A systematic review of endpoint definitions in late phase pulmonary tuberculosis therapeutic trials.

BACKGROUND: Safe, more efficacious treatments are needed to address the considerable morbidity and mortality associated with pulmonary tuberculosis (TB). However, the current practice in TB therapeutics trials is to use composite binary outcomes, which in the absence of standardization may inflate false positive and negative errors in evaluating regimens. The lack of standardization of outcomes is a barrier to the identification of highly efficacious regimens and the introduction of innovative methodologies METHODS: We conducted a systematic review of trials designed to advance new pulmonary TB drugs or regimens for regulatory approval and inform practice guidelines. Trials were primarily identified from the WHO International Clinical Trial Registry Platform (ICTRP). Only trials that collected post-treatment follow-up data and enrolled at least 100 patients were included. Protocols and Statistical Analysis Plans (SAP) for eligible trials from 1995 to the present were obtained from trial investigators. Details of outcome data, both explicit and implied, were abstracted and organized into three broad categories: favorable, unfavorable, and not assessable. Within these categories, individual trial definitions were recorded and collated, and areas of broad consensus and disagreement were identified and described. RESULTS: From 2205 trials in any way related to TB, 51 were selected for protocol and SAP review, from which 31 were both eligible and had accessible documentation. Within the three designated categories, we found broad consensus in the definitions of favorable and unfavorable outcomes, although specific details were not always provided, and when explicitly addressed, were heterogeneous. Favorable outcomes were handled the most consistently but were widely variable with respect to specification. In some cases, the same events were defined differently by different protocols, particularly in distinguishing unfavorable from not assessable events. Death was often interpreted as conditional on cause. Patients who did not complete the study because of withdrawal or loss to follow-up presented a particular challenge to consistent interpretation and analytic treatment of outcomes. CONCLUSIONS: In a review of 31 clinical trials, we found that outcome definitions were heterogeneous, highlighting the need to establish clearer specification and a move towards universal standardization of outcomes across pulmonary TB trials. The ICH E9 (R1) addendum provides guidelines for undertaking and achieving this goal. PROSPERO REGISTRATION: PROSPERO CRD42020197993 . Registration 11 August 2020.

Factors Associated with Receiving Late HIV Testing Among Women Delivering at Hung Vuong Hospital, Ho Chi Minh City, Vietnam, 2014.

HIV testing during pregnancy facilitates timely antiretroviral treatment for HIV-positive women. This study identifies reasons for late HIV testing among pregnant women delivering at a hospital in Ho Chi Minh City. We conducted a case-control study in which 160 cases were women who were tested for HIV late (i.e., at labor and delivery) and 160 controls were women who were tested during antenatal care (ANC). In multivariable logistic regression analysis, six variables were associated with late HIV testing: age less than 30 years, nine or fewer years of education, working as a homemaker or worker/farmer, living 20 km or more from the hospital, having received ANC at a private clinic/hospital only, and not believing that HIV testing is important during pregnancy. We recommend that national programs should provide additional effort for HIV testing during pregnancy to young women, less educated women, homemakers, and those receiving ANC at private clinics and hospitals.

Clinical and Imaging Characteristics of Arteriopathy Subtypes in Children with Arterial Ischemic Stroke: Results of the VIPS Study.

