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Summary: DNA sequencing is becoming more affordable and faster through advances in high-throughput technologies. This rise in data availability has contributed to the development of novel algorithms to elucidate previously obscure features and led to an increased reliance on complex workflows to integrate such tools into analyses pipelines. To facilitate the analysis of DNA sequencing data, we created metapipeline-DNA, a highly configurable and extensible pipeline. It encompasses a broad range of processing including raw sequencing read alignment and recalibration, variant calling, quality control and subclonal reconstruction. Metapipeline-DNA also contains configuration options to select and tune analyses while being robust to failures. This standardizes and simplifies the ability to analyze large DNA sequencing in both clinical and research settings. Availability: Metapipeline-DNA is an open-source Nextflow pipeline under the GPLv2 license and is freely available at https://github.com/uclahs-cds/metapipeline-DNA .

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Background: Better understanding differences associated with antibiotic prescribing for acute sinusitis can help inform antibiotic stewardship strategies. We characterized antibiotic prescribing patterns for acute sinusitis among commercially insured adults and explored differences by patient- and prescriber-level factors. Methods: Outpatient encounters among adults aged 18 to 64 years diagnosed with sinusitis between 2016 and 2020 were identified by national administrative claims data. We classified antibiotic agents-first-line (amoxicillin-clavulanate or amoxicillin) and second-line (doxycycline, levofloxacin, or moxifloxacin)-and ≤7-day durations as guideline concordant based on clinical practice guidelines. Modified Poisson regression was used to examine the association between patient- and prescriber-level factors and guideline-concordant antibiotic prescribing. Results: Among 4 689 850 sinusitis encounters, 53% resulted in a guideline-concordant agent, 30% in a guideline-discordant agent, and 17% in no antibiotic prescription. About 75% of first-line agents and 63% of second-line agents were prescribed for >7 days, exceeding the length of therapy recommended by clinical guidelines. Adults with sinusitis living in a rural area were less likely to receive a prescription with guideline-concordant antibiotic selection (adjusted risk ratio [aRR], 0.92; 95% CI, .92-.92) and duration (aRR, 0.77; 95% CI, .76-.77). When compared with encounters in an office setting, urgent care encounters were less likely to result in a prescription with a guideline-concordant duration (aRR, 0.76; 95% CI, .75-.76). Conclusions: Opportunities still exist to optimize antibiotic agent selection and treatment duration for adults with acute sinusitis, especially in rural areas and urgent care settings. Recognizing specific patient- and prescriber-level factors associated with antibiotic prescribing can help inform antibiotic stewardship interventions.

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BACKGROUND: The Advisory Committee on Immunization Practices (ACIP) recommends early childhood vaccinations, but knowledge is limited about the magnitude and timing of vaccine delay for each recommended dose on a population level. We sought to characterize longitudinal patient-level patterns of early childhood vaccination schedule adherence. METHODS: Using the Merative MarketScan Commercial Database (2009-2019), we identified commercially-insured infants who received at least one timely dose of a 2-month recommended vaccine. We categorized the number of recommended vaccines administered on the same date at 2, 4, 6, and 12-15 months of age (grace period: -7, +21 days). A Sankey diagram illustrated the number of vaccines received concomitantly during each age window and depicted transitions to different states over time (e.g., no vaccine delay to vaccine delay). For each vaccine dose, we estimated the cumulative incidence of receipt. RESULTS: Among 1,239,364 eligible children, 28% of infants aged 4 months and 38% of infants aged 6 months did not receive timely, concomitant administration of all recommended vaccines. The number of timely vaccines received concomitantly and age at receipt varied most for doses recommended during the second year of life. Children with a previously delayed (versus timely) dose consistently experienced longer time to subsequent dose. CONCLUSIONS: National coverage improved over time for all recommended vaccine doses under study, most notably for measles, mumps, and rubella. However, many children do not receive vaccines on schedule. Interventions to maintain adherence to the recommended schedule are needed early in life.

