Category: Nevin Manimala

Semin Arthritis Rheum. 2024 May 27;67:152478. doi: 10.1016/j.semarthrit.2024.152478. Online ahead of print.

ABSTRACT

Drug-induced dermatomyositis (DIDM) is a rare and underestimated variant of dermatomyositis (DM) characterized by muscle damage and skin rash and related to certain drug exposure. The spectrum of drugs causing DIDM has evolved over time, originally implicating hydroxyurea, penicillamine, and statins as causative agents. Tumor necrosis factor α inhibitors and immune checkpoint inhibitors have also been associated with such conditions. To bridge the gap between current literature and clinical practice, and therefore guide clinicians, we conducted a comprehensive review of English literature from Pubmed, EMBASE, and MEDLINE. Our analysis included demographic data, clinical features, laboratory findings, therapeutic outcomes, and extant research pertaining to the probable pathogenesis of DIDM induced by various drugs. Furthermore, we categorized the drugs involved in DIDM cases into biologics and traditional agents for subsequent statistical analysis. Over time, there has been a gradual accumulation of reported DIDM cases. A total of 69 published DIDM cases were documented in our study, among which 33 should be attributed to biologics and the remaining 36 to traditional drugs. Interestingly, 41 of all DIDM cases had a previous history of malignancies. Additionally, DIDM cases exhibited similar cutaneous and muscular manifestations to classic DM, with the exception of cases induced by hydroxyurea, which did not entail muscle damage. Positive antinuclear antibodies and anti-TIF1-γ autoantibodies have been predominantly observed in biologics-induced cases, while positive anti-TIF1-γ antibodies were merely reported in the cases that were primarily diagnosed with malignant diseases and exposed to ICIs afterwards. Anti-TIF1-γ antibodies may potentially serve as a red flag in the identification of co-existing malignant diseases in DM patients. We also provided a comprehensive summary and exploration of potential mechanisms lying behind drug-induced dermatomyositis. In conclusion, our review consolidates the current literature on DIDM, highlighting the evolving spectrum of medications and elucidating the differences in clinical manifestations, laboratory findings, and underlying mechanisms.

PMID:38833729 | DOI:10.1016/j.semarthrit.2024.152478

J Am Acad Orthop Surg. 2024 May 29. doi: 10.5435/JAAOS-D-23-00723. Online ahead of print.

ABSTRACT

INTRODUCTION: Hip fractures are life-changing injuries with associated one-year mortality up to 30%. Five locations in the world have been termed “blue zones,” where the longevity of the population is markedly higher than that of surrounding areas and there are 10 times more centenarians. The United States has one blue zone (Loma Linda, California), which is believed to be because of the lifestyle of the Seventh-day Adventist population living there. We hypothesized that patients from the blue zone experience low-energy, frailty-driven, osteoporotic hip fractures later in life and an increased postinjury longevity relative to non-blue zone control subjects.

METHODS: A review of patients treated for hip fracture between January 2010 and August 2020 from a single institution was conducted. Demographic data were collected, and the end point of mortality was assessed using death registry information, queried in April 2024. Groups were divided into blue zone and non-blue zone. Statistical analysis was conducted with P < 0.05 considered significant.

RESULTS: Complete data were available for 1,032 patients. The blue zone cohort sustained low-energy hip fractures 12 years later in life (83.2 versus 71.1, P < 0.01). Propensity score matching was used to account for this difference. After propensity score matching, age, body mass index, American Society of Anesthesiologists score, surgery performed, sex, mechanism, ethnicity, diabetes, chronic obstructive pulmonary disease, CHF, chronic kidney disease grade, dementia, surgical time, and drug/tobacco/marijuana use were similar between groups. Blue zone patients had lower mortality at both 1 and 2 years postoperatively (12% versus 24%, P = 0.03 and 20% versus 33%, P = 0.03, respectively), had more hypertension (76% versus 62%, P = 0.03), reported lower alcohol use (7% versus 20%, P < 0.01), and included more Seventh-day Adventists (64% versus 15%, P < 0.01).

CONCLUSION: The blue zone lifestyle affected the onset of frailty and delayed osteoporotic hip fracture by 12 years in this propensity-matched cohort study. Postoperative mortality was also markedly lower in the blue zone cohort.

PMID:38833726 | DOI:10.5435/JAAOS-D-23-00723

J Med Internet Res. 2024 Jun 4;26:e48092. doi: 10.2196/48092.

ABSTRACT

BACKGROUND: Asynchronous outpatient patient-to-provider communication is expanding in UK health care, requiring evaluation. During the pandemic, Aberdeen Royal Infirmary in Scotland expanded its outpatient asynchronous consultation service from dermatology (deployed in May 2020) to gastroenterology and pain management clinics.

