Novel fusion sarcomas including targetable NTRK and ALK.

BACKGROUND: Challenging emerging entities with distinctive molecular signatures may benefit from algorithms for diagnostic work-up. METHODS: Fusion sarcomas (2020-2021, during pandemic) were diagnosed by clinicoradiology, morphology, phenotype, and next-generation sequencing (NGS). RESULTS: Six fusion sarcomas in two males and four females involved the chest-wall, neck, or extremities; ages ranged 2-73, median 18 years. Sizes ranged 5.3-25.0, median 9.1 cm. These include high grade 1) TPR-NTRK1 of proximal femur with a larger rounded soft tissue mass, previously considered osteosarcoma yet without convincing tumor matrix. A pathologic fracture necessitated emergency hemipelvectomy (NED) and 2) novel KANK1-NTRK2 sarcoma of bone and soft tissue with spindled pleomorphic to epithelioid features (AWD metastases). 3) Novel ERC1-ALK unaligned fusion, a low grade infiltrative deep soft tissue hand sarcoma with prominent-vascularity, myopericytoid/lipofibromatosis-like ovoid cells, and collagenized stroma, was successfully treated with ALK-inhibitor (Crizotinib), avoiding amputation. These NTRK and ALK tumors variably express S100 and CD34 and were negative for SOX10. 4) and 5) CIC-DUX4 round cell tumors (rapid metastases/demise), one with COVID superinfection, were previously treated as Ewing sarcoma. These demonstrated mild pleomorphism and necrosis, variable myxoid change and CD99 reactivity, and a distinctive dot-like-Golgi WT1 immunostaining pattern. 6) A chest wall/thoracic round cell sarcoma, focal CD34/ keratins/CK7, revealed nuclear-STAT6, STAT6-NAB2 by NGS, confirming malignant solitary fibrous tumor, intermediate-risk-stratification (AWD metastases). CONCLUSIONS: Recent fusion sarcomas include new KANK1-NTRK2 and ERC1-ALK, the latter successfully treated by targeted-therapy. ALK/NTRK fusion partners TPR and KANK1 suggest unusual high-grade morphology/behavior. Clinicoradiologic, morphologic, and phenotypic algorithms can prompt molecular-targeted immunostains or NGS for final classification and promising inhibitor therapy.

High value care education in general surgery residency programs: A multi-institutional needs assessment.

BACKGROUND: The ACGME mandates that residency programs provide training related to high value care (HVC). The purpose of this study was to explore HVC education in general surgery residency programs. METHODS: An electronic survey was distributed to general surgery residents in geographically diverse programs. RESULTS: The response rate was 29% (181/619). Residents reported various HVC components in their curricula. Less than half felt HVC is very important for their future practice (44%) and only 15% felt confident they could lead a QI initiative in practice. Only 20% of residents reported participating in a root cause analysis and less than one-third of residents (30%) were frequently exposed to cost considerations. CONCLUSION: Few residents feel prepared to lead quality improvement initiatives, have participated in patient safety processes, or are aware of patients' costs of care. This underscores the need for improved scope and quality of HVC education and establishment of formal curricula.

Novel FEMASK-score, a histopathologic assessment for destructive Charcot neuropathic arthropathy, reveals intraneural vasculopathy and correlates with progression and best treatment.

BACKGROUND: Charcot neuropathic arthropathy is a debilitating, rapidly destructive degenerative joint disease that occurs in diabetic, neuropathic midfoot. Clinicoradiologic assessment for Charcot neuropathic arthropathy previously relied on Eichenholtz stage. There is limited histopathologic data on this entity. We wanted to independently develop a histopathologic scoring system for Charcot neuropathic arthropathy. DESIGN: Retrieval of surgical pathology midfoot specimens from Charcot patients (2012-2019) were analyzed to evaluate joint soft tissue and bone. Considering progression from large (≥half 40× hpf) to small (

Ready-to-eat cereal fortification: a modelling study on the impact of changing ready-to-eat cereal fortification levels on population intake of nutrients.

