Hepatoblastomas with carcinoma features represent a biological spectrum of aggressive neoplasms in children and young adults.

BACKGROUND & AIMS: Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the predominant liver cancers in children, though their respective treatment options and associated outcomes differ dramatically. Risk stratification using a combination of clinical, histological, and molecular parameters can improve treatment selection, but it is particularly challenging for tumors with mixed histological features, including those in the recently created hepatocellular neoplasm not otherwise specified (HCN NOS) provisional category. We aimed to perform the first molecular characterization of clinically annotated cases of HCN NOS. METHODS: We tested whether these histological features are associated with genetic alterations, cancer gene dysregulation, and outcomes. Namely, we compared the molecular features of HCN NOS, including copy number alterations, mutations, and gene expression profiles, with those in other pediatric hepatocellular neoplasms, including HBs and HCCs, as well as HBs demonstrating focal atypia or pleomorphism (HB FPAs), and HBs diagnosed in older children (>8). RESULTS: Molecular profiles of HCN NOS and HB FPAs revealed common underlying biological features that were previously observed in HCCs. Consequently, we designated these tumor types collectively as HBs with HCC features (HBCs). These tumors were associated with high mutation rates (∼3 somatic mutations/Mb) and were enriched with mutations and alterations in key cancer genes and pathways. In addition, recurrent large-scale chromosomal gains, including gains of chromosomal arms 2q (80%), 6p (70%), and 20p (70%), were observed. Overall, HBCs were associated with poor clinical outcomes. CONCLUSIONS: Our study indicates that histological features seen in HBCs are associated with combined molecular features of HB and HCC, that HBCs are associated with poor outcomes irrespective of patient age, and that transplanted patients are more likely to have good outcomes than those treated with chemotherapy and surgery alone. These findings highlight the importance of molecular testing and early therapeutic intervention for aggressive childhood hepatocellular neoplasms. LAY SUMMARY: We molecularly characterized a class of histologically aggressive childhood liver cancers and showed that these tumors are clinically aggressive and that their observed histological features are associated with underlying recurrent molecular features. We proposed a diagnostic algorithm to identify these cancers using a combination of histological and molecular features, and our analysis suggested that these cancers may benefit from specialized treatment strategies that may differ from treatment guidelines for other childhood liver cancers.

Synchronous Health Care Delivery for the Optimization of Cardiovascular and Renal Care in Patients with Type 2 Diabetes.

PURPOSE OF REVIEW: The current care model of type 2 diabetes (T2D) and its complications appears to be "asynchronous" with patient care divided by specialty. This model is associated with low use of guideline-directed medical therapies. RECENT FINDINGS: The use of integrated care models has been well described in the management of patients with T2D; this usually includes an endocrinologist coupled with a nutritionist and nurse. However, physician-based care models are largely "asynchronous," whereby the patient requires multiple different siloed specialties to manage their health care. To date, there has been limited exploration of synchronous care delivery, i.e., whereby multi-comorbid patients with T2D are seen simultaneously by health care providers from endocrinology, cardiology, and nephrology to optimize use of guideline-directed medical therapies (GDMT). Given the rising complexity of patients with T2D, further research is needed on the role of synchronous health care delivery in optimizing the use of GDMT and improving patient outcomes.

Associations of overweight and gestational diabetes mellitus with free sugars from solid and liquid sources: cross-sectional and nested case-control analyses.

