Faculty Bibliography

OBJECTIVE/UNASSIGNED:To describe interventions that target patient, provider, and system barriers to sedative-hypnotic (SH) deprescribing in the community and suggest strategies for healthcare teams. DATA SOURCES/UNASSIGNED:Ovid MEDLINE ALL and EMBASE Classic + EMBASE (March 10, 2021). STUDY SELECTION AND DATA EXTRACTION/UNASSIGNED:English-language studies in primary care settings. DATA SYNTHESIS/UNASSIGNED:20 studies were themed as patient-related and prescriber inertia, physician skills and awareness, and health system constraints. Patient education strategies reduced SH dose for 10% to 62% of participants, leading to discontinuation in 13% to 80% of participants. Policy interventions reduced targeted medication use by 10% to 50%. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE/UNASSIGNED:Patient engagement and empowerment successfully convince patients to deprescribe chronic SHs. Quality improvement strategies should also consider interventions directed at prescribers, including education and training, drug utilization reviews, or computer alerts indicating a potentially inappropriate prescription by medication, age, dose, or disease. Educational interventions were effective when they facilitated patient engagement and provided information on the harms and limited evidence supporting chronic use as well as the effectiveness of alternatives. Decision support tools were less effective than prescriber education with patient engagement, although they can be readily incorporated in the workflow through prescribing software. CONCLUSIONS/UNASSIGNED:Several strategies with demonstrated efficacy in reducing SH use in community practice were identified. Education regarding SH risks, how to taper, and potential alternatives are essential details to provide to clinicians, patients, and families. The strategies presented can guide community healthcare teams toward reducing the community burden of SH use.

Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes that trigger an anti-tumor T cell response in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic.

Mycobacterium abscessus is a rapidly growing nontuberculous mycobacterial species that comprises three subspecies; M. abscessus subsp. abscessus,M. abscessus subsp. massiliense, andM. abscessus subsp. bolletii These predominantly environmental microorganisms have emerged as life-threatening chronic pulmonary pathogens in both immunocompetent and immunocompromised patients and their acquisition of macrolide resistance due to the erm(41) gene and mutations in the 23S rrl has dramatically impacted patient outcome. However, standard microbiology laboratories typically have limited diagnostic tools for the subspeciation of M. abscessus, and the testing for macrolide resistance is often not done. Here we describe the development of a real-time multiplex assay using molecular beacons to establish a robust, rapid and highly accurate method to both distinguish M. abscessus sub-species and to determine which strains are susceptible to macrolides. We report a bioinformatic approach to identify robust subspeciation sequence targets, the design and optimization of six molecular beacons to identify all genotypes, and the development and application of a two-tube 3-color multiplex assay that can provide clinically significant treatment information in less than 3 hours.

BACKGROUND:Recent studies indicated that the monosubstituted deoxystreptamine aminoglycoside apramycin is a potent antibiotic against a wide range of MDR Gram-negative pathogens. OBJECTIVES/OBJECTIVE:To evaluate the in vitro activity of apramycin against carbapenem-resistant Klebsiella pneumoniae (CRKp) isolates from New York and New Jersey, and to explore mechanisms of apramycin resistance. METHODS:Apramycin MICs were determined by broth microdilution for 155 CRKp bloodstream isolates collected from 2013 to 2018. MLST STs, wzi capsular types and apramycin resistance gene aac(3')-IV were examined by PCR and Sanger sequencing. Selected isolates were further characterized by conjugation experiments and WGS. RESULTS:Apramycin MIC50/90 values were 8 and >128 mg/L for CRKp isolates, which are much higher than previously reported. Twenty-four isolates (15.5%) were apramycin resistant (MIC ≥64 mg/L) and they were all from the K. pneumoniae ST258 background. The 24 apramycin-resistant K. pneumoniae ST258 strains belonged to six different capsular types and 91.7% of them harboured the apramycin resistance gene aac(3')-IV. Sequencing analysis showed that different ST258 capsular type strains shared a common non-conjugative IncR plasmid, co-harbouring aac(3')-IV and blaKPC. A novel IncR and IncX3 cointegrate plasmid, p59494-RX116.1, was also identified in an ST258 strain, demonstrating how apramycin resistance can be spread from a non-conjugative plasmid through cointegration. CONCLUSIONS:We described a high apramycin resistance rate in clinical CRKp isolates in the New York/New Jersey region, mainly among the epidemic K. pneumoniae ST258 strains. The high resistance rate in an epidemic K. pneumoniae clone raises concern regarding the further optimization and development of apramycin and apramycin-like antibiotics.

