Faculty Bibliography

Importance/UNASSIGNED:Multiple myeloma is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). Risk models that estimate the risk of progression from MGUS to multiple myeloma use data from a single time point, usually the initial workup. Objective/UNASSIGNED:To longitudinally investigate the alterations of serum immune markers with stable vs progressive MGUS. Design, Setting, and Participants/UNASSIGNED:This prospective cross-sectional cohort study included 77 469 adult participants aged 55 to 74 years in the screening arm of the National Cancer Institute Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had a diagnosis of progressing MGUS (n = 187) or stable MGUS (n = 498), including light-chain subtype, from November 1993, through December 2011. For each participant, all available serially stored prediagnostic serum samples (N = 3266) were obtained. Data analysis was performed from April 2018, to December 2018. Main Outcomes and Measures/UNASSIGNED:Serum protein and monoclonal immunoglobulin levels, serum free light chains, and serum light chains within each immunoglobulin class were measured. Results/UNASSIGNED:Of 685 individuals included in the study, 461 (67.3%) were men; the mean (SD) age was 69.1 (5.6) years. In cross-sectional modeling, risk factors associated with progressive MGUS were IgA isotype (adjusted odds ratio [OR], 1.80; 95% CI, 1.03-3.13; P = .04), 15 g/L or more monoclonal spike (adjusted OR, 23.5; 95% CI, 8.9-61.9; P < .001), skewed (<0.1 or >10) serum free light chains ratio (adjusted OR, 46.4; 95% CI, 18.4-117.0; P < .001), and severe immunoparesis (≥2 suppressed uninvolved immunoglobulins) (adjusted OR, 19.1; 95% Cl, 7.5-48.3; P < .001). Risk factors associated with progressive light-chain MGUS were skewed serum free light chains ratio (adjusted OR, 44.0; 95% CI, 14.2-136.3; P < .001) and severe immunoparesis (adjusted OR, 48.6; 95% CI, 9.5-248.2; P < .001). In longitudinal analysis of participants with serial samples prior to progression, 23 of 43 participants (53%) had high-risk MGUS before progression; 16 of these 23 (70%) experienced conversion from low-risk or intermediate-risk MGUS within 5 years. Similar results were found for light-chain MGUS. Conclusions and Relevance/UNASSIGNED:The findings of evolving risk patterns support annual blood testing and risk assessment for patients with MGUS or light-chain MGUS.

Carbapenem-resistant Enterobacteriaceae (CRE) strains are an urgent public health threat. We evaluated the in vitro activities of 19 antimicrobial agents, including imipenem-relebactam, against (i) 106 CRE bloodstream isolates that primarily expressed Klebsiella pneumoniae carbapenemase (KPC) and (ii) 20 OXA-48-like-expressing CRE isolates. Ninety-five percent of CRE bloodstream isolates were susceptible to imipenem-relebactam. In contrast to their comparable activities against KPC-producing CRE strains, ceftazidime-avibactam was more active in vitro against OXA-48-like CRE strains than was imipenem-relebactam (90% susceptible versus 15% susceptible).

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.

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.

The Dietary Approaches to Stop Hypertension (DASH) diet is recommended for lowering blood pressure and preventing cardiovascular disease (CVD), but little data exist on these associations in US Hispanics/Latinos. We sought to assess associations between DASH score and prevalence of metabolic syndrome (MetS) and its components in diverse Hispanics/Latinos. We studied 10,741 adults aged 18-74 in the multicenter Hispanic Community Health Study/Study of Latinos. Dietary intake was measured using two 24-hour recalls, and MetS defined per the 2009 harmonized guidelines. We assessed cross-sectional associations of DASH score and MetS (and its dichotomized components) using survey logistic regression, and DASH and MetS continuous components using linear regression. We also stratified these models by Hispanic/Latino heritage group to explore heritage-specific associations. We found no associations between DASH and MetS prevalence. DASH was inversely associated with both measures of blood pressure (p < 0.01 for systolic and p < 0.001 for diastolic) in the overall cohort. DASH was also inversely associated with diastolic blood pressure in the Mexican (p < 0.05), Central American (p < 0.05), and South American (p < 0.01) groups; triglycerides (p < 0.05) in the Central American group; fasting glucose overall (p < 0.01) and in the Mexican group (p < 0.01); and waist circumference overall (p < 0.05) and in the South American group (p < 0.01). DASH was positively associated with HDL-cholesterol (p < 0.01) in the Central American group. DASH may better capture diet-MetS associations in Hispanic/Latino subpopulations such as Central/South Americans; this study also adds evidence that Hispanics/Latinos should be analyzed by heritage. Further research, and/or culturally tailored DASH measures will help further explain between-heritage differences.

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.

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.