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Background: The involvement of older adults in research on digital health is uneven with respect to e.g. age, gender, health status, and digital skills. However, little is known regarding the impact of the uneven involvement of older adults in digital health research on researched outcomes. This study helps to fill this knowledge gap and identifies the effects of uneven involvement of older adults in digital health research on researched outcomes, and also develops a correction for this., Methods: Data are retrieved from a digital health intervention for postoperative monitoring of people who underwent day surgery in Sweden. Based on field information on the recruitment process and researched outcomes for the intervention, this study (1) tested intervention effects by using two standard unweighted procedures in a sample of 281 individuals aged 50 years or older, and then (2) used the information on participants, non-participants and their respective probabilities to be involved in the intervention study to perform a weighting of the intervention effects for each step of selection and for the study group membership., Results: The intervention effects were found to be overestimated due to overrepresentation of groups which gained from receiving the intervention. No intervention effects were found after adjustment for participation bias., Conclusions: Selective participation of older adults in digital health research biases research outcomes and can lead to overestimation of intervention effects. Weighting allows researchers to correct and describe the impact of selective participation on researched outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Diabetic ketoacidosis (DKA) is a potentially life-threatening disorder associated with severe alterations in metabolism and acid-base status. Mitochondrial dysfunction is associated with diabetes and its complications. Thiamine and coenzyme Q10 (CoQ10) are important factors in aerobic metabolism. In this study, we measured cellular oxygen consumption rates (OCRs) and the effects of in vitro administration of thiamine and CoQ10 on OCRs in patients with DKA versus healthy controls., Methods: Blood samples were collected from a prospective cohort of patients with DKA and from controls. Cellular OCRs were measured in peripheral blood mononuclear cells (PBMC) without treatment and after treatment with thiamine, CoQ10, or both. The mitochondrial profile was measured using an XFe96 Extracellular Flux Analyzer and XF Cell Mito Stress Test Kit (Seahorse Bioscience). A linear quantile mixed model was used to compare OCRs and estimate treatment effects., Results: A total of 62 patients with DKA and 48 controls were included in the study. The median basal and maximal OCRs were lower in the DKA group than in the control group (basal: 4.7 [IQR: 3.3, 7.9] vs. 7.9 [5.0, 9.5], p = 0.036; maximal: 16.4 [9.5, 28.1] vs. 31.5 [20.6, 46.0] pmol/min/µg protein, p < 0.001). In DKA samples, basal and maximal OCRs were significantly increased when treated with thiamine, CoQ10, or both. In controls, basal and maximal OCR were significantly increased only with thiamine treatment., Conclusion: Mitochondrial metabolic profiles of patients with DKA demonstrated lower cellular oxygen consumption when compared to healthy controls. Oxygen consumption increased significantly in cells of patients with DKA treated with thiamine or CoQ10. These results suggest that thiamine and CoQ10 could potentially have therapeutic benefits in DKA via their metabolic effects on mitochondrial cellular respiration., (© 2024. The Author(s).)

Background: Frailty is strongly correlated with mortality in intensive care unit patients, yet routine screening among intensive care patients is rarely performed. The aim of this study is to assess frailty and health-related quality of life (HRQoL) in patients before intensive care admission and to compare this with outcomes after 3 and 12-months. The Clinical Frailty Scale and EQ-5D-5L will be used to assess frailty and HRQoL, respectively., Methods: This is an ongoing, prospective observational study including patients from five Norwegian ICU's. Inclusion criteria are patients aged ≥65 years requiring invasive mechanical ventilation for ≥24 h. The Clinical Frailty Scale and EQ-5D-5L are administered at baseline (before critical illness) and at 3- and 12-months post-inclusion. Additional data collected includes patient characteristics, ICU treatment details, illness severity and mortality. The EQ-5D-5L will be compared to Norwegian population norms and assessed for measurement properties., Results: Inclusion started July 2022 and will be stopped at 350 patients. The study will be completed in 2025., Conclusion: The study will assess the feasibility and measurement properties of the Clinical Frailty Scale and EQ-5D-5L in ICU survivors by telephone at long-term follow-up study and will give additional information on the frailty and HRQoL of intensive care survivors., Clinical Trial Registration: The study is registered in ClinicalTrials.gov NCT06012942. Protocol version 2.7.1, 19.05.2023., (© 2024 The Author(s). Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Paget's disease of bone (PDB) is characterised by increased and disorganised bone remodelling leading to various complications, such as bone deformity, deafness, secondary osteoarthritis, and pathological fracture. Pain is the most common presenting symptom of PDB, but it is unclear to what extent this is due to increased metabolic activity of the disease, complications, or unrelated causes. We conducted a cross-sectional study of 168 people with PDB attending secondary care referral centres in the UK. We documented the presence of musculoskeletal pain and sought to determine its underlying causes. Musculoskeletal pain was reported by 122/168 (72.6%) individuals. The most common cause was osteoarthritis of joints distant from an affected PDB site in 54 (44.3%), followed by metabolically active PDB in 18 (14.7%); bone deformity in 14 (11.4%); osteoarthritis of a joint neighbouring an affected site in 11 (9.0%), neuropathic pain in 10 (8.2%), and various other causes in the remainder. Pain was more common in women (p<0.019) and in older individuals (p<0.001). Circulating concentrations of macrophage colony-stimulating factor (M-CSF) were significantly higher in those with pain (p = 0.008), but there was no difference between groups of patients with and without pain in concentrations of interleukin-6 (IL-6) or biochemical markers of bone turnover. Pain is a common symptom in PDB but is most often due to osteoarthritis at an unaffected site. The study illustrates the importance of fully evaluating people with PDB to determine the underlying cause of pain so that management can be tailored appropriately., (© 2024. The Author(s).)

Introduction: Endometriosis is the leading cause of chronic pelvic pain among women. The pain associated with endometriosis significantly impacts various aspects of patients' quality of life. A notable void in the literature is the absence of a systematic review exploring pain communication between patients with endometriosis and healthcare professionals. Hence, the aim of this qualitative systematic review was to synthesize findings on how patients with endometriosis experience communicating with healthcare professionals about pain and how healthcare professionals experience these interactions., Material and Methods: A systematic literature search was conducted related to patients with endometriosis and pain communication in CINAHL PLUS with full text and MEDLINE (via EBSCO host) on May 12, 2023, and updated January 26, 2024. Searches were supplemented by backward searching reference lists and forward searching citations of included reports in Scopus and Google Scholar. The review was guided by the four-step meta-synthesis methodology by Sandelowski and Barosso. Critical appraisal of included studies was conducted using Critical Appraisal Skill Program (CASP). Findings were analyzed thematically, using the approach described by Thomas and Harden. The meta-synthesis was based on a registered protocol in PROSPERO (CRD 42023425430), and the study is reported adhering to the PRISMA 2020 checklist., Results: Overall, 37 reports published from 2003 until 2023 contributed to the review, including 4842 participants. Through thematic analysis, we developed the following themes: "Navigating the double burden," "Lack of mutual understanding," and "The complexities of conveying pain.", Conclusions: The communication of pain between patients with endometriosis and healthcare professionals is complex, encompassing patterns of disbelief, normalization, and psychological attribution. Engaging in discussions about pain presents diverse challenges stemming from insufficient communication skills and assessment tools. Further research is warranted to comprehensively explore the perspectives of both patients and healthcare professionals, aiming to devise strategies that enhance communication and patient care., (© 2024 The Author(s). Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Pediatric chronic pain is common and frequently results in reduced wellbeing and functioning. Limited knowledge among health care professionals has motivated a national care program for pediatric chronic pain to increase the standard of care for this group. Emphasizing a biopsychosocial approach, treatment should focus on self-management of pain and distress to increase resilience, functioning and wellbeing. Furthermore, close collaborations between relevant stakeholders, such as families, healthcare, and school, is critical for optimal and sustained effects.