BACKGROUND AND PURPOSE: Childhood arteriopathies are rare but heterogenous, and difficult to diagnose and classify, especially by nonexperts. We quantified clinical and imaging characteristics associated with childhood arteriopathy subtypes to facilitate their diagnosis and classification in research and clinical settings. MATERIALS AND METHODS: The Vascular Effects of Infection in Pediatric Stroke (VIPS) study prospectively enrolled 355 children with arterial ischemic stroke (2010-2014). A central team of experts reviewed all data to diagnose childhood arteriopathy and classify subtypes, including arterial dissection and focal cerebral arteriopathy-inflammatory type, which includes transient cerebral arteriopathy, Moyamoya disease, and diffuse/multifocal vasculitis. Only children whose stroke etiology could be conclusively diagnosed were included in these analyses. We constructed logistic regression models to identify characteristics associated with each arteriopathy subtype. RESULTS: Among 127 children with definite arteriopathy, the arteriopathy subtype could not be classified in 18 (14%). Moyamoya disease (n = 34) occurred mostly in children younger than 8 years of age; focal cerebral arteriopathy-inflammatory type (n = 25), in children 8-15 years of age; and dissection (n = 26), at all ages. Vertigo at stroke presentation was common in dissection. Dissection affected the cervical arteries, while Moyamoya disease involved the supraclinoid internal carotid arteries. A banded appearance of the M1 segment of the middle cerebral artery was pathognomonic of focal cerebral arteriopathy-inflammatory type but was present in <25% of patients with focal cerebral arteriopathy-inflammatory type; a small lenticulostriate distribution infarct was a more common predictor of focal cerebral arteriopathy-inflammatory type, present in 76%. It remained difficult to distinguish focal cerebral arteriopathy-inflammatory type from intracranial dissection of the anterior circulation. We observed only secondary forms of diffuse/multifocal vasculitis, mostly due to meningitis. CONCLUSIONS: Childhood arteriopathy subtypes have some typical features that aid diagnosis. Better imaging methods, including vessel wall imaging, are needed for improved classification of focal cerebral arteriopathy of childhood.

Inpatient statin use predicts improved ischemic stroke discharge disposition.

OBJECTIVE: To determine whether statin use is associated with improved discharge disposition after ischemic stroke. METHODS: We used generalized ordinal logistic regression to analyze discharge disposition among 12,689 patients with ischemic stroke over a 7-year period at 17 hospitals in an integrated care delivery system. We also analyzed treatment patterns by hospital to control for the possibility of confounding at the individual patient level. RESULTS: Statin users before and during stroke hospitalization were more likely to have a good discharge outcome (odds ratio [OR] for discharge to home = 1.38, 95% confidence interval [CI] 1.25-1.52, p < 0.001; OR for discharge to home or institution = 2.08, 95% CI 1.72-2.51, p < 0.001). Patients who underwent statin withdrawal were less likely to have a good discharge outcome (OR for discharge to home = 0.77, 95% CI 0.63-0.94, p = 0.012; OR for discharge to home or institution = 0.43, 95% CI 0.33-0.55, p < 0.001). In grouped-treatment analysis, an instrumental variable method using treatment patterns by hospital, higher probability of inpatient statin use predicted a higher likelihood of discharge to home (OR = 2.56, 95% CI 1.71-3.85, p < 0.001). In last prior treatment analysis, a novel instrumental variable method, patients with a higher probability of statin use were more likely to have a good discharge outcome (OR for each better level of ordinal discharge outcome = 1.19, 95% CI 1.09-1.30, p = 0.001). CONCLUSIONS: Statin use is strongly associated with improved discharge disposition after ischemic stroke.

Decreased risk of graft failure with maternal liver transplantation in patients with biliary atresia.

The presence of maternal cells in offspring may promote tolerance to noninherited maternal antigens (NIMAs). Children with biliary atresia (BA) have increased maternal cells in their livers, which may impact tolerance. We hypothesized that patients with BA would have improved outcomes when receiving a maternal liver. We reviewed all pediatric liver transplants recorded in the SRTR database from 1996 to 2010 and compared BA and non-BA recipients of maternal livers with recipients of paternal livers for the incidences of graft failure and retransplantation. Rejection episodes after parental liver transplantation were examined for patients transplanted at our institution. BA patients receiving a maternal graft had lower rates of graft failure compared to those receiving a paternal graft (3.7% vs. 10.5%, p = 0.02) and, consequently, fewer episodes of retransplantation (2.7% vs. 7.5%, p = 0.04). These differences were not seen among non-BA patients or among BA patients who received female deceased donor grafts. In patients transplanted at our institution, paternal liver transplantation was associated with an increased incidence of refractory rejection compared to maternal liver transplantation only in BA. Our data support the concept that maternal cells in BA recipients promote tolerance to NIMAs and may be important in counseling BA patients who require liver transplantation.

