Telehealth Mindfulness-Based Interventions for Chronic Pain: The LAMP Randomized Clinical Trial.

Importance: Although mindfulness-based interventions (MBIs) are evidence-based treatments for chronic pain and comorbid conditions, implementing them at scale poses many challenges, such as the need for dedicated space and trained instructors. Objective: To examine group and self-paced, scalable, telehealth MBIs, for veterans with chronic pain, compared to usual care. Design, Setting, and Participants: This was a randomized clinical trial of veterans with moderate to severe chronic pain, recruited from 3 Veterans Affairs facilities from November 2020 to May 2022. Follow-up was completed in August 2023. Interventions: Two 8-week telehealth MBIs (group and self-paced) were compared to usual care (control). The group MBI was done via videoconference with prerecorded mindfulness education and skill training videos by an experienced instructor, accompanied by facilitated discussions. The self-paced MBI was similar but completed asynchronously and supplemented by 3 individual facilitator calls. Main Outcomes and Measures: The primary outcome was pain-related function using the Brief Pain Inventory interference scale at 3 time points: 10 weeks, 6 months, and 1 year. Secondary outcomes included biopsychosocial outcomes: pain intensity, physical function, anxiety, fatigue, sleep disturbance, participation in social roles and activities, depression, patient ratings of improvement of pain, and posttraumatic stress disorder. Results: Among 811 veterans randomized (mean [SD] age, 54.6 [12.9] years; 387 [47.7%] women), 694 participants (85.6%) completed the trial. Averaged across all 3 time points, pain interference scores were significantly lower for both MBIs compared to usual care (group MBI vs control difference: -0.4 [95% CI, -0.7 to -0.2]; self-paced vs control difference: -0.7 [95% CI, -1.0 to -0.4]). Additionally, both MBI arms had significantly better scores on the following secondary outcomes: pain intensity, patient global impression of change, physical function, fatigue, sleep disturbance, social roles and activities, depression, and posttraumatic stress disorder. Both group and self-paced MBIs did not significantly differ from one another. The probability of 30% improvement from baseline compared to control was greater for group MBI at 10 weeks and 6 months, and for self-paced MBI, at all 3 time points. Conclusions and Relevance: In this randomized clinical trial, scalable telehealth MBIs improved pain-related function and biopsychosocial outcomes compared to usual care among veterans with chronic pain. Relatively low-resource telehealth-based MBIs could help accelerate and improve the implementation of nonpharmacological pain treatment in health care systems. Trial Registration: ClinicalTrials.gov Identifier: NCT04526158.

Relationships Between Applied Mindfulness Practice, Chronic Pain, and Pain-Related Functioning in Veterans.

Mindfulness-based interventions (MBIs) have been shown to improve chronic pain and associated conditions like depression, anxiety, and sleep disorders. However, there is limited research on how veterans with chronic pain apply mindfulness skills to manage pain in daily life. This cross-sectional study examined the association between applied mindfulness practice, pain, and several pain-related conditions among 1,737 veterans with chronic pain prior to enrollment in a trial of 2 MBIs. Applied mindfulness practice was assessed using the Applied Mindfulness Process Scale (AMPS). The outcomes included pain interference, pain intensity, pain catastrophizing, fatigue, sleep disturbance, anxiety, depression, post-traumatic stress disorder, physical function, and social participation. Higher overall AMPS scores, as well as the positive and negative emotional regulation subscales of the AMPS, were associated with less pain interference and catastrophizing, as well as better outcomes for all pain-related conditions. The positive emotional regulation subscale had the strongest associations with outcomes. There was no significant association between the AMPS and pain intensity. The results suggest applied mindfulness practice, especially positive emotional regulation, may improve pain and functioning. In addition, the AMPS shows promise as a process measure of mindfulness skills applied in daily life. Additional research is needed to examine different aspects of mindfulness in the context of MBIs. PERSPECTIVE: This article describes the relationship between applied mindfulness practice and pain-related outcomes, prior to a MBI, using a novel measure of mindfulness practice. These findings underscore the importance of measuring applied mindfulness practice prior to and during clinical interventions to treat chronic pain.

