Acceptability, feasibility and cost of point of care testing for sexually transmitted infections among South African adolescents where syndromic management is standard of care.

BACKGROUND: Young people (YP) in southern Africa are at substantial risk of HIV and sexually transmitted infections (STIs). Despite the epidemiological and biological link between STIs and HIV transmission and acquisition, infections such as Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) remain widely undiagnosed. Syndromic STI management is the standard of care in low- and middle-income countries (LMICs) despite a high prevalence of asymptomatic infections. We conducted an observational study to explore the acceptability, feasibility, and cost of a STI test-and-treat service for YP in Cape Town. METHODS: YP attending a mobile clinic (MC) and a youth centre clinic (YC) were offered STI screening. Urine testing for CT and NG using a 90-min molecular point-of-care (POC) test on the GeneXpert platform was conducted and treatment provided. Data were collated on demographics, sexual behaviour, presence of symptoms, uptake of same-day treatment, prevalence of CT/NG, and service acceptability. RESULTS: Three hundred sixty six participants were enrolled (median age 20, 83% female).57% (209/366) of participants tested positive for either CT (126/366, 34%) or NG (57/366, 16%) or co-infection (26/366, 7%). Clinical symptoms were a poor predictor of GeneXpert diagnosed CT or NG, with a sensitivity of 46.8% and 54.0% for CT and NG respectively. Although half of participants initially chose to receive same day results and treatment, only a third waited for results on the day. The majority of participants (91%) rated the service highly via a post-visit acceptability questionnaire. CONCLUSION: Curable STIs are highly prevalent in this population. STI screening using POC testing was feasible and acceptability was high. The study provides further impetus for moving policy beyond syndromic management of STIs in South Africa.

Tildrakizumab efficacy and safety in patients with psoriasis and concomitant metabolic syndrome: post hoc analysis of 5-year data from reSURFACE 1 and reSURFACE 2.

BACKGROUND: Limited data are available on long-term efficacy and safety of biologics in patients with psoriasis and metabolic syndrome (MetS), a common comorbidity. OBJECTIVES: This analysis updates tildrakizumab efficacy and safety for up to 5 years in patients with and without MetS. METHODS: This was a post hoc analysis of the double-blind, randomized, placebo-controlled, phase 3 reSURFACE 1 (NCT01722331) and reSURFACE 2 (NCT01729754) trials in adult patients with moderate to severe chronic plaque psoriasis. Analyses included data through Week 244 from patients who continuously received tildrakizumab 100 (TIL100) or 200 mg (TIL200) and entered the extension studies, stratified by baseline MetS status. Efficacy was assessed via Psoriasis Area and Severity Index (PASI) scores. Safety was evaluated from exposure-adjusted incidence rates (EAIRs) of treatment-emergent adverse events (TEAEs). RESULTS: reSURFACE 1 and reSURFACE 2 analyses included 26 and 44 TIL100-treated patients with MetS, 98 and 167 TIL100-treated patients without MetS, 34 and 30 TIL200-treated patients with MetS, and 111 and 130 TIL200-treated patients without MetS, respectively. There were no clinically relevant differences in PASI 75/90/100 response rates at Week 244 between patients with vs without MetS. The proportion of patients with vs without MetS achieving absolute PASI score <3 at Week 244 was 53.8% vs 69.4% and 77.3% vs 80.8% in reSURFACE 1 and 2, respectively, for TIL100-treated patients and 58.8% vs 72.1% and 63.3% vs 72.3%, respectively, for TIL200-treated patients. In both studies, median reduction from baseline PASI score at all time points in patients with vs without MetS was >83% vs >89% for TIL100 and >85% vs >90% for TIL200. Pooled EAIRs of TEAEs, serious TEAEs, and TEAEs of special interest were similar in patients with and without MetS. CONCLUSIONS: Tildrakizumab maintains efficacy and a favorable safety profile over 5 years in patients with psoriasis regardless of MetS status.

Disease activity and treatment efficacy using patient-level Psoriasis Area and Severity Index scores from tildrakizumab phase 3 clinical trials.