OPINION STATEMENT/UNASSIGNED:Treatment sequencing in early-stage breast cancer has significantly evolved in recent years, particularly in the triple negative (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive subsets. Instead of surgery first followed by chemotherapy, several clinical trials showed benefits to administering systemic chemotherapy (and HER2-targeted therapies) prior to surgery. These benefits include more accurate prognostic estimates based on the extent of residual cancer that can also guide adjuvant treatment, and frequent tumor downstaging that can lead to smaller surgeries in patients with large tumors at diagnosis. Patients with extensive invasive residual cancer after neoadjuvant therapy are at high risk for disease recurrence, and two pivotal clinical trials, CREATE-X and KATHERINE, demonstrated improved recurrence free survival with adjuvant capecitabine and ado-trastuzumab-emtansine (T-DM1) in TNBC and HER2-positive residual cancers, respectively. Patients who achieve pathologic complete response (pCR) have excellent long-term disease-free survival regardless of what chemotherapy regimen induced this favorable response. This allows escalation or de-escalation of adjuvant therapy: patients who achieved pCR could be spared further chemotherapy, while those with residual cancer could receive additional chemotherapy postoperatively. Ongoing clinical trials are testing this strategy (CompassHER2-pCR: NCT04266249). pCR also provides an opportunity to assess de-escalation of locoregional therapies. Currently, for patients with residual disease in the lymph nodes (ypN+), radiation therapy entails coverage of the undissected axilla, and may include supra/infraclavicular/internal mammary nodes in addition to the whole breast or chest wall, depending on the type of surgery. Ongoing trials are testing the safety of omitting post-mastectomy breast and post-lumpectomy nodal irradiation (NCT01872975) as well as omitting axillary lymph node dissection (NCT01901094) in the setting of pCR. Additionally, evolving technologies such as minimal residual disease (MRD) monitoring in the blood during follow-up may allow early intervention with "second-line systemic adjuvant therapy" for patients with molecular relapse which might prevent impending clinical relapse.

OBJECTIVES/OBJECTIVE:To assess the risk of adverse diagnoses and laboratory abnormalities associated with a 300 mg or 150 mg daily dose of 3TC initiated by people living with HIV (PLWH) with an estimated glomerular filtration rate (eGFR) between ≥30 and ≤49 ml/min/1.73m2. DESIGN/METHODS:Longitudinal study based on electronic health records of 539 PLWH with eGFR between ≥30 and ≤49 ml/min/1.73m2 from the Observational Pharmaco-Epidemiology Research and Analysis (OPERA®) cohort. METHODS:Common unintended effects of 3TC were evaluated as composite outcomes. We estimated the incidence (univariate Poisson regression) and association between dose and incident composite outcomes (multivariate Poisson regression) among PLWH without the relevant diagnoses or laboratory abnormalities at 3TC initiation. RESULTS:PLWH initiating 150 mg 3TC had higher HIV RNA, lower eGFR, and more comorbidities than those initiating 300 mg 3TC. The prevalence of relevant diagnoses and laboratory abnormalities was similar in both groups. The most common lab abnormality was low hemoglobin. There was no statistically significant difference in incident adverse diagnoses/severe lab abnormalities with 300 mg versus 150 mg (incidence rate ratio [IRR]: 1.51; 95% confidence interval [CI]: 0.59, 3.92). However, a statistically significant association was observed when gastrointestinal symptoms/moderate lab abnormalities were included in the outcome (IRR: 3.07, 95% CI: 1.12, 8.40). CONCLUSIONS:Because 3TC is a well-tolerated drug with a wide therapeutic window, dose adjustment may be unnecessary among PLWH with eGFR between ≥30 and ≤49 ml/min/1.73m2. Clinical judgement is key when weighing the risks and benefits of 3TC dose adjustment for PLWH experiencing gastrointestinal symptoms or moderate lab abnormalities.