BACKGROUND: Sugar-sweetened beverages have obesogenic and diabetogenic effects ascribed to free sugars. These include added sugars and naturally occurring sugars in juices. A meta-analysis indicates that some foods with added sugars are associated with lower type 2 diabetes rates. To expand the evidence relevant to free sugars from solid sources, we examined a young to middle-aged population with respect to overweight and gestational diabetes (GDM) outcomes. METHODS: We studied female participants (12-50 years old) from the 2004-2005 Canadian Community Health Survey 2.2 (CCHS) with data linked to the hospital Discharge Abstract Database (DAD) until 2017, providing 13 years of follow-up. We estimated free sugars by solid and liquid sources from 24-h dietary recalls as percent total energy intake (TE%), and computed body mass index (BMI). We applied ICD-10 diagnostic codes for deliveries and GDM to DAD. We conducted multivariable logistic regression analyses to evaluate associations between free sugars with overweight at baseline (cross-sectional component) and, in those who delivered, with GDM during follow-up (nested case control component). We compared those with consumption above versus below various thresholds of intake for free sugars, considering solid and liquid sources separately (2.TE%, 5TE%, 10TE% and 15TE% thresholds). RESULTS: Among 6305 participants, 2505 (40%) were overweight, defined as BMI ≥ 85th percentile below 18 years and BMI ≥ 25 kg/m2 for adults. Free sugars from solid sources were associated with lower odds of overweight above versus below the 2.5TE% (adjusted odds ratio [adjOR] 0.80, 95%CI 0.70-0.92), 5TE% (adjOR 0.89, 95%CI 0.79-0.99), and 10TE% (adjOR 0.86, 95%CI 0.75-0.97) thresholds. Free sugars from liquid sources were associated with greater odds of overweight across the 2.5TE% (adjOR 1.20, 95%CI 1.07-1.36), 10TE% (adjOR 1.17, 95%CI 1.02-1.34), and 15TE% (adjOR 1.43, 95%CI 1.23-1.67) thresholds. There were 113 cases of GDM among the 1842 women who delivered (6.1%). Free sugars from solid sources were associated with lower odds of GDM above versus below the 5TE% threshold (adjOR 0.56, 95%CI 0.36-0.85). CONCLUSIONS: Our findings support limiting free sugars from liquid sources, given associations with overweight. We did not identify adverse associations of free sugars from solid sources across any of the thresholds examined.

Clinical Phenotypes in Patients With Type 2 Diabetes Mellitus: Characteristics, Cardiovascular Outcomes and Treatment Strategies.

PURPOSE OF REVIEW: With recent advances in the pharmacological management of type 2 diabetes mellitus (T2DM), there is a growing need to understand which patients optimally benefit from these novel therapies. Various clinical clustering methodologies have emerged that utilise data-agnostic strategies to categorise patients that have similar clinical characteristics and outcomes; broadly, this characterisation is termed phenotyping. In patients with T2DM, we aimed to describe patient characteristics from phenotype studies, their cardiovascular risk profiles and the impact of antihyperglycemic treatment. RECENT FINDINGS: Numerous phenotypic studies have been undertaken that have utilised a combination of clinical, biochemical, imaging and genetic variables. Each of these has produced phenotypes that display a spectrum of cardiovascular risk. Studies that aimed to describe pathophysiological phenotypes generally identified five phenotypes: autoimmune phenotype, insulin-related phenotypes (including permutations of insulin deficiency and resistance), obesity phenotype, ageing phenotype, and a sex-related phenotype. Studies examining risk profiles have demonstrated that across such phenotypes there is a spectrum of risk for diabetic complications. Few studies have examined treatment effects across these phenotypes, and thus provide little insights towards making phenotype-guided treatment decisions Clustering analyses in patients with T2DM have identified distinct phenotypes with unique risk profiles. Further studies are needed that harness the use of clinical, biochemical, imaging and genetic data to explore therapeutic heterogeneity and response to antihyperglycemic treatment across the spectrum of patient phenotypes.

Exercise in Pregnant Women with Diabetes.