BACKGROUND: It is unclear whether primary efficacy outcomes in plaque psoriasis clinical trials represent residual disease during treatment. OBJECTIVES: To evaluate supplementing dichotomous efficacy with residual disease activity. METHODS: This post hoc analysis used pooled, patient-level data after tildrakizumab 100 mg (N = 616) or placebo (N = 309) treatment from reSURFACE 1/2 (NCT01722331/NCT01729754) phase 3 clinical trials of patients with moderate to severe plaque psoriasis. RESULTS: Median baseline Psoriasis Area and Severity Index (PASI) was 17.9 for patients receiving tildrakizumab 100 mg. At Week 12, median PASI was 2.9, whereas dichotomous PASI 90 response rate was 36.9%, and absolute PASI <5.0, <3.0, and <1.0 were 64.0%, 50.8%, and 23.3%, respectively. At Week 28, median PASI was 1.7, whereas PASI 90 response rate was 51.9%, and absolute PASI <5.0, <3.0, and <1.0 were 75.3%, 62.8%, and 38.0%, respectively. Dermatology Life Quality Index and PASI scores were correlated through Week 28 (r = 0.51, p ≤ .0001). CONCLUSIONS: Disease activity was more reliably estimated by PASI scores than percentage PASI improvement; this may partially explain efficacy disparities between clinical trials and practice. These results suggest supplementing dichotomous PASI improvement with PASI scores and consideration of patient treatment goals could facilitate clinical decisions.

Five-year efficacy and safety of tildrakizumab in patients with moderate-to-severe psoriasis who respond at week 28: pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2).

BACKGROUND: The phase III reSURFACE 1 and reSURFACE 2 (NCT01722331/NCT01729754) trials of the anti-interleukin-23p19 monoclonal antibody tildrakizumab (TIL) for psoriasis treatment are complete. OBJECTIVES: We present 5-year pooled data from reSURFACE 1 and reSURFACE 2. METHODS: reSURFACE 1 and reSURFACE 2 were double-blind, randomized, controlled studies with optional long-term extensions. Adults with moderate-to-severe chronic plaque psoriasis were randomized 2 : 2 : 1 to TIL 100 mg (TIL 100) or 200 mg (TIL 200) or placebo at weeks 0 and 4, and every 12 weeks thereafter [reSURFACE 2 included an etanercept (ETN) arm]. Efficacy outcomes included proportions of patients achieving absolute and relative improvement from baseline Psoriasis Area and Severity Index (PASI) score through week 244 in TIL responders (≥ 75% improvement from baseline PASI; PASI 75 response) continuously receiving the same dose and ETN partial responders and nonresponders (PASI < 75 response) switched to TIL 200 at week 28. Safety was assessed from adverse events (AEs) in all patients as treated. RESULTS: Efficacy analyses included 329 and 227 week 28 responders to TIL 100 and TIL 200, respectively, and 121 ETN partial responders/nonresponders switched to TIL 200 at week 28. Of TIL 100 or TIL 200 responders and ETN partial responders/nonresponders entering the extensions, 235/302, 176/213 and 85/107, respectively, were evaluated at week 244, and 88·7%, 92·5% and 81·3%, respectively, achieved PASI 75 response. Exposure-adjusted rates of serious AEs were 6·3 and 6·0 patients with events per 100 patient-years of TIL 100 and TIL 200, respectively. CONCLUSIONS: TIL treatment provided sustained disease control over 5 years in week 28 TIL responders and ETN partial responders/nonresponders, with a reassuring safety profile.

From initial segment to cauda: a regional characterization of mouse epididymal CD11c+ mononuclear phagocytes based on immune phenotype and function.

Successful sperm maturation and storage rely on a unique immunological balance that protects the male reproductive organs from invading pathogens and spermatozoa from a destructive autoimmune response. We previously characterized one subset of mononuclear phagocytes (MPs) in the murine epididymis, CX3CR1+ cells, emphasizing their different functional properties. This population partially overlaps with another subset of understudied heterogeneous MPs, the CD11c+ cells. In the present study, we analyzed the CD11c+ MPs for their immune phenotype, morphology, and antigen capturing and presenting abilities. Epididymides from CD11c-EYFP mice, which express enhanced yellow fluorescent protein (EYFP) in CD11c+ MPs, were divided into initial segment (IS), caput/corpus, and cauda regions. Flow cytometry analysis showed that CD11c+ MPs with a macrophage phenotype (CD64+ and F4/80+) were the most abundant in the IS, whereas those with a dendritic cell signature [CD64- major histocompatibility complex class II (MHCII)+] were more frequent in the cauda. Immunofluorescence revealed morphological and phenotypic differences between CD11c+ MPs in the regions examined. To assess the ability of CD11c+ cells to take up antigens, CD11c-EYFP mice were injected intravenously with ovalbumin. In the IS, MPs expressing macrophage markers were most active in taking up the antigens. A functional antigen-presenting coculture study was performed, whereby CD4+ T cells were activated after ovalbumin presentation by CD11c+ epididymal MPs. The results demonstrated that CD11c+ MPs in all regions were capable of capturing and presenting antigens. Together, this study defines a marked regional variation in epididymal antigen-presenting cells that could help us understand fertility and contraception but also has larger implications in inflammation and disease pathology.

