Pulmonary BRAF-driven Langerhans cell histiocytosis following selpercatinib use in metastatic medullary thyroid cancer.

Summary: RET mutations are implicated in 60% of medullary thyroid cancer (MTC) cases. The RET-selective tyrosine kinase inhibitor selpercatinib is associated with unprecedented efficacy compared to previous multi-kinase treatments. Langerhans cell histiocytosis (LCH) is a clonal histiocytic neoplasm usually driven by somatic BRAF mutations, resulting in dysregulated MAPK signalling. We describe a 22-year-old woman with metastatic MTC to regional lymph nodes, lung and liver. Tumour tissue harboured a somatic pathogenic RET variant p.(M918T) and selpercatinib was commenced. She experienced sustained clinical, biochemical and radiological responses. Two years later, she developed rapidly progressive apical lung nodules, prompting biopsy. Histopathology demonstrated LCH with a rare BRAF variant p.(V600_K601>D). The lung nodules improved with inhaled corticosteroids. We hypothesize that selective pressure from RET blockade may have activated a downstream somatic BRAF mutation, resulting in pulmonary LCH. We recommend continued vigilance for neoplasms driven by dysregulated downstream MAPK signalling in patients undergoing selective RET inhibition. Learning points: Patients with RET-altered MTC can experience rapid disease improvement and sustained disease stability with selective RET blockade (selpercatinib). LCH is a clonal neoplasm driven by MAPK activation, for which the most common mechanism is BRAF mutation. Both MTC and pulmonary LCH are driven by dysregulated MAPK signalling pathway activation. We hypothesise that the RET-specific inhibitor selpercatinib may have caused the activation of dormant LCH secondary to selective pressure and clonal proliferation.

Associations between epicardial, visceral and subcutaneous adipose tissue with diastolic function in men with and without HIV.

BACKGROUND: People with HIV (PWH) are at greater risk for diastolic dysfunction (DD) compared to persons without HIV (PWOH). An increase in visceral adipose tissue (AT) is common among PWH and greater visceral AT is associated with DD among PWOH. We investigated associations of visceral AT, subcutaneous AT and other fat depots with subclinical DD among men with and without HIV (MWH/MWOH). DESIGN: Cross-sectional analysis of MWH and MWOH in the Multicenter AIDS Cohort Study (MACS). METHODS: Participants underwent echocardiography for DD assessment and CT scanning including subcutaneous, visceral, epicardial, and liver adiposity measurements. DD was defined by Characterizing Heart Function on Antiretroviral Therapy criteria. Odds for DD with each measure of adiposity were estimated using multivariable logistic regression. RESULTS: Among 403 participants (median age 57, 55% white, median BMI 26 kg/m2), 25% met criteria for DD and 59% MWH (82% undetectable plasma HIV RNA). Greater epicardial AT area was associated with higher odds of DD (odds ratio:1.54 per SD;95%CI:1.15-2.05) when adjusted for demographics, HIV serostatus, and cardiovascular risk factors. This association did not differ by HIV serostatus and persisted when excluding MWH who were not virally suppressed. Less subcutaneous AT was associated with a higher odds of DD. Other adipose depots were not associated with DD. CONCLUSIONS: Greater epicardial AT and less subcutaneous AT were associated with DD, regardless of HIV serostatus and viral suppression. Greater epicardial AT and less subcutaneous AT observed among PWH may contribute to risk for heart failure with preserved ejection fraction in this population.

Classification of Free-Living Body Posture with ECG Patch Accelerometers: Application to the Multicenter AIDS Cohort Study.

