Additional Months Of Treatment Research Articles

Risk of suicide attempts and intentional self-harm on alprazolam

BackgroundFrom 2000–2021, U.S. suicide deaths have risen 36 %. Identification of pharmacological agents associated with increased suicide risk and safer alternatives may help reduce this trend. MethodsAn exposure-only within-subject time-to-event pharmacoepidemiologic study of the dynamic association between alprazolam treatment and suicide attempts over 2-years. Parallel analyses were conducted for diazepam, lorazepam and buspirone. Data for 2,495,520 patients were obtained from U.S. private insurance medical claims MarketScan from 2010 to 2019. FindingsAlprazolam was associated with over a doubling of risk of suicide attempts (HR=2.21, 95 % CI=2.06,2.38). A duration-response analysis for the modal dose (0.5 mg) revealed a 5 % increase in suicidal events per additional month of treatment (HR=1.05, 95 % CI=1.04,1.07). Parallel analyses with long-acting (diazepam) and short-acting (lorazepam), found similar associations (diazepam HR=2.87, 95 % CI=2.56,3.21; lorazepam HR=1.83, 95 % CI=1.69,2.00), whereas the non-benzodiazepine anxiolytic, buspirone, showed significantly less risk (HR=1.25, 95 % CI=1.13,1.38), and no increased risk in patients with an attempt history (HR=1.05, 95 % CI=0.70,1.59). InterpretationThis study confirmed an earlier signal linking alprazolam to increased suicide attempt risk. The increased risk extends to benzodiazepines in general, regardless of half-life and risk of withdrawal seizure. Buspirone appears to be a safer treatment than benzodiazepines, particularly in patients at increased risk for suicide.

(112) Penile Rehabilitation by Daily Intake of 5 mg Tadalafil for Erectile Dysfunction After Penile Fracture

Abstract Introduction Penile fracture is a rare complication to penile trauma, characterized by a sudden injury of the tunica albuginea of one or both corpora cavernosa of the penis. This commonly occurs during the erect state, when the tunica is thinner and under tension of fully engorged corpora cavernosa. Erectile dysfunction (ED) may occur in up to 12% of these patients due to organic and psychosexual factors including penile fibrosis. Objective This study aimed to assess the potential predictors of erectile dysfunction in patients who had penile fracture repair and the role of rehabilitation course of daily tadalafil 5 mg in management of ED following penile fracture. Methods From January 2022 to February 2023, 25 patients were included. Patients' baseline data as well as history including the time of presentation, the pattern and length of the tunical tear, and the presence of urethral injury, were obtained. After a week, all patients were followed up on and told to resume intercourse after at least two weeks if their wound had epithelialized. Only patients with a complaint of a weak erection, as determined by the Arabic validated version of the international index of erectile function (ArIIEF-5), were started on daily tadalafil 5 mg as a penile rehabilitation for at least one month, or until they regained their normal erection. The Hospital Anxiety and Depression Scale (HADS) was used for assessing patients. Patients with confounding disease as metabolic syndrome or mental illness were eliminated. Results Significant indicators predicting erectile dysfunction, according to the multiple logistic regression model, are the patients' age and the length of the tunical tear. A 1% increase in age was linked with a 73.6% rise in the probability of erectile dysfunction (p = 0.046), and a 1 cm increase in tunical tear length was associated with a 20.04 times increased risk of erectile dysfunction (p = 0.04). With a mean score of 20 on the Arabic-approved version of the internal index of erectile function, 5 of 9 patients with erectile dysfunction (55%) had improved erections after one month of penile rehabilitation, while only 4 of 9 patients (44%) required an additional month of treatment. Conclusions We propose that patients with penile fractur be counselled about erectile dysfunction and begin penile rehabilitation as soon as possible following repair to regain a normal erection. Disclosure No.

Use of direct oral anticoagulants (DOACs) in oncology: A phase IV study on impact of edoxaban treatment in Italian patients with cancer with venous thromboembolism during antineoplastic therapy (EDOI trial, GOIRC 05-2018).

