Nuclear-localized androgen receptor content following resistance exercise training is associated with hypertrophy in males but not females.

Androgen receptor (AR) content has been implicated in the differential response between high and low responders following resistance exercise training (RET). However, the influence of AR expression on acute skeletal muscle damage and whether it may influence the adaptive response to RET in females is poorly understood. Thus, the purpose of this exploratory examination was to 1) investigate changes in AR content during skeletal muscle repair and 2) characterize AR-mediated sex-based differences following RET. A skeletal muscle biopsy from the vastus lateralis was obtained from 26 healthy young men (n = 13) and women (n = 13) at baseline and following 300 eccentric kicks. Subsequently, participants performed 10 weeks of full-body RET and a final muscle biopsy was collected. In the untrained state, AR mRNA expression was associated with paired box protein-7 (PAX7) mRNA in males. For the first time in human skeletal muscle, we quantified AR content in the myofiber and localized to the nucleus where AR has been shown to trigger cellular outcomes related to growth. Upon eccentric damage, nuclear-associated AR (nAR) content increased (p < .05) in males and not females. Males with the greatest increase in cross-sectional area (CSA) post-RET had more (p < .05) nAR content than females with the greatest gain CSA. Collectively, skeletal muscle damage and RET increased AR protein, and both gene and hypertrophy measures revealed sex differences in relation to AR. These findings suggest that AR content but more importantly, nuclear localization, is a factor that differentiates RET-induced hypertrophy between males and females.

Dupilumab response onset, maintenance, and durability in patients with severe CRSwNP.

BACKGROUND: Responder analyses of SINUS phase 3 study data have shown clinically meaningful improvements across multiple chronic rhinosinusitis with nasal polyps (CRSwNP) outcomes with dupilumab. OBJECTIVE: To gain a better understanding of dupilumab response dynamics over 52 weeks. METHODS: Post hoc analysis using data from the SINUS-52 (NCT02898454) intention-to-treat population, of patients with severe CRSwNP who received dupilumab 300 mg once every 2 weeks (q2w) or placebo. Response, defined as an improvement from baseline of ≥ 1 point for Nasal Polyp Score (NPS), nasal congestion (NC), and loss of smell (LoS), and ≥ 8.9 points for 22-item Sino-Nasal Outcome Test (SNOT-22), was assessed for rapidity, maintenance, and durability. RESULTS: 303 patients (dupilumab, n = 150; placebo, n = 153) were included. For each outcome measure, a greater proportion of patients achieved first response by Week 16 (rapidity) with dupilumab vs placebo: NPS, 75.3% vs 39.2%; NC, 60.0% vs 24.2%; LoS, 60.7% vs 15.7%; and SNOT-22, 83.3% vs 66.0%. Among dupilumab patients with a response by Week 16, more than 80% maintained response at Week 52 (maintenance). Over 52 weeks, greater proportions of dupilumab patients were responders at ≥ 80% of time points: NPS, 46.7% vs 2.6%; NC, 46.7% vs 9.2%; LoS, 47.3% vs 3.9%; and SNOT-22, 62.0% vs 21.6% (durability). CONCLUSION: Most CRSwNP patients achieve clinically meaningful responses to dupilumab by Week 16, and most of these patients had maintenance and durability of response with continued treatment over time.

A quantitative systems pharmacology workflow toward optimal design and biomarker stratification of atopic dermatitis clinical trials.

BACKGROUND: The development of atopic dermatitis (AD) drugs is challenged by many disease phenotypes and trial design options, which are hard to explore experimentally. OBJECTIVE: We aimed to optimize AD trial design using simulations. METHODS: We constructed a quantitative systems pharmacology model of AD and standard of care (SoC) treatments and generated a phenotypically diverse virtual population whose parameter distribution was derived from known relationships between AD biomarkers and disease severity and calibrated using disease severity evolution under SoC regimens. RESULTS: We applied this workflow to the immunomodulator OM-85, currently being investigated for its potential use in AD, and calibrated the investigational treatment model with the efficacy profile of an existing trial (thereby enriching it with plausible marker levels and dynamics). We assessed the sensitivity of trial outcomes to trial protocol and found that for this particular example the choice of end point is more important than the choice of dosing regimen and patient selection by model-based responder enrichment could increase the expected effect size. A global sensitivity analysis revealed that only a limited subset of baseline biomarkers is needed to predict the drug response of the full virtual population. CONCLUSIONS: This AD quantitative systems pharmacology workflow built around knowledge of marker-severity relationships as well as SoC efficacy can be tailored to specific development cases to optimize several trial protocol parameters and biomarker stratification and therefore has promise to become a powerful model-informed AD drug development and personalized medicine tool.

