Faculty Bibliography

A summary genetic measure, called a "polygenic score," derived from a genome-wide association study (GWAS) of education can modestly predict a person's educational and economic success. This prediction could signal a biological mechanism: Education-linked genetics could encode characteristics that help people get ahead in life. Alternatively, prediction could reflect social history: People from well-off families might stay well-off for social reasons, and these families might also look alike genetically. A key test to distinguish biological mechanism from social history is if people with higher education polygenic scores tend to climb the social ladder beyond their parents' position. Upward mobility would indicate education-linked genetics encodes characteristics that foster success. We tested if education-linked polygenic scores predicted social mobility in >20,000 individuals in five longitudinal studies in the United States, Britain, and New Zealand. Participants with higher polygenic scores achieved more education and career success and accumulated more wealth. However, they also tended to come from better-off families. In the key test, participants with higher polygenic scores tended to be upwardly mobile compared with their parents. Moreover, in sibling-difference analysis, the sibling with the higher polygenic score was more upwardly mobile. Thus, education GWAS discoveries are not mere correlates of privilege; they influence social mobility within a life. Additional analyses revealed that a mother's polygenic score predicted her child's attainment over and above the child's own polygenic score, suggesting parents' genetics can also affect their children's attainment through environmental pathways. Education GWAS discoveries affect socioeconomic attainment through influence on individuals' family-of-origin environments and their social mobility.

Neisseria cinerea is a commensal which usually resides in the human respiratory tract. Very rarely, the organism finds its way into the bloodstream causing severe bacteremia. So far, very few cases of Neisseria bacteremia have been reported. We report a case of a 78-year-old male, post-splenectomy, who presented with high fever, cough and shortness of breath. The patient was initially managed for septic shock with fluid resuscitations, vasopressors and broad-spectrum antibiotics. Later, the blood cultures grew gram-negative coccobacilli, Neisseria cinerea. The patient was successfully treated with intravenous ceftriaxone. This is the first case ever of Neisseria cinerea bacteremia in a post-splenectomy patient and ninth case overall. This case illustrates that the physicians should maintain heightened awareness for Neisseria cinerea bacteremia in post-splenectomy patients.

We report a case of a complex orthopaedic infection in a patient returning to New York City from Bangladesh where he was involved in a serious motor vehicle accident. He developed extensive osteomyelitis with a carbapenem-resistant Klebsiella pneumoniae The isolate was unique due to the coexistence of New Delhi metallo-β-lactamase-1 and Oxacillinase type-181 carbapenemases, which are relatively uncommon in North America and were presumably acquired in Bangladesh. Herein, we explore challenges associated with management of carbapenem-resistant Enterobacteriaceae infections, including limited available data on effective antimicrobial therapy. We also highlight the added value of rapid diagnostic technology in guiding clinical management. Ultimately, the patient required both aggressive surgical management and combination therapy with aztreonam and ceftazidime-avibactam for true source control and favourable clinical outcome.

In-hospital continuous electrocardiographic monitoring, commonly referred to as telemetry, has allowed for rapid recognition of life-threatening conditions, including complex arrhythmias and myocardial ischemia. However, inappropriate use can lead to unnecessary downstream testing from "false alarms," which in turn affects clinician efficiency and increases health care costs without benefiting patients. For these reasons, the Society of Hospital Medicine's Choosing Wisely campaign recommended use of a protocol-driven discontinuation of telemetry. The American Heart Association (AHA) developed a set of Practice Standards for the appropriate use of telemetry monitoring in 2004, which they updated in 2017. Unfortunately, the AHA Practice Standards have not been widely adopted-with as many as 43% of monitored patients lacking a recommended indication for monitoring. Thus, we created an overview discussing the safety and efficacy of incorporating the AHA Practice Standards and a review of studies highlighting their successful incorporation within patient care workflow. We conclude by outlining an "implementation blueprint" for health system professionals and administrators seeking to change their institution's culture of telemetry use. As the health care landscape continues to shift, enacting high-value initiatives that improve patient safety and efficiency of care will be critical.