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BACKGROUND AND OBJECTIVE: There is no consensus on de-escalation of monitoring during active surveillance (AS) for prostate cancer (PCa). Our objective was to determine clinical criteria that can be used in decisions to reduce the intensity of AS monitoring. METHODS: The global prospective AS cohort from the Global Action Plan prostate cancer AS consortium was retrospectively analyzed. The 24656 patients with complete outcome data were considered. The primary goal was to develop a model identifying a subgroup with a high ratio of other-cause mortality (OCM) to PCa-specific mortality (PCSM). Nonparametric competing-risks models were used to estimate cause-specific mortality. We hypothesized that the subgroup with the highest OCM/PCSM ratio would be good candidates for de-escalation of AS monitoring. KEY FINDINGS AND LIMITATIONS: Cumulative mortality at 15 yr, accounting for censoring, was 1.3% for PCSM, 11.5% for OCM, and 18.7% for death from unknown causes. We identified body mass index (BMI) >25 kg/m2 and <11% positive cores at initial biopsy as an optimal set of criteria for discriminating OCM from PCSM. The 15-yr OCM/PCSM ratio was 34.2 times higher for patients meeting these criteria than for those not meeting the criteria. According to these criteria, 37% of the cohort would be eligible for de-escalation of monitoring. Limitations include the retrospective nature of the study and the lack of external validation. CONCLUSIONS: Our study identified BMI >25 kg/m2 and <11% positive cores at initial biopsy as clinical criteria for de-escalation of AS monitoring in PCa. PATIENT SUMMARY: We investigated factors that could help in deciding on when to reduce the intensity of monitoring for patients on active surveillance for prostate cancer. We found that patients with higher BMI (body mass index) and lower prostate cancer volume may be good candidates for less intensive monitoring. This model could help doctors and patients in making decisions on active surveillance for prostate cancer.

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PURPOSE: To characterize antibiotic utilization for outpatient community-acquired pneumonia (CAP) in the United States. METHODS: We conducted a cohort study among adults 18-64 years diagnosed with outpatient CAP and a same-day guideline-recommended oral antibiotic fill in the MarketScan® Commercial Database (2008-2019). We excluded patients coded for chronic lung disease or immunosuppressive disease; recent hospitalization or frequent healthcare exposure (e.g., home wound care, patients with cancer); recent antibiotics; or recent infection. We characterized utilization of broad-spectrum antibiotics (respiratory fluoroquinolone, ß-lactam + macrolide, ß-lactam + doxycycline) versus narrow-spectrum antibiotics (macrolide, doxycycline) overall and by patient- and provider-level characteristics. Per 2007 IDSA/ATS guidelines, we stratified analyses by otherwise healthy patients and patients with comorbidities (coded for diabetes; chronic heart, liver, or renal disease; etc.). RESULTS: Among 263 914 otherwise healthy CAP patients, 35% received broad-spectrum antibiotics (not recommended); among 37 161 CAP patients with comorbidities, 44% received broad-spectrum antibiotics (recommended). Ten-day antibiotic treatment durations were the most common for all antibiotic classes except macrolides. From 2008 to 2019, broad-spectrum antibiotic use substantially decreased from 45% to 19% in otherwise healthy patients (average annual percentage change [AAPC], -7.5% [95% CI -9.2%, -5.9%]), and from 55% to 29% in patients with comorbidities (AAPC, -5.8% [95% CI -8.8%, -2.6%]). In subgroup analyses, broad-spectrum antibiotic use varied by age, geographic region, provider specialty, and provider location. CONCLUSIONS: Real-world use of broad-spectrum antibiotics for outpatient CAP declined over time but remained common, irrespective of comorbidity status. Prolonged duration of therapy was common. Antimicrobial stewardship is needed to aid selection according to comorbidity status and to promote shorter courses.

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Objective: To determine the relationship between severe acute respiratory syndrome coronavirus 2 infection, hospital-acquired infections (HAIs), and mortality. Design: Retrospective cohort. Setting: Three St. Louis, MO hospitals. Patients: Adults admitted ≥48 hours from January 1, 2017 to August 31, 2020. Methods: Hospital-acquired infections were defined as those occurring ≥48 hours after admission and were based on positive urine, respiratory, and blood cultures. Poisson interrupted time series compared mortality trajectory before (beginning January 1, 2017) and during the first 6 months of the pandemic. Multivariable logistic regression models were fitted to identify risk factors for mortality in patients with an HAI before and during the pandemic. A time-to-event analysis considered time to death and discharge by fitting Cox proportional hazards models. Results: Among 6,447 admissions with subsequent HAIs, patients were predominantly White (67.9%), with more females (50.9% vs 46.1%, P = .02), having slightly lower body mass index (28 vs 29, P = .001), and more having private insurance (50.6% vs 45.7%, P = .01) in the pre-pandemic period. In the pre-pandemic era, there were 1,000 (17.6%) patient deaths, whereas there were 160 deaths (21.3%, P = .01) during the pandemic. A total of 53 (42.1%) coronavirus disease 2019 (COVID-19) patients died having an HAI. Age and comorbidities increased the risk of death in patients with COVID-19 and an HAI. During the pandemic, Black patients with an HAI and COVID-19 were more likely to die than White patients with an HAI and COVID-19. Conclusions: In three Midwestern hospitals, patients with concurrent HAIs and COVID-19 were more likely to die if they were Black, elderly, and had certain chronic comorbidities.