Trajectories of CD4 T-cell count, CD8 T-cell count, and CD4/CD8 ratio in patients with HIV and long-term virological suppression based on Yunnan HIV cohort.

OBJECTIVE: Our objective was to evaluate the trajectory of immunology in patients with HIV with different baseline CD4 T-cell count strata after antiretroviral therapy (ART) under long-term viral suppression. METHODS: This was a sub-analysis focused on patients with virological suppression for at least 5 years after ART. Data were obtained from the Yunnan HIV cohort in China. Patients were categorized according to prespecified baseline CD4 T-cell counts. The trajectories of CD4 T-cell count, CD8 T-cell count, and CD4/CD8 ratio changing over time were fitted using a B-spline regression model. The Cox proportional hazards regression model was used to assess the association of baseline CD4 T-cell count with the risk of both immunological responder (IR) and CD4/CD8 ratio normalization. RESULTS: A total of 2618 patients with a median follow-up of 7.25 years (interquartile range [IQR] 5.92-8.75) were included. Over a period of 12 years, the mean CD4 T-cell count remained above 500 cells/µL in all groups. The mean CD4/CD8 ratio was solely normalized in patients whose baseline CD4 T-cell counts were above 350 cells/µL. Patients with higher baseline CD4 T-cell counts showed higher risks of both IR and CD4/CD8 ratio normalization than those with the lowest (all p trend <0.001). A higher baseline CD4 T-cell count predicted a shorter time for both IR and CD4/CD8 ratio normalization. CONCLUSIONS: Long-term, sustained viral suppression may not be able to fully normalize immunological functions in patients with HIV. A high baseline CD4 T-cell count benefits IR and CD4/CD8 ratio normalization.

Twelve-Month Health Status Response Following Peripheral Vascular Intervention for Femoropopliteal Lesions Using Zilver PTX Databases Focusing on the Role of Preprocedural Health Status, Comorbid Risks, and Global Setting.

OBJECTIVE: Tailoring resources of peripheral vascular interventions (PVIs) to those who stand to gain the most, would allow for more equitable and value-based care. One way of evaluating the benefit of PVIs in patients with symptomatic peripheral artery disease (PAD) is evaluating their health status and identifying predictors of health status response 12 months following the intervention. METHODS: Patients undergoing femoropopliteal PVI between March 2005 and August 2008 from the Zilver PTX randomized trial and single-arm study were combined into a single cohort for secondary data analysis. The pre-procedural and 12-month health status was assessed by the EuroQol-5D-3L (EQ-5D). First, we evaluated the 12-month EQ-5D index (per 1-unit increase), adjusted for treatment condition and patient characteristics using a linear regression. Second, using the minimally clinically important difference (MCID) threshold for the EQ-5D index, we identified 12-month non-responders (worsened or no change) vs. responders (improved) and conducted an adjusted logistic regression model. RESULTS: A total of 513 patients were included (mean age 67.8 ± 9.2 years; 25.1% female), with 17.8% USA and 82.2% non-USA global enrollment sites. The MCID for the EQ-5D was 0.058. For 12-month post PVI health status, a total of 57.9% improved, 31.4% experienced no change, and 10.7% worsened, relative to their preprocedural health status. Patients who were more likely to be non-responders were more likely to have a history of carotid artery disease or were situated at a USA enrolling center. CONCLUSION: The majority of patients reported improved or stable health status after femoral-popliteal PVI. About 4 in 10 were non-responders, with the highest risk for non-response including individuals with existing carotid disease or those undergoing PVIs in the USA vs. non-USA settings.

Protocol change improves live birth and recurrent cycle cancellation rates after a previous IVF cycle cancellation: an analysis of 13 000 autologous cycles reported to SART CORS.

