Informational Postcards Increase Engagement with Remote Monitoring Among Veterans with Pacemakers and Implantable Cardioverter-Defibrillators: a Stepped-Wedge Randomized Controlled Trial.

BACKGROUND: Remote monitoring (RM) of pacemakers and implantable cardioverter-defibrillators (ICDs) reduces morbidity and mortality. However, many patients are not adherent to RM. OBJECTIVE: To test the effect of informational postcards on RM adherence. DESIGN/PATIENTS: Stepped-wedge randomized controlled trial among Veterans with pacemakers and ICDs. INTERVENTION: In wave 1, Veterans who had sent at least 1 transmission within the past 2 years but had become non-adherent were randomly assigned to receive a postcard or no postcard. Those receiving postcards were randomized to 1 of 2 messages: (1) a"warning" postcard describing risks of non-adherence or (2) an "encouraging" postcard describing benefits of adherence. In wave 2, Veterans who had either not received a postcard in wave 1 or had since become non-adherent were mailed a postcard (again, randomized to 1 of 2 messages). Patients who did not send an RM transmission within 1 month were mailed a second, identical postcard. MAIN MEASURES: Transmission within 70 days. KEY RESULTS: Overall, 6351 Veterans were included. In waves 1 and 2, postcards were mailed to 5657 Veterans (2821 "warning" messages and 2836 "encouraging" messages). Wave 1 included 2178 Veterans as controls (i.e., not mailed a postcard), some of whom received a postcard in wave 2 if they remained non-adherent. In wave 2, 3473 postcards were sent. Of the 5657 patients mailed a postcard, 2756 (48.7%) sent an RM transmission within 70 days, compared to 530 (24.3%) of 2178 controls (absolute difference 24.4%, 95% confidence interval [CI] 22.2%, 26.6%). Of those who sent a transmission, 71.8% did so after the first postcard. Transmission rates at 70 days did not significantly differ between "warning" and "encouraging" messages (odds ratio 1.04, 95% CI 0.92, 1.18). CONCLUSIONS: Informational postcards led to a 24.4% absolute increase in adherence at 70 days among Veterans with pacemakers and ICDs who were non-adherent to RM.

Serum bile acid change correlates with improvement in pruritus in patients with primary biliary cholangitis receiving linerixibat.

BACKGROUND & AIMS: Total serum bile acid (TSBA) levels are elevated in patients with primary biliary cholangitis (PBC) and may mediate cholestatic pruritus. Linerixibat, an ileal bile acid transporter inhibitor, improved pruritus in patients with PBC. We explored the relationship between linerixibat dose, TSBA concentration, and pruritus. METHODS: Data from Phase 1/2 trials were used to develop a population kinetic-pharmacodynamic model to characterize the linerixibat dose-TSBA relationship. Individual Bayesian parameter estimates for participants in the GLIMMER study were used to derive the area under the TSBA concentration curve over 24 h (AUC0-24). Time-matched post hoc estimates of AUC0-24 were correlated with pruritus reported on a 0-10 numerical rating scale. Baseline TSBA concentration was correlated with change from baseline (ΔBL) in monthly itch score (MIS). ΔBL in model-estimated TSBA AUC0-24 was correlated with time-matched ΔBL in weekly itch score (WIS) or MIS. RESULTS: Linerixibat dose dependently reduced TSBA AUC0-24, reaching steady state after 5 days. Baseline TSBA levels in GLIMMER did not correlate with ΔBL in MIS. ΔBL in TSBA AUC0-24 correlated with improved WIS over 12 weeks of treatment (r = 0.52, p < 0.0001). Of participants with a ≥30% decrease in TSBA AUC0-24, 60% were pruritus responders (≥2-point improvement in WIS from baseline). CONCLUSIONS: Linerixibat treatment leads to rapid, dose-dependent TSBA reductions. Baseline TSBA levels do not correlate with on-treatment pruritus change, suggesting they do not predict linerixibat response. Change in TSBA AUC0-24 correlates significantly with, and can be predictive of, pruritus improvement in patients with PBC.

Adherence to integrated management of childhood illness (IMCI) guidelines by community health workers in Kano State, Nigeria through use of a clinical decision support (CDS) platform.