OBJECTIVE: Ready-to-eat (RTE) cereal is an important source of nutrients in the American diet. Recent regulatory changes to labelling requirements may impact the fortification of RTE cereal. We used an evidence-based approach to optimize the fortification of RTE cereal considering current dietary patterns and nutrition policy. DESIGN: A US modelling study of cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2013-2014. The percentage of the population below the Estimated Average Requirement (EAR) and above the Upper Tolerable Intake Level (UL) was modelled under three scenarios: baseline, zero fortification and optimized fortification. SETTING: USA. PARTICIPANTS: Toddlers aged 1-3 years, n 559; children aged 4-12 years, n 1540; adolescents aged 13-18 years, n 992; and adults aged ≥19 years, n 576. RESULTS: Comparing current with optimized fortification, nutrient/100 g RTE cereal decreased for vitamin A, thiamin, riboflavin, niacin, vitamin B6, folic acid, vitamin B12, Ca and Fe (by 2-82 %). The amount of vitamins C and D increased (by 13 and 50 %, respectively). Among RTE cereal eaters, these changes resulted in modest increases in the percentage of the population aged ≥1 year below the EAR (+0·5 to +11·5 percentage points). Decreases were observed in the percentage of the population above the UL. CONCLUSIONS: Fortification of RTE cereal can be optimized to provide key nutrients and minimize the percentage of the population below the EAR and above the UL. Dietary intake modelling is useful to ensure that RTE cereal continues to help the population meet their nutrient needs.

Association between Ready-to-Eat Cereal Consumption and Nutrient Intake, Nutritional Adequacy, and Diet Quality in Adults in the National Health and Nutrition Examination Survey 2015-2016.

This study examined differences in dietary intake between ready-to-eat cereal eaters and non-eaters in adults from the United States. Participants (n = 5163) from the National Health and Nutrition Examination Survey 2015-2016 were included. One-day dietary recall was used to define ready-to-eat cereal consumption status and estimate dietary intake in eaters and non-eaters. Data from Food Patterns Equivalent Database 2015-2016 were used to compare intakes of food groups by consumption status. Diet quality was assessed by Healthy Eating Index 2015. Nineteen percent of US adults were ready-to-eat cereal eaters; they had a similar level of energy intake as non-eaters, but they had significantly higher intake of dietary fiber, and several vitamins and minerals, such as calcium, iron, magnesium, potassium, zinc, vitamin A, thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, and vitamin D. They were also more likely to meet nutrient recommendations. Compared to non-eaters, ready-to-eat cereal eaters had the same level of added sugar intake but they had significantly higher intake of whole grains, total fruits, and dairy products. The diet quality of ready-to-eat cereal eaters was significantly higher than that of non-eaters. The study supports that ready-to-eat cereal eaters have better dietary intake with a healthier dietary pattern than non-eaters in the United States.

Association between Ready-to-Eat Cereal Consumption and Nutrient Intake, Nutritional Adequacy, and Diet Quality among Infants, Toddlers, and Children in the National Health and Nutrition Examination Survey 2015-2016.

Ready-to-eat (RTE) cereal is a popular food among children. However, there are no recent data on the associations between RTE cereal consumption and dietary outcomes in the U.S. Therefore, we sought to investigate how RTE cereal was associated with nutrient and food group intakes and overall dietary quality among children aged 0.5 to 17 years using the latest data from the National Health and Nutrition Examination Survey (NHANES 2015-2016). Thirty-six percent of children reported consuming RTE cereal. RTE cereal eaters consumed the same number of calories as non-eaters but had higher intakes of total carbohydrates, total sugar, fiber, calcium, iron, magnesium, potassium, zinc, vitamin A, thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, and vitamin D, as well as lower intakes of total fat and saturated fat (p ≤ 0.0007). We also found that children who consumed RTE cereal had 29% higher total dairy intake (p < 0.0001) and 61% higher whole grain intake (p < 0.0001). Lastly, children who ate RTE cereal had higher diet quality than the children that did not eat RTE cereal, as shown by Healthy Eating Index 2015 total score (52.6 versus 47.7, p < 0.0001). Therefore, consumption of whole-grain fortified RTE cereals should be encouraged as part of healthy dietary patterns for children.

