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There is growing interest in the secondary use of healthcare data to evaluate medication safety in pregnancy. Tree-based scan statistics (TBSS) offer an innovative approach to help identify potential safety signals. TBSS utilize hierarchically organized outcomes, generally based on existing clinical coding systems that group outcomes by organ system. When assessing teratogenicity, such groupings often lack a sound embryologic basis given the etiologic heterogeneity of congenital malformations. The study objective was to enhance the grouping of congenital malformations to be used in scanning approaches through implementation of hierarchical clustering analysis (HCA) and to pilot test an HCA-enhanced TBSS approach for medication safety surveillance in pregnancy in two test cases using >4.2 million mother-child dyads from two US-nationwide databases. HCA identified (1) malformation combinations belonging to the same organ system already grouped in existing classifications, (2) known combinations across different organ systems not previously grouped, (3) unknown combinations not previously grouped, and (4) malformations seemingly standing on their own. Testing the approach with valproate and topiramate identified expected signals, and a signal for an HCA-cluster missed by traditional classification. Augmenting existing classifications with clusters identified through large data exploration may be promising when defining phenotypes for surveillance and causal inference studies.
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BACKGROUND: Osteoarthritis (OA) patients taking prescription opioids for pain are at increased risk of fall or fracture, and the concomitant use of interacting drugs may further increase the risk of these events. AIMS: To identify prescription opioid-related medication combinations associated with fall or fracture. MATERIALS & METHODS: We conducted a case-crossover-based screening of two administrative claims databases spanning 2003 through 2021. OA patients were aged 40 years or older with at least 365 days of continuous enrollment and 90 days of continuous prescription opioid use before their first eligible fall or fracture event. The primary analysis quantified the odds ratio (OR) between fall and non-opioid medications dispensed in the 90 days before the fall date after adjustment for prescription opioid dosage and confounding using a case-time-control design. A secondary analogous analysis evaluated medications associated with fracture. The false discovery rate (FDR) was used to account for multiple testing. RESULTS: We identified 41 693 OA patients who experienced a fall and 24 891 OA patients who experienced a fracture after at least 90 days of continuous opioid therapy. Top non-opioid medications by ascending p-value with OR > 1 for fall were meloxicam (OR 1.22, FDR = 0.08), metoprolol (OR 1.06, FDR >0.99), and celecoxib (OR 1.13, FDR > 0.99). Top non-opioid medications for fracture were losartan (OR 1.20, FDR = 0.80), alprazolam (OR 1.14, FDR > 0.99), and duloxetine (OR 1.12, FDR = 0.97). CONCLUSION: Clinicians may seek to monitor patients who are co-prescribed drugs that act on the central nervous system, especially in individuals with OA.
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Fracturas Óseas , Osteoartritis , Medicamentos bajo Prescripción , Humanos , Analgésicos Opioides/efectos adversos , Osteoartritis/tratamiento farmacológico , Osteoartritis/epidemiología , Osteoartritis/inducido químicamente , Fracturas Óseas/etiología , Fracturas Óseas/inducido químicamente , PrescripcionesRESUMEN
Importance: Buprenorphine combined with naloxone is commonly used to treat opioid use disorders outside of pregnancy. In pregnancy, buprenorphine alone is generally recommended because of limited perinatal safety data on the combination product. Objective: To compare perinatal outcomes following prenatal exposure to buprenorphine with naloxone vs buprenorphine alone. Design, Settings, and Participants: Population-based cohort study using health care utilization data from Medicaid-insured beneficiaries in the US from 2000 to 2018. The cohort was restricted to pregnant individuals linked to their liveborn infants, with maternal Medicaid enrollment from 3 months before pregnancy to 1 month after delivery and infant enrollment for the first 3 months after birth, unless they died sooner. Exposure: Use of buprenorphine with naloxone vs buprenorphine alone during the first trimester based on outpatient dispensings. Main Outcomes and Measures: Outcomes included major congenital malformations, low birth weight, neonatal abstinence syndrome, neonatal intensive care unit admission, preterm birth, respiratory symptoms, small for gestational age, cesarean delivery, and maternal morbidity. Confounder-adjusted risk ratios were calculated using propensity score overlap weights. Results: This study identified 3369 pregnant individuals exposed to buprenorphine with naloxone during the first trimester (mean [SD] age, 28.8 [4.6] years) and 5326 exposed to buprenorphine alone or who switched from the combination to buprenorphine alone by the end of the first trimester (mean [SD] age, 28.3 [4.5] years). When comparing buprenorphine combined with naloxone with buprenorphine alone, a lower risk for neonatal abstinence syndrome (absolute risk, 37.4% vs 55.8%; weighted relative risk, 0.77 [95% CI, 0.70-0.84]) and a modestly lower risk for neonatal intensive care unit admission (absolute risk, 30.6% vs 34.9%; weighted relative risk, 0.91 [95% CI, 0.85-0.98]) and small for gestational age (absolute risk, 10.0% vs 12.4%; weighted relative risk, 0.86 [95% CI, 0.75-0.98]) was observed. For maternal morbidity, the comparative rates were 2.6% vs 2.9%, respectively, and the weighted relative risk was 0.90 (95% CI, 0.68-1.19). No differences were observed with respect to major congenital malformations overall, low birth weight, preterm birth, respiratory symptoms, or cesarean delivery. Results were consistent across sensitivity analyses. Conclusions and Relevance: There were similar and, in some instances, more favorable neonatal and maternal outcomes for pregnancies exposed to buprenorphine combined with naloxone compared with buprenorphine alone. For the outcomes assessed, compared with buprenorphine alone, buprenorphine with naloxone during pregnancy appears to be a safe treatment option. This supports the view that both formulations are reasonable options for the treatment of opioid use disorder in pregnancy, affirming flexibility in collaborative treatment decision-making.
