Comprehension of clitic pronouns by children with cochlear implants: the role of sentence stress.

OBJECTIVES: This study investigates the role of sentence stress on the comprehension of sentences with clitic pronouns (unstressed morphemes and a typical feature of Romance languages) by children with cochlear implants (CIs). METHODS: Thirteen children (seven girls) with CIs and 15 children (seven girls) with NH between eight and 12 years who are monolingual speakers of Brazilian Portuguese participated on a computerized sentence comprehension task that involved manipulation of stress placement of possible antecedent words to clitic pronouns. RESULTS: Children with CIs were significantly less accurate than children with NH in comprehending sentences with clitics, regardless of sentence stress. For children with NH, stress on the correct antecedent significantly increased sentence comprehension accuracy. For children with CI, there was no significant effect of sentence stress on selecting the correct antecedent for clitic pronouns. DISCUSSION: Comprehension of sentences with clitic pronouns is challenging for children with CIs and this challenge holds cross-linguistically. Furthermore, children with CIs do not use prosodic information to support comprehension of sentences with clitics similarly to NH children. CONCLUSION: Language-specific syntactic, morphosyntactic, and prosodic contrasts affecting sentence comprehension need to be assessed in children with CIs to plan an effective intervention.

Longitudinal trends (2011-2020) of premature mortality and years of potential life loss (YPLL) and associated covariates of the 62 New York State counties.

BACKGROUND: New York State (NYS) is the 27th largest state and the 4th most populous state in the U.S., with close to 20 million people in 62 counties. Territories with diverse populations present the best opportunity to study health outcomes and associated covariates, and how these differ across different populations and groups. The County Health Ranking and Roadmaps (CHR&R) ranks counties by linking the population's characteristics and health outcomes and contextual factors in a synchronic approach. METHODS: The goal of this study is to analyze the longitudinal trends in NYS counties of age-adjusted premature mortality rate and years of potential life loss rate (YPLL) from 2011-2020 using (CHR&R) data to identify similarities and trends among the counties of the state. This study used a weighted mixed regression model to analyze the longitudinal trend in health outcomes as a function of the time-varying covariates and clustered the 62 counties according to the trend over time in the covariates. RESULTS: Four clusters of counties were identified. Cluster 1, which represents 33 of the 62 counties in NYS, contains the most rural counties and the least racially and ethnically diverse counties. Clusters 2 and 3 mirror each other in most covariates and Cluster 4 is comprised of 3 counties (Bronx, Kings/Brooklyn, Queens) representing the most urban and racial and ethnic diverse counties in the state. CONCLUSION: The analysis clustered counties according to the longitudinal trends of the covariates, and by doing so identified clusters of counties that shared similar trends among the covariates, to later examine trends in the health outcomes through a regression model. The strength of this approach lies in the predictive feature of what is to come for the counties by understanding the covariates and setting prevention goals.

Effects of Long-Term Sertraline Use on Pediatric Growth and Development: The Sertraline Pediatric Registry for The Evaluation of Safety (SPRITES).

Objective: To describe the results of the Sertraline Pediatric Registry for The Evaluation of Safety (SPRITES) outcome measures of cognitive, emotional, and physical development following long-term treatment with sertraline (for up to 3 years) in children and adolescents aged 6-16 years. Methods: SPRITES was a long-term, multicenter, open-label, prospective observational study designed to compare physical and psychological development in pediatric patients exposed to sertraline (with or without psychotherapy) or psychotherapy alone in usual care settings. Data were summarized descriptively, and outcomes were evaluated using a marginal structural model. Results: Between April 2012 and September 2020, 941 patients across 44 U.S. sites participated in the study. At baseline, 695 participants were exposed to sertraline (physician prescribed) with or without psychotherapy, and 245 participants were exposed to psychotherapy alone. Of these, 432 participants (46.0%) completed the full 3-year study follow-up. No significant changes across time were found in standardized height, BRIEF (Behavior Rating Inventory of Executive Function), Trails B, and Tanner stage based on cumulative sertraline exposure or exposure since the last visit. Change in mean standardized weight across time was positively associated with both cumulative sertraline exposure (p = 0.02) and exposure since the last visit (p = 0.029). The mean changes from baseline across time in standardized weight were standard deviations of 0.02, 0.03, 0.16, and 0.17 at months 3, 6, 30, and 36, respectively. However, this finding was not observed in the mean change across time in standardized body mass index, which was not statistically significant. Conclusions: Results are consistent with normal development. Although a statistically significant finding for standardized weight was observed in comparative analyses, the magnitude of the change is small and observed at higher doses of sertraline only. No other significant differences were observed between the "sertraline" group and the "no pharmacological therapy" group on other primary outcome measures. ClinicalTrials.gov identifier: NCT01302080.