Use of a novel chitosan-based dressing on split-thickness skin graft donor sites: a pilot study.

OBJECTIVE: Split-thickness skin graft (STSG) donor site dressings can play an integral role in reducing donor site morbidity. This study tested a novel, chitosan-based wound dressing, Opticell Ag, as an STSG donor site dressing for wounds <10% total body surface area (TBSA). METHOD: Between January and December 2016, the chitosan-based dressing was placed on participating patients' donor sites immediately following graft harvest and covered with a transparent occlusive dressing. Pain was evaluated on postoperative day one, before dressing change between days 5-7, and before and after dressing removal between days 10-14 using the Visual Analog Scale (VAS). The extent of re-epithelialisation was determined between day 10-14 and at one month, and healing quality was also evaluated at one month post-operatively using the Vancouver Scar Scale (VSS). RESULTS: A total of 19 patients were recruited, of which 16 completed the study. Patients experienced mild-to-moderate pain in their donor sites when the chitosan-based dressing was used. Pain decreased significantly between postoperative day one and days 10-14, as well as between days 5-7 and 10-14. The mean percentage of re-epithelialisation on days 10-14 was 92% and by one month was 99%. The mean VSS at one month was 3.2±1.4. There were no statistically significant differences between patients' re-epithelialisation rates or VSS scores. There were unplanned dressing changes in four patients. No donor site infections or other adverse events were identified. CONCLUSION: The chitosan-based dressing tested in this study is safe, effective, and associated with reasonable pain control and acceptable healing quality. The results suggest that it is a promising STSG donor site dressing.

Prolyl Hydroxylase Domain-2 Inhibition Improves Skeletal Muscle Regeneration in a Male Murine Model of Obesity.

Obesity leads to a loss of muscle mass and impaired muscle regeneration. In obese individuals, pathologically elevated levels of prolyl hydroxylase domain enzyme 2 (PHD2) limit skeletal muscle hypoxia-inducible factor-1 alpha and vascular endothelial growth factor (VEGF) expression. Loss of local VEGF may further impair skeletal muscle regeneration. We hypothesized that PHD2 inhibition would restore vigorous muscle regeneration in a murine model of obesity. Adult (22-week-old) male mice were fed either a high-fat diet (HFD), with 60% of calories derived from fat, or a regular diet (RD), with 10% of calories derived from fat, for 16 weeks. On day 5 following cryoinjury to the tibialis anterior muscle, newly regenerated muscle fiber cross-sectional areas were significantly smaller in mice fed an HFD as compared to RD, indicating an impaired regenerative response. Cryoinjured gastrocnemius muscles of HFD mice also showed elevated PHD2 levels (twofold higher) and reduced VEGF levels (twofold lower) as compared to RD. Dimethyloxalylglycine, a cell permeable competitive inhibitor of PHD2, restored VEGF levels and significantly improved regenerating myofiber size in cryoinjured mice fed an HFD. We conclude that pathologically increased PHD2 in the obese state drives impairments in muscle regeneration, in part by blunting VEGF production. Inhibition of PHD2 over activity in the obese state normalizes VEGF levels and restores muscle regenerative potential.

CVD Prevention Through Policy: a Review of Mass Media, Food/Menu Labeling, Taxation/Subsidies, Built Environment, School Procurement, Worksite Wellness, and Marketing Standards to Improve Diet.

Poor diet is the leading cause of cardiovascular disease in the USA and globally. Evidence-based policies are crucial to improve diet and population health. We reviewed the effectiveness for a range of policy levers to alter diet and diet-related risk factors. We identified evidence to support benefits of focused mass media campaigns (especially for fruits, vegetables, salt), food pricing strategies (both subsidies and taxation, with stronger effects at lower income levels), school procurement policies (for increasing healthful or reducing unhealthful choices), and worksite wellness programs (especially when comprehensive and multicomponent). Evidence was inconclusive for food and menu labeling (for consumer or industry behavior) and changes in local built environment (e.g., availability or accessibility of supermarkets, fast food outlets). We found little empiric evidence evaluating marketing restrictions, although broad principles and large resources spent on marketing suggest utility. Widespread implementation and evaluation of evidence-based policy strategies, with further research on other strategies with mixed/limited evidence, are essential "population medicine" to reduce health and economic burdens and inequities of diet-related illness worldwide.