Purpose: As health studies increasingly monitor free-living heart performance via ECG patches with accelerometers, researchers will seek to investigate cardio-electrical responses to physical activity and sedentary behavior, increasing demand for fast, scalable methods to process accelerometer data. We extend a posture classification algorithm for accelerometers in ECG patches when researchers do not have ground-truth labels or other reference measurements (i.e., upright measurement). Methods: Men living with and without HIV in the Multicenter AIDS Cohort study wore the Zio XT® for up to two weeks (n = 1,250). Our novel extensions for posture classification include (1) estimation of an upright posture for each individual without a reference upright measurement; (2) correction of the upright estimate for device removal and re-positioning using novel spherical change-point detection; and (3) classification of upright and recumbent periods using a clustering and voting process rather than a simple inclination threshold used in other algorithms. As no posture labels exist in the free-living environment, we perform numerous sensitivity analyses and evaluate the algorithm against labelled data from the Towson Accelerometer Study, where participants wore accelerometers at the waist. Results: On average, 87.1% of participants were recumbent at 4am and 15.5% were recumbent at 1pm. Participants were recumbent 54 minutes longer on weekends compared to weekdays. Performance was good in comparison to labelled data in a separate, controlled setting (accuracy = 96.0%, sensitivity = 97.5%, specificity = 95.9%). Conclusions: Posture may be classified in the free-living environment from accelerometers in ECG patches even without measuring a standard upright position. Furthermore, algorithms that fail to account for individuals who rotate and re-attach the accelerometer may fail in the free-living environment.

Intersectional stigma and the non-communicable disease syndemic in the context of HIV: protocol for a multisite, observational study in the USA.

INTRODUCTION: The increasing burden of non-communicable diseases, such as hypertension, diabetes and dyslipidaemia, presents key challenges to achieving optimal HIV care outcomes among ageing people living with HIV. These diseases are often comorbid and are exacerbated by psychosocial and structural inequities. This interaction among multiple health conditions and social factors is referred to as a syndemic. In the USA, there are substantial disparities by social position (ie, racial, ethnic and socioeconomic status) in the prevalence and/or control of non-communicable diseases and HIV. Intersecting stigmas, such as racism, classism and homophobia, may drive these health disparities by contributing to healthcare avoidance and by contributing to a psychosocial syndemic (stress, depression, violence victimisation and substance use), reducing success along the HIV and non-communicable disease continua of care. Our hypothesis is that marginalised populations experience disparities in non-communicable disease incidence, prevalence and control, mediated by intersectional stigma and the psychosocial syndemic. METHODS AND ANALYSIS: Collecting data over a 4 year period, we will recruit sexual minority men (planned n=1800) enrolled in the MACS/WIHS Combined Cohort Study, a long-standing mixed-serostatus observational cohort in the USA, to investigate the following specific aims: (1) assess relationships between social position, intersectional stigma and the psychosocial syndemic among middle-aged and ageing sexual minority men, (2) assess relationships between social position and non-communicable disease incidence and prevalence and (3) assess relationships between social position and HIV and non-communicable disease continua of care outcomes, mediated by intersectional stigma and the psychosocial syndemic. Analyses will be conducted using generalised structural equation models using a cross-lagged panel model design. ETHICS AND DISSEMINATION: This protocol is approved as a single-IRB study (Advarra Institutional Review Board: Protocol 00068335). We will disseminate results via peer-reviewed academic journals, scientific conferences, a dedicated website, site community advisory boards and forums hosted at participating sites.

The pleiotropic functions of reactive oxygen species in cancer.

Cellular redox homeostasis is an essential, dynamic process that ensures the balance between reducing and oxidizing reactions within cells and thus has implications across all areas of biology. Changes in levels of reactive oxygen species can disrupt redox homeostasis, leading to oxidative or reductive stress that contributes to the pathogenesis of many malignancies, including cancer. From transformation and tumor initiation to metastatic dissemination, increasing reactive oxygen species in cancer cells can paradoxically promote or suppress the tumorigenic process, depending on the extent of redox stress, its spatiotemporal characteristics and the tumor microenvironment. Here we review how redox regulation influences tumorigenesis, highlighting therapeutic opportunities enabled by redox-related alterations in cancer cells.

Proteomic Signature of HIV-Associated Subclinical Left Atrial Remodeling and Incident Heart Failure.