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In a US adult population aged <65 years, attributable costs due to Clostridioides difficile infection (CDI) were highest in persons with hospital onset and lowest in those with community-associated CDI treated outside a hospital. The economic burden of CDI in younger adults underscores the need for additional CDI-preventive strategies.

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In this retrospective cohort from 3 Missouri hospitals from January 2017 to August 2020, hospital-onset Clostridioides difficile infections were more common during the severe acute respiratory syndrome coronavirus 2 pandemic at the tertiary care hospital. Risk factors associated with hospital-onset C difficile infection included the year of hospitalization, age, high-risk antibiotic use, acid-reducing medications, chronic comorbidities, and severe acute respiratory syndrome coronavirus 2 infection.

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OBJECTIVE: To examine the risk of developing an overweight or obese (O/O) body condition score (BCS) in gonadectomized versus intact dogs and, separately, the impact of age at gonadectomy on O/O outcomes among sterilized dogs. ANIMALS: Dogs were patients of Banfield Pet Hospital in the US from 2013 to 2019. After exclusion criteria were applied, the final sample consisted of 155,199 dogs. PROCEDURES: In this retrospective cohort study, Cox proportional hazards models evaluated associations between O/O and gonadectomy status, sex, age at gonadectomy, and breed size. Models were used to estimate the risk of becoming O/O in gonadectomized versus intact dogs and, separately, to estimate risk of O/O BCS according to age at surgery among gonadectomized dogs. RESULTS: Gonadectomy increased O/O risk for most dogs compared to intact dogs. Unlike most prior findings, O/O hazard ratios among gonadectomized versus intact dogs were larger for males than females. O/O risk varied according to breed size but not linearly. Sterilizing at 1 year old tended to yield a lower O/O risk compared to doing so later. Comparative O/O risk among dogs gonadectomized at 6 months versus 1 year varied by breed size. Overall patterns for obesity related to size were similar to patterns in the O/O analysis. CLINICAL RELEVANCE: Veterinarians are uniquely positioned to help prevent O/O in their patients. Results extend understanding of risk factors for O/O development in dogs. In combination with information about other benefits and risks associated with gonadectomy, these data can help tailor recommendations regarding gonadectomy in individual dogs.

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Objective: To use interrupted time-series analyses to investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on healthcare-associated infections (HAIs). We hypothesized that the pandemic would be associated with higher rates of HAIs after adjustment for confounders. Design: We conducted a cross-sectional study of HAIs in 3 hospitals in Missouri from January 1, 2017, through August 31, 2020, using interrupted time-series analysis with 2 counterfactual scenarios. Setting: The study was conducted at 1 large quaternary-care referral hospital and 2 community hospitals. Participants: All adults ≥18 years of age hospitalized at a study hospital for ≥48 hours were included in the study. Results: In total, 254,792 admissions for ≥48 hours occurred during the study period. The average age of these patients was 57.6 (±19.0) years, and 141,107 (55.6%) were female. At hospital 1, 78 CLABSIs, 33 CAUTIs, and 88 VAEs were documented during the pandemic period. Hospital 2 had 13 CLABSIs, 6 CAUTIs, and 17 VAEs. Hospital 3 recorded 11 CLABSIs, 8 CAUTIs, and 11 VAEs. Point estimates for hypothetical excess HAIs suggested an increase in all infection types across facilities, except for CLABSIs and CAUTIs at hospital 1 under the "no pandemic" scenario. Conclusions: The COVID-19 era was associated with increases in CLABSIs, CAUTIs, and VAEs at 3 hospitals in Missouri, with variations in significance by hospital and infection type. Continued vigilance in maintaining optimal infection prevention practices to minimize HAIs is warranted.

