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Background: Recent work has shown that two-thirds of patients report functional disability 1 week after an emergency department (ED) visit for nontraumatic musculoskeletal low back pain (LBP). Nearly half of these patients report functional disability 3 months later. Identifying high-risk predictors of functional disability at each of these 2 time points will allow emergency clinicians to provide individual patients with an evidence-based understanding of their risk of protracted symptoms.Object: The aim of the present study was to determine whether 5 high-risk features previously identified in various primary care settings predict poor functional outcomes among patients in the ED. The hypothesized predictors are as follows: LBP-related functional disability at baseline, radicular signs, depression, a work-related injury, or a history of chronic or recurrent LBP before the index episode.Methods: We conducted a prospective observational cohort study of patients in the ED with a chief complaint of nontraumatic LBP, which the ED attending physician classified as musculoskeletal. We interviewed patients in the ED before discharge and performed a baseline assessment of functional disability using the 24-item Roland-Morris questionnaire. We also trichotomized the patient's baseline history of LBP into chronic (defined as 30 straight days with continuous LBP or a history of acute exacerbations more frequently than once per week); episodic (acute exacerbations more frequently than once per year but less frequently than once per week), or rarely/never (less frequently than once per year or no history of LBP). We performed telephone follow-up 1 week and 3 months after ED discharge using a scripted closed-question data collection instrument. The primary outcome was any functional limitation attributable to LBP at 1 week and 3 months, defined as a score greater than zero on the Roland-Morris questionnaire. We used logistic regression, adjusted for age, sex, and educational level, to assess the independent association between functional disability and each of the 5 hypothesized predictors listed above.Results: We approached 894 patients for participation and included 556. We obtained follow-up on 97% and 92% of our sample at 1 week and 3 months, respectively. Two of the 5 hypothesized variables predicted functional disability at both time points: higher baseline Roland-Morris score (odds ratio [OR], 4.3; 95% confidence interval [CI], 2.6-6.9) and chronic LBP (OR, 2.3; 95% CI, 1.1-4.8) were associated with 7-day functional disability. These same 2 variables predicted functional disability 3 months after ED discharge-higher baseline Roland-Morris score (OR, 2.3; 95% CI, 1.4-3.9) and chronic LBP (OR, 2.8; 95% CI, 1.5-5.2). The remaining 3 hypothesized predictors (depression, radicular signs, and on-the-job injury) did not predict functional outcome at either time point.Conclusions: Patients in the ED with worse baseline functional impairment and a history of chronic LBP are 2 to 4 times most likely to have poor short- and longer-term outcomes. [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVE: We test the efficacy and safety of the '1+1' (1 mg plus 1 mg 15 minutes later if needed) hydromorphone protocol against usual care of emergency department (ED) patients with acute severe pain. METHODS: This was a prospective, randomized clinical trial of ED patients with acute severe pain. The 1+1 protocol specifies administration of 1 mg intravenous hydromorphone, followed by a second dose of 1 mg intravenous hydromorphone 15 minutes after the first bolus if the patient answers yes to the question, 'Do you want more pain medication?' Usual care is the administration of any intravenous opioid, with type and dose chosen by the ED attending physician. Usual care patients who wanted more medication at 15 minutes were treated at the physician's discretion. At 60 minutes, all patients were asked again whether they wanted more pain medication. The primary outcome was successful treatment defined a priori as not wanting additional analgesia at either 15 or 60 minutes after the initial bolus. The primary endpoint was the difference in the proportion of patients with successful treatment who received the complete 1+1 protocol versus usual care with a per-protocol analysis. An intention-to-treat analysis was also performed. A 10% difference in rate of successful treatment was chosen a priori as a clinically meaningful difference. RESULTS: Of 167 patients in the 1+1 group, 156 received the full 1+1 protocol, whereas 171 received usual care. Of patients who received the 1+1 protocol, 92.3% (144/156) had successful treatment versus 76.6% (131/171) of usual care patients (difference=15.7%; 95% confidence interval 7.9% to 23.3%). In the intention-to-treat analysis, 86.8% (145/167) of patients randomized to the 1+1 group received successful treatment versus 76.6% (131/171) of usual care patients (difference=10.2%; 95% confidence interval 2.0% to 18.3%). No patient required naloxone. One patient in the 1+1 group and 2 patients in the usual care group had transient oxygen saturation less than 95%. The incidence of all adverse effects was similar in both groups. CONCLUSION: When analyzed per protocol or with the more conservative intention-to-treat analysis, the 1+1 hydromorphone protocol is statistically and clinically more efficacious than usual care. Safety profiles were similar in both groups. [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVE: We evaluate the safety and efficacy of a pain protocol using 1 mg intravenous (IV) hydromorphone followed by an optional dose of 1 mg IV hydromorphone 15 minutes later. METHODS: Prospective interventional study at an urban academic emergency department (ED). One milligram of IV hydromorphone was administered to adults 21 to 64 years of age who had acute severe pain. Fifteen minutes later, patients were asked whether they wanted more pain medication. If they answered yes, they received another 1 mg of IV hydromorphone and were again asked 15 minutes later whether they wanted more pain medication. The primary efficacy outcome was the proportion of patients who had adequate analgesia, defined as declining additional hydromorphone within 1 hour of entering the protocol. The primary safety outcome was incidence of oxygen desaturation less than 95%. Secondary outcomes included numeric rating scale pain scores and adverse events. RESULTS: Of the 223 patients with complete data, 1 mg IV hydromorphone provided adequate analgesia for 77% (95% confidence interval 71% to 82%) within 15 minutes and 96% (95% confidence interval 92% to 98%) within 1 hour of entering the protocol. Eighty-six percent of patients reported pain scores that decreased by 2 or more numeric rating scale units. Five percent experienced transient oxygen desaturation below 95%, which was corrected promptly with oxygen. CONCLUSION: A rapid titration protocol using IV hydromorphone (1 mg hydromorphone followed by an optional 1 mg 15 minutes later) is efficacious in nonelderly ED patients with acute severe pain. There were no serious adverse events. [ABSTRACT FROM AUTHOR]