Muscle hypertrophy and strength gains after resistance training with different volume-matched loads: a systematic review and meta-analysis.

The purpose of this paper was to conduct a systematic review and meta-analysis of studies that compared muscle hypertrophy and strength gains between resistance training protocols employing very low (VLL < 30% of 1-repetition maximum (RM) or >35RM), low (LL30%-59% of 1RM, or 16-35RM), moderate (ML60%-79% of 1RM, or 8-15RM), and high (HL ≥ 80% of 1RM, or ≤7RM) loads with matched volume loads (sets × repetitions × weight). A pooled analysis of the standardized mean difference for 1RM strength outcomes across the studies showed a benefit favoring HL vs. LL and vs. ML and favoring ML vs. LL. The LL and VLL results showed little difference. A pooled analysis of the standardized mean difference for hypertrophy outcomes across all studies showed no differences between training loads. Our findings indicate that when the volume load is equal between conditions, the highest loads induce superior dynamic strength gains. Alternatively, hypertrophic adaptations were similar irrespective of the load magnitude. Novelty: Training with higher loads elicits greater gains in 1RM muscle strength when compared to lower loads, even when the volume load is equal between conditions. Muscle hypertrophy is similar irrespective of the magnitude of the load, even when the volume load is equal between conditions.

Effects of resistance training performed to repetition failure or non-failure on muscular strength and hypertrophy: A systematic review and meta-analysis.

PURPOSE: We aimed to perform a systematic review and meta-analysis of the effects of training to muscle failure or non-failure on muscular strength and hypertrophy. METHODS: Meta-analyses of effect sizes (ESs) explored the effects of training to failure vs. non-failure on strength and hypertrophy. Subgroup meta-analyses explored potential moderating effects of variables such as training status (trained vs. untrained), training volume (volume equated vs. volume non-equated), body region (upper vs. lower), exercise selection (multi- vs. single-joint exercises (only for strength)), and study design (independent vs. dependent groups). RESULTS: Fifteen studies were included in the review. All studies included young adults as participants. Meta-analysis indicated no significant difference between the training conditions for muscular strength (ES = -0.09, 95% confidence interval (95%CI): -0.22 to 0.05) and for hypertrophy (ES = 0.22, 95%CI: -0.11 to 0.55). Subgroup analyses that stratified the studies according to body region, exercise selection, or study design showed no significant differences between training conditions. In studies that did not equate training volume between the groups, the analysis showed significant favoring of non-failure training on strength gains (ES = -0.32, 95%CI: -0.57 to -0.07). In the subgroup analysis for resistance-trained individuals, the analysis showed a significant effect of training to failure for muscle hypertrophy (ES = 0.15, 95%CI: 0.03-0.26). CONCLUSION: Training to muscle failure does not seem to be required for gains in strength and muscle size. However, training in this manner does not seem to have detrimental effects on these adaptations, either. More studies should be conducted among older adults and highly trained individuals to improve the generalizability of these findings.

Sertraline Pediatric Registry for the Evaluation of Safety: Design and Clinical Characteristics of Pediatric Patients Prescribed Sertraline.

Objectives: To describe the study design and clinical characteristics of patients in the Sertraline Pediatric RegIstry for The Evaluation of Safety (SPRITES). Methods: SPRITES is an open-label postmarketing study of development and safety outcomes in patients aged 6 to 16 years treated with sertraline (with or without psychotherapy) compared with psychotherapy alone for up to 3 years in the United States. Baseline data included demographics and psychiatric history. Primary outcomes included measures of cognitive and emotional development (Trails B, Behavior Rating Inventory of Executive Function [BRIEF]), physical development (height and weight), and pubertal status (Tanner Stage). Data were also collected on present/lifetime risk of suicide-related events using the Columbia-Suicide Severity Rating Scale. Results: SPRITES enrolled 941 patients between the ages of 6 and 16 years. Patients' baseline mean age was 11.9 years (2.9), 57.2% were female, and 84.8% were white. Most patients (78.4%) had an anxiety disorder, and 15.6% were diagnosed with obsessive-compulsive disorder. The mean age at onset of first mental illness was 7.9 years. A higher percentage of sertraline-treated patients compared with patients who received no pharmacological treatment received prior psychotherapy (59.0% vs. 34.4%, p < 0.001), psychotropic medications for a psychiatric disorder (14.1% vs. 3.3%, p < 0.001), and other non-sertraline selective serotonin reuptake inhibitors (8.6% vs. 1.2%, p < 0.001). Most patients were moderately ill on the Clinical Global Impressions-Severity scale, and a higher (p < 0.001) percentage of sertraline-treated patients had a moderate-to-severe mental illness score compared with the no pharmacological treatment group (73.0% vs. 57.8%, respectively). Although patients at high and imminent risk of a suicidal event were excluded at study entry, the sertraline-treated patients reported higher levels of lifetime suicidal behavior compared with patients treated with no pharmacological treatment (5.8% vs. 2.5%, p = 0.039). Conclusions: Baseline data from this nonrandomized observational study suggest that patients prescribed sertraline are reflective of a more mentally ill study population compared with patients receiving psychotherapy. ClinicalTrials.gov identifier: NCT01302080.