STUDY QUESTION: After an IVF cycle cancellation, does changing the stimulation protocol affect the odds of live birth and recurrent cancellation in the subsequent cycle? SUMMARY ANSWER: After IVF cycle cancellation, compared to those who repeated the same stimulation protocol, those who changed their protocol had higher odds of live birth and lower odds of recurrent cycle cancellation. WHAT IS KNOWN ALREADY: There is limited data addressing the effect of changing the stimulation protocol after an IVF cycle is cancelled during initial stimulation. The odds of live birth outcomes are not known so far in studies addressing the effect of changing the protocol. STUDY DESIGN, SIZE, DURATION: Retrospective Cohort Study using the 2014-2017 Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) database. PARTICIPANTS/MATERIALS, SETTING, METHODS: The data included 13 135 patients with a first autologous IVF cycle that resulted in a cycle cancellation and was followed by a second autologous cycle within the study period. We excluded fertility preservation cycles, supernumerary cycle attempts after the second IVF cycle attempt, and cycles with more than one stimulation protocol documented per cycle start. Patients who received the same protocol for both cycles (n = 6434) were compared to those who changed their protocol in the second cycle (n = 6701). Multivariable logistic regression analyses were performed to estimate the adjusted odds of live birth and recurrent cancellation. MAIN RESULTS AND THE ROLE OF CHANCE: Changing the protocol in the second cycle resulted 14% lower odds of recurrent cycle cancellation (P = 0.01) and 17% higher odds of live birth after fresh transfers (P = 0.04). When stratifying the data by specific combinations of protocol change (agonist flare, agonist suppression, antagonist), there was an increase in live birth when switching from antagonist to agonist suppression (odds ratio (OR) = 1.36, P = 0.03) and from agonist suppression to antagonist (OR = 1.73, P = 0.01) compared to those who repeated their same stimulation protocol. Specifically in poor responders, outcomes were worse when using the agonist flare protocol and significantly improved with the agonist suppression protocol. LIMITATIONS, REASONS FOR CAUTION: Comparison of response to stimulation between first and second cycles cannot be made in this study because the index IVF cycle was cancelled during ovarian stimulation, and thus there is no reportable outcome data for that cycle. Additionally, SART only tracks the three stimulation protocols addressed in this study and does not have data on more contemporary protocols that are used in poor responders thus limiting the generalizability of our findings. WIDER IMPLICATIONS OF THE FINDINGS: Using the SART CORS database, which includes >90% of all reported IVF cycles in the USA, provides generalizability to the demographically diverse IVF populations found here. In agreement with prior studies assessing change in IVF protocols, the agonist flare protocol seems to result in worse IVF outcomes, and based on our results, we believe that there is no role for the agonist flare protocol in patients with a prior poor response to stimulation. STUDY FUNDING/COMPETING INTEREST(S): None declared. TRIAL REGISTRATION NUMBER: N/A.

Clinician's Approach to Advanced Statistical Methods: Win Ratios, Restricted Mean Survival Time, Responder Analyses, and Standardized Mean Differences.

Novel statistical methods have emerged in recent medical literature, which clinicians must understand to properly appraise and integrate evidence into their practice. Some of these key concepts include win ratios, restricted mean survival time, responder analyses, and standardized mean difference. This article offers guidance to busy clinicians on the comprehension and practical applicability of the results to patients. Win ratios provide an alternative method to analyze composite outcomes by prioritizing individual components of the composite; prioritization of the outcomes should be evidence-based, pre-specified, and patient-centered. Restricted mean survival time presents a method to analyze Kaplan-Meier curves when assumptions required for Cox proportional hazards analysis are not met. As it only considers outcomes that occur within a specific timeframe, the duration of follow-up must be appropriately defined and based on prior epidemiologic and mechanistic evidence. Researchers can analyze continuous outcomes with responder analyses, in which participants are dichotomized into "responders" or "non-responders." While clinicians and patients may more easily grasp outcomes analyzed in this way, they should be aware of the loss of information and resulting imprecision, as well as potential to manipulate data presentation. When meta-analyzing continuous outcomes, point estimates can be converted to standardized mean differences to facilitate the combination of data utilizing various outcome measures. However, clinicians may find it challenging to grasp the clinical meaningfulness of a standardized mean difference, and may benefit from converting it to well-known outcomes. By providing the background knowledge of these statistical methods, along with practical applicability, benefits, and inevitable limitations, this article aims to provide clinicians with an approach to appraise the literature and apply the results in clinical practice.

Predicting the Speed of Response to Omalizumab in Chronic Spontaneous Urticaria.