Context:Increased renal sodium reabsorption contributes to hypertension in Cushing syndrome (CS). Renal sodium transporters can be analyzed noninvasively in urinary extracellular vesicles (uEVs). Objective:To analyze renal sodium transporters in uEVs of patients with CS and hypertension. Design:Observational study. Setting:University hospital. Participants:The uEVs were isolated by ultracentrifugation and analyzed by immunoblotting in 10 patients with CS and 7 age-matched healthy participants. In 7 patients with CS, uEVs were analyzed before and after treatment. Main Outcome Measure:Abundance of protein in uEVs. Results:The 10 patients with CS were divided in those with suppressed and nonsuppressed renin-angiotensin-aldosterone system (RAAS; n = 5 per group). Patients with CS with suppressed RAAS had similar blood pressure but significantly lower serum potassium than patients with CS with nonsuppressed RAAS. Compared with healthy participants, only patients with suppressed RAAS had higher phosphorylated Na+-K+-Cl- cotransporter type 2 (pNKCC2) and higher total and phosphorylated Na+-Cl- cotransporter (pNCC) in uEVs. Serum potassium but not urinary free cortisol correlated with pNKCC2, pNCC, and Na+-Cl- cotransporter (NCC) in uEVs. Treatment of CS reversed the increases in pNKCC2, NCC, and pNCC. Conclusions:CS increases renal sodium transporter abundance in uEVs in patients with hypertension and suppressed RAAS. Potassium has recently been identified as an important driver of NCC activity, and low serum potassium may also contribute to increased renal sodium reabsorption and hypertension in CS. These results may also be relevant for hypertension induced by exogenous glucocorticoids.

Polymyxin B and fosfomycin are two 'old' antibiotics that consistently maintain activity against Klebsiella pneumoniae carbapenemase (KPC)-producing organisms based on in vitro susceptibility testing. However, each antibiotic's use in monotherapy has been associated with high rates of treatment failure. Therefore, our objective was to investigate the combinatorial pharmacodynamics of polymyxin B and fosfomycin against KPC-producing K. pneumoniae. Polymyxin B front-loading (3.33 mg/kg for 1 dose followed by 1.43 mg/kg q12h starting 12h later) and burst (5.53 mg/kg for 1 dose followed by no subsequent doses) simulated dosing regimens were explored in combination with fosfomycin (4g q8h) against KPC-2-producing K. pneumoniae ST258 in a hollow fibre infection model over 120h. Population analysis profiles were used to track the temporal polymyxin B and fosfomycin resistance profiles. Against isolate KPC-Kp 9A (polymyxin B MIC: 0.5mg/L, fosfomycin MIC: ≤8mg/L), monotherapies resulted in >3 log₁₀CFU/mL killing within 3h, but regrowth and proliferation of resistant subpopulations within 48h. Polymyxin B combinations with fosfomycin demonstrated rapid bacterial killing (>6 log₁₀CFU/mL reductions) while preventing propagation of polymyxin and fosfomycin resistance. Against isolate KPC-Kp 24A with a higher fosfomycin MIC (polymyxin B MIC: 0.5mg/L, fosfomycin MIC: 32g/L), a polymyxin B burst and fosfomycin combination caused a >6 log₁₀CFU/mL reduction within 1 hour, although bacterial regrowth occurred with the amplification of fosfomycin-resistant subpopulations. Polymyxin B in combination with fosfomycin may provide a practicable treatment strategy against KPC-producing K. pneumoniae and warrants further investigation.

BACKGROUND:Hepatocellular carcinoma (HCC) is a complication of chronic hepatitis B and C virus (HBV and HCV) infection. New York City (NYC) has a high prevalence of HBV and HCV, and infected persons likely face increased mortality from HCC and other causes. We describe the mortality profile of NYC residents with HBV or HCV, emphasizing the contributions of HCC and HIV coinfection. METHODS: Two existing data sets were combined to examine all individuals diagnosed with HBV or HCV in NYC first reported to the Health Department during 2001-2012 and their HCC, HIV, and vital status. Logistic regression was used to calculate the odds of HCC diagnosis by viral hepatitis status, whereas Cox proportional hazard regression was used to estimate the hazard of death by HCC/HIV status. RESULTS:In total, 120 952 and 127 933 individuals were diagnosed with HBV or HCV, respectively. HCV-infected individuals had 17% higher odds of HCC diagnosis than HBV-infected individuals and 3.2 times higher odds of HIV coinfection. Those with HCV were twice as likely to die during the study period (adjusted hazard ratio, 2.04; 95% confidence interval, 1.96-2.12). The risk of death increased for those with HIV or HCC and was highest for those with both conditions. CONCLUSIONS:HCC and HIV represent substantial risks to survival for both HBV- and HCV-infected individuals. Individuals with HBV need close monitoring and treatment, when indicated, and routine HCC screening. Those with HCV need increased, timely access to curative medications before developing liver disease.