Sudden gains in routine clinical care: application of a permutation test for trauma-focused cognitive behavioural therapy.

Background: Sudden gains, defined as large and stable improvements of psychopathological symptoms, are a ubiquitous phenomenon in psychotherapy. They have been shown to occur across several clinical contexts and to be associated with better short-term and long-term treatment outcome. However, the approach of sudden gains has been criticized for its tautological character: sudden gains are included in the computation of treatment outcomes, ultimately resulting in a circular conclusion. Furthermore, some authors criticize sudden gains as merely being random fluctuations.Objective: Use of efficient methods to evaluate whether the amount of sudden gains in a given sample lies above chance level.Method: We used permutation tests in a sample of 85 patients with posttraumatic stress disorder (PTSD) treated with trauma-focused cognitive behaviour therapy in routine clinical care. Scores of self-reported PTSD symptom severity were permuted 10.000 times within sessions and between participants to receive a random distribution.Results: Altogether, 18 participants showed a total of 24 sudden gains within the first 20 sessions. The permutation test yielded that the frequency of sudden gains was not beyond chance level. No significant predictors of sudden gains were identified and sudden gains in general were not predictive of treatment outcome. However, subjects with early sudden gains had a significantly lower symptom severity after treatment.Conclusions: Our data suggest that a significant proportion of sudden gains are due to chance. Further research is needed on the differential effects of early and late sudden gains.

Treatment-related sudden gains exhibit clinical significance when their manifestation is above chance level.We used permutation tests to examine their occurrence in trauma-focused cognitive behaviour therapy as applied in a naturalistic treatment setting.The occurrence of sudden gains in general was not significantly higher than chance, yet early sudden gains were associated with improved treatment outcome.

Association of Sputum Eosinophilia With Easily Measured Type-2 Inflammatory Biomarkers in Untreated Mild Persistent Asthma.

BACKGROUND: A multicenter clinical trial in patients with mild persistent asthma indicated that response to inhaled corticosteroids (ICS) is limited to those with sputum eosinophilia. However, testing for sputum eosinophilia is impractical in most clinical settings. OBJECTIVE: We examined associations between sputum eosinophilia and type 2 inflammatory biomarkers in untreated mild persistent asthma. METHODS: Induced sputum, blood eosinophil count (BEC), fractional exhaled nitric oxide (FeNO), and serum periostin were obtained twice during the 6-week run-in period in a clinical trial that enrolled patients 12 years and older with symptomatic, mild persistent asthma without controller therapy. The optimal threshold for each biomarker was based on achieving 80% or greater sensitivity. Performance of biomarkers (area under the receiver operating characteristics curve [AUC], range 0.0-1.0) in predicting sputum eosinophilia 2% or greater was determined; AUCs of 0.8 to 0.9 and more than 0.9 define excellent and outstanding discrimination, respectively. RESULTS: Of 564 participants, 27% were sputum eosinophilic, 83% were atopic, 70% had BEC of 200/uL or higher or FeNO of 25 ppb or greater; 64% of participants without sputum eosinophilia had elevated BEC or FeNO. The AUCs for BEC, FeNO, and both together in predicting sputum eosinophilia were all below the threshold for excellent discrimination (AUC 0.75, 0.78, and 0.79, respectively). Periostin (in adults) had poor discrimination (AUC 0.59; P = .02). CONCLUSIONS: In untreated mild persistent asthma, there is substantial discordance between sputum eosinophilia, BEC, and FeNO. Until prospective trials test the ability of alternative biomarkers to predict ICS response, BEC or FeNO phenotyping may be an option to consider ICS through a shared decision-making process with consideration of other clinical features.

Do changes in dysfunctional posttraumatic cognitions differentially predict PTSD symptom clusters?

OBJECTIVE: In recent years, it has been suggested that the modification of dysfunctional posttraumatic cognitions plays a central role as a mechanism of change in cognitive behavioral therapy (CBT) for posttraumatic stress disorder (PTSD). Indeed, several studies have shown that changes in dysfunctional posttraumatic cognitions precede and predict symptom change. However, these studies have investigated the influence on overall symptom severity-despite the well-known multidimensionality of PTSD. The present study therefore aimed to explore differential associations between change in dysfunctional conditions and change in PTSD symptom clusters. METHOD: As part of a naturalistic effectiveness study evaluating trauma-focused cognitive behavioral therapy for PTSD in routine clinical care, 61 patients with PTSD filled out measures of dysfunctional posttraumatic cognitions and PTSD symptom severity every five sessions during the course of treatment. Lagged associations between dysfunctional cognitions and symptom severity at the following timepoint were examined using linear mixed models. RESULTS: Over the course of therapy, both dysfunctional cognitions and PTSD symptoms decreased. Posttraumatic cognitions predicted subsequent total PTSD symptom severity, although this effect was at least partly explained by the time factor. Moreover, dysfunctional cognitions predicted three out of four symptom clusters as expected. However, these effects were no longer statistically significant when the general effect for time was controlled for. CONCLUSION: The present study provides preliminary evidence that dysfunctional posttraumatic cognitions predict PTSD symptom clusters differentially. However, different findings when employing a traditional versus a more rigorous statistical approach make interpretation of findings difficult. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Urine eosinophil-derived neurotoxin: A potential marker of activity in select eosinophilic disorders.