The 5-year direct medical cost of neonatal and childhood stroke in a population-based cohort.

BACKGROUND: Despite increasing awareness of the long-term impact of pediatric stroke, there are few estimates of the costs of care. We examined acute and 5-year direct costs of neonatal and childhood stroke in a population-based cohort in Northern California. METHODS: We obtained electronic cost data for 266 children with neurologist-confirmed strokes, and 786 age-matched stroke-free controls, within the population of all children (<20 years) enrolled in a large managed care plan from 1996 through 2003. Cost data included all inpatient and outpatient health service costs including care at out-of-plan facilities. Costs were assessed for 5 years after stroke, expressed in 2003 US dollars, and stratified by age at stroke onset (neonatal, defined as <29 days of life, vs childhood). Stroke costs were adjusted for costs in stroke-free age-matched controls. RESULTS: Average adjusted 5-year costs for pediatric stroke are substantial: $51,719 for neonatal stroke and $135,161 for childhood stroke. The average cost of a childhood stroke admission was $81,869. The average birth admission cost for a neonatal stroke was $39,613; adjustment for control birth admission costs reduced this by only $4,792, suggesting the stroke accounted for 88% of costs. Even among neonates whose strokes were not recognized until later in childhood ("presumed perinatal strokes"), admission costs exceeded those of controls. Chronic costs were highest in the first year poststroke, but continued to exceed control costs even in the fifth year by an average of $2,016. CONCLUSIONS: The economic burden of neonatal and childhood stroke is both large and sustained.

Persistence of human papillomavirus type 16 infection is associated with lack of cytotoxic T lymphocyte response to the E6 antigens.

Our cross-sectional study suggested that cytotoxic T lymphocyte (CTL) responses have a protective effect in squamous intraepithelial lesion (SIL) development. More CTL responses in women with human papillomavirus type 16 (HPV 16) infection without SILs than with SILs were detected. In the current longitudinal study, the role of CTL in clearing HPV 16 infection in women without SILs was investigated. Women with HPV 16 infection (n=51) were enrolled, along with HPV 16-negative control women (n=3). Twenty-two (55%) of 40 women who cleared HPV 16 infection had an E6 CTL response at least once, compared with none of 9 women who had HPV 16 persistence (P=.003). Such a difference was not demonstrated for E7; 25 (63%) of 40 women who cleared HPV 16 infection responded, versus 5 (56%) of 9 women with persistence (P=.720). It appears that lack of response to E6 is important in the persistence of HPV 16 infection.

Risk factors for abnormal anal cytology in young heterosexual women.

Although anal cancers are up to four times more common in women than men, little is known about the natural history of anal human papillomavirus (HPV) infections and HPV-related anal lesions in women. This study reports on the prevalence of and risks for anal cytological abnormalities over a 1-year period in a cohort of young women participating in a study of the natural history of cervical HPV infection. In addition to their regularly scheduled sexual behavior interviews and cervical testing, consenting women received anal HPV DNA and cytological testing. Anal cytology smears were obtained from 410 women whose mean age was 22.5 +/- 2.5 years at the onset of the study. Sixteen women (3.9%) were found to have abnormal anal cytology: 4 women had low-grade squamous intraepithelial lesions (SILs) or condyloma; and 12 women had atypical cells of undetermined significance. Factors found to be significantly associated with abnormal anal cytology were a history of anal sex [odds ratio (OR), 6.90; 95% confidence interval (CI), 1.7-47.2], a history of cervical SILs (OR, 4.13; 95% CI, 1.3-14.9), and a current anal HPV infection (OR, 12.28; 95% CI, 3.9-43.5). The strong association between anal intercourse and the development of HPV-induced SILs supports the role of sexual transmission of HPV in anal SILs. Young women who had engaged in anal intercourse or had a history of cervical SILs were found to be at highest risk.