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Jisoo Park,1 Eun-Kyung Kim,1 Se Hee Lee,1 Mi-Ae Kim,1 Jung-Hyun Kim,1 Sang Min Lee,2,3 Jae Seung Lee,4,5 Yeon-Mok Oh,4,5 Sang-Do Lee,4,5 Ji-Hyun Lee1 On behalf of the KOLD Study Group1Department of Pulmonology, Allergy and Critical Care Medicine, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea; 2Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 3Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 4Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 5Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaCorrespondence: Ji-Hyun Lee, Department of Pulmonology, Allergy and Critical Care Medicine, CHA Bundang Medical Center, CHA University, 59, Yatap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13496, Republic of Korea, Tel +82-31-780-5205, Fax +82-31-780-2992, Email plmjhlee@cha.ac.krPurpose: We explored the differences in clinical manifestations of COPD patients regarding emphysema distribution along with evidence of airway involvement in chest computed tomography (CT) scans.Patients and Methods: The patients were divided into three groups according to the emphysema distribution: the upper dominant (UD), lower dominant (LD), and homogeneous (HD) groups. Airway wall thickness was quantitatively measured and the presence of bronchiectasis and/or bronchial wall thickening (BE/BWT) was visually assessed. Baseline characteristics including the evidence of airway involvement and long-term outcomes were compared among the three groups. Non-severe patients of each group were first treated with 3 months of ICS/LABA combination after 2 weeks of wash-out period and lung functions before and after the treatment were compared.Results: Of the 425 patients, 141 were in the UD, 107 in LD, and 177 in HD. The LD had more severe airway obstruction with lower emphysema index (EI) than the UD (LD vs UD; FEV1, 49.5– 14.9 vs 54.6– 16.5; EI, 21.0 [IQR: 14.0– 33.1] vs 26.3 [IQR: 15.8– 39.0]). The LD showed thicker airways (higher WA% and Pi10) and more severe air trapping (higher RV and RV/TLC) than UD. A larger proportion of patients in LD had BE/BWT (35.5% in LD vs 11.3% in UD). In LD, more patients experienced acute exacerbations and the time to first exacerbation was shorter than UD. Non-severe patients in LD treated with 3 months of ICS/LABA combined inhalers showed a notable reduction of RV than UD (LD vs UD; − 531.1– 936.5 vs − 86.5– 623.5).Conclusion: The LD showed a more prominent airway involvement than UD, which may cause more frequent exacerbations and a marked reduction of RV after the ICS/LABA combination treatment in LD. Phenotyping of the COPD patients using quantitatively measured emphysema distribution would be useful for predicting treatment response and exacerbation.Keywords: pulmonary disease, chronic obstructive, computed tomography, emphysema

Minseok Albert Kim,1 Heejoon Jang,1 Na Ryung Choi,1 Joon Yeul Nam,1 Yun Bin Lee,1 Eun Ju Cho,1 Jeong-Hoon Lee,1 Su Jong Yu,1 Hyo-Cheol Kim,2 Jin Wook Chung,2 Jung-Hwan Yoon,1 Yoon Jun Kim1 1Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea; 2Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South KoreaCorrespondence: Yoon Jun KimDepartment of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South KoreaTel +82-2-2072-3081Fax +82-2-743-6701Email yoonjun@snu.ac.krBackground: Both trans-arterial radioembolization (TARE) and conventional trans-arterial chemoembolization (TACE) can effectively control hepatocellular carcinoma (HCC) in patients who are not suitable for curative resection. This study compared the effectiveness of TARE and conventional TACE as the initial trans-arterial treatment for hepatocellular carcinoma (HCC) assessed by tumor response and clinical outcomes.Material and Methods: Data were retrospectively analyzed the propensity score-matched cohort for overall survival (OS), progression-free survival (PFS), and intrahepatic PFS in patients who have received TARE or TACE as the first HCC treatment from March 2012 to December 2017.Results: A total of 138 patients initially treated with TARE (n = 54) or TACE (n = 84) was included in this study. Of 138 patients, median age was 59 years and the mean follow-up period was 27.6 months. TARE showed better OS (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.31– 0.92, log-rank P = 0.02), better PFS (HR = 0.51, 95% CI = 0.36– 0.97, log-rank P = 0.04), and better intrahepatic PFS (HR = 0.51, 95% CI = 0.30– 0.88, log-rank P = 0.01) compared with TACE. TARE was an independent prognostic factor for OS (adjusted HR [aHR] = 0.52, 95% CI = 0.30– 0.90, P = 0.02), PFS (aHR = 0.57, 95% CI = 0.35– 0.94, P = 0.03), and intrahepatic PFS (aHR = 0.49, 95% CI = 0.28– 0.84, P = 0.01).Conclusion: TARE as initial trans-arterial treatment is associated with better clinical outcomes such as longer OS compared with TACE in patients with HCC.Keywords: liver neoplasms, brachytherapy, yttrium radioisotopes, embolization

Eun Kyung Kim,1 Mi-Ae Kim,1 Jae Seung Lee,2 Sang Min Lee,3 Soyeoun Lim,4 Jisoo Park,1 Jung-Hyun Kim,1 Yeon-Mok Oh,2 Sang-Do Lee,2 Se Hee Lee,1 Ji-Hyun Lee1 On behalf of the KOLD Study Group1Department of Pulmonology, Allergy and Critical Care Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; 2Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 3Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 4Department of Radiology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of KoreaCorrespondence: Ji-Hyun LeeDepartment of Pulmonology, Allergy and Critical Care Medicine, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, Republic of KoreaTel +82-31-780-5205Fax +82-31-780-2992Email plmjhlee@cha.ac.krPurpose: Bronchiectasis (BE) is a poor prognostic factor in COPD. However, it is not clear whether the poor prognosis is a result of BE alone or accompanying chronic bronchitis symptoms. Therefore, we investigated the effect of chronic bronchitis symptoms on clinical outcomes in COPD patients with BE.Patients and Methods: We analyzed data of COPD patients from the Korean Obstructive Lung Disease (KOLD) cohort. The presence of BE was verified by chest computed tomography. Chronic bronchitis symptoms were determined using items in the symptomatic domain of the SGRQ, which is also used as an alternative definition of chronic bronchitis (CB). Patients were divided into four groups according to the presence of BE and CB symptoms: BE/CB, BE-only, CB-only, and no BE/CB. Demographic features and clinical outcomes were compared among these groups.Results: In total, 389 COPD patients were included in the analysis. BE was present in 148 (38%) patients and CB symptoms were found in 123 patients (33.2%). The patients were divided according to BE and CB symptoms, and the numbers and percentages of each group were as follows: BE/CB, 52 (13.4%); BE-only, 96 (24.7%); CB-only, 77 (19.8%); no BE/CB, 164 (42.2%). No significant differences were observed in baseline characteristics of lung function, radiological findings, and inflammatory markers among the four groups. The proportion of annual exacerbators was higher in the BE/CB and CB-only groups than the other two groups. After adjusting other parameters, the BE/CB group was significantly associated with acute exacerbation of COPD (AE-COPD) (OR = 2.110, p = 0.045).Conclusion: BE accompanying CB symptoms is associated with AE-COPD, while BE alone was not significantly associated. This finding suggests that it is more important to examine chronic bronchitis symptoms of BE to predict acute exacerbation than simply to identify BE in COPD patients.Keywords: COPD, bronchiectasis, chronic bronchitis, exacerbation

