG surgery for the regeneration of ischemic myocardium. The primary endpoints of the study represent (1) major cardiac events and (2) changes in left-ventricular function 12 months after treatment. Secondary endpoints include 6-min walk test distance, improvement of symptoms and assessment of quality of life. Discussion This study aims to investigate the safety and efficacy of cardiac SWT during CABG surgery for myocardial regeneration. The induction of angiogenesis, decrease of fibrotic scar tissue formation and, thus, improvement of left-ventricular function could lead to improved quality of life and prognosis for patients with ischemic heart failure. Thus, it could become the first clinically available treatment strategy for the regeneration of ischemic myocardium alleviating the socio-economic burden of heart failure. Trial registration ClinicalTrials.gov NCT03859466. Registered on 1 March 2019.

Abstract Introduction Despite increased focus on development of mental health services worldwide, many adolescents still hesitate to reach out to the services when they need them. This might be linked to the lack of adolescent involvement in the development of services. This study aimed to explore adolescents' perspectives on the ideal healthcare services to meet their mental health needs. Methods A two‐stage qualitative study was carried out to explore the perspectives of adolescents on the healthcare services to support their mental health. In the first stage, data from 295 adolescents attending a mental health seminar were analysed using qualitative content analysis. In the second stage, in‐depth perspectives of 10 adolescent coresearchers were gathered through self‐reflection and group discussions to further explore the categories developed in the first stage. Thematic analysis was used to develop the themes answering the research question. Ten adolescent coresearchers planned the study, collected and analysed data and authored the manuscript, with the support of a senior researcher. Results Five themes describe adolescents' perspectives on the ideal healthcare services to meet their mental health needs: (1) Culturally Sensitive and Responsive; (2) Communication of Information; (3) Easy Access; (4) Variety of Support; and (5) Consistency. Culturally Sensitive and Responsive services influenced all other themes. The themes describe suggestions for mental health service improvement, including how to manage the barriers that adolescents face to receive help from the mental health services. Discussion This study highlights the importance of culturally sensitive and responsive services. It raises the need for an expanded definition of culture going beyond nationality and ethnic background. Adolescents need flexible services that meet their individual mental health needs. This has implications for practitioners, educators, system organizers and researchers, who should also involve adolescents in planning, implementing and assessing the services. There is a need for a self‐learning system to continuously adapt to user feedback. Conclusion This study provides insight into adolescents' perspectives on the ideal mental health services. It offers suggestions for ways to improve services to better meet the individual mental health needs of adolescents. Additional research is needed to further develop and implement service changes, as well as to assess their acceptability, effectiveness, cost‐effectiveness and safety. Patient or Public Contribution This is a study lead by adolescents. Adolescent coresearchers have, with the support of a senior researcher, planned and carried out the study, collected and analysed data and authored the manuscript.