Faculty Bibliography

We describe an educational intervention for neurology residents aimed at developing feedback skills. An objective structured clinical examination case was designed to simulate the provision of feedback to a medical student. After the simulated case session, residents received structured, individualized feedback on their performance and then participated in a group discussion about feedback methods. Survey data were collected from the standardized medical student regarding residents' performance and from residents for assessments of their performance and of the OSCE case. This manuscript aims to describe this educational intervention and to demonstrate the feasibility of this approach for feedback skills development.

INTRODUCTION/BACKGROUND:Perfluoroalkyl substances (PFAs) are ubiquitous, anthropogenic organic compounds that have been linked with cardiovascular disease and cardiovascular risk factors. Older, long-chain PFAs have been phased out due to adverse cardiometabolic health effect and replaced by newer short-chain PFAs. However, emerging research suggests that short-chain PFAs may also have adverse cardiovascular effects. Non-invasive measures of vascular function can detect preclinical cardiovascular disease and serve as a useful surrogate for early CVD risk. We hypothesized that serum concentrations of PFAs would be associated with noninvasive measures of vascular function, carotid-femoral pulse wave velocity (PWV) and brachial artery reactivity testing (BART), in adults with non-occupational exposure to PFAs. METHODS:We measured serum concentrations of 14 PFAs with hybrid solid-phase extraction and ultrahigh-performance liquid chromatography-tandem mass spectrometry in 94 adult outpatients with no known cardiovascular disease. We collected clinical and demographic data; and measured vascular function, PWV and BART, using standard protocols. We assessed associations of individual PFAs with log-transformed BART and PWV using linear regression. We used weighted quantile sum regression to assess effects of correlated PFA mixtures on BART and PWV. RESULTS:Ten PFAs were measured above the limit of detection in >50% of participants. Each standard deviation increase in concentration of perfluoroheptanoic acid (PFHpA) was associated with 15% decrease in BART (95% CI: -28.5, -0.17). The weighted index of a mixture of PFAs with correlated concentrations was inversely associated with BART: each tertile increase in the weighted PFA mixture was associated with 25% lower BART, with 73% of the effect driven by PFHpA. In contrast, no PFAs or mixtures were associated with PWV. CONCLUSIONS:Serum concentration of PFHpA, a new, short-chain PFA, was associated with impaired vascular function among outpatients without CVD. Our findings support a potential adverse cardiovascular effect of newer, short-chain PFAs.

Misfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that a previously unsolved amyloid fibril composed of a 135 amino acid C-terminal fragment of TMEM106B is a common finding in distinct human neurodegenerative diseases, including cases characterized by abnormal aggregation of TDP-43, tau, or α-synuclein protein. A combination of cryoelectron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 Å from postmortem human brain tissue afflicted with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, n = 2), or dementia with Lewy bodies (DLB, n = 1). The commonality of abundant amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, to a broad range of debilitating human disorders indicates a shared fibrillization pathway that may initiate or accelerate neurodegeneration.

Autoantibodies are present in healthy individuals and altered in chronic diseases. We used repeated samples collected from participants in the NYU Women's Health Study to assess autoantibody reproducibility and repertoire stability over a one-year period using the HuProt array. We included two samples collected one year apart from each of 46 healthy women (92 samples). We also included eight blinded replicate samples to assess laboratory reproducibility. A total of 21,211 IgG and IgM autoantibodies were interrogated. Of those, 86% of IgG (n = 18,303) and 34% of IgM (n = 7,242) autoantibodies showed adequate lab reproducibility (coefficient of variation [CV] < 20%). Intraclass correlation coefficients (ICCs) were estimated to assess temporal reproducibility. A high proportion of both IgG and IgM autoantibodies with CV < 20% (76% and 98%, respectively) showed excellent temporal reproducibility (ICC > 0.8). Temporal reproducibility was lower after using quantile normalization suggesting that batch variability was not an important source of error, and that normalization removed some informative biological information. To our knowledge this study is the largest in terms of sample size and autoantibody numbers to assess autoantibody reproducibility in healthy women. The results suggest that for many autoantibodies a single measurement may be used to rank individuals in studies of autoantibodies as etiologic markers of disease.

As the nation seeks to recruit and retain physician-scientists, gaps remain in understanding and addressing mitigatable challenges to the success of faculty from underrepresented minority (URM) backgrounds. The Doris Duke Charitable Foundation Fund to Retain Clinical Scientists program, implemented in 2015 at 10 academic medical centers in the United States, seeks to retain physician-scientists at risk of leaving science because of periods of extraordinary family caregiving needs, hardships that URM faculty-especially those who identify as female-are more likely to experience. At the annual Fund to Retain Clinical Scientists program directors conference in 2018, program directors-21% of whom identify as URM individuals and 13% as male-addressed issues that affect URM physician-scientists in particular. Key issues that threaten the retention of URM physician-scientists were identified through focused literature reviews; institutional environmental scans; and structured small- and large-group discussions with program directors, staff, and participants. These issues include bias and discrimination, personal wealth differential, the minority tax (i.e., service burdens placed on URM faculty who represent URM perspectives on committees and at conferences), lack of mentorship training, intersectionality and isolation, concerns about confirming stereotypes, and institutional-level factors. The authors present recommendations for how to create an environment in which URM physician-scientists can expect equitable opportunities to thrive, as institutions demonstrate proactive allyship and remove structural barriers to success. Recommendations include providing universal training to reduce interpersonal bias and discrimination, addressing the consequences of the personal wealth gap through financial counseling and benefits, measuring the service faculty members provide to the institution as advocates for URM faculty issues and compensating them appropriately, supporting URM faculty who wish to engage in national leadership programs, and sustaining institutional policies that address structural and interpersonal barriers to inclusive excellence.