Background: Studies of IV magnesium sulfate as a treatment for acute asthma have had mixed results, with some data suggesting a benefit for acute severe asthma, but not for mild-to-moderate asthma. In a multicenter cohort, this study tests the hypothesis that administration of magnesium sulfate improves pulmonary function in patients with acute severe asthma.Design: Placebo-controlled, double-blind, randomized clinical trial.Setting: Emergency departments (EDs) of eight hospitals.Patients: Patients aged 18 to 60 years presenting with acute asthma and FEV1 < or = 30% predicted on arrival to the ED.Intervention: All patients received nebulized albuterol at regular intervals and IV methylprednisolone. Two grams of IV magnesium sulfate or placebo were administered 30 min after ED arrival. The primary efficacy end point was FEV1 at 240 min, and the data analysis was intent to treat.Results: Two hundred forty-eight patients were included, and the mean FEV1 on ED arrival was 22.9% predicted. At 240 min, patients receiving magnesium had a mean FEV1 of 48.2% predicted, compared to 43.5% predicted in the placebo-treated group (mean difference, 4.7%; 95% confidence interval [CI], 0.29 to 9.3%; p = 0.045). A regression model confirmed the effect of magnesium compared to placebo was greater in patients with a lower initial FEV1 (p < 0.05). If the initial FEV1 was < 25% predicted, the final FEV1 was 45.3% predicted in the magnesium-treated group and 35.6% predicted in the placebo-treated group (mean difference, 9.7%; 95% CI, 4.0 to 15.3%; p = 0.001). If the initial FEV was > or = 25% predicted, magnesium administration was not beneficial; the final FEV1 was 51.1% predicted in the magnesium-treated group and 53.9% predicted in the placebo-treated group (mean difference, - 2.9%, 95% CI, - 9.4 to 3.7; p = not significant). Overall, the use of magnesium sulfate did not improve hospital admission rates.Conclusion: Administration of 2 g of IV magnesium sulfate improves pulmonary function when used as an adjunct to standard therapy in patients with very severe, acute asthma. [ABSTRACT FROM AUTHOR]

Objective: To examine the independent relationship between effectiveness of bystander cardiopulmonary resuscitation (CPR) and survival following out-of-hospital cardiac arrest.Design: Prospective observational cohort.Setting: New York City.Participants: A total of 2071 consecutive out-of-hospital cardiac arrests meeting Utstein criteria.Intervention: Trained prehospital personnel assessed the quality of bystander CPR on arrival at the scene. Satisfactory execution of CPR required performance of both adequate compressions and ventilations in conformity with current American Heart Association guidelines.Main Outcome Measure: Adjusted association between CPR effectiveness and survival. Survival was defined as discharge from hospital to home.Results: Outcome was determined on all members of the inception cohort--none were lost to follow-up. When the association between bystander CPR and survival was adjusted for effectiveness of CPR in the parent data set (N = 2071), only effective CPR was retained in the logistic model (adjusted odds ratio [OR] = 5.7; 95% confidence interval [CI], 2.7 to 12.2; P < .001). Of the subset of 662 individuals (32%) who received bystander CPR, 305 (46%) had it performed effectively. Of these, 4.6% (14/305) survived vs 1.4% (5/357) of those with ineffective CPR (OR = 3.4; 95% CI, 1.1 to 12.1; P < .02). After adjustment for witness status, initial rhythm, interval from collapse to CPR, and interval from collapse to advanced life support, effective CPR remained independently associated with improved survival (adjusted OR = 3.9; 95% CI, 1.1 to 14.0; P < .04).Conclusion: The association between bystander CPR and survival in out-of-hospital cardiac arrest appears to be confounded by CPR quality. Effective CPR is independently associated with a quantitatively and statistically significant improvement in survival. [ABSTRACT FROM AUTHOR]

Objective: To determine survival from out-of-hospital cardiac arrest in New York City and to compare this with other urban, suburban, and rural areas.Design: Observational cohort study.Setting: New York City.Participants: Consecutive out-of-hospital cardiac arrests occurring between October 1, 1990, and April 1, 1991.Intervention: Trained paramedics performed immediate postarrest interviews with care providers, using a standardized questionnaire.Main Outcome Measures: Entry criteria, elapsed time intervals, and nodal events conformed to Utstein recommendations. The single target end point was death or discharge home.Results: Of 3243 consecutive cardiac arrests on which resuscitation was attempted, 2329 (72%) met entry criteria as primary cardiac events. Overall survival was 1.4% (99% confidence interval [CI], 0.9% to 2.3%). No patients were lost to follow-up. Survival from witnessed ventricular fibrillation was 5.3% (99% CI, 2.9% to 8.8%). Using survival from witnessed ventricular fibrillation for intersystem comparison, our survival rate was similar to that of Chicago, Ill (4.0%; 99% CI, 1.9% to 7.5%; P = .41), the only other large city on which data were available. However, it was significantly lower than that reported from midsized urban/suburban areas (33.0%; 99% CI, 30.4% to 35.6%; P < .0001) and suburban/rural areas (12.6%; 99% CI, 8.9% to 16.3%; P < .0001). Survival rate among arrests occurring after arrival of emergency medical services personnel (8.5%; 99% CI, 4.7% to 14.0%) was comparable with Chicago (6.6%; 99% CI, 3.3% to 11.5%; P = .41) but markedly lower than King County, Washington (36%; 99% CI, 28.6% to 43.8%; P < .0001).Conclusions: Survival from out-of-hospital cardiac arrest in New York City was poor. This was partly attributable to lengthy elapsed time intervals at every step in the chain of survival. However, examination of survival among arrests occurring after emergency medical services arrival suggests that other features may predispose residents of large cities to higher cardiac arrest mortality than individuals living in more suburban or rural settings. Since half the US population resides in large metropolitan areas, this represents a public health problem of considerable magnitude. [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVE: Nearly 3 million patients present to US emergency departments (EDs) annually with undifferentiated musculoskeletal low back pain. Little is known about short- and longer-term outcomes in this group. We seek to describe the pain and functional outcomes 1 week and 3 months after discharge in a sample of ED patients presenting with undifferentiated musculoskeletal low back pain. METHODS: We used a prospective observational descriptive cohort design, enrolling ED patients with a chief complaint of low back pain classified as musculoskeletal in origin by the ED attending physician. We defined low back pain as pain originating in the posterior back between the tips of the scapulae and upper buttocks and excluded any patient with a traumatic back injury occurring within the previous month. We interviewed patients in the ED and then by telephone follow-up 1 week and 3 months after ED discharge, using a scripted closed-question data collection instrument. Our primary outcome was functional limitation attributable to low back pain assessed with a validated scale. Secondary outcomes included pain and analgesic use during the 24 hours before each follow-up telephone call. RESULTS: During a 9-month period beginning in July 2009, we approached 894 patients, of whom 556 were enrolled. We obtained follow-up on 97% of our sample at 1 week and 92% at 3 months. One week after ED discharge, 70% (95% confidence interval [CI] 66% to 74%) of patients reported back pain-related functional impairment, 59% (95% CI 55% to 63%) reported moderate or severe low back pain, and 69% (95% CI 65% to 73%) reported analgesic use within the previous 24 hours. Three months after ED discharge, 48% (95% CI 44% to 52%) of patients reported functional impairment, 42% (95% CI 38% to 46%) reported moderate or severe pain, and 46% (95% CI 44% to 50%) reported analgesic use within the previous 24 hours. CONCLUSION: There is substantial short- and longer-term morbidity and ongoing analgesic use among patients who present to an ED with undifferentiated musculoskeletal low back pain. [ABSTRACT FROM AUTHOR]