OBJECTIVE: We conducted a mixed methods study using staff, patient, and public perspectives and National Health Service (NHS) numerical data to obtain a rounded picture of innovation as it happened.

METHODS: Focus groups (3 web-based and 1 face-to-face; n=22) assessed public readiness for this service, and 14 interviews with staff focused on service design and delivery. The service’s effects were examined using NHS Grampian service use data, a patient satisfaction survey (n=66), and 6 follow-up patient interviews. Survey responses were descriptively analyzed. Demographics, acceptability, nonattendance rates, and appointment outcomes of users were compared across levels of area deprivation in which they live and medical specialties. Interviews and focus groups underwent theory-informed thematic analysis.

RESULTS: Staff anticipated a simple technical system transfer from dermatology to other receptive medical specialties, but despite a favorable setting and organizational assistance, it was complicated. Key implementation difficulties included pandemic-induced technical integration delays, misalignment with existing administrative processes, and discontinuity in project management. The pain management clinic began asynchronous consultations (digital appointments) in December 2021, followed by the gastroenterology clinic in February 2022. Staff quickly learned how to explain and use this service. It was thought to function better for pain management as it fitted preexisting practices. From May to September 2022, the dermatology (adult and pediatric), gastroenterology, and pain management clinics offered 1709 appointments to a range of patients (n=1417). Digital appointments reduced travel by an estimated 44,712 miles (~71,956.81 km) compared to the face-to-face mode. The deprivation profile of people who chose to use this service closely mirrored that of NHS Grampian’s population overall. There was no evidence that deprivation impacted whether digital appointment users subsequently received treatment. Only 18% (12/66) of survey respondents were unhappy or very unhappy with being offered a digital appointment. The benefits mentioned included better access, convenience, decreased travel and waiting time, information sharing, and clinical flexibility. Overall, patients, the public, and staff recognized its potential as an NHS service but highlighted informed choice and flexibility. Better communication-including the use of the term assessment instead of appointment-may increase patient acceptance.

CONCLUSIONS: Asynchronous pain management and gastroenterology consultations are viable and acceptable. Implementing this service is easiest when existing administrative processes face minimal disruption, although continuous support is needed. This study can inform practical strategies for supporting staff in adopting asynchronous consultations (eg, preparing for nonlinearity and addressing task issues). Patients need clear explanations and access to technical support, along with varied consultation options, to ensure digital inclusion.

PMID:38833695 | DOI:10.2196/48092

Am J Occup Ther. 2024 Jul 1;78(4):7804185080. doi: 10.5014/ajot.2024.050590.

ABSTRACT

IMPORTANCE: Although play and positive caregiving strategies have been associated with child well-being, little is known about the relationship between play type and strategies used by caregivers in early childhood.

OBJECTIVE: To investigate whether a relationship exists between play type and positive caregiving strategies.

DESIGN: Exploratory correlational nonexperimental design.

SETTING: Early childhood center.

PARTICIPANTS: A convenience sample that included 60 observations of 14 caregivers during a therapeutic playgroup with 14 children with and without disabilities ages 15 mo to 3 yr (4 fathers, 3 mothers, 1 nanny, and 6 female early childhood teachers; age range = 30-39 yr). The caregivers were Black (n = 1; 7.1%), Hispanic (n = 5; 35.7%), and White (n = 8; 57.1%).

OUTCOMES AND MEASURES: Positive caregiving strategies were scored using the Parenting Interactions with Children: Checklist of Observations Linked to Outcomes.

RESULTS: Results revealed no significant correlations between play type and positive caregiving strategy. There was a positive, significant correlation between caregiving strategies (affection, responsiveness, encouragement, teaching, and total; rpbs = .767-.970, n = 58, p = .001). The play type and caregiver type variables did not predict total positive caregiving strategies, F(2, 57) = 2.147, p = .126. One variable, caregiver type, added statistical significance to the prediction (p = .045).

CONCLUSIONS AND RELEVANCE: The findings show no relationship between play type and positive caregiving strategy. Consideration of the types of caregivers participating in a therapeutic playgroup and their roles and use of positive strategies during play is worthy of further investigation. Plain-Language Summary: This study explored how parent and teacher caregivers supported children (both with and without disabilities) during a therapeutic playgroup at an early childhood center. Therapeutic playgroups are a special type of group play in which a trained professional helps guide play activities to support participation. The researchers wanted to see whether there was a connection between the type of play the children engaged in and how the adult caregivers interacted with them. The surprising finding was that there was no link between play type and how caregivers interacted. However, the caregivers often used positive strategies with the children, regardless of the play activity. Interestingly, type of caregiver (parent, teacher) seemed to make a slight difference in how they interacted with the children during playtime. Overall, this study suggests that more research is needed to understand how the types of play activities and objects might influence caregiver interactions during group play.