BACKGROUND: The World Health Organization (WHO) Integrated Management of Childhood Illness (IMCI) guidelines established in 1992 to decrease preventable under-five child morbidity and mortality, was adopted by Nigeria in 1997. Over 20 years later, while under-five child mortality remains high, less than 25% of first level facilities have trained 60% of community health workers (CHW) who care for sick children with IMCI. This study investigated the impact in CHWs overall adherence to IMCI guidelines, particularly for critical danger signs, as well as usability and feasible following the implementation of THINKMD's IMCI-based digital clinical decision support (CDS) platform. METHODS: Adherence to IMCI guidelines was assessed by observational and digital data acquisition of key IMCI clinical data points by 28 CHWs, prior, during, and post CDS platform implementation. Change in IMCI adherence was determined for individual CHW and for the cohort by analyzing the number of IMCI data points acquired by each CHW per clinical evaluation. Consistency of adherence was also calculated by averaging the percentage of total evaluations each data point was observed. Usability and acceptability surveys were administered following use of the CDS platform. RESULTS: THINKMD CDS platform implementation notably enhanced the CHWs' ability to capture key IMCI clinical data elements. We observed a significant increase in the mean percentage of data points captured between the baseline period and during the CDS technology implementation (T-test, t = -31.399, p < 0.016, Holm-Bonferroni correction, two-sided), with the mean values going from 30.7% to 72.4%. Notably, even after the completion of the technology implementation phase, the mean percentage of IMCI elements captured by CHWs remained significantly elevated compared to the baseline, with a 26.72 percentage point increase (from 30.7% to 57.4%, T-test, t = -15.779, p < 0.05, Holm-Bonferroni correction, two-sided). Usability and feasibility of the platform was high. CHWs reported that the CDS platform was easy to learn and use (93%) and enabled them to identify sick children (100%). CONCLUSION: These results demonstrate that utilization of a digital clinical decision support tool such as THINKMD's IMCI based CDS platform can significantly increase CHW adherence to IMCI guidelines over paper-based utilization, increase clinical quality and capacity, and improve identification of key danger signs for under-five children while being highly accepted and adopted.

GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus.

BACKGROUND & AIMS: GLIMMER assessed dose-response, efficacy, and safety of linerixibat, an ileal bile acid transporter inhibitor in development for cholestatic pruritus associated with primary biliary cholangitis (PBC). METHODS: GLIMMER was a Phase 2b, multicenter, randomized, parallel-group study in adults with PBC and moderate-to-severe pruritus (≥4 on 0-10 numerical rating scale [NRS]). After 4 weeks of single-blind placebo, patients with NRS ≥3 were randomized (3:1) to double-blind linerixibat/placebo for 12 weeks (to week 16), followed by single-blind placebo (to week 20). The primary objective was to investigate dose-related changes in mean worst daily itch (MWDI) score. RESULTS: One hundred forty-seven patients received placebo (n = 36) or linerixibat (once daily: 20 mg, n = 16; 90 mg, n = 23; 180 mg, n = 27; twice daily: 40 mg, n = 23; 90 mg, n = 22). Linerixibat groups exhibited ≥2-point mean reductions in MWDI from baseline at week 16; however, differences from placebo were not significant. Post hoc analysis of change from baseline in monthly itch score over the treatment period (Phase 3 endpoint) showed significant differences between placebo and linerixibat 180 mg once daily (P = .0424), 40 mg twice daily (P = .0105), and 90 mg twice daily (P = .0370). A significant relationship between total daily dose and response was observed post hoc in the per protocol population (P = .0542). Consistent with mechanism of action, diarrhea was the most frequent adverse event, and incidence increased with dose. CONCLUSIONS: Linerixibat effect on itch was not significantly different versus placebo in the primary intent-to-treat analysis but was associated with a significant dose-dependent reduction in itch in the per protocol population. A well-tolerated dose was identified for Phase 3 investigation for cholestatic pruritus in PBC. CLINICALTRIALS: gov ID: NCT02966834.

Implementing Heart Plus: Design and Early Results of a Novel Comanagement Clinic for Patients With Stimulant-associated Cardiomyopathy.