Small molecular weight epigenetic inhibitors modulate the extracellular matrix during pancreatic acinar ductal metaplasia.

The pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment is distinguished by a high degree of fibrosis and inflammation, known as desmoplasia. Desmoplasia increases the stromal deposition and extracellular matrix (ECM) stiffness observed in the tumor microenvironment, contributing to the dampened penetration of pharmacological agents. The molecular and biophysical composition of the ECM during the earliest cellular changes in the development of PDAC, i.e. acinar ductal metaplasia (ADM), has not been extensively explored. We report that the mRNA expression of key protein components of the ECM increases during ADM in p48Cre/+;LSL-KrasG12D (KC) mouse acinar organoids cultured in Matrigel. Treatment of the organoids with small molecular weight epigenetic modulating compounds that inhibit or reverse ADM (largazole, FK228 and chaetocin) dramatically reduced the tissue mRNA expression of collagens, hyaluronan synthase, laminin and fibronectin. The storage moduli, determined by video tracking of fluorescent nanoparticles embedded into the Matrigel, increased during ADM and was reduced following treatment with the epigenetic modulating compounds. We report that the ECM of mouse organoids stiffens during ADM and is further enhanced by the presence of mutant Kras. Moreover, select HDAC and HMT inhibitors reduced the mRNA expression of ECM components and ECM stiffness during inhibition and reversal of ADM, suggesting that these compounds may be useful as adjuvants to enhance the tumor penetration of agents used to treat PDAC.

Barriers and Facilitators to Integrating Acupuncture into the U.S. Health Care System: A Scoping Review.

Background: Acupuncture is a widely practiced complementary and integrative health modality that has multiple clinical applications. The use of acupuncture in the United States is rapidly increasing. Although studies have shown the efficacy and effectiveness of acupuncture for various ailments, the integration of acupuncture into the U.S. health care system remains a challenge. Little is known about the factors affecting this integration. Objective: To provide a systematic review of the barriers and facilitators affecting the integration of acupuncture into the U.S. health care system. Methods: Four electronic databases were searched. Three independent reviewers were involved in the screening and data charting processes. Findings were synthesized and categorized into four levels based on the Social Ecological Model. Results: A total of 22 studies were included in the final review. The barriers and facilitators affecting the integration of acupuncture were mapped into four levels (individual, interpersonal, organizational, and policy). The most frequently reported barriers and facilitators were mapped into the Social Ecological Model constructs within the "Individual" level (i.e., beliefs and attitudes of acupuncture, and practical issues) and the "Organizational" level (i.e., credentialing, space and facility, referral system). Conclusion: This review has identified and synthesized the breadth of evidence on the barriers and facilitators to the integration of acupuncture into the U.S. health care system. Results of this review will guide future implementation studies to develop and test implementation strategies to integrate acupuncture into the U.S. health care system.

Financial hardship after COVID-19 infection among US Veterans: a national prospective cohort study.