INTRODUCTION: Two distinct chronic spontaneous urticaria (CSU) endotypes, IgE-mediated autoallergic and IgG-mediated autoimmune, were defined based on the response patterns to omalizumab. However, the coexistence of IgE and IgG autoantibodies in a subset of patients might complicate the prediction of the treatment outcomes. This study aimed to evaluate the effectiveness and safety of omalizumab in CSU patients, focusing on the factors predicting the response patterns. METHODS: This was a retrospective cross-sectional single-center study investigating CSU patients treated with omalizumab for at least 6 months between September 2015 and February 2023. Patients were evaluated regarding demographics, clinical findings, baseline laboratory parameters, treatment outcomes, and side effects. Early and late responders were defined depending on the time for response, within or after 3 months, respectively. RESULTS: Among 82 patients, 75 (91.5%) responded to omalizumab during the first 6 months, classified as early (n = 51) and late responders (n = 24). The IgG anti-thyroid peroxidase (anti-TPO)/total IgE ratio was an independent predictor for determining the speed of response (p < 0.05). Of 29 patients who discontinued omalizumab, 19 (65.5%) experienced relapse with a good response to retreatment (n = 18/19, 94.7%). Early responders relapsed more frequently than late responders (77.3% vs. 28.6%) (p < 0.05). Only mild side effects were observed in a minority of patients (n = 8/82, 9.8%). CONCLUSION: Omalizumab is an effective and safe treatment in CSU. The IgG anti-TPO/total IgE ratio seems a valuable tool to predict the early and late responders, the former having a higher possibility of relapse upon drug withdrawal.

Management of a patient with sickle cell disease and multiple red blood cell alloantibodies in preparation for a hematopoietic stem cell transplantation.

BACKGROUND: Hematopoietic stem cell transplant (HSCT) is currently the only widely available curative option for patients with sickle cell disease (SCD). Alloimmunization in this population is frequent and can complicate transfusion management during the HSCT period. The case of a pediatric patient with severe SCD clinical phenotype, multiple alloantibodies (9), and hyperhemolysis syndrome who underwent haploidentical HSCT is described. STUDY DESIGN AND METHODS: The patient was known for an anti-e, despite RHCE*01.01 allele, which predicts a C- c+ E- weak e+ phenotype. Donors matching the patient's extended phenotype were targeted for RHCE genotyping. RESULTS: Donors homozygotes or heterozygotes for RHCE*01.01 were selected for compatibility analyses and ranked based on strength of reactions. Discordance between zygosity and strength of reactions was observed, as the most compatible donors were heterozygotes for RHCE*01.01. In total, the patient received seven RBC units from two different donors during HSCT process without transfusion reaction or development of new alloantibodies. Six months post-HSCT, his hemoglobin level is stable at around 120 g/L and his chimerism is 100%. DISCUSSION: This case highlights the complexity of transfusion management during HSCT of alloimmunized patients with SCD. Collecting sufficient compatible units requires early involvement of transfusion medicine teams and close communication with the local blood provider. Genotyping of donors self-identifying as Black is useful for identifying compatible blood for those patients but has some limitations. HSCT for heavily alloimmunized patients is feasible and safe with early involvement of transfusion medicine specialists. Further research on the clinical impact of genotypic matching is needed.

The gap between statistical and clinical significance: time to pay attention to clinical relevance in patient-reported outcome measures of insomnia.

BACKGROUND: Appropriately defining and using the minimal important change (MIC) and the minimal clinically important difference (MCID) are crucial for determining whether the results are clinically significant. The aim of this study is to survey the status of randomized controlled trials (RCTs) for insomnia interventions to assess the inclusion and interpretation of MIC/MCID values. METHODS: We conducted a cross-sectional study to survey the status of RCTs for insomnia interventions to assess the inclusion and appropriate interpretation of MIC/MCID values. A literature search was conducted by searching the main sleep medicine journals indexed in PubMed, the Excerpta Medica Database (EMBASE), and the Cochrane Central Register of Controlled Trials (CENTRAL) to identify a broad range of search terms. We included RCTs with no restriction on the intervention. The included studies used the Insomnia Severity Index (ISI) or the Pittsburgh Sleep Quality Index (PSQI) questionnaire as the outcome measures. RESULTS: 81 eligible studies were identified, and more than one-third of the included studies used MIC/MCID (n = 31, 38.3%). Among them, 21 studies with ISI as the outcome used MIC defined as a relative decrease ranging from 3 to 8 points. The most frequently used MIC value was a 6-point decrease (n = 7), followed by 8-point (n = 6) and 7-point decrease (n = 4), a 4 to 5-points decrease (n = 3), and a 30% reduction from baseline; 6 studies used MCID values, ranging from 2.8 to 4 points. The most frequently used MCID value was a 4-point decrease in the ISI (n = 4). 4 studies with PSQI as the outcome used a 3-point change as the MIC (n = 2) and a 2.5 to 2.7-point difference as MCID (n = 2). 4 non-inferiority design studies considered interval estimation when drawing clinically significant conclusions in their MCID usage. CONCLUSIONS: The lack of consistent MIC/MCID interpretation and usage in outcome measures for insomnia highlights the urgent need for further efforts to address this issue and improve reporting practices.