Efficacy of tildrakizumab by patient demographic and disease characteristics across a phase 2b and 2 phase 3 trials in patients with moderate-to-severe chronic plaque psoriasis.

BACKGROUND: Tildrakizumab is a high-affinity, anti-interleukin-23p19 monoclonal antibody approved for treatment of moderate-to-severe plaque psoriasis. OBJECTIVES: To evaluate the effects of patient demographic and disease characteristics on tildrakizumab efficacy using phase 2b/3 trial data. METHODS: Data from patients who received placebo, or tildrakizumab 100 or 200 mg, in P05495 [NCT01225731], reSURFACE 1 [NCT01722331] and reSURFACE 2 [NCT01729754] were analysed. Patient subgroups were defined by age, sex, race, weight, self-reported psoriatic arthritis, failure of ≥1 traditional systemic treatment and prior biologic use. Percentage of Psoriasis Area and Severity Index (PASI) 75 and 90 responders at Week 12 were compared across treatment arms in each subgroup. Absolute PASI at Weeks 0 and 12 was also determined for each subgroup. RESULTS: Among patients randomized in P05495 (N = 355), reSURFACE 1 (N = 772) and 2 (N = 1090), percentage of PASI 75 and 90 responders were significantly greater for each tildrakizumab dose vs. placebo (P < 0.0001). PASI 75 and 90 responder percentages were numerically greater in patients <65 years of age, bodyweight ≤90 kg, without psoriatic arthritis and with no prior biologic exposure (only PASI 90), vs. their counterparts in corresponding subgroups. There were no clear or consistent differences in efficacy between the other subgroups. Absolute PASI scores were generally similar across subgroups. CONCLUSIONS: Small numerical differences in tildrakizumab efficacy were observed between subgroups defined by patient age and weight, presence of psoriatic arthritis and prior biologic use. These differences were not clinically meaningful; however, analyses of long-term data may be of value. Tildrakizumab efficacy did not differ with respect to patient sex or race, or number of prior failed conventional systemic treatments. Overall, these results suggest tildrakizumab may be appropriate for treatment of moderate-to-severe plaque psoriasis in patients with a range of demographic and disease characteristics.

Tildrakizumab efficacy and impact on quality of life up to 52 weeks in patients with moderate-to-severe psoriasis: a pooled analysis of two randomized controlled trials.

BACKGROUND: Two randomized controlled trials (reSURFACE 1 and 2) have demonstrated the effectiveness of tildrakizumab, a high-affinity, humanized, IgG1κ, anti-interleukin-23 monoclonal antibody, for treating moderate-to-severe plaque psoriasis in the first 28 weeks. OBJECTIVES: To examine the efficacy of tildrakizumab and its impact on quality of life (QoL) in patients with different levels of week-28 Psoriasis Area and Severity Index (PASI) improvement. METHODS: Patients treated with tildrakizumab 100 mg or 200 mg from baseline to week 28 were pooled from reSURFACE 1 and reSURFACE 2 and classified into five mutually exclusive week-28 PASI improvement groups for each dose: PASI 0-49, 50-74, 75-89, 90-99 and 100. Mean PASI improvement and Dermatology Life Quality Index (DLQI) 0/1 over time were examined for each group. RESULTS: Of 1156 patients, 575 were in the 100-mg and 578 in the 200-mg cohorts, respectively. At week 28, 8.3%, 14.3%, 23.8%, 30.4% and 23.1% in the 100-mg and 4.0%, 18.1%, 19.6%, 29.1% and 29.3% in the 200-mg cohort achieved PASI < 50, 50-74, 75-89, 90-99 and 100, respectively. Patients with PASI < 50 at week 28 could be identified as early as week 8, and those with week-28 PASI ≥ 90 had approximately 50% PASI improvement by week 4. Among patients achieving PASI > 50 at week 28 who continued the same dose of tildrakizumab to week 52, mean PASI improvement was maintained or improved over time. Similar results were observed for both doses. Higher proportions of patients achieved DLQI 0/1 in higher week-28 PASI groups, and DLQI 0/1 was maintained or improved to week 52. However, not all patients with PASI 100 had DLQI 0/1. CONCLUSION: Patients unlikely to respond to tildrakizumab could be identified by week 8, and those likely to achieve a PASI ≥ 90 response could be identified as early as week 4. Week-28 PASI improvement level correlated with QoL improvement.

