Outpatient antibiotic prescription trends in the United States: A national cohort study

OBJECTIVETo characterize trends in outpatient antibiotic prescriptions in the United StatesDESIGNRetrospective ecological and temporal trend study evaluating outpatient antibiotic prescriptions from 2013 to 2015SETTINGNational administrative claims data from a pharmacy benefits manager PARTICIPANTS. Prescription pharmacy beneficiaries from Express Scripts Holding CompanyMEASUREMENTSAnnual and seasonal percent change in antibiotic prescriptionsRESULTSApproximately 98 million outpatient antibiotic prescriptions were filled by 39 million insurance beneficiaries during the 3-year study period. The most commonly prescribed antibiotics were azithromycin, amoxicillin, amoxicillin/clavulanate, ciprofloxacin, and cephalexin. No significant changes in individual or overall annual antibiotic prescribing rates were found during the study period. Significant seasonal variation was observed, with antibiotics being 42% more likely to be prescribed during February than September (peak-to-trough ratio [PTTR], 1.42; 95% confidence interval [CI], 1.39–1.61). Similar seasonal trends were found for azithromycin (PTTR, 2.46; 95% CI, 2.44–3.47), amoxicillin (PTTR, 1.52; 95% CI, 1.42–1.89), and amoxicillin/clavulanate (PTTR, 1.78; 95% CI, 1.68–2.29).CONCLUSIONSThis study demonstrates that annual national outpatient antibiotic prescribing practices remained unchanged during our study period. Furthermore, seasonal peaks in antibiotics generally used to treat viral upper respiratory tract infections remained unchanged during cold and influenza season. These results suggest that inappropriate prescribing of antibiotics remains widespread, despite the concurrent release of several guideline-based best practices intended to reduce inappropriate antibiotic consumption; however, further research linking national outpatient antibiotic prescriptions to associated medical conditions is needed to confirm these findings.Infect Control Hosp Epidemiol 2018;39:584–589</jats:sec

The impact of overdiagnosis on the selection of efficient lung cancer screening strategies

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136362/1/ijc30602_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136362/2/ijc30602.pd

Biological and prognostic impact of apobec-induced mutations in the spectrum of plasma cell dyscrasias

In multiple myeloma (MM), whole exome sequencing (WES) studies have revealed four mutational signatures: two associated with aberrant activities of APOBEC cytidine deaminases (Signatures #2 and #13) and two clock-like signatures associated with "cancer age" (Signatures #1 and #5). Mutational signatures have not been investigated systematically in larger series, nor in other primary plasma cell dyscrasias such as monoclonal gammopathy of unknown significance (MGUS) or primary plasma cell leukemia (pPCL). Finally, while APOBEC activity has been correlated to increased mutational burden and poor-prognosis MAF/MAFB translocations in MM at diagnosis, this has never been confirmed in multivariate analysis in an independent series. To answer these questions, we mined 1151 MM samples from public WES datasets, including samples from the IA9 public release of the CoMMpass trial. The CoMMpass data were generated as part of the Multiple Myeloma Research Foundation Personalized Medicine Initiatives. We also analyzed 6 MGUS/Smoldering MM as well as 5 previously published pPCLs. Extraction of mutational signatures was performed using the NNMF algorithm as previously described (Alexandrov et al. Nature 2013). NNMF in the whole cohort extracted the known 4 signatures pertaining to distinct mutational processes: the two clock-like processes (signatures #1 and #5) and aberrant APOBEC deaminase activity (signatures #2 and #13). While the clock-like processes were more prominent in the cohort as a whole (median 70%, range 0-100%), the APOBEC showed a heterogeneous contribution, more visible in samples with the highest mutation burden. In fact, the absolute and relative contribution of APOBEC activity to the mutational repertoire correlated with the overall number of mutations (r=0.71, p= < 0.0001). As previously described, APOBEC contribution was significantly enriched among MM patients with t(14;16) and with t(14;20) (p<0.001), but the association between relative APOBEC contribution and mutational load remained significant across all cytogenetic subgroups with the exception of t(11;14). In the MGUS/SMM series, APOBEC contribution was generally low. Conversely, APOBEC activity was preponderant in three out of five pPCL samples, all of them characterized by the t(14;16)( IGH / MAF); in the remaining two pPCL the absolute number of APOBEC mutations was similar to MM. Overall, the APOBEC contribution was characterized by a progressive increment from MGUS/SMM to MM and pPCL. We next went on to investigate the prognostic impact of APOBEC signatures at diagnosis. Patients with APOBEC contribution in the 4th quartile had shorter PFS (2-y PFS 47% vs 66%, p<0.0001) and OS (2-y OS 70% vs 85%, p=0.0033) than patients in quartiles 1-3 (Figure 1a-b). This was independent from the association of APOBEC activity with MAF translocations and higher mutational burden, as shown by multivariate analysis with Cox regression (Figure 1c-d). ISS stage III was the only other variable that retained its independent prognostic value for both PFS and OS. We therefore combined both variables and found that co-occurrence of ISS III and APOBEC 4th quartile identifies a fraction of high-risk patients with 2-y OS of 53.8% (95% CI 36.6%-79%), while their simultaneous absence identifies long term survivors with 2-y OS of 93.3% (95% CI 89.6-97.2%). In this study, we provided a global overview on the contribution of mutational processes in the largest whole exome series of plasma cell dyscrasias investigated to date by NNMF. We propose that cases with high APOBEC activity may represent a novel prognostic subgroup that is transversal to conventional cytogenetic subgroups, advocating for closer integration of next-generation sequencing studies and clinical annotation to confirm this finding in independent series