PURPOSE OF REVIEW: Diabetes affects an increasing number of pregnancies. Regular exercise is recommended for pregnant women without diabetes, but whether exercise during pregnancy also benefits women with gestational diabetes (GDM) or preexisting (type 1 or type 2) diabetes or if these women have any specific risks is unclear. RECENT FINDINGS: Recent evidence suggests that low- to moderate-intensity exercise improves blood glucose and may delay insulin initiation for women with GDM. Exercise is also safe, with no reports of increased maternal or neonatal complications. Few studies evaluated exercise as adjunct therapy for pregnant women with preexisting diabetes, precluding a thorough assessment in this population. Low- to moderate-intensity exercise during pregnancy safely improves glycemic control among women with GDM. More studies are needed to evaluate the impact of exercise in pregnant women with preexisting diabetes. Whether a specific type, volume, or timing of activity is most effective is not known.

CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions.

BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+ CD33+ CD163+ P2RY12- ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20. © 2018 American Cancer Society.

BCOR-CCNB3 fusions are frequent in undifferentiated sarcomas of male children.

The BCOR-CCNB3 fusion gene, resulting from a chromosome X paracentric inversion, was recently described in translocation-negative 'Ewing-like' sarcomas arising in bone and soft tissue. Genetic subclassification of undifferentiated unclassified sarcomas may potentially offer markers for reproducible diagnosis and substrates for therapy. Using whole transcriptome paired-end RNA sequencing (RNA-seq) we unexpectedly identified BCOR-CCNB3 fusion transcripts in an undifferentiated spindle-cell sarcoma. RNA-seq results were confirmed through direct RT-PCR of tumor RNA and cloning of the genomic breakpoints from tumor DNA. Five additional undifferentiated sarcomas with BCOR-CCNB3 fusions were identified in a series of 42 pediatric and adult unclassified sarcomas. Genomic breakpoint analysis demonstrated unique breakpoint locations in each case at the DNA level even though the resulting fusion mRNA was identical in all cases. All patients with BCOR-CCNB3 sarcoma were males diagnosed in mid childhood (7-13 years of age). Tumors were equally distributed between axial and extra-axial locations. Five of the six tumors were soft-tissue lesions with either predominant spindle-cell morphology or spindle-cell areas interspersed with ovoid to round cells. CCNB3 immunohistochemistry showed strong nuclear positivity in five tumors before oncologic therapy, but was patchy to negative in post-treatment tumor samples. An RT-PCR assay developed to detect the fusion transcript in archival formalin-fixed tissue was positive in all six cases, with high sensitivity and specificity in both pre- and post-treated samples. This study adds to recent reports on the clinicopathologic spectrum of BCOR-CCNB3 fusion-positive sarcomas, a newly emerging entity within the undifferentiated unclassified sarcoma category and describes a simple RT-PCR assay that in conjunction with CCNB3 immunohistochemistry can be useful in diagnosing these tumors.

Does Insulin Delivery Technology Change Our Relationship with Foods? A Scoping Review.

Introduction: Automated insulin delivery (AID) systems reduce burden and improve glycemic management for people with type 1 diabetes (PwT1D) by automatically adjusting insulin as a response to measured glucose levels. There is a lack of evidence on AID and nutrition variables such as dietary intake, eating behaviors, and disordered eating. Objectives: This scoping review aims to provide a summary of the literature regarding AID and nutrition variables and to identify gaps that require further investigation. Methods: Two researchers conducted a blinded search of Medline (OVID) and PubMed for studies, including AID use (compared to non-AID use) and nutrition variables. Studies from January 2000 to July 2023 were included, as were PwT1D of all ages. Results: A total of 3132 articles were screened for appropriateness. After exclusions, 7 studies were included (2017-2023): 4 qualitative, 1 crossover, 1 randomized controlled, and 1 observational. Studies included adolescents (n = 1), adults (n = 3) or both (n = 2), and all ages (n = 1). In quantitative studies, AID was associated with lower eating distress (-0.43 ± 0.12, P = 0.004) and higher quality of life (3.1, 95% confidence interval [CI]: 0.8-5.4, P = 0.01), but not grams of carbohydrates at meals (1.0; 95% CI: -0.7 to 3.0; P = 0.24) and snacks (0.004; 95% CI: -0.8 to 0.8; P = 0.99) compared to non-AID use. In qualitative studies, AID increased the frequency and portions of food intake and led to less dietary control from parents. AID users reported eating foods higher in energy density. PwT1D were less worried about achieving accurate carbohydrate counting (CC) when using AID. Conclusions: AID use appears to influence eating behaviors, dietary patterns, and CC, although evidence was limited. AID may reduce food management burden due to the perception that AID can correct for CC inaccuracy. Significance: Further research needs to determine if AID allows for simplification of CC and improves eating behaviors while maintaining glycemic stability.