Examining the psychometric properties of a refined perceived stress scale during the COVID-19 pandemic.

The Perceived Stress Scale (PSS) measures general life stress and the Impact of Events Scale (IES) measures retrospective stress from a specific event; both have been validated across various audiences and settings. However, neither measure stress during an evolving public health crisis. The aim was to refine the PSS to measure stress during an event (e.g. COVID-19 pandemic) and examine its psychometric properties within a 4-year Hispanic-Serving Institution in the Bronx, NY. Three items from the IES were added to and one PSS item was removed from the PSS-10, creating a new PSS-12. Cronbach's α for the scale was 0.902 for faculty and 0.903 for students, indicating high internal consistency. Factor analyses also supported calculation of two subtotals similarly across groups. The PSS-12 is a valid instrument to measure perceived stress during a public health crisis, particularly among populations that already experience community health disparities.

Interchangeability of Biosimilars: What Level of Clinical Evidence is Needed to Support the Interchangeability Designation in the United States?

A biosimilar is a biologic drug that is "highly similar to a reference (originator) product, with no clinically meaningful differences between the two products in safety, purity, and potency". Regulatory approval of a biosimilar is based on analytical, structural, and functional comparisons with the reference product, comparative nonclinical (in vivo) studies, clinical pharmacokinetics and/or pharmacodynamics, and immunogenicity. In addition, comparative clinical efficacy and safety assessments are usually conducted and, taken together, comprise the "totality of the evidence" supporting biosimilarity. For a biosimilar to meet the additional designation of interchangeability in the United States (US), the applicant must demonstrate that the biological drug can be expected to produce the "same clinical result as the reference product in any given patient" and "if the biological drug is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological drug and the reference product is no greater than the risk of using the reference product without such alternation or switch". The challenges faced in conducting clinical studies to support a designation of interchangeability, as defined in the final interchangeability guidance from the US Food and Drug Administration, are considered. Potential alternative approaches to generating adequate and sufficient clinical data to support a designation of interchangeability are also presented.

Effects of Resistance Training on Muscle Size and Strength in Very Elderly Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Effects of resistance training on muscle strength and hypertrophy are well established in adults and younger elderly. However, less is currently known about these effects in the very elderly (i.e., 75 years of age and older). OBJECTIVE: To examine the effects of resistance training on muscle size and strength in very elderly individuals. METHODS: Randomized controlled studies that explored the effects of resistance training in very elderly on muscle strength, handgrip strength, whole-muscle hypertrophy, and/or muscle fiber hypertrophy were included in the review. Meta-analyses of effect sizes (ESs) were used to analyze the data. RESULTS: Twenty-two studies were included in the review. The meta-analysis found a significant effect of resistance training on muscle strength in the very elderly [difference in ES = 0.97; 95% confidence interval (CI) 0.50, 1.44; p = 0.001]. In a subgroup analysis that included only the oldest-old participants (80 + years of age), there was a significant effect of resistance training on muscle strength (difference in ES = 1.28; 95% CI 0.28, 2.29; p = 0.020). For handgrip strength, we found no significant difference between resistance training and control groups (difference in ES = 0.26; 95% CI - 0.02, 0.54; p = 0.064). For whole-muscle hypertrophy, there was a significant effect of resistance training in the very elderly (difference in ES = 0 30; 95% CI 0.10, 0.50; p = 0.013). We found no significant difference in muscle fiber hypertrophy between resistance training and control groups (difference in ES = 0.33; 95% CI - 0.67, 1.33; p = 0.266). There were minimal reports of adverse events associated with the training programs in the included studies. CONCLUSIONS: We found that very elderly can increase muscle strength and muscle size by participating in resistance training programs. Resistance training was found to be an effective way to improve muscle strength even among the oldest-old.