Comparing Benefits from Many Possible Computed Tomography Lung Cancer Screening Programs: Extrapolating from the National Lung Screening Trial Using Comparative Modeling

Background: The National Lung Screening Trial (NLST) demonstrated that in current and former smokers aged 55 to 74 years, with at least 30 pack-years of cigarette smoking history and who had quit smoking no more than 15 years ago, 3 annual computed tomography (CT) screens reduced lung cancer-specific mortality by 20% relative to 3 annual chest X-ray screens. We compared the benefits achievable with 576 lung cancer screening programs that varied CT screen number and frequency, ages of screening, and eligibility based on smoking. Methods and Findings: We used five independent microsimulation models with lung cancer natural history parameters previously calibrated to the NLST to simulate life histories of the US cohort born in 1950 under all 576 programs. ‘Efficient’ (within model) programs prevented the greatest number of lung cancer deaths, compared to no screening, for a given number of CT screens. Among 120 ‘consensus efficient’ (identified as efficient across models) programs, the average starting age was 55 years, the stopping age was 80 or 85 years, the average minimum pack-years was 27, and the maximum years since quitting was 20. Among consensus efficient programs, 11% to 40% of the cohort was screened, and 153 to 846 lung cancer deaths were averted per 100,000 people. In all models, annual screening based on age and smoking eligibility in NLST was not efficient; continuing screening to age 80 or 85 years was more efficient. Conclusions: Consensus results from five models identified a set of efficient screening programs that include annual CT lung cancer screening using criteria like NLST eligibility but extended to older ages. Guidelines for screening should also consider harms of screening and individual patient characteristics

Comparing benefits from many possible computed tomography lung cancer screening programs: Extrapolating from the National Lung Screening Trial using comparative modeling

Background: The National Lung Screening Trial (NLST) demonstrated that in current and former smokers aged 55 to 74 years, with at least 30 pack-years of cigarette smoking history and who had quit smoking no more than 15 years ago, 3 annual computed tomography (CT) screens reduced lung cancer-specific mortality by 20% relative to 3 annual chest X-ray screens. We compared the benefits achievable with 576 lung cancer screening programs that varied CT screen number and frequency, ages of screening, and eligibility based on smoking. Methods and Findings: We used five independent microsimulation models with lung cancer natural history parameters previously calibrated to the NLST to simulate life histories of the US cohort born in 1950 under all 576 programs. 'Efficient' (within model) programs prevented the greatest number of lung cancer deaths, compared to no screening, for a given number of CT screens. Among 120 'consensus efficient' (identified as efficient across models) programs, the average starting age was 55 years, the stopping age was 80 or 85 years, the average minimum pack-years was 27, and the maximum years since quitting was 20. Among consensus efficient programs, 11% to 40% of the cohort was screened, and 153 to 846 lung cancer deaths were averted per 100,000 people. In all models, annual screening based on age and smoking eligibility in NLST was not efficient; continuing screening to age 80 or 85 years was more efficient. Conclusions: Consensus results from five models identified a set of efficient screening programs that include annual CT lung cancer screening using criteria like NLST eligibility but extended to older ages. Guidelines for screening should also consider harms of screening and individual patient characteristics

Cost-effectiveness evaluation of the 2021 US Preventive Services Task Force recommendation for lung cancer screening