We describe the methodology, design, and early results of a novel multidisciplinary co management clinic model with Addiction Medicine and Cardiology providers using contingency management to engage patients with stimulant-associated cardiomyopathy (SA-CMP). Stimulant use, including methamphetamine and cocaine, is increasing in prevalence nationally and is associated with cardiovascular complications. People with SA-CMP have higher rates of mortality and acute care use (eg, emergency department visits, hospital admissions) and lower rates of outpatient care engagement than individuals with non-SA-CMP. This population also has disproportionately elevated rates of mental health and other medical comorbidities, challenges with social determinants of health, including housing and food insecurity, and representation from communities of color. This multidisciplinary comanagement care delivery model, called Heart Plus, was developed and funded as a quality improvement project. It led to a 5-fold increase in outpatient care engagement with a concomitant 53% decrease in acute care use. All participants reported a decrease in stimulant use. With increased clinical stability, patients were able to better engage with outpatient resources for social determinants of health, such as case management, social work, and housing and food service programs. Patients were also empowered to take control over their health while knowing that health care providers cared about their well-being.

Japanese subgroup analysis of GLIMMER: A global Phase IIb study of linerixibat for the treatment of cholestatic pruritus in patients with primary biliary cholangitis.

AIM: To compare patient characteristics and outcomes between the overall and Japanese populations of GLIMMER. METHODS: GLIMMER was a multicenter, double-blind, randomized, placebo-controlled, Phase IIb study evaluating linerixibat for the treatment of pruritus in patients with primary biliary cholangitis. RESULTS: In total, 147 patients were randomized in the GLIMMER overall population with 38 patients comprising the Japanese population. Demographics and baseline clinical characteristics were similar across treatment groups and between both populations. A reduction in mean worst daily itch score from baseline to week 16 (primary endpoint) was seen in all groups, with the largest reduction observed with linerixibat 40 mg twice daily (BID; -2.92 [95% confidence interval: -5.07, -0.76] and -2.86 [95% confidence interval: -3.76, -1.95] for Japanese and overall populations, respectively). The highest proportion of responders was generally in the 40 mg BID group in both populations regardless of the responder definition applied. Improvements in health-related quality of life were generally consistent in both populations. In the Japanese and overall populations, on-treatment drug-related adverse events were reported in 25% and 19% of patients in the placebo group and 0%-86% and 31%-78% of patients in the linerixibat groups, respectively. Consistent with the mechanism of action, the most common events were gastrointestinal in nature. The effects of linerixibat on pharmacodynamic biomarkers favored BID dosing. CONCLUSIONS: Therapeutic responses and safety of linerixibat were consistent between the Japanese and overall populations of GLIMMER. Linerixibat may provide an effective treatment option for cholestatic pruritus in patients with primary biliary cholangitis. CLINICAL TRIAL REGISTRATION: NCT02966834.

Cholestatic Pruritus Treatments in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: A Systematic Literature Review.

BACKGROUND AND AIMS: We conducted a systematic literature review to understand the evidence supporting treatment decisions for cholestatic pruritus associated with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). METHODS: Studies that enrolled ≥ 75% participants with PBC or PSC and reported ≥ 1 endpoint(s) related to efficacy, safety, health-related quality of life (HRQoL) or other patient-reported outcomes were included. Bias was assessed using the Cochrane risk of bias tool for randomised controlled trials (RCTs) and the Quality of Cohort studies tool for non-RCTs. RESULTS: Thirty-nine publications were identified, covering 42 studies and six treatment classes (including investigational and approved products): anion-exchange resins, antibiotics (rifampicin/derivatives), opiates, selective serotonin reuptake inhibitors, fibrates, ileal bile acid transporter inhibitors and other agents not categorised in these six classes. Across studies, median sample size was small (n = 18), 20 studies were over 20 years old, 25 followed patients for ≤ 6 weeks, only 25 were RCTs. Pruritus was assessed using several different tools, with inconsistencies in their application. Cholestyramine, considered first-line therapy for moderate-severe cholestatic pruritus, was assessed in six studies (two RCTs) including 56 patients with PBC and 2 with PSC, with evidence of efficacy demonstrated in only three studies, among which, two RCTs were assessed as having a high risk of bias. Findings were similar for other drug classes. CONCLUSIONS: There is a lack of consistent and reproducible evidence available on efficacy, impact on HRQoL, and safety of cholestatic pruritus treatments, leaving physicians to rely on clinical experience rather than evidence-based medicine for treatment selection.