Patterns of cortical oxygenation may predict the response to stenting in subjects with renal artery stenosis: A radiomics-based model.

BACKGROUND: Percutaneous-transluminal renal angioplasty (PTRA) and stenting aim to halt the progression of kidney disease in patients with renal artery stenosis (RAS), but its outcome is often suboptimal. We hypothesized that a model incorporating markers of renal function and oxygenation extracted using radiomics analysis of blood oxygenation-level dependent (BOLD)-MRI images may predict renal response to PTRA in swine RAS. MATERIALS AND METHODS: Twenty domestic pigs with RAS were scanned with CT and BOLD MRI before and 4 weeks after PTRA. Stenotic (STK) and contralateral (CLK) kidney volume, blood flow (RBF), and glomerular filtration rate (GFR) were determined, and BOLD-MRI R2 * maps were generated before and after administration of furosemide, a tubular reabsorption inhibitor. Radiomics features were extracted from pre-PTRA BOLD maps and Robust features were determined by Intraclass correlation coefficients (ICC). Prognostic models were developed to predict post-PTRA renal function based on the baseline functional and BOLD-radiomics features, using Lasso-regression for training, and testing with resampling. RESULTS: Twenty-six radiomics features passed the robustness test. STK oxygenation distribution pattern did not respond to furosemide, whereas in the CLK radiomics features sensitive to oxygenation heterogeneity declined. Radiomics-based model predictions of post-PTRA GFR (r = 0.58, p = 0.007) and RBF (r = 0.68; p = 0.001) correlated with actual measurements with sensitivity and specificity of 92% and 67%, respectively. Models were unsuccessful in predicting post-PTRA systemic measures of renal function. CONCLUSIONS: Several radiomics features are sensitive to cortical oxygenation patterns and permit estimation of post-PTRA renal function, thereby distinguishing subjects likely to respond to PTRA and stenting.

Coronary artery wall contrast enhancement imaging impact on disease activity assessment in IgG4-RD: a direct marker of coronary involvement.

BACKGROUND: Coronary artery wall contrast enhancement (CE) has been applied to non-invasive visualization of changes to the coronary artery wall in systemic lupus erythematosus (SLE). This study investigated the feasibility of quantifying CE to detect coronary involvement in IgG4-related disease (IgG4-RD), as well as the influence on disease activity assessment. METHODS: A total of 93 subjects (31 IgG4-RD; 29 SLE; 33 controls) were recruited in the study. Coronary artery wall imaging was performed in a 3.0 T MRI scanner. Serological markers and IgG4-RD Responder Index (IgG4-RD-RI) scores were collected for correlation analysis. RESULTS: Coronary wall CE was observed in 29 (94 %) IgG4-RD patients and 22 (76 %) SLE patients. Contrast-to-noise ratio (CNR) and total CE area were significantly higher in patient groups compared to controls (CNR: 6.1 ± 2.7 [IgG4-RD] v. 4.2 ± 2.3 [SLE] v. 1.9 ± 1.5 [control], P < 0.001; Total CE area: 3.0 [3.0-6.6] v. 1.7 [1.5-2.6] v. 0.3 [0.3-0.9], P < 0.001). In the IgG4-RD group, CNR and total CE area were correlated with the RI (CNR: r = 0.55, P = 0.002; total CE area: r = 0.39, P = 0.031). RI´ scored considering coronary involvement by CE, differed significantly from RI scored without consideration of CE (RI v. RI´: 15 ± 6 v. 16 ± 6, P < 0.001). CONCLUSIONS: Visualization and quantification of CMR coronary CE by CNR and total CE area could be utilized to detect subclinical and clinical coronary wall involvement, which is prevalent in IgG4-RD. The potential inclusion of small and medium-sized vessel involvements in the assessment of disease activity in IgG4-RD is worthy of further investigation.