BACKGROUND: Biomarkers of eosinophilic disease activity, especially in the context of novel therapies that reduce blood eosinophil counts, are an unmet need. Absolute eosinophil count (AEC) does not accurately reflect tissue eosinophilia or eosinophil activation. Therefore, the aims of this study were to compare the reliability of plasma and urine eosinophil major basic protein 1, eosinophil cationic protein, eosinophil-derived neurotoxin (EDN), and eosinophil peroxidase measurement and to evaluate the usefulness of eosinophil granule protein (EGP) measurement for the assessment of disease activity in patients with eosinophil-associated diseases treated with mepolizumab, benralizumab, or dexpramipexole. METHODS: Eosinophil granule protein concentrations were measured in serum, plasma, and urine from healthy volunteers and patients with hypereosinophilic syndrome (HES), eosinophilic granulomatosis with polyangiitis (EGPA), and eosinophilic asthma using a multiplex assay. RESULTS: Urine EGP concentrations remained stable, whereas serum and plasma EGP concentrations increased significantly with delayed processing. Plasma (p) EDN, but not urine (u) EDN, concentration correlated with AEC and negatively correlated with prednisone dose. Both pEDN and uEDN decreased significantly following treatment of HES patients with benralizumab and EGPA patients with mepolizumab. uEDN appeared to increase with clinical relapse in both patient groups. CONCLUSIONS: Measurement of EGP in urine is noninvasive and unaffected by cellular lysis. Although plasma and urine EDN concentrations showed a similar pattern following benralizumab and mepolizumab treatment, the lack of correlation between AEC or prednisone dose and uEDN concentrations suggests that measurement of uEDN may provide a potential biomarker of disease activity in patients with HES and EGPA.

Rationale and Design for the Diabetes RElated to Acute Pancreatitis and Its Mechanisms Study: A Prospective Cohort Study From the Type 1 Diabetes in Acute Pancreatitis Consortium.

ABSTRACT: Acute pancreatitis (AP) is a disease characterized by an acute inflammatory phase followed by a convalescent phase. Diabetes mellitus (DM) was historically felt to be a transient phenomenon related to acute inflammation; however, it is increasingly recognized as an important late and chronic complication. There are several challenges that have prevented precisely determining the incidence rate of DM after AP and understanding the underlying mechanisms. The DREAM (Diabetes RElated to Acute Pancreatitis and its Mechanisms) Study is a prospective cohort study designed to address these and other knowledge gaps to provide the evidence needed to screen for, prevent, and treat DM after AP. In the following article, we summarize literature regarding the epidemiology of DM after AP and provide the rationale and an overview of the DREAM study.

Standard Operating Procedures for Biospecimen Collection, Processing, and Storage: From the Type 1 Diabetes in Acute Pancreatitis Consortium.

ABSTRACT: Differences in methods for biospecimen collection, processing, and storage can yield considerable variability and error. Therefore, best practices for standard operating procedures are critical for successful discovery, development, and validation of disease biomarkers. Here, we describe standard operating procedures developed for biospecimen collection during the DREAM (Diabetes RElated to Acute pancreatitis and its Mechanisms) Study within the Type 1 Diabetes in Acute Pancreatitis Consortium. Notably, these protocols were developed using an integrative process based on prior consortium experience and with input from working groups with expertise in immunology, pancreatitis, and diabetes. Publication and adoption consistent biospecimen protocols will inform future studies and allow for better comparisons across different metabolic research efforts.

Recruitment and Retention Strategies for the Diabetes RElated to Acute Pancreatitis and Its Mechanisms Study: From the Type 1 Diabetes in Acute Pancreatitis Consortium.