BACKGROUND: Research suggests an association between COVID-19 infection and certain financial hardships in the shorter term and among single-state and privately insured samples. Whether COVID-19 is associated with financial hardship in the longer-term or among socially vulnerable populations is unknown. Therefore, we examined whether COVID-19 was associated with a range of financial hardships 18 months after initial infection among a national cohort of Veterans enrolled in the Veterans Health Administration (VHA)-the largest national integrated health system in the US. We additionally explored the association between Veteran characteristics and financial hardship during the pandemic, irrespective of COVID-19. METHODS: We conducted a prospective, telephone-based survey. Out of 600 Veterans with COVID-19 from October 2020 through April 2021 who were invited to participate, 194 Veterans with COVID-19 and 194 matched comparators without a history of infection participated. Financial hardship outcomes included overall health-related financial strain, two behavioral financial hardships (e.g., taking less medication than prescribed due to cost), and seven material financial hardships (e.g., using up most or all savings). Weighted generalized estimating equations were used to estimate risk ratios (RR) and 95% confidence intervals (CI) of financial hardship by COVID-19 status, and to assess the relationship between infection and Veteran age, VHA copay status, and comorbidity score, irrespective of COVID-19 status. RESULTS: Among 388 respondents, 67% reported at least one type of financial hardship since March 2020, with 21% reporting behavioral hardships and 64% material hardships; 8% reported severe-to-extreme health-related financial strain. Compared with uninfected matched comparators, Veterans with a history of COVID-19 had greater risks of severe-to-extreme health-related financial strain (RR: 4.0, CI: 1.4-11.2), taking less medication due to cost (RR: 2.9, 95% CI: 1.0-8.6), and having a loved one take time off work to care for them (RR: 1.9, CI: 1.1-3.6). Irrespective of COVID-19 status, Veterans aged < 65 years had a greater risk of most financial hardships compared with Veterans aged ≥ 65 years. CONCLUSIONS: Health-related financial hardships such as taking less medication due to cost and severe-to-extreme health-related financial strain were more common among Veterans with a history of COVID-19 than among matched comparators. Strategies are needed to address health-related financial hardship after COVID-19. TRIAL REGISTRATION: NCT05394025, registered 05-27-2022.

Host ecotype and rearing environment are the main drivers of threespine stickleback gut microbiota diversity in a naturalistic experiment.

Host-microbiota interactions play a critical role in the hosts' biology, and thus, it is crucial to elucidate the mechanisms that shape gut microbial communities. We leveraged threespine stickleback fish (Gasterosteus aculeatus) as a model system to investigate the contribution of host and environmental factors to gut microbiota variation. These fish offer a unique opportunity for experiments in naturalistic conditions; we reared benthic and limnetic ecotypes from three different lakes in experimental ponds, allowing us to assess the relative effects of shared environment (pond), geographic origin (lake-of-origin), trophic ecology and genetics (ecotype) and biological sex on gut microbiota α- and ß-diversity. Host ecotype had the strongest influence on α-diversity, with benthic fish exhibiting higher diversity than limnetic fish, followed by the rearing environment. ß-diversity was primarily shaped by rearing environment, followed by host ecotype, indicating that environmental factors play a crucial role in determining gut microbiota composition. Furthermore, numerous bacterial orders were differentially abundant across ponds, underlining the substantial contribution of environmental factors to gut microbiota variation. Our study illustrates the complex interplay between environmental and host ecological or genetic factors in shaping the stickleback gut microbiota and highlights the value of experiments conducted under naturalistic conditions for understanding gut microbiota dynamics.

Childhood eczema prevalence in New Zealand using topical corticosteroid dispensing data.

OBJECTIVES: To determine the prevalence of eczema among children in New Zealand. METHODS: Population-based retrospective observational study utilising national pharmaceutical dispensing records for topical corticosteroids and emollients for all New Zealand children aged 0-14 years from 1st January 2006 to 31st December 2019. Data are reported using descriptive statistics, with comparisons between ethnicities and socioeconomic quintiles undertaken with rate ratios. RESULTS: Based on dispensing data, the prevalence of eczema for New Zealand children aged 0-14 years in 2018 was 14.0% (95% CI 14.0%-14.1%), with prevalence decreasing in older age groups (children aged <1 year 26.0% (25.6%-26.4%); children aged 10-14 years 8.8% (8.7%-8.9%)). Prevalence was higher in Pacific children (23.6% (23.3%-24.0%)), but slightly lower in Maori children (13.2% (13.0%-13.3%)). CONCLUSION: Eczema is a common condition affecting a considerable proportion of children in New Zealand. This study provides nationwide paediatric prevalence data for New Zealand, and highlights the increased burden of eczema in Pacific children. Inequity in dispensing of topical corticosteroids is postulated to explain the reduced rates found for Maori children compared to previous studies. These results support the need for further research to determine factors contributing to differing eczema prevalence rates in New Zealand.

Email recruitment for chronic pain clinical trials: results from the LAMP trial.

