Faculty Bibliography

Tigecycline is one of the last-resort antibiotics to treat complicated infections caused by both multidrug-resistant Gram-negative and Gram-positive bacteria¹. Tigecycline resistance has sporadically occurred in recent years, primarily due to chromosome-encoding mechanisms, such as overexpression of efflux pumps and ribosome protection^2,3. Here, we report the emergence of the plasmid-mediated mobile tigecycline resistance mechanism Tet(X4) in Escherichia coli isolates from China, which is capable of degrading all tetracyclines, including tigecycline and the US FDA newly approved eravacycline. The tet(X4)-harbouring IncQ1 plasmid is highly transferable, and can be successfully mobilized and stabilized in recipient clinical and laboratory strains of Enterobacteriaceae bacteria. It is noteworthy that tet(X4)-positive E. coli strains, including isolates co-harbouring mcr-1, have been widely detected in pigs, chickens, soil and dust samples in China. In vivo murine models demonstrated that the presence of Tet(X4) led to tigecycline treatment failure. Consequently, the emergence of plasmid-mediated Tet(X4) challenges the clinical efficacy of the entire family of tetracycline antibiotics. Importantly, our study raises concern that the plasmid-mediated tigecycline resistance may further spread into various ecological niches and into clinical high-risk pathogens. Collective efforts are in urgent need to preserve the potency of these essential antibiotics.

PURPOSE/OBJECTIVE:There is variability in survival within IDH mutant gliomas determined by chromosomal events. Copy number variation (CNV) abundance associated with survival in low-grade and IDH mutant astrocytoma has been reported. Our purpose was to correlate the extent of genome-wide CNV abundance in IDH mutant astrocytomas with MRI features. METHODS:Presurgical MRI and CNV plots derived from Illumina 850k EPIC DNA methylation arrays of 18 cases of WHO grade II-IV IDH mutant astrocytomas were reviewed. IDH mutant astrocytomas were divided into CNV stable group (CNV-S) with ≤ 3 chromosomal gains or losses and lack of focal gene amplifications and CNV unstable group (CNV-U) with > 3 large chromosomal gains/losses and/or focal amplifications. The associations between MR features, relative cerebral blood volume (rCBV), CNV abundance, and time to progression were assessed. Tumor rCBV estimates were obtained using DSC T2* perfusion analysis. RESULTS:There were nine (50%) CNV-S and nine (50%) CNV-U IDH mutant astrocytomas. CNV-U tumors showed larger mean tumor size (P = 0.004) and maximum diameter on FLAIR (P = 0.004) and also demonstrated significantly higher median rCBV than CNV-S tumors (2.62 vs 0.78, P = 0.019). CNV-U tumors tended to have shorter time to progression although without statistical significance (P = 0.393). CONCLUSIONS:Larger size/diameter and higher rCBVs were seen associated CNV-U astrocytomas, suggesting a correlation of aggressive imaging phenotype with unstable and aggressive genotype in IDH mutant astrocytomas.

INTRODUCTION/BACKGROUND:Systems-based Practice 3 (SBP 3) in the orthopedic residency developmental milestones evaluates residents' knowledge, understanding, and utilization of the electronic medical record (EMR). In order to better assess SBP 3, we conducted a review of residents' clinical notes in order to quantify the current state of orthopedic residents' documentation in the EMR. The purpose of this study was to objectively evaluate orthopedic resident documentation in the EMR. METHODS:Orthopedic resident medical notes from a single orthopedic residency at one academic medical center were scored by faculty members who had directly observed the clinical encounter. These notes were then independently scored by one investigator (N.F.) using clinical contentspecific, objective criteria. Sixty-five medical records were reviewed. All 62 orthopedic residents anonymously completed an 84-question survey on the value of EMR utilization and documentation within the medical record. RESULTS:Many key elements necessary to diagnosing a patient's injury and developing a treatment plan were often omitted (e.g., "Mechanism of Injury" in 32.3% of records), and the majority of notes did not include "Decision Making and Patient Preference" (95.2%) or "Risks/Benefits of Surgery" (93.7%). However, 95.2% of residents agreed that their notes reflect their medical knowledge and 96.8% agreed that their notes reflect their clinical reasoning. DISCUSSION/CONCLUSIONS:The results of this objective review revealed significant deficits in orthopedic resident documentation not identified by faculty observers.