Voluntary first responders' experiences of being dispatched to suspected out-of-hospital cardiac arrest in rural areas: an interview study.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a leading cause of death, and survival outcomes vary across countries and regions. To improve survival, the European Resuscitation Council Guidelines encourage the implementation of technologies like smartphone applications to alert voluntary first responders (VFRs) who are near a suspected OHCA. VFRs are of great importance in the ´chain of survival´, but there is still a lack of knowledge about their experiences; especially of those operating in rural areas. Understanding those experiences is crucial in developing appropriate interventions to train, encourage, and safeguard VFRs in their mission. Therefore, the aim of this study was to describe VFRs´ experiences of being dispatched to suspected OHCA in rural areas. METHODS: The study used an inductive design. The data were collected using individual interviews with 16 VFRs and analysed using qualitative content analysis. RESULTS: The results are presented in terms of six generic categories ''Being motivated and prepared'', ''Having strategies to undertake the mission'', ''Collaborating with others'', ''Being ethically aware'', ''Supporting the family members'', and ''Coping with the mission'', which formed the basis of the main category 'Desire to save lives and help others'. The findings showed that VFRs had a genuine desire to contribute to save lives in this rural area. Regardless of the circumstances, they were prepared to leave everything and act to the best for the victim and their family members. In theirs' missions they collaborated with others at the scene and were guided by ethics while they acted in complex circumstances. CONCLUSIONS: VFRs dispatched in rural areas express a desire to save lives. In their missions, they acted in complex situations and experienced both emotional and ethical challenges. The design, implementation, and evaluation of support interventions directed at VFRs should be prioritised, especially in rural areas, as it can contribute to more people becoming and remaining VFRs, which in turn could contribute to sustainable development.

Tighter is better: Can a simple and cost-free parameter predict response to cardiac synchronization therapy?

BACKGROUND: Several studies have evaluated the role of QRS duration (QRSd) or QRS narrowing as a predictor of response to cardiac resynchronization therapy (CRT) to reduce nonresponders. AIM: Our study aimed to determine the correlation between the relative change in QRS index (QI) compared to clinical outcome and prognosis in patients who underwent CRT implantation. METHODS: A three-centers study involving 398 patients with a CRT device was conducted. Clinical, echocardiographic and pharmacological variables, QRSd before and after CRT implantation and QI were measured. RESULTS: In a 6-month follow-up, a significant improvement in left ventricular ejection fraction (LVEF), left ventricular end-diastolic and systolic volumes (LVEDV and LVESV) were observed. QI was related to reverse remodeling (multiple r-squared: 0.48, adjusted r-squared: 0.43, p = .001), and the cut-off value that best predicted LV reverse remodeling after 6 months of CRT was 12.25% (AUC 0.7, p = .001). At 24 months, a statistically significant difference was found between patients with a QI ≤ 12.25% and those with a QI > 12.25% regarding NYHA class worsening (p = .04). The mean of the QI of patients who died from cardiovascular causes was lower than patients who died of other causes (p = .0179). A correlation between pre-CRT QRSd/LVEDV and QI was observed (r = + 0.20; p = .0003). A higher QRSd/LVEDV ratio was associated with an improved LVEF, LVEDV, and LVESV (p < .0001) at follow-up. CONCLUSIONS: QI narrowing after CRT was related to greater echocardiographic reverse remodeling and a lower rate of adverse events (death or cardiovascular hospitalizations). The QI can improve the prediction of adverse events in a population with CRT regardless of comorbidities according to the Charlson Comorbidity Index. QI could be used to predict CRT response.

PeerOnCall: Exploring how organizational culture shapes implementation of a peer support app for public safety personnel.

BACKGROUND: Public safety personnel (PSP) such as firefighters, paramedics, and police are exposed to traumatic situations, which increase their risk for mental health issues. However, many PSP do not seek help in a timely manner. Peer support interventions have the potential to decrease stigma and increase treatment-seeking behaviours among PSP. However, little is known regarding how the organizational culture of public safety organizations (PSOs) affects the implementation of a peer-based intervention. This study aims to understand the extent to which organizational culture, including masculinity contest cultures (MCC), within Canadian PSOs could affect implementation of PeerOnCall, a new peer support app for PSP. METHODS: A qualitative multiple case study design was adopted, integrating semi-structured interviews with organizational champions from five PSOs. One to three champions from each PSO acted as key informants regarding their organizations. Interviews explored champions' perceptions of how organizational culture might shape implementation. Interview data were analyzed using inductive thematic analysis. RESULTS: Three themes were identified in analysis of the champion interviews. The first theme focused on external drivers and the second theme focused on internal drivers of organizational culture shift. The third theme focused on how culture can create resistance to implementation. Importantly, the MCC norm of show no weakness was described as a source of potential resistance when implementing the app. CONCLUSIONS: Each PSO had a unique and changing culture. Understanding how champions anticipate the role of culture in shaping implementation of an app-based intervention like PeerOnCall can guide the creation of contextually relevant strategies that optimize implementation within PSOs. Recommendations for optimizing implementation and areas for further study are provided.