The influence of sociodemographic factors on trauma center transport for severely injured older adults.

OBJECTIVE: To examine sociodemographic predictors of trauma center (TC) transport of severely injured older adults. DATA SOURCES: The data source was the Healthcare Cost and Utilization Project, New York Inpatient Database (2014). STUDY DESIGN: This study was a secondary analysis of injured older adults. Key sociodemographic variables were age, gender, race/ethnicity, median household income, and primary payer. Confounding variables were injury severity, geographic location, number of chronic conditions, and injury mechanism. The outcome variable was TC transport. DATA COLLECTION/EXTRACTION METHODS: The database was filtered on the following criteria: age =/> 55 years, primary diagnosis of injury (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM], 800.0-957.9, excluding poisoning, late effects, and interfacility transfers), admitted to an acute care hospital in New York. PRINCIPAL FINDINGS: Records of 33 696 patients were included. Multivariate logistic regression analysis revealed that all variables were statistically significant predictors of TC transport except primary payer. Predictors of TC transport were as follows: higher injury severity (OR 2.1, CI 1.79-2.46; 3.39, CI 2.85-4.05); Asian/Pacific and Hispanic race/ethnicity (OR 2.51, CI 1.92-3.27; OR 1.1, CI 0.86-1.42), highest median household income (OR 1.24, CI 1.01-1.52), high population density (OR 1.32, CI 1.12-1.55; OR 3.2, CI 2.68-2.83), and vehicle crashes (OR 3.39, CI 2.79-4.11). Predictors of non-TC transport were as follows: older age groups (OR 0.92, CI 0.76-1.11; OR 0.79, CI 0.64-0.96; OR 0.77, CI 0.63-0.95), females (OR 0.65, CI 0.57-0.74), Black and "other" race (OR 0.75, CI 0.0.56-1.0; OR 0.96, CI 0.77-1.20), lower median household income (OR 0.76, CI 0.62-0.93; OR 0.86, CI 0.71-1.05), low population density (OR 0.96, CI 0.67-1.36; OR 0.89, CI 0.53-1.51), and number of chronic conditions (OR 0.89, CI 0.87-0.91). CONCLUSIONS: Sociodemographic factors are a source of disparity for access to TCs. Further research is needed to confirm bias and test bias reduction strategies. Comprehensive education and policies are needed to reduce disparities in access to trauma care.

An Adjustable Dalteparin Sodium Dose Regimen for the Prevention of Clotting in the Extracorporeal Circuit in Hemodialysis: A Clinical Trial of Safety and Efficacy (the PARROT Study).

BACKGROUND: Dalteparin sodium, a low-molecular-weight heparin, is indicated for prevention of clotting in the extracorporeal circuit during hemodialysis (HD). Product labeling recommends a fixed single-bolus dose of 5000 international units (IU) for HD sessions lasting up to 4 hours, but adjustable dosing may be beneficial in clinical practice. OBJECTIVE: The aim of the PARROT study was to investigate the safety and efficacy of an adjustable dose of dalteparin in patients with end-stage renal disease requiring 3 to 4 HD sessions per week. DESIGN: A 7-week, open-label, multicenter study with a single treatment arm, conducted between October 2013 and March 2016. SETTING: Ten sites in Canada. PATIENTS: A total of 152 patients with end-stage renal disease requiring 3 to 4 HD sessions per week. MEASUREMENTS: The primary outcome was the proportion of HD sessions completed without premature termination due to inadequate anticoagulation. METHODS: All participants initially received a dose of 5000 IU dalteparin, which could be adjusted at subsequent HD sessions when clinically indicated, by increment or decrement of 500 or 1000 IU, with no specified dose limits. RESULTS: Patients were followed for 256 patient-months. Nearly all (99.9%; 95% confidence interval [CI]: 99.7-100) evaluable HD sessions were completed without premature clotting. Dose was adjusted for more than half (52.3%) of participants, mostly owing to clotting or access compression time >10 minutes. Median dalteparin dose was 5000 IU (range: 500-13 000 IU). There were no major bleeds, and minor bleeding was reported in 2.3% of all HD sessions. There was no evidence of bioaccumulation. LIMITATIONS: This short-term study, with a single treatment arm, was designed to optimize dalteparin dose using a flexible dosing schedule; it was not designed to specifically evaluate dalteparin dose minimization, provide a direct comparison of dalteparin versus unfractionated heparin, or provide information on long-term safety for flexible dalteparin dosing. Patients were excluded if they were at high risk of bleeding, including those on anticoagulants and those on antiplatelet agents other than aspirin <100 mg/d. CONCLUSIONS: Overall, an adjustable dalteparin sodium dose regimen allowed safe completion of HD, with clinical benefits over fixed dosing. TRIAL REGISTRATION: ClinicalTrials.gov NCT01879618, registered June 13, 2013.