ABSTRACT: Recruitment and retention of patients with acute pancreatitis (AP) in clinical studies can be challenging. While some obstacles are similar to other clinical conditions, some are unique to AP. Identifying potential barriers early and developing targeted solutions can help optimize recruitment and retention in AP studies. Such pre-emptive and detailed planning can help prospective, longitudinal studies focus on exocrine and endocrine complications of AP in accurately measuring outcomes. This article highlights the challenges in recruitment and retention strategies in AP studies and reviews available resources to create opportunities to address them. We describe the multifaceted approach used by the Recruitment and Retention Committee of the Type 1 Diabetes in Acute Pancreatitis Consortium, which builds upon earlier experiences to develop a recruitment and retention plan for the DREAM (Diabetes RElated to Acute pancreatitis and its Mechanisms) study.

Rationale and Development of a Data Coordinating Center to Support the Type 1 Diabetes in Acute Pancreatitis Consortium.

ABSTRACT: A data coordinating center (DCC) is a critical member of any multicenter research undertaking, and that is especially true for the Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC). We describe how the T1DAPC DCC supports the consortium via its experience and expertise in project management, administration, financial management, regulatory compliance, scientific coordination, data management, research computing, and biostatistics and in facilitating scientific publications. The DCC's matrix management system has been extremely effective in managing all of its responsibilities. The first 16 months in the life of the T1DAPC have been dedicated to the development of its first protocol, titled Diabetes RElated to Acute pancreatitis and its Mechanisms (DREAM), addressing the institutional review board and regulatory components, developing the T1DAPC data management system, and providing training and certification of clinical center staff. As a result of its efforts, the DCC was a major contributor to the T1DAPC being able to initiate recruitment for the DREAM study in January 2022.

Comparing PTSD symptom networks in type I vs. type II trauma survivors.

Background: Network analysis has gained increasing attention as a new framework to study complex associations between symptoms of post-traumatic stress disorder (PTSD). A number of studies have been published to investigate symptom networks on different sets of symptoms in different populations, and the findings have been inconsistent. Objective: We aimed to extend previous research by testing whether differences in PTSD symptom networks can be found in survivors of type I (single event; sudden and unexpected, high levels of acute threat) vs. type II (repeated and/or protracted; anticipated) trauma (with regard to their index trauma). Method: Participants were trauma-exposed individuals with elevated levels of PTSD symptomatology, most of whom (94%) were undergoing assessment in preparation for PTSD treatment in several treatment centres in Germany and Switzerland (n = 286 with type I and n = 187 with type II trauma). We estimated Bayesian Gaussian graphical models for each trauma group and explored group differences in the symptom network. Results: First, for both trauma types, our analyses identified the edges that were repeatedly reported in previous network studies. Second, there was decisive evidence that the two networks were generated from different multivariate normal distributions, i.e. the networks differed on a global level. Third, explorative edge-wise comparisons showed moderate or strong evidence for specific 12 edges. Edges which emerged as especially important in distinguishing the networks were between intrusions and flashbacks, highlighting the stronger positive association in the group of type II trauma survivors compared to type I survivors. Flashbacks showed a similar pattern of results in the associations with detachment and sleep problems (type II > type I). Conclusion: Our findings suggest that trauma type contributes to the heterogeneity in the symptom network. Future research on PTSD symptom networks should include this variable in the analyses to reduce heterogeneity.

Antecedentes: El análisis de redes ha ganado cada vez más atención como un nuevo marco para estudiar asociaciones complejas entre síntomas del Trastorno de Estrés Postraumático (TEPT). Se han publicado una cantidad de estudios para investigar las redes de síntomas en diferentes conjuntos de síntomas en distintas poblaciones, y los hallazgos han sido inconsistentes.Objetivos: Nuestro objetivo fue ampliar la investigación previa probando si se pueden encontrar diferencias entre las redes de síntomas del TEPT en sobrevivientes de trauma de tipo 1 (evento único; súbito e inesperado, niveles elevados de amenaza aguda) versus los de tipo 2 (eventos repetidos y/o prolongados; anticipados) (con respecto a su trauma índice).Métodos: Los participantes eran individuos expuestos al trauma con niveles elevados de sintomatología de TEPT, la mayoría de los cuales (94%) se sometían a una evaluación en preparación para el tratamiento del TEPT en varios centros de Alemania y Suiza (n = 286 con tipo 1 y n = 187 con tipo 2 de trauma). Estimamos modelos gráficos Bayesianos Gaussianos para cada tipo de grupo de trauma y exploramos las diferencias entre los grupos en la red de síntomas.Resultados: En primer lugar, para ambos tipos de trauma, nuestros análisis identificaron los bordes que se reportaron repetidamente en estudios de redes anteriores. En segundo lugar, hubo evidencia decisiva que las dos redes fueron generadas de diferentes distribuciones normales multivariadas, es decir, las redes diferían a nivel global. En tercer lugar, las comparaciones exploratorias de los bordes mostraron una evidencia de moderada a fuerte para 12 bordes específicos. Los bordes que surgieron como especialmente importantes para distinguir las redes fueron las intrusiones y flashbacks, destacando la asociación fuertemente positiva entre los grupos de tipo 2 en comparación con los sobrevivientes de trauma del grupo de tipo 1. Los flashbacks mostraron un patrón similar de resultados en las asociaciones con desapego y problemas de sueño (tipo 2 > tipo 1).Conclusiones: Nuestros resultados sugieren que el tipo de trauma contribuye a la heterogeneidad en los síntomas de red. La investigación futura sobre las redes de los síntomas de TEPT debería incluir esta variable en los análisis para reducir la heterogeneidad.