PMID:38833688 | DOI:10.5014/ajot.2024.050590

Eur J Cardiothorac Surg. 2024 Jun 4:ezae229. doi: 10.1093/ejcts/ezae229. Online ahead of print.

ABSTRACT

OBJECTIVES: The causal association between immune cell traits and aortic aneurysm remains unknown.

METHODS: We performed a bidirectional two-sample mendelian randomization analysis to explore the causality between 731 immune cell characteristics and the risk of abdominal aortic aneurysm and thoracic aortic aneurysms through publicly available genetic data, respectively. To examine heterogeneity and horizontal pleiotropy, Cochran’s Q test and MR-Egger intercept were utilized. Additionally, multivariable mendelian randomization analysis and meta-analysis were performed in further analysis.

RESULTS: We found that 20 immune phenotypes had a suggestive causality on abdominal aortic aneurysm and 15 immune phenotypes had a suggestive causal effect on thoracic aortic aneurysm. After further FDR adjustment (q value < 0.1), CD20 on IgD+ CD38- B cell (q = 0.053) and CD127 on CD28+ CD4+ T cell (q = 0.096) were associated with an increased risk of abdominal aortic aneurysm, respectively, indicating a significant causality between them. After adjusting for smoking, there is still statistical significance between CD127 on CD28+ CD4+ T cell and abdominal aortic aneurysm. However, after adjusting for lipids, no statistical significance can be observed between CD127 on CD28+ CD4+ T cells and abdominal aortic aneurysm. Furthermore, there is still statistical significance between CD20 on IgD+ CD38- B cells and abdominal aortic aneurysm after adjusted for lipids and smoking, which further identified by meta-analysis.

CONCLUSIONS: We found a causal association between immune cell traits and aortic aneurysm by genetic methods, thus providing new avenues for future mechanism studies.

PMID:38833686 | DOI:10.1093/ejcts/ezae229

J Clin Oncol. 2024 Jun 4:JCO2302736. doi: 10.1200/JCO.23.02736. Online ahead of print.

ABSTRACT

PURPOSE: Treatment options are limited for patients with previously treated metastatic colorectal cancer (mCRC). In the LEAP-017 study, we evaluate whether lenvatinib in combination with pembrolizumab improves outcomes compared with standard of care (SOC) in previously treated mismatch repair proficient or not microsatellite instability high (pMMR or not MSI-H) mCRC.

METHODS: In this international, multicenter, randomized, controlled, open-label, phase III study, eligible patients age 18 years and older with unresectable, pMMR or not MSI-H mCRC, that had progressed on or after, or could not tolerate, standard treatment, were randomly assigned 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 400 mg intravenously once every 6 weeks or investigator’s choice of regorafenib or trifluridine/tipiracil (SOC). Randomization was stratified by presence or absence of liver metastases. The primary end point was overall survival (OS). LEAP-017 is registered at ClinicalTrials.gov (NCT04776148), and has completed recruitment.

RESULTS: Between April 8, 2021, and December 21, 2021, 480 patients were randomly assigned to lenvatinib plus pembrolizumab (n = 241) or SOC (n = 239). At final analysis (median follow-up of 18.6 months [IQR, 3.9]), median OS with lenvatinib plus pembrolizumab versus SOC was 9.8 versus 9.3 months (hazard ratio [HR], 0.83 [95% CI, 0.68 to 1.02]; P = .0379; prespecified threshold P = .0214). Grade ≥3 treatment-related adverse events occurred in 58.4% (lenvatinib plus pembrolizumab) versus 42.1% (SOC) of patients. Two participants died due to treatment-related adverse events, both in the lenvatinib plus pembrolizumab arm.

CONCLUSION: In patients with pMMR or not MSI-H mCRC that had progressed on previous therapy, there was no statistically significant improvement in OS after lenvatinib plus pembrolizumab treatment versus SOC. No new safety signals were observed.

PMID:38833658 | DOI:10.1200/JCO.23.02736

Neurology. 2024 Jul 9;103(1):e209397. doi: 10.1212/WNL.0000000000209397. Epub 2024 Jun 4.

ABSTRACT

BACKGROUND AND OBJECTIVES: Individuals with epilepsy have increased risk of suicidal ideation (SI) and behaviors when compared with the general population. This relationship has remained largely unexplored in adolescents. We investigated the prevalence of suicidality in adolescents with newly diagnosed focal epilepsy within 4 months of treatment initiation and over the following 36 months.