CONTEXTE: La daltéparine sodique, une héparine de faible poids moléculaire, est indiquée pour prévenir la formation de caillots dans le circuit extracorporel durant l'hémodialyse (HD). Pour une séance de dialyse d'une durée maximale de quatre heures, l'étiquette du produit recommande une dose fixe de 5 000 unités internationales (U.I.) administrée en bolus. Cependant, il est possible qu'il puisse être bénéfique d'ajuster la dose en pratique. OBJECTIF: Le but de l'étude PARROT était d'analyser l'innocuité et l'efficacité d'une dose ajustable de daltéparine chez des patients atteints d'insuffisance rénale terminale (IRT) et nécessitant trois à quatre séances d'HD par semaine. TYPE D'ÉTUDE: Il s'agit d'une étude ouverte et multicentrique à traitement unique d'une durée de sept semaines couvrant la période entre octobre 2013 et mars 2016. CADRE: L'étude a eu lieu dans dix centres de dialyse au Canada. SUJETS: L'étude a inclus 152 patients atteints d'IRT et nécessitant trois à quatre séances d'HD par semaine. MESURES: Le résultat principal était la proportion de séances d'HD complétées, non interrompues de manière prématurée en raison d'une anticoagulation inadéquate. MÉTHODOLOGIE: Tous les participants ont initialement reçu 5000 U.I. de daltéparine, dose qui a pu être ajustée lors des séances subséquentes, lorsqu'indiqué par le contexte clinique, à raison d'augmentation ou de réduction de 500 ou 1 000 U.I., sans spécification quant aux doses limites. RÉSULTATS: Les patients ont été suivis sur une période de 256 mois-patients. Pratiquement toutes les séances d'HD évaluables (99,9 %; IC 95 % : 99,7-100) ont été complétées sans coagulation prématurée. La dose de daltéparine a été ajustée pour plus de la moitié (52,3 %) des participants, essentiellement en raison de coagulation ou d'un besoin de procéder à une compression de l'accès vasculaire au-delà de 10 minutes. La dose médiane de daltéparine était de 5 000 U.I. (entre 500 et 13 000 U.I.). Aucune hémorragie majeure n'a été rapportée, mais une hémorragie mineure est survenue dans 2,3 % de toutes les séances d'HD analysées. Aucune bioaccumulation n'a été détectée. LIMITES: Cette étude de courte durée à traitement unique a été conçue pour optimiser le dosage de daltéparine à l'aide d'un schéma de posologie flexible. Elle ne visait pas à évaluer spécifiquement la minimisation de la dose ou à fournir des informations sur l'innocuité à long terme d'une posologie flexible pour la daltéparine. Également, les patients à haut risque d'hémorragie ont été exclus de l'étude, notamment ceux qui prenaient des anticoagulants ou des antiplaquettaires autres qu'une dose quotidienne de moins de 100 mg d'aspirine. CONCLUSION: Dans l'ensemble, un schéma posologique flexible pour la daltéparine sodique a permis de compléter les séances d'HD de façon sécuritaire, en plus de fournir des avantages cliniques par rapport à une dose fixe.