The dissociative subtype of PTSD in trauma-exposed individuals: a latent class analysis and examination of clinical covariates.

Background: A dissociative subtype of posttraumatic stress disorder (D-PTSD) was introduced into the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) but latent profiles and clinical correlates of D-PTSD remain controversial. Objective: The aims of our study were to identify subgroups of individuals with distinct patterns of PTSD symptoms, including dissociative symptoms, by means of latent class analyses (LCA), to compare these results with the categorization of D-PTSD vs. PTSD without dissociative features according to the CAPS-5 interview, and to explore whether D-PTSD is associated with higher PTSD severity, difficulties in emotion regulation, and depressive symptoms. Method: A German sample of treatment-seeking individuals was investigated (N = 352). We conducted an LCA on the basis of symptoms of PTSD and dissociation as assessed by the CAPS-5. Moreover, severity of PTSD (PCL-5), difficulties in emotion regulation (DERS), and depressive symptoms (BDI-II) were compared between patients with D-PTSD according to the CAPS-5 interview and patients without dissociative symptoms. Results: LCA results suggested a 5-class model with one subgroup showing the highest probability to fulfill criteria for the dissociative subtype and high scores on both BDI and DERS. Significantly higher scores on the DERS, BDI and PCL-5 were found in the D-PTSD group diagnosed with the CAPS-5 (n = 75; 35.7%). Sexual trauma was also reported more often by this subgroup. When comparing the dissociative subtype to the LCA results, only a partial overlap could be found. Conclusions: Our findings suggest that patients with D-PTSD have significantly more problems with emotion regulation, more depressive symptoms, and more severe PTSD-symptoms. Given the results of our LCA, we conclude that the dissociative subtype seems to be more complex than D-PTSD as diagnosed by means of the CAPS-5.

Antecedentes: Un subtipo disociativo del trastorno de estrés postraumático (TEPT-D) fue introducido en la 5ª edición del Manual Diagnóstico y Estadístico de los Trastornos Mentales (DSM-5), pero los perfiles latentes y los correlatos clínicos del TEPT-D siguen siendo controversiales. Objetivo Los objetivos de nuestro estudio fueron identificar subgrupos de individuos con distintos patrones de síntomas de TEPT, incluyendo síntomas disociativos, mediante análisis de clases latentes (LCA, por sus siglas en inglés), comparar estos resultados con la categorización de TEPT-D vs. TEPT sin rasgos disociativos según la entrevista CAPS-5, y explorar si el TEPT-D se asocia con una mayor gravedad del TEPT, dificultades en la regulación de las emociones y síntomas depresivos.Método: Se investigó una muestra alemana de individuos que buscaban tratamiento (N = 352). Se realizó un LCA sobre la base de los síntomas de TEPT y disociación evaluados por el CAPS-5. Además, se comparó la gravedad del TEPT (PCL-5), las dificultades en la regulación de las emociones (DERS) y los síntomas depresivos (BDI-II) entre los pacientes con TEPT según la entrevista CAPS-5 y los pacientes sin síntomas disociativos.Resultados: Los resultados del LCA sugirieron un modelo de 5 clases con un subgrupo que mostraba la mayor probabilidad de cumplir los criterios del subtipo disociativo y altas puntuaciones tanto en el BDI como en el DERS. Se encontraron puntuaciones significativamente más altas en el DERS, el BDI y el PCL-5 en el grupo de TEPT-D diagnosticado con el CAPS-5 (n = 75; 35,7%). Este subgrupo también informó con más frecuencia de traumas sexuales. Al comparar el subtipo disociativo con los resultados del LCA, sólo se pudo encontrar una superposición parcial. Conclusiones Nuestros resultados sugieren que los pacientes con TEPT-D tienen significativamente más problemas con la regulación emocional, más síntomas depresivos y síntomas de TEPT más graves. Dados los resultados de nuestro LCA, concluimos que el subtipo disociativo parece ser más complejo que el TEPT-D diagnosticado mediante el CAPS-5.