IMPORTANCE: The US Preventive Services Task Force (USPSTF) issued its 2021 recommendation on lung cancer screening, which lowered the starting age for screening from 55 to 50 years and the minimum cumulative smoking exposure from 30 to 20 pack-years relative to its 2013 recommendation. Although costs are expected to increase because of the expanded screening eligibility criteria, it is unknown whether the new guidelines for lung cancer screening are cost-effective. OBJECTIVE: To evaluate the cost-effectiveness of the 2021 USPSTF recommendation for lung cancer screening compared with the 2013 recommendation and to explore the cost-effectiveness of 6 alternative screening strategies that maintained a minimum cumulative smoking exposure of 20 pack-years and an ending age for screening of 80 years but varied the starting ages for screening (50 or 55 years) and the number of years since smoking cessation (≤15, ≤20, or ≤25). DESIGN, SETTING, AND PARTICIPANTS: A comparative cost-effectiveness analysis using 4 independently developed microsimulation models that shared common inputs to assess the population-level health benefits and costs of the 2021 recommended screening strategy and 6 alternative screening strategies compared with the 2013 recommended screening strategy. The models simulated a 1960 US birth cohort. Simulated individuals entered the study at age 45 years and were followed up until death or age 90 years, corresponding to a study period from January 1, 2005, to December 31, 2050. EXPOSURES: Low-dose computed tomography in lung cancer screening programs with a minimum cumulative smoking exposure of 20 pack-years. MAIN OUTCOMES AND MEASURES: Incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) of the 2021 vs 2013 USPSTF lung cancer screening recommendations as well as 6 alternative screening strategies vs the 2013 USPSTF screening strategy. Strategies with a mean ICER lower than $100 000 per QALY were deemed cost-effective. RESULTS: The 2021 USPSTF recommendation was estimated to be cost-effective compared with the 2013 recommendation, with a mean ICER of$72 564 (range across 4 models, $59 493-$85 837) per QALY gained. The 2021 recommendation was not cost-effective compared with 6 alternative strategies that used the 20 pack-year criterion. Strategies associated with the most cost-effectiveness included those that expanded screening eligibility to include a greater number of former smokers who had not smoked for a longer duration (ie, ≤20 years and ≤25 years since smoking cessation vs ≤15 years since smoking cessation). In particular, the strategy that screened former smokers who quit within the past 25 years and began screening at age 55 years was associated with screening coverage closest to that of the 2021 USPSTF recommendation yet yielded greater cost-effectiveness, with a mean ICER of $66 533 (range across 4 models,$55 693-$80 539). CONCLUSIONS AND RELEVANCE: This economic evaluation found that the 2021 USPSTF recommendation for lung cancer screening was cost-effective; however, alternative screening strategies that maintained a minimum cumulative smoking exposure of 20 pack-years but included individuals who quit smoking within the past 25 years may be more cost-effective and warrant further evaluation.Accepted manuscrip

Heterogeneity of genomic evolution and mutational profiles in multiple myeloma.

Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment

Male-Mediated Gene Flow in Patrilocal Primates

BACKGROUND: Many group-living species display strong sex biases in dispersal tendencies. However, gene flow mediated by apparently philopatric sex may still occur and potentially alters population structure. In our closest living evolutionary relatives, dispersal of adult males seems to be precluded by high levels of territoriality between males of different groups in chimpanzees, and has only been observed once in bonobos. Still, male-mediated gene flow might occur through rare events such as extra-group matings leading to extra-group paternity (EGP) and female secondary dispersal with offspring, but the extent of this gene flow has not yet been assessed. METHODOLOGY/PRINCIPAL FINDINGS: Using autosomal microsatellite genotyping of samples from multiple groups of wild western chimpanzees (Pan troglodytes verus) and bonobos (Pan paniscus), we found low genetic differentiation among groups for both males and females. Characterization of Y-chromosome microsatellites revealed levels of genetic differentiation between groups in bonobos almost as high as those reported previously in eastern chimpanzees, but lower levels of differentiation in western chimpanzees. By using simulations to evaluate the patterns of Y-chromosomal variation expected under realistic assumptions of group size, mutation rate and reproductive skew, we demonstrate that the observed presence of multiple and highly divergent Y-haplotypes within western chimpanzee and bonobo groups is best explained by successful male-mediated gene flow. CONCLUSIONS/SIGNIFICANCE: The similarity of inferred rates of male-mediated gene flow and published rates of EGP in western chimpanzees suggests this is the most likely mechanism of male-mediated gene flow in this subspecies. In bonobos more data are needed to refine the estimated rate of gene flow. Our findings suggest that dispersal patterns in these closely related species, and particularly for the chimpanzee subspecies, are more variable than previously appreciated. This is consistent with growing recognition of extensive behavioral variation in chimpanzees and bonobos

Impact of Second Primary Malignancy Post–Autologous Transplantation on Outcomes of Multiple Myeloma: A CIBMTR Analysis

The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P \u3c .001 and HR 5.01, P \u3c .001, respectively) and OS (HR 3.85, P \u3c .001 and HR 8.13, P \u3c .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post-auto-HSCT