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Fecal glucocorticoid metabolite (FGM) concentrations, activity, and personality were assessed for 35 fennec foxes (Vulpes zerda) to determine whether animals managed as ambassadors differed from exhibit or off-exhibit animals. A FGM assay, pedometer, and personality assessment tool were validated. Then, fecal samples and movement data were collected during winter and summer periods. Handling was recorded, and the personality of each fox was evaluated. Generalized linear mixed models assessed the relationships between FGM concentrations, activity, personality, handling, sex, season, rearing type, and role. FGM concentrations did not differ in relation to role or handling. Foxes were most active at night; the time of peak activity did not vary with role or handling. Foxes were more active in winter; males were more active than females, and ambassador foxes were more active than off-exhibit animals. Hand-reared foxes were more sociable, and, at one institution, ambassador foxes were more sociable than foxes in other roles. These results suggest that management for ambassador programs is not associated with changes in glucocorticoid production or circadian patterns but may increase activity and be associated with greater sociability.

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BACKGROUND: The dimorphic mycoses (DMs) of the United States-Histoplasma, Coccidioides, and Blastomyces-commonly known as endemic mycoses of North America (in addition to Paracoccidioides) are increasingly being diagnosed outside their historical areas of endemicity. Despite this trend, the maps outlining their geographic distributions have not been updated in more than half a century using a large, nationwide database containing individual-patient-level data. METHODS: This was a retrospective analysis of >45 million Medicare fee-for-service beneficiaries from 1 January 2007 through 31 December 2016. Diagnoses of histoplasmosis, coccidioidomycosis, and blastomycosis were defined by International Classification of Diseases, Ninth/10th Revision, codes. The primary outcome was the incidence of histoplasmosis, coccidioidomycosis, and blastomycosis for each US county. Clinically meaningful thresholds for incidence were defined as 100 cases/100 000 person-years for histoplasmosis and coccidioidomycosis and 50 cases/100 000 person-years for blastomycosis. RESULTS: There were 79 749 histoplasmosis, 37 726 coccidioidomycosis, and 6109 blastomycosis diagnoses in unique persons from 2007-2016 across 3143 US counties. Considering all US states plus Washington, DC, 94% (48/51) had ≥1 county above the clinically relevant threshold for histoplasmosis, 69% (35/51) for coccidioidomycosis, and 78% (40/51) for blastomycosis. CONCLUSIONS: Persons with histoplasmosis, coccidioidomycosis, and blastomycosis are diagnosed in significant numbers outside their historical geographic distributions established >50 years ago. Clinicians should consider DM diagnoses based on compatible clinical syndromes with less emphasis placed on patients' geographic exposure. Increased clinical suspicion leading to a subsequent increase in DM diagnostic testing would likely result in fewer missed diagnoses, fewer diagnostic delays, and improved patient outcomes.

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PURPOSE: Acute otitis media (AOM) is a common indication for antibiotics in children. We sought to characterize the frequency of nonguideline concordant antibiotic therapy for AOM in the United States, by agent and duration. METHODS: Using national administrative claims data (2016-2019), we identified children aged 6 months to 17 years with an oral antibiotic dispensed within 3 days of a new diagnosis of suppurative AOM. Use of nonguideline concordant agents and durations, defined based on national treatment guidelines, were summarized by age, race, rurality, region, and insurance type. Subsequent oral antibiotic dispensing within the year after AOM diagnosis was also evaluated. We created sunburst diagrams to visualize longitudinal patterns of within-person antibiotic utilization for AOM, by agent and duration. RESULTS: We identified 789 424 eligible commercially-insured and 502 239 medicaid-insured children. Among commercially insured children, 35% received nonguideline concordant agents for AOM, including cefdinir (16%), amoxicillin-clavulanate (12%), and azithromycin (7%). Fewer children age <2 years received a nonguideline concordant initial agent (27%) compared to age ≥6 years (41%). More children age <2 years received three or more antibiotics over the following year (34% vs. 3% for children age ≥6 years). The most common treatment duration was 10 days for all ages; treatment duration for the initial antibiotic was nonguideline concordant for 95% and 89% of children age 2-5 years and ≥6 years, respectively. Patterns were similar for medicaid-insured children. CONCLUSIONS: Nonguideline concordant antibiotic use is common when treating AOM in children, including use of broad-spectrum agents and longer-than-recommended antibiotic durations.

