Faculty Bibliography

To assess the impact of allopurinol on diabetes in a retrospective cohort of Veterans' Affairs patients with gout.The New York Harbor VA computerized patient record system was searched to identify patients with an ICD-9 code for gout meeting at least 4 modified 1977 American Rheumatology Association gout diagnostic criteria. Patients were divided into subgroups based on >30 continuous days of allopurinol, versus no allopurinol. New diagnoses of diabetes, defined according to American Diabetes Association diagnostic criteria or clinical documentation explicitly stating a new diagnosis of diabetes, were identified during an observation period from January 1, 2000 through December 31, 2015.Six hundred six gout patients used allopurinol >30 continuous days, and 478 patients never used allopurinol. Over an average 7.9 ± 4.8 years of follow-up, there was no significant difference in diabetes incidence between the allopurinol and non-allopurinol groups (11.7/1000 person-years vs 10.0/1000 person-years, P = .27). A lower diabetes incidence in the longest versus shortest quartiles of allopurinol use (6.3 per 1000 person-years vs 19.4 per 1000 person-years, P<.0001) was attributable to longer duration of medical follow-up.In this study, allopurinol use was not associated with decreased diabetes incidence. Prospective studies may further elucidate the relationship between hyperuricemia, gout, xanthine oxidase activity, and diabetes, and the potential impact of gout treatments on diabetes incidence.

Objectives While the need to address patients' social determinants of health (SDoH) is widely recognized, less is known about physicians' actual clinical problem-solving when it comes to SDoH. Do physicians include SDoH in their assessment strategy? Are SDoH incorporated into their diagnostic thinking and if so, do they document as part of their clinical reasoning? And do physicians directly address SDoH in their "solution" (treatment plan)? Methods We used Unannounced Standardized Patients (USPs) to assess internal medicine residents' clinical problem solving in response to a patient with asthma exacerbation and concern that her moldy apartment is contributing to symptoms - a case designed to represent a clear and direct link between a social determinant and patient health. Residents' clinical practices were assessed through a post-visit checklist and systematic chart review. Patterns of clinical problem solving were identified and then explored, in depth, through review of USP comments and history of present illness (HPI) and treatment plan documentation. Results Residents fell into three groups when it came to clinical problem-solving around a housing trigger for asthma: those who failed to ask about housing and therefore did not uncover mold as a potential trigger (neglectors - 21%; 14/68); those who asked about housing in negative ways that prevented disclosure and response (negative elicitors - 24%, 16/68); and those who elicited and explored the mold issue (full elicitors - 56%; 28/68). Of the full elicitors 53% took no further action, 26% only documented the mold; and 21% provided resources/referral. In-depth review of USP comments/explanations and residents' notes (HPI, treatment plan) revealed possible influences on clinical problem solving. Failure to ask about housing was associated with both contextual factors (rushed visit) and interpersonal skills (not fully engaging with patient) and with possible differences in attention ("known" vs. unknown/new triggers, usual symptoms vs. changes, not attending to relocation, etc.,). Use of close-ended questions often made it difficult for the patient to share mold concerns. Negative responses to sharing of housing information led to missing mold entirely or to the patient not realizing that the physician agreed with her concerns about mold. Residents who fully elicited the mold situation but did not take action seemed to either lack knowledge or feel that action on SDoH was outside their realm of responsibility. Those that took direct action to help the patient address mold appeared to be motivated by an enhanced sense of urgency. Conclusions Findings provide unique insight into residents' problem solving processes including external influences (e.g., time, distractions), the role of core communication and interpersonal skills (eliciting information, creating opportunities for patients to voice concerns, sharing clinical thinking with patients), how traditional cognitive biases operate in practice (premature closure, tunneling, and ascertainment bias), and the ways in which beliefs about expectancies and scope of practice may color clinical problem-solving strategies for addressing SDoH.

Ceftazidime-avibactam is a potent antibiotic combination against Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae Here, we describe a unique ceftazidime-avibactam-resistant and carbapenem-susceptible K. pneumoniae strain harboring a novel bla_KPC-14 variant. This strain was isolated from a New York City patient in 2003, which predates the introduction of avibactam. Despite resistance to ceftazidime-avibactam, the strain was susceptible to imipenem-relebactam and meropenem-vaborbactam. Comprehensive genomic sequencing revealed that bla_KPC-14 is harbored on an ST6 IncN plasmid associated with the early spread of bla_KPCIMPORTANCE KPC is currently the most common carbapenemase identified in the United States. More than 40 KPC variants have been described, of which KPC-2 and KPC-3 are the most frequent clinical variants. However, our understanding of the genetic structures and β-lactam resistance profiles of other novel KPC variants remains incomplete. Here, we report a novel bla_KPC variant (bla_KPC-14) and the complete genome sequence of bla_KPC-14-harboring K. pneumoniae strain BK13048, which is susceptible to carbapenems but resistant to ceftazidime-avibactam. To the best of our knowledge, this is one of the earliest KPC-producing K. pneumoniae strains exhibiting resistance to ceftazidime-avibactam.