Confirmatory factor analysis of the Clinician-Administered PTSD Scale (CAPS-5) based on DSM-5 vs. ICD-11 criteria.

Introduction: Many studies have investigated the latent structure of the DSM-5 criteria for posttraumatic stress disorder (PTSD). However, most research on this topic was based on self-report data. We aimed to investigate the latent structure of PTSD based on a clinical interview, the Clinician-Administered PTSD Scale (CAPS-5). Method: A clinical sample of 345 participants took part in this multi-centre study. Participants were assessed with the CAPS-5 and the Posttraumatic Stress Disorder Checklist (PCL-5). We evaluated eight competing models of DSM-5 PTSD symptoms and three competing models of ICD-11 PTSD symptoms. Results: The internal consistency of the CAPS-5 was replicated. In CFAs, the Anhedonia model emerged as the best fitting model within all tested DSM-5 models. However, when compared with the Anhedonia model, the non-nested ICD-11 model as a less complex three-factor solution showed better model fit indices. Discussion: We discuss the findings in the context of earlier empirical findings as well as theoretical models of PTSD.

Introducción: Muchos estudios han investigado la estructura latente de los criterios DSM-5 para el trastorno de estrés postraumático (TEPT). Sin embargo, la mayoría de la investigación en este tema estuvo basada en datos de auto-reporte. Nuestro objetivo fue investigar la estructura latente del TEPT basado en una entrevista clínica, la Escala de TEPT administrada por el Clínico (CAPS-5 por su sigla en inglés).Método: En este estudio multicéntrico participó una muestra clínica de 345 personas. Los participantes fueron evaluados con la CAPS-5 y la Lista de Chequeo de Trastorno de Estrés Postraumático (PCL-5, por su sigla en inglés). Evaluamos ocho modelos competitivos de síntomas de TEPT del DSM-5 y tres modelos competitivos de síntomas de TEPT de la CIE-11.Resultados: La consistencia interna de la CAPS-5 fue replicada. En los AFC el modelo de anhedonia emergió como el de mejor ajuste entre todos los modelos del DSM-5 evaluados. Sin embargo, cuando se comparó con el modelo de anhedonia, el modelo no anidado de CIE-11 como una solución menos compleja de tres factores mostró mejores índices de ajuste de modelo.Discusión: Discutimos los hallazgos en el contexto de los resultados empíricos previos y de los modelos teóricos del TEPT.

Mechanisms of Change in Trauma-Focused Treatment for PTSD: The Role of Rumination.

OBJECTIVE: Cognitive behavioral therapy (CBT) has been well established in the treatment of posttraumatic stress disorder (PTSD). In recent years, researchers have begun to investigate its underlying mechanisms of change. Dysfunctional cognitive content, i.e. excessively negative appraisals of the trauma or its consequences, has been shown to predict changes in PTSD symptoms over the course of treatment. However, the role of change in cognitive processes, such as trauma-related rumination, needs to be addressed. The present study investigates whether changes in rumination intensity precede and predict changes in symptom severity. We also explored the extent to which symptom severity predicts rumination. METHOD: As part of a naturalistic effectiveness study evaluating CBT for PTSD in routine clinical care, eighty-eight patients with PTSD completed weekly measures of rumination and symptom severity. Lagged associations between rumination and symptoms in the following week were examined using linear mixed models. RESULTS: Over the course of therapy, both ruminative thinking and PTSD symptoms decreased. Rumination was a significant predictor of PTSD symptoms in the following week, although this effect was at least partly explained by the time factor (e.g., natural recovery or inseparable treatment effects). Symptom severity predicted ruminative thinking in the following week even with time as an additional predictor. CONCLUSIONS: The present study provides preliminary evidence that rumination in PTSD is reduced by CBT for PTSD but does not give conclusive evidence that rumination is a mechanism of change in trauma-focused treatment for PTSD.

Biomarkers to Predict Response to Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists in Adolescents and Adults with Mild Persistent Asthma.