Background: People living with HIV (PLWH) are at higher risk of heart failure (HF) and preceding subclinical cardiac abnormalities, including left atrial dilation, compared to people without HIV (PWOH). Hypothesized mechanisms include premature aging linked to chronic immune activation. We leveraged plasma proteomics to identify potential novel contributors to HIV-associated differences in indexed left atrial volume (LAVi) among PLWH and PWOH and externally validated identified proteomic signatures with incident HF among a cohort of older PWOH. Methods: We performed proteomics (Olink Explore 3072) on plasma obtained concurrently with cardiac magnetic resonance imaging among PLWH and PWOH in the United States. Proteins were analyzed individually and as agnostically defined clusters. Cross-sectional associations with HIV and LAVi were estimated using multivariable regression with robust variance. Among an independent general population cohort, we estimated associations between identified signatures and LAVi using linear regression and incident HF using Cox regression. Results: Among 352 participants (age 55±6 years; 25% female), 61% were PLWH (88% on ART; 73% with undetectable HIV RNA) and mean LAVi was 29±9 mL/m 2 . Of 2594 analyzed proteins, 439 were associated with HIV serostatus, independent of demographics, hepatitis C virus infection, renal function, and substance use (FDR<0.05). We identified 73 of these proteins as candidate contributors to the independent association between positive HIV serostatus and higher LAVi, enriched in tumor necrosis factor (TNF) signaling and immune checkpoint proteins regulating T cell, B cell, and NK cell activation. We identified one protein cluster associated with LAVi and HIV regardless of HIV viral suppression status, which comprised 42 proteins enriched in TNF signaling, ephrin signaling, and extracellular matrix (ECM) organization. This protein cluster and 30 of 73 individual proteins were associated with incident HF among 2273 older PWOH (age 68±9 years; 52% female; 8.5±1.4 years of follow-up). Conclusion: Proteomic signatures that may contribute to HIV-associated LA remodeling were enriched in immune checkpoint proteins, cytokine signaling, and ECM organization. These signatures were also associated with incident HF among older PWOH, suggesting specific markers of chronic immune activation, systemic inflammation, and fibrosis may identify shared pathways in HIV and aging that contribute to risk of HF.

Complementing the United States Household Food Security Survey Module with Items Reflecting Social Unacceptability.

BACKGROUND: Social unacceptability of food access is part of the lived experience of food insecurity but is not assessed as part of the United States Household Food Security Survey Module (HFSSM). OBJECTIVES: The objectives were as follows: 1) to determine the psychometric properties of 2 additional items on social unacceptability in relation to the HFSSM items and 2) to test whether these 2 items provided added predictive accuracy to that of the HFSSM items for mental health outcomes. METHODS: Cross-sectional data used were from the Intersection of Material-Need Insecurities and HIV and Cardiovascular Health substudy of the Multicenter AIDS Cohort Study/Women's Interagency HIV Study Combined Cohort Study. Data on the 10-item HFSSM and 2 new items reflecting social unacceptability were collected between Fall 2020 and Fall 2021 from 1342 participants from 10 United States cities. The 2 social unacceptability items were examined psychometrically in relation to the HFSSM-10 items using models from item response theory. Linear and logistic regression was used to examine prediction of mental health measured by the 20-item Center for Epidemiologic Studies Depression scale and the 10-item Perceived Stress Scale. RESULTS: The social unacceptability items were affirmed throughout the range of severity of food insecurity but with increasing frequency at higher severity of food insecurity. From item response theory models, the subconstructs reflected in the HFSSM-10 and the subconstruct of social unacceptability were distinct, not falling into one dimension. Regression models confirmed that social unacceptability was distinct from the subconstructs reflected in the HFSSM-10. The social unacceptability items as a separate scale explained more (∼1%) variation in mental health than when combined with the HFSSM-10 items in a single scale, and the social unacceptability subconstruct explained more (∼1%) variation in mental health not explained by the HFSSM-10. CONCLUSIONS: Two social unacceptability items used as a separate scale along with the HFSSM-10 predicted mental health more accurately than did the HFSSM-10 alone.