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BACKGROUND: While healthcare utilization data are useful for postmarketing surveillance of drug safety in pregnancy, the start of pregnancy and gestational age at birth are often incompletely recorded or missing. Our objective was to develop and validate a claims-based live birth gestational age algorithm. METHODS: Using the Medicaid Analytic eXtract (MAX) linked to birth certificates in three states, we developed four candidate algorithms based on: preterm codes; preterm or postterm codes; timing of prenatal care; and prediction models - using conventional regression and machine-learning approaches with a broad range of prespecified and empirically selected predictors. We assessed algorithm performance based on mean squared error (MSE) and proportion of pregnancies with estimated gestational age within 1 and 2 weeks of the gold standard, defined as the clinical or obstetric estimate of gestation on the birth certificate. We validated the best-performing algorithms against medical records in a nationwide sample. We quantified misclassification of select drug exposure scenarios due to estimated gestational age as positive predictive value (PPV), sensitivity, and specificity. RESULTS: Among 114,117 eligible pregnancies, the random forest model with all predictors emerged as the best performing algorithm: MSE 1.5; 84.8% within 1 week and 96.3% within 2 weeks, with similar performance in the nationwide validation cohort. For all exposure scenarios, PPVs were >93.8%, sensitivities >94.3%, and specificities >99.4%. CONCLUSIONS: We developed a highly accurate algorithm for estimating gestational age among live births in the nationwide MAX data, further supporting the value of these data for drug safety surveillance in pregnancy. See video abstract at, http://links.lww.com/EDE/B989 .
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Nacimiento Vivo , Medicaid , Recién Nacido , Estados Unidos/epidemiología , Femenino , Embarazo , Humanos , Edad Gestacional , Certificado de Nacimiento , AlgoritmosRESUMEN
OBJECTIVES: To characterise the incidence rate of skin cancer associated with methotrexate and hydroxychloroquine in older adults with rheumatoid arthritis (RA). METHODS: RA patients aged ≥65 years who initiated methotrexate or hydroxychloroquine as their first disease modifying antirheumatic drugs (DMARDs). The primary outcome was new occurrence of any skin cancer (i.e. malignant melanoma or non-melanoma skin cancer; NMSC) based on validated algorithms (positive predictive value >83%). Secondary outcomes were malignant melanoma, NMSC, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). We estimated the incidence rates (IRs) and hazard ratios (HRs) for each outcome in the 1:1 propensity score (PS)-matched methotrexate and hydroxychloroquine groups. RESULTS: We included 24,577 PS-matched pairs of methotrexate and hydroxychloroquine initiators. Compared with hydroxychloroquine (IR 25.20/1,000 person-years), methotrexate initiators (IR 26.21/1,000 person-years) had a similar risk of any skin cancer [HR 1.03 -(95%CI 0.92, 1.14)] over a mean follow-up of 388 days. The HR (95%CI) associated with methotrexate was 1.39 (0.87, 2.21) for malignant melanoma, 1.01(0.90, 1.12) for NMSC, 1.37 (1.13, 1.66) for BCC, and 0.79 (0.63, 0.99) for SCC compared with hydroxychloroquine. CONCLUSIONS: In this large cohort of older RA patients initiating methotrexate or hydroxychloroquine as their first DMARD, we found no difference in the risk of skin cancer including malignant melanoma and NMSC. However, for specific components of NMSC, methotrexate initiators had higher risk of BCC but lower risk of SCC compared with hydroxychloroquine initiators.