Importance: Women with cystic fibrosis (CF) historically experience a high prevalence of urinary incontinence (UI). However, this area is understudied, especially in the modern era of highly effective modulator therapy (HEMT)., Objective: This study aimed to explore the UI experiences, knowledge, care-seeking behavior, and treatment preferences of women with CF., Study Design: We recruited women aged ≥18 years through the CF Foundation's Community Voice national registry if they had a diagnosis of CF and reported UI. Participants underwent individual, semistructured interviews exploring their experiences, attitudes, and preferences toward UI that were audiorecorded and transcribed. Two coders performed thematic analysis using deductive and inductive coding approaches., Results: Twenty-six participants completed interviews (average age, 45.1 years; range, 24-61 years). Key themes included the following: (1) most women with CF and UI report low bother from symptoms likely related to stress UI, and HEMT has greatly improved UI symptoms and decreased bother; (2) most women with CF and UI had previously discussed UI symptoms with family and/or peers but had not sought care due to stigma or low priority; (3) women with CF and UI had minimal knowledge about UI in general and how it relates to CF; (4) most desired broad screening for UI from their CF team and improved multidisciplinary care; and (5) highly effective UI treatment options with low-time commitment and easily accessible resources are desired., Conclusions: Women with CF and UI report low knowledge and care-seeking behavior related to this condition and desire improved care provision. Importantly, HEMT may improve UI symptoms among people with CF., Competing Interests: Megan Bradley reports grant funding from Axonics. The remaining authors report no conflict of interest., (Copyright © 2024 American Urogynecologic Society. All rights reserved.)

Objective: The aim of this study was to explore the instruction of social determinants of health (SDOH) for people with disabilities (PWD) in doctor of physical therapy (DPT) education programs., Methods: A sequential mixed methods study informed by a five-member disability community advisory panel was conducted. Qualitative semi-structured interviews with educators (n = 10) across 4 DPT programs in the Midwest were conducted and analyzed thematically. The qualitative findings formed the basis of the quantitative phase. An online survey was conducted with faculty of DPT programs in the United States (n = 254) with the most knowledge of instruction of SDOH and health equity for PWD (n = 74; 29% response rate). Quantitative data were analyzed with descriptive statistics and triangulated with qualitative data., Results: SDOH for PWD is an emerging component of instruction in DPT curricula. Five themes included: emerging instruction of SDOH for PWD; conceptual frameworks informing instruction; instructional strategies; barriers to integration of SDOH for PWD; and facilitators to integration of SDOH for PWD. Quantitative analysis revealed that 71 respondents (95.9%) included disability in health equity discussions primarily focused on health care access. Limited time (n = 49; 66.2%) was the most frequently reported barrier, and educator interest in disability health equity was the most frequently reported facilitator (n = 62; 83.7%) to inclusion of the SDOH for PWD in health equity discussions., Conclusion: Opportunities exist in DPT curricula to build on instructional strategies, integrate SDOH frameworks, and amplify facilitators to integration of SDOH for PWD., Impact: To meet the needs of the 67 million Americans living with disabilities, students must have the knowledge and skills to address the complex needs of this historically marginalized population. Understanding the DPT education landscape around SDOH for PWD can guide DPT educators to more fully prepare their students to recognize and ameliorate health disparities faced by PWD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Bipolar disorder is a severe mental health problem with limited treatment success. There is a call for improving interventions, requiring an increased understanding of factors driving mood instability. One promising avenue is to study temporal associations between factors that appear relevant according to the emotional amplifier model of Holmes are changes in mood, anxiety and mental imagery., Methods: The current study used data from a recent RCT for a secondary analysis which applied a network analysis approach to explore temporal associations between weekly measurements of mania, depression, anxiety and mental imagery measured during 32 weeks in two randomised groups (N = 55) receiving either imagery-focused cognitive therapy (ImCT) or group psychoeducation (PE)., Results: Both negative intrusive mental imagery and anxiety appeared central in the network analyses, driving changes in both mania and depression, but only in the PE group. In the ImCT group, only anxiety was driving changes in mania and depression., Conclusion: Although exploratory, findings suggest that prior increases in anxiety and negative intrusive mental imagery might be associated with subsequent increases in depression and mania symptoms in patients with bipolar disorder. Anxiety might in turn increase negative intrusive imagery and associated negative emotions. Although more research is needed, results are in line with the emotional amplifier model and stress that future interventions with a focus on anxiety and imagery might help to improve psychosocial therapies for patients with bipolar disorder. In addition, this study suggests that a network approach is a helpful and feasible way to study mood instability, anxiety and mental imagery to increase our understanding of mechanisms underpinning mood instability., (© 2024 The Author(s). Clinical Psychology & Psychotherapy published by John Wiley & Sons Ltd.)