Identification of high-risk imaging features in hypertrophic cardiomyopathy using electrocardiography: A deep-learning approach.

BACKGROUND: Patients with hypertrophic cardiomyopathy (HCM) are at risk of sudden death, and individuals with ≥1 major risk markers are considered for primary prevention implantable cardioverter-defibrillators. Guidelines recommend cardiac magnetic resonance (CMR) imaging to identify high-risk imaging features. However, CMR imaging is resource intensive and is not widely accessible worldwide. OBJECTIVE: The purpose of this study was to develop electrocardiogram (ECG) deep-learning (DL) models for the identification of patients with HCM and high-risk imaging features. METHODS: Patients with HCM evaluated at Tufts Medical Center (N = 1930; Boston, MA) were used to develop ECG-DL models for the prediction of high-risk imaging features: systolic dysfunction, massive hypertrophy (≥30 mm), apical aneurysm, and extensive late gadolinium enhancement. ECG-DL models were externally validated in a cohort of patients with HCM from the Amrita Hospital HCM Center (N = 233; Kochi, India). RESULTS: ECG-DL models reliably identified high-risk features (systolic dysfunction, massive hypertrophy, apical aneurysm, and extensive late gadolinium enhancement) during holdout testing (c-statistic 0.72, 0.83, 0.93, and 0.76) and external validation (c-statistic 0.71, 0.76, 0.91, and 0.68). A hypothetical screening strategy using echocardiography combined with ECG-DL-guided selective CMR use demonstrated a sensitivity of 97% for identifying patients with high-risk features while reducing the number of recommended CMRs by 61%. The negative predictive value with this screening strategy for the absence of high-risk features in patients without ECG-DL recommendation for CMR was 99.5%. CONCLUSION: In HCM, novel ECG-DL models reliably identified patients with high-risk imaging features while offering the potential to reduce CMR testing requirements in underresourced areas.

Acceptability of Dyad Care Management After Preterm Birth: A Qualitative Study.

OBJECTIVES: Care management programs for medically complex infants interact with parents after complicated pregnancies, when gaps in maternal health care are well documented. These care managers may have the relationships and skills to promote postpartum and interconception health and health care access. It is unknown whether expanding these care management models to address maternal needs would be acceptable. METHODS: We conducted qualitative interviews with women with a history of preterm birth and clinicians. For women with a history of preterm birth, additional inclusion criteria were Medicaid-insured infant in one health system and English proficiency. We purposively oversampled women whose infants received care management. Clinicians worked in two geographically adjacent health systems. Interviews explored priorities after preterm birth and perceived acceptability of mother-infant dyad care management. Interviews were audio recorded, transcribed, and coded following an integrated approach in which we applied a priori codes and captured emergent themes. RESULTS: We interviewed 33 women (10/2018-7/2021) and 24 clinicians (3/2021-8/2021). Women were predominantly non-Hispanic Black, and 15 had infants receiving care management. Clinicians included physicians, nurses, and social workers from Pediatrics, Obstetrics, and Family Medicine. Subgroups converged thematically, finding care management acceptable. Tailoring programs to address stress and sleep, emphasizing care managers with strong interpersonal skills and shared experiences with care management users, and program flexibility would contribute to acceptability. CONCLUSIONS FOR PRACTICE: Dyad care management after preterm birth is acceptable to potential program end-users and clinicians. Dyad health promotion may contribute to improved birth outcomes, infant, and parent health.

Integrating Care for Mother-Infant Dyads After Preterm Birth: A Qualitative Study of Clinician Perspectives on Feasibility.