Diagnostic value of sentinel lymph node biopsy in head and neck cancer: a meta-analysis.

This study aimed to evaluate the diagnostic reliability of sentinel lymph node biopsy in patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx by reviewing the published literature. A systematic literature review was performed using MEDLINE from 1970 to 2011. With Boolean search strings, search terms included sentinel node, supraglottic, supraglottis, tongue, head and neck, oral, pharynx, laryngeal, and larynx. Additional studies were identified through article references. Duplicate data and articles were excluded based on treating institution and study inclusion time period. Additional studies were excluded if the head and neck subsite or tumor stage was not specifically identified or if the sentinel lymph node biopsy occurred in previously treated necks. All patients had sentinel lymph node biopsy performed followed by a concurrent neck dissection. Twenty-six studies met our inclusion criteria (n = 766 patients). The pooled sensitivity and negative predictive value of SLNB for all head and neck tumors was 95 % (95 % CI 91-99 %) and 96 % (95 %CI 94-99 %), respectively. The overall sensitivity and negative predictive value of SLNB in the subset of oral cavity tumors (n = 631) was 94 % (95 % CI 89-98 %) and 96 % (95 % CI 93-99 %), respectively. One-hundred percent of oropharyngeal (n = 72), hypopharyngeal (n = 5), and laryngeal (n = 58) tumor sentinel lymph biopsy results correlated with subsequent neck dissections giving a negative predictive value of 100 %, showing that, sentinel lymph node biopsy is a valid diagnostic technique to correctly stage regional metastases in patients with head and neck squamous cell carcinoma.

Population pharmacokinetics of ustekinumab in patients with active psoriatic arthritis.

PURPOSE: To characterize the population pharmacokinetics of subcutaneous ustekinumab, a human IgG1Kappa; monoclonal antibody against interleukin-12/23p40, using data from a randomized, double-blind, placebo-controlled Phase II study in patients with active psoriatic arthritis (PsA). METHODS: A total of 786 quantifiable serum ustekinumab concentrations from 130 patients were analyzed using a nonlinear mixed-effects modeling approach. A 1-compartment model with first-order absorption and elimination was selected as the structural model. RESULTS: The population typical mean (percent relative standard error (%RSE)) values for apparent clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (ka) obtained from the final covariate model were 0.465 l × day-1 (5.1%), 14.3 l (4.4%), and 0.427 day-1 (3.9%), respectively. The between-subject variability in CL/F, V/F, and ka were 53.9%, 42.3%, and 82.4%, respectively. Patient body weight and antibody-to-ustekinumab status were significant covariates affecting the CL/F and/or V/F of ustekinumab. None of the other factors evaluated, such as age, sex, race, baseline disease characteristics, concomitant methotrexate or nonsteroidal anti-inflammatory drugs, and past use of immunosuppressives, biologics, systemic corticosteroids, or disease-modifying antirheumatic drugs, were found to have significant effects on the pharmacokinetics of ustekinumab. CONCLUSION: The pharmacokinetics of ustekinumab in patients with PsA are comparable to those in patients with moderate-to-severe plaque psoriasis which was previously investigated.

Screening for maternal depression in a low education population using a two item questionnaire.

OBJECTIVE: To assess a two-question screening tool, the Patient Health Questionnaire-2 (PHQ-2), for identifying depressive symptomatology in economically disadvantaged mothers of children in pediatric settings and to explore risk factors associated with a positive depression screen. METHODS: A convenience sample of mothers was enrolled at an inner city well-child clinic with children age 3 days to 5 years. The PHQ-2 and Edinburgh Postnatal Depression Scale (EPDS) (as reference scale) were completed. RESULTS: Ninety-four mothers participated. Agreement of the PHQ-2 and EPDS was moderate. The sensitivity of the PHQ-2 for identifying a positive screen on the EPDS was 43.5%; the specificity was 97.2%. The sensitivity of the PHQ-2 was higher for mothers with education beyond high school compared to those with less education. Perceived lack of support with child care and having two or more children were associated with a positive screen. The rate of positive screen was similar for mothers with infants and with older children. CONCLUSION: Given the low sensitivity of the PHQ-2 in lower educated mothers, additional research in populations with varying sociodemographic characteristics is indicated. Similar rates of symptoms for mothers within and beyond the postpartum period and mothers previously screened support the need for periodic screening.