Impact of Pruritus on Quality of Life and Current Treatment Patterns in Patients with Primary Biliary Cholangitis.

BACKGROUND AND AIMS: Patients with primary biliary cholangitis (PBC) often suffer with pruritus. We describe the impact of pruritus on quality of life and how it is managed in a real-world cohort. METHODS: TARGET-PBC is a longitudinal observational cohort of patients with PBC across the USA. Data include information from medical records for three years prior to the date of consent up to 5 years of follow-up. Enrolled patients were asked to complete patient-reported outcome surveys: PBC-40, 5-D itch, and the PROMIS fatigue survey. Kruskal-Wallis tests were used to compare differences in symptoms between groups. RESULTS: A total of 211 patients with completed PRO surveys were included in the current study. PRO respondents were compared with non-respondents in the TARGET-PBC population and were broadly similar. Pruritus was reported in 170 patients (81%), with those reporting clinically significant pruritus (30%) scoring worse across each domain of the PBC-40 and 5-D itch, more frequently having cirrhosis, and having significantly greater levels of fatigue. Patients reporting clinically significant pruritus were more likely to receive treatment, but 33% had never received treatment (no itch = 43.9%, mild itch = 38.3%). CONCLUSIONS: The prevalence of pruritus was high in this population, and those reporting clinically significant pruritus had a higher likelihood of having advanced disease and worse quality of life. However, this study found that pruritus in PBC is under-treated. This may be due in part to ineffectiveness of current treatments, poor tolerance, or the lack of FDA-approved medications for pruritus.

DNA polymerase ι compensates for Fanconi anemia pathway deficiency by countering DNA replication stress.

Fanconi anemia (FA) is caused by defects in cellular responses to DNA crosslinking damage and replication stress. Given the constant occurrence of endogenous DNA damage and replication fork stress, it is unclear why complete deletion of FA genes does not have a major impact on cell proliferation and germ-line FA patients are able to progress through development well into their adulthood. To identify potential cellular mechanisms that compensate for the FA deficiency, we performed dropout screens in FA mutant cells with a whole genome guide RNA library. This uncovered a comprehensive genome-wide profile of FA pathway synthetic lethality, including POLI and CDK4 As little is known of the cellular function of DNA polymerase iota (Pol ι), we focused on its role in the loss-of-function FA knockout mutants. Loss of both FA pathway function and Pol ι leads to synthetic defects in cell proliferation and cell survival, and an increase in DNA damage accumulation. Furthermore, FA-deficient cells depend on the function of Pol ι to resume replication upon replication fork stalling. Our results reveal a critical role for Pol ι in DNA repair and replication fork restart and suggest Pol ι as a target for therapeutic intervention in malignancies carrying an FA gene mutation.

Injection and Sexual Behavior Profiles among People Who Inject Drugs in Miami, Florida.

BACKGROUND: The dynamics of injection drug use and higher-risk sexual practices compound the risk of HIV and HCV acquisition. Published literature on people who inject drugs (PWID) has examined risk of infection assuming homogeneity of cohort behavior. Categorizing subgroups by injection and sexual risk can inform a more equitable approach to how syringe services programs (SSPs) adapt harm reduction resources and implementation of evidence-based interventions. We explored injection and sexual risk profiles among PWID to determine significant predictors of class membership. METHODS: Data were collected from 1,272 participants at an SSP in Miami-Dade County. Latent Class Analysis (LCA) examined how 10 injection/sexual behavior indicators cluster together to create profiles. Model fit statistics and multivariable multinomial latent class regression identified the optimal class structure and significant predictors of class membership. We assessed SSP visits, naloxone access, HIV/HCV testing and prevalence, and incidence of self-reported wounds. RESULTS: Three distinct profiles of injection/sexual risk were determined: Low Injection/High Sexual (LIHS) (9.4%); High Injection/Moderate Sexual (HIMS) (18.9%); and Low Injection/Low Sexual (LILS) (71.7%). Participants reporting gay/bisexual orientation and methamphetamine injection more likely belonged to the LIHS class. LIHS class members had higher prevalence of HIV, while those of HIMS reported increased hepatitis C prevalence. Compared to members of LILS, those of HIMS more likely experienced unstable housing, gay/bisexual orientation, heroin or speedball injection, and identifying as women. HIMS cohort members had more SSP visits, naloxone accessed, and higher wound incidence than those of LILS. CONCLUSIONS: Understanding PWID subgroups amplifies the importance of implementing evidencebased interventions such as PrEP for those engaging in highest risk behavior, with focused interventions of antiretroviral management and access to condoms for members of the LIHS class and HCV screening with wound care for those belonging to HIMS.