Introduction: Many institutions seek to engage postsecondary students in research to grow future researchers. Despite this common goal, the means to achieve that end is often unknown creating difficulties for students as they seek out research opportunities., Objective: This article will share first-hand reports on the experiences of graduate students, undergraduate students, and family partners following their engagement as an interdisciplinary research team., Methods: This is a qualitative study using individual open-ended interviews with undergraduate students, graduate students, and patient family partners. The research was conducted using a Patient-Oriented Research approach. The transcripts were analyzed inductively by using Braun and Clarke's six phases of reflexive thematic analysis., Results: Two themes were developed from the analysis. The theme of Benefits & Facilitators was developed based on the many positive thoughts, feelings, resiliency, and learning expressed by the students and family partners. The undergraduate students found the experience of "doing" research fulfilling and a great tool for learning how to better use research in practice. Within the second theme Perceived Hierarchy , undergraduate students described themselves as helpers, not responsible, and they did not have the power to make decisions., Conclusion: Given the challenges identified in this study, future efforts in this approach should carefully consider the culture and how to best engage graduate students, undergraduate students, and family partners in research teams., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Acute agitation in youth is a challenging presentation to the emergency department. In many cases, however, youth can be behaviorally de-escalated using a combination of environmental modification and verbal de-escalation. In cases where additional strategies such as pharmacologic de-escalation or physical restraint are needed, using the least restrictive means possible, including the youth in the decision-making process, and providing options are important. This paper reviews specific considerations on the approach to a youth with acute agitation and strategies and techniques to successfully de-escalate agitated youth who pose a danger to themselves and/or others., Competing Interests: The authors declare they have no conflicts of interest., (© 2024 The Author(s). Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Objectives: Patient-centredness of care during wait time before surgery can be improved. In this study we aimed to assess (1) patients' experiences with and preferences regarding wait time before surgery; (2) the impact of wait time on quality of life (QoL) and (3) which factors influence patients' wait time experience., Design, Setting, Participants: We performed an exploratory sequential mixed-methods study among women with gynaecological cancer in two tertiary hospitals. We conducted semistructured interviews and identified aspects of QoL and factors that influenced wait time acceptability through thematic analysis. We developed a questionnaire from this thematic analysis which was completed by 97 women. Descriptive statistics and univariate and multivariate regression analyses were performed., Results: Average ideal wait time was 3.5 weeks (±1.7 weeks), minimum and maximum acceptable wait times were 2.2 and 5.6 weeks. Many patients scored above the threshold of the Hospital Anxiety and Depression Scale for anxiety (48%) or depression (34%), had sleeping problems (56%) or experienced pain (54%). A number of factors were more common in patients who indicated that their wait time had been too long: low education level (OR 7.4, 95% CI 0.5 to 5.0, p=0.007), time to surgery >4 weeks (OR 7.0, 95% CI 0.8 to 4.4, p=0.002) and experienced sleep disturbance (OR 3.27, 95% CI 0.0 to 3.1, p=0.05). If patients expectation of wait time was >4 weeks (OR 0.20, 95% CI -4.0 to -0.5 p=0008) or if patients experienced pain (OR 0.26, 95% CI -3.6 to -0.3, p=0.03), they less frequently indicated that wait time had been too long., Conclusion: To improve patient-centredness of care, healthcare providers should aim to reduce wait time to 3-4 weeks and ensure that patients are well informed about the length of wait time and are aware of high levels of anxiety, depression and pain during this time. Future studies should evaluate what interventions can improve QoL during wait time., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Strategies to minimize ischemic damage during heart transplantation (HTX) by donation after circulatory death (DCD) are warranted because the inevitable ischemic injury linked to DCD HTX deteriorates mitochondrial respiratory capacity and ultimately graft quality. This study aimed to examine the myocardial mitochondrial function during DCD HTX with hypothermic oxygenated machine perfusion (HOPE) and compare the effect of normothermic regional perfusion (NRP) with that of direct procurement and perfusion (DPP)., Methods: A porcine DCD HTX model was used with hearts subjected to either DPP (n = 6) or NRP (n = 7) followed by HOPE and orthotopic HTX. Mitochondrial respiratory function was analyzed by high-resolution respirometry in left ventricle biopsies at baseline, after 180 min of HOPE, and after 60 min of reperfusion post-HTX., Results: Mitochondrial oxidative phosphorylation (P = 0.0008), respiratory control ratio (P = 0.04), and coupling efficiency (P = 0.04) declined during DCD HTX. Fatty acid oxidation was preserved after 3 h of HOPE with a modest, statistically nonsignificant decline after reperfusion (P = 0.2). Oxidative phosphorylation was inversely correlated with troponin-T levels (r = -0.70, P = 0.0004). No statistically significant difference in mitochondrial respiratory capacity was observed between participants exposed to NRP and DPP., Conclusions: Mitochondrial respiratory capacity declined gradually throughout the course of DCD HTX and correlated with the degree of myocardial damage. Following HOPE, the extent of mitochondrial deterioration was comparable between NRP and DPP., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Alarms at hospitals are frequent and can lead to alarm fatigue posing patient safety risks. We aimed to describe alarm burden over a 1-year period and explored variations in alarm rates stratified by unit type, alarm source, and cause., Methods: A retrospective study of inpatient alarm and patient census data at 1 children's hospital from January 1, 2019, to December 31, 2019, including 8 inpatient units: 6 medical/surgical unit (MSU), 1 PICU, and 1 NICU. Rates of alarms per patient day (appd) were calculated overall and by unit type, alarm source, and cause. Poisson regression was used for comparisons., Results: There were 7 934 997 alarms over 84 077 patient days (94.4 appd). Significant differences in alarm rates existed across inpatient unit types (MSU 81.3 appd, PICU 90.7, NICU 117.5). Pulse oximetry (POx) probes were the alarm source with highest rate, followed by cardiorespiratory leads (54.4 appd versus 31). PICU had lowest rate of POx alarms (33.3 appd, MSU 37.6, NICU 92.6), whereas NICU had lowest rate of cardiorespiratory lead alarms (16.2 appd, MSU 40.1, PICU 31.4). Alarms stratified by cause displayed variation across unit types where "low oxygen saturation" had the highest overall rate, followed by "technical" alarms (43.4 appp versus 16.3). ICUs had higher rates of low oxygenation saturation alarms, but lower rates of technical alarms than MSUs., Conclusions: Clinical alarms are frequent and vary across unit types, sources, and causes. Unit-level alarm rates and frequent alarm sources (eg, POx) should be considered when implementing alarm reduction strategies., (Copyright © 2024 by the American Academy of Pediatrics.)

Background: Per and polyfluoroalkyl substances (PFAS), a class of environmentally and biologically persistent chemicals, have been used across many industries since the middle of the 20 th century. Some PFAS have been linked to adverse health effects., Objective: Our objective was to incorporate known and potential PFAS sources, physical characteristics of the environment, and existing PFAS water sampling results into a PFAS risk prediction map that may be used to develop a PFAS water sampling prioritization plan for the Colorado Department of Public Health and Environment (CDPHE)., Methods: We used random forest classification to develop a predictive surface of potential groundwater contamination from two PFAS, perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA). The model predicted PFAS risk at locations without sampling data into one of three risk categories after being "trained" with existing PFAS water sampling data. We used prediction results, variable importance ranking, and population characteristics to develop recommendations for sampling prioritization., Results: Sensitivity and precision ranged from 58% to 90% in the final models, depending on the risk category. The model and prioritization approach identified private wells in specific census blocks, as well as schools, mobile home parks, and public water systems that rely on groundwater as priority sampling locations. We also identified data gaps including areas of the state with limited sampling and potential source types that need further investigation., Impact Statement: This work uses random forest classification to predict the risk of groundwater contamination from two per- and polyfluoroalkyl substances (PFAS) across the state of Colorado, United States. We developed the prediction model using data on known and potential PFAS sources and physical characteristics of the environment, and "trained" the model using existing PFAS water sampling results. This data-driven approach identifies opportunities for PFAS water sampling prioritization as well as information gaps that, if filled, could improve model predictions. This work provides decision-makers information to effectively use limited resources towards protection of populations most susceptible to the impacts of PFAS exposure., (© 2024. The Author(s).)