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BACKGROUND: Little is known about the clinical and financial consequences of inappropriate antibiotics. We aimed to estimate the comparative risk of adverse drug events and attributable healthcare expenditures associated with inappropriate versus appropriate antibiotic prescriptions for common respiratory infections. METHODS: We established a cohort of adults aged 18 to 64 years with an outpatient diagnosis of a bacterial (pharyngitis, sinusitis) or viral respiratory infection (influenza, viral upper respiratory infection, nonsuppurative otitis media, bronchitis) from 1 April 2016 to 30 September 2018 using Merative MarketScan Commercial Database. The exposure was an inappropriate versus appropriate oral antibiotic (ie, non-guideline-recommended vs guideline-recommended antibiotic for bacterial infections; any vs no antibiotic for viral infections). Propensity score-weighted Cox proportional hazards models were used to estimate the association between inappropriate antibiotics and adverse drug events. Two-part models were used to calculate 30-day all-cause attributable healthcare expenditures by infection type. RESULTS: Among 3 294 598 eligible adults, 43% to 56% received inappropriate antibiotics for bacterial and 7% to 66% for viral infections. Inappropriate antibiotics were associated with increased risk of several adverse drug events, including Clostridioides difficile infection and nausea/vomiting/abdominal pain (hazard ratio, 2.90; 95% confidence interval, 1.31-6.41 and hazard ratio, 1.10; 95% confidence interval, 1.03-1.18, respectively, for pharyngitis). Thirty-day attributable healthcare expenditures were higher among adults who received inappropriate antibiotics for bacterial infections ($18-$67) and variable (-$53 to $49) for viral infections. CONCLUSIONS: Inappropriate antibiotic prescriptions for respiratory infections were associated with increased risks of patient harm and higher healthcare expenditures, justifying a further call to action to implement outpatient antibiotic stewardship programs.

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BACKGROUND: Although hospital-onset Clostridioides difficile infection (CDI) is associated with significant healthcare costs, the economic burden of CDI with onset in other facilities or the community has not been well studied. METHODS: Incident CDI cases were identified using 2011-2017 Medicare fee-for-service data. Controls were randomly selected in a 4:1 ratio matching to the CDI case surveillance definition. Inverse probability of exposure weights were used to balance on measured confounders. One-, 3-, and 5-year cumulative costs attributable to CDI were computed using a 3-part estimator (parametric survival model and pair of 2-part models predicting costs separately in intervals where death did and did not occur). RESULTS: A total of 60 492 CDI cases were frequency-matched to 241 968 controls. One-, 3-, and 5-year adjusted attributable costs were highest for hospital-onset CDI at $14 257, $18 953, and $21 792, respectively, compared with hospitalized controls and lowest for community-associated CDI compared with community controls at $1013, $3161, and $6454, respectively. Adjusted 1-, 3-, and 5-year costs attributable to community-onset healthcare facility-associated CDI were $8222, $13 066, and $16 329 and for other healthcare facility-onset CDI were $5345, $6764, and $7125, respectively. CONCLUSIONS: Economic costs attributable to CDI in elderly persons were highest for hospital-onset and community-onset healthcare facility-associated CDI. Although lower, attributable costs due to CDI were significantly higher in cases with CDI onset in the community or other healthcare facility than for comparable persons without CDI. Additional strategies to prevent CDI in the elderly are needed to reduce morbidity and healthcare expenditures.