Pharmacokinetics and ADME Characterization of Intravenous and Oral [14C]-Linerixibat in Healthy Male Volunteers.

Linerixibat, an oral small-molecule ileal bile acid transporter inhibitor under development for cholestatic pruritus in primary biliary cholangitis, was designed for minimal absorption from the intestine (site of pharmacological action). This study characterized the pharmacokinetics, absorption, metabolism, and excretion of [14C]-linerixibat in humans after an intravenous microtracer concomitant with unlabeled oral tablets and [14C]-linerixibat oral solution. Linerixibat exhibited absorption-limited flip-flop kinetics: longer oral versus intravenous half-life (6-7 hours vs. 0.8 hours). The short intravenous half-life was consistent with high systemic clearance (61.9 l/h) and low volume of distribution (16.3 l). In vitro studies predicted rapid hepatic clearance via cytochrome P450 3A4 metabolism, which predicted human hepatic clearance within 1.5-fold. However, linerixibat was minimally metabolized in humans after intravenous administration: ∼80% elimination via biliary/fecal excretion (>90%-97% as unchanged parent) and ∼20% renal elimination by glomerular filtration (>97% as unchanged parent). Absolute oral bioavailability of linerixibat was exceedingly low (0.05%), primarily because of a very low fraction absorbed (0.167%; fraction escaping first-pass gut metabolism (fg) ∼100%), with high hepatic extraction ratio (77.0%) acting as a secondary barrier to systemic exposure. Oral linerixibat was almost entirely excreted (>99% recovered radioactivity) in feces as unchanged and unabsorbed linerixibat. Consistent with the low oral fraction absorbed and ∼20% renal recovery of intravenous [14C]-linerixibat, urinary elimination of orally administered radioactivity was negligible (<0.04% of dose). Linerixibat unequivocally exhibited minimal gastrointestinal absorption and oral systemic exposure. Linerixibat represents a unique example of high CYP3A4 clearance in vitro but nearly complete excretion as unchanged parent drug via the biliary/fecal route. SIGNIFICANCE STATEMENT: This study conclusively established minimal absorption and systemic exposure to orally administered linerixibat in humans. The small amount of linerixibat absorbed was eliminated efficiently as unchanged parent drug via the biliary/fecal route. The hepatic clearance mechanism was mispredicted to be mediated via cytochrome P450 3A4 metabolism in vitro rather than biliary excretion of unchanged linerixibat in vivo.

Lp-PLA2 activity is associated with increased risk of diabetic retinopathy: a longitudinal disease progression study.

AIMS/HYPOTHESIS: The aim of the study was to examine the association between lipoprotein-associated phospholipase A2 (Lp-PLA2) activity levels and incident diabetic retinopathy and change in retinopathy grade. METHODS: This was a cohort study of diabetic participants with serum collected at baseline and routinely collected diabetic retinal screening data. Participants with type 2 diabetes from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) cohort were used. This cohort is composed of individuals of white Scottish ancestry from the Tayside region of Scotland. Survival analysis accounting for informative censoring by modelling death as a competing risk was performed for the development of incident diabetic retinopathy from a disease-free state in a 3 year follow-up period (n = 1364) by stratified Lp-PLA2 activity levels (in quartiles). The same analysis was performed for transitions to more severe grades. RESULTS: The hazard of developing incident diabetic retinopathy was 2.08 times higher (95% CI 1.64, 2.63) for the highest quartile of Lp-PLA2 activity compared with the lowest. Higher Lp-PLA2 activity levels were associated with a significantly increased risk for transitions to all grades. The hazards of developing observable (or more severe) and referable (or more severe) retinopathy were 2.82 (95% CI 1.71, 4.65) and 1.87 (95% CI 1.26, 2.77) times higher for the highest quartile of Lp-PLA2 activity compared with the lowest, respectively. CONCLUSIONS/INTERPRETATION: Higher Lp-PLA2 levels are associated with increased risk of death and the development of incident diabetic retinopathy, as well as transitions to more severe grades of diabetic retinopathy. These associations are independent of calculated LDL-cholesterol and other traditional risk factors. Further, this biomarker study shows that the association is temporally sensitive to the proximity of the event to measurement of Lp-PLA2.