Assays that measure morphology, proliferation, motility, deformability, and migration are used to study the invasiveness of cancer cells. However, native invasive potential of cells may be hidden from these contextual metrics because they depend on culture conditions. We created a micropatterned chip that mimics the native environmental conditions, quantifies the invasive potential of tumor cells, and improves our understanding of the malignancy signatures. Unlike conventional assays, which rely on indirect measurements of metastatic potential, our method uses three-dimensional microchannels to measure the basal native invasiveness without chemoattractants or microfluidics. No change in cell death or proliferation is observed on our chips. Using six cancer cell lines, we show that our system is more sensitive than other motility-based assays, measures of nuclear deformability, or cell morphometrics. In addition to quantifying metastatic potential, our platform can distinguish between motility and invasiveness, help study molecular mechanisms of invasion, and screen for targeted therapeutics.

Purpose: Approximately 15% of women who receive ovarian function suppression (OFS) as adjuvant treatment for high-risk, localized hormone receptor-positive (HR+) breast cancer may have inadequate estradiol suppression which can require therapeutic modification when used in combination with an aromatase inhibitor (AI). We previously reported that abemaciclib may interfere with the estradiol Abbott Alinity chemiluminescent microparticle immunoassay (CMIA) commonly used to monitor estradiol levels and suggested liquid chromatography-mass spectrometry (LC-MS/MS) is preferred in this setting. The aim of this study was to determine discrepancies in estradiol levels using CMIA compared to LC-MS/MS and subsequent treatment changes in a larger patient population., Methods: We conducted a retrospective review of premenopausal women with early-stage HR+ breast cancer at our institution who received adjuvant OFS and abemaciclib with at least 1 CMIA estradiol level drawn during abemaciclib therapy from October 2021 to April 2023., Results: Of the 22 women who met criteria for review, 20 (90.9%) had CMIA estradiol levels in the premenopausal range, of whom 9 also had estradiol measured by LC-MS/MS. All 9 women receiving OFS and abemaciclib with estradiol measurements by both methods had premenopausal range CMIA estradiol levels and postmenopausal range LC-MS/MS estradiol levels. Of the 20 patients with premenopausal estradiol levels by CMIA estradiol, treatment changes included increased OFS dosage or preparation (n = 7), change from AI to tamoxifen (n = 3), and surgical oophorectomy (n = 7)., Conclusion: Our findings suggest the likely interference of abemaciclib with the Abbott Alinity immunoassay which may lead to unnecessary treatment changes. It is recommended that the LC-MS/MS assay be used when monitoring estradiol levels in patients receiving abemaciclib concurrently with OFS., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Physician-scientists play a crucial role in advancing medical knowledge and patient care, yet the long periods of time required to complete training may impede expansion of this workforce. We examined the relationship between postgraduate training and time to receipt of NIH or Veterans Affairs career development awards (CDAs) for physician-scientists in internal medicine. Data from NIH RePORTER were analyzed for internal medicine residency graduates who received specific CDAs (K08, K23, K99, or IK2) in 2022. Additionally, information on degrees and training duration was collected. Internal medicine residency graduates constituted 19% of K awardees and 28% of IK2 awardees. Of MD-PhD internal medicine-trained graduates who received a K award, 92% received a K08 award; of MD-only graduates who received a K award, a majority received a K23 award. The median time from medical school graduation to CDA was 9.6 years for K awardees and 10.2 years for IK2 awardees. The time from medical school graduation to K or IK2 award was shorter for US MD-PhD graduates than US MD-only graduates. We propose that the time from medical school graduation to receipt of CDAs must be shortened to accelerate training and retention of physician-scientists.

Purpose: Black women are more likely than White women to have obesity, and obesity is associated with worse breast cancer prognosis. Weight perception, however, has not been studied as a potential mediator of obesity disparities in women with breast cancer. In this study, we sought to describe racial differences and the association of lifestyle factors with weight perception., Methods: In this cross-sectional study design, Black and White women with a new primary breast cancer were surveyed about socio-demographics, weight perception, diet, and exercise habits. Height and weight were measured at enrollment. We classified women with a BMI ≥ 25 kg/m 2 or waist circumference ≥ 88 cm who reported that they were "about the right weight" as under-perceivers. Chi-square and t tests were used to assess study variables (e.g., race, physical activity) associated with under-perception of weight. Logistic regression models were fit to evaluate for racial differences in under-perception while controlling for other covariates., Results: Of 1,197 women with newly diagnosed breast cancer, the average age was 58 years, and 909 (75.9%) were White. Nine hundred eighteen (77%) had stage I cancer, 1,035 (87%) had estrogen receptor positive cancer, and 795 (66%) were privately insured at time of diagnosis. Seven hundred eighty-nine (66%) women had abdominal obesity (waist circumference ≥ 88 cm), while 366 (31%) women had a BMI ≥ 25 kg/m 2 . Overall, 24% of women were under-perceivers. Compared to White women, Black women with WC ≥ 88 cm more frequently under-perceived their weight (24% vs. 14% p < 0.0001) were more obese with BMI > 30 kg/m 2 (51% vs. 23%, p < 0.0001) and had lower physical activity (22% vs. 77%, p < 0.0001). After controlling for age, education, and stage, Black women remained more likely to under-perceive their weight relative to White women for those with BMI ≥ 25 kg/m 2 (OR: 2.64; 95% CI: 1.4-4.6) or waist circumference ≥ 88 cm (OR: 2.89; 95% CI: 1.8-4.5). With respect to lifestyle factors, among women with BMI ≥ 25 kg/m 2 , those who met physical activity guidelines were less likely to under-perceive their weight compared to those who did not meet physical activity guidelines (OR: 0.37; 95% CI: 0.2-0.6), regardless of race., Conclusions: We found racial differences in weight perception and identified social determinants and lifestyle factors such as lower education and physical inactivity that influenced under-perception of weight among newly diagnosed breast cancer patients., Implications for Cancer Survivors: Since obesity is associated with worse breast cancer outcomes, identifying optimal modifiable factors to intervene upon to support weight management among breast cancer survivors is clinically important. Breast cancer patients' perceptions about their weight provide insight that may inform lifestyle behavior interventions to reduce obesity during survivorship care., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hyperglycemia and rash are expected but challenging adverse events of phosphatidylinositol-3-kinase inhibition (such as with alpelisib). Two modified Delphi panels were conducted to provide consensus recommendations for managing hyperglycemia and rash in patients taking alpelisib. Experts rated the appropriateness of interventions on a 1-to-9 scale; median scores and dispersion were used to classify the levels of agreement. Per the hyperglycemia panel, it is appropriate to start alpelisib in patients with HbA1c 6.5% (diabetes) to <8%, or at highest risk for developing hyperglycemia, if they have a pre-treatment endocrinology consult. Recommend prophylactic metformin in patients with baseline HbA1c 5.7% to 6.4%. Metformin is the preferred first-line anti-hyperglycemic agent. Per the rash panel, initiate prophylactic nonsedating H1 antihistamines in patients starting alpelisib. Nonsedating H1 antihistamines and topical steroids are the preferred initial management for rash. In addition to clinical trial evidence, these recommendations will help address gaps encountered in clinical practice., (© 2024. The Author(s).)