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Antirreumáticos , Artritis Reumatoide , Carcinoma Basocelular , Carcinoma de Células Escamosas , Melanoma , Neoplasias Cutáneas , Humanos , Anciano , Metotrexato/uso terapéutico , Hidroxicloroquina/uso terapéutico , Estudios de Cohortes , Artritis Reumatoide/tratamiento farmacológico , Neoplasias Cutáneas/epidemiología , Antirreumáticos/uso terapéutico , Carcinoma Basocelular/epidemiología , Carcinoma de Células Escamosas/epidemiología , Melanoma/tratamiento farmacológico , Melanoma Cutáneo MalignoRESUMEN
PURPOSE: Healthcare utilization databases often lack information on glycemic control, a key confounder when studying the safety of antidiabetic treatments, since patients with worse control are channeled to second-line agents, in particular insulin, versus first-line agents such as metformin. We evaluated whether adjustment for measured characteristics attains balance in glycemic control when comparing antidiabetic treatment strategies in pregnant women with pregestational type 2 diabetes (T2DM). METHODS: In a US insurance claims database, we identified 3360 women with T2DM pregnant between 2004 and 2015, of whom a subset of 996 had data on hemoglobin A1c (HbA1c ) levels. We selected insulin only as the comparator group and used propensity score (PS)-matching on comorbidities and proxies of diabetes severity, but not on HbA1c , to adjust for confounding. We used standardized differences (st.diff) to assess balance in claims-based covariates and mean HbA1c (% ± SD) in the subset. RESULTS: There were imbalances in claims-based covariates before PS-matching, with smaller differences when both treatment strategies included insulin. After PS-matching, balance was achieved in most claims-based covariates (st.diff <0.1). Mean HbA1c was similar before and after PS-matching when both treatments included insulin (e.g., 7.1 ± 1.5 vs. 7.7 ± 1.8 and 7.1 ± 1.5 vs. 7.5 ± 1.7, respectively, for metformin + insulin vs. insulin only). Differences in mean HbA1c remained after PS-matching when non-insulin treatments were compared to treatments including insulin (e.g., 6.3 ± 1.1 vs. 7.6 ± 1.7 for metformin only vs. insulin only). CONCLUSIONS: Balance in both claims-based characteristics and glycemic control was attained after restricting the population to women with T2DM and comparing treatment strategies indicated for patients with similar diabetes severity. When comparing treatment strategies with versus without insulin, differences in glycemic control persisted after PS-matching even when balance was attained for other measured characteristics.
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Diabetes Mellitus Tipo 2 , Metformina , Femenino , Humanos , Embarazo , Hipoglucemiantes/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Control Glucémico , Glucemia , Metformina/uso terapéutico , Insulina/uso terapéutico , Estudios RetrospectivosRESUMEN
Little is known about the impact of dose, duration, and timing of prenatal prescription opioid exposure on the risk of neonatal opioid withdrawal syndrome (NOWS). Using a cohort of 18,869 prepregnancy chronic opioid users nested within the 2000-2014 Medicaid Analytic eXtract, we assessed average opioid dosage within biweekly gestational age intervals, created group-based trajectory models, and evaluated the association between trajectory groups and NOWS risk. Women were grouped into 6 distinct opioid use trajectories which, based on observed patterns, were categorized as 1) continuous very low-dose use, 2) continuous low-dose use, 3) initial moderate-dose use with a gradual decrease to very low-dose/no use, 4) initial high-dose use with a gradual decrease to very low-dose use, 5) continuous moderate-dose use, and 6) continuous high-dose use. Absolute risk of NOWS per 1,000 infants was 7.7 for group 1 (reference group), 28.8 for group 2 (relative risk (RR) = 3.7, 95% confidence interval (CI): 2.8, 5.0), 16.5 for group 3 (RR = 2.1, 95% CI: 1.5, 3.1), 64.9 for group 4 (RR = 8.4, 95% CI: 5.6, 12.6), 77.3 for group 5 (RR = 10.0, 95% CI: 7.5, 13.5), and 172.4 for group 6 (RR = 22.4, 95% CI: 16.1, 31.2). Trajectory models-which capture information on dose, duration, and timing of exposure-are useful for gaining insight into clinically relevant groupings to evaluate the risk of prenatal opioid exposure.