PEGylation is a biochemical modification process of bioactive molecules with polyethylene glycol (PEG), which lends several desirable properties to proteins/peptides, antibodies, and vesicles considered to be used for therapy or genetic modification of cells. However, PEGylation of proteins is a complex process and can be carried out using more than one strategy that depends on the nature of the protein and the desired application. Proteins of interest are covalently conjugated or non-covalently complexed with inert PEG strings. Purification of PEGylated protein is another critical step, which is mainly carried out based on electrostatic interactions or molecular sizes using chromatography. Several PEGylated drugs are being used for diseases like anemia, kidney disease, multiple sclerosis, hemophilia and cancers. With the advancement and increased specificity of the PEGylation process, the world of drug therapy, and specifically cancer therapy could benefit by utilizing this technique to create more stable and non-immunogenic therapies. In this article we describe the structure and functions of PEGylation and how this chemistry helps in drug discovery. Moreover, special emphasis has been given to CCN-family proteins that can be targeted or used as therapy to prevent or block cancer progression through PEGylation technology.

Objective: To compare morbidity and mortality of Acute Coronary Syndrome (ACS) patients, with hemoglobin level above 7g/dl in transfused or not transfused groups.
Method(s): We conducted a retrospective cohort study of patients admitted with ACS to both campuses of NYU Langone Hospital. Of 1080 patients screened in, 82 met inclusion criteria and were included in our analysis. Patients with hemoglobin less than 7 g/dL or greater than 10 g/dL during their ischemic event were excluded. The outcomes of interest were length of stay (LOS) and negative clinical events as ascertained by physician chart review. The Mann-Whitney U test, was used to compare continuous variables, and the chi-squared test compared categorical variables.
Result(s): 54 patients were transfused, and 28 were not transfused. Mean age (72.5 vs 74.4 years), and race did not differ significantly between groups. Proportion with heart failure, known anemia and mean baseline hemoglobin of anemic patients prior to admission were similar between both groups. ACS diagnosis and proportion of patients receiving medical management were similar between groups as well. However, transfused patients were more likely to be male, have Chronic Kidney Disease (51.9% vs 28.6%), have known Coronary Artery Disease (77.8 vs 42.6%) and those with Congestive Heart Failure had a lower baseline ejection fraction (34.5 vs 57.5%). For outcomes, blood transfusion was associated with a longer LOS (mean 11.48 vs 6.36 days, p=0.002). Furthermore, transfusion was associated with a higher likelihood to have a combined negative outcome which included new or worsening respiratory distress, hypoxia, volume overload, upgrade to the Intensive Care Unit and death (79% vs 24%, RR=3.29, P<0.001), driven by a significant increase in volume overload (40.7 vs 4.0% P<0.001) and a non-significant tendency towards increased mortality (16.7 vs 4.0%, p=0.12).
Conclusion(s): ACS patients who underwent blood transfusion had worse outcomes, namely longer LOS, increased risk for volume overload and a pronounced but not significant trend towards increased mortality. This effect was confounded by more severe comorbidities in the transfused group. However, given the size and significance of this harmful association, it is possible or perhaps even likely that transfusion itself was a factor in the worsened outcomes in the transfused group. Though transfusion for a hemoglobin > 7g/dl and even > 8g/dl is common in ACS patients, the harms associated with blood transfusions may outweigh the possible risk of worsened myocardial ischemia in the setting of lower oxygen carrying capacity