Sung Won Chung,1,* Min Kyung Park,1,* Young Youn Cho,1,2,* Youngsu Park,1 Cheol-Hyung Lee,1 Hyunwoo Oh,1 Heejoon Jang,1 Minseok Albert Kim,1 Sun Woong Kim,1 Joon Yeul Nam,1 Yun Bin Lee,1 Eun Ju Cho,1 Su Jong Yu,1 Hyo-Cheol Kim,3 Yoon Jun Kim,1 Jin Wook Chung,3 Jung-Hwan Yoon,1 Jeong-Hoon Lee1 1Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea; 2Department of Internal Medicine, Chung-Ang University Hospital, Seoul, Korea; 3Department of Radiology, Seoul National University College of Medicine, Seoul, Korea*These authors contributed equally to this workCorrespondence: Jeong-Hoon LeeDepartment of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, KoreaTel +82-2-2072-2228Fax +82-2-743-6701Email pindra@empal.comBackground: Still in real-world practice, advanced hepatocellular carcinoma (HCC) patients are treated with transarterial chemoembolization (TACE). This study compared the therapeutic effectiveness of initial TACE treatment and initial sorafenib treatment in advanced HCC patients.Patient and Methods: Advanced HCC patients initially treated with sorafenib or TACE were included in this study. Treatment crossover due to an unfavorable response to initial treatment was allowed. Propensity score (PS) matching was applied for balancing baseline characteristics. The primary outcome was overall survival (OS) and the secondary outcomes included tumor response.Results: A total of 554 patients were included in this study: 85 were initially treated with sorafenib (the sorafenib-first group) and 469 with TACE (the TACE-first group). In the entire cohort, the TACE-first group was associated with lower risk of death [adjusted hazard ratio (HR)=0.75, P=0.04]. In the PS-matched cohort (85 patients per group), the TACE-first group showed longer OS than the sorafenib-first group in both univariable (HR=0.68, P=0.02) and multivariable analyses (adjusted HR=0.58, P=0.002). Specifically, within both the entire and the PS-matched cohorts, the TACE-first group showed longer OS in subgroups with major portal vein tumor thrombosis (HR=0.72, P=0.048; HR=0.52, P=0.003) or infiltrative HCC (HR=0.42, P< 0.001; HR=0.30, P=0.004, respectively). The objective response rate was higher in the TACE-first group (29.3% vs 14.7%, P=0.03) within the PS-matched cohort.Conclusion: For advanced HCC, initial TACE leads to longer OS with a more favorable tumor response than initial sorafenib treatment. Intrahepatic tumor control with initial locoregional therapy may be a potent strategy for advanced HCC.Keywords: liver cancer, transarterial therapy, locoregional therapy, tyrosine kinase inhibitor

Gyu Chul Oh,1 Kwon Wook Joo,2 Myung-A Kim,3 Dong-Ju Choi,4 Yoon Jun Kim,5 Hae-Young Lee1 1Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; 2Division of Nephrology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; 3Division of Cardiology, Department of Internal Medicine, Seoul Metropolitan Government Boramae Hospital, Seoul, Korea; 4Division of Cardiology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea; 5Division of Hepatology, Department of Internal Medicine, Seoul National University Hospital, Seoul, KoreaCorrespondence: Hae-Young Lee; Yoon Jun Kim 101 Daehak-ro, Jongno-gu, Seoul, KoreaTel +82 2 2072 0698; +82 2 2072 3081Fax +82 2 3674 0805Email hylee612@snu.ac.kr; yoonjun@snu.ac.krPurpose: Fimasartan, the ninth and most recent angiotensin receptor blocker (ARB) approved by the Korea Food and Drug Administration, has shown similar efficacy and safety profiles compared to other ARBs. However, due to being predominantly excreted by the hepatobiliary system, concerns on safety have been raised regarding its use in patients with underlying liver disease.Patients and Methods: This prospective, 12-month, observational study evaluated patients with essential hypertension (HTN) receiving ≥ 1 dose of fimasartan. Self-reported and physician-reported events were recorded and classified according to organ class and severity. Outcomes were compared according to the absence and presence of underlying liver disease.Results: A total of 601 patients were screened, and 566 patients who met predefined inclusion criteria were grouped according to the presence of underlying liver disease. Adverse events (AE) were reported in 28.7% (128/446) of patients without prior liver disease, while 42.5% (51/120) experienced events in the group with chronic liver disease. There was no difference in discontinuations due to liver function between patients with and without baseline liver disease (1.1% [5] vs 2.5% [3], p=0.376), and only a non-significant increase was observed in events associated to the hepatobiliary system in patients with chronic liver disease (9.7% [7] vs 2.7% [9], p=0.061). There were no deaths or serious adverse drug reactions (SADR) during the study period. In multivariate regression analysis, the presence of chronic liver disease (OR 2.01), female sex (OR 1.49) and old age (OR 1.12 for every 5-year increase) were independent predictors for the development of AE. Finally, no significant difference was observed in the reduction of systolic blood pressure after 12 months of treatment (least square mean change − 6.57 ± 0.80 mmHg for normal liver function group; − 7.65 ± 1.59 mmHg for chronic liver disease group; p=0.546).Conclusion: Long-term use of fimasartan for treatment of HTN was associated with a low rate of adverse events overall, especially in the absence of underlying liver disease. Even for patients with chronic liver disease, fimasartan treatment was well tolerated. Fimasartan could be a safe option for long-term treatment of essential HTN. ClinicalTrials.gov identifier: NCT02385721.Keywords: fimasartan, safety, liver disease, essential hypertension, hepatobiliary excretion, adverse event

Mi-Ae Kim,1 Min-Kang Suh,1 Jisoo Park,1 Jung-Hyun Kim,1 Tae-Hoon Kim,1 Eun Kyung Kim,1 Yeon-Mok Oh,2 Sang-Do Lee,2 Ji-Hyun Lee1 1Department of Pulmonology, Allergy and Critical Care Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; 2Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaCorrespondence: Ji-Hyun LeeDepartment of Pulmonology, Allergy and Critical Care Medicine, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam 463-712, Republic of KoreaTel +82 31 780 5205Fax +82 31 780 2992Email plmjhlee@cha.ac.krPurpose: We compared clinical characteristics of COPD patients according to symptom variability and evaluated the effect of symptom variability during the first year of enrollment on clinical outcomes of COPD.Methods: We analyzed COPD patients’ data from the Korean Obstructive Lung Disease (KOLD) cohort. Symptom variability was defined based on the value of standard deviation (SD) of mMRC scores obtained every 3 months during the follow-up period of the first year. Patients were divided into 2 groups: the consistent (SD of mMRC scores =0) and variable (SD of mMRC scores >0) groups. Clinical characteristics and outcomes were compared in terms of symptom variability.Results: A total of 407 patients were included in the analysis. Patient age was 67.2 years and 97.8% of the subjects were male. Initial mMRC was 1.5 and the SD of mMRC scores during the first year was 0.5. There were 137 subjects (33.7%) in the consistent group and 270 (66.3%) in the variable group. The variable group showed a lower FEV1 (P=0.019) and a higher mMRC score (P=0.001). The annual incidence of acute exacerbation of COPD (AE-COPD) tended to be higher in the variable group (P=0.078) and that of severe AE-COPD was higher in the variable group than in the consistent group (P=0.002). The variable group showed a higher proportion of annual exacerbators (P=0.001) and frequent exacerbators (P=0.017). In multivariate logistic regression analysis, the variable group was significantly associated with annual exacerbators (OR =1.963, P=0.011) and frequent exacerbators (OR =2.090, P=0.055).Conclusion: COPD patients with symptom variability may have higher exacerbation risk as well as lower lung function and more severe respiratory symptoms.Keywords: COPD, symptom, variability, exacerbation, death, lung function