Abstract: Multiple myeloma (MM) is twice as common in Black individuals compared with in White individuals, and diabetes mellitus (DM) disproportionately affects Black patients. Although numerous studies have shown a correlation between DM and MM, this has not been studied in the context of race and in vivo mechanisms. We conducted a retrospective clinical study of 5383 patients with MM of which 15% had DM (White, 12% and Black, 25%). Multivariable Cox models showed reduced overall survival (OS) for patients with DM (hazard ratio, 1.27; 95% confidence interval, 1.11-1.47; P < .001). This appeared to be driven by a marked difference in OS between White patients with and without DM but not in Black patients. In contrast, obesity was associated with better OS in Black patients but not in White patients. To complement this analysis, we assessed MM growth in a genetically engineered immunocompromised nonobese diabetic (Rag1-/-/muscle creatinine kinase promoter expression of a human IGF1R [M] with a lysine [K] to arginine [R] point mutation) mouse model to evaluate the mechanisms linking DM and MM. MM.1S xenografts grew in more Rag1-/-/MKR mice and grew more rapidly in the Rag1-/-/MKR mice compared with in controls. Western blot analysis found that MM1.S xenografts from Rag1-/-/MKR mice had higher phosphorylated S6 ribosomal protein (Ser235/236) levels, indicating greater activation of the mammalian target of rapamycin pathway. Our study is, to our knowledge, the first to evaluate racial differences in DM prevalence and survival in MM, as well as the effect of DM on tumor growth in mouse models. Our results suggest that DM may contribute to the higher incidence of MM in Black patients; and to improve survival in MM, DM management cannot be ignored., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The growing complexities of clinical medicine and biomedical research have clouded the career path for physician-scientists. In this perspective piece, we address one of the most opaque career stage transitions along the physician-scientist career path, the transition from medical school to research-focused internal medicine residency programs, or physician-scientist training programs (PSTPs). We present the perspectives of medical scientist training program (MSTP) and PSTP directors on critical features of PSTPs that can help trainees proactively align their clinical and scientific training for successful career development. We aim to provide both trainees and MSTP directors with a conceptual framework to better understand and navigate PSTPs. We also offer interview-specific questions to help trainees gather data and make informed decisions in choosing a residency program that best supports their career., Competing Interests: CW, OA, PH Reviewing Editor, eLife, EG, DR, BK, CK, JV, KR No competing interests declared, MZ Deputy Editor, eLife

Objective: The management of insulin injections and insulin pumps before 18F-fluorodeoxyglucose-positron emission tomography integrated computerized tomography (FDG-PET/CT) scans is an important area to investigate given the rising rate of diabetes, the significant association between diabetes and cancer, and the complex relationship among glucose, insulin, and FDG tumor uptake. The purpose of this study was to determine the recommendations around subcutaneous insulin administration, insulin pumps, and hybrid closed-loop systems before FDG-PET scans., Methods: We examined the websites of 100 hospitals selected from the 2022 US News and World Report top cancer hospitals for specific strategies around diabetes medication management before FDG-PET/CT scans., Results: Of the 100 hospital websites, 61 had instructions addressing patients with diabetes. Of the 61 hospitals, 47.5% (n = 29) referred patients to their provider for further instructions, 18% (n = 11) referred patients to their own internal radiology department for further instructions, 16.4% (n = 10) had instructions on oral diabetic medications, 23% (n = 14) had instructions on insulin, and 3.3% (n = 2) had instructions on insulin pump management. Most commonly, instructions were to stop insulin 3 to 4 hours before the study and direct patients to their referring provider for more detailed instructions (n = 7)., Conclusion: There is a lack of guidance and consensus among US cancer hospitals on managing insulin and continuous subcutaneous insulin infusions before FDG-PET/CT studies and a majority rely on referring providers to advise patients. However, society guidelines offer inconsistent recommendations and little research has been carried out to help guide referring providers. A multidisciplinary panel of specialists could help to guide practitioners on optimal management., Competing Interests: Disclosure S.S. reports no conflicts of interest. E.J.G. reports consulting for Flare Therapeutics, Novartis, and Seagen., (Copyright © 2023 AACE. Published by Elsevier Inc. All rights reserved.)