6564 Background: The EDOI Study (EUDRACT 2018-003833-14) was designed to evaluate venous thromboembolism (VTE), a common complication of cancer and cancer therapy. VTE contributes to mortality and morbidity, and may interfere with therapy. When drafting the protocol, the standard treatment for VTE consisted of low-molecular weight heparin followed by vitamin K antagonists. DOACs are as effective as vitamin K antagonists in the treatment of VTE. Edoxaban has been confirmed to be effective and safe in the treatment of VTE. Adverse events (AEs) associated with DOACs can delay or interfere with chemotherapy; to date, data regarding the impact of Edoxaban treatment on cancer treatment AEs are scanty. Methods: In this multicentric, phase IV study, patients receiving an antineoplastic treatment (and candidates for at least 3 additional months of treatment) and diagnosed with VTE, received Edoxaban as per clinical practice. Patients received between 6 and 12 months of Edoxaban and were evaluated at baseline and after 1, 3 and 6 months. Primary endpoint was the impact of Edoxaban-related AEs on antineoplastic therapy, defined as delays/interruptions/reductions due to adverse drug reactions (ADR) related to Edoxaban (bleeding, hepatobiliary toxicity, renal toxicity, anemia, hypersensitivity reactions). As secondary endpoint, we assessed patient-reported outcomes (PROs) during treatment with Edoxaban (health-related quality of life: FACT-G, expectations and satisfaction with anticoagulant treatment: PACT-Q2 and ACTS). For each tool, mean scores at each time point were calculated. Results: One hundred and fifty patients were enrolled, 147 patients were evaluable. The Incidence density rate of antineoplastic therapy delay/interruption/reduction due to ADR related to Edoxaban was 0,8% per person-month (90% CI: [0,4; 1,5%] and 95% CI: [0,4; 1,6%]). For all the patient-reported outcomes, mean scores were maintained at different time points. Conclusions: The results of the study clearly show that the edoxaban treatment is well tolerated and has no relevant impact on the delivery of cancer treatments. Results in terms of quality of life and patients’ satisfaction with anticoagulant treatment are reassuring. Clinical trial information: EUDRACT 2018-003833-14 . [Table: see text]

Effect of treatment with paliperidone palmitate versus oral antipsychotics on frontal lobe intracortical myelin volume in participants with recent-onset schizophrenia: Magnetic resonance imaging results from the DREaM study.

We investigated changes in brain intracortical myelin (ICM) volume in the frontal lobe after 9months of treatment with paliperidone palmitate (PP) compared with 9months of treatment with oral antipsychotics (OAP) in participants with recent-onset schizophrenia or schizophreniform disorder from the Disease Recovery Evaluation and Modification (DREaM) study, a randomized, open-label, delayed-start trial. DREaM included 3 phases: Part I, a 2-month oral run-in; Part II, a 9-month disease progression phase (PP or OAP); and Part III, 9months of additional treatment (participants receiving PP continued PP [PP/PP] and participants receiving OAP were rerandomized to receive either PP [OAP/PP] or OAP [OAP/OAP]). In Part II, magnetic resonance imaging (MRI) and functional and symptomatic assessment was performed at baseline, day 92, and day 260. ICM volume as a fraction of the entire brain volume was quantified by subtraction of a proton density image from an inversion recovery image. Within-treatment-group changes from baseline were assessed by paired t-tests. Analysis of covariance was used to analyze ICM volume changes between treatment groups, adjusting for country. The MRI analysis sample size included 71 DREaM participants (PP, 23; OAP, 48) and 64 healthy controls. At baseline, mean adjusted ICM fraction values did not differ between groups (PP, 0.057; OAP, 0.058, p=0.79). By day 92, the adjusted ICM fraction in the OAP group had decreased significantly (change from baseline, -0.002; p=0.001), whereas the adjusted ICM fraction remained unchanged from baseline in the PP group (0.000; p=0.80). At day 260, the change from baseline in adjusted ICM fraction was -0.004 (p=0.004) in the OAP group and-0.001 (p=0.728) in the PP group. The difference between treatment groups did not reach statistical significance (p=0.147). In participants with recent-onset schizophrenia or schizophreniform disorder, frontal ICM volume was preserved at baseline levels in those treated with PP over 9months. However, a decrease of frontal ICM volume was observed among participants treated with OAPs. clinicaltrials.gov identifier NCT02431702.

Topical 1% cyclosporine eyedrops for the treatment of crystalline corneal dystrophy in dogs.