Warm autoimmune hemolytic anemia (wAIHA) is the most common form of AIHA, with corticosteroids in first-line treatment resulting in a 60–80% response rate. Atypical wAIHA and IgG plus complement mediated disease have a higher treatment failure rate and higher recurrence rate. We report a case of severe wAIHA secondary to Waldenström macroglobulinemia with life threatening intravascular hemolysis refractory to prednisone, rituximab, splenectomy, and plasmapheresis. A four-week treatment of eculizumab in this heavily pretreated patient resulted in a sustained increase in hemoglobin and transfusion independence, suggesting a role for complement inhibition in refractory wAIHA.

Publicly available internal tobacco industry documents were analyzed to answer the following questions regarding menthol cigarettes and the uptake of smoking by youth: 1) Does menthol make it easier for young or new/inexperienced smokers to start smoking cigarettes? 2) Do menthol smokers start smoking earlier than non-menthol smokers? Is there a higher use among youth who have been smoking for less than one year? 3) Did current smokers start smoking menthol cigarettes before switching to non-menthol cigarettes? 4) Does menthol accelerate progression toward established smoking? 5) Did the tobacco industry market menthols to the youth market and what images did they use? 6) To what extent do non-menthol smokers use menthol cigarettes? Researchers reviewed 2,634 documents and 102 were deemed relevant to one or more of the research questions.The internal business records of the tobacco industry make it clear that menthol flavoring is added to cigarettes in part because it is known to be an attractive feature to inexperienced, primarily youthful smokers who perceive menthol flavored cigarettes to be less harsh and easier to smoke and because of their availability from friends and family. Secondarily, the tobacco industry found that some youth smoke menthols because they perceive them to be less harmful than non-menthol cigarettes. Because of the acknowledged importance of capturing a large share of the youth market to long term profitability, all of the major cigarette companies have introduced menthol brands. A key product design issue concerned whether to increase brand menthol levels to appeal to the taste preferences of long-term menthol smokers or keep menthol levels lower to appeal to inexperienced smokers.Internal marketing studies showed that the companies carefully researched the menthol segment of the market with an eye towards recruiting younger smokers to their brands. The tobacco industry tracked menthol cigarette usage by age, gender and race to inform product development and marketing decisions. Studies were done to test how menthol impacted the ease of smoking, consumer perceptions of menthol flavoring, and brand loyalty. Based upon this review, menthol as a characterizing flavor has been a prominent design feature used by cigarette manufacturers to attract and retain youthful smokers.

Abstract Background Anxiety disorders are among the most prevalent mental health concerns affecting children and adolescents. Despite their high prevalence, statistics indicate that fewer than 25% of individuals in this demographic seek professional assistance for their condition. Consequently, there is a pressing need to develop innovative interventions aimed at improving treatment accessibility. Objectives This study aims to assess the effectiveness of Internet-delivered Cognitive Behavioral Therapy (iCBT) for adolescents with anxiety, with a specific emphasis on involving parents in the treatment process. Methods The study is structured as a parallel three-armed randomized controlled trial, comparing Internet-delivered Cognitive Behavioral Therapy (iCBT) with planned feedback, iCBT with on-demand feedback, and a waitlist control group, each group including 56 participants. Participants in the two iCBT conditions will undergo a 14-week treatment regimen, while those in the waitlist control group will wait for 14 weeks before starting iCBT with planned feedback. Additionally, participants in the iCBT groups will be randomly assigned to receive a booster session or not. The study design is factorial including two factors: type of therapist feedback (factor 1) and booster or no booster (factor 2). The study population comprises adolescents aged between 12 and 17 years, residing in Denmark, diagnosed with an anxiety disorder according to DSM-5 criteria. The primary outcome measures are the Youth Online Diagnostic Assessment and the Spence Children’s Anxiety Scale. Assessments will occur at baseline, post-treatment, and at 3-, 6-, and 12-month follow-ups post-treatment. Discussion The findings of this study are anticipated to contribute to improving the accessibility of evidence-based treatments for adolescents with anxiety. Trial registration The study is registered at clinicalTrials.gov, under protocol ID 22/59602. The Initial release was the 16.10.2023, first posted due to technical problems 16.04.2024. https://clinicaltrials.gov/study/NCT06368557?locStr=Odense,%20Denmark&country=Denmark&city=Odense&page=2&rank=13 .

Abstract The present longitudinal study examined a large sample of individuals with PIMD/Polyhandicap to: (i) describe the evolution over time of the health status in terms of severity, (ii) identify the potential predictors of health status change. This study used the data of the French national EVAL-PLH cohort. Inclusion criteria were: individuals with PIMD/Polyhandicap; age > 3 years at the time of inclusion; age at onset of cerebral lesion younger than 3 years old. The definition of the change in health status over the 5-year period was derived from the Polyhandicap Severity Scale. Among the 875 individuals included in 2015–2016, 492 (56.2%) individuals were assessed in 2020–2021. According to the definition, 68.8% (n = 309), 64.7% (n = 310), and 80.2% (n = 368) of the individuals presented with a worsened or stable severity status based on the global score, the abilities score, and the comorbidities score, respectively. Compared with the individuals with a non-worsened health status (global score), the individuals with a stable or worsened health status were more likely to receive care in specialized rehabilitation centres, more likely to have an antenatal or progressive aetiology, and more likely to have a higher dependency level. The current study provides a robust perspective of the worsened health among persons with PIMD/Polyhandicap over time.