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Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Síndrome de Abstinencia Neonatal/epidemiología , Trastornos Relacionados con Opioides/epidemiología , Complicaciones del Embarazo/epidemiología , Efectos Tardíos de la Exposición Prenatal/epidemiología , Adolescente , Adulto , Niño , Relación Dosis-Respuesta a Droga , Femenino , Edad Gestacional , Humanos , Recién Nacido , Medicaid/estadística & datos numéricos , Persona de Mediana Edad , Trastornos Relacionados con Opioides/complicaciones , Embarazo , Factores Sociodemográficos , Factores de Tiempo , Estados Unidos , Adulto JovenRESUMEN
OBJECTIVES: Giant cell arteritis (GCA) afflicts older adults who may have age- and comorbidity-related risks for infection and is treated with immunosuppressants that increase risk of infection. We examined GCA treatment patterns and rates of serious infections in two real-world cohorts in the U.S. METHODS: We identified two GCA cohorts using two U.S. health insurance databases, Medicare (public, 2007-2017) and MarketScan (commercial, 2015-2019), by applying a validated claims-based algorithm with positive predictive value 79.0% for GCA. We required age ≥50 years and assessed baseline comorbidities, dispensing of immunosuppressants and prophylactic antibiotics, and vaccine administration. We calculated incidence rates (IR) of serious infections, defined as bacterial or viral infections requiring hospitalisation based on primary inpatient diagnosis code. Multivariable Cox proportional hazards models estimated hazard ratios for risk of serious infection for prespecified covariates. RESULTS: The Medicare cohort included 734 patients, 28% male, mean age 77.1; the MarketScan cohort included 1022 patients, 30% male, mean age 68.4. More than 85% used prednisone ≥60mg daily at index date and <10% used tocilizumab. Serious infections developed in 27.9% of Medicare and 7.2% of MarketScan patients: IR per 100 person-years = 10.7 (95% CI 9.3, 12.2) in Medicare and 6.3 (95% CI 5.0, 7.9) in MarketScan. Older age and higher frailty score were significantly associated with increased risk for serious infection. CONCLUSIONS: In these two U.S. GCA cohorts, high-dose glucocorticoids were the most common initial treatment, and over 25% of Medicare and 7% of MarketScan patients developed serious infection during follow-up. Older age and higher frailty score were associated with higher risk of serious infections, though maximum daily prednisone dose was not. Pneumocystis jiroveci pneumonia was rare in two GCA cohorts despite infrequent use of prophylactic antibiotics.
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Fragilidad , Arteritis de Células Gigantes , Anciano , Antibacterianos/efectos adversos , Femenino , Arteritis de Células Gigantes/complicaciones , Arteritis de Células Gigantes/tratamiento farmacológico , Arteritis de Células Gigantes/epidemiología , Humanos , Inmunosupresores/efectos adversos , Masculino , Medicare , Persona de Mediana Edad , Prednisona/uso terapéutico , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVE: We aimed to investigate the prevalence, incidence and cause-specific mortality of RA-associated interstitial lung disease (RA-ILD) among older US patients with RA. METHODS: We performed a nationwide cohort study using Medicare claims data (parts A, B and D for 2008-2017). RA was identified with a validated algorithm using RA diagnosis codes and DMARD prescription. RA-ILD was identified with a validated algorithm using ILD diagnosis codes by a rheumatologist/pulmonologist. RA-ILD was categorized as prevalent or incident relative to the initial RA observation (baseline/index date). We compared the total mortality of RA-ILD to RA without ILD using multivariable Cox regression, adjusting for baseline covariates. For cause-specific mortality, Fine and Gray subdistribution hazard ratios (sdHRs) were estimated to handle competing risks of alternative mortality causes. RESULTS: Among 509 787 RA patients (mean age 72.6 years, 76.2% female), 10 306 (2.0%) had prevalent RA-ILD at baseline. After baseline, 13 372 (2.6%) developed RA-ILD during 1 873 127 person-years of follow-up (median 3.0 years/person). During follow-up, 38.7% of RA-ILD patients died compared with 20.7% of RA patients without ILD. After multivariable adjustment, RA-ILD had an HR of 1.66 (95% CI 1.60, 1.72) for total mortality. Accounting for competing risk of other causes of death, RA-ILD had an sdHR of 4.39 (95% CI 4.13, 4.67) for respiratory mortality and an sdHR of 1.56 (95% CI 1.43, 1.71) for cancer mortality compared with RA without ILD. CONCLUSIONS: RA-ILD was present or developed in nearly 5% of patients in this nationwide study of older patients with RA. Compared with RA without ILD, RA-ILD was associated with excess total, respiratory and cancer mortality that was not explained by measured factors.