METHODS: This was a post hoc analysis of the enrollment and follow-up data from the Human Epilepsy Project, an international, multi-institutional study that enrolled participants between 2012 and 2017. Participants enrolled were 11-17 years of age within 4 months of treatment initiation for focal epilepsy. We used data from the Columbia Suicide Severity Rating Scale (C-SSRS), administered at enrollment and over the 36-month follow-up period, along with data from medical records.

RESULTS: A total of 66 adolescent participants were enrolled and completed the C-SSRS. At enrollment, 14 (21%) had any lifetime SI and 5 (8%) had any lifetime suicidal behaviors (SBs). Over the following 36 months, 6 adolescents reported new onset SI and 5 adolescents reported new onset SB. Thus, the lifetime prevalence of SI within this population increased from 21% to 30% (14-20 adolescents), and the lifetime prevalence of SB increased from 8% to 15% (5-10).

DISCUSSION: The prevalence of suicidality in adolescents with newly diagnosed focal epilepsy reported in our study is consistent with previous findings of significant suicidality observed in epilepsy. We identify adolescents as an at-risk population at the time of epilepsy diagnosis and in the following years.

PMID:38833656 | DOI:10.1212/WNL.0000000000209397

Neurology. 2024 Jul 9;103(1):e209533. doi: 10.1212/WNL.0000000000209533. Epub 2024 Jun 4.

ABSTRACT

BACKGROUND AND OBJECTIVES: Pivotal trials for neurologic drugs in clinical development are often initiated without a phase 2 trial (“bypass”) or despite a negative phase 2 efficacy result (“override”). Such practices may degrade the risk/benefit ratio of phase 3 trials. The aim of this study is to estimate the proportion of phase 3 trials for 10 neurologic diseases started without a positive phase 2 trial, to identify factors associated with this practice, and to investigate any association with unfavorable phase 3 trial outcomes.

METHODS: We searched ClinicalTrials.gov for phase 3 trials completed during 2011-2021, with at least 1 research site in the United States, Canada, the European Union, the United Kingdom, or Australia, and investigating drugs or biologics for treatment of 10 neurologic conditions. Our primary objective was to assess the prevalence of phase 2 bypass/override by searching for preceding phase 2 trials. We used Fisher exact tests to determine whether phase 3 trial characteristics and trial results were associated with phase 2 bypass/override.

RESULTS: Of the 1,188 phase 3 trials captured in our search, 113 met eligibility for inclusion. Of these, 46% were not preceded by a phase 2 trial that was positive on an efficacy endpoint (31% bypassed and 15% overrode phase 2 trial). Phase 2 bypass/override was not associated with industry funding (77% vs 89%, 95% CI 0.75-7.55, p = 0.13) or testing already approved interventions (23% vs 15%, 95% CI 0.60-5.14, p = 0.33). Overall, phase 3 trials based on phase 2 bypassed/override were statistically significantly less likely to be positive on their primary outcome (31% vs 57%, respectively, 95% CI 1.21-6.92, p = 0.01). This effect disappeared when indications characterized by nearly universal positive or negative results were excluded. Trials that bypassed/overrode phase 2 trials were not statistically significantly more likely to be terminated early because of safety or futility (29% vs 15%, respectively, 95% CI 0.15-1.18, p = 0.11) and did not show increased risk of adverse events in experimental arms (RR = 1.46, 95% CI 1.19-1.79, vs RR = 1.36, 95% CI 1.10-1.69, respectively, p = 0.65).

DISCUSSION: Almost half of the neurologic disease phase 3 trials were initiated without the support of a positive phase 2 trial. Although our analysis does not establish harm with bypass/override, its prevalence and the scientific rationale for phase 2 trial testing favor development of criteria defining when phase 2 bypass/override is justified.

PMID:38833654 | DOI:10.1212/WNL.0000000000209533

J Clin Oncol. 2024 Jun 4:JCO2302344. doi: 10.1200/JCO.23.02344. Online ahead of print.

ABSTRACT

PURPOSE: Phosphatidylinositol 3-kinase/AKT-serine threonine kinase/mammalian target of rapamycin (mTOR) pathway abnormalities contribute to endocrine resistance. Everolimus, an mTOR inhibitor, improved progression-free survival in hormone receptor-positive metastatic breast cancer (BC) when combined with endocrine therapy (ET). In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC after adjuvant/neoadjuvant chemotherapy.