CONTEXT: The Modified Checklist for Autism in Toddlers, Revised with Follow-up (M-CHAT-R/F) is used worldwide to screen for autism spectrum disorder (ASD). OBJECTIVE: To calculate psychometric properties of the M-CHAT-R/F for subsequent diagnosis of ASD. DATA SOURCES: Systematic searches of Medline, Embase, SCOPUS, and Trip Pro databases from January 2014 to November 2021. STUDY SELECTION: Studies were included if they (1) used the M-CHAT-R/F (2) applied standard scoring protocol, (3) used a diagnostic assessment for ASD, and (4) reported at least 1 psychometric property of the M-CHAT-R/F. DATA EXTRACTION: Two independent reviewers completed screening, full-text review, data extraction, and quality assessment, following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. A random-effects model was used to derive pooled estimates and assess for between-study heterogeneity. RESULTS: Of 667 studies identified, 15 with 18 distinct samples from 10 countries (49 841 children) were used in the meta-analysis. Pooled positive predictive value (PPV), was 57.7% (95% confidence interval [CI] 48.6-66.8, τ² 5 0.031). PPV was higher among high-risk (75.6% [95% CI 66.0-85.2]) than low-risk samples (51.2% [95% CI 43.0-59.5]). Pooled negative predictive value was 72.5% (95% CI 62.5-82.4 τ² 5 0.031), sensitivity was 82.6% (95% CI 76.2-88.9) and specificity 45.7% (95% CI 25.0-66.4). LIMITATIONS: Negative predictive value, sensitivity, and specificity were calculated based on small sample sizes because of limited or no evaluation of screen-negative children. CONCLUSIONS: These results support use of the M-CHAT-R/F as a screening tool for ASD. Caregiver counseling regarding likelihood of an ASD diagnosis after positive screen should acknowledge the moderate PPV. [ABSTRACT FROM AUTHOR]

Digital technology in education includes artificial intelligence, Internet of Things, cloud computing, etc. contributes to transforming teaching methods from traditional to digital environment. This article presents the levels and characteristics of digital technology in education according to the ecosystem approach in general education in Vietnam. Based on this structure, digital technology ensures convenient, rich access to digital transformation, open connection, increased collaboration, and high automation in education, helping educational institutions, administrators, teachers, and students adapt to rapidly developing and sustainable digital technologies.

Abstract Background Mediation analysis, often completed as secondary analysis to estimating the main treatment effect, investigates situations where an exposure may affect an outcome both directly and indirectly through intervening mediator variables. Although there has been much research on power in mediation analyses, most of this has focused on the power to detect indirect effects. Little consideration has been given to the extent to which the strength of the mediation pathways, i.e., the intervention-mediator path and the mediator-outcome path respectively, may affect the power to detect the total effect, which would correspond to the intention-to-treat effect in a randomized trial. Methods We conduct a simulation study to evaluate the relation between the mediation pathways and the power of testing the total treatment effect, i.e., the intention-to-treat effect. Consider a sample size that is computed based on the usual formula for testing the total effect in a two-arm trial. We generate data for a continuous mediator and a normal outcome using the conventional mediation models. We estimate the total effect using simple linear regression and evaluate the power of a two-sided test. We explore multiple data generating scenarios by varying the magnitude of the mediation paths whilst keeping the total effect constant. Results Simulations show the estimated total effect is unbiased across the considered scenarios as expected, but the mean of its standard error increases with the magnitude of the mediator-outcome path and the variability in the residual error of the mediator, respectively. Consequently, this affects the power of testing the total effect, which is always lower than planned when the mediator-outcome path is non-trivial and a naive sample size was employed. Analytical explanation confirms that the intervention-mediator path does not affect the power of testing the total effect but the mediator-outcome path. The usual effect size consideration can be adjusted to account for the magnitude of the mediator-outcome path and its residual error. Conclusions The sample size calculation for studies with efficacy and mechanism evaluation should account for the mediator-outcome association or risk the power to detect the total effect/intention-to-treat effect being lower than planned.

Abstract Background A platform trial approach allows adding arms to on-going trials to speed up intervention discovery programs. A control arm remains open for recruitment in a platform trial while intervention arms may be added after the onset of the study and could be terminated early for efficacy and/or futility when early stopping is allowed. The topic of utilising non-concurrent control data in the analysis of platform trials has been explored and discussed extensively. A less familiar issue is the presence of heterogeneity, which may exist for example due to modification of enrolment criteria and recruitment strategy. Method We conduct a simulation study to explore the impact of heterogeneity on the analysis of a two-stage platform trial design. We consider heterogeneity in treatment effects and heteroscedasticity in outcome data across stages for a normally distributed endpoint. We examine the performance of some hypothesis testing procedures and modelling strategies. The use of non-concurrent control data is also considered accordingly. Alongside standard regression analysis, we examine the performance of a novel method that was known as the pairwise trials analysis. It is similar to a network meta-analysis approach but adjusts for treatment comparisons instead of individual studies using fixed effects. Results Several testing strategies with concurrent control data seem to control the type I error rate at the required level when there is heteroscedasticity in outcome data across stages and/or a random cohort effect. The main parameter of treatment effects in some analysis models correspond to overall treatment effects weighted by stage wise sample sizes; while others correspond to the effect observed within a single stage. The characteristics of the estimates are not affected significantly by the presence of a random cohort effect and/ or heteroscedasticity. Conclusion In view of heterogeneity in treatment effect across stages, the specification of null hypotheses in platform trials may need to be more subtle. We suggest employing testing procedure of adaptive design as opposed to testing the statistics from regression models; comparing the estimates from the pairwise trials analysis method and the regression model with interaction terms may indicate if heterogeneity is negligible.

Abstract Trastuzumab deruxtecan (T‐DXd; DS‐8201; ENHERTU®) is a human epithelial growth factor receptor 2 (HER2)‐directed antibody drug conjugate (ADC) with demonstrated antitumor activity against a range of tumor types. Aiming to understand the relationship between antigen expression and downstream efficacy outcomes, T‐DXd was administered in tumor‐bearing mice carrying NCI‐N87, Capan‐1, JIMT‐1, and MDA‐MB‐468 xenografts, characterized by varying HER2 levels. Plasma pharmacokinetics (PK) of total antibody, T‐DXd, and released DXd and tumor concentrations of released DXd were evaluated, in addition to monitoring γΗ2AX and pRAD50 pharmacodynamic (PD) response. A positive relationship was observed between released DXd concentrations in tumor and HER2 expression, with NCI‐N87 xenografts characterized by the highest exposures compared to the remaining cell lines. γΗ2AX and pRAD50 demonstrated a sustained increase over several days occurring with a time delay relative to tumoral‐released DXd concentrations. In vitro investigations of cell‐based DXd disposition facilitated the characterization of DXd kinetics across tumor cells. These outputs were incorporated into a mechanistic mathematical model, utilized to describe PK/PD trends. The model captured plasma PK across dosing arms as well as tumor PK in NCI‐N87, Capan‐1, and MDA‐MB‐468 models; tumor concentrations in JIMT‐1 xenografts required additional parameter adjustments reflective of complex receptor dynamics. γΗ2AX longitudinal trends were well characterized via a unified PD model implemented across xenografts demonstrating the robustness of measured PD trends. This work supports the application of a mechanistic model as a quantitative tool, reliably projecting tumor payload concentrations upon T‐DXd administration, as the first step towards preclinical‐to‐clinical translation.