Background: Diabetes is a common comorbidity in patients with early-stage non-small cell lung cancer (NSCLC), a growing population due to increased LC screening. However, it is unknown if diabetes is associated with less aggressive NSCLC treatment and worse NSCLC outcomes. This study aimed to investigate treatment patterns and outcomes of older patients with Stage I NSCLC and diabetes., Methods: Using national cancer registry data linked to Medicare, we identified patients ≥65 years old with Stage I NSCLC. Patients were categorized as having no diabetes, diabetes without severe complications (DM-c), or diabetes with ≥1 severe complication (DM + c). We used multinomial logistic regression to assess the association of diabetes and NSCLC treatment. The association of diabetes category with NSCLC and non-NSCLC survival was analyzed with Fine-Grey competing-risks regression., Results: In 25,358 patients (75% no diabetes, 12% DM-c and 13% had DM + c), adjusted analyses showed that DM-c and DM + c were associated with increased odds of receiving limited resection rather than lobectomy (odds ratio [OR]: 1.22, 95% confidence interval [CI]: 1.07-1.37 and OR 1.42, 95% CI 1.26-1.59, respectively). Competing risk regression showed diabetes was associated with increased risk of non-NSCLC death (DM-c hazard ratio [HR] 1.16, 95% CI: 1.08-1.25, DM + c HR 1.49, 95% CI: 1.40-1.59), but not NSCLC-specific death., Conclusion: This study uncovers critical information on how diabetes is associated with less aggressive early-stage NSCLC care in older patients. This study also confirms that diabetes increases death from non-lung cancer causes and managing comorbidities is crucial to improving outcomes in older early-stage NSCLC survivors., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: EJG has served on an advisory board for Novartis pharmaceuticals and as a consultant for Seattle Genetics and SynDevRx. DLR has served on the advisory boards for Mannkind and Astra Zeneca. JPW reports consulting honoraria from Atea, Sanofi, and Banook, and PPD and research grants from Sanofi, Regeneron and Arnold Consultants. AL, CS, GM, KS, JJL, and CYK have no disclosures to report., (© 2023 The Authors.)

Purpose: Stress-induced adrenergic signaling can suppress the immune system. In animal models, pharmacological beta-blockade stimulates CD8 + T-cell activity and improves clinical activity of immune checkpoint blockade (ICB) in inhibiting tumor growth. Herein, we investigated the effect of BB on clinical outcomes of patients receiving ICB in advanced solid tumors., Methods: We retrospectively evaluated patients with solid tumors treated with ICB at our institution from January 1, 2011 to April 28, 2017. The primary clinical outcome was disease control. Secondary clinical outcomes were overall survival (OS), and duration of therapy (DoT). The primary predictor was use of BB. Association between disease control status and BB use was assessed in univariable and multivariable logistic regression. OS was calculated using hazard ratios of BB-recipient patients vs. BB non-recipient patients via Cox proportional hazards regression models. All tests were two-sided at a significance level of 0.05., Results: Of 339 identified patients receiving ICB, 109 (32%) also received BB. In covariate-adjusted analysis, odds of disease control were significantly higher among BB recipients compared to BB-non-recipients (2.79; [1.54-5.03]; P = 0.001). While we did not observe significant association of OS with the use of BB overall, significant association with better OS was observed for the urothelial carcinoma cohort (HR: 0.24; [0.09, 0.62]; P = 0.0031)., Conclusions: Concurrent use of BB may enhance the clinical activity of ICB and influence overall survival, particularly in patients with urothelial carcinoma. Our findings warrant further investigation to understand the interaction of beta adrenergic signaling and antitumor immune activity and explore a combination strategy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Weight gain is a known adverse effect of ruxolitinib, a JAK1/2 inhibitor that is the mainstay of treatment for many patients with myelofibrosis. The mechanisms behind weight increase with ruxolitinib is incompletely understood, although decreased adipose tissue lipolysis and increased appetite due to blocking the effects of leptin in the hypothalamus have been proposed. In order to explore the metabolic changes in ruxolitinib-treated patients with myelofibrosis, we performed a pilot study to assess the feasibility of using a portable indirect calorimeter to quantify energy expenditure before and during ruxolitinib treatment and report the results of two patients. Waist circumference increased during ruxolitinib treatment in both patients. Energy expenditure initially increased followed by a decrease and then increase again, but to levels below baseline. These results suggest that weight gain secondary to ruxolitinib may be related to changes in whole body energy expenditure., Competing Interests: DT receives research funding paid to his institution from CTI Biopharma, Astellas Pharma and Gilead and consulting fees from AbbVie, Sierra Oncology, GSK and Cogent. JM receives research funding paid to his institution from Incyte, CTI Bio, Novartis, PharmaEssentia, Merck, Kartos, Geron, BMS, Roche, and consulting fees from Incyte, CTI Bio, Novartis, Roche, BMS, Celgene, Geron, PharmaEssentia, Morphosys, Sierra Oncology, GSK, Galecto, Karyopharm, Kartos, and Imago. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tremblay, Dougherty, Mascarenhas and Gallagher.)