A Novel Liver Fibrosis Marker FIB-5 Index Predicted Response to Cardiac Resynchronization Therapy and Prognostic Outcomes in Patients With Heart Failure.

BACKGROUND: The fibrosis-5 (FIB-5) index is a noninvasive marker for assessing the progression of liver fibrosis and predictor in patients with heart failure (HF). This study investigated the association between the FIB-5 index and response to cardiac resynchronization therapy (CRT) and evaluated its predictive value for prognosis. METHODS: In total, 203 patients who underwent CRT/CRT-defibrillator (CRT-D) implantation were retrospectively included. The FIB-5 index was calculated using blood samples obtained before and after CRT/CRT-D. Response to CRT was defined as a relative reduction in left ventricular end-systolic volume of ≥15% 6 months after CRT/CRT-D. We compared the prognosis after CRT/CRT-D between the groups according to the FIB-5 index. RESULTS: One hundred and twenty-three patients (61%) responded to CRT. The responder group demonstrated a significantly higher FIB-5 index than the nonresponder group (-2.76 ± 3.85 vs. -4.67 ± 3.29, p < 0.001). Receiver-operating characteristic analysis demonstrated that the area under the curve of the FIB-5 index was 0.660 with a cutoff value of -4.00 for responders. In multivariate analysis, FIB-5 index ≥ -4.00 was an independent predictor for CRT response (odds ratio: 3.665, p = 0.003), in addition to QRS duration ≥ 150 ms and echocardiographic dysynchrony. The FIB-5 index increased significantly after 6 months in the responder group but not in the nonresponder group. The FIB-5 index ≥ -4.00 group showed a significantly better prognosis for cardiac death, HF hospitalization, and composite endpoint than the FIB-5 index < -4.00 group. CONCLUSION: The FIB-5 index in addition to classical predictors may be a useful marker for predicting response to CRT.

Changes in intraocular pressure following intravitreal dexamethasone implant in patients with history of glaucoma filtration surgery.

PURPOSE: This study aimed to evaluate changes in intraocular pressure following intravitreal dexamethasone implant injection, specifically in patients undergoing glaucoma filtration surgery. METHODS: The degree of increase in intraocular pressure was compared retrospectively among three groups. Group 1 comprised patients who underwent prior glaucoma filtration surgery (54 eyes). Group 2 included patients with or suspected glaucoma without such surgical history (20 eyes). Group 3 included patients without glaucoma (33 eyes). Pressure measurements were taken before the injection and at 1, 2, 3, and 6 months post-injection. A subgroup analysis was performed for pressure > 35 mmHg, > 30 mmHg, > 25 mmHg, and a difference > 10 mmHg between the peak and baseline pressure. RESULTS: Group 1 consistently displayed lower pressures compared with Group 2, with significant difference at both 1- and 6-month post-injections (15.09 mmHg vs. 18.10 mmHg, P = 0.042 and 13.91 mg vs. 17.25 mmHg, P = 0.040). The proportion of patients in Group 1 and Group 3 with pressures > 25 mmHg, > 30 mmHg, and a difference > 10 mmHg did not significantly differ (15.6% vs. 9.5%, P = 0.231; 3.1% vs. 2.3%, P = 0.867; and 17.1% vs. 7.1%, P = 0.231). Notably, Group 2 exhibited a significantly higher proportion within each category (> 25 mmHg, 24.0%; > 30 mmHg, 20.0%; > 10 mmHg difference, 28.0%). CONCLUSION: Intravitreal dexamethasone implant did not increase the risk of elevated intraocular pressure in patients with a history of glaucoma filtration surgery compared with patients with suspected glaucoma; the risk was similar to those without glaucoma.

Evaluating time until ligation in a novel tourniquet - A crossover randomized-controlled trial.