Introduction Recurrent shoulder dislocations often cause attrition of the labrum and progressive loss of the anterior bony contour of the glenoid. Treatment options for this pathology involve either soft tissue repair or bony augmentation procedure. The optimal management for patients with shoulder instability with subcritical bone loss remains unknown and current clinical practice is highly varied.Methods and analysis The Shoulder instability Trial comparing Arthroscopic stabilisation Benefits compared with Latarjet procedure Evaluation (STABLE) is an ongoing multicentre, randomised controlled trial of 114 patients diagnosed with recurrent anterior shoulder instability and subcritical glenoid bone loss (10%–20%, measured on 3D CT using circle of best fit technique). Patients are randomised either arthroscopic capsuloligamentous repair (Bankart repair+remplissage) or open or arthroscopic coracoid transfer (Latarjet procedure). The primary outcome of this trial will be the between-group difference in the change from baseline to 24 months postintervention in Western Ontario Shoulder Instability Index scores. Secondary outcomes include: (1) rates of recurrent shoulder dislocations and symptoms of instability up to 24 months’ postsurgery; (2) clinical outcomes measured by American Shoulder and Elbow Society score, Shoulder Activity Scale, EQ-5D and Patient Satisfaction Scale; (3) physical examination (range of motion, stability); (4) return to previous level of activity/sport; (5) rate of shoulder-related complications and serious adverse events.Ethics and dissemination This protocol has been reviewed and approved by the Hamilton Integrated Research Ethics Board (HiREB; project number 15998) prior to commencement of the trial. Results from the study will be submitted for publication in a peer-reviewed journal regardless of whether there are statistically significant findings.Trial registration number NCT05705479; this study was prospectively registered on clinicaltrials.gov.

Titanium carbide (Ti3C2Tx) MXene has attracted significant attention due to its exceptional properties and versatile solution processibility. However, MXene dispersions are prone to various degradation processes, leading to the formation of byproducts that negatively affect its morphological, electrical, and mechanical properties. Through the years, several methods have been developed to mitigate MXene degradation; however, divergent viewpoints on the understanding of degradation mechanisms are prevalent, hindering the development of versatile strategies in producing environmentally stable MXene dispersions. This review provides a chronological analysis of the research efforts aimed at unraveling the underlying mechanisms of MXene degradation and highlights strategies for circumventing this process. This review discusses apparent inconsistencies in experimental findings and theoretical models. These discrepancies prompt further investigation for a clearer understanding of the degradation process in MXene. This narrative allows readers to follow the evolution of dominant theories and disputes and to ultimately stimulate further investigation, aiming for a better understanding of this process. It is anticipated that identifying the fundamental factors affecting the oxidation of MXene dispersions will enable their full‐scale processing into higher‐order structures and practical devices with greater longevity and long‐term performance.

ContextThis study proposes a Bayesian network model to aid mental health specialists making data-driven decisions on suitable treatments. The aim is to create a probabilistic machine learning model to assist psychologists in selecting the most suitable treatment for individuals for four potential mental disorders: Depression, Panic Disorder, Social Phobia, or Specific Phobia.MethodsThis study utilized a dataset from 1,094 individuals in Denmark containing socio-demographic details and mental health information. A Bayesian network was initially employed in a purely data-driven approach and was later refined with expert knowledge, referred to as a hybrid model. The model outputted probabilities for each disorder, with the highest probability indicating the most suitable disorder for treatment.ResultsBy incorporating expert knowledge, the model demonstrated enhanced performance compared to a strictly data-driven approach. Specifically, it achieved an AUC score of 0.85 vs 0.80 on the test data. Furthermore, we evaluated some cases where the predictions of the model did not match the actual treatment. The symptom questionnaires indicated that these participants likely had comorbid disorders, with the actual treatment being proposed by the model with the second highest probability.ConclusionsIn 90.1% of cases, the hybrid model ranked the actual disorder treated as either the highest (67.3%) or second-highest (22.8%) on the test data. This emphasizes that instead of suggesting a single disorder to be treated, the model can offer the probabilities for multiple disorders. This allows individuals seeking treatment or their therapists to incorporate this information as an additional data-driven factor when collectively deciding on which treatment to prioritize.

Background: Phenylketonuria (PKU) is an inherited metabolic disease. If left untreated, it can lead to severe irreversible intellectual disability and can cause seizures, behavior disturbance, and white matter disease. This study aimed at evaluating the health economic impact of patients with PKU in France. Methods: This retrospective observational study used health insurance claims data from the French SNDS (Système National des Données de Santé) database, which contains data from over 66 million French inhabitants. Patients with PKU were identified by ICD-10 diagnosis codes E70.0 (PKU) and E70.1 (Other hyperphenylalaninemia) documented as a chronic condition (affection de longue durée – ALD) or in the inpatient setting in the SNDS database between 2006 and 2018. Patients with PKU were matched to controls without PKU by age, sex, and region. Patients with early- and late-diagnosed PKU were defined as patients born after and before the implementation of nationwide newborn screening in France in 1972, respectively. Outcomes were analyzed for the year 2018. Results: Overall, 3549 patients with PKU were identified in the database on January 1st, 2018. Of those, 3158 patients versus 15,703 controls with at least one healthcare consumption in 2018 were available for outcome analyses. Patients with PKU had 7.7 times higher healthcare costs than non-PKU controls in 2018 (€11,144 versus 1456 mean costs; p

A study was implemented to determine whether stormwater from Oscar 1 Pier outfall is a contributing source of polychlorinated biphenyls (PCBs) to Decision Unit (DU) N-2, Pearl Harbor Sediment Site, Honolulu, Hawaii USA. Results suggested that PCBs were discharged from the outfall, remained in suspension, and dispersed elsewhere before settling. Stormwater PCBs were characterized by heavier congeners, likely associated with particles. Surface water PCB samples collected throughout DU N-2 exhibited heavier congeners and lighter congeners that are typically associated with the dissolved phase. These lighter congeners could have originated from a different source(s) and/or partitioned from the suspended phase.

Abstract Background Total knee arthroplasty is a common surgery for end-stage knee osteoarthritis. Partial knee arthroplasty is also a treatment option for patients with arthritis present in only one or two knee compartments. Partial knee arthroplasty can preserve the natural knee biomechanics, but these replacements may not last as long as total knee replacements. Robotic-assisted orthopedic techniques can help facilitate partial knee replacements, increasing accuracy and precision. This trial will investigate the feasibility and assess clinical outcomes for a larger definitive trial. Methods This is a protocol for an ongoing parallel randomized pilot trial of 64 patients with uni- or bicompartmental knee arthritis. Patients are randomized to either receive robot-assisted partial knee arthroplasty or manual total knee arthroplasty. The primary outcome of this pilot is investigating the feasibility of a larger trial. Secondary (clinical) outcomes include joint awareness, return to activities, knee function, patient global impression of change, persistent post-surgical pain, re-operations, resource utilization and cost-effectiveness, health-related quality of life, radiographic alignment, knee kinematics during walking gait, and complications up to 24 months post-surgery. Discussion The RoboKnees pilot study is the first step in determining the outcome of robot-assisted partial knee replacements. Conclusions from this study will be used to design future large-scale trials. This study will inform surgeons about the potential benefits of robot-assisted partial knee replacements. Trial registration This study was prospectively registered on clinicaltrials.gov (identifier: NCT04378049) on 4 May 2020, before the first patient was randomized.