Rationale: Whether biomarkers can be used to predict response to inhaled corticosteroids (ICS) or long-acting muscarinic antagonists (LAMA) in mild persistent asthma is unclear. Objectives: In a prespecified exploratory analysis of a randomized clinical trial of 295 participants 12 years of age or older with uncontrolled mild persistent asthma, we sought to identify biomarkers of treatment response after 12 weeks of ICS (mometasone, 200 µg or 220 µg twice/d), LAMA (tiotropium, 5 µg/d), or placebo in adults (⩾18 yr) and adolescents (12-17 yr) separately. Methods: The primary outcome was a composite outcome of asthma control (treatment failure, asthma control days, and forced expiratory volume in 1 second [FEV1]). Analyses examined type 2 inflammatory biomarkers and physiologic biomarkers. We assessed the area under the receiver operating characteristic curve (AUC) for response to ICS and LAMA (each versus placebo). An AUC of 0.5 suggests no discrimination, 0.7-0.8 is considered acceptable, more than 0.8-0.9 is considered excellent, and more than 0.9 is considered outstanding. Results: In 237 adults, sputum and blood eosinophil levels and fractional exhaled nitric oxide (FeNO) each predicted ICS response (AUCs: 0.61 [95% confidence interval (CI), 0.53-0.69], 0.64 [95% CI, 0.56-0.72], and 0.62 [95% CI, 0.54-0.70], respectively; all P < 0.01); the AUC for blood eosinophil levels and FeNO together was 0.66 (95% CI, 0.58-0.74; P < 0.001). In 58 adolescents, the number of positive aeroallergens and total serum immunoglobulin E each predicted ICS response (AUCs: 0.69 [95% CI, 0.52-0.85] and 0.73 [95% CI, 0.58-0.87], respectively; both P < 0.03); the AUC for both together was 0.73 (95% CI, 0.58-0.87; P = 0.003). After ipratropium bromide, FEV1 reversibility predicted LAMA response in adults (AUC: 0.61 [95% CI, 0.53-0.69], P = 0.007) but not in adolescents. Conclusions: The AUCs of the type 2 inflammatory biomarkers and physiological biomarkers we examined may not be high enough to confidently identify individuals with asthma who respond to ICS and LAMA. However, our findings indicate that the biomarkers that predict response to ICS or LAMA may differ in adults versus adolescents with uncontrolled mild persistent asthma. Prospective, biomarker-stratified clinical trials are needed to confirm these findings and to identify first-line controllers tailored for each population.

Association Between Baseline Diastolic Blood Pressure and the Efficacy of Intensive vs Standard Blood Pressure-Lowering Therapy.

Importance: Low diastolic blood pressure (DBP) has been found to be associated with increased adverse cardiovascular events; however, it is unknown whether intensifying blood pressure therapy in patients with an already low DBP to achieve a lower systolic blood pressure (SBP) target is safe or effective. Objective: To evaluate whether there is an association of baseline DBP and intensification of blood pressure-lowering therapy with the outcomes of all-cause death and cardiovascular events. Design, Setting, and Participants: This cohort study analyzed patients who were randomized to intensive or standard BP control in the Action to Control Cardiovascular Risk in Diabetes-Blood Pressure (ACCORD-BP) trial and Systolic Blood Pressure Intervention Trial (SPRINT). Data were collected from September 1999 to June 2009 (ACCORD-BP) and from October 2010 to August 2015 (SPRINT). Data were analyzed from December 2020 to June 2021. Exposures: Baseline DBP as a continuous variable. Main Outcomes and Measures: All-cause death and a composite cardiovascular end point (CVE) that included cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Results: A total of 14 094 patients (mean [SD] age, 66.2 [8.9] years; 8504 [60.4%] men) were included in this analysis. There were significant nonlinear associations between baseline DBP and all-cause death (eg, baseline DBP 50 vs 80 mm Hg: hazard ratio [HR], 1.48; 95% CI, 1.06-2.08; P = .02) and the composite CVE (eg, baseline DBP 50 vs 80 mm Hg: HR, 1.45; 95% CI, 1.27-3.04; P = .003) observed among all participants. Findings for the interaction between baseline DBP and treatment group assignment for all cause death did not reach statistical significance. For intensive vs standard therapy, the HR of death for a baseline DBP of 50 mm Hg was 1.80 (95% CI, 0.95-3.39; P = .07) and that for a baseline DBP of 80 mm Hg was 0.77 (95% CI, 0.59-1.01; P = .05). Overall, there was no interaction found between baseline DBP and treatment group assignment for the composite CVE. Over the range of baseline DBP values, significant reductions in the composite CVE for patients assigned to intensive vs standard therapy were found for baseline DBP values of 80 mm Hg (HR, 0.78; 95% CI, 0.62-0.98; P = .03) and 90 mm Hg (HR, 0.74; 95% CI, 0.55-0.98; P = .04). Conclusions and Relevance: This pooled cohort study found no evidence of a significant interaction between baseline DBP and treatment intensity for all-cause death or for a composite CVE. These results are hypothesis generating and merit further study.

Effects of Diet and Exercise-Induced Weight Loss on Biomarkers of Inflammation in Breast Cancer Survivors: A Systematic Review and Meta-analysis.