Community-Based Accompaniment with Supervised Antiretrovirals for HIV-Positive Adults in Peru: A Cluster-Randomized Trial.

We conducted a cluster-randomized trial to estimate effects of directly observed combination antiretroviral therapy (DOT-cART) on retention with viral suppression among HIV-positive adults in Peru. We randomly allocated facilities to receive the 12-month intervention plus the standard of care, including adherence support provided through accompaniment. In the intervention arm, health workers supervised doses, twice daily, and accompanied patients to appointments. Among 356 patients, intention-to-treat analyses showed no statistically significant benefit of DOT, relative to no-DOT, at 12 or 24 months (adjusted probability of primary outcome: 0.81 vs. 0.73 and 0.76 vs. 0.68, respectively). A statistically significant benefit of DOT was found in per-protocol and as-treated analyses at 12 months (0.83 for DOT vs. 0.73 for no DOT, p value: 0.02 per-protocol, 0.01 as-treated), but not 24 months. Rates of retention with viral suppression were high in both arms. Among adults receiving robust adherence support, the added effect of time-limited DOT, if any, is small-to-moderate.

Superiority of dutasteride 0.5 mg and tamsulosin 0.2 mg for the treatment of moderate-to-severe benign prostatic hyperplasia in Asian men.

OBJECTIVES: To assess the effectiveness and safety of dutasteride 0.5 mg + tamsulosin 0.2 mg combination compared with tamsulosin 0.2 mg in Asian men with moderate-to-severe benign prostatic hyperplasia. METHODS: A 4-week, single-blind, placebo, run-in was followed by a 2-year double-blind randomized controlled trial in men age ≥50 years with symptomatic benign prostatic hyperplasia, International Prostate Symptom Score ≥12, prostate volume ≥30 cc, prostate-specific antigen ≥1.5 and ≤10 ng/mL, peak urinary flow >5 and ≤15 mL/s, and voided volume of ≥125 mL. Participants were randomized to oral daily dutasteride 0.5 mg + tamsulosin 0.2 mg combination or tamsulosin 0.2 mg. The primary efficacy end-point was change in International Prostate Symptom Score at year 2. RESULTS: Data from 607 participants showed a significant reduction in International Prostate Symptom Score (P < 0.05) at month 24, along with greater improvements (P ≤ 0.006) in peak urinary flow at every assessment and significant prostate volume reduction at months 12 and 24 (P < 0.001) in the combination group. Combination therapy was associated with a significant reduction in the risk of acute urinary retention or benign prostatic hyperplasia-related surgery (P = 0.012), primarily due to a significant reduction in the risk of acute urinary retention (P = 0.005). The safety and tolerability profile of combination therapy was consistent with the known profiles for the individual monotherapies. CONCLUSIONS: Dutasteride 0.5 mg + tamsulosin 0.2 mg combination therapy showed better clinical outcomes than tamsulosin 0.2 mg monotherapy, making it an effective and safe treatment option for Asian men with moderate-to-severe benign prostatic hyperplasia.

Large-scale interaction profiling of PDZ domains through proteomic peptide-phage display using human and viral phage peptidomes.