Measurement of leisure time satisfaction in family caregivers.

Caregiving is known to limit participation in a variety of roles. Leisure roles are increasingly recognized as important for the well-being of older adults. Little is known, however, about the impact of caregiving on leisure activities, and existing measures are of limited utility in caregiving research. We developed the Leisure Time Satisfaction (LTS) measure to allow further study of the impact of caregiving on caregivers' leisure time satisfaction, the role of leisure in understanding the caregiving process, and whether caregiving interventions improve leisure time satisfaction. The six-item LTS measure shows excellent psychometric properties, including internal consistency, a single factor structure, and convergent validity. Psychometric features are robust across diverse groups of caregivers, including subgroups varying by race/ethnicity and relationship to the care recipient. The LTS measure appears to be a promising tool for inclusion in caregiving research.

Involvement of tumor necrosis factor alpha in hippocampal development and function.

Tumor necrosis factor alpha (TNFalpha) is a cytokine produced mainly by cells of the immune system. It is also expressed by brain neurons and glia. The physiological role of TNFalpha in the brain is not yet fully clear. Using TNFalpha-deficient mice, we have examined its role in hippocampal development and function. We report here that TNFalpha is involved in the regulation of morphological development in the hippocampus. TNFalpha-deficient mice exhibited an accelerated maturation of the dentate gyrus region and smaller dendritic trees in CA1 and CA3 regions in young mouse. In addition to its involvement in hippocampal morphogenesis, TNFalpha deficiency specifically improved performance of affected mice in behavioral tasks related to spatial memory. Moreover, lack of TNFalpha increased the expression of nerve growth factor (NGF), but not brain-derived neurotrophic factor (BDNF), following performance of the learning task. Our results suggest that TNFalpha actively influences hippocampal development and function. In adult mice, TNFalpha may interfere with memory consolidation, perhaps by regulating NGF levels.

Invasive meningococcal disease in adolescents and young adults.

CONTEXT: Incidence of invasive meningococcal disease has increased recently in persons aged 15 through 24 years. OBJECTIVE: To characterize meningococcal infection in adolescents and young adults in Maryland during the 1990s. DESIGN AND SETTING: Population-based surveillance study for meningococcal disease from January 1, 1990, through December 31, 1999, in Maryland. PATIENTS: Maryland residents diagnosed as having invasive meningococcal disease. MAIN OUTCOME MEASURE: Invasive meningococcal infection. RESULTS: Of 295 total cases, 71 (24.1%) occurred among persons aged 15 through 24 years. Sixteen (22.5%) of these cases were fatal. The annual incidence rate increased from 0.9 to 2.1 cases per 100 000 among 15 through 24 year olds (P =.01). The proportion of all disease increased from 16.0% to 28.9% (P =.03). The incidence and proportion of cases subsequently decreased to 1.0 and 16.4% in 1998 through 1999, respectively. Infection in 15 through 24 year olds was more likely to be fatal than infection in those younger than age 15 years (22.5% vs 4.6%; P =.001). Infection in 15 through 24 year olds, compared with those aged 25 years or older, was more likely to be associated with male sex (66.2% vs 34.8%; P<.001) and serogroup C infection (46.9% vs 20.2%; P<.001), respectively. Infections were potentially preventable with the licensed meningococcal vaccine in 82.8% of 15 through 24 year olds, 68.1% of those younger than 15 years, and 76.8% of adults aged 25 years or older. CONCLUSIONS: Incidence of meningococcal infection in 15 through 24 year olds in Maryland increased and then declined during the 1990s. Infection in this age group was associated with an unusually high case-fatality ratio, and the vast majority of cases were potentially vaccine preventable.

Double-chambered right ventricle in an adult patient.

A 65-year-old male was referred for to our facility for right and left heart catheterization and coronary angiography for evaluation of a ventricular septal defect and to rule out significant coronary artery disease. During the procedure, the patient was diagnosed with a double-chambered right ventricle (DCRV). Most DCRV cases are diagnosed at a young age; presentation in an adult is extremely rare.