Abstract Background Knee arthritis is a leading cause of limited function and long-term disability in older adults. Despite a technically successful total knee arthroplasty (TKA), around 20% of patients continue to have persisting pain with reduced function, and low quality of life. Many of them continue using opioids for pain control, which puts them at risk for potential long-term adverse effects such as dependence, overdose and risk of falls. Although persisting pain and opioid use after TKA have been recognised to be important issues, individual strategies to decrease their burden have limitations and multi-component interventions, despite their potential, have not been well studied. In this study, we propose a multi-component pathway including personalized pain management, facilitated by a pain management coordinator. The objectives of this pilot trial are to evaluate feasibility (recruitment, retention, and adherence), along with opioid-free pain control at 8 weeks after TKA. Methods This is a protocol for a multicentre pilot randomised controlled trial using a 2-arm parallel group design. Adult participants undergoing unilateral total knee arthroplasty will be considered for inclusion and randomised to control and intervention groups. Participants in the intervention group will receive support from a pain management coordinator who will facilitate a multicomponent pain management pathway including (1) preoperative education on pain and opioid use, (2) preoperative risk identification and mitigation, (3) personalized post-discharge analgesic prescriptions and (4) continued support for pain control and recovery up to 8 weeks post-op. Participants in the control group will undergo usual care. The primary outcomes of this pilot trial are to assess the feasibility of participant recruitment, retention, and adherence to the interventions, and key secondary outcomes are persisting pain and opioid use. Discussion The results of this trial will determine the feasibility of conducting a definitive trial for the implementation of a multicomponent pain pathway to improve pain control and reduce harms using a coordinated approach, while keeping an emphasis on patient centred care and shared decision making. Trial registration Prospectively registered in Clinicaltrials.gov (NCT04968132).

Abstract Background Back pain is the leading cause of disability worldwide. Despite guidelines discouraging opioids as first-line treatment, opioids remain the most prescribed drugs for back pain. There is renewed interest in exploring the potential medical applications of cannabis, and with the recent changes in national legislation there is a unique opportunity to investigate the analgesic properties of cannabis. Methods This was a multi-center survey-based study examining patient perceptions regarding cannabis for spine pain. We included patients presenting with back or neck pain to one of three Orthopedic clinics in Ontario. Our primary outcome was perceived effect of cannabis on back pain, while secondary outcomes were perceptions regarding potential applications and barriers to cannabis use. Results 259 patients participated in this study, 35.3% (90/255) stating they used cannabis medically. Average pain severity was 6.5/10 ± 0.3 (95% CI 6.2–6.8). Nearly three-quarters were prescribed opioids (73.6%, 148/201), with oxycodone/oxycontin (45.9% 68/148) being the most common, and almost half of (49.3%, 73/148) had used an opioid in the last week. Patients estimated cannabis could treat 54.3% ± 4.0 (95% CI 50.3–58.3%) of their spine pain and replace 46.2% ± 6. 6 (95% CI 39.6–52.8%) of their current analgesics. Age (β = − 0.3, CI − 0.6–0.0), higher pain severity (β = 0.4, CI 0.1–0.6) and previous cannabis use (β = 14.7, CI 5.1–24.4) were associated with a higher perceived effect of cannabis. Patients thought cannabis would be beneficial to treat pain (129/146, 88.4%), and reduce (116/146, 79.5%) or eliminate opioids (102/146, 69.9%). Not considering using cannabis for medical purposes (65/150, 43.3%) was the number one reported barrier. Conclusions Patients estimated medical cannabis could treat more than half of their spine pain, with one in three patients already using medical cannabis. 79% of patients also believe cannabis could reduce opioid usage. This data will help support more research into cannabis for musculoskeletal pain.

Abstract Background The care organization of persons with profound intellectual and multiple disabilities (PIMD) varies by country according to the health care system. This study used a large sample of French individuals with severe PIMD/polyhandicap to assess: 1) the adequacy of care setting over a 5-year period and 2) health care consumption. Methods The longitudinal study used data from the French EVALuation PoLyHandicap (EVAL-PLH) cohort of persons with severe PIMD/polyhandicap who were receiving managed in specialized care centres and residential facilities. Two assessments were performed: wave 1 (T1) in 2015–2016 and wave 2 (T2) in 2020–2021. The inclusion criteria were as follows: age > 3 years at the time of inclusion; age at onset of cerebral lesion younger than 3 years old; and severe PIMD. The adequacy of the care setting was based on the following: i) objective indicators, i.e., adequacy for age and adequacy for health status severity; ii) subjective indicators, i.e., self-perception of the referring physician about medical care adequacy and educational care adequacy. Health care consumption was assessed based on medical and paramedical care. Results Among the 492 persons assessed at the 2 times, 50% of individuals at T1 and 46% of individuals at T2 were in an inadequate care setting based on age and severity. Regarding global subjective inadequacy, the combination of medical adequacy and educational adequacy, 7% of individuals at T1 and 13% of individuals at T2 were in an inadequate care setting. At T2, a majority of individuals were undermonitored by medical care providers (general practitioners, physical medicine rehabilitation physicians, neurologists, orthopaedists, etc.). Important gaps were found between performed and prescribed sessions of various paramedical care (physiotherapy, occupational therapy, psychomotor therapy, etc.). Conclusions This study revealed key elements of inadequate care management for persons with severe PIMD/polyhandicap in France. Based on these important findings, healthcare workers, familial caregivers, patients experts, and health decision-makers should develop appropriate care organizations to optimize the global care management of these individuals. Trial registration NCT02400528, registered 27/03/2015.

Nanoplastics are detected in surface water, yet accurately quantifying their particle number concentrations remains a significant challenge. In this study, we tested the applicability of a gold-labelling method to quantify nanoplastics in natural organic matter (NOM) containing water matrices. Gelatin-coated gold nanoparticles (Au-gel NPs) form conjugates with nanoplastics via electrostatic interaction which produces peak signals which can be translated into particle number concentration using single-particle inductively coupled plasma–mass spectrometry (SP-ICP-MS). We used water samples with various NOM concentrations, with and without the addition of 1 × 107 particle–1 nanoplastics. Our results indicate that nanoplastics in low NOM samples (15 mg·C L−1), only 13–19% of added nanoplastics were successfully quantified. Further digestion to remove NOM yielded only 10% of spiked nanoplastics. This discrepancy in high NOM samples could likely be attributed to the competition between nanoplastics and NOM existing in the water sample to bind with Au-gel NPs. Our study highlights the suitability of the Au-gel labelling method for quantifying nanoplastics in low NOM water samples. Nevertheless, further optimization, including pre-digestion steps, is essential to apply this method for high NOM water samples effectively. HIGHLIGHTS Quantification of nanoplastic with gold-labelling using single-particle ICP-MS.; Application of nanoplastic labelling in natural waters.; Underestimation of nanoplastic due to competing negatively charged NOM.; Inefficient digestion to remove NOM.;