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis., Methods: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms., Discussion: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options., Registration: NCT05172024., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Helen Chu reported consulting for Merck, GSK, Pfizer, Ellume, Janssen, Vindico CME, and the Bill and Melinda Gates Foundation, and receiving research support from Gates Ventures, Ellume, and Sanofi Pasteur. She also serves as a co-investigator on studies funded by Pfizer, Novavax, and GSK. Maged Costantine reported receiving grant support for work not related to RECOVER work/publications from Baxter International and Siemens Healthcare and personal consulting fees not related to this paper from Progenity, Quidel Ortho, and Siemens Healthcare. Kristine Erlandson reported research funding from Gilead Sciences and consulting payments from Gilead Sciences, Merck, and ViiV Pharmaceuticals, all paid to the University of Colorado. Emily Gallagher reported consulting for Novartis, Flare Therapeutics and Seagen. Edward Gardner reported research support (clinical trials) from Gilead Sciences, ViiV Healthcare, and Cepheid. Jason Goldman reported research support from Gilead, Eli Lilly and Regeneron; grants from Gilead, Merck (BARDA); personal fees for consulting from Gilead, Eli Lilly; and non-financial support from Adaptive Biotechnologies and Labcorp/Monogram Biosciences outside the submitted work. Timothy Heinrich reported grant support from Merck Inc. and consulting fees from Roche. Rachel Hess reported serving as Data Safety Monitoring Board member for Astellas Pharmaceuticals unrelated to the current work. Leora Horwitz reported being a member of the National Academy of Medicine Committee on the Long-Term Health Effects Stemming from COVID-19 and Implications for the Social Security Administration. Priscilla Hsue reported receiving honoraria from Gilead and Merck unrelated to study topic, receiving study drug from Regeneron unrelated to study topic, and receiving a research grant from Novartis. Judith James reported OMRF has licensed her IP to Progentec Biosciences, has received grant support from Progentec Biosciences, and serves on Advisory Committees to Glaxo Smith Klein, Merck and Novartis. Arthur Kim reports providing educational materials to Clinical Care Options and UpToDate and serving on a Data Safety Monitoring board for Kintor Pharmaceuticals, Ltd. Bruce Levy reported serving as a consultant for AstraZeneca, Entrinsic Biosciences, Gossamer Bio and Nocion Therapeutics and receiving research support from Amgen, Genentech, GlaxoSmithKline, Pieris Pharmaceuticals, SRA and Sanofi unrelated to the current work. Vincent Marconi reported receiving grants from NIH during the conduct of the study and grants from NIH, Veteran Affairs, and Centers for Disease Control and Prevention; grants, personal fees, nonfinancial support, and other from Lilly and Gilead; grants and personal fees from ViiV; and nonfinancial support from Bayer outside the submitted work. Grace McComsey reported serving as consultant for Merck, Gilead, ViiV, Janssen and have received research support from Pfizer, Vanda, Genentech, Roche, Redhill and Cognivue. Torri Metz reported being a site PI and a participant in the medical advisory board for the planning of a Pfizer clinical trial of SARS-CoV-2 vaccination in pregnancy. She also reported being a site PI for a Pfizer study evaluating the pharmacokinetics of Paxlovid in pregnant people with COVID-19. Janet Mullington reported support for investigator-initiated research by "Open Medicine Foundation and the Patient-Led Research Collaborative" Princess Ogbogu reported research support from Astrazeneca, GSK, Blueprint medical; advisory board for Astrazeneca, GSK, Sanofi, Kalvista; and consulting for Astrazeneca, GSK Sairam Parthasarathy reported research funding to Institution from Sergey Brin foundation of COVID and Long-COVID research. Michael Peluso reported consulting fees from Gilead Sciences and AstraZeneca, and service on data safety monitoring board for American Gene Technologies. Sean Quigley reported service on speaker Board for Servier, Alnylam, Agios; service on advisory board for Recordati, Alexion. Franz Rischard reported research support from NIH/NHLBI, United Therapeutics, Acceleron/Merck, Janssen, Insmed, Aerovate, and Bayer; and consulting/advisory compensation from Acceleron and Bayer. Nadine Rouphael reported being a consultant for ICON and EMMES as a safety consultant for clinical trials; service on the advisory boards for Moderna; funds to institution from Sanofi, Lilly, Merck, Quidel and Pfizer. PJ Utz reported stock ownership of Gilead and PI of biomarker studies for Pfizer STOP-PASC paxlovid trial Juan Wisnivesky received receiving consulting honorarium from Sanofi, Banook, Prospero, PPD and Atea and research grants from Sanofi, Regeneron, Axella, and Arnold Consultants., (Copyright: © 2023 Horwitz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: To evaluate the association of subjective social status (SSS) with metabolic syndrome (MetS) severity and its potential contribution to racial health disparities in women with breast cancer., Methods: Multicenter cross-sectional study (10 US hospitals) in women (n = 1206) with primary diagnosis of invasive breast cancer received during Mar/2013-Feb/2020. Participants, self-identified as non-Hispanic White or Black, underwent physical and laboratory examinations and survey questions assessing socioeconomic parameters, medical history, and behavioral risks. SSS was measured with the 10-rung MacArthur scale. MetS severity was measured with a validated Z-Score. Generalized linear mixed modeling was used to analyze the associations. Missing data were handled using multiple imputation., Results: Average age was 58 years. On average, the SSS of Black women, given equivalent level of income and education, was lower than the SSS of White women: 6.6 (6.1-7.0) vs 7.7 (7.54-7.79) among college graduates and 6.8 (6.4-7.2) vs 7.6 (7.5-7.8) among women in the high-income category (> $75,000). In multivariable analysis, after controlling for age, income, education, diet, and physical activity, increasing SSS was associated with a decrease in MetS-Z score, - 0.10 (- 0.16 to - 0.04) per every 2 rung increase in the MacArthur scale., Conclusion: Black women with breast cancer rank their SSS lower than White women with breast cancer do at each level of income and education. As SSS is strongly associated with MetS severity these results identify potentially modifiable factors that contribute to racial disparities., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Abemaciclib is approved for use in the adjuvant setting in combination with endocrine therapy for patients with high-risk, hormone receptor-positive, HER2-negative early-stage breast cancer based on the monarchE trial. Options for endocrine therapy for premenopausal women include an aromatase inhibitor with ovarian function suppression or tamoxifen with or without ovarian suppression. We describe a unique case of a premenopausal woman with early-stage breast cancer receiving adjuvant abemaciclib and an aromatase inhibitor with elevated estradiol levels as measured by the Abbott Alinity chemiluminescent immunoassay despite chemical and surgical ovarian function suppression. Given low estradiol levels using liquid chromatography-mass spectrometry testing following a bilateral salpingo-oopherectomy, our case report suggests an interference of abemaciclib with the Abbott Alinity immunoassay. This possible interference has significant impacts on clinical care as false elevations in estradiol levels measured by immunoassays can lead to unnecessary treatment changes, including surgery.