Objective: There are gaps in receipt of maternal preventive services in the interconception period. Yet mother-infant dyads have frequent health care visits. Health systems have opportunities to better capitalize on existing visits to address dyad needs, but this possibility has not been fully explored. Methods: In this qualitative study we conducted semistructured interviews with clinical team members involved with birthing parents or infants after preterm birth. We conducted snowball sampling from teams in pediatrics, obstetrics, and family medicine at two geographically adjacent health systems. Interviews explored perspectives on existing barriers and facilitators to integrating dyad care across adult and infant teams. Interviews were audio-recorded, professionally transcribed, and coded using an integrated approach. Results: We interviewed 24 physicians, nurses, midwives, and social workers (March-November 2021). Participants identified barriers to integrated care including infrequent communication between clinical teams, which was generalizable to care of the birthing parent or infant as individuals, and additional barriers related to privacy, credentialing, and visit design that were specific to dyad care. To improve integration of dyad care, clinicians proposed adapting a variety tools and procedures currently used in their practices, including electronic health record tools for communication, dedicated roles to support communication or navigation, centralized information on resources for dyad care, referral protocols, identifying dyads for proactive outreach, and opportunities for clinicians to connect face-to-face about shared patients or families. Conclusions: Clinicians believe existing health care structures and processes can be adapted to address current substantial barriers to integrated dyad care.

Massive Biochemically Silent Pheochromocytoma Masquerading as Nonfunctioning Adrenocortical Cancer.

Pheochromocytomas are rare catecholamine-secreting neuroendocrine tumors of the adrenal medulla chromaffin cells, usually associated with features of catecholamine excess. Clinically and biochemically silent pheochromocytoma without adrenergic symptoms or elevated catecholamine concentrations are rare. A 71-year-old female presented with acute right flank pain with abdominal computed tomography (CT) scan revealing a hemorrhagic right adrenal mass. She had no preceding adrenergic symptoms, and normal serum electrolytes, on a background of well-controlled hypertension on amlodipine monotherapy. After conservative management and discharge, an outpatient CT adrenal scan confirmed an 88 × 64 mm right adrenal mass demonstrating intense avidity (maximum standardized uptake value, 20.2) on fluorodeoxyglucose F 18-positron emission tomography (FDG-PET)/CT scan. Biochemical screening supported a nonfunctional adrenal lesion with normal-range plasma normetanephrines and metanephrines. She underwent a right adrenalectomy for presumed nonfunctioning adrenocortical cancer; however, histopathology demonstrated a 120-mm pheochromocytoma. Succinate dehydrogenase subunit B (SDHB) and fumarate hydratase (FH) staining were retained; however, weakly positive 2SC staining raised concerns for FH-deficient pheochromocytoma. Germline DNA sequencing was negative for pathogenic RET, VHL, SDHB, SDHD, or FH variants. Tumor cells stained positive for tyrosine hydroxylase and negative for dopamine ß hydroxylase. Four months postoperatively, progress FDG-PET/CT scan demonstrated no focal avidity. Massive biochemically silent pheochromocytomas are exceedingly rare, and we discuss various mechanisms that may predispose patients to this phenomenon.

The Weight of Inevitability-My Journey With BRCA2.

In this essay, the author grapples with the possibility of a diagnosis of BRCA2.

Association of epicardial and intramyocardial fat with ventricular arrhythmias.