Perovskite solar cells (PSCs) have emerged as the prominent candidate for next-generation solar cells. To achieve feasible high-power conversion efficiency in cells, many research groups have developed electron transport materials. This study explores the photovoltaic characteristics of a two-stage SnO2 based electron transport layer fabricated by the spin coating process. The spin coating processed two-stage tin oxide (SnO2) improved the power conversion efficiency by 15.16% in comparison to the single stage compact SnO2 based electron transporting layer for PSCs. However, the annealing process remains at a low temperature. This reduced the roughness of the two-stage film, which improved the performance. [ABSTRACT FROM AUTHOR]

BackgroundIncreasing interest has centered on the psychotherapeutic working alliance as a means of understanding clinical change in digital mental health interventions in recent years. However, little is understood about how and to what extent a digital mental health program can have an impact on the working alliance and clinical outcomes in a blended (therapist plus digital program) cognitive behavioral therapy (bCBT) intervention for depression. ObjectiveThis study aimed to test the difference in working alliance scores between bCBT and treatment as usual (TAU), examine the association between working alliance and depression severity scores in both arms, and test for an interaction between system usability and working alliance with regard to the association between working alliance and depression scores in bCBT at 3-month assessments. MethodsWe conducted a secondary data analysis of the E-COMPARED (European Comparative Effectiveness Research on Blended Depression Treatment versus Treatment-as-usual) trial, which compared bCBT with TAU across 9 European countries. Data were collected in primary care and specialized services between April 2015 and December 2017. Eligible participants aged 18 years or older and diagnosed with major depressive disorder were randomized to either bCBT (n=476) or TAU (n=467). bCBT consisted of 6-20 sessions of bCBT (involving face-to-face sessions with a therapist and an internet-based program). TAU consisted of usual care for depression. The main outcomes were scores of the working alliance (Working Alliance Inventory-Short Revised–Client [WAI-SR-C]) and depressive symptoms (Patient Health Questionnaire-9 [PHQ-9]) at 3 months after randomization. Other variables included system usability scores (System Usability Scale-Client [SUS-C]) at 3 months and baseline demographic information. Data from baseline and 3-month assessments were analyzed using linear regression models that adjusted for a set of baseline variables. ResultsOf the 945 included participants, 644 (68.2%) were female, and the mean age was 38.96 years (IQR 38). bCBT was associated with higher composite WAI-SR-C scores compared to TAU (B=5.67, 95% CI 4.48-6.86). There was an inverse association between WAI-SR-C and PHQ-9 in bCBT (B=−0.12, 95% CI −0.17 to −0.06) and TAU (B=−0.06, 95% CI −0.11 to −0.02), in which as WAI-SR-C scores increased, PHQ-9 scores decreased. Finally, there was a significant interaction between SUS-C and WAI-SR-C with regard to an inverse association between higher WAI-SR-C scores and lower PHQ-9 scores in bCBT (b=−0.030, 95% CI −0.05 to −0.01; P=.005). ConclusionsTo our knowledge, this is the first study to show that bCBT may enhance the client working alliance when compared to evidence-based routine care for depression that services reported offering. The working alliance in bCBT was also associated with clinical improvements that appear to be enhanced by good program usability. Our findings add further weight to the view that the addition of internet-delivered CBT to face-to-face CBT may positively augment experiences of the working alliance. Trial RegistrationClinicalTrials.gov NCT02542891, https://clinicaltrials.gov/study/NCT02542891; German Clinical Trials Register DRKS00006866, https://drks.de/search/en/trial/DRKS00006866; Netherlands Trials Register NTR4962, https://www.onderzoekmetmensen.nl/en/trial/25452; ClinicalTrials.Gov NCT02389660, https://clinicaltrials.gov/study/NCT02389660; ClinicalTrials.gov NCT02361684, https://clinicaltrials.gov/study/NCT02361684; ClinicalTrials.gov NCT02449447, https://clinicaltrials.gov/study/NCT02449447; ClinicalTrials.gov NCT02410616, https://clinicaltrials.gov/study/NCT02410616; ISRCTN Registry ISRCTN12388725, https://www.isrctn.com/ISRCTN12388725?q=ISRCTN12388725&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10; ClinicalTrials.gov NCT02796573, https://classic.clinicaltrials.gov/ct2/show/NCT02796573 International Registered Report Identifier (IRRID)RR2-10.1186/s13063-016-1511-1

BackgroundThe period before, during, and after pregnancy presents an opportunity to reduce diabetes-related risks, which in Australia disproportionately impact Aboriginal and Torres Strait Islander women. Collaboration with Aboriginal and Torres Strait Islander women/communities is essential to ensure acceptability and sustainability of lifestyle modifications. Using a novel co-design approach, we aimed to identify shared priorities and potential lifestyle strategies. We also reflected on learnings from this approach.MethodsWe conducted 11 workshops and 8 interviews at two sites in Australia’s Northern Territory (Central Australia and Top End), using experience-based co-design (EBCD) and incorporating principles of First Nations participatory research. Workshops/interviews explored participant’ experiences and understanding of diabetes in pregnancy, contextual issues, and potential lifestyle strategies. Participants included three groups: 1) Aboriginal and Torres Strait Islander women of reproductive age (defined as aged 16-45 years); 2) Aboriginal and Torres Strait Islander community members; and 3) health/community services professionals. The study methodology sought to amplify the voices of Aboriginal women.FindingsParticipants included 23 women between ages 16-45 years (9 with known lived experience of diabetes in pregnancy), 5 community members and 23 health professionals. Key findings related to identified priority issues, strategies to address priorities, and reflections on use of EBCD methodology. Priorities were largely consistent across study regions: access to healthy foods and physical activity; connection to traditional practices and culture; communication regarding diabetes and related risks; and the difficulty for women of prioritising their health among competing priorities. Strategies included implementation of a holistic women’s program in Central Australia, while Top End participants expressed the desire to improve nutrition, peer support and community awareness of diabetes. EBCD provided a useful structure to explore participants’ experiences and collectively determine priorities, while allowing for modifications to ensure co-design methods were contextually appropriate. Challenges included the resource-intensive nature of stakeholder engagement, and collaborating effectively with services and communities when researchers were “outsiders”.ConclusionsA hybrid methodology using EBCD and First Nations participatory research principles enabled collaboration between Aboriginal women, communities and health services to identify shared priorities and solutions to reduce diabetes-related health risks. Genuine co-design processes support self-determination and enhance acceptability and sustainability of health strategies.

Abstract Melanoma brain metastases (MBM) are clinically challenging to treat and exhibit variable responses to immune checkpoint therapies. Prior research suggests that MBM exhibit poor tumor immune responses and are enriched in oxidative phosphorylation. Here, we report results from a multi-omic analysis of a large, real-world melanoma cohort. MBM exhibited lower interferon-gamma (IFNγ) scores and T cell-inflamed scores compared to primary cutaneous melanoma (PCM) or extracranial metastases (ECM), which was independent of tumor mutational burden. Among MBM, there were fewer computationally inferred immune cell infiltrates, which correlated with lower TNF and IL12B mRNA levels. Ingenuity pathway analysis (IPA) revealed suppression of inflammatory responses and dendritic cell maturation pathways. MBM also demonstrated a higher frequency of pathogenic PTEN mutations and angiogenic signaling. Oxidative phosphorylation (OXPHOS) was enriched in MBM and negatively correlated with NK cell and B cell-associated transcriptomic signatures. Modulating metabolic or angiogenic pathways in MBM may improve responses to immunotherapy in this difficult-to-treat patient subset.