Background: Studies preceding the COVID-19 pandemic found that slower time-to-return was associated with first-time, deferred, and mobile drive blood donors. How donor return dynamics changed during the COVID-19 pandemic is not well understood., Methods: We analyzed visits by whole blood donors from 2017 to 2022 in South Africa (SA) and the United States (US) stratified by mobile and fixed environment, first-time and repeat donor status, and pre-COVID19 (before March 2020) and intra-COVID19. We used Kaplan-Meier curves to characterize time-to-return, cumulative incidence functions to analyze switching between donation environments, and Cox proportional hazards models to analyze factors influencing time-to-return., Results: Overall time-to-return was shorter in SA. Pre-COVID19, the proportion of donors returning within a year of becoming eligible was lower for deferred donors in both countries regardless of donation environment and deferral type. Intra-COVID19, the gap between deferred and non-deferred donors widened in the US but narrowed in SA, where efforts to schedule return visits from deferred donors were intensified, particularly for non-hemoglobin-related deferrals. Intra-COVID19, the proportion of donors returning within a year in SA was higher for deferred first-time donors (>81%) than for successful first-time donors (80% at fixed sites; 69% at mobile drives)., Conclusions: The pandemic complicated efforts to recruit new donors and schedule returning visits after completed donations. Concerted efforts to improve time-to-return for deferred donors helped mitigate donation loss in SA during the public health emergency., (© 2024 The Author(s). Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Background: Attention deficit hyperactivity disorder (ADHD) is a mental health disorder affecting five to eight percent of children and youth worldwide. Inattention, impulsivity, and hyperactivity are core symptoms, which often leads to comorbid disorders and impairments. Increased prevalence of ADHD among youth requires development of accessible and scalable interventions. Digital interventions for ADHD show promising results for adults, yet insight into youths perspectives and needs from digital ADHD interventions is lacking. This study is set in a person-based approach and explore what youths want and need from a therapist-guided digital intervention for ADHD., Methods: Exploratory individual interviews were conducted with youths aged 13-16 years diagnosed with ADHD ( N  = 16). Participants with an ADHD diagnosis were recruited primarily via social media. The interview guide was based on research, treatment guidelines, and clinical expertise. The study applied reflexive thematic analysis, within a Big Q framework. Codes and themes were generated in Nvivo., Results: Four main themes and sub-themes were generated: (1) Tailoring the intervention to youths with ADHD (Push the right buttons; Stumbling blocks), (2) Managing ADHD (Planning and Focus; Regulation and Balance; Social interactions), (3) Me and my ADHD (Insight and Understanding; Accept and Normalization), and (4) Balance between support and independence., Discussion: The findings suggest that youths with ADHD prefer stimulating and interactive treatment and are aversive to overwhelming, passive content. The intervention and therapist should encourage empowerment by supporting the youths autonomy in managing their ADHD. Future research is needed to investigate feasibility for person-based approaches to digital mental health treatments. Furthermore, parent perspectives on digital treatment for youths with ADHD should be investigated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Storetvedt, Kahlon, Berg, Sundfjord and Nordgreen.)

While the relationships between spectral resolution, temporal resolution, and speech recognition are well defined in adults with cochlear implants (CIs), they are not well defined for prelingually deafened children with CIs, for whom language development is ongoing. This cross-sectional study aimed to better characterize these relationships in a large cohort of prelingually deafened children with CIs (N = 47; mean age = 8.33 years) by comprehensively measuring spectral resolution thresholds (measured via spectral modulation detection), temporal resolution thresholds (measured via sinusoidal amplitude modulation detection), and speech recognition (measured via monosyllabic word recognition, vowel recognition, and sentence recognition in noise via both fixed signal-to-noise ratio (SNR) and adaptively varied SNR). Results indicated that neither spectral or temporal resolution were significantly correlated with speech recognition in quiet or noise for children with CIs. Both age and CI experience had a moderate effect on spectral resolution, with significant effects for spectral modulation detection at a modulation rate of 0.5 cyc/oct, suggesting spectral resolution may improve with maturation. Thus, it is possible we may see an emerging relationship between spectral resolution and speech perception over time for children with CIs. While further investigation into this relationship is warranted, these findings demonstrate the need for new investigations to uncover ways of improving spectral resolution for children with CIs., (© 2024. The Author(s).)

Depression is a major global health concern expected to worsen by 2030. In 2019, 28 million individuals were affected by depressive disorders. Dietary and supplemental vitamins show overall favorable preventative and therapeutic effects on depression. B vitamins are crucial for neurological function and mood regulation. Deficiencies in these vitamins are linked to depression. Studies on individual B vitamins show promise in improving depressive symptoms, particularly thiamin, riboflavin, niacin, and folate. Vitamin C deficiency may heighten depressive symptoms, but its exact role is not fully understood. Seasonal Affective Disorder (SAD) is associated with insufficient sunlight exposure and vitamin D deficiency. Vitamin D supplementation for SAD shows inconsistent results due to methodological variations. Further investigation is needed to understand the mechanisms of vitamins in depression treatment. Moreover, more research on SAD and light therapy's efficacy and underlying mechanisms involving photoreceptors, enzymes, and immune markers is needed. Although dietary and supplemental vitamins show overall favorable preventative and therapeutic effects on depression, dietitians treating psychiatric disorders face challenges due to diverse study designs, making direct comparisons difficult. Therefore, this article reviews the current literature to assess the role of dietary and supplemental vitamins in the prevention and treatment of depression. This review found that, although evidence supports the role of B vitamins and vitamins C and D in preventing and treating depression, further research is needed to clarify their mechanisms of action and determine the most effective intervention strategies.

Nasal xenobiotic metabolizing enzymes (XMEs) are important for the sense of smell because they influence odorant availability and quality. Since the major part of the human nasal cavity is lined by a respiratory mucosa, we hypothesized that this tissue contributed to nasal odorant metabolism through XME activity. Thus, we built human respiratory tissue models and characterized the XME profiles using single-cell RNA sequencing. We focused on the XMEs dicarbonyl and l-xylulose reductase, aldehyde dehydrogenase (ALDH) 1A1, and ALDH3A1, which play a role in food odorant metabolism. We demonstrated protein abundance and localization in the tissue models and showed the metabolic activity of the corresponding enzyme families by exposing the models to the odorants 3,4-hexandione and benzaldehyde. Using gas chromatography coupled with mass spectrometry, we observed, for example, a significantly higher formation of the corresponding metabolites 4-hydroxy-3-hexanone (39.03 ± 1.5%, p = 0.0022), benzyl alcohol (10.05 ± 0.88%, p = 0.0008), and benzoic acid (8.49 ± 0.57%, p = 0.0004) in odorant-treated tissue models compared to untreated controls (0 ± 0, 0.12 ± 0.12, and 0.18 ± 0.18%, respectively). This is the first study that reveals the XME profile of tissue-engineered human respiratory mucosa models and demonstrates their suitability to study nasal odorant metabolism.

Objectives: Severe chronic obstructive pulmonary disease affects and changes the lives of both affected persons and next of kin. There is a need for support and a sense of coherence to manage the life situation and minimize the symptom and caregiver burden. The aim of this study was to diverge or converge views of symptom burden, caregiver burden, the need for support, and sense of coherence in persons with chronic obstructive pulmonary disease and their next of kin to gain a deeper and broader knowledge and understanding., Methods: A mixed methods study with data from interviews and four validated questionnaires from persons affected by chronic obstructive pulmonary disease in GOLD stages III and IV and their next of kin., Results: Questionnaires from 112 persons affected by chronic obstructive pulmonary disease, and 71 next of kin, together with 25 and 21 interviews, show that; there is a difference between estimated symptoms and caregiver burden and experiences expressed in their own words. There is also a defect regarding meaningfulness, comprehensibility, and manageability affecting daily life. Symptoms and caregiver burden, together with the sense of coherence, strengthen the need for support., Discussion: The complexity of the life situation leads to a need for supportive interventions to strengthen internal and external resources., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Objectives: Accurate HIV incidence estimates among blood donors are necessary to assess the effectiveness of programs aimed at limiting transfusion-transmitted HIV. We assessed the impact of undisclosed HIV status and antiretroviral (ARV) use on HIV recency and incidence estimates using increasingly comprehensive recent infection testing algorithms., Materials and Methods: Using 2017 donation data from first-time and lapsed donors, we populated four HIV recency algorithms: (1) serology and limiting-antigen avidity testing, (2) with individual donation nucleic amplification testing (ID-NAT) added to Algorithm 1, (3) with viral load added to Algorithm 2 and (4) with ARV testing added to Algorithm 3. Algorithm-specific mean durations of recent infection (MDRI) and false recency rates (FRR) were calculated and used to derive and compare incidence estimates., Results: Compared with Algorithm 4, progressive algorithms misclassified fewer donors as recent: Algorithm 1: 61 (12.1%); Algorithm 2: 14 (2.8%) and Algorithm 3: 3 (0.6%). Algorithm-specific MDRI and FRR values resulted in marginally lower incidence estimates: Algorithm 1: 0.19% per annum (p.a.) (95% confidence interval [CI]: 0.13%-0.26%); Algorithm 2: 0.18% p.a. (95% CI: 0.13%-0.22%); Algorithm 3: 0.17% p.a. (95% CI: 0.13%-0.22%) and Algorithm 4: 0.17% p.a. (95% CI: 0.13%-0.21%)., Conclusion: We confirmed significant misclassification of recent HIV cases when not including viral load and ARV testing. Context-specific MDRI and FRR resulted in progressively lower incidence estimates but did not fully account for the context-specific variability in incidence modelling. The inclusion of ARV testing, in addition to viral load and ID-NAT testing, did not have a significant impact on incidence estimates., (© 2024 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.)