Crystalline corneal dystrophy (CCD) is the most common type of corneal lipidic deposition in dogs. CCD is a primary metabolic disorder of the corneal fibroblast featuring an accumulation of extracellular and intracellular lipid deposits. Corneal lipid deposits create a corneal opacity and modify the interfibrillar collagen distance, inducing light scattering. Corneal vascularization is not usually associated with the disease, but, in case of chronicity, cell death may produce inflammation, and new corneal vessels are developed. To the best of the authors' knowledge, this is the first report of a medical approach for CCD treatment in veterinary medicine. To evaluate the efficacy of topical 1% cyclosporine eyedrops (1% CsA) for the treatment of CCD in dogs. Medical records of dogs with CCD were retrospectively reviewed (2009-2020). Corneal opacification description (COD) [size (mm), depth, and opacification degree (0-3)] was evaluated at 0, 3, 6, 9, 12, and 15 months postinitial diagnosis. Dogs were classified into three groups: the control group (G0), the group receiving topical 1% CsA once per day (G1), and the group receiving topical 1% CsA twice daily (G2). Ninety-two client-owned dogs (163 eyes) of different breeds, ages, and gender fulfilled the inclusion criteria. When compared to G0, where the eyes significantly increased COD (p < 0.001), G1 and G2 significantly decreased COD (p < 0.001). In fact, the probability of reducing COD was about three times higher in G2 than in G1, being nearly the same for the right [odds ratio (OR) = 2.94; 95% confidence interval (95% CI) = 0.55-15.78] and left eye (OR = 2.92; 95% CI = 0.49-17.26). In addition, for each additional month of treatment in G2, the probability of reducing COD increased significantly (OR = 1.12; 95%CI = 1.00-1.26 for the right eye and OR = 1.16; 95%CI = 1.02-1.32 for the left eye). Long-term treatment with topical 1% CsA eyedrops significantly improved CCD in dogs, being the probability of reducing COD higher when applying the treatment twice daily.

Study finds association between folic acid and reduction in suicide attempts

A cohort study using results from a private health insurance database has found an association between folic acid prescription fills and reduced rates of suicide attempt. An analysis involving individuals taking a 1 mg/day dose of folic acid found a 5% decrease in suicidal event rates for every additional month of treatment.

Evaluation of major treatment failure in patients with recent-onset schizophrenia or schizophreniform disorder: A post hoc analysis from the Disease Recovery Evaluation and Modification (DREaM) study

ObjectiveA post hoc analysis of the Disease Recovery Evaluation and Modification (DREaM) study was conducted to evaluate time to first major treatment failure (ie, arrest/incarceration or psychiatric hospitalization) in participants with recent-onset schizophrenia or schizophreniform disorder treated with paliperidone palmitate (PP) versus oral antipsychotics (OAPs). MethodsDREaM was an open-label, delayed-start, randomized, multipart trial consisting of: Part I, 2-month oral run-in; Part II, 9-month disease progression phase (PP or OAP); and Part III, 9 months of additional treatment (PP/PP; OAP re-randomized: OAP/OAP or OAP/PP). PP/PP and OAP/OAP comprised the 18-month extended disease progression (EDP) analysis. ResultsIn Part II (PP, n = 78; OAP, n = 157), similar proportions of participants experienced a major treatment failure across groups (PP: 12.8 %; OAP: 13.4 %); no difference in time to first major treatment failure was identified (P = 0.918). Significant differences favoring PP emerged after 9 months; in Part III, no participants in the PP/PP group, 3.5 % of participants in the OAP/PP group, and 15.9 % in the OAP/OAP group experienced a major treatment failure (P = 0.002). In the EDP analysis, 10.2 % (PP/PP) and 25.4 % (OAP/OAP) of participants experienced a major treatment failure (P = 0.045; number needed to treat = 6). Safety results were similar between groups and consistent with the known safety profile of PP in adults with schizophrenia. ConclusionsInitiation of PP during the early stages of schizophrenia spectrum disorders significantly delayed time to hospitalization and arrest/incarceration, outcomes with important personal and economic consequences, compared with OAP during this 18-month study.Clinicaltrials.gov identifier: NCT02431702

A Toxic Anterior Segment Syndrome-like Ocular Inflammatory Reaction after COVID-19 Vaccination