Effect of diabetes technologies on the fear of hypoglycaemia among people living with type 1 diabetes: a systematic review and meta-analysis.

Background: Fear of hypoglycaemia (FOH) significantly disrupts the daily management of type 1 diabetes (T1D) and increases the risk of complications. Recent technological advances can improve glucose metrics and reduce hypoglycaemia frequency, yet their impact on FOH is unclear. This systematic review and meta-analysis (SRMA) aimed to synthesize the current literature to understand the impact of diabetes technologies on FOH in T1D. Methods: In this SRMA, we searched PubMed, Medline, Scopus, and Web of Science from inception up to May 21st, 2023 for studies assessing the effect of using real-time or intermittently scanned continuous glucose monitors (rtCGM or isCGM); insulin pumps (CSII); and their combinations on FOH as the primary outcome, measured using the Hypoglycaemia Fear Survey (HFS; including total, worries [HFS-W], and behaviours [HFS-B] scores), in non-pregnant adults with T1D. Data was extracted by the first and second authors. Results were pooled using a random-effects model based on study design (RCT and non-RCT), with subgroup analysis based on the type of technology, reported change in hypoglycaemia frequency, and duration of use. Risk of bias was evaluated with Cochrane and Joanna Briggs Institute tools. This study is registered with PROSPERO, CRD42021253618. Findings: A total of 51 studies (n = 8966) were included, 22 of which were RCTs. Studies on rtCGM and CSII reported lower FOH levels with ≥8 weeks of use. Studies on CSII and rtCGM combinations reported lower FOH levels after ≥13 weeks of automated insulin delivery (AID) use or 26 weeks of sensor-augmented pump (SAP) use. The meta-analysis showed an overall lower FOH with technologies, specifically for the HFS-W subscale. The RCT meta-analysis showed lower HFS-W scores with rtCGM use (standard mean difference [95%CI]: -0.14 [-0.23, -0.05], I2 = 0%) and AID (-0.17 [-0.33, -0.01], I2 = 0%). Results from non-RCT studies show that SAP users (-0.33 [-0.38, -0.27], I2 = 0%) and rtCGM users (-0.38 [-0.61, -0.14], I2 = 0%) had lower HFS-W. Interpretation: We found consistent, yet small to moderate, effects supporting that diabetes technologies (specifically rtCGM, SAP, and AID) may reduce hypoglycaemia-related worries in adults with T1D. Current literature, however, has limitations including discrepancies in baseline characteristics and limited, mainly descriptive, statistical analysis. Thus, future studies should assess FOH as a primary outcome, use validated surveys, and appropriate statistical analysis to evaluate the clinical impacts of technology use beyond just glucose metrics. Funding: Canadian Institutes of Health Research, Juvenile Diabetes Research Foundation Ltd.

Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells.