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Artritis Reumatoide/complicaciones , Enfermedades Pulmonares Intersticiales/epidemiología , Anciano , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Femenino , Humanos , Incidencia , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/mortalidad , Masculino , Prevalencia , Modelos de Riesgos ProporcionalesRESUMEN
PURPOSE: To evaluate recent trends in inpatient postoperative utilization of opioid and non-opioid analgesics in US hospitals. METHODS: Using Premier Research database (October 2007-September 2017), we identified adults who were hospitalized for inpatient surgical procedures (N = 6 068 133). For each month, we calculated proportion of patients admitted that month who were administered (1) opioids, (2) acetaminophen, (3) non-steroidal anti-inflammatory drugs (NSADs), and (4) gabapentinoids (gabapentin or pregabalin) during the postoperative period, defined as inpatient postoperative days 1-7, unless discharged earlier. For patients administered opioids, we estimated total and average daily postoperative opioid dose in morphine milligram equivalents (MMEs). Monthly measures were standardized to the distribution of surgeries and the length of postoperative stay within each surgery during the last year of available data. RESULTS: Overall, 90.8% of patients were administered opioids postoperatively; mean total postoperative dose was 304 MMEs (median 130). Both the frequency and the amount of opioids administered remained stable over 2007-2017. Postoperative use of acetaminophen increased from mean standardized monthly prevalence of 78% in 2007-2008 to 85% in 2017, while the use of NSAIDs remained stable at a standardized mean of 37%. The use of gabapentinoids increased from below 10% in 2007-2008 to the mean standardized monthly prevalence of 23% in 2017. CONCLUSION: Despite growing awareness of risks associated with postoperative opioid use, we observed no change in postoperative utilization of opioids in US hospitals. Increasing the use of non-opioid pain management approaches could constitute an important target in our efforts to curtail US opioid epidemic.
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Analgésicos Opioides , Pacientes Internos , Adulto , Hospitales , Humanos , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/epidemiología , Periodo Posoperatorio , Estudios Retrospectivos , Estados Unidos/epidemiologíaRESUMEN
PURPOSE: To evaluate chronic opioid utilization patterns during pregnancy using nationwide data from publicly and commercially insured women. METHODS: Pregnancy cohorts were identified using data from the Medicaid Analytic eXtract 2008-2014 and the IBM Health MarketScan Research Database 2008-2015. Opioid dispensing was evaluated using claims from filled prescriptions. Two different definitions of chronic opioid use were employed: ≥90 days' supply and ≥180 days' supply of prescription opioids during pregnancy. Patient characteristics were assessed and variations in the prevalence of chronic opioid therapy were described by geographic region and over time. RESULTS: 1.50% of 975 169 Medicaid-insured and 0.32% of 1 037 599 commercially insured beneficiaries filled opioid prescriptions for ≥90 days' supply; 0.78% (Medicaid) and 0.17% (commercially insured) filled prescriptions for ≥180 days' supply. Prevalence approximately doubled in Medicaid beneficiaries during the study period, while it remained relatively stable for commercial insurance beneficiaries. The most commonly prescribed opioid for chronic therapy was hydrocodone, followed by oxycodone and tramadol. Indications commonly associated with chronic use were back/neck pain, abdominal/pelvic pain, musculoskeletal pain and migraine/headache. Substantial regional variation was observed, with several states reporting a frequency of ≥90 days' supply in excess of 3% in Medicaid-insured patients. CONCLUSIONS: Despite growing awareness of the risks associated with chronic opioid use and emphasis on improving opioid prescription patterns, prevalence of chronic use in pregnancy among publicly insured women nearly doubled from 2008-2014 and was 5-fold more common when compared to commercially insured women. Findings call for the development of guidelines on chronic pain management during pregnancy.
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Analgésicos Opioides , Trastornos Relacionados con Opioides , Analgésicos Opioides/efectos adversos , Prescripciones de Medicamentos , Femenino , Humanos , Medicaid , Trastornos Relacionados con Opioides/tratamiento farmacológico , Trastornos Relacionados con Opioides/epidemiología , Pautas de la Práctica en Medicina , Embarazo , Prescripciones , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVES: To measure the relationship between randomized controlled trial (RCT) efficacy and real-world effectiveness for oncology treatments as well as how this relationship varies depending on an RCT's use of surrogate versus overall survival (OS) endpoints. METHODS: We abstracted treatment efficacy measures from 21 phase III RCTs reporting OS and either progression-free survival or time to progression endpoints in breast, colorectal, lung, ovarian, and pancreatic cancers. For these treatments, we estimated real-world OS as the mortality hazard ratio (RW MHR) among patients meeting RCT inclusion criteria in Surveillance and Epidemiology End Results-Medicare data. The primary outcome variable was real-world OS observed in the Surveillance and Epidemiology End Results-Medicare data. We used a Cox proportional hazard regression model to calibrate the differences between RW MHR and the hazard ratios on the basis of RCTs using either OS (RCT MHR) or progression-free survival/time to progression surrogate (RCT surrogate hazard ratio [SHR]) endpoints. RESULTS: Treatment arm therapies reduced mortality in RCTs relative to controls (average RCT MHR = 0.85; range 0.56-1.10) and lowered progression (average RCT SHR = 0.73; range 0.43-1.03). Among real-world patients who used either the treatment or the control arm regimens evaluated in the relevant RCT, RW MHRs were 0.6% (95% confidence interval -3.5% to 4.8%) higher than RCT MHRs, and RW MHRs were 15.7% (95% confidence interval 11.0% to 20.5%) higher than RCT SHRs. CONCLUSIONS: Real-world OS treatment benefits were similar to those observed in RCTs based on OS endpoints, but were 16% less than RCT efficacy estimates based on surrogate endpoints. These results, however, varied by tumor and line of therapy.