Nucleoside analogues like 4-thiouridine (4sU) are used to metabolically label newly synthesized RNA. Chemical conversion of 4sU before sequencing induces T-to-C mismatches in reads sequenced from labelled RNA, allowing to obtain total and labelled RNA expression profiles from a single sequencing library. Cytotoxicity due to extended periods of labelling or high 4sU concentrations has been described, but the effects of extensive 4sU labelling on expression estimates from nucleotide conversion RNA-seq have not been studied. Here, we performed nucleotide conversion RNA-seq with escalating doses of 4sU with short-term labelling (1h) and over a progressive time course (up to 2h) in different cell lines. With high concentrations or at later time points, expression estimates were biased in an RNA half-life dependent manner. We show that bias arose by a combination of reduced mappability of reads carrying multiple conversions, and a global, unspecific underrepresentation of labelled RNA emerging during library preparation and potentially global reduction of RNA synthesis. We developed a computational tool to rescue unmappable reads, which performed favourably compared to previous read mappers, and a statistical method, which could fully remove remaining bias. All methods developed here are freely available as part of our GRAND-SLAM pipeline and grandR package., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Rationale: F18-FDG PET/CT may be helpful in baseline staging of patients with high-risk LARC presenting with vascular tumor deposits (TDs), in addition to standard pelvic MRI and CT staging. Methods: All patients with locally advanced rectal cancer that had TDs on their baseline MRI of the pelvis and had a baseline F18-FDG PET/CT between May 2016 and December 2020 were included in this retrospective study. TDs as well as lymph nodes identified on pelvic MRI were correlated to the corresponding nodular structures on a standard F18-FDG PET/CT, including measurements of nodular SUVmax and SUVmean. In addition, the effects of partial volume and spill-in on SUV measurements were studied. Results: A total number of 62 patients were included, in which 198 TDs were identified as well as 106 lymph nodes (both normal and metastatic). After ruling out partial volume effects and spill-in, 23 nodular structures remained that allowed for reliable measurement of SUVmax: 19 TDs and 4 LNs. The median SUVmax between TDs and LNs was not significantly different ( p = 0.096): 4.6 (range 0.8 to 11.3) versus 2.8 (range 1.9 to 3.9). For the median SUVmean, there was a trend towards a significant difference ( p = 0.08): 3.9 (range 0.7 to 7.8) versus 2.3 (range 1.5 to 3.4). Most nodular structures showing either an SUVmax or SUVmean ≥ 4 were characterized as TDs on MRI, while only two were characterized as LNs. Conclusions: SUV measurements may help in separating TDs from lymph node metastases or normal lymph nodes in patients with high-risk LARC.

Suicide is a leading cause of death among youth, and emergency departments (EDs) play an important role in caring for youth with suicidality. Shortages in outpatient and inpatient mental and behavioral health capacity combined with a surge in ED visits for youth with suicidal ideation (SI) and self-harm challenge many EDs in the United States. This review highlights currently identified best practices that all EDs can implement in suicide screening, assessment of youth with self-harm and SI, care for patients awaiting inpatient psychiatric care, and discharge planning for youth determined not to require inpatient treatment. We will also highlight several controversies and challenges in implementation of these best practices in the ED. An enhanced continuum of care model recommended for youth with mental and behavioral health crises utilizes crisis lines, mobile crisis units, crisis receiving and stabilization units, and also maximizes interventions in home- and community-based settings. However, while local systems work to enhance continuum capacity, EDs remain a critical part of crisis care. Currently, EDs face barriers to providing optimal treatment for youth in crisis due to inadequate resources including the ability to obtain emergent mental health consultations via on-site professionals, telepsychiatry, and ED transfer agreements. To reduce ED utilization and better facilitate safe dispositions from EDs, the expansion of community- and home-based services, pediatric-receiving crisis stabilization units, inpatient psychiatric services, among other innovative solutions, is necessary., Competing Interests: None., (© 2024 The Authors. Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Objectives: Hepatitis B virus (HBV) infection remains a global health problem. Risk factors for HBV infection are usually assessed in prevalent rather than incident infections. To identify demographic and behavioral risks associated with incident HBV among South African blood donors., Methods: A case-control study was performed between November 2014 and January 2018. Cases were blood donors testing positive for HBV DNA with or without hepatitis B surface antigen but negative for antibody to hepatitis B core antigen. Participants completed an audio computer-assisted structured interview on exposures during the previous 6 months. Sex-specific multivariable logistic regression yielded independent associations between risks and HBV infection., Results: 56 females and 37 males with incident HBV were compared to 438 female and 439 male controls, respectively. For females, risk factors were accepting money or goods for sex, using agents to prepare one's anus prior to anal sex, penetrating injury, non-Black race, and lower educational status. Men reporting homosexual or bisexual orientation or sex with other men, previous injury, referral for HBV testing, or lack of medical insurance were at increased risk. For both sexes, having more than two male sexual partners increased risk., Conclusions: Sexual behaviors predominated over parenteral exposures as risks for incident HBV in both female and male blood donors., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Polyurethane coatings have strong material properties due to the hydrogen bonding inherent to the urethane groups. However, installing this urethane moiety usually requires curing through difficult-to-handle isocyanates. In this work, we show the development of a polyurethane-based crosslinker that can be used to formulate a one-component polyurethane coating with material properties similar to those of isocyanate-based polyurethane coatings. To achieve this, we used diazirine functionalities that generate carbenes upon heating, which react with alcohol functionalities in a polyol to generate a crosslinked network with a high storage modulus., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background and Objectives: Confirmed COVID-19 diagnoses underestimate the total number of infections. Blood donors can provide representative seroprevalence estimates, which can be leveraged into reasonable estimates of total infection counts and infection fatality rate (IFR)., Materials and Methods: Blood donors who donated after each of three epidemic waves (Beta, Delta and first Omicron waves) were tested for anti-SARS-CoV-2 nucleocapsid antibodies using the Roche Elecsys anti-SARS-CoV-2 total immunoglobulin assay. Roche Elecsys anti-spike antibody testing was done for the post-Omicron sampling. Prevalence of antibodies was estimated by age, sex, race and province and compared to official case reporting. Province and age group-specific IFRs were estimated using external excess mortality estimates., Results: The nationally weighted anti-nucleocapsid seroprevalence estimates after the Beta, Delta and Omicron waves were 47% (46.2%-48.6%), 71% (68.8%-73.5%) and 87% (85.5%-88.4%), respectively. There was no variation by age and sex, but there were statistically and epidemiologically significant differences by province (except at the latest time point) and race. There was a 13-fold higher seroprevalence than confirmed case counts at the first time point. Age-dependent IFR roughly doubled for every 10 years of age increase over 6 decades from 0.014% in children to 6.793% in octogenarians., Conclusion: Discrepancies were found between seroprevalence and confirmed case counts. High seroprevalence rates found among Black African donors can be ascribed to historical inequities. Our IFR estimates were useful in refining previous large disagreements about the severity of the epidemic in South Africa. Blood donor-based serosurveys provided a valuable and efficient way to provide near real-time monitoring of the ongoing SARS-CoV-2 outbreak., (© 2023 International Society of Blood Transfusion.)