A Comparison of Different Methods for Evaluating Diet, Physical Activity, and Long-Term Weight Gain in 3 Prospective Cohort Studies.

BACKGROUND: The insidious pace of long-term weight gain (∼ 1 lb/y or 0.45 kg/y) makes it difficult to study in trials; long-term prospective cohorts provide crucial evidence on its key contributors. Most previous studies have evaluated how prevalent lifestyle habits relate to future weight gain rather than to lifestyle changes, which may be more temporally and physiologically relevant. OBJECTIVE: Our objective was to evaluate and compare different methodological approaches for investigating diet, physical activity (PA), and long-term weight gain. METHODS: In 3 prospective cohorts (total n = 117,992), we assessed how lifestyle relates to long-term weight change (up to 24 y of follow-up) in 4-y periods by comparing 3 analytic approaches: 1) prevalent diet and PA and 4-y weight change (prevalent analysis); 2) 4-y changes in diet and PA with a 4-y weight change (change analysis); and 3) 4-y change in diet and PA with weight change in the subsequent 4 y (lagged-change analysis). We compared these approaches and evaluated the consistency across cohorts, magnitudes of associations, and biological plausibility of findings. RESULTS: Across the 3 methods, consistent, robust, and biologically plausible associations were seen only for the change analysis. Results for prevalent or lagged-change analyses were less consistent across cohorts, smaller in magnitude, and biologically implausible. For example, for each serving of a sugar-sweetened beverage, the observed weight gain was 0.01 lb (95% CI: -0.08, 0.10) [0.005 kg (95% CI: -0.04, 0.05)] based on prevalent analysis; 0.99 lb (95% CI: 0.83, 1.16) [0.45 kg (95% CI: 0.38, 0.53)] based on change analysis; and 0.05 lb (95% CI: -0.10, 0.21) [0.02 kg (95% CI: -0.05, 0.10)] based on lagged-change analysis. Findings were similar for other foods and PA. CONCLUSIONS: Robust, consistent, and biologically plausible relations between lifestyle and long-term weight gain are seen when evaluating lifestyle changes and weight changes in discrete periods rather than in prevalent lifestyle or lagged changes. These findings inform the optimal methods for evaluating lifestyle and long-term weight gain and the potential for bias when other methods are used.

Changes in intake of protein foods, carbohydrate amount and quality, and long-term weight change: results from 3 prospective cohorts.

BACKGROUND: Dietary guidelines recommend interchanging protein foods (e.g., chicken for red meat), but they may be exchanged for carbohydrate-rich foods varying in quality [glycemic load (GL)]. Whether such exchanges occur and how they influence long-term weight gain are not established. OBJECTIVE: Our objective was to determine how changes in intake of protein foods, GL, and their interrelationship influence long-term weight gain. DESIGN: We investigated the association between 4-y changes in consumption of protein foods, GL, and their interaction with 4-y weight change over a 16- to 24-y follow-up, adjusted for other lifestyle changes (smoking, physical activity, television watching, sleep duration), body mass index, and all dietary factors simultaneously in 3 prospective US cohorts (Nurses' Health Study, Nurses' Health Study II, and Health Professionals Follow-Up Study) comprising 120,784 men and women free of chronic disease or obesity at baseline. RESULTS: Protein foods were not interchanged with each other (intercorrelations typically <|0.05|) but with carbohydrate (negative correlation as low as -0.39). Protein foods had different relations with long-term weight gain, with positive associations for meats, chicken with skin, and regular cheese (per increased serving/d, 0.13-1.17 kg; P = 0.02 to P < 0.001); no association for milk, legumes, peanuts, or eggs (P > 0.40 for each); and relative weight loss for yogurt, peanut butter, walnuts, other nuts, chicken without skin, low-fat cheese, and seafood (-0.14 to -0.71 kg; P = 0.01 to P < 0.001). Increases in GL were independently associated with a 0.42-kg greater weight gain per 50-unit increase (P < 0.001). Significant interactions (P-interaction < 0.05) between changes in protein foods and GL were identified; for example, increased cheese intake was associated with weight gain when GL increased, with weight stability when GL did not change, and with weight loss when exchanged for GL (i.e., decrease in GL). CONCLUSION: Protein foods were commonly interchanged with carbohydrate, and changes in protein foods and GL interacted to influence long-term weight gain.