METHODS: Patients were randomly assigned 1:1 to physician’s choice ET and 1 year of everolimus (10 mg orally once daily) or placebo stratified by risk group. The primary end point was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test with the hazard ratio (HR) estimated by Cox regression. Subset analyses included preplanned evaluation by risk group and exploratory analyses by menopausal status and age. Secondary end points included overall survival (OS) and safety. Everolimus did not improve IDFS/OS when added to ET in patients with early-stage high-risk, hormone receptor-positive BC.

RESULTS: One thousand and nine hundred thirty-nine patients were randomly assigned with 1,792 eligible for analysis. Overall, no benefit of everolimus was seen for IDFS (HR, 0.94 [95% CI, 0.77 to 1.14]) or OS (HR, 0.97 [95% CI, 0.75 to 1.26]). The assumption of proportional hazards was not met suggesting significant variability in the HR over time since the start of treatment. In an unplanned subgroup analysis among postmenopausal patients (N = 1,221), no difference in IDFS (HR, 1.08 [95% CI, 0.86 to 1.36]) or OS (HR, 1.19 [95% CI, 0.89 to 1.60]) was seen. In premenopausal patients (N = 571), everolimus improved both IDFS (HR, 0.64 [95% CI, 0.44 to 0.94]) and OS (HR, 0.49 [95% CI, 0.28 to 0.86]). Treatment completion rates were lower in the everolimus arm compared with placebo (48% v 73%) with higher grade 3 and 4 adverse events (35% v 7%).

CONCLUSION: One year of adjuvant everolimus + ET did not improve overall outcomes. Subset analysis suggests mTOR inhibition as a possible target for patients who remain premenopausal after chemotherapy.

PMID:38833643 | DOI:10.1200/JCO.23.02344

Cardiovasc Res. 2024 Jun 4:cvae123. doi: 10.1093/cvr/cvae123. Online ahead of print.

ABSTRACT

AIMS: Evaluate sex differences in cardiovascular disease (CVD) risk prediction, including use of i) optimal sex-specific risk predictors and ii) sex-specific risk thresholds.

METHODS AND RESULTS: Prospective cohort study using UK Biobank, including 121,724 and 182,632 healthy men and women, respectively, aged 38-73 years at baseline. There were 11,899 (men) and 9,110 (women) incident CVD cases (hospitalization or mortality) with median 12.1 years follow-up. We used recalibrated Pooled Cohort Equations (PCE, 7.5% 10-year risk threshold as per US guidelines), QRISK3 (10% 10-year risk threshold as per UK guidelines) and Cox survival models using sparse sex-specific variable sets (via LASSO stability selection) to predict CVD risk separately in men and women. LASSO stability selection included 12 variables in common between men and women, with three additional variables selected for men and one for women. C-statistics were slightly lower for PCE than QRISK3 and models using stably-selected variables, but were similar between men and women: 0.67 [0.66-0.68], 0.70 [0.69-0.71], and 0.71 [0.70-0.72] in men and 0.69 [0.68-0.70], 0.72 [0.71-0.73], and 0.72 [0.71-0.73] in women for PCE, QRISK3 and models using stably-selected variables, respectively. At current clinically implemented risk thresholds, test sensitivity was markedly lower in women than men for all models: at 7.5% 10-year risk, sensitivity was 65.1% and 68.2% in men and 24.0% and 33.4% in women for PCE and models using stably-selected variables, respectively; at 10% 10-year risk, sensitivity was 53.7% and 52.3% in men and 16.8% and 20.2% in women for QRISK3 and models using stably-selected variables, respectively. Specificity was correspondingly higher in women than men. However, the sensitivity in women at 5% 10-year risk threshold increased to 50.1%, 58.5% and 55.7% for PCE, QRISK3 and models using stably-selected variables, respectively.

CONCLUSIONS: Use of sparse sex-specific variables improved CVD risk prediction compared with PCE but not QRISK3. At current risk thresholds, PCE and QRISK3 work less well for women than men but sensitivity was improved in women using a 5% 10-year risk threshold. Use of sex-specific risk thresholds should be considered in any re-evaluation of CVD risk calculators.

TRANSLATIONAL PERSPECTIVE: Cardiovascular disease (CVD) risk prediction is an important component of clinical risk management and disease prevention. We find that at risk prediction thresholds used by currently applied risk prediction algorithms (PCE 7.5% 10-year risk threshold in the US and QRISK3 10% risk threshold in the UK), sensitivity of these risk prediction tools is markedly lower in women than in men. This sex inequality implies that women are proportionately less likely to receive appropriate clinical management including lipid-lowering therapy. If the risk prediction threshold is lowered to 5% 10-year risk in women, then sensitivity in women is substantially increased.

PMID:38833617 | DOI:10.1093/cvr/cvae123