This study reports the first assessment of published comments in the family medicine literature using structured codes, which produced commentary annotations that will be the foundation of a knowledge base of appraisals of family medicine trials. Evidence appraisal occurs in a variety of formats and serves to shed light on the quality of research. However, scientific discourse generally and evidence appraisal in particular has not itself been analyzed for insights. A search strategy was devised to identify all journal comments indexed in PubMed linked to controlled intervention studies published in a recent 15-year period in major family medicine journals. A previously developed structured representation in the form of a list of appraisal concepts was used to formally annotate and categorize the journal comments through an iterative process. Trends in family medicine evidence appraisal were then analyzed. A total of 93 comments on studies from five journals over 15 years were included in the analysis. Two thirds of extracted appraisals were negative criticisms. All appraisals of measurement instruments were negative (100%). The participants baseline characteristics, the author discussions, and the design of the interventions were also criticized (respectively 91.7%, 84.6% and 83.3% negative). In contrast, appraisals of the scientific basis of the studies were positive (81.8%). The categories with the most appraisals were, most generally, those focused on the study design, and most specifically, those focused on the scientific basis. This study provides a new data-driven approach to review scientific discourse regarding the strengths and limitations of research within academic family medicine. This methodology can potentially generalize to other medical domains. Structured appraisal data generated here will enable future clinical, scientific, and policy decision-making and broader meta-research in family medicine.

BACKGROUND:Topical corticosteroids are available in many vehicles. However, patients' preference for vehicles are variable and could be tailored to maximize patient adherence. Spray vehicles may offer, convenience, and strong efficacy. METHODS:A literature review was conducted using keywords: clobetasol, desoximetasone, betamethasone, triamcinolone, corticosteroid, topical, spray, vehicles, treatment, and clinical trial. RESULTS:For moderate-to-severe plaque psoriasis, 87% of subjects achieved an Overall Disease Severity (ODS) Score ≤2 at week two and 78% achieved an ODS ≤1 after four weeks with clobetasol propionate (CP) 0.05% spray compared to 17% and 3% in the control group, respectively (P&lt;0.001). For desoximetasone 0.25% spray, 31%-53% with moderate-to-severe psoriasis achieve Physician's Global Assessment (PGA) score ≤1 at day 28 versus 5%-18% in the vehicle spray group (P&lt;0.01). For betamethasone dipropionate 0.05% spray, 19% with mild-to-moderate plaque psoriasis achieved an Investigator's Global Assessment (IGA) score ≤1 or a 2-grade reduction in IGA versus 2.3% in vehicle group (P≤0.001). For mild-to-severe steroid responsive inflammatory dermatoses, 64% using triamcinolone acetonide 0.2% spray achieved clear or almost clear skin at day 14 (no P value reported). Adverse events including burning, irritation, and dryness were similar across all corticosteroids.

Recent scholarship suggests that the genomes of those around us affect our own phenotypes. Much of the empirical evidence for such "metagenomic" effects comes from animal studies, where the socio-genetic environment can be easily manipulated. Among humans, it is more difficult to identify such effects given the nonrandom distribution of genes and environments. Here we leverage the as-if-random distribution of grade-mates' genomes conditional on school-level variation in a nationally representative sample. Specifically, we evaluate whether one's peers' genetic propensity to smoke affects one's own smoking behavior net of one's own genotype. Results show that peer genetic propensity to smoke has a substantial effect on an individual's smoking outcome. This is true not only when the peer group includes direct friends, and therefore where the individual plays an active role in shaping the metagenomic context but also when the peer group includes all grade-mates and thus in cases where the individual does not select the metagenomic environment. We explore these effects further and show that a small minority with high genetic risk to smoke ('bad apples') can greatly affect the smoking behavior of an entire grade. The methodology used in this paper offers a potential solution to many of the challenges inherent in estimating peer effects in nonexperimental settings and can be utilized to study a wide range of outcomes with a genetic basis. On a policy level, our results suggest that efforts to reduce adolescent smoking should take into account metagenomic effects, especially bad apples, within social networks.