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BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are associated with weight gain in people with HIV (PWH). Less is known about the risk of other metabolic outcomes such as diabetes mellitus and hyperglycemia. METHODS: IBM® MarketScan® databases for commercially and Medicaid-insured adults were used to identify PWH newly initiating antiretroviral therapy (ART). The primary outcome was a composite of new-onset diabetes mellitus/hyperglycemia in the 6 months following ART initiation and was identified using International Classification of Disease, Ninth revision, Clinical Modification (ICD-9-CM) and ICD-10-CM diagnosis and procedure codes and Current Procedural Terminology, 4th Edition (CPT-4) codes. To examine the relationship between INSTI use and the composite outcome, we estimated the risk using Cox proportional hazards models with calendar time-specific standardized mortality ratio weights. RESULTS: Of 42 382 PWH who initiated ART between 1 July 2007 and 30 June 2018, 22 762 (54%) were treated with INSTI-based regimens. Mean age was 38 years, 74% were male, and 19% were Medicaid insured. PWH on INSTIs were 31% more likely to develop new-onset diabetes mellitus/hyperglycemia (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.15-1.48]) compared with those who initiated non-INSTI-based regimens. When examined individually, the highest risk was associated with elvitegravir (HR, 1.54; 95% CI, 1.32-1.97; P < .001) and the lowest risk with raltegravir (HR, 1.19; 95% CI, 1.03-1.37; P = .02). CONCLUSIONS: INSTI use was associated with increased risk of new-onset diabetes mellitus/hyperglycemia in the 6 months following ART initiation.

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Importance: Nonguideline antibiotic prescribing for the treatment of pediatric infections is common, but the consequences of inappropriate antibiotics are not well described. Objective: To evaluate the comparative safety and health care expenditures of inappropriate vs appropriate oral antibiotic prescriptions for common outpatient pediatric infections. Design, Setting, and Participants: This cohort study included children aged 6 months to 17 years diagnosed with a bacterial infection (suppurative otitis media [OM], pharyngitis, sinusitis) or viral infection (influenza, viral upper respiratory infection [URI], bronchiolitis, bronchitis, nonsuppurative OM) as an outpatient from April 1, 2016, to September 30, 2018, in the IBM MarketScan Commercial Database. Data were analyzed from August to November 2021. Exposures: Inappropriate (ie, non-guideline-recommended) vs appropriate (ie, guideline-recommended) oral antibiotic agents dispensed from an outpatient pharmacy on the date of infection. Main Outcomes and Measures: Propensity score-weighted Cox proportional hazards models were used to estimate hazards ratios (HRs) and 95% CIs for the association between inappropriate antibiotic prescriptions and adverse drug events. Two-part models were used to calculate 30-day all-cause attributable health care expenditures by infection type. National-level annual attributable expenditures were calculated by scaling attributable expenditures in the study cohort to the national employer-sponsored insurance population. Results: The cohort included 2 804 245 eligible children (52% male; median [IQR] age, 8 [4-12] years). Overall, 31% to 36% received inappropriate antibiotics for bacterial infections and 4% to 70% for viral infections. Inappropriate antibiotics were associated with increased risk of several adverse drug events, including Clostridioides difficile infection and severe allergic reaction among children treated with a nonrecommended antibiotic agent for a bacterial infection (among patients with suppurative OM, C. difficile infection: HR, 6.23; 95% CI, 2.24-17.32; allergic reaction: HR, 4.14; 95% CI, 2.48-6.92). Thirty-day attributable health care expenditures were generally higher among children who received inappropriate antibiotics, ranging from $21 to $56 for bacterial infections and from -$96 to $97 for viral infections. National annual attributable expenditure estimates were highest for suppurative OM ($25.3 million), pharyngitis ($21.3 million), and viral URI ($19.1 million). Conclusions and Relevance: In this cohort study of children with common infections treated in an outpatient setting, inappropriate antibiotic prescriptions were common and associated with increased risks of adverse drug events and higher attributable health care expenditures. These findings highlight the individual- and national-level consequences of inappropriate antibiotic prescribing and further support implementation of outpatient antibiotic stewardship programs.