Langerhans cell histiocytosis (LCH) is a rare disease characterized by heterogeneous lesions containing CD207(+) Langerhans cells (LCs) and lymphocytes that can arise in almost any tissue and cause significant morbidity and mortality. After decades of research, the cause of LCH remains speculative. A prevailing model suggests that LCH arises from malignant transformation and metastasis of epidermal LCs. In this study, CD207(+) cells and CD3(+) T cells were isolated from LCH lesions to determine cell-specific gene expression. Compared with control epidermal CD207(+) cells, the LCH CD207(+) cells yielded 2113 differentially expressed genes (false discovery rate < 0.01). Surprisingly, the expression of many genes previously associated with LCH, including cell-cycle regulators, proinflammatory cytokines, and chemokines, were not significantly different from control LCs in our study. However, several novel genes whose products activate and recruit T cells to sites of inflammation, including SPP1 (osteopontin), were highly overexpressed in LCH CD207(+) cells. Furthermore, several genes associated with immature myeloid dendritic cells were overexpressed in LCH CD207(+) cells. Compared with the peripheral CD3(+) cells from LCH patients, the LCH lesion CD3(+) cells yielded only 162 differentially regulated genes (false discovery rate < 0.01), and the expression profile of the LCH lesion CD3(+) cells was consistent with an activated regulatory T cell phenotype with increased expression of FOXP3, CTLA4, and SPP1. Results from this study support a model of LCH pathogenesis in which lesions do not arise from epidermal LCs but from accumulation of bone marrow-derived immature myeloid dendritic cells that recruit activated lymphocytes.

Validity of a short questionnaire to assess physical activity in 10 European countries.

To accurately examine associations of physical activity (PA) with disease outcomes, a valid method of assessing free-living activity is required. We examined the validity of a brief PA questionnaire (PAQ) used in the European Prospective Investigation into Cancer and Nutrition (EPIC). PA energy expenditure (PAEE) and time spent in moderate and vigorous physical activity (MVPA) was measured in 1,941 healthy individuals from 10 European countries using individually-calibrated combined heart-rate and movement sensing. Participants also completed the short EPIC-PAQ, which refers to past year's activity. Pearson (r) and Spearman (σ) correlation coefficients were calculated for each country, and random effects meta-analysis was used to calculate the combined correlation across countries to estimate the validity of two previously- and one newly-derived ordered, categorical PA indices ("Cambridge index", "total PA index", and "recreational index") that categorized individuals as inactive, moderately inactive, moderately active, or active. The strongest associations with PAEE and MVPA were observed for the Cambridge index (r = 0.33 and r = 0.25, respectively). No significant heterogeneity by country was observed for this index (I(2) = 36.3%, P = 0.12; I(2) = 0.0%, P = 0.85), whereas heterogeneity was suggested for other indices (I(2) > 48%, P < 0.05, I(2) > 47%, P < 0.05). PAEE increased linearly across self-reported PA categories (P for trend <0.001), with an average difference of approximately 460 kJ/d for men and 365 kJ/d for women, between categories of the Cambridge index. The EPIC-PAQ is suitable for categorizing European men and women into four distinct categories of overall physical activity. The difference in PAEE between categories may be useful when estimating effect sizes from observational research.

Neither IL-17A mRNA nor IL-17A protein are detectable in Langerhans cell histiocytosis lesions.

Langerhans cell histiocytosis (LCH) is a rare disease characterized by heterogeneous lesions including CD207(+)/CD1a(+) dendritic cells that can result in significant morbidity and mortality. The etiology of LCH remains speculative, and neoplastic and inflammatory origins have been debated for decades. A recent study identified abundant interleukin-17 (IL-17A) protein in dendritic cells in LCH lesions as well as in plasma from patients with active disease. Furthermore, it identified dendritic cells as a novel source of IL-17A expression. However, subsequent studies from our research group failed to identify any IL-17A gene expression from CD207(+) dendritic cells or CD3(+) T cells in LCH lesions. In this study, further investigation once again fails to identify any cells in LCH lesions with IL-17A gene expression. Furthermore, IL-17A antigen is undetectable in LCH lesion lysates with western blotting, immunoprecipitation, spectral analysis, and enzyme-linked immunosorbent assay (ELISA). Western blots, immunoprecipitation, and ELISA experiments also demonstrate that antibodies used in original studies that established the IL-17A hypothesis for pathogenesis of LCH recognize nonspecific proteins. We conclude that evidence for IL-17A as a significant factor in LCH remains inadequate and clinical trials targeting IL-17A remain unjustified.

