RESUMO
Background: Atopic dermatitis (AD) is a chronic skin condition that millions of people around the world live with each day. Performing research studies into identifying the causes and treatment for this disease has great potential to provide benefit for these individuals. However, AD clinical trial recruitment is a non-trivial task due to variance in diagnostic precision and phenotypic definitions leveraged by different clinicians as well as time spent finding, recruiting, and enrolling patients by clinicians to become study subjects. Thus, there is a need for automatic and effective patient phenotyping for cohort recruitment. Objective: Our study aims to present an approach for identifying patients whose electronic health records suggest that they may have AD. Methods: We created a vectorized representation of each patient and trained various supervised machine learning methods to classify when a patient has AD. Each patient is represented by a vector of either probabilities or binary values where each value indicates whether they meet a different criteria for AD diagnosis. Results: The most accurate AD classifier performed with a class-balanced accuracy of 0.8036, a precision of 0.8400, and a recall of 0.7500 when using XGBoost (Extreme Gradient Boosting). Conclusions: Creating an automated approach for identifying patient cohorts has the potential to accelerate, standardize, and automate the process of patient recruitment for AD studies; therefore, reducing clinician burden and informing knowledge discovery of better treatment options for AD.
RESUMO
Atopic dermatitis (AD) is a common chronic skin disease. Although generally thought to be a disease of T-cell dysregulation, recent studies have suggested that immune dysregulation of NK cells is also important. Killer cell Ig-like receptors (KIRs) are involved with NK cell regulation. The Pediatric Eczema Elective Registry is a U.S. nationwide longitudinal cohort with up to 10 y of follow-up in which 655 children had DNA available for full allelic KIR sequencing. Every 6 mo, AD activity was reported by Pediatric Eczema Elective Registry children. Using generalized estimating equations, we evaluated the association of KIR allelic variation in concert with known HLA binding ligands and whether the child reported AD in "remission" (no skin lesions and not using AD medication). KIR2DS4*001:01 (odds ratio 0.53, 95% CI [0.32, 0.88]) and KIR2DL4*001:02 (0.54, [0.33, 0.89]) in the presence of C*04:01 had the largest effect on decreasing the likelihood of AD remission. The haplotype KIR 2DL4*001:02 â¼ 2DS4*001:01 â¼ 3DL2*002:01 (0.77, [0.60, 0.99]) was also associated with a decreased likelihood of AD remission. Our findings add to the general body of evidence of a growing literature on the importance of NK cells with respect to the immunopathogenesis and natural history of AD.
Assuntos
Dermatite Atópica , Eczema , Humanos , Criança , Dermatite Atópica/genética , Receptores KIR/genética , Haplótipos , Células Matadoras NaturaisRESUMO
BACKGROUND: Long-acting injectable cabotegravir is a novel integrase inhibitor currently in advanced clinical development for HIV prevention and treatment. We aimed to assess the terminal phase pharmacokinetics and safety of long-acting injectable cabotegravir in participants included in the HPTN 077 trial. METHODS: HPTN 077 was a multicentre, double-blind, randomised, placebo-controlled phase 2a trial done at eight sites in Brazil, Malawi, South Africa, and the USA. Participants (aged 18-65 years), who were HIV-uninfected and at low-risk for HIV, were randomly assigned (3:1) to long-acting injectable cabotegravir (800 mg given three times at 12 week intervals or 600 mg given five times, administered at one 4 week interval, and every 8 weeks thereafter) or placebo. Participants were followed up to 76 weeks after final injection. In a prespecified analysis of secondary and exploratory outcomes, we assessed the safety, measured by the proportion of participants with grade 2 or worse adverse events, and pharmacokinetics, measured by apparent terminal phase half-life (t1/2app) and estimated time to lower limit of quantification (LLOQ) of long-acting injectable cabotegravir during the injection phase (defined as the time between first injection and 12 weeks or 8 weeks after the last injection in cohort 1 or cohort 2 respectively) and tail phase (defined as the time between final injection and 52-76 weeks