Efficacy and Safety of a Chewable Methylphenidate Extended-Release Tablet in Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: This phase 3, laboratory classroom study assessed the efficacy and safety of methylphenidate hydrochloride extended-release chewable tablets (MPH ERCT) compared with placebo in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Following a 6-week, open-label, dose-optimization period, children 6-12 years of age (n = 90) with ADHD were randomly assigned to double-blind MPH ERCT at the final optimized dose (20-60 mg/day) or placebo. After 1 week of double-blind treatment, efficacy was assessed predose and 0.75, 2, 4, 8, 10, 12, and 13 hours postdose in a laboratory classroom setting. The primary efficacy measure was the average of postdose Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale-Combined scores, analyzed using a mixed-model, repeated-measures analysis. Secondary efficacy measures included Permanent Product Measure of Performance (PERMP) total number of problems attempted and total number of problems correct. Safety assessments included adverse event (AE) monitoring and the Columbia-Suicide Severity Rating Scale (C-SSRS). RESULTS: MPH ERCT treatment statistically significantly reduced the average of all postdose SKAMP-Combined scores versus placebo (least-squares mean difference [95% confidence interval], -7.0 [-10.9, -3.1]; p < 0.001). Statistically significant treatment differences in SKAMP-Combined scores were observed at 2 hours postdose through 8 hours postdose (p-values <0.001). Statistically significant differences between MPH ERCT and placebo in PERMP total number of problems attempted and total number of problems correct were observed at 0.75 hours postdose through 8 hours postdose (p-values ≤0.049). Common AEs in the open-label period (≥5%) were decreased appetite, upper abdominal pain, mood swings, irritability, insomnia, upper respiratory tract infection (URTI), dysgeusia, and headache; URTI was the only AE reported by >1 subject receiving MPH ERCT in the double-blind period (placebo: URTI, contusion, wound, and initial insomnia). No suicidal ideation or behavior was reported on the C-SSRS at baseline or at any postbaseline assessment. CONCLUSIONS: MPH ERCT 20-60 mg significantly improved ADHD symptoms compared with placebo at 2 hours postdose through at least 8 hours postdose. MPH ERCT was generally safe and well tolerated, with a safety profile consistent with other MPH ER formulations. ClinicalTrials.gov Identifier: NCT01654250. www.clinicaltrials.gov/ct2/show/NCT01654250 .

Impact of Out-of-Pocket Costs on Prescription Fills Among New Initiators of Biologic Therapies for Rheumatoid Arthritis.

BACKGROUND: Biologic disease-modifying antirheumatic drug (DMARD) therapies are a mainstay of treatment for rheumatoid arthritis (RA), yet high member out-of-pocket (OOP) costs for such therapies may limit patient access to these therapies. OBJECTIVE: To understand whether there is a relationship between OOP costs and the initial fill and subsequent refills of biologic DMARD treatments for RA members. METHODS: Members of a national Medicare Advantage and Prescription Drug (MAPD) plan with an adjudicated (paid or reversed) claim for a biologic DMARD indicated for RA were identified from July 1, 2007, to December 31, 2012, and followed retrospectively. The first adjudicated claim date was the index date. Members were required to have 180 days of continuous enrollment pre- and post-index and ≥ 1 diagnosis for RA (ICD-9-CM: 714.0 or 714.2) during pre-index or ≤ 30 days post-index. Low-income subsidy and Medicaid-Medicare dual-eligible patients were excluded. The analysis used multivariate regression models to examine associations between initial prescription (Rx) abandonment rates and OOP costs and factors influencing the refill of a biologic DMARD therapy based on pharmacy claims. RESULTS: The final sample size included 864 MAPD members with an adjudicated claim for a biologic DMARD. The majority were female (77.4%) and mean age was 63.5 years (SD = 10.9). Most (78%) had conventional nonbiologic DMARD utilization during pre-index. The overall initial abandonment rate was 18.2% for biologic DMARDs, ranging from 1.3% for the lowest OOP cost group ($0-$250) to 32.7% for the highest OOP cost group (> $550; P < 0.0001 for Cochran-Armitage trend test). ORs for abandonment rose from 18.4 to 32.7 to 41.2 for OOP costs of $250.01-$400.00, $400.01-$550.00, and > $550.00 respectively, relative to OOP costs of ≤ $250.00 (all P < 0.0001). Meeting the catastrophic coverage limit and utilization of a specialty pharmacy for the index claim were both associated with a decreased likelihood of abandoning therapy (OR = 0.29 and OR = 0.14, respectively; both P < 0.05). Among the subset of 533 members with a paid claim, 82.4% had at least 1 refill post-index. The negative association between OOP cost and likelihood of refilling an Rx was highly significant (P < 0.0001). CONCLUSIONS: This study suggests that the higher the member OOP cost, the less likely an MAPD member is to initiate or refill a biologic DMARD therapy for RA. Further research is needed to understand reasons for initial Rx abandonment and lack of refills, including benefit design and adverse events.

Creative solutions to extraordinary challenges in clinical trials: methodology of a phase III trial of azithromycin and chloroquine fixed-dose combination in pregnant women in Africa.