Ethnic influences on the relations between abdominal subcutaneous and visceral adiposity, liver fat, and cardiometabolic risk profile: the International Study of Prediction of Intra-Abdominal Adiposity and Its Relationship With Cardiometabolic Risk/Intra-Abdominal Adiposity.

BACKGROUND: Ethnic differences in cardiometabolic risk (CMR) may be related to patterns of ethnic-specific body fat distribution. OBJECTIVE: We aimed to identify differences across ethnic groups in interrelations between BMI, abdominal adiposity, liver fat, and CMR profile. DESIGN: In the International Study of Prediction of Intra-Abdominal Adiposity and Its Relationship With Cardiometabolic Risk/Intra-Abdominal Adiposity, 297 physicians recruited 4504 patients (from 29 countries). In the current cross-sectional analyses, 2011 whites, 166 African Caribbean blacks, 381 Hispanics, 1192 East Asians, and 347 Southeast Asians were included. Computed tomography was used to assess abdominal fat distribution and to estimate liver fat content. Anthropometric variables and CMR profile were measured. RESULTS: Higher ranges of BMI were associated with higher levels of visceral [visceral adipose tissue (VAT)] and deep subcutaneous [deep subcutaneous adipose tissue (DSAT)] adiposity, with significant ethnic differences regarding the slope of these relations. Despite lower absolute BMI values, East Asians presented the largest accumulation of VAT but the lowest accumulation of DSAT with increasing adiposity. The association of BMI with liver fat did not differ between ethnic groups. Liver fat and DSAT were positively correlated with VAT with no ethnic variation. All ethnic groups had a similar association between a 1-SD increase in VAT, DSAT, or liver fat with hypertension, type 2 diabetes, hypertriglyceridemia, low HDL-cholesterol concentration, or high C-reactive protein concentration. CONCLUSIONS: Ethnicity significantly affects abdominal adiposity and liver fat partitioning, and East Asians have the most deleterious abdominal fat distribution. Irrespective of ethnicity, abdominal and hepatic fat depots are strongly interrelated and increased with obesity. Higher amounts of VAT or liver fat are associated with a more deteriorated CMR profile in all ethnic groups.

Visceral adipose tissue indicates the severity of cardiometabolic risk in patients with and without type 2 diabetes: results from the INSPIRE ME IAA study.

BACKGROUND: Visceral adiposity is an important correlate of cardiometabolic risk, yet its association after the diagnosis of type 2 diabetes remains unclear. METHODS: Our objective was to assess the independent and combined associations of visceral adiposity and type 2 diabetes to cardiometabolic risk. The INternational Study of Prediction of Intra-abdominal adiposity and its RElationships with cardioMEtabolic risk/Intra-Abdominal Adiposity (INSPIRE ME IAA) is a cross-sectional computed tomography imaging study with data collected from June 2006 to May 2008. General physicians, cardiologists, and diabetologists (n = 297) in 29 countries recruited 4144 (51.8% men) men (39-71 yr) and women (44-71 yr). Patients were categorized according to visceral adiposity tertiles, type 2 diabetes status, and sex. All results were adjusted for age, body mass index, region, and physician's specialty. RESULTS: Markers of insulin resistance, lipid/lipoproteins, inflammatory markers, and liver fat increased with visceral adiposity in men and women with and without type 2 diabetes. Prevalent cardiovascular disease increased with visceral adiposity tertiles, regardless of type 2 diabetes status. Visceral adiposity [odds ratio = 1.25 (1.09-1.44) for men and 1.78 (1.50-2.12) for women] was positively associated with type 2 diabetes, whereas liver attenuation (inversely related to liver fat) was negatively associated with type 2 diabetes [odds ratio = 0.66 (0.59-0.75) for men and 0.63 (0.55-0.72) for women]. Subcutaneous adipose tissue was inversely related to type 2 diabetes in women [0.76 (0.0.66-0.88)] and not associated with type 2 diabetes in men [0.97 (0.85-1.11)]. CONCLUSIONS: Visceral, but not sc, abdominal adiposity is strongly related to cardiometabolic risk factors and to the prevalence of cardiovascular disease and may be an important driver of cardiometabolic risk in patients regardless of type 2 diabetes status.