BACKGROUND: Recruitment for clinical trials and large-scale studies is challenging, especially for patients with complex conditions like chronic pain. Email recruitment has the potential to increase efficiency, to reduce costs, and to improve access for underrepresented patient populations. The objective of this study was to examine the effectiveness, efficiency, and equitability of email versus postal mail recruitment for the Learning to Apply Mindfulness to Pain (LAMP) study, a three-site clinical trial of mindfulness-based interventions for chronic pain. METHODS: Patients with chronic pain diagnoses were recruited from three United States Department of Veterans Affairs (VA) facilities using the VA electronic health record (EHR). Recruitment materials were sent using either postal mail (n = 7986) or email (n = 19,333). Patients in the email recruitment group were also mailed introductory postcards before any emails. Mailing addresses and email addresses were obtained from the EHR. Effectiveness was measured by the response rate of patients who logged into the secure LAMP study website. Efficiency was measured by the number of days from when the recruitment materials were sent to when patients logged into the LAMP portal as well as the estimated costs of each recruitment approach. To assess equitability, we examined whether email recruitment was less effective for underrepresented populations, based on demographic information from the EHR. RESULTS: Effectiveness-unadjusted response rates were greater for email versus postal-mail recruitment (18.9% versus 6.3%), and adjusted response rates were over three times greater for email recruitment (RR = 3.5, 95% CI 3.1-3.8) based on a multivariable analysis controlling for age, gender, race, ethnicity, rurality, and site. Efficiency-email recruitment had a significantly lower mean response time (1 day versus 8 days) and a lower cost. Equity-email recruitment led to higher response rates for all subpopulations, including older, non-White, Hispanic, rural, and female Veterans. CONCLUSIONS: Email recruitment is an effective, efficient, and equitable way to recruit VA patients to large-scale, chronic pain clinical trials. TRIAL REGISTRATION: Clinical Trial Registration Number: NCT04526158. Patient enrollment began on December 4, 2020.

Prevalence of Anxiety and Depression among PCOS Patients Seen in a Tertiary Government Hospital Using the Hospital Anxiety and Depression Scale - English/Pilipino Version (HADS/HADS-P).

Background: PCOS is a common gynecologic disorder and recent studies have found that they are more prone in developing depression and anxiety compared to the general population. The Hospital Anxiety and Depression Scale (HADS) is a popular and simple self-administered instrument reliable for detecting states of anxiety and depression. Using this simple screening tool, it may lead to the identification of such mental disorders that may warrant timely psychiatric referral. Objectives: The study aims to determine the prevalence of anxiety and depression among PCOS patients using the HADS-P questionnaire and to determine the association between depression and anxiety and disease characteristics. Methods: Convenience sampling was done to recruit PCOS patients >18 years old in Philippine General Hospital. Cross-sectional design was used for the prevalence of depression and anxiety, while nested case control design for the evaluation of the predictors of depression and anxiety. The HADS-P, a self-administered rating scale with independent subscales for anxiety and depression, was administered to the participants after securing consent. A cut-off score of >8 points on either of the depression and anxiety subscale was used to determine their respective prevalence. Logistic regression analysis was used to determine the association of clinical variables with anxiety or depression. Results: A total of 253 patients with PCOS were recruited. On the basis of a HADS-P score of >8.0 per category, the prevalence of PCOS patients who were suggestive to have anxiety was 46.25% (n: 117, 95% CI: 39.98-52.60%), while 9.09% (n: 23, 95% CI: 5.85-13.33%) of them were suggestive to have depression. Crude logistic regression identified presence of depression, infertility, impaired glucose tolerance, and prominent acne as predictors of anxiety; whereas low parity, hirsutism, and presence of anxiety were predictors of depression. Adjusted logistic regression identified only presence of depression and infertility were significant predictors of anxiety (n: 116, LR χ2 (5): 15.46, p<0.01); while presence of anxiety increased the odds of depression by 2- to 13-fold, it was not statistically significant (n: 116, LR χ2 (5): 9.79, p: 0.08). Conclusion: There is a high prevalence of anxiety and depression among PCOS patients. The factors that were seen to be significantly associated with the development of anxiety were the presence of depression, impaired glucose tolerance, infertility and prominent acne, while for the development of depression were the presence of anxiety, hirsutism, and low parity. Screening for anxiety and depression is of paramount importance and physicians should be vigilant for the need of possible psychiatric intervention.