BACKGROUND: Adiponectin, leptin, and pro- and anti-inflammatory cytokines are implicated in breast cancer risk and recurrence. Weight loss, via the dynamic interplay of energy balance through exercise and/or caloric restriction, decreases risk of breast cancer recurrence. METHODS: We investigated the effects of lifestyle modifications (exercise only, or combined caloric restriction and exercise) on adipokines, IL2, IL6, IL8, IL10, C-reactive protein (CRP), and TNFα biomarkers in breast cancer survivors. Searches were completed in June and July of 2019 to identify randomized controlled trials that met inclusion criteria. Weighted mean difference was calculated using random- or fixed-effects models based on the heterogeneity of the studies. RESULTS: 2501 records were identified, with 30 ultimately meeting inclusion criteria of the systematic review; 21 studies provided data suitable for meta-analysis. We observed leptin levels were significantly reduced in the exercise-only group compared with sedentary control [WMD -5.66; 95% confidence interval (CI), -11.0 to -0.33; P = 0.04]. CONCLUSIONS: Leptin may be a primary mediator of exercise-induced improvements in breast cancer recurrence. IMPACT: This is the first review and meta-analysis to examine combined exercise and caloric restriction programs in breast cancer survivors. Future studies should further examine combined programs and their efficacy for altering leptin.

Misinformation and other elements in HPV vaccine tweets: an experimental comparison.

Our study examined how misinformation and other elements of social media messages affect antecedents to human papillomavirus (HPV) vaccination of adolescents. In 2017-2018, we randomly assigned a national sample of 1206 U.S. parents of adolescents to view one tweet using a 2 × 2 × 2 × 2 between-subjects factorial experiment. The 16 experimental tweets varied four messaging elements: misinformation (misinformation or not), source (person or organization), narrative style (storytelling or scientific data), and topic (effectiveness or safety). Parents reported their motivation to vaccinate (primary outcome), trust in social media content, and perceived risk about HPV-related diseases. Tweets without misinformation elicited higher HPV vaccine motivation than tweets with misinformation (25% vs. 5%, OR = 6.60, 95% CI:4.05, 10.75). Motivation was higher for tweets from organizations versus persons (20% vs. 10%, OR = 2.47, 95% CI:1.52, 4.03) and about effectiveness versus safety (20% vs. 10%, OR = 2.03, 95% CI:1.24, 3.30). Tweets with misinformation produced lower trust and higher perceived risk (both p < .01), with impact varying depending on source and topic. In conclusion, misinformation was the most potent social media messaging element. It may undermine progress in HPV vaccination.

A Multimorbidity-Based, Risk-Stratified Reanalysis of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Trial.

INTRODUCTION: Multimorbidity is common in patients with cardiovascular disease. Clinical trials in cardiovascular medicine mostly enroll patients who are younger, healthier, and more affluent than average patients with the condition of interest. These trials rarely account for patient-level multimorbidity in a systematic fashion. Further, treatment effect heterogeneity is usually tested across subgroups of patients based on the presence or absence of individual variables, not on the basis of summative risk scores that account for multimorbidity. Thus, the impact of multimorbidity on treatment effects is poorly understood. METHODS: In this study, we performed a multimorbidity-based risk-stratified reanalysis of the AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) trial. Our objectives were to describe the distribution of multimorbidity using a modified version of the Charlson Comorbidity Index (mCCI), scale 0-14, and to assess its impact on the original primary endpoint of all-cause mortality. RESULTS: The majority of patients in the AFFIRM trial had an mCCI score of ≤  4 (55.5%), and there was no statistically significant difference in the risk of death for rate versus rhythm control in these patients (7.9 vs. 8.8%; p = 0.44). However, for patients with an mCCI ≥ 5 (44.5%), there was a strong trend toward a reduction in death with rate control that nearly reached statistical significance despite being underpowered (24.5 vs. 28.3%; p = 0.07). CONCLUSION: This proof-of-concept study supports the idea that clinical trials in cardiovascular medicine should systematically assess for multimorbidity and investigate its potential impact on treatment effects.

Acute Kidney Injury and Risk of CKD and Hypertension after Pediatric Cardiac Surgery.