Immune checkpoint inhibitors (ICIs) are a rapidly expanding class of targeted therapies effective in the treatment of various cancers. However, while efficacious, ICIs have been associated with treatment complications, namely immune-related adverse events (irAEs). IrAEs of the endocrine system are among the most commonly reported irAEs, but despite their high incidence, standardized disease definitions and endocrine IrAE-specific International Classification of Diseases (ICD) codes remain lacking. This dearth of standardized nomenclature and ICD codes has in many ways impeded both the clinical care of patients and the progress of endocrine irAE-related research. ICD codes are used internationally and are essential for medical claims reporting in the health care setting, and they provide a universal language system for recording, reporting, and monitoring diseases. These codes are also a well-accepted form of electronic health record data capture that facilitates the collection, storage, and sharing of data. Therefore, the lack of standardized disease definitions and ICD codes has been associated with misclassification and suboptimal management of individuals with endocrine irAEs and has also been associated with reduced data availability, comparability, and quality. Harmonized and clinically relevant disease definitions along with the subsequent development of endocrine-irAE-specific ICD codes will provide a systematic approach to understanding the spectrum and burden of endocrine irAE diseases, and will have a positive effect across clinical, public health, and research settings., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Tumor uptake of exogenous cholesterol has been associated with the proliferation of various cancers. Previously, we and others have shown that hypercholesterolemia promotes tumor growth and silencing of the LDL receptor (LDLR) in high LDLR-expressing tumors reduces growth. To advance understanding of how LDL uptake promotes tumor growth, LDLR expression was amplified in breast cancer cell lines with endogenously low LDLR expression. Murine (Mvt1) and human (MDA-MB-468) breast cancer cell lines were transduced to overexpress human LDLR (LDLROE). Successful transduction was confirmed by RNA and protein analysis. Fluorescence-labeled LDL uptake was increased in both Mvt1 and MDA-MD-468 LDLROE cells. The expression of the cholesterol-metabolizing genes, ABCA1 and ABCG1, was increased, while HMGCR was decreased in the MDA-MB-468 LDLROE cells. In contrast, Mvt1 LDLROE cells showed no differences in Abca1 and Abcg1 expression and increased Hmgcr expression. Using a Seahorse analyzer, Mvt1 LDLROE cells showed increased respiration (ATP-linked and maximal) relative to controls, while no statistically significant changes in respiration in MDA-MB-468 LDLROE cells were observed. Growth of LDLROE cells was reduced in culture and in hypercholesterolemic mice by two-fold. However, the expression of proliferation-associated markers (Ki67, PCNA and BrdU-label incorporation) was not decreased in the Mvt1 LDLROE tumors and cells. Caspase-3 cleavage, which is associated with apoptosis, was increased in both the Mvt1 and MDA-MB-468 LDLROE cells relative to controls, with the Mvt1 LDLROE cells also showing decreased phosphorylation of p44/42MAPK. Taken together, our work suggests that while additional LDL can promote tumor growth, unregulated and prolonged LDL uptake is detrimental.

Introduction: The acquisition of a metastatic phenotype is the critical event that determines patient survival from breast cancer. Several receptor tyrosine kinases have functions both in promoting and inhibiting metastasis in breast tumors. Although the insulin-like growth factor 1 receptor (IGF1R) has been considered a target for inhibition in breast cancer, low levels of IGF1R expression are associated with worse overall patient survival., Methods: To determine how reduced IGF1R impacts tumor phenotype in human breast cancers, we used weighted gene co-expression network analysis (WGCNA) of Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) patient data to identify gene modules associated with low IGF1R expression. We then compared these modules to single cell gene expression analyses and phenotypes of mouse mammary tumors with reduced IGF1R signaling or expression in a tumor model of triple negative breast cancer., Results: WGCNA from METABRIC data revealed gene modules specific to cell cycle, adhesion, and immune cell signaling that were inversely correlated with IGF1R expression in human breast cancers. Integration of human patient data with single cell sequencing data from mouse tumors revealed similar pathways necessary for promoting metastasis in basal-like mammary tumors with reduced signaling or expression of IGF1R. Functional analyses revealed the basis for the enhanced metastatic phenotype including alterations in E- and P-cadherins., Discussion: Human breast and mouse mammary tumors with reduced IGF1R are associated with upregulation of several pathways necessary for promoting metastasis supporting the conclusion that IGF1R normally helps maintain a metastasis suppressive tumor microenvironment. We further found that reduced IGF1R signaling in tumor epithelial cells dysregulates cadherin expression resulting in reduced cell adhesion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Obr, Bulatowicz, Chang, Ciliento, Lemenze, Maingrette, Shang, Gallagher, LeRoith and Wood.)

The survival for breast cancer (BC) is improving but remains lower in Black women than White women. A number of factors potentially drive the racial differences in BC outcomes. The aim of our study was to determine if insulin resistance (defined as homeostatic model assessment for insulin resistance (HOMA-IR)), mediated part of the relationship between race and BC prognosis (defined by the improved Nottingham prognostic index (iNPI)). We performed a cross-sectional study, recruiting self-identified Black and White women with newly diagnosed primary invasive BC from 10 US hospitals between March 2013 and February 2020. Survey, anthropometric, laboratory, and tumor pathology data were gathered, and we compared the results between Black and White women. We calculated HOMA-IR as well as iNPI scores and examined the associations between HOMA-IR and iNPI. After exclusions, the final cohort was 1206: 911 (76%) White and 295 (24%) Black women. Metabolic syndrome and insulin resistance were more common in Black than White women. Black women had less lobular BC, three times more triple-negative BC, and BCs with higher stage and iNPI scores than White women (P < 0.001 for all comparisons). Fewer Black women had BC genetic testing performed. HOMA-IR mediated part of the association between race and iNPI, particularly in BCs that carried a good prognosis and were hormone receptor (HR)-positive. Higher HOMA-IR scores were associated with progesterone receptor-negative BC in White women but not Black women. Overall, our results suggest that HOMA-IR contributes to the racial disparities in BC outcomes, particularly for women with HR-positive BCs.