Serologic extracellular matrix remodeling markers are related to fibrosis stage and prognosis in a phase 2b trial of simtuzumab in patients with primary sclerosing cholangitis.

BACKGROUND: Novel noninvasive predictors of disease severity and prognosis in primary sclerosing cholangitis (PSC) are needed. This study evaluated the ability of extracellular matrix remodeling markers to diagnose fibrosis stage and predict PSC-related fibrosis progression and clinical events. METHODS: Liver histology and serum markers of collagen formation (propeptide of type III collagen [Pro-C3], propeptide of type IV collagen, propeptide of type V collagen), collagen degradation (type III collagen matrix metalloproteinase degradation product and type IV collagen matrix metalloproteinase degradation product), and fibrosis (enhanced liver fibrosis [ELF] score and its components [metalloproteinase-1, type III procollagen, hyaluronic acid]) were assessed in samples from baseline to week 96 in patients with PSC enrolled in a study evaluating simtuzumab (NCT01672853). Diagnostic performance for advanced fibrosis (Ishak stages 3-6) and cirrhosis (Ishak stages 5-6) was evaluated by logistic regression and AUROC. Prognostic performance for PSC-related clinical events and fibrosis progression was assessed by AUROC and Wilcoxon rank-sum test. RESULTS: Among 234 patients, 51% had advanced fibrosis and 11% had cirrhosis at baseline. Baseline Pro-C3 and ELF score and its components provided moderate diagnostic ability for discrimination of advanced fibrosis (AUROC 0.73-0.78) and cirrhosis (AUROC 0.73-0.81). Baseline Pro-C3, ELF score, and type III procollagen provided a moderate prognosis for PSC-related clinical events (AUROC 0.70-0.71). Among patients without cirrhosis at baseline, median changes in Pro-C3 and ELF score to week 96 were higher in those with than without progression to cirrhosis (both p < 0.001). CONCLUSIONS: Pro-C3 correlated with fibrosis stage, and Pro-C3 and ELF score provided discrimination of advanced fibrosis and cirrhosis and predicted PSC-related events and fibrosis progression. The results support the clinical utility of Pro-C3 and ELF score for staging and as prognostic markers in PSC.

Intensity, Characteristics, and Factors Associated With Receipt of Care Coordination Among High-Risk Veterans in the Veterans Health Administration.

BACKGROUND: The Veterans Health Administration (VHA) has initiatives underway to enhance the provision of care coordination (CC), particularly among high-risk Veterans. Yet, evidence detailing the characteristics of and who receives VHA CC is limited. OBJECTIVES: We examined intensity, timing, setting, and factors associated with VHA CC among high-risk Veterans. RESEARCH DESIGN: We conducted a retrospective observational cohort study, following Veterans for 1 year after being identified as high-risk for hospitalization or mortality, to characterize their CC. Demographic and clinical factors predictive of CC were identified via multivariate logistic regression. SUBJECTS: A total of 1,843,272 VHA-enrolled high-risk Veterans in fiscal years 2019-2021. MEASURES: We measured 5 CC variables during the year after Veterans were identified as high risk: (1) receipt of any service, (2) number of services received, (3) number of days to first service, (4) number of days between services, and (5) type of visit during which services were received. RESULTS: Overall, 31% of high-risk Veterans in the sample received CC during one-year follow-up. Among Veterans who received ≥1 service, a median of 2 [IQR (1, 6)] services were received. Among Veterans who received ≥2 services, there was a median of 26 [IQR (10, 57)] days between services. Most services were received during outpatient psychiatry (46%) or medicine (16%) visits. Veterans' sociodemographic and clinical characteristics were associated with receipt of CC. CONCLUSIONS: A minority of Veterans received CC in the year after being identified as high-risk, and there was variation in intensity, timing, and setting of CC. Research is needed to examine the fit between Veterans' CC needs and preferences and VHA CC delivery.