BACKGROUND: Malaria in pregnancy is one of the most common preventable causes of maternal and neonatal morbidity and mortality in sub-Saharan Africa. To prevent its adverse effects, such as maternal anaemia, placental parasitaemia and low birth weight (LBW) neonates, the World Health Organization recommends effective malaria case management, use of insecticide-treated bed nets and intermittent preventive therapy in pregnancy (IPTp). Sulphadoxine-pyrimethamine (SP) has been the standard for IPTp in several countries, but parasite resistance to SP is growing. Therefore, new IPTp therapies are urgently needed. One candidate being evaluated for IPTp is a fixed-dose combination of azithromycin and chloroquine (AZCQ). This paper describes the challenges and the innovative solutions implemented in designing and conducting a pivotal AZCQ-IPTp trial, sponsored by Pfizer Inc and co-funded by Pfizer Inc and the Medicines for Malaria Venture. METHODS: The AZCQ-IPTp pivotal trial is a multicentre, multicountry, phase III, open-label, randomized superiority study of AZCQ-IPTp versus SP-IPTp in pregnant women of sub-Saharan Africa. The trial was designed to meet stringent regulatory agency scientific advice and IPTp policy makers' recommendations, and incorporates an innovative adaptive design to manage programme risk, maintain the operating characteristics of the study and optimize resources. The trial's novel composite primary endpoint is the proportion of participants with a suboptimal pregnancy outcome (abortion [≤28 weeks], stillbirths [>28 weeks], premature [<37 weeks] deliveries, LBW [<2,500 g] live neonates, missing neonatal birth weight data or loss to follow-up). The study employs a prospective group sequential design with three unblinded analyses when 50%, 70% and 100% of participants achieve the primary endpoint; the study team will remain blinded to the analyses until after the completion of the study. The number of participants randomized will be adaptive, based on the blinded review of the observed pooled primary endpoint data across the two treatment arms, when approximately 1,000 participants complete the primary endpoint assessments. RESULTS: This study is ongoing and expected to complete in 2014. CONCLUSION: This report describes the unique challenges and innovative solutions implemented in designing and conducting this pivotal AZCQ-IPTp trial, which may serve as a prototype for future IPTp and other studies involving similar conditions.

Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease.

BACKGROUND: Recent trials have demonstrated better outcomes with intensive than with moderate statin treatment. Intensive treatment produced greater reductions in both low-density lipoprotein (LDL) cholesterol and C-reactive protein (CRP), suggesting a relationship between these two biomarkers and disease progression. METHODS: We performed intravascular ultrasonography in 502 patients with angiographically documented coronary disease. Patients were randomly assigned to receive moderate treatment (40 mg of pravastatin orally per day) or intensive treatment (80 mg of atorvastatin orally per day). Ultrasonography was repeated after 18 months to measure the progression of atherosclerosis. Lipoprotein and CRP levels were measured at baseline and follow-up. RESULTS: In the group as a whole, the mean LDL cholesterol level was reduced from 150.2 mg per deciliter (3.88 mmol per liter) at baseline to 94.5 mg per deciliter (2.44 mmol per liter) at 18 months (P<0.001), and the geometric mean CRP level decreased from 2.9 to 2.3 mg per liter (P<0.001). The correlation between the reduction in LDL cholesterol levels and that in CRP levels was weak but significant in the group as a whole (r=0.13, P=0.005), but not in either treatment group alone. In univariate analyses, the percent change in the levels of LDL cholesterol, CRP, apolipoprotein B-100, and non-high-density lipoprotein cholesterol were related to the rate of progression of atherosclerosis. After adjustment for the reduction in these lipid levels, the decrease in CRP levels was independently and significantly correlated with the rate of progression. Patients with reductions in both LDL cholesterol and CRP that were greater than the median had significantly slower rates of progression than patients with reductions in both biomarkers that were less than the median (P=0.001). CONCLUSIONS: For patients with coronary artery disease, the reduced rate of progression of atherosclerosis associated with intensive statin treatment, as compared with moderate statin treatment, is significantly related to greater reductions in the levels of both atherogenic lipoproteins and CRP.

Sildenafil citrate for erectile dysfunction in men receiving multiple antihypertensive agents: a randomized controlled trial.