PURPOSE/OBJECTIVE:The 80-gene molecular subtyping signature (80-GS) reclassifies a proportion of immunohistochemistry (IHC)-defined luminal breast cancers (estrogen receptor-positive [ER+], human epidermal growth factor receptor 2-negative [HER2-]) as Basal-Type. We report the association of 80-GS reclassification with neoadjuvant treatment response and 5-year outcome in patients with breast cancer. METHODS:Neoadjuvant Breast Registry Symphony Trial (NBRST; NCT01479101) is an observational, prospective study that included 1,069 patients with early-stage breast cancer age 18-90 years who received neoadjuvant therapy. Pathologic complete response (pCR) and 5-year distant metastasis-free survival (DMFS) and overall survival (OS) were assessed in 477 patients with IHC-defined ER+, HER2- tumors and in a reference group of 229 patients with IHC-defined triple-negative breast cancer (TNBC). RESULTS:< .001) tumors. The 5-year DMFS (%, [95% CI]) was significantly lower for patients with ER+/Basal tumors (66% [52.6 to 77.3]), compared with those with ER+/Luminal A tumors (92.3% [85.2 to 96.1]) and ER+/Luminal B tumors (73.5% [44.5 to 79.3]). Importantly, patients with ER+/Basal or TNBC/Basal tumors that had a pCR exhibited significantly improved DMFS and OS compared with those with residual disease. By contrast, patients with ER+/Luminal B tumors had comparable 5-year DMFS and OS whether or not they achieved pCR. CONCLUSION/CONCLUSIONS:Significant differences in chemosensitivity and 5-year outcome suggest patients with ER+/Basal molecular subtype may benefit from neoadjuvant regimens optimized for patients with TNBC/Basal tumors compared with patients with ER+/Luminal subtype. These data highlight the importance of identifying this subset of patients to improve treatment planning and long-term survival.

Introduction: Mimicking physiological pan-creatic pulsatile insulin secretion has led to the concept of pulsatile insulin infusion therapy (PIT).
Method(s): This exploratory pilot study investigated the effect of PIT for three months once weekly on kidney function in patients with type 2 diabetes and chronic renal failure (glomerular filtration rate (GFR) < 60 ml/min or GFR < 75 ml/min with mac-roproteinurea).
Result(s): Seventeen type 2 patients com-pleted the trial per protocol (7 women, 10 men, age: 69 +/- 7 yrs., HbA1c: 7.9 +/- 1.0 %). After three months, mean GFR improved by 12 % (from 47.6 +/- 10.0 ml/ min to 53.3 +/- 11.9 ml/min, p < 0.01) while mean serum creatinine decreased by 7 % (1.4 +/- 0.3 mg/dl/1.3 +/- 0.3 mg/dl, p < 0.05). Blood pressure medication was kept constant during the study; systolic blood pressure improved by 6 % (p < 0.05) while HbA1c and body weight remained stable. Treatment satisfaction scores improved from 3.7 +/- 2.7 to 2.7 +/- 2.1 (p < 0.005). The PIT procedures were well tolerated; only few cases of muscle cramps were consid-ered related to the treatments.
Conclusion(s): Improvements in kidney func-tion, systolic blood pressure and treatmensatisfaction were observed. These results will now be used to plan for appropriately designed controlled confirmatory studies.
Copyright

Dietary sodium (Na) restriction is universally prescribedfor hemodialysis patients to decrease adverse outcomes.1 However, few studies have investigated the impact of Na restriction on volume status and blood pressure (BP), and none in American community-dwelling populations in prospective, randomized controlled trial (RCT). The purpose of this feasibility RCT was to assess the effects of three levels of Na intake (unrestricted [control group; CG], 1.5G, 2.4G) on interdialytic weight gain (IDWG) and BP in patients undergoing hemodialysis. We conducted a three-group, double-blinded, RCT of 42 individuals living with end stage kidney disease in a domiciled feeding study. We examined the effects of 5 days of unrestricted Na in the control group (CG, n=14) and Na restriction to 1.5G (n=11) or 2.4G (n=14) per day on IDWG and BP. Our sample was overwhelmingly African American (85%), male (52.2%), with hypertension as the primary etiology of kidney disease (45%). The mean IDWG on Day 1 was 2.62kg (SD=1.54) and BP was 143/75.44 (SD=29.77/17.74). There were no significant differences in the change in IDWG regardless of group membership, although the trend demonstrated a decrease by Day 5. Decreases in BP were also not statistically significant across the groups, but there were potentially meaningful differences in systolic BP of 7mmHg and 11mmHg in the 1.5G and 2.4G groups respectfully, and diastolic BP in the 2.4G group of 7.31mmHg Our small pilot study suggests that Na restriction can reduce IDWG and systolic and diastolic BP in potentially clinically meaningful amounts. The optimal Na intake prescription and the long-term impact on hemodialysis-specific variables and cardiovascular disease remains unclear. A prospective, longitudinal study, with a sample sufficient to achieve adequate power is needed to gain a better understanding of the interplay between dietary sodium and outcomes.
Copyright