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PURPOSE/BACKGROUND: Antipsychotic drugs are well established to alter circulating prolactin levels by blocking dopamine D2 receptors in the pituitary. Prolactin activates many genes important in the development of breast cancer. Prior studies have found an association with antipsychotic use and risk of breast cancer. METHODS/PROCEDURES: The IBM MarketScan Commercial and Medicaid Databases were used to establish a large, observational cohort of women taking antipsychotics drugs compared with anticonvulsants or lithium. A new user design was used that required 12 months of insurance enrollment before the first antipsychotic or anticonvulsant/lithium prescription. Invasive breast cancer was identified using diagnostic codes. Multivariable Cox proportional hazards models were used to evaluate the risk of breast cancer with antipsychotic drug exposure controlling for age and other risk factors. FINDINGS/RESULTS: A total of 914 cases (0.16%) of invasive breast cancer were identified among 540,737 women. Exposure to all antipsychotics was independently associated with a 35% increased risk of breast cancer (aHR [adjusted hazard ratio], 1.35; 95% confidence interval, 1.14-1.61). Category 1 drugs (high prolactin) were associated with a 62% increased risk (aHR, 1.62; 95% CI, 1.30-2.03), category 2 drugs a 54% increased risk (aHR, 1.54; 95% CI, 1.19-1.99), and category 3 drugs were not associated with breast cancer risk. IMPLICATIONS/CONCLUSIONS: In the largest study of antipsychotics taken by US women, a higher risk between antipsychotic drug use and increased risk for breast cancer was observed, with a differential higher association with antipsychotic categories that elevate prolactin. Our study confirms other recent observational studies of increased breast cancer risk with antipsychotics that elevate prolactin.

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BACKGROUND AND AIMS: Persons with opioid use disorder (OUD) and co-occurring alcohol use disorder (AUD) are understudied. We identified whether co-occurring AUD was associated with OUD treatment type, compared associations between treatment type and six-month treatment retention and determined whether co-occurring AUD moderated these relationships. METHODS: We used an observational cohort study design to analyze insurance claims data from 2011 to 2016 from persons aged 12-64 with an opioid abuse or opioid dependence diagnosis and OUD treatment claim. Our unit of analysis was the treatment episode; we used logistic regression for analyses. RESULTS: Of 211,047 treatment episodes analyzed, 14 % had co-occurring alcohol abuse or dependence diagnoses. Among persons with opioid dependence, persons with co-occurring alcohol dependence were 25 % less likely to receive medication treatment relative to those without AUD. Further, alcohol dependence was associated with decreased likelihood of treatment with buprenorphine (AOR 0.47, 95 % CI 0.44-0.49) or methadone (AOR 0.31, 95 % CI 0.28-0.35) and increased likelihood of treatment with extended-release (AOR 1.36, 95 % CI 1.21-1.54) or oral (AOR 1.73, 95 % CI 1.57-1.90) naltrexone relative to psychosocial treatment. Buprenorphine and methadone were associated with highest retention prevalence regardless of OUD or AUD severity. Co-occurring alcohol abuse or dependence did not meaningfully change retention prevalence associated with buprenorphine or methadone. Co-occurring AUD was not associated with improved retention among persons receiving either formulation of naltrexone. CONCLUSIONS: Buprenorphine and methadone are associated with relatively high likelihood of treatment retention among persons opioid and alcohol dependence, but are disproportionately under-prescribed.

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BACKGROUND: Important questions exist regarding the comparative effectiveness of alternative childhood vaccine schedules; however, optimal approaches to studying this complex issue are unclear. METHODS: We applied methods for studying dynamic treatment regimens to estimate the comparative effectiveness of different rotavirus vaccine (RV) schedules for preventing acute gastroenteritis-related emergency department (ED) visits or hospitalization. We studied the effectiveness of six separate protocols: one- and two-dose monovalent rotavirus vaccine (RV1); one-, two-, and three-dose pentavalent rotavirus vaccine (RV5); and no RV vaccine. We used data on all infants to estimate the counterfactual cumulative risk for each protocol. Infants were censored when vaccine receipt deviated from the protocol. Inverse probability of censoring-weighted estimation addressed potentially informative censoring by protocol deviations. A nonparametric group-based bootstrap procedure provided statistical inference. RESULTS: The method yielded similar 2-year effectiveness estimates for the full-series protocols; weighted risk difference estimates comparing unvaccinated children to those adherent to either full-series (two-dose RV1, three-dose RV5) corresponded to four fewer hospitalizations and 12 fewer ED visits over the 2-year period per 1,000 children. We observed dose-response relationships, such that additional doses further reduced risk of acute gastroenteritis. Under a theoretical intervention to fully vaccinate all children, the 2-year risk differences comparing full to observed adherence were 0.04% (95% CI = 0.03%, 0.05%) for hospitalizations and 0.17% (95% CI = 0.14%, 0.19%) for ED visits. CONCLUSIONS: The proposed approach can generate important evidence about the consequences of delaying or skipping vaccine doses, and the impact of interventions to improve vaccine schedule adherence.

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