BACKGROUND: Erectile dysfunction (ED) is common among men taking antihypertensive drugs to control blood pressure. We evaluated the safety and efficacy of sildenafil citrate for treating ED in men taking multiple antihypertensive medications in a randomized, double-blind, placebo-controlled trial. METHODS: A total of 568 men (> or =18 years) with ED and hypertension who were taking two or more antihypertensives were randomized to sildenafil (n = 281) or matching placebo (n = 287) for a 6-week double-blind trial followed by a 6-week open-label phase during which all patients received sildenafil. Primary efficacy variables were questions (Q) 3 and 4 (frequency of erections and penetration) of the International Index of Erectile Function (IIEF), and secondary efficacy variables were two global efficacy assessment (GEA) questions regarding improvement in erections and intercourse. RESULTS: A total of 562 men (mean age, 59 years) took > or =1 dose of study drug. At week 6, mean scores on both Q3 and Q4 improved significantly among sildenafil-treated compared with placebo-treated patients. In regard to Q3 and Q4 there were no differences between patients taking two and those taking three or more antihypertensive agents. In all, 71% and 69% of sildenafil-treated patients reported improved erections (GEA1) and intercourse (GEA2) compared with 18% and 20% of placebo-treated patients, respectively. By week 12, >80% of all patients (regardless of initial treatment group) had improved erections and intercourse. During double-blind treatment, 40% of sildenafil-treated and 25% of placebo-treated patients experienced adverse events; fewer than 2% in each group discontinued because of adverse events. CONCLUSIONS: Sildenafil was an effective and well tolerated treatment for ED in men receiving multiple antihypertensives. The results suggest that there were no additional safety risks associated with the use of sildenafil in these patients.

A large, community-based, open-label trial of donepezil in the treatment of Alzheimer's disease.

This phase III trial was conducted to evaluate the safety and efficacy of donepezil in Alzheimer's disease (AD) patients with a greater range of comorbid conditions and concomitant medication use than those previously evaluated in placebo-controlled studies. Patients (n = 1,035) with mild to moderate probable or possible AD were enrolled from 255 sites in the USA; 894 (86%) completed the trial. Mean age was 74.9 years (+/- 7.8); baseline standardized Mini-Mental State Examination (sMMSE) score was 19.77 (+/- 5.4). Nearly all patients had at least 1 prior or comorbid medical condition (97%) or were taking at least 1 concomitant medication (93%). Safety assessments included recording treatment-emergent adverse events (AEs). To confirm comparability with past studies, efficacy was measured using the sMMSE. Over the 12-week study period, the mean sMMSE score increased by 1.54 points over baseline (p < 0.0001) in donepezil-treated patients. Most AEs (64%) were mild, and the occurrence of cholinergic-induced AEs was significantly lower after a dose increase at 4 weeks than that seen with a dose increase after 1 week in previous trials. Risk ratios for gastrointestinal side effects were not significantly increased by the use of aspirin or nonsteroidal anti-inflammatory drugs. Risk ratios for bradycardia were not significantly increased by the use of beta-blockers, nondihydropyridine calcium channel blockers or digoxin. Therefore, donepezil improved cognition, as measured by the sMMSE, and was well tolerated despite high concomitant medication use and extensive comorbidity. These results highlight donepezil as a safe and effective treatment for AD patients typically seen by community-based physicians.

Effectiveness of ipsapirone, a 5-HT-1A partial agonist, in major depressive disorder: support for the role of 5-HT-1A receptors in the mechanism of action of serotonergic antidepressants.

Desensitisation of serotonin 1A (5-HT-1A) receptors is a leading hypothesis for the mechanism of action of antidepressants which block serotonin reuptake. This hypothesis predicts that direct-acting 5-HT-1A agonists should also exhibit anti-depressant properties. Here we report the results of the first large-scale controlled study of the efficacy and tolerability of a 5-HT-1A agonist in outpatients with major depressive disorder (MDD). Three hundred and seventy-three subjects meeting DSM-III-R criteria for MDD participated in this randomised, double-blind comparison of the 5-HT-1A partial agonist ipsapirone (5 mg, 7.5 mg and 10 mg t.i.d.) to placebo t.i.d. Improvement in depressive symptoms relative to placebo, as measured by the Hamilton Depression Rating Scale, occurred in the ipsapirone (7.5 mg t.i.d.) group with a magnitude of effect (D=-2.53 points) that was statistically significant (p=0.010). Adverse events occurred in 76% of the placebo patients and 92% of the ipsapirone patients. A dose-related increase in the incidence of adverse events led to discontinuation of treatment with the 10 mg t.i.d. Results of this study demonstrate that ipsapirone, at a dose of 7.5 mg t.i.d., is an effective antidepressant agent in the treatment of MDD, supporting the hypothesised role of 5-HT-1A receptors in the mechanism of action of serotonin reuptake inhibitors. However, as a potential therapeutic agent for depression, ipsapirone shows only a modest magnitude of drug-placebo differences as well as a side-effect profile less favorable than many of the newer antidepressants.