Surveillance for emerging pathogens is critical for developing early warning systems to guide preparedness efforts for future outbreaks of associated disease. To better define the epidemiology and burden of associated respiratory disease and acute flaccid myelitis (AFM), as well as to provide actionable data for public health interventions, we developed a multimodal surveillance program in Colorado, USA, for enterovirus D68 (EV-D68). Timely local, state, and national public health outreach was possible because prospective syndromic surveillance for AFM and asthma-like respiratory illness, prospective clinical laboratory surveillance for EV-D68 among children hospitalized with respiratory illness, and retrospective wastewater surveillance led to early detection of the 2022 outbreak of EV-D68 among Colorado children. The lessons learned from developing the individual layers of this multimodal surveillance program and how they complemented and informed the other layers of surveillance for EV-D68 and AFM could be applied to other emerging pathogens and their associated diseases.

Purpose: The shift from adjuvant to neoadjuvant treatment in colon cancer demands the radiological selection of patients for systemic therapy. The aim of this study was to evaluate the accuracy of the CT-based TNM stage and high-risk features, including extramural venous invasion (EMVI) and tumour deposits, in the identification of patients with histopathological advanced disease, currently considered for neoadjuvant treatment (T3-4 disease)., Methods: All consecutive patients surgically treated for non-metastatic colon cancer between January 2018 and January 2020 in a referral centre for colorectal cancer were identified retrospectively. All tumours were staged on CT according to the TNM classification system. Additionally, the presence of EMVI and tumour deposits on CT was evaluated. The histopathological TNM classification was used as reference standard., Results: A total of 176 patients were included. Histopathological T3-4 colon cancer was present in 85.0% of the patients with CT-detected T3-4 disease. Histopathological T3-4 colon cancer was present in 96.4% of the patients with CT-detected T3-4 colon cancer in the presence of both CT-detected EMVI and CT-detected tumour deposits. Histopathological T0-2 colon cancer was present in 50.8% of the patients with CT-detected T0-2 disease, and in 32.4% of the patients without CT-detected EMVI and tumour deposits., Conclusion: The diagnostic accuracy of CT-based staging was comparable with previous studies. The presence of high-risk features on CT increased the probability of histopathological T3-4 colon cancer. However, a substantial part of the patients without CT-detected EMVI and tumour deposits was diagnosed with histopathological T3-4 disease. Hence, more accurate selection criteria are required to correctly identify patients with locally advanced disease., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The critical care management of patients after cardiac arrest is burdened by a lack of high-quality clinical studies and the resultant lack of high-certainty evidence. This results in limited practice guideline recommendations, which may lead to uncertainty and variability in management. Critical care management is crucial in patients after cardiac arrest and affects outcome. Although guidelines address some relevant topics (including temperature control and neurological prognostication of comatose survivors, 2 topics for which there are more robust clinical studies), many important subject areas have limited or nonexistent clinical studies, leading to the absence of guidelines or low-certainty evidence. The American Heart Association Emergency Cardiovascular Care Committee and the Neurocritical Care Society collaborated to address this gap by organizing an expert consensus panel and conference. Twenty-four experienced practitioners (including physicians, nurses, pharmacists, and a respiratory therapist) from multiple medical specialties, levels, institutions, and countries made up the panel. Topics were identified and prioritized by the panel and arranged by organ system to facilitate discussion, debate, and consensus building. Statements related to postarrest management were generated, and 80% agreement was required to approve a statement. Voting was anonymous and web based. Topics addressed include neurological, cardiac, pulmonary, hematological, infectious, gastrointestinal, endocrine, and general critical care management. Areas of uncertainty, areas for which no consensus was reached, and future research directions are also included. Until high-quality studies that inform practice guidelines in these areas are available, the expert panel consensus statements that are provided can advise clinicians on the critical care management of patients after cardiac arrest., (© 2023. The Author(s).)

Objective . Deep learning models, such as convolutional neural networks (CNNs), can take full dose comparison images as input and have shown promising results for error identification during treatment. Clinically, complex scenarios should be considered, with the risk of multiple anatomical and/or mechanical errors occurring simultaneously during treatment. The purpose of this study was to evaluate the capability of CNN-based error identification in this more complex scenario. Approach . For 40 lung cancer patients, clinically realistic ranges of combinations of various treatment errors within treatment plans and/or computed tomography (CT) images were simulated. Modified CT images and treatment plans were used to predict 2580 3D dose distributions, which were compared to dose distributions without errors using various gamma analysis criteria and relative dose difference as dose comparison methods. A 3D CNN capable of multilabel classification was trained to identify treatment errors at two classification levels, using dose comparison volumes as input: Level 1 (main error type, e.g. anatomical change, mechanical error) and Level 2 (error subtype, e.g. tumor regression, patient rotation). For training the CNNs, a transfer learning approach was employed. An ensemble model was also evaluated, which consisted of three separate CNNs each taking a region of interest of the dose comparison volume as input. Model performance was evaluated by calculating sample F1-scores for training and validation sets. Main results . The model had high F1-scores for Level 1 classification, but performance for Level 2 was lower, and overfitting became more apparent. Using relative dose difference instead of gamma volumes as input improved performance for Level 2 classification, whereas using an ensemble model additionally reduced overfitting. The models obtained F1-scores of 0.86 and 0.62 on an independent test set for Level 1 and Level 2, respectively. Significance . This study shows that it is possible to identify multiple errors occurring simultaneously in 3D dose verification data., (Creative Commons Attribution license.)

The critical care management of patients after cardiac arrest is burdened by a lack of high-quality clinical studies and the resultant lack of high-certainty evidence. This results in limited practice guideline recommendations, which may lead to uncertainty and variability in management. Critical care management is crucial in patients after cardiac arrest and affects outcome. Although guidelines address some relevant topics (including temperature control and neurological prognostication of comatose survivors, 2 topics for which there are more robust clinical studies), many important subject areas have limited or nonexistent clinical studies, leading to the absence of guidelines or low-certainty evidence. The American Heart Association Emergency Cardiovascular Care Committee and the Neurocritical Care Society collaborated to address this gap by organizing an expert consensus panel and conference. Twenty-four experienced practitioners (including physicians, nurses, pharmacists, and a respiratory therapist) from multiple medical specialties, levels, institutions, and countries made up the panel. Topics were identified and prioritized by the panel and arranged by organ system to facilitate discussion, debate, and consensus building. Statements related to postarrest management were generated, and 80% agreement was required to approve a statement. Voting was anonymous and web based. Topics addressed include neurological, cardiac, pulmonary, hematological, infectious, gastrointestinal, endocrine, and general critical care management. Areas of uncertainty, areas for which no consensus was reached, and future research directions are also included. Until high-quality studies that inform practice guidelines in these areas are available, the expert panel consensus statements that are provided can advise clinicians on the critical care management of patients after cardiac arrest.