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Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Biomarcadores/análisis , Ensayos Clínicos Fase III como Asunto , Supervivencia sin Enfermedad , Humanos , Modelos de Riesgos Proporcionales , Programa de VERF , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
UNLABELLED: The development of immunomonitoring models to determine HIV-1 vaccine efficacy is a major challenge. Studies suggest that HIV-1specific CD8 T cells play a critical role in subjects achieving spontaneous viral control (HIV-1 controllers) and that they will be important in immune interventions. However, no single CD8 T-cell function is uniquely associated with controller status and the heterogeneity of responses targeting different epitopes further complicates the discovery of determinants of protective immunity. In the present study, we describe immunomonitoring models integrating multiple functions of epitope-specific CD8 T cells that distinguish controllers from subjects with treated or untreated progressive infection. Models integrating higher numbers of variables and trained with the least absolute shrinkage and selection operator (LASSO) variant of logistic regression and 10-fold cross-validation produce "diagnostic tests" that display an excellent capacity to delineate subject categories. The test accuracy reaches 75% area under the receiving operating characteristic curve in cohorts matched for prevalence of protective alleles. Linear mixed-effects model analyses show that the proliferative capacity, cytokine production, and kinetics of cytokine secretion are associated with HIV-1 control. Although proliferative capacity is the strongest single discriminant, integrated modeling of different dimensions of data leverages individual associations. This strategy may have important applications in predictive model development and immune monitoring of HIV-1 vaccine trials. KEY POINTS: Immune monitoring models integrating multiple functions of HIV-1-specific CD8 T cells distinguish controllers from subjects with progressive HIV-1 infection. This strategy may have important applications in predictive model development and immune monitoring of HIV-1 vaccine trials.
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Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Vigilancia Inmunológica , Modelos Inmunológicos , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/uso terapéutico , Adulto , Linfocitos T CD8-positivos/patología , Citocinas/inmunología , Femenino , Infecciones por VIH/patología , Infecciones por VIH/terapia , Humanos , Cinética , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: We examined national patterns in adult diet-beverage consumption and caloric intake by body-weight status. METHODS: We analyzed 24-hour dietary recall with National Health and Nutrition Examination Survey 1999-2010 data (adults aged ≥ 20 years; n = 23 965). RESULTS: Overall, 11% of healthy-weight, 19% of overweight, and 22% of obese adults drink diet beverages. Total caloric intake was higher among adults consuming sugar-sweetened beverages (SSBs) compared with diet beverages (2351 kcal/day vs 2203 kcal/day; P = .005). However, the difference was only significant for healthy-weight adults (2302 kcal/day vs 2095 kcal/day; P < .001). Among overweight and obese adults, calories from solid-food consumption were higher among adults consuming diet beverages compared with SSBs (overweight: 1965 kcal/day vs 1874 kcal/day; P = .03; obese: 2058 kcal/day vs 1897 kcal/day; P < .001). The net increase in daily solid-food consumption associated with diet-beverage consumption was 88 kilocalories for overweight and 194 kilocalories for obese adults. CONCLUSIONS: Overweight and obese adults drink more diet beverages than healthy-weight adults and consume significantly more solid-food calories and a comparable total calories than overweight and obese adults who drink SSBs. Heavier US adults who drink diet beverages will need to reduce solid-food calorie consumption to lose weight.