Medication Engagement, Determinants of Health, and A1C Levels Among Adults With Type 2 Diabetes within a Tribal Health System.

PURPOSE: The purpose of this study was to examine the association between determinants of health, medication engagement, and A1C levels in adults with type 2 diabetes (T2DM) receiving Tribal health and pharmacy services. METHODS: A retrospective analysis of 2020-2021 electronic health record data was conducted and included adult patients with T2DM using Choctaw Nation Health Services Authority prescribed ≥1 noninsulin glucose-lowering medication in 2020, had ≥1 A1C value in 2020 and 2021, and had a valid zip code in 2021. Patients receiving both insulin and other noninsulin glucose-lowering medication were included. The proportion of days covered (PDC) was used to calculate medication engagement. Statistical analyses included bivariate analysis and linear regression. RESULTS: There were 3787 patients included in the analyses; 62.5% were considered engaged (PDC ≥ 0.8). The mean 2020 A1C level was 8.0 (64 mmol/mol) ± 1.8; 33% had an A1C of <7%, 42% had an A1C of 7% to 9%, and 25% had an A1C >9%. The mean A1C in 2021 was 7.9 (63 mmol/mol) ± 1.7; 34% had an A1C of <7%, 44% had an A1C of 7% to 9%, and 22% had an A1C >9%. Older age was weakly correlated with higher engagement; higher engagement was associated with lower A1C levels while adjusting for covariates. CONCLUSIONS: Medication engagement was associated with lower A1C levels, and older age was weakly associated with higher engagement to noninsulin glucose-lowering medications, consistent with previous literature. No determinants of health were significantly associated with A1C levels while adjusting for covariates.

The genetic basis of divergent melanic pigmentation in benthic and limnetic threespine stickleback.

Pigmentation is an excellent trait to examine patterns of evolutionary change because it is often under natural selection. Benthic and limnetic threespine stickleback (Gasterosteus aculeatus) exhibit distinct pigmentation phenotypes, likely an adaptation to occupation of divergent niches. The genetic architecture of pigmentation in vertebrates appears to be complex. Prior QTL mapping of threespine stickleback pigmentation phenotypes has identified several candidate loci. However-relative to other morphological phenotypes (e.g., spines or lateral plates)-the genetic architecture of threespine stickleback pigmentation remains understudied. Here, we performed QTL mapping for two melanic pigmentation traits (melanophore density and lateral barring) using benthic-limnetic F2 crosses. The two traits mapped to different chromosomes, suggesting a distinct genetic basis. The resulting QTLs were additive, but explained a relatively small fraction of the total variance (~6%). QTLs maps differed by F1 family, suggesting variation in genetic architecture or ability to detect loci of small effect. Functional analysis identified enriched pathways for candidate loci. Several of the resulting candidate loci for pigmentation, including three loci in enriched pathways (bco1, sulf1, and tyms) have been previously indicated to affect pigmentation in other vertebrates. These findings add to a growing body of evidence suggesting pigmentation is often polygenic.

Pneumomediastinum and pneumothorax in coronavirus disease-2019: Description of a case series and a matched cohort study.