The Nuclear Medicine Technologist's Role in Theranostics: SNMMI-TS Advocacy's Vision.

SNMMI-TS Advocacy Committee would now like to answer the following questions and cast a level of opinion on Nuclear Medicine Technologists performing theranostics-therapy clinical work: What training does a nuclear medicine technologist (NMT) need to participate and complete theranostics? What does the SNMMI-TS Advocacy Committee feel are important initiatives to have NMTs fully engaged in theranostics today and in the long-term?

Are nocturnal hypoglycemia prevention strategies influenced by diabetes technology usage? A BETTER registry analysis.

AIM: To assess the association of nocturnal hypoglycemia prevention strategies (NH-PS) and diabetes technology usage (insulin pump and/or continuous glucose monitors [CGM]) in people with type 1 diabetes (PWT1D). METHODS: Logistic regression models were used to describe associations between self-reported NH-PS and diabetes technology (pump with intermittently-scanned or real-time CGM (isCGM or rtCGM), or automated insulin delivery (AID)), hypoglycemia history, and fear of hypoglycemia (FOH). RESULTS: Among 831 adults (65 % female, aged 44 ± 15 years, T1D duration 26 ± 15 years), 32 % reported HbA1c ≤ 7.0 %, 88 % used ≥ 1 diabetes technology, 66 % reported ≥ 1 symptomatic NH in the past month, and 64 % used ≥ 2 NH-PS. Compared to multiple daily injections (MDI) + capillary blood glucose (CBG), bedtime snack consumption was less likely among pump + isCGM (OR [95 %CI]: 0.55 [0.31, 0.98]), pump + rtCGM (0.40 [0.20, 0.81]), and AID (0.34 [0.17, 0.66]) users, while evening insulin basal reduction was associated with CSII + CBG (3.15 [1.25, 7.99]), pump + isCGM 4.00 [1.99, 8.01]), and pump + rtCGM 2.89 [1.28, 6.50] use. Elevated FOH was associated with snack consumption (1.37 [1.00, 1.89]), evening bolus insulin avoidance (1.77 [1.11, 2.83]), limiting exercise (2.50 [1.30, 4.82]), and limiting alcohol consumption (2.33 [1.15, 4.70]) as NH-PS. CONCLUSION: Technology use and elevated FOH might influence PWT1D' choice of NH-PS.

Clinical Prediction Models for Heart Failure Hospitalization in Type 2 Diabetes: A Systematic Review and Meta-Analysis.

Background Clinical prediction models have been developed for hospitalization for heart failure in type 2 diabetes. However, a systematic evaluation of these models' performance, applicability, and clinical impact is absent. Methods and Results We searched Embase, MEDLINE, Web of Science, Google Scholar, and Tufts' clinical prediction registry through February 2021. Studies needed to report the development, validation, clinical impact, or update of a prediction model for hospitalization for heart failure in type 2 diabetes with measures of model performance and sufficient information for clinical use. Model assessment was done with the Prediction Model Risk of Bias Assessment Tool, and meta-analyses of model discrimination were performed. We included 15 model development and 3 external validation studies with data from 999 167 people with type 2 diabetes. Of the 15 models, 6 had undergone external validation and only 1 had low concern for risk of bias and applicability (Risk Equations for Complications of Type 2 Diabetes). Seven models were presented in a clinically useful manner (eg, risk score, online calculator) and 2 models were classified as the most suitable for clinical use based on study design, external validity, and point-of-care usability. These were Risk Equations for Complications of Type 2 Diabetes (meta-analyzed c-statistic, 0.76) and the Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (meta-analyzed c-statistic, 0.78), which was the simplest model with only 5 variables. No studies reported clinical impact. Conclusions Most prediction models for hospitalization for heart failure in patients with type 2 diabetes have potential concerns with risk of bias or applicability, and uncertain external validity and clinical impact. Future research is needed to address these knowledge gaps.