Abstract Introduction Parents of persons with profound intellectual and multiple disabilities (PIMD) play a major and often lifelong role in the care and support of their child. A better understanding of parents' perspectives regarding their experiences of parenting their child with PIMD is essential to support them more effectively. Although this topic has been explored extensively in Anglo‐Saxon and Northern European countries, little is known about the experience of these parents in a highly institutionalized context such as that in France. Objective We explored parents' experiences of the activities they performed to care for their child with PIMD (namely, the ‘parenting work’) in the French context. Method Qualitative semistructured interviews were conducted by telephone with 34 parents of persons with PIMD aged 8–35. The resulting data were analyzed using thematic analysis. Results The analysis highlighted the diversity of activities performed by parents as well as the influence of context on the forms of this parenting work. Five themes were developed: (1) navigating the challenges of obtaining medical recognition; (2) negotiating a concealed domain and becoming an expert; (3) unfolding medical and medicosocial care management; (4) navigating the challenges of daily living and (5) shaping one's child's possibilities. Conclusion This study offers a better understanding of the challenges, levers and expectations of parents of children with PIMD in France. Contextual factors such as the lack of knowledge of PIMD among health professionals, access to knowledge and know‐how associated with care management, the administrative complexity of access to care and equipment, institutional issues (e.g., professional turnover) and societal ableism (e.g., access to infrastructures, interpersonal discrimination) shape the work parents perform to support their child's needs. It is necessary to consider contextual aspects to better support these parents and their children. Suggestions for applications are provided in the discussion. Patient or Public Contribution One of the researchers, a parent of a child with PIMD, supported the research design and provided feedback on the study's procedures and manuscript.

BackgroundPulmonary Rehabilitation (PR) services typically offer programmes to support individuals living with COPD make rehabilitation choices that best meet their needs, however, uptake remains low. Shared Decision-Making (SDM; e.g., Patient Decision Aids (PtDA)) interventions increase informed and values-based decision-making between individuals and healthcare professionals (HCPs). We aimed to develop an intervention to facilitate PR SDM which was acceptable to individuals living with COPD and PR HCPs.MethodsAn iterative development process involving qualitative methods was adopted. Broad overarching frameworks included: complex intervention development framework, the multiple stakeholder decision making support model, and the Ottawa Decision Support Framework. Development included: assembling a steering group, outlining the scope for the PtDA, collating data to inform the PtDA design, prototype development, alpha testing with individuals with COPD (n = 4) and PR HCPs (n = 8), PtDA finalisation, and design and development of supporting components. This took nine months.ResultsThe PtDA was revised six times before providing an acceptable, comprehensible, and usable format for all stakeholders. Supporting components (decision coaching training and a consultation prompt) were necessary to upskill PR HCPs in SDM and implement the intervention into the PR pathway.ConclusionsWe have developed a three-component SDM intervention (a PtDA, decision coaching training for PR healthcare professionals, and a consultation prompt) to support individuals living with COPD make informed and values-based decision about PR together with their PR healthcare professional. Clear implementation strategies are outlined which should support its integration into the PR pathway.

People living with HIV (PLWH) experience unique stressors that contribute to emotional distress, and PLWH are more than twice as likely to die by suicide when compared to the general population. In countries like Tanzania, there is a relatively high burden of HIV but few resources to support mental health needs. To gain a better understanding of mental health challenges experienced by PLWH in northern Tanzania and identify opportunities for intervention, we interviewed 12 mental health professionals working in the Kilimanjaro region. Thematic analysis was used to explore drivers and impacts of emotional distress, community influences on mental health, and gaps and barriers to existing mental health care. Perspectives from mental health workers highlight the compounding effects of stress related to HIV status, family conflict, finances, and other social challenges, which can lead to poor HIV treatment outcomes and suicidal ideation. Cultural beliefs and stigma surrounding both mental health and HIV limit care-seeking behavior for mental health issues. Those who do seek care often encounter barriers related to poor mental health infrastructure, including a lack of providers, limited financial resources, and little integration into other health services. There is a clear need for investment in the mental health care system, as well as interventions to improve knowledge and perceptions of mental health and comprehensively address stressors. We describe feedback on a proposed telehealth counseling intervention integrated into routine HIV services, which shows strong potential to mitigate barriers to mental health treatment, reduce suicidal ideation, and support the wellbeing of PLWH.

ABSTRACT COVID-19 has challenged the scientific community in the search for biological markers and information that can contribute to the early management of the severe disease. Given the global scale of COVID-19, including reports of reinfection even in the presence of effective vaccines; consequently, the eradication of SARS-CoV-2 is far from happening. This study aimed to characterize the neutralizing antibody (Nab) geometric mean titers (GMTs) in hospitalized patients with COVID-19 and to evaluate the association with length of stay, comorbidities, and patient outcome. Among the 103 participants, 84 (81.5%) had some previous conditions associated with worsening health and 34 (33%) died. We found that neutralization potency varied greatly across individuals and was significantly higher in patients discharged before 14 days than in patients who stayed longer in the hospital. During the study period, 15 people living with HIV (PLWH) were hospitalized, and no significant difference in clinical characteristics or anti-SARS-CoV-2 Nabs was observed. However, PLWH with severe COVID-19 were younger [42, interquartile range (IQR) = 17.5] than other hospitalized COVID-19 patients (59, IQR = 22, P < 0.01). A high anti-HIV-1 antibody GMT of 583.9 (95% confidence interval: 344–990) was detected, demonstrating maintenance of anti-HIV-1 Nab production among PLWH coinfected with SARS-CoV-2. Therefore, these results indicate that neutralizing antibodies are not the only immunological response capable of controlling disease progression, but a high neutralizing response was associated with a shorter length of stay, suggesting the benefit of early-stage immunotherapy treatment of COVID-19. Nevertheless, these data highlight the importance of more Nab screening studies to predict faster recovery. IMPORTANCE The study provides valuable insights into the sociodemographic characteristics, clinical outcomes, and humoral immune response of those affected by the virus that has devastated every field of human life since 2019; the COVID-19 patients. Firstly, the association among clinical manifestations, comorbidities, and the production of neutralizing antibodies (Nabs) against SARS-CoV-2 is explored. Secondly, varying levels of Nabs among patients are revealed, and a significant correlation between the presence of Nabs and a shorter duration of hospitalization is identified, which highlights the potential role of Nabs in predicting clinical outcomes. Lastly, a follow-up conducted 7 months later demonstrates the progression and persistence of Nabs production in recovered unvaccinated individuals. The study contributes essential knowledge regarding the characteristics of the study population, the early humoral immune response, and the dynamics of Nabs production over time. These findings have significant implications for understanding the immune response to COVID-19 and informing clinical management approaches.