Purpose: We report a case with bilateral, ocular inflammatory adverse reactions developing a few hours after COVID-19 vaccination.Case summary: A 70-year-old woman complained of headache and sudden visual impairment (both eyes) a few hours after COVID-19 vaccination (Astrazeneca). She had undergone bilateral cataract surgery 4 days before vaccination and her eyesight was good immediately after surgery. The best-corrected visual acuities (BCVA) were 0.2 and 0.1 in the right and left eyes, respectively. Diffuse corneal edema, anterior chamber reactions, inflammatory fibrinoid membranes on the anterior surfaces of the intraocular lenses (IOLs), and cystoid macular edema were observed in both eyes. The anterior chamber and IOL fibrinoid reactions much improved 7 days after the prescription of topical and oral corticosteroids. The aqueous humor polymerase chain reaction was positive for varicella zoster virus (VZV) in both eyes. The BCVA improved to 20/30 in the right eye and 20/50 in the left eye after 3 months of additional treatment. However, the cystoid macular edema did not improve.Conclusions: In patients with a history of herpes zoster infection, adverse ocular inflammatory reactions associated with VZV may occur immediately after COVID-19 vaccination.

The Disease Recovery Evaluation and Modification (DREaM) study: Effectiveness of paliperidone palmitate versus oral antipsychotics in patients with recent-onset schizophrenia or schizophreniform disorder

We report primary results of the Disease Recovery Evaluation and Modification (DREaM) study, a randomized, open-label, delayed-start trial designed to compare the effectiveness of paliperidone palmitate (PP) versus oral antipsychotics (OAP) in delaying time to first treatment failure (TtFTF) in participants with recent-onset schizophrenia or schizophreniform disorder. DREaM included: Part I, 2-month oral run-in; Part II, 9-month disease progression phase (PP or OAP); Part III, 9 months of additional treatment (PP/PP; OAP rerandomized: OAP/OAP or OAP/PP). PP/PP and OAP/OAP comprised the 18-month extended disease progression (EDP) analysis. A total of 235 participants were randomized to PP (n = 78) or OAP (n = 157) in Part II. No statistically significant differences in TF between treatment groups were identified during Part II (PP 29.5%, OAP 24.8%; P = 0.377), Part III (PP/PP 14.3%, OAP/PP 15.8%, OAP/OAP 28.6%; P = 0.067) or the EDP analysis (PP/PP 28.6%, OAP/OAP 44.4%; NNT = 6; P = 0.080). Using a modified definition of TF excluding treatment supplementation with another antipsychotic, a common approach to managing dose adjustments, significant differences were observed between treatment groups in Part III (PP/PP 4.1%, OAP/PP 14.0%, OAP/OAP 27.0%; P = 0.002) and EDP (PP/PP 14.3%, OAP/OAP 42.9%; P = 0.001). Safety results were consistent with the known safety profile of PP. Although significant treatment differences were not observed during the first 9 months of DREaM, numerical differences favoring PP emerged in the last 9 months and significant differences were observed when TF criteria were limited to their most impactful components. These results highlight the potential benefit of initiating PP early in the course of schizophrenia and provide valuable insights for future clinical trials in recent-onset schizophrenia or schizophreniform disorder. Clinicaltrials.gov identifier: NCT02431702.

A 12-month extension study to evaluate the safety and efficacy of asoprisnil in women with heavy menstrual bleeding and uterine fibroids.