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Peso Corporal , Bebidas Gaseosas/estadística & datos numéricos , Ingestión de Energía , Edulcorantes no Nutritivos/administración & dosificación , Adulto , Anciano , Estudios Transversales , Conducta Alimentaria , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Encuestas Nutricionales , Estados Unidos , Adulto JovenRESUMEN
BACKGROUND: Although the clinical importance of preeclampsia is widely recognized, few treatment options are available for prevention. TNF-α inhibitors have been hypothesized to potentially prevent the disease. We aimed to examine whether exposure to TNF-α inhibitors during pregnancy reduces the risk of preeclampsia. METHODS: We conducted a population-based pregnancy cohort study using nationwide samples of publicly (Medicaid data, 2000-2018) and commercially (MarketScan Research Database, 2003-2020) insured pregnant women linked to their liveborn infants. Exposure was ascertained based on a filled prescription or administration code for TNF-α inhibitors during the first and second trimester of pregnancy. The outcomes included early-onset preeclampsia, late-onset preeclampsia, and small-for-gestational age. For baseline confounding adjustment, we leveraged propensity score overlap weights to estimate risk ratios (RR). RESULTS: Among 4â315â658 pregnancies in the Medicaid and the MarketScan cohort, 2736 (0.063%) were exposed to TNF-α inhibitors during the first trimester and 1712 (0.040%) during the second trimester. After adjustment, the risk of early-onset preeclampsia was not decreased among mothers exposed during the first trimester compared with unexposed women with treatment indications [RR pooled : 1.25, 95% confidence interval (CI) 0.93-1.67]. Similarly, the risk of late-onset preeclampsia was not decreased among mothers exposed during the second trimester compared with unexposed women (RR pooled : 0.99, 95% CI 0.81-1.22). CONCLUSION: Contrary to the hypothesis, exposure to TNF-α inhibitors during pregnancy did not appear to be associated with a reduced risk of early-onset or late-onset preeclampsia. These findings do not support consideration of the use of TNF-α inhibitors for the prevention of preeclampsia.
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Preeclampsia , Factor de Necrosis Tumoral alfa , Humanos , Embarazo , Femenino , Preeclampsia/epidemiología , Preeclampsia/prevención & control , Adulto , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Estudios de Cohortes , Adulto Joven , Estados Unidos/epidemiología , Segundo Trimestre del Embarazo , Factores de Riesgo , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Inhibidores del Factor de Necrosis Tumoral/efectos adversos , Primer Trimestre del EmbarazoRESUMEN
OBJECTIVE: This study investigates patients' medication-taking routines and the feasibility of harnessing habit formation through context cues and rewards to improve medication adherence. METHODS: Semistructured qualitative interviews with patients with gout from an urban health care system were conducted to explore typical medication-taking behavior, experiences using electronic pill bottles, barriers to adherence, existing context cues, and potential cues and rewards for habit-forming behavior. Medication-taking patterns were recorded for six weeks using electronic pill bottles before interviews to inform discussion. Transcribed interviews were analyzed to generate themes using codes developed by the study team, with representative quotations selected as illustrations. RESULTS: We conducted interviews with 15 individuals (mean age 60.6 [SD 20.3] years, three women [20%], and nine White patients [60%]). Pill bottle-recorded adherence to urate-lowering therapy (ULT) was high (mean 0.91 [SD 0.10]), and one patient was experiencing an active gout flare. Five key themes emerged: (1) reasons for nonadherence, (2) internal and external motivations for adherence, (3) structured routines around taking medications, (4) rewards for good medication adherence, and (5) the role of pill cap technology in medication-taking. CONCLUSION: The importance of a predictable, structured routine in which participants could incorporate their medication-taking behavior emerged as a key factor that promoted consistent adherence. Further, identifying context cues and reminders seemed to promote incorporation of medication-taking into routines. Therefore, habit-based interventions that use context cues to establish routines around medication-taking may be a feasible strategy to improve adherence in patients with chronic conditions such as gout.
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Importance: Use of buprenorphine or methadone to treat opioid use disorder is recommended in pregnancy; however, their teratogenic potential is largely unknown. Objective: To compare the risk of congenital malformations following in utero exposure to buprenorphine vs methadone. Design, Setting, and Participants: This population-based cohort study used health care utilization data from publicly insured Medicaid beneficiaries in the US from 2000 to 2018. A total of 13â¯360 pregnancies with enrollment from 90 days prior to pregnancy start through 1 month after delivery and first trimester use of buprenorphine or methadone were included and linked to infants. Data were analyzed from July to December 2022. Exposure: A pharmacy dispensing of buprenorphine or a code for administration of methadone in the first trimester. Main Outcomes and Measures: Primary outcomes included major malformations overall and malformations previously associated with opioids (any cardiac malformations, ventricular septal defect, secundum atrial septal defect/nonprematurity-related patent foramen ovale, neural tube defects, clubfoot, and oral clefts). Secondary outcomes included other organ system-specific malformations. Risk differences and risk ratios (RRs) were estimated comparing buprenorphine with methadone, adjusting for confounders with propensity score overlap weights. Results: The cohort included 9514 pregnancies with first-trimester buprenorphine exposure (mean [SD] maternal age, 28.4 [4.6] years) and 3846 with methadone exposure (mean [SD] maternal age, 28.8 [4.7] years). The risk of malformations overall was 50.9 (95% CI, 46.5-55.3) per 1000 pregnancies for buprenorphine and 60.6 (95% CI, 53.0-68.1) per 1000 pregnancies for methadone. After confounding adjustment, buprenorphine was associated with a lower risk of malformations compared with methadone (RR, 0.82; 95% CI, 0.69-0.97). Risk was lower with buprenorphine for cardiac malformations (RR, 0.63; 95% CI, 0.47-0.85), including both ventricular septal defect (RR, 0.62; 95% CI, 0.39-0.98) and secundum atrial septal defect/nonprematurity-related patent foramen ovale (RR, 0.54; 95% CI, 0.30-0.97), oral clefts (RR, 0.65; 95% CI, 0.35-1.19), and clubfoot (RR, 0.55; 95% CI, 0.32-0.94). Results for neural tube defects were uncertain given low event counts. In secondary analyses, buprenorphine was associated with a decreased risk of central nervous system, urinary, and limb malformations but a greater risk of gastrointestinal malformations compared with methadone. These findings were consistent in sensitivity and bias analyses. Conclusions and Relevance: In this cohort study, the risk of most malformations previously associated with opioid exposure was lower in buprenorphine-exposed infants compared with methadone-exposed infants, independent of measured confounders. Malformation risk is one factor that informs the individualized patient decision regarding medications for opioid use disorder in pregnancy.