The human proteome contains a plethora of short linear motifs (SLiMs) that serve as binding interfaces for modular protein domains. Such interactions are crucial for signaling and other cellular processes, but are difficult to detect because of their low to moderate affinities. Here we developed a dedicated approach, proteomic peptide-phage display (ProP-PD), to identify domain-SLiM interactions. Specifically, we generated phage libraries containing all human and viral C-terminal peptides using custom oligonucleotide microarrays. With these libraries we screened the nine PSD-95/Dlg/ZO-1 (PDZ) domains of human Densin-180, Erbin, Scribble, and Disks large homolog 1 for peptide ligands. We identified several known and putative interactions potentially relevant to cellular signaling pathways and confirmed interactions between full-length Scribble and the target proteins ß-PIX, plakophilin-4, and guanylate cyclase soluble subunit α-2 using colocalization and coimmunoprecipitation experiments. The affinities of recombinant Scribble PDZ domains and the synthetic peptides representing the C termini of these proteins were in the 1- to 40-µM range. Furthermore, we identified several well-established host-virus protein-protein interactions, and confirmed that PDZ domains of Scribble interact with the C terminus of Tax-1 of human T-cell leukemia virus with micromolar affinity. Previously unknown putative viral protein ligands for the PDZ domains of Scribble and Erbin were also identified. Thus, we demonstrate that our ProP-PD libraries are useful tools for probing PDZ domain interactions. The method can be extended to interrogate all potential eukaryotic, bacterial, and viral SLiMs and we suggest it will be a highly valuable approach for studying cellular and pathogen-host protein-protein interactions.

Darapladib, a lipoprotein-associated phospholipase A2 inhibitor, in diabetic macular edema: a 3-month placebo-controlled study.

PURPOSE: To investigate the potential of lipoprotein-associated phospholipase A2 inhibition as a novel mechanism to reduce edema and improve vision in center-involved diabetic macular edema (DME). DESIGN: Prospective, multicenter, randomized, double-masked, placebo-controlled phase IIa study. PARTICIPANTS: Fifty-four center-involved DME patients randomized 2:1 to receive darapladib (n = 36) or placebo (n = 18). METHODS: Darapladib 160 mg or placebo monotherapy was administered orally once daily for 3 months, and patients were followed up monthly for 4 months. MAIN OUTCOME MEASURES: Mean change from baseline in best-corrected visual acuity (BCVA) and the center subfield and center point of the study eye at month 3 as determined by spectral-domain optical coherence tomography. RESULTS: Five patients in the study received intravitreal anti-vascular endothelial growth factor rescue therapy before the day 90 assessment, 2 of 36 (6%) in the darapladib arm and 3 of 18 (17%) in the placebo arm. Administration of 160 mg darapladib for 3 months resulted in statistically significant mean improvements, from baseline to month 3, in BCVA of 4.1 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (95% confidence interval [CI], 2.3-5.8) and of 57 µm in central subfield thickness (95% CI, -84 to -30) in the study eyes. An increase in BCVA of 1.7 ETDRS letters (95% CI, -1.0 to 4.4) and a decrease in center subfield thickness of 34 µm (95% CI, -75 to 6.8) for the placebo group were not significant. No ocular severe adverse events (SAEs) or SAEs considered related to darapladib were reported. One SAE of myocardial infarction, not considered related to darapladib, was reported, and 1 SAE of severe diarrhea was reported in a placebo patient, subsequently withdrawn from the study. Study eye ocular adverse events (AEs) and nonocular AEs were similar between treatment groups. CONCLUSIONS: Once-daily oral darapladib administered for 3 months demonstrated modest improvements in vision and macular edema that warrant additional investigation of this novel lipoprotein-associated phospholipase A2 inhibitory mechanism for the treatment of DME.

A systematic review and meta-analysis to compare the efficacy of acyclovir 3% ophthalmic ointment to idoxuridine in curing herpetic keratitis by Day 7 of treatment.