STUDY QUESTIONWhat is the safety and efficacy profile during long-term (12–24 months) uninterrupted treatment with the selective progesterone receptor modulator asoprisnil, 10 and 25 mg in women with heavy menstrual bleeding (HMB) associated with uterine fibroids?SUMMARY ANSWERUninterrupted treatment with asoprisnil should be avoided due to endometrial safety concerns and unknown potential long-term consequences.WHAT IS KNOWN ALREADYAsoprisnil was well tolerated in shorter-term studies and effectively suppressed HMB and reduced fibroid volume.STUDY DESIGN, SIZE, DURATIONWomen with uterine fibroids who had previously received placebo (n = 87) or asoprisnil 10 mg (n = 221) or 25 mg (n = 215) for 12 months in two double-blind studies entered this randomized uncontrolled extension study and received up to 12 additional months of treatment followed by 6 months of post-treatment follow-up. Women who previously received placebo were re-randomized to either asoprisnil 10 or 25 mg for the extension study. This report focuses on the 436 women who received asoprisnil in the double-blind studies and this extension study. Results for women who previously received placebo in the double-blind studies are not described.PARTICIPANTS/MATERIALS, SETTING, METHODSWomen ≥18 years of age who completed a 12-month, double-blind, placebo-controlled study, had estradiol levels indicating that they were not menopausal and had no endometrial hyperplasia or other significant endometrial pathology were eligible. The safety endpoints were focused on endometrial assessments. The composite primary efficacy endpoint was the proportion of women who demonstrated a response to treatment by meeting all three of the following criteria at the final month for participants who prematurely discontinued or at month 12 for those who completed the study: a reduction from initial baseline to final visit of ≥50% in the menstrual pictogram score, hemoglobin concentration ≥11 g/dl or an increase of ≥1 g/dl from initial baseline at the final visit, and no surgical or invasive intervention for uterine fibroids. Other efficacy endpoints included rates for amenorrhea and suppression of bleeding, changes in fibroid and uterine volume and changes in hematologic parameters. No statistical tests were planned or performed for this uncontrolled study.MAIN RESULTS AND ROLE OF CHANCEImaging studies revealed a progressive increase in endometrial thickness and cystic changes that frequently prompted invasive diagnostic procedures. Endometrial biopsy results were consistent with antiproliferative effects of asoprisnil. Two cases of endometrial cancer were diagnosed. At the final month of this extension study (total duration of uninterrupted treatment up to 24 months), the primary efficacy endpoint was achieved in 86 and 92% of women in the asoprisnil 10- and 25-mg groups, respectively. During each month of treatment, amenorrhea was observed in the majority of women (up to 77 and 94% at 10 and 25 mg, respectively). There was a progressive, dose-dependent decrease in the volume of the primary fibroid with asoprisnil 10 and 25 mg (−55.7 and −75.2% median decrease, respectively, from baseline [i.e. the beginning of the placebo-controlled study] to month 12 [cumulative months 12–24] of this extension study). These effects were associated with improvements in quality of life measures.LIMITATIONS, REASONS FOR CAUTIONThis study was uncontrolled, which limits the interpretation of safety and efficacy findings. The study also had multiple protocol amendments with the addition of diagnostic procedures and, because no active comparator was included, the potential place of asoprisnil in comparison to therapies such as GnRH agonists and surgery cannot be determined.WIDER IMPLICATIONS OF THE FINDINGSLong-term, uninterrupted treatment with asoprisnil leads to prominent cystic endometrial changes that are consistent with the ‘late progesterone receptor modulator’ effects, which prompted invasive diagnostic procedures, although treatment efficacy is maintained. Although endometrial cancers were uncommon during both treatment and follow-up, these findings raise concerns regarding endometrial safety during uninterrupted long-term treatment with asoprisnil. This study shows that uninterrupted treatment with asoprisnil should be avoided due to safety concerns and unknown potential long-term consequences.STUDY FUNDING/COMPETING INTEREST(S)AbbVie Inc. (prior sponsor, TAP Pharmaceutical Products Inc.) sponsored the study and contributed to the design and conduct of the study, data management, data analysis, interpretation of the data and the preparation and approval of the manuscript. Financial support for medical writing and editorial assistance was provided by AbbVie Inc. M. P. Diamond received research funding for the conduct of the study paid to the institution and is a consultant to AbbVie. He is a stockholder and board and director member of Advanced Reproductive Care. He has also received funding for study conduct paid to the institution for Bayer and ObsEva. E. A. Stewart participated as a site investigator in the phase 2 study of asoprisnil and served as a consultant to TAP Pharmaceuticals during the time of design and conduct of the studies while on the faculty of Harvard Medical School and Brigham and Women’s Hospital, Boston, MA. In the last 3 years, she has received support from National Institutes of Health grants HD063312, HS023418 and HD074711. She has served as a consultant for AbbVie Inc., Allergan, Bayer HealthCare AG and Myovant for consulting related to uterine leiomyoma and to Welltwigs for consulting related to infertility. She has received royalties from UpToDate and the Med Learning Group. A.R.W. Williams has acted as a consultant for TAP Pharmaceutical Products Inc. and Repros Therapeutics Inc. He has current consultancies with PregLem SA, Gedeon Richter, HRA Pharma and Bayer. B.R. Carr has served as consultant and received research funding from AbbVie Inc. and Synteract (Medicines360). E.R. Myers has served as consultant for AbbVie Inc., Allergan and Bayer. R.A. Feldman received compensation for serving as a principal investigator and participating in the conduct of the trial. W. Elger was a co-inventor of several patents related to asoprisnil.C. Mattia-Goldberg is a former employee of AbbVie Inc. and owns AbbVie stock or stock options. B.M. Schwefel and K. Chwalisz are employees of AbbVie Inc. and own AbbVie stock or stock options.TRIAL REGISTRATION NUMBERNCT00156195 at clinicaltrials.gov.