Plasma adipokine and hormone changes in mountaineers on ascent to 5300 meters.

OBJECTIVE: The current study evaluated multiple metabolic and inflammatory hormone responses in recreational climbers (7 men and 3 women, age 26-49 years) over 9 days. In particular, acylation-stimulating protein (ASP), which influences fat storage in adipose tissue, has not been measured at high altitude. METHODS: Serial measurements were taken at sea level (SL), or 353 m, on day 0, 4000 m on day 3, 4750 m on day 6, and 5300 m on day 9 of the expedition. RESULTS: Body mass index (BMI) decreased upon ascent to 5300 m from SL (SL 23.2 ± 1.5 kg/m(2); 4000 m 23.2 ± 1.4 kg/m(2); 4750 m 22.9 ± 1.3 kg/m(2); 5300 m 22.3 ± 1.2 kg/m(2); P<.001). Similarly, plasma non-esterified fatty acids and triglycerides increased, while HDL cholesterol decreased (P<.05 to <.001) from SL to 5300 m. Acylation-stimulating protein (SL 42.2 ± 40.2 nm; 4000 m 117.0 ± 69.6 nm; 4750 m 107.9 ± 44.5 nm; 5300 m 82.2 ± 20.2 nm; P=.019) and adiponectin (SL 10.4 ± 6.5 ng/mL, 4000 m 13.9 ± 8.5 ng/mL, 4750 m 18.3 ± 8.3 ng/mL, 5300 m 14.7 ± 8.0 ng/mL; P=.015) increased, as did insulin and Interleukin-6 (IL-6) levels (up to 71% and 168%, respectively; P<.05) with no change in leptin, complement C3 (C3), high sensitivity C-reactive protein (hsCRP) or cortisol levels throughout the mountain ascent from SL to 5300 m. CONCLUSION: Acylation-stimulating protein and adiponectin are increased during a 9-day period of high altitude (SL to 5300 m) exposure despite weight loss in healthy mountaineers.

Acylation stimulating protein is higher in Inuit from Nunavik compared to a southern Quebec population.

OBJECTIVES: The Inuit of Nunavik in northern Quebec have a lower risk for ischemic heart disease (IHD) compared to Caucasian populations. Acylation stimulating protein (ASP), which is involved in the storage of dietary fat, may play a role. The objective of the study was to determine plasma concentration of ASP in an Inuit and a southern Quebec Caucasian population. STUDY DESIGN: This is a cross-sectional study evaluating the relationship between ASP and dietary factors, such as retinol, whose intake is higher in the Inuit. As well, concentrations of ASP were evaluated in relationship to components of the metabolic syndrome. METHODS: Medical history was collected via a questionnaire and anthropometric measurements and blood samples were collected. RESULTS: ASP was significantly higher in both the Inuit men and women compared to Caucasian men (66.1 +/- 4.1 nM vs 27.5 +/- 2.5 nM, p < 0.0001) and women (71.8 +/- 3.8 nM vs 29.4 +/- 1.3 nM, p < 0.0001). In addition, ASP significantly correlated with total retinol (r = 0.17, p = 0.02) and free retinol (r = 0.15, p = 0.04) in Inuit men but not with other distinctive dietary markers such as omega-3 fatty acids. CONCLUSIONS: Inuit men and women have higher ASP which was unrelated to the number of risk factors for IHD that were present.