BACKGROUND: This objective of the review and analysis is to demonstrate that acyclovir (ACV) 3% ophthalmic ointment is superior to idoxuridine (IDU) in treating herpetic keratitis (HK) presenting as dendritic and geographic ulcer sub-types. DATA SOURCES: Publications in human subjects were identified by searching the Ovid MEDLINE database through April 2011, combining medical subject headings (MESH) "Keratitis, Herpetic/" AND "Acyclovir/" limiting by the key words "topical" OR "ointment" and also restricted to MESH "Administration, Topical/" OR "Ointments/". The results were cross checked with the references used in the Cochrane Database Syst Rev. 1:1-134, 2009 and GlaxoSmithKline clinical documents related to acyclovir. STUDY SELECTION: Randomized, double-masked studies in subjects diagnosed with HK with head to head comparator arms of ACV ophthalmic ointment and topical IDU that had actual or calculable healing rates at Day seven. DATA EXTRACTION: Data independently extracted from identified articles by two authors of this manuscript. DATA SYNTHESIS: Data from seven randomized, controlled trials (RCT) evaluating 432 subjects that met inclusion criteria (214 were treated with ACV and 218 were treated with IDU) and had Day seven healing rates calculable. All sub-classified lesions were identified as either dendritic ulcers (n = 185) or geographic ulcers (n = 35). The Cochran-Mantel-Haenszel (CMH) method in Biometrics 10:417-51, 1954 and JNCI 22:719-48, 1959, controlling for study, was performed as the primary analysis using SAS v9. Homogeneity was assessed using Breslow-Day-Tarone (BDT) test in IARC 1:1-32, 1980 and Biometrika 72:91-5, 1985. The analysis was performed with outliers removed to assess their impact. RESULTS: ACV showed statistically significant greater odds of healing HK at Day seven in all subjects (Odds Ratio 3.95, 95% CI2.60, 6.00, p < 0.0001), in dendritic ulcers (Odds Ratio 4.22, 95% CI: 2.14, 8.32; p < 0.0001) and geographic ulcers (Odds Ratio 5.31, 95% CI: 1.09, 25.93; p = 0.0244). CONCLUSION: ACV 3% ophthalmic ointment is a valuable intervention for dendritic and geographic corneal ulcers. ACV and IDU were generally well tolerated in the studies reviewed.

On the spread and control of MDR-TB epidemics: an examination of trends in anti-tuberculosis drug resistance surveillance data.

BACKGROUND: Multidrug resistant tuberculosis (MDR-TB) poses serious challenges for tuberculosis control in many settings, but trends of MDR-TB have been difficult to measure. METHODS: We analyzed surveillance and population-representative survey data collected worldwide by the World Health Organization between 1993 and 2012. We examined setting-specific patterns associated with linear trends in the estimated per capita rate of MDR-TB among new notified TB cases to generate hypotheses about factors associated with trends in the transmission of highly drug resistant tuberculosis. RESULTS: 59 countries and 39 sub-national settings had at least three years of data, but less than 10% of the population in the WHO-designated 27-high MDR-TB burden settings were in areas with sufficient data to track trends. Among settings in which the majority of MDR-TB was autochthonous, we found 10 settings with statistically significant linear trends in per capita rates of MDR-TB among new notified TB cases. Five of these settings had declining trends (Estonia, Latvia, Macao, Hong Kong, and Portugal) ranging from decreases of 3% to 14% annually, while five had increasing trends (four individual oblasts of the Russian Federation and Botswana) ranging from 14% to 20% annually. In unadjusted analysis, better surveillance indicators and higher GDP per capita were associated with declining MDR-TB, while a higher existing absolute burden of MDR-TB was associated with an increasing trend. CONCLUSIONS: Only a small fraction of countries in which the burden of MDR-TB is concentrated currently have sufficient surveillance data to estimate trends in drug-resistant TB. Where trend analysis was possible, smaller absolute burdens of MDR-TB and more robust surveillance systems were associated with declining per capita rates of MDR-TB among new notified cases.

Suboptimal antiretroviral therapy adherence among HIV-infected adults in Guangzhou, China.

Despite China's free antiretroviral therapy (ART) program, there are high rates of treatment failure, large sociodemographic disparities in care outcomes and emerging medication resistance. Understanding patient medication adherence behaviors and challenges could inform adherence interventions to maximize the individual and prevention benefits of ART. This study assessed recent nonadherence and treatment interruption among 813 HIV-infected adult outpatients in Guangzhou, China. Participants completed a behavioral survey, underwent chart review, and were tested for syphilis, gonorrhea, and chlamydia. Factors associated with suboptimal adherence were identified using univariate and multivariate logistic regression. Among 721 HIV-infected adults receiving ART, 18.9% reported recent nonadherence (any missed ART in the past four weeks) and 6.8% reported treatment interruption (four or more weeks of missed ART in the past year). Lower education, living alone, alcohol use, and being on ART one to three years were associated with recent nonadherence. Male gender, lower education, and being on ART one to three years were associated with treatment interruption. ART medication adherence interventions are needed in China that include individualized, long-term adherence plans sensitive to patients' educational and economic situations. These interventions should also consider possible gender disparities in treatment outcomes and address the use of alcohol during ART. Successful ART medication adherence interventions in China can inform other international settings that face similar adherence challenges and disparities.