Normothermic regional perfusion (NRP) allows assessment of therapeutic interventions prior to donation after circulatory death transplantation. Sodium-3-hydroxybutyrate (3-OHB) increases cardiac output in heart failure patients and diminishes ischemia-reperfusion injury, presumably by improving mitochondrial metabolism. We investigated effects of 3-OHB on cardiac and mitochondrial function in transplanted hearts and in cardiac organoids. Donor pigs (n = 14) underwent circulatory death followed by NRP. Following static cold storage, hearts were transplanted into recipient pigs. 3-OHB or Ringer's acetate infusions were initiated during NRP and after transplantation. We evaluated hemodynamics and mitochondrial function. 3-OHB mediated effects on contractility, relaxation, calcium, and conduction were tested in cardiac organoids from human pluripotent stem cells. Following NRP, 3-OHB increased cardiac output (P < 0.0001) by increasing stroke volume (P = 0.006), dP/dt (P = 0.02) and reducing arterial elastance (P = 0.02). Following transplantation, infusion of 3-OHB maintained mitochondrial respiration (P = 0.009) but caused inotropy-resistant vasoplegia that prevented weaning. In cardiac organoids, 3-OHB increased contraction amplitude (P = 0.002) and shortened contraction duration (P = 0.013) without affecting calcium handling or conduction velocity. 3-OHB had beneficial cardiac effects and may have a potential to secure cardiac function during heart transplantation. Further studies are needed to optimize administration practice in donors and recipients and to validate the effect on mitochondrial function., (© 2024. The Author(s).)

Mandatory reporting of elder abuse aims to detect and prevent mistreatment and improve services. Service users and their relatives can raise concerns, but only staff can file mandatory reports. This article examines how the concerns of service users and relatives were managed by designated officials in reports of mistreatments in care for older adults in Sweden. We lean on sociological theories of "interpersonal trouble" and organizational "disputes domains." The thematic analysis is based on 28 incident reports initiated by service users or their relatives. The analysis shows that the reports were managed in one of three ways: asymmetrically, by 1) dismissing or 2) supporting the complainant's position, or symmetrically, by 3) treating complainants' accounts as credible but minimizing their seriousness. There were differences between reports initiated by service users and relatives. Dismissing concerns about abuse, mainly those made by relatives, risks support for service users failing.

Background: To promote quality improvement in Dutch mental health care, it is imperative to line up methods of quality improvement with daily care practice. In value-based healthcare the joint vision of medical professionals and patients is leading in the design and execution of care improvements., Aim: To demonstrate the value of value-based care., Method: Description of a practical example of the application of value based healthcare in mental healthcare, including a practical example of value-based improvement of patient care., Results: A multidisciplinary improvement team was formed, consisting of patients and employees who were involved in the depression care pathway. The team determined important outcomes of care from the patient&rsquo;s perspective, and successfully executed several improvement initiatives., Conclusion: The bottom-up approach of value-based healthcare is in line with day-to-day care practice and provides opportunities for effectively improving the quality of mental health care.

Background: Immune-checkpoint inhibitors (ICIs) represent a revolution in cancer therapy and are currently implemented as standard therapy within several cancer indications. Nevertheless, the treatment is only effective in a subset of patients, and immune-related adverse effects complicate the improved survival. Adjuvant treatments that can improve the efficacy of ICIs are highly warranted, not only to increase the response rate, but also to reduce the therapeutic ICI dosage. Several treatment modalities have been suggested as ICI adjuvants including vascular targeted treatments and photodynamic therapy (PDT). Photochemical internalization (PCI) is a drug delivery system, based on PDT. PCI is long known to generate an immune response in murine models and was recently shown to enhance the cellular immune response of a vaccine in a clinical study. In the present work we evaluated PCI in combination with the vascular targeting toxin VEGF 121 /rGel with respect to induction of immune-mediated cell death as well as in vitro ICI enhancement., Methods: DAMP signaling post VEGF 121 /rGel-PCI was assessed in CT26 and MC38 murine colon cancer cell lines. Hypericin-PDT, previously indicated as an highly efficient DAMP inducer (but difficult to utilize clinically), was used as a control. ATP release was detected by a bioluminescent kit while HMGB1 and HSP90 relocalization and secretion was detected by fluorescence microscopy and western blotting. VEGF 121 /rGel-PCI was further investigated as an αCTLA enhancer in CT26 and MC38 tumors by measurement of tumor growth delay. CD8+ Dependent efficacy was evaluated in vivo using a CD8+ antibody., Results: VEGF 121 /rGel-PCI was shown to induce increased DAMP signaling as compared to PDT and VEGF 121 /rGel alone and the magnitude was found similar to that induced by Hypericin-PDT. Furthermore, a significant CD8+ dependent enhanced αCTLA-4 treatment effect was observed when VEGF 121 /rGel-PCI was used as an adjuvant in both tumor models., Conclusions: VEGF 121 /rGel-PCI describes a novel concept for ICI enhancement which induces a rapid CD8+ dependent tumor eradication in both CT26 and MC38 tumors. The concept is based on the combination of intracellular ROS generation and vascular targeting using a plant derived toxin and will be developed towards clinical utilization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Longva, Berg and Weyergang.)