post-final injection). Safety was analysed in all participants who received at least one injection. Pharmacokinetic analyses included all participants who had received at least one injection and had at least three cabotegravir measurements higher than the LLOQ after the final injection. Pharmacokinetic outcomes were estimated using non-compartmental methods. The trial is completed, and was registered with ClinicalTrials.gov, NCT02178800. FINDINGS: Between Feb 9, 2015, and May 27, 2016, 177 participants (134 participants in the cabotegravir group [74 participants in cohort 1; 60 participants in cohort 2] and 43 participants in the placebo group [25 participants in cohort 1; 18 participants in cohort 2) were enrolled and received at least one injection and thus were included in the safety analysis. The incidence of grade 2 or worse adverse events was significantly lower during the tail phase than the injection phase (p<0·0001). At 52-60 weeks after final injection, nine (23%) of 40 male participants had detectable cabotegravir concentrations and at week 76, four (13%) of 30 male participants had detectable cabotegravir concentrations compared with 52 (63%) of 82 female participants and 27 (42%) of 64 female participants at the same timepoints. The median time from the last injection to the time when cabotegravir concentration decreased below the LLOQ was 43·7 weeks (IQR 31·1-66·6; range 20·4-152·5) for male participants and 67·3 weeks (29·1-89·6; 17·7-225·5) for female participants (p=0·0003). t1/2app was longer for female participants than male participants (geometric mean fold-change 1·33, 95% CI 1·06-1·68; p=0·014), and longer for participants with a high body-mass index (BMI) than those with a low BMI (1·31, 1·06-1·63; p=0·015). INTERPRETATION: The clinical significance of the long pharmacokinetic tail of cabotegravir observed in female participants compared with male participants, and those with higher BMI compared with a lower BMI, need to be addressed in future trials. FUNDING: National Institute of Allergy and Infectious Diseases.
Assuntos
Fármacos Anti-HIV/farmacocinética , Infecções por HIV/prevenção & controle , Inibidores de Integrase de HIV/farmacologia , Piridonas/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Brasil , Estudos de Coortes , Método Duplo-Cego , Feminino , Inibidores de Integrase de HIV/administração & dosagem , Humanos , Injeções , Malaui , Masculino , Pessoa de Meia-Idade , Placebos , Piridonas/administração & dosagem , África do Sul , Estados Unidos , Adulto JovemRESUMO
OBJECTIVES: To evaluate whether hormonal contraceptive use among cisgender women is associated with differences in pharmacokinetic (PK) parameters of a long-acting injectable formulation of the integrase strand transfer inhibitor, cabotegravir (CAB-LA). SETTING: This is a secondary analysis of 85 cisgender women enrolled in HPTN 077, a phase 2a multicenter study that enrolled HIV-uninfected, low-risk individuals in Malawi, Brazil, South Africa, and the United States. METHODS: Participants received 4-week daily oral cabotegravir lead-in, followed by CAB-LA 800 mg injection every 12 weeks (cohort 1) or 600 mg every 8 weeks (after 4-week initial interval between injections, cohort 2), over 41 weeks. Participants were followed 52-76 weeks subsequent to final injection. Generalized estimating equations and linear regression were used to evaluate differences in CAB-LA PK parameters (peak concentration, trough concentration, area under the curve, apparent terminal half-life, and time to lower limit of quantification) and self-reported hormonal contraceptive stratified by type (oral, injectable, implants, and other), controlling for body mass index and cohort. RESULTS: Compared to women reporting no hormonal contraception (n = 6), oral contraceptive use (n = 18) was associated with lower CAB-LA peak concentration but was not associated with differences in other PK parameters. No other hormonal contraceptive type (injectable, implants, and other) was associated with significant differences in CAB-LA PK parameters. CONCLUSION: Although oral contraceptive use was associated with differences in CAB-LA peak concentration, no differences were observed in other PK parameters, suggesting that this association is not likely to be clinically significant. However, these data highlight the need for further research exploring potential drug-drug interactions between CAB-LA and hormonal contraceptives.