Changes in the concentration of anti-Leishmania antibodies in saliva of dogs with clinical leishmaniosis after short-term treatment

The aim of this study was to evaluate the possible changes in the concentration of anti-Leishmania antibodies in saliva samples from dogs with clinical leishmaniosis after short-term treatment. Twenty dogs with clinical signs and laboratory abnormalities compatible with canine leishmaniosis (CanL) were diagnosed and treated with a standard antimonial plus allopurinol therapy. The concentration of anti-Leishmania IgG2 and IgA antibodies in saliva was measured at the time of diagnosis (day 0) and after treatment (day 30) by time-resolved immunofluorometric assays (TR-IFMAs) and results were compared with those of serum. In addition, correlations between antibody concentrations in saliva and serum, clinical scores and selected laboratory analytes were calculated. TR-IFMA results were expressed as Units of Fluorometry for Leishmania (UFL). Most dogs that adequately responded to treatment (n = 17) showed a reduction of anti-Leishmania antibodies in saliva [median IgG2: from 678.0 (day 0) to 201.1 UFL (day 30), p < 0.0001; median IgA: from 91.3 (day 0) to 60.2 UFL (day 30), p < 0.01] in accordance with clinical improvement (p < 0.0001). However, two of these dogs showed an increase of anti-Leishmania antibodies in saliva. Among dogs that did not improve after one month of treatment (n = 3), two showed a reduction in serum and saliva antibodies. In these two dogs, clinical recovery was achieved after one additional month of treatment with allopurinol. The other dog that did not respond to treatment showed increases in the concentration of anti-Leishmania antibodies, both in saliva and serum, and did not adequately respond to an additional month of treatment with allopurinol. From this pilot study, it could be concluded that, despite the low number of dogs used, the measurement of anti-Leishmania IgG2 and IgA antibodies in saliva could have a potential use for treatment monitoring of CanL, provided that a sufficient amount of specific antibodies is present at diagnosis. This is because, especially in the case of IgG2, there is a high correlation between the saliva and serum concentrations, and the reduction of antibodies is generally in accordance with the clinical improvement. Further long-term studies with a larger population should be undertaken to confirm this potential.

Babies Living Safe & Smokefree: randomized controlled trial of a multilevel multimodal behavioral intervention to reduce low-income children\u2019s tobacco smoke exposure

BackgroundAddressing children’s tobacco smoke exposure (TSE) remains a public health priority. However, there is low uptake and ineffectiveness of treatment, particularly in low-income populations that face numerous challenges to smoking behavior change. A multilevel intervention combining system-level health messaging and advice about TSE delivered at community clinics that disseminate the Special Supplemental Nutrition Program for Women, Infants and Children (WIC), combined with nicotine replacement and intensive multimodal, individual-level behavioral intervention may improve TSE control efforts in such high-risk populations.Methods/DesignThis trial uses a randomized two-group design with three measurement points: baseline, 3-month and 12-month follow-up. The primary outcome is bioverified child TSE; the secondary outcome is bioverified maternal quit status. Smoking mothers of children less than 6 years old are recruited from WIC clinics. All participants receive WIC system-level intervention based on the “Ask, Advise, Refer (AAR)” best practices guidelines for pediatrics clinics. It includes training all WIC staff about the importance of maternal tobacco control; and detailing clinics with AAR intervention prompts in routine work flow to remind WIC nutrition counselors to ask all mothers about child TSE, advise about TSE harms and benefits of protection, and refer smokers to cessation services. After receiving the system intervention, mothers are randomized to receive 3 months of additional treatment or an attention control intervention: (1) The multimodal behavioral intervention (MBI) treatment includes telephone counseling sessions about child TSE reduction and smoking cessation, provision of nicotine replacement therapy, a mobile app to support cessation efforts, and multimedia text messages about TSE and smoking cessation; (2) The attention control intervention offers equivalent contact as the MBI and includes nutrition-focused telephone counseling, mobile app, and multimedia text messages about improving nutrition. The control condition also receives a referral to the state smoking cessation quitline.DiscussionThis study tests an innovative community-based, multilevel and integrated multimodal approach to reducing child TSE in a vulnerable, low-income population. The approach is sustainable and has potential for wide reach because WIC can integrate the tobacco intervention prompts into routine workflow and refer smokers to free evidence-based behavioral counseling interventions, such as state quitlines.Trial registrationClinicaltrials.gov NCT