Global Pathology Training in Residency and Fellowship: A Mutually Beneficial Intervention.

CONTEXT.­: Most cancers occur in lower and middle income countries, where pathologists are scarce. Despite this, few pathology training programs offer global health electives, and trainees are not exposed to challenges associated with practicing in resource-restricted settings. OBJECTIVE.­: To implement a global health elective model aimed at exposing trainees to global health while alleviating overburdened pathologists in resource-restricted settings. DESIGN.­: For 1 year, trainees at 2 US institutions reviewed cases shipped weekly from a pathology lab serving Trinidad and Tobago and Guyana. Turnaround time, specimen type, and trainee and clinician satisfaction were assessed. RESULTS.­: Trainees reviewed an average of 16 cases per week. Average turnaround time was 6 days. There was no significant difference between the turnaround time for the US trainees and the pathologist based in the lab in Trinidad. Trainees and clinicians reported a high level of satisfaction, and the collaboration was fruitful, resulting in the publication of a case report. CONCLUSIONS.­: We demonstrate that collaboration between US trainees and laboratories in resource-restricted settings, in the form of a global health elective, is mutually beneficial.

Sex Differences in the Risk of Coronary Heart Disease Associated With Type 2 Diabetes: A Mendelian Randomization Analysis.

OBJECTIVE: Observational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding. RESEARCH DESIGN AND METHODS: Using 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (251,420 women and 212,049 men). Weighted median, MR-Egger, MR-pleiotropy residual sum and outlier, and radial MR from summary-level analyses were used for pleiotropy assessment. RESULTS: MR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio 1.13 [95% CI 1.08-1.18] per 1-log unit increase in odds of type 2 diabetes) and men (1.21 [1.17-1.26] per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy; however, results were similar after correction for outlier SNPs. CONCLUSIONS: This MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes.

Physical activity and postmenopausal breast cancer risk in the NIH-AARP diet and health study.

BACKGROUND: Although physical activity has been associated with reduced breast cancer risk, whether this association varies across breast cancer subtypes or is modified by reproductive and lifestyle factors is unclear. METHODS: We examined physical activity in relation to postmenopausal breast cancer risk in 182,862 U.S. women in the NIH-AARP Diet and Health Study. Physical activity was assessed by self-report at baseline (1995-1996), and 6,609 incident breast cancers were identified through December 31, 2003. Cox regression was used to estimate the relative risk (RR) and 95% confidence interval (95% CI) of postmenopausal breast cancer overall and by tumor characteristics. Effect modification by select reproductive and lifestyle factors was also explored. RESULTS: In multivariate models, the most active women experienced a 13% lower breast cancer risk versus inactive women (RR, 0.87; 95% CI, 0.81-0.95). This inverse relation was not modified by tumor stage or histology but was suggestively stronger for estrogen receptor (ER)-negative (RR, 0.75; 95% CI, 0.54-1.04) than ER-positive (RR, 0.97; 95% CI, 0.84-1.12) breast tumors and was suggestively stronger for overweight/obese (RR, 0.86; 95% CI, 0.77-0.96) than lean (RR, 0.95; 95% CI, 0.87-1.05) women. The inverse relation with physical activity was also more pronounced among women who had never used menopausal hormone therapy and those with a positive family history of breast cancer than their respective counterparts. CONCLUSIONS: Physical activity was associated with reduced postmenopausal breast cancer risk, particular to ER-negative tumors. These results, along with heterogeneity in the physical activity-breast cancer relation for subgroups of menopausal hormone therapy use and adiposity, indicate that physical activity likely influences breast cancer risk via both estrogenic and estrogen-independent mechanisms.