Asunto(s)
Buprenorfina , Pie Equinovaro , Foramen Oval Permeable , Cardiopatías Congénitas , Defectos del Tabique Interventricular , Defectos del Tubo Neural , Trastornos Relacionados con Opioides , Complicaciones del Embarazo , Embarazo , Lactante , Femenino , Humanos , Adulto , Metadona/efectos adversos , Buprenorfina/efectos adversos , Primer Trimestre del Embarazo , Estudios de Cohortes , Pie Equinovaro/complicaciones , Pie Equinovaro/tratamiento farmacológico , Foramen Oval Permeable/complicaciones , Foramen Oval Permeable/tratamiento farmacológico , Complicaciones del Embarazo/tratamiento farmacológico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Analgésicos Opioides/efectos adversos , Cardiopatías Congénitas/inducido químicamente , Cardiopatías Congénitas/epidemiología , Cardiopatías Congénitas/complicaciones , Defectos del Tubo Neural/complicaciones , Defectos del Tubo Neural/tratamiento farmacológico , Defectos del Tabique Interventricular/complicaciones , Defectos del Tabique Interventricular/tratamiento farmacológicoRESUMEN
Text messaging can promote healthy behaviors, like adherence to medication, yet its effectiveness remains modest, in part because message content is rarely personalized. Reinforcement learning has been used in consumer technology to personalize content but with limited application in healthcare. We tested a reinforcement learning program that identifies individual responsiveness ("adherence") to text message content and personalizes messaging accordingly. We randomized 60 individuals with diabetes and glycated hemoglobin A1c [HbA1c] ≥ 7.5% to reinforcement learning intervention or control (no messages). Both arms received electronic pill bottles to measure adherence. The intervention improved absolute adjusted adherence by 13.6% (95%CI: 1.7%-27.1%) versus control and was more effective in patients with HbA1c 7.5- < 9.0% (36.6%, 95%CI: 25.1%-48.2%, interaction p < 0.001). We also explored whether individual patient characteristics were associated with differential response to tested behavioral factors and unique clusters of responsiveness. Reinforcement learning may be a promising approach to improve adherence and personalize communication at scale.
RESUMEN
Analyses of the breadth and specificity of virus-specific CD8(+) T cell responses associated with control of HIV have largely relied on measurement of cytokine secretion by effector T cells. These have resulted in the identification of HIV elite controllers with low or absent responses in which non-T-cell mechanisms of control have been suggested. However, successful control of HIV infection may be associated with central memory T cells, which have not been consistently examined in these individuals. Gag-specific T cells were characterized using a peptide-based cultured enzyme-linked immunosorbent spot assay (ELISpot). Peripheral blood mononuclear cells from HIV elite controllers (n = 10), progressors (n = 12), and antiretroviral-treated individuals (n = 9) were cultured with overlapping peptides for 12 days. Specificity was assessed by tetramer staining, functional features of expanded cells were assessed by cytokine secretion, and virus inhibition and phenotypic characteristics were assessed by cell sorting and coculture assays. After peptide stimulation, elite controllers showed a greater number of previously undetectable (new) responses compared to progressors (P = 0.0008). These responses were highly polyfunctional, with 64.5% of responses having 3 to 5 functions. Expandable epitope-specific CD8(+) T cells from elite controllers had strong virus inhibitory capacity and predominantly displayed a central memory phenotype. These data indicate that elite controllers with minimal T cell responses harbor a highly functional, broadly directed central memory T cell population that is capable of suppressing HIV in vitro. Comprehensive examination of this cell population could provide insight into the immune responses associated with successful containment of viremia.