De novo variants affecting monoubiquitylation of histone H2B (H2Bub1) are enriched in human congenital heart disease. H2Bub1 is required in stem cell differentiation, cilia function, post-natal cardiomyocyte maturation and transcriptional elongation. However, how H2Bub1 affects cardiogenesis is unknown. We show that the H2Bub1-deposition complex (RNF20-RNF40-UBE2B) is required for mouse cardiogenesis and for differentiation of human iPSCs into cardiomyocytes. Mice with cardiac-specific Rnf20 deletion are embryonic lethal and have abnormal myocardium. We then analyzed H2Bub1 marks during differentiation of human iPSCs into cardiomyocytes. H2Bub1 is erased from most genes at the transition from cardiac mesoderm to cardiac progenitor cells but is preserved on a subset of long cardiac-specific genes. When H2Bub1 is reduced in iPSC-derived cardiomyocytes, long cardiac-specific genes have fewer full-length transcripts. This correlates with H2Bub1 accumulation near the center of these genes. H2Bub1 accumulation near the center of tissue-specific genes was also observed in embryonic fibroblasts and fetal osteoblasts. In summary, we show that normal H2Bub1 distribution is required for cardiogenesis and cardiomyocyte differentiation, and suggest that H2Bub1 regulates tissue-specific gene expression by increasing the amount of full-length transcripts., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Background and Objectives: CBT for patients with bipolar disorder has modest effects. Across disorders, mental imagery has been used to update CBT to increase effectiveness. In order to enhance CBT for bipolar disorder with imagery techniques, research is needed into emotional imagery quality and, related appraisals of imagery and their relationships with mood instability and subsequent behaviour in bipolar disorder., Methods: Patients with bipolar disorder (n = 106), unipolar depression (n = 51), creative imagery prone participants (n = 53) and participants without a history of a mood disorder (n = 135) completed the Dutch Imagery Survey (DImS), an online imagery survey, adapted from the Imagery Interview, assessing self-reported emotional imagery aspects. Imagery quality, appraisals and their self-perceived effects on emotion and behaviour were compared between groups. As unexpected differences within the bipolar group appeared, these were additionally explored., Results: Imagery appraisals but not imagery quality discriminated between the patient groups and non-patient groups Imagery was perceived as an emotional amplifier in all groups, but this was specifically apparent in bipolar manic and bipolar depressed groups. Only in the bipolar group imagery was experienced to amplify behavioural tendencies., Limitations: Results need to be replicated using a larger sample of patients with BD who are currently manic or depressed., Conclusions: Not only quality of imagery, but especially appraisals associated with imagery are differentiating between imagery prone people with and without mood disorder. Imagery amplifies emotion in all groups, but only in those patients with bipolar disorder currently manic or depressed did this influence behaviour., Competing Interests: Declaration of competing interest The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Pregnancy-associated osteoporosis (PAO) is a rare syndrome which typically presents with vertebral fractures during pregnancy or lactation. The medical records of sixteen patients with PAO who presented to a specialist clinic at the Western General Hospital in Edinburgh over a 20-year period were reviewed to evaluate the mode of presentation, potential risk factors and response to treatment. The most common presentation was back pain occurring in 13/16 (81.2%) individuals due to multiple vertebral fractures. The diagnosis was usually made postpartum and in 12/16 individuals (75.0%), PAO presented during the woman's first pregnancy. Medicines which could have contributed to the development of PAO included thromboprophylaxis therapies in 8 subjects (50.0%), inhaled or injected corticosteroids in 5 (31.3%), anticonvulsants in 2 (12.5%) and a LHRH agonist in 1 (6.3%). Five individuals reported a family history of osteoporosis, and two pregnancies were complicated by hyperemesis gravidarum. Treatments administered included calcium and vitamin D supplements, bisphosphonates and teriparatide. Bone mineral density increased following the diagnosis in all cases, regardless of treatment given. One patient had further fracture during follow-up, but four patients had subsequent pregnancies without fractures. We estimated that in this locality, the incidence of PAO was 6.8/100,000 pregnancies with a point prevalence of 4.1 per 100,000 women. This case series indicates the importance of family history of osteoporosis and thromboprophylaxis drugs as risk factors for PAO while also demonstrating that the reductions in bone density tend to reverse with time, irrespective of the treatment given., (© 2023. The Author(s).)

Background: Myocarditis is a condition that can have severe adverse outcomes and lead to sudden cardiac death if remaining undetected. This study tested the capability of cardiac magnetic field mapping to detect patients with clinically suspected myocarditis. This could open up the way for rapid, non-invasive, and cost-effective screening of suspected cases before a gold standard assessment via endomyocardial biopsy., Methods: Historical cardiac magnetic field maps ( n  = 97) and data from a state-of-the-art magnetocardiography device ( n  = 30) were analyzed using the Kullback-Leibler entropy (KLE) for dimensionality reduction and topological quantification. Linear discriminant analysis was used to discern between patients with ongoing myocarditis and healthy controls., Results: The STT segment of a magnetocardiogram, i.e., the section between the end of the S wave and the end of the T wave, was best suited to discern both groups. Using a 250-ms excerpt from the onset of the STT segment gave a reliable classification between the myocarditis and control group for both historic data (sensitivity: 0.83, specificity: 0.85, accuracy: 0.84) and recent data (sensitivity: 0.69, specificity: 0.88, accuracy: 0.80) using the KLE to quantify the topology of the cardiac magnetic field map., Conclusion: The implementation based on KLE can reliably distinguish between clinically suspected myocarditis patients and healthy controls. We implemented an automatized feature selection based on LDA to replace the observer-dependent manual thresholding in previous studies., Competing Interests: JP is affiliated with BMPH. NW, MP, and KB receive funding from BMPH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2023 Pille, Gapelyuk, Berg, Bannasch, Mockler, Park, Park and Wessel.)

Purpose: The developmental trajectory of learning during residency may be attributed to multiple factors, including variation in individual trainee performance, program-level factors, graduating medical school effects, and the learning environment. Understanding the relationship between medical school and learner performance during residency is important in prioritizing undergraduate curricular strategies and educational approaches for effective transition to residency and postgraduate training. This study explores factors contributing to longitudinal and developmental variability in resident Milestones ratings, focusing on variability due to graduating medical school, training program, and learners using national cohort data from emergency medicine (EM) and family medicine (FM)., Method: Data from programs with residents entering training in July 2016 were used (EM: n=1,645 residents, 178 residency programs; FM: n=3,997 residents, 487 residency programs). Descriptive statistics were used to examine data trends. Cross-classified mixed-effects regression were used to decompose variance components in Milestones ratings., Results: During postgraduate year (PGY)-1, graduating medical school accounted for 5% and 6% of the variability in Milestones ratings, decreasing to 2% and 5% by PGY-3 for EM and FM, respectively. Residency program accounted for substantial variability during PGY-1 (EM=70%, FM=53%) but decreased during PGY-3 (EM=62%, FM=44%), with greater variability across training period in patient care (PC), medical knowledge (MK), and systems-based practice (SBP). Learner variance increased significantly between PGY-1 (EM=23%, FM=34%) and PGY-3 (EM=34%, FM=44%), with greater variability in practice-based learning and improvement (PBLI), professionalism (PROF), and interpersonal communication skills (ICS)., Conclusions: The greatest variance in Milestone ratings can be attributed to the residency program and to a lesser degree, learners, and medical school. The dynamic impact of program-level factors on learners shifts during the first year and across the duration of residency training, highlighting the influence of curricular, instructional, and programmatic factors on resident performance throughout residency., (Copyright © 2023 by the Association of American Medical Colleges.)

Objective: To determine the accuracy of computed tomography (CT)-based staging in selecting high-risk colon cancer patients who would benefit from neoadjuvant chemotherapy while avoiding overtreatment., Methods: Data of adult patients diagnosed with non-metastatic primary colon cancer in 2005-2020, who underwent surgical resection without neoadjuvant chemotherapy, were retrospectively collected from the Netherlands Cancer Registry. Agreement between clinical and pathological evaluation for each T and N stage was calculated. Sensitivity and specificity analyses were conducted to predict T3-T4 and N1-N2 stages, with histopathology as the reference standard., Results: Data from 44,471 patients (median age, 71 years, 50% female) were evaluated. We included 38,915 patients with complete T stage and 39,565 patients with complete N stage for analyses. The overall clinical-pathological agreement for T stage was 59% and for N stage 57%. The sensitivity and specificity of CT to detect T3-T4 tumours were 80% (95% confidence interval (CI): 0.79, 0.80) and 76% (95% CI: 0.75, 0.77), respectively, with a positive predictive value (PPV) of 92% (95% CI: 0.92, 0.92). The sensitivity and specificity of CT to detect N1-N2 category were 62% (95% CI: 0.61, 0.63) and 70% (95% CI: 0.69, 0.71), respectively, with PPV 60% (95% CI: 0.59, 0.60)., Conclusion: CT-based staging shows limited accuracy in selecting colon cancer patients who would benefit from neoadjuvant therapy without risking overtreatment. Detection of lymph node metastases with CT remains unreliable., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)