BACKGROUND: Among patients with ischemic cardiomyopathy (ICM) and nonischemic cardiomyopathy (NICM), myocardial fibrosis is associated with an increased risk for ventricular arrhythmia (VA). Growing evidence suggests that myocardial fat contributes to ventricular arrhythmogenesis. However, little is known about the volume and distribution of epicardial adipose tissue and intramyocardial fat and their relationship with VAs. OBJECTIVE: The purpose of this study was to assess the association of contrast-enhanced computed tomography (CE-CT)-derived left ventricular (LV) tissue heterogeneity, epicardial adipose tissue volume, and intramyocardial fat volume with the risk of VA in ICM and NICM patients. METHODS: Patients enrolled in the PROSE-ICD registry who underwent CE-CT were included. Intramyocardial fat volume (voxels between -180 and -5 Hounsfield units [HU]), epicardial adipose tissue volume (between -200 and -50 HU), and LV tissue heterogeneity were calculated. The primary endpoint was appropriate ICD shocks or sudden arrhythmic death. RESULTS: Among 98 patients (47 ICM, 51 NICM), LV tissue heterogeneity was associated with VA (odds ratio [OR] 1.10; P = .01), particularly in the ICM cohort. In the NICM subgroup, epicardial adipose tissue and intramyocardial fat volume were associated with VA (OR 1.11, P = .01; and OR = 1.21, P = .01, respectively) but not in the ICM patients (OR 0.92, P =.22; and OR = 0.96, P =.19, respectively). CONCLUSION: In ICM patients, increased fat distribution heterogeneity is associated with VA. In NICM patients, an increased volume of intramyocardial fat and epicardial adipose tissue is associated with a higher risk for VA. Our findings suggest that fat's contribution to VAs depends on the underlying substrate.

Risk of Arrhythmic Death in Patients With Nonischemic Cardiomyopathy: JACC Review Topic of the Week.

Nonischemic cardiomyopathy (NICM) is common and patients are at significant risk for early mortality secondary to ventricular arrhythmias. Current guidelines recommend implantable cardioverter-defibrillator (ICD) therapy to decrease sudden cardiac death (SCD) in patients with heart failure and reduced left ventricular ejection fraction. However, in randomized clinical trials comprised solely of patients with NICM, primary prevention ICDs did not confer significant mortality benefit. Moreover, left ventricular ejection fraction has limited sensitivity and specificity for predicting SCD. Therefore, precise risk stratification algorithms are needed to define those at the highest risk of SCD. This review examines mechanisms of sudden arrhythmic death in patients with NICM, discusses the role of ICD therapy and treatment of heart failure for prevention of SCD in patients with NICM, examines the role of cardiac magnetic resonance imaging and computational modeling for SCD risk stratification, and proposes new strategies to guide future clinical trials on SCD risk assessment in patients with NICM.

Comparison of Hemispheric Surgery Techniques for Pediatric Drug-Resistant Epilepsy: An Individual Patient Data Meta-analysis.

BACKGROUND AND OBJECTIVES: Hemispheric surgery effectively treats unihemispheric pediatric drug-resistant epilepsy (DRE) by resecting and/or disconnecting the epileptic hemisphere. Modifications to the original anatomic hemispherectomy have generated multiple functionally equivalent, disconnective techniques for performing hemispheric surgery, termed functional hemispherotomy. While a myriad of hemispherotomy variants exist, all of them can be categorized according to the anatomic plane they are performed in, which includes vertical approaches at or near the interhemispheric fissure and lateral approaches at or near the Sylvian fissure. This meta-analysis of individual patient data (IPD) aimed to compare seizure outcomes and complications between the hemispherotomy approaches to better characterize their relative efficacy and safety in the modern neurosurgical treatment of pediatric DRE, given emerging evidence that outcomes may differ between them. METHODS: CINAHL, Embase, PubMed, and Web of Science were searched from inception to September 9, 2020, for studies reporting IPD from pediatric patients with DRE who underwent hemispheric surgery. Outcomes of interest were seizure freedom at last follow-up, time-to-seizure recurrence, and complications including hydrocephalus, infection, and mortality. The χ2 test compared the frequency of seizure freedom and complications. Multivariable mixed-effects Cox regression controlling for predictors of seizure outcome was performed on propensity score-matched patients to compare time-to-seizure recurrence between approaches. Kaplan-Meier curves were made to visualize differences in time-to-seizure recurrence. RESULTS: Fifty-five studies reporting on 686 unique pediatric patients treated with hemispheric surgery were included for meta-analysis. Among the hemispherotomy subgroup, vertical approaches resulted in a greater proportion of seizure free patients (81.2% vs 70.7%, p = 0.014) than lateral approaches. While there were no differences in complications, lateral hemispherotomy had higher rates of revision hemispheric surgery due to incomplete disconnection and/or recurrent seizures than vertical hemispherotomy (16.3% vs 1.2%, p < 0.001). After propensity score matching, vertical hemispherotomy approaches independently conferred longer time-to-seizure recurrence than lateral hemispherotomy approaches (hazard ratio 0.44, 95% CI 0.19-0.98). DISCUSSION: Among functional hemispherotomy techniques, vertical hemispherotomy approaches confer more durable seizure freedom than lateral approaches without compromising safety. Future prospective studies are required to definitively determine whether vertical approaches are indeed superior and how it should influence clinical guidelines for performing hemispheric surgery.