Objective: To describe the characteristics of COVID-19 patients with pneumothorax and pneumomediastinum (PTX/PM) and their association with patient outcomes. Patients and methods: Adults admitted to five Mayo Clinic hospitals with COVID-19 between 03/2020-01/2022 were evaluated. PTX/PM was defined by imaging. Descriptive analyses and a matched (age, sex, admission month, COVID-19 severity) cohort comparison was performed. Hospital mortality, length of stay (LOS), and predisposing factors were assessed. Results: Among 6663 patients, 197 had PTX/PM (3 %) (75 PM, 40 PTX, 82 both). The median age was 59, with 71 % males. Exposure to invasive and non-invasive mechanical ventilation and high-flow nasal cannula before PTX/PM were 42 %, 17 %, and 20 %, respectively. Among isolated PTX and PM/PTX patients 70 % and 53.7 % underwent an intervention, respectively, while 96 % of the PM-only group was followed conservatively.A total of 171 patients with PTX/PM were compared to 171 matched controls. PTX/PM patients had more underlying lung disease (40.9 vs. 23.4 %, p < 0.001) and lower median body mass index (BMI) (29.5 vs. 31.3 kg/m2, p = .007) than controls. Among patients with available data, PTX/PM patients had higher median positive end-expiratory and plateau pressures than controls; however, differences were not significant (10 vs. 8 cmH2O; p = 0.38 and 28 vs. 22 cmH2O; p = 0.11, respectively). PTX/PM patients had a higher odds of mortality (adjusted odds ratio [95%CI]: 3.37 [1.61-7.07]) and longer mean LOS (percent change [95%CI]: 39 [9-77]) than controls. Conclusion: In COVID-19 patients with similar severity, PTX/PM patients had more underlying lung disease and lower BMI. They had significantly increased mortality and LOS.

The Ambiguous Cue Task: Measurement reliability of an experimental paradigm for the assessment of interpretation bias and associations with mental health.

Interpretation biases in the processing of ambiguous affective information are assumed to play an important role in the onset and maintenance of emotional disorders. Reports of low reliability for experimental measures of cognitive biases have called into question previous findings on the association of these measures with markers of mental health and demonstrated the need to systematically evaluate measurement reliability for measures of cognitive biases. We evaluated reliability and correlations with self-report measures of mental health for interpretation bias scores derived from the Ambiguous Cue Task (ACT), an experimental paradigm for the assessment of approach-avoidance behavior towards ambiguous affective stimuli. For a non-clinical sample, the measurement of an interpretation bias with the ACT showed high internal consistency (rSB = .91 - .96, N = 354) and acceptable 2-week test-retest correlations (rPearson = .61 - .65, n = 109). Correlations between the ACT interpretation bias scores and mental health-related self-report measures of personality and well-being were generally small (r ≤ |.11|) and statistically not significant when correcting for multiple comparisons. These findings suggest that in non-clinical populations, individual differences in the interpretation of ambiguous affective information as assessed with the ACT do not show a clear association with self-report markers of mental health. However, in allowing for a highly reliable measurement of interpretation bias, the ACT provides a valuable tool for studies considering potentially small effect sizes in non-clinical populations by studying bigger samples as well as for work on clinical populations, for which potentially greater effects can be expected.

Cluster analysis of blood biomarkers to identify molecular patterns in pulmonary fibrosis: assessment of a multicentre, prospective, observational cohort with independent validation.