Objective: To test whether body mass index (BMI) amongst patients with metastatic castration-resistant prostate cancer (mCRPC) is associated with overall survival (OS) and cancer-specific survival., Methods: Individual patient data from 1577 men with mCRPC treated with docetaxel and prednisone from the control arms of ASCENT2, VENICE, and MAINSAIL were considered. The role of BMI on survival outcomes was investigated both as a continuous and categorical variable (≤24.9 vs. 25-29.9 vs. ≥30 km/m 2 ). BMI ≥ 30 kg/m 2 was considered obese. Analyses were adjusted for age, PSA, ECOG performance status, number of metastases and prior treatment. The Cox semi-proportional hazard model was used to predict OS, whereas competing risks regression was used for predicting cancer-specific mortality (CSM). To exclude any possible effect attributable to higher doses of chemotherapy (titrated according to body-surface area), we checked for eventual interactions between BMI and chemotherapy dose (both as continuous-continuous and categorical-continuous interactions)., Results: The median (IQR) age for the patient population was 69 (63,74) years with a median (IQR) BMI of 28 (25-31) kg/m 2 . Median follow-up for survivors was 12 months. Of the 1577 patients included, 655 were deceased by the end of the studies. Regarding OS, BMI emerged as a protective factor both as a continuous variable (HR: 0.96; 95% CI: 0.94, 0.99; p = 0.015) and as a categorical variable (obesity: HR: 0.71, 95% CI: 0.53, 0.96; p = 0.027, relatively to normal weight). The protective effect of high BMI on CSM was confirmed both as a continuous (SHR: 0.94; 95% CI: 0.91, 0.98; p = 0.002) and as a categorical variable (obesity SHR: 0.65; 95% CI: 0.45, 0.93; p = 0.018). No interaction was detected between the BMI categories and the docetaxel dose at any level in our analyses (all p » 0.05)., Conclusions: Obese patients with mCRPC had better cancer-specific and overall survival as compared to overweight and normal weight patients. The protective effect of BMI was not related to receiving higher chemotherapy doses. Further studies aimed at elucidating the biological mechanism behind this effect are warranted., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: Response to immune checkpoint inhibitor (ICI) remains limited to a subset of patients and predictive biomarkers of response remains an unmet need, limiting our ability to provide precision medicine. Using real-world data, we aimed to identify potential clinical prognosticators of ICI response in solid tumor patients., Methods: We conducted a retrospective analysis of all solid tumor patients treated with ICIs at the Mount Sinai Hospital between January 2011 and April 2017. Predictors assessed included demographics, performance status, co-morbidities, family history of cancer, smoking status, cancer type, metastatic pattern, and type of ICI. Outcomes evaluated include progression free survival (PFS), overall survival (OS), overall response rate (ORR) and disease control rate (DCR). Univariable and multivariable Cox proportional hazard models were constructed to test the association of predictors with outcomes., Results: We identified 297 ICI-treated patients with diagnosis of non-small cell lung cancer (N = 81, 27.3%), melanoma (N = 73, 24.6%), hepatocellular carcinoma (N = 51, 17.2%), urothelial carcinoma (N = 51, 17.2%), head and neck squamous cell carcinoma (N = 23, 7.7%), and renal cell carcinoma (N = 18, 6.1%). In multivariable analysis, good performance status of ECOG ≤ 2 (PFS, ORR, DCR and OS) and family history of cancer (ORR and DCR) associated with improved ICI response. Bone metastasis was associated with worse outcomes (PFS, ORR, and DCR)., Conclusions: Mechanisms underlying the clinical predictors of response observed in this real-world analysis, such as genetic variants and bone metastasis-tumor microenvironment, warrant further exploration in larger studies incorporating translational endpoints. Consistently positive clinical correlates may help inform patient stratification when considering ICI therapy., (© 2022. The Author(s).)

Postgraduate physician-scientist training programs (PSTPs) enhance the experiences of physician-scientist trainees following medical school graduation. PSTPs usually span residency and fellowship training, but this varies widely by institution. Applicant competitiveness for these programs would be enhanced, and unnecessary trainee anxiety relieved, by a clear understanding of what factors define a successful PSTP matriculant. Such information would also be invaluable to PSTP directors and would allow benchmarking of their admissions processes with peer programs. We conducted a survey of PSTP directors across the US to understand the importance they placed on components of PSTP applications. Of 41 survey respondents, most were from internal medicine and pediatrics residency programs. Of all components in the application, two elements were considered very important by a majority of PSTP directors: (a) having one or more first-author publications and (b) the thesis advisor's letter. Less weight was consistently placed on factors often considered more relevant for non-physician-scientist postgraduate applicants - such as US Medical Licensing Examination scores, awards, and leadership activities. The data presented here highlight important metrics for PSTP applicants and directors and suggest that indicators of scientific productivity and commitment to research outweigh traditional quantitative measures of medical school performance.

Obesity is a common comorbidity of type 2 diabetes (T2D). Therefore, increased risk of fragility fractures in T2D is often confounded by the effects of obesity. This study was conducted to elucidate the mechanistic basis by which T2D alone leads to skeletal fragility. We hypothesized that obesity independent T2D would deteriorate bone's material quality by accumulating defects in the mineral matrix and undesired modifications in its organic matrix associated with increased oxidative stress and hyperglycemia. To test this hypothesis, we used 15-week-old male non-obese mice with engineered muscle creatine kinase promoter/human dominant negative insulin growth factor 1 (IGF-I) receptor (MKR) and FVB/N wild-type (WT) controls ( n  = 12/group). MKR mice exhibit reduced insulin production and loss of glycemic control leading to diabetic hyperglycemia, verified by fasting blood glucose measurements (>250 mg/dL), without an increase in body weight. MKR mice showed a significant decrease in femoral radial geometry (cortical area, moment of inertia, cortical thickness, endosteal diameter, and periosteal diameter). Bone mineral density (BMD), as assessed by micro-computed tomography (μCT), remained unchanged; however, the quality of bone mineral was altered. In contrast to controls, MKR mice had significantly increased hydroxyapatite crystal thickness, measured by small-angle X-ray scattering, and elongated c -axis length of the crystals evaluated by confocal Raman spectroscopy. There was an increase in changes in the organic matrix of MKR mice, associated with enhanced glycoxidation (carboxymethyl-lysine [CML] and pentosidine) and overall glycation (fluorescent advanced glycation end products), both of which were associated with various measures of bone fragility. Moreover, increased CML formation positively correlated with elongated mineral crystal length, supporting the role of this negatively charged side chain to attract calcium ions, promote growth of hydroxyapatite, and build a physical link between mineral and collagen. Collectively, our results show, for the first time, changes in bone matrix in a non-obese T2D model in which skeletal fragility is attributable to alterations in the mineral quality and undesired organic matrix modifications. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., Competing Interests: All authors state that they have no conflicts of interest., (© 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

TMEM176B is a member of the membrane spanning 4-domains (MS4) family of transmembrane proteins, and a putative ion channel that is expressed in immune cells and certain cancers. We aimed to understand the role of TMEM176B in cancer cell signaling, gene expression, cell proliferation, and migration in vitro, as well as tumor growth in vivo. We generated breast cancer cell lines with overexpressed and silenced TMEM176B, and a therapeutic antibody targeting TMEM176B. Proliferation and migration assays were performed in vitro, and tumor growth was evaluated in vivo. We performed gene expression and Western blot analyses to identify the most differentially regulated genes and signaling pathways in cells with TMEM176B overexpression and silencing. Silencing TMEM176B or inhibiting it with a therapeutic antibody impaired cell proliferation, while overexpression increased proliferation in vitro. Syngeneic and xenograft tumor studies revealed the attenuated growth of tumors with TMEM176B gene silencing compared with controls. We found that the AKT/mTOR signaling pathway was activated or repressed in cells overexpressing or silenced for TMEM176B, respectively. Overall, our results suggest that TMEM176B expression in breast cancer cells regulates key signaling pathways and genes that contribute to cancer cell growth and progression, and is a potential target for therapeutic antibodies.