Employment and leave while parenting children with medical complexity.

INTRODUCTION: Children with medical complexity (CMC) require frequent medical care and are at risk of recurrent hospitalizations. The Family Medical Leave Act (FMLA) allows some workers to take unpaid leave from work to care for family members. This study examines caregiving obligations of parents of CMC, the availability and appropriateness of FMLA in facilitating their roles as caregivers and employees, and how these challenges affect employment and financial security. METHOD: Parents of CMC were recruited from a primary care pediatric care management program for semistructured interviews. An integrated approach, using both deductive and inductive codes, was used to conduct a thematic analysis. RESULTS: All 16 respondents were female, with half working full-time, five working part-time, and three not employed at the time of participation. On average, their CMC experienced 1.8 hospitalizations in the prior 12 months. Parents described that caring for CMC required ongoing and unpredictable time commitments that conflicted with job duties and schedules. This conflict led to frequent employment changes that negatively impacted parents' eligibility for FMLA, their financial health, and their own well-being. Parents often described not having access to FMLA due to exhausting the allotted time, part-time status, insufficient tenure at their job, or the inability to take unpaid leave. Parents depended on informal workplace policies and relationships with supervisors to maintain employment, as well as personal and formal supports to care for CMC and their families' financial stability. DISCUSSION: Parents want and need to work in order to support their families and pay for the added expenses related to care for their CMC. Remaining active in the workforce requires that they have flexible schedules that accommodate their unpredictable and ongoing caregiving responsibilities. The eligibility criteria and unpaid nature of FMLA, however, make employment and financial stability elusive for caregivers of CMC. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Diffuse sclerosing variant papillary thyroid carcinoma has worse survival than classic papillary thyroid carcinoma: a meta-analysis.

Diffuse sclerosing variant (DSV) of papillary thyroid carcinomais a rare form of thyroid cancer that demonstrates more aggressive histopathology than classical papillary thyroid carcinoma (c-PTC); however, if this leads to worse survival is debated. Many DSVs are driven by fusion events which are of recent clinical importance due to the advent of targeted RET inhibitors. A systematic search and meta-analysis of the literature was performed to compare outcomes of disease-specific mortality (DSM), metastatic and recurrent disease and the incidence of fusion events between DSV and c-PTC to July 2022. The Newcastle-Ottawa Quality Assessment studies was used to assess quality. An odds ratio (OR) was utilised to measure outcomes with 95% CIs. The Preferred Reporting Items for Systematic Reviews and Meta-analysis guideline was followed. Seventeen studies were included with 874 DSV patients compared to 76,013 c-PTC patients. DSV patients had worse DSM (OR=2.50, 95% CI 1.39-4.51) and presented with a higher rate of metastatic lymph nodes (OR = 5.85, 95% CI 2.73-12.53) and more distant metastases (OR = 3.83, 95% CI 2.17-6.77). DSV patients had higher odds of recurrent disease (OR = 3.23, 95% CI 2.00-5.23) and overall distant metastasis (OR = 2.70, 95% CI 1.74-4.17). Rates of RET fusion alterations for DSV ranged from 25 to 83%. DSV has a worse prognosis than c-PTC with higher rates of recurrent disease and distant metastasis. The high prevalence of RET fusions offers the potential to improve outcomes for patients with DSV.