Although novel agents (NAs) have improved outcomes for patients with chronic lymphocytic leukemia (CLL), a subset will progress through all available NAs. Understanding outcomes for potentially curative modalities including allogeneic hematopoietic stem cell transplantation (alloHCT) following NA therapy is critical while devising treatment sequences aimed at long-term disease control. In this multicenter, retrospective cohort study, we examined 65 patients with CLL who underwent alloHCT following exposure to ≥1 NA, including baseline disease and transplant characteristics, treatment preceding alloHCT, transplant outcomes, treatment following alloHCT, and survival outcomes. Univariable and multivariable analyses evaluated associations between pre-alloHCT factors and progression-free survival (PFS). Twenty-four-month PFS, overall survival (OS), nonrelapse mortality, and relapse incidence were 63%, 81%, 13%, and 27% among patients transplanted for CLL. Day +100 cumulative incidence of grade III-IV acute graft-vs-host disease (GVHD) was 24%; moderate-severe GVHD developed in 27%. Poor-risk disease characteristics, prior NA exposure, complete vs partial remission, and transplant characteristics were not independently associated with PFS. Hematopoietic cell transplantation-specific comorbidity index independently predicts PFS. PFS and OS were not impacted by having received NAs vs both NAs and chemoimmunotherapy, 1 vs ≥2 NAs, or ibrutinib vs venetoclax as the line of therapy immediately pre-alloHCT. AlloHCT remains a viable long-term disease control strategy that overcomes adverse CLL characteristics. Prior NAs do not appear to impact the safety of alloHCT, and survival outcomes are similar regardless of number of NAs received, prior chemoimmunotherapy exposure, or NA immediately preceding alloHCT. Decisions about proceeding to alloHCT should consider comorbidities and anticipated response to remaining therapeutic options.

OBJECTIVE:<0.001). Rates of adverse events increased with the magnitude of D-dimer elevation; individuals with presenting D-dimer >2000 ng/mL had the highest risk of critical illness (66%), thrombotic event (37.8%), acute kidney injury (58.3%), and death (47%). CONCLUSIONS:Abnormal D-dimer was frequently observed at admission with COVID-19 and was associated with higher incidence of critical illness, thrombotic events, acute kidney injury, and death. The optimal management of patients with elevated D-dimer in COVID-19 requires further study.

Combating plasmid-mediated carbapenem resistance is essential to control and prevent the dissemination of carbapenem-resistant Enterobacteriaceae (CRE). Here we conducted a proof-of-concept study to demonstrate CRISPR/Cas9-mediated resistance gene and plasmid curing can effectively re-sensitize CRE to carbapenems. A novel CRISPR/Cas9-mediated plasmid-curing system (pCasCure) was developed and electrotransferred into various clinical CRE isolates. The results showed that pCasCure can effectively cure bla_KPC, bla_NDM and bla_OXA-48 in various Enterobacteriaceae species of Klebsiella pneumoniae, Escherichia coli, Enterobacter hormaechei, E. xiangfangensis and Serratia marcescens clinical isolates, with > 94% curing efficiency. In addition, we also demonstrated that pCasCure can efficiently eliminate several epidemic carbapenem-resistant plasmids, including the bla_KPC-harboring IncFIIK-pKpQIL and IncN pKp58_N, bla_OXA-48-harboring pOXA-48-like, bla_NDM-harboring IncX3 plasmids, by targeting their replication and partitioning (parA in pKpQIL) genes. However, curing bla_OXA-48 gene failed to eliminate its corresponding pOXA-48-like plasmid in a clinical K. pneumoniae isolate 49210, while further next generation sequencing revealed that it was due to IS1R mediated recombination outside the CRISPR/Cas9 cleavage site, resulting in bla_OXA-48 truncation and therefor escaped plasmid curing. Nevertheless, the curing of carbapenemase genes or plasmids, including the truncation of bla_OXA-48 in 49210, successfully restore their susceptibility to carbapenems, with > 8-fold reduction of minimum inhibitory concentration (MIC) values in all tested isolates. Taken together, our study confirmed the concept of using CRISPR/Cas9-mediated carbapenemase genes and plasmids curing to re-sensitize CRE to carbapenems. Further work is needed to integrate pCasCure in an optimal delivery system to make it applicable for clinical intervention.

BACKGROUND:Little is known about long-term recovery from severe COVID-19 disease. Here, we characterize overall health, physical health and mental health of patients one month after discharge for severe COVID-19. METHODS:This was a prospective single health system observational cohort study of patients ≥18 years hospitalized with laboratory-confirmed COVID-19 disease who required at least 6 liters of oxygen during admission, had intact baseline cognitive and functional status and were discharged alive. Participants were enrolled between 30 and 40 days after discharge. Outcomes were elicited through validated survey instruments: the PROMIS Dyspnea Characteristics and PROMIS Global Health-10. RESULTS:A total of 161 patients (40.6% of eligible) were enrolled; 152 (38.3%) completed the survey. Median age was 62 years (interquartile range [IQR], 50-67); 57 (37%) were female. Overall, 113/152 (74%) participants reported shortness of breath within the prior week (median score 3 out of 10 [IQR 0-5]), vs. 47/152 (31%) pre-COVID-19 infection (0, IQR 0-1), p<0.001. Participants also rated their physical health and mental health as worse in their post-COVID state (43.8, standard deviation 9.3; mental health 47.3, SD 9.3) compared to their pre-COVID state, (54.3, SD 9.3; 54.3, SD 7.8, respectively), both p <0.001. A total of 52/148 (35.1%) patients without pre-COVID oxygen requirements needed home oxygen after hospital discharge; 20/148 (13.5%) reported still using oxygen at time of survey. CONCLUSIONS:Patients with severe COVID-19 disease typically experience sequelae affecting their respiratory status, physical health and mental health for at least several weeks after hospital discharge.