INTRODUCTION AND AIM: Severe external hemorrhage is a significant reason for morbidity and mortality in adults; thus, the swift and correct application of a tourniquet by laypersons can be lifesaving. We conducted this randomized-controlled cross-over study to investigate the use of a novel tourniquet. METHODS: Participants were recruited at the Heidelberg University Hospital. Eligible participants were ≥ 18 years old with a medical background but without prior experience in applying a tourniquet. Participants were 1:1 randomized to the intervention group (PAX tourniquet) or the control group (SAM or CAT tourniquet). In the control group, participants underwent another randomization to either the SAM or CAT tourniquet without a predefined allocation ratio. Hyperspectral measurements were undertaken (i) before ligation, (ii) 30 s after ligation, and (iii) 30 s after the reopening of the tourniquet. The primary outcome was time until ligation before crossover between the respective groups. The analysis of secondary endpoints included all attempts to assess a possible learning effect, intraoperator variability, and hyperspectral measurements. Participants were crossed to the other study group after a brief wash-out phase. RESULTS: In total, 50 participants were recruited, resulting in 100 attempts. A success rate of 98% was observed across the study population. Time until ligation was 49 s and 56 s (p = 0.572) in the intervention and control group, respectively. However, there was a significant difference between the PAX and SAM (54 vs 75 s; p = 0.037) and the SAM and CAT tourniquet (75 vs. 47 s; p = 0.015). Further, we observed a significant learning effect in participants allocated to the control group first, with a median reduction of 9 s in the time until ligation. Hyperspectral measurements showed a significant decrease in perfusion and tissue oxygenation after ligation. Further, a significant increase in perfusion and tissue oxygenation was found after reopening the tourniquet compared to the baseline measurement. CONCLUSION: The novel PAX tourniquet can be applied quickly and effectively by medical personnel without prior experience in applying a tourniquet.

Relationships between job stress, post-traumatic stress and musculoskeletal symptoms in firefighters and the role of job burnout and depression mediators: a bayesian network model.

INTRODUCTION: Job stress, post-traumatic stress disorder (PTSD), and negative psychological outcomes in firefighters can be caused, or aggravated, by their work. These mental disorders can impart musculoskeletal symptoms. This study aimed to investigate relationships between musculoskeletal and psychological disorders in a population of firefighters using a Bayesian network model. METHODS: This cross-sectional study, conducted in 2022, included 2339 firefighters who completed questionnaires during their rest periods. The questionnaires comprised of demographical information, the Occupational Stress Questionnaire-HSE, the PTSD Checklist, Maslach Burnout Inventory, Center for Epidemiologic Studies - Depression scale (CES-D), and Nordic Musculoskeletal Questionnaire. GeNIe academic software was used to analyze the Bayesian network. RESULTS: High job stress and high PTSD each increased the probability of musculoskeletal symptoms by 34%. When combined, high job stress and high PTSD increased the probability of musculoskeletal symptoms by 37%. Among the mediator's burnout and depression, depression had the highest association with musculoskeletal symptoms. CONCLUSIONS: Job stress and PTSD can increase musculoskeletal symptoms and are influenced by psychological mediators (like burnout and depression). Adopting preventive and therapeutic measures to mitigate job stress and PTSD, mitigate and rehabilitate WMSD, and manage associated mediators are critical for the mental and physical health of firefighters.

Modelling inter-individual variability in acute and adaptive responses to interval training: insights into exercise intensity normalisation.

PURPOSE: To investigate the influence of exercise intensity normalisation on intra- and inter-individual acute and adaptive responses to an interval training programme. METHODS: Nineteen cyclists were split in two groups differing (only) in how exercise intensity was normalised: 80% of the maximal work rate achieved in an incremental test (% W ˙ max) vs. maximal sustainable work rate in a self-paced interval training session (% W ˙ max-SP). Testing duplicates were conducted before and after an initial control phase, during the training intervention, and at the end, enabling the estimation of inter-individual variability in adaptive responses devoid of intra-individual variability. RESULTS: Due to premature exhaustion, the median training completion rate was 88.8% for the % W ˙ max group, but 100% for the % W ˙ max-SP the group. Ratings of perceived exertion and heart rates were not sensitive to how intensity was normalised, manifesting similar inter-individual variability, although intra-individual variability was minimised for the % W ˙ max-SP group. Amongst six adaptive response variables, there was evidence of individual response for only maximal oxygen uptake (standard deviation: 0.027 L·min-1·week-1) and self-paced interval training performance (standard deviation: 1.451 W·week-1). However, inter-individual variability magnitudes were similar between groups. Average adaptive responses were also similar between groups across all variables. CONCLUSIONS: To normalise completion rates of interval training, % W ˙ max-SP should be used to prescribe relative intensity. However, the variability in adaptive responses to training may not reflect how exercise intensity is normalised, underlining the complexity of the exercise dose-adaptation relationship. True inter-individual variability in adaptive responses cannot always be identified when intra-individual variability is accounted for.