BACKGROUND: Pulmonary fibrosis results from alveolar injury, leading to extracellular matrix remodelling and impaired lung function. This study aimed to classify patients with pulmonary fibrosis according to blood biomarkers to differentiate distinct disease patterns, known as endotypes. METHODS: In this cluster analysis, we first classified patients from the PROFILE study, a multicentre, prospective, observational cohort of individuals with incident idiopathic pulmonary fibrosis or non-specific interstitial pneumonia in the UK (Nottingham University Hospitals, Nottingham; and Royal Brompton Hospital, London). 13 blood biomarkers representing extracellular matrix remodelling, epithelial stress, and thrombosis were measured by ELISA in the PROFILE study. We classified patients by unsupervised consensus clustering. To evaluate generalisability, a machine learning classifier trained on biomarker signatures derived from consensus clustering was applied to a replication dataset from the Australian Idiopathic Pulmonary Fibrosis Registry (AIPFR). Biomarker associations with mortality and change in percentage of predicted forced vital capacity (FVC%) were assessed, adjusting for age, gender, baseline FVC%, and antifibrotic treatment and steroid treatment before and after baseline. Mortality risk associated with the clusters in the PROFILE cohort was evaluated with Cox proportional hazards models, and mixed-effects models were used to analyse how clustering was associated with longitudinal FVC% in the PROFILE and AIPFR cohorts. FINDINGS: 455 of 580 participants from the PROFILE study (348 [76%] men and 107 [24%] women; mean age 72·4 years [SD 8·3]) were included in the analysis. Within this group, three clusters were identified based on blood biomarkers. A basement membrane collagen (BM) cluster (n=248 [55%]) showed high concentrations of PRO-C4, PRO-C28, C3M, and C6M, whereas an epithelial injury (EI) cluster (n=109 [24%]) showed high concentrations of MMP-7, SP-D, CYFRA211, CA19-9, and CA-125. The third cluster (crosslinked fibrin [XF] cluster; n=98 [22%]) had high concentrations of X-FIB. In the replication dataset (117 of 833 patients from AIPFR; 87 [74%] men and 30 [26%] women; mean age 72·9 years [SD 7·9]), we identified the same three clusters (BM cluster, n=93 [79%]; EI cluster, n=8 [7%]; XF cluster, n=16 [14%]). These clusters showed similarities with clusters in the PROFILE dataset regarding blood biomarkers and phenotypic signatures. In the PROFILE dataset, the EI and XF clusters were associated with increased mortality risk compared with the BM cluster (EI vs BM: adjusted hazard ratio [HR] 1·88 [95% CI 1·42-2·49], p<0·0001; XF vs BM: adjusted HR 1·53 [1·13-2·06], p=0·0058). The EI cluster showed the greatest annual FVC% decline, followed by the BM and XF clusters. A similar FVC% decline pattern was observed in these clusters in the AIPFR replication dataset. INTERPRETATION: Blood biomarker clustering in pulmonary fibrosis identified three distinct blood biomarker signatures associated with lung function and prognosis, suggesting unique pulmonary fibrosis biomarker patterns. These findings support the presence of pulmonary fibrosis endotypes with the potential to guide targeted therapy development. FUNDING: None.

John Henryism-racial stressors among older black men with low back pain.

The relationship between adaptive pain-coping skills, such as John Henryism, and pain and function remains unclear in non-Hispanic Black populations. This cross-sectional, observational study included sixty older Black men with low back pain in Jacksonville, Florida. Key measures were: self-reported 0-10 pain intensity in the past 24 h, 13-item pain catastrophizing, functional performance from the Back Performance Scale, and the John Henryism Active Coping Scale. Structural equation modeling was applied to 57 complete cases for analysis using R v4.2.0. There was a significant association for both John Henryism (ß = -0.320, p = .038) and pain catastrophizing (ß = 0.388, p = .007) with pain intensity but not functional performance (ß = -0.095, p = .552; ß = 0.274, p = .068, respectively) in the older Black men. The study underscores the future importance of evaluating John Henryism using longitudinal methods to explore causality with complex structural equation models among Black Americans.

Prenatal AAV9-GFP administration in fetal lambs results in transduction of female germ cells and maternal exposure to virus.

Prenatal somatic cell gene therapy (PSCGT) could potentially treat severe, early-onset genetic disorders such as spinal muscular atrophy (SMA) or muscular dystrophy. Given the approval of adeno-associated virus serotype 9 (AAV9) vectors in infants with SMA by the U.S. Food and Drug Administration, we tested the safety and biodistribution of AAV9-GFP (clinical-grade and dose) in fetal lambs to understand safety and efficacy after umbilical vein or intracranial injection on embryonic day 75 (E75) . Umbilical vein injection led to widespread biodistribution of vector genomes in all examined lamb tissues and in maternal uteruses at harvest (E96 or E140; term = E150). There was robust GFP expression in brain, spinal cord, dorsal root ganglia (DRGs), without DRG toxicity and excellent transduction of diaphragm and quadriceps muscles. However, we found evidence of systemic toxicity (fetal growth restriction) and maternal exposure to the viral vector (transient elevation of total bilirubin and a trend toward elevation in anti-AAV9 antibodies). There were no antibodies against GFP in ewes or lambs. Analysis of fetal gonads demonstrated GFP expression in female (but not male) germ cells, with low levels of integration-specific reads, without integration in select proto-oncogenes. These results suggest potential therapeutic benefit of AAV9 PSCGT for neuromuscular disorders, but warrant caution for exposure of female germ cells.