Assuntos
Anticoncepcionais Femininos/farmacologia , Infecções por HIV/prevenção & controle , Inibidores de Integrase de HIV/farmacocinética , HIV-1 , Piridonas/farmacocinética , Brasil , Anticoncepcionais Femininos/administração & dosagem , Interações Medicamentosas , Feminino , Inibidores de Integrase de HIV/administração & dosagem , Soronegatividade para HIV , Contracepção Hormonal , Humanos , Malaui , Masculino , Profilaxia Pré-Exposição , Piridonas/administração & dosagem , África do Sul , Adulto JovemRESUMO
The Fitzpatrick Skin Phototypes (FSP) were developed to classify skin color and response to ultraviolet radiation. FSP are used clinically to assess risk for sunburn and skin cancer. Our aim was to determine the criterion-related validity of self-reported FSP when compared with skin color and sunburn history, controlling for age, race/ethnicity, and seasonality/geography. We performed a secondary analysis of data (N=466) from an observational study. The racial/ethnic composition of the sample was 45% White/White Hispanic (WWH), 40% Black/Black Hispanic (BBH), and 15% Other Identities. Outcome measures were self-reported FSP and sunburn history, as well as physiological measures of skin color (L* lightness/darkness, a* redness/greenness, b* yellowness/blueness). Correlation between FSP and L* was -.77 (95% CI -.81, -.73; P<.001). Although 60% of the variance in FSP was accounted for by L* values for the entire sample, only 5% of the variance was accounted for among BBH participants (r=-.23), and up to 30% for WWH/Other Identity participants (r=-.48 and -.52). Multiple regression analysis indicated L* and b* values, sunburn history, and race/ethnicity, but not geography/seasonality or a* values significantly and collectively accounted for 72% of the variance in FSP. While the criterion validity of FSP was established by the strong relationship between L* values and FSP for the entire sample, when examined at the level of individual racial/ethnic subgroups, criterion validity of FSP was not demonstrated. When self-reported FSP are used for clinical skin assessment and sun cancer screening, they provide a restricted range of options for people with darker skin that does not capture variations in their skin color. Inaccuracy of clinical data may lead to unequal treatment or inadequate cancer risk assessment.
Assuntos
Suscetibilidade a Doenças/classificação , Etnicidade/estatística & dados numéricos , Neoplasias Cutâneas/prevenção & controle , Pigmentação da Pele , Queimadura Solar/classificação , Adulto , Suscetibilidade a Doenças/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Medição de Risco , Autorrelato , Neoplasias Cutâneas/classificação , Queimadura Solar/diagnóstico , Raios UltravioletaRESUMO
BACKGROUND: Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States. METHODS AND FINDINGS: HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18-65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population. CONCLUSIONS: In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress. TRIAL REGISTRATION: ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Infecções por HIV/prevenção & controle , Piridonas/administração & dosagem , Piridonas/farmacocinética , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/sangue , Brasil , Preparações de Ação Retardada , Método Duplo-Cego , Esquema de Medicação , Monitoramento de Medicamentos , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/transmissão , Infecções por HIV/virologia , Humanos , Injeções Intramusculares , Malaui , Masculino , Pessoa de Meia-Idade , Piridonas/efeitos adversos , Piridonas/sangue , Medição de Risco , Fatores de Risco , África do Sul , Resultado do Tratamento , Estados Unidos , Adulto JovemRESUMO
The purpose of this study was to explore perceptions among people with type 2 diabetes about foot ulcers and lower extremity amputations. This was a qualitative observational study utilizing open-ended, semistructured interviews of 39 people with diabetes who were purposively selected because they had either a foot ulcer (n = 19) or a lower extremity amputation (n = 20). Interviews were audio-recorded, deidentified, and entered into NVivo 10.0 for coding and analysis. Our integrated analytic approach combined inductively and deductively derived codes that were applied to all transcripts. Coded data were summarized and examined for patterns. Participants' description of the relationship between diabetes and their foot ulcer or amputation revealed a limited understanding of the disease process. Disruption and loss of independence was expressed whether the person had a foot ulcer or an amputation. Treatment recommendations for foot ulcers were viewed by most as extremely difficult. Amputation was a feared outcome, but some learned to adapt and, at times felt that the amputation enhanced their quality of life. Clinicians have assumed that a focus on limb salvage is preferred over a major amputation. However, because of the complexity of care requiring frequent healthcare provider visits, the frequency of care failure, the frequency of recurrence, and mortality associated with having had a foot ulcer, it may be more appropriate for clinicians to prioritize quality-of-life salvage. Foot ulcer treatment failure may be due to a lack of providers' understanding of the impact of treatment on a patient's life.