BACKGROUND AND OBJECTIVES: The association of AKI after pediatric cardiac surgery with long-term CKD and hypertension development is unclear. The study objectives were to determine whether AKI after pediatric cardiac surgery is associated with incident CKD and hypertension. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a prospective cohort study of children of 1 month to 18 years old who were undergoing cardiac surgery at two tertiary care centers (Canada, United States). Participants were recruited before cardiac surgery and were followed during hospitalization and at 3, 12, 24, 36, and 48 months after discharge. Exposures were postoperative AKI, based on the Kidney Disease Improving Global Outcomes (KDIGO) definition, and age <2 years old at surgery. Outcomes and measures were CKD (low eGFR or albuminuria for age) and hypertension (per the 2017 American Academy of Pediatrics guidelines) at follow-up, with the composite outcome of CKD or hypertension. RESULTS: Among 124 participants, 57 (46%) developed AKI. AKI versus non-AKI participants had a median (interquartile range) age of 8 (4.8-40.8) versus 46 (6.0-158.4) months, respectively, and higher preoperative eGFR. From the 3- to 48-month follow-up, the cohort prevalence of CKD was high (17%-20%); hypertension prevalence was also high (22%-30%). AKI was not significantly associated with the development of CKD throughout follow-up. AKI was associated with hypertension development at 12 months after discharge (adjusted relative risk, 2.16; 95% confidence interval, 1.18 to 3.95), but not at subsequent visits. Children aged <2 years old at surgery had a significantly higher prevalence of hypertension during follow-up than older children (40% versus 21% at 3-month follow-up; 32% versus 13% at 48-month follow-up). CONCLUSIONS: CKD and hypertension burden in the 4 years after pediatric cardiac surgery is high. Young age at surgery, but not AKI, is associated with their development.

Distinct associations of sputum and oral microbiota with atopic, immunologic, and clinical features in mild asthma.

BACKGROUND: Whether microbiome characteristics of induced sputum or oral samples demonstrate unique relationships to features of atopy or mild asthma in adults is unknown. OBJECTIVE: We sought to determine sputum and oral microbiota relationships to clinical or immunologic features in mild atopic asthma and the impact on the microbiota of inhaled corticosteroid (ICS) treatment administered to ICS-naive subjects with asthma. METHODS: Bacterial microbiota profiles were analyzed in induced sputum and oral wash samples from 32 subjects with mild atopic asthma before and after inhaled fluticasone treatment, 18 atopic subjects without asthma, and 16 nonatopic healthy subjects in a multicenter study (NCT01537133). Associations with clinical and immunologic features were examined, including markers of atopy, type 2 inflammation, immune cell populations, and cytokines. RESULTS: Sputum bacterial burden inversely associated with bronchial expression of type 2 (T2)-related genes. Differences in specific sputum microbiota also associated with T2-low asthma phenotype, a subgroup of whom displayed elevations in lung inflammatory mediators and reduced sputum bacterial diversity. Differences in specific oral microbiota were more reflective of atopic status. After ICS treatment of patients with asthma, the compositional structure of sputum microbiota showed greater deviation from baseline in ICS nonresponders than in ICS responders. CONCLUSIONS: Novel associations of sputum and oral microbiota to immunologic features were observed in this cohort of subjects with or without ICS-naive mild asthma. These findings confirm and extend our previous report of reduced bronchial bacterial burden and compositional complexity in subjects with T2-high asthma, with additional identification of a T2-low subgroup with a distinct microbiota-immunologic relationship.

Pulmonary Eosinophilic Granulomatosis with Polyangiitis Has IgG4 Plasma Cells and Immunoregulatory Features.

The immunologic mechanisms promoting eosinophilic granulomatosis with polyangiitis (EGPA) are unclear. To characterize the mechanisms underlying pulmonary EGPA, we examined and compared EGPA paraffin-embedded lung biopsies with normal lung biopsies, using immunostaining, RNA sequencing, and RT-PCR. The results revealed novel type 2 as well as immuneregulatory features. These features included basophils and increased mast cell contents; increased immunostaining for tumor necrosis factor ligand superfamily member 14; sparse mast cell degranulation; numerous forkhead box protein P3 (FoxP3)+ regulatory T cells and IgG4 plasma cells; and abundant arachidonate 15-lipoxygenase and 25-hydroxyvitamin D-1 α hydroxylase, mitochondrial. Significantly decreased 15-hydroxyprostaglandin dehydrogenase [NAD(+)], which degrades eicosanoids, was observed in EGPA samples. In addition, there was significantly increased mRNA for chemokine (C-C motif) ligands 18 and 13 and major collagen genes, IgG4-rich immune complexes coating alveolar macrophages, and increased immunostaining for phosphorylated mothers against decapentaplegic homolog 2/SMAD2, suggesting transforming growth factor-ß activation. These findings suggest a novel self-promoting mechanism of activation of alveolar macrophages by arachidonate 15-lipoxygenase-derived eicosanoids to express chemokines that recruit a combined type 2/immunoregulatory immune response, which produces these eicosanoids. These results suggest that the pulmonary EGPA immune response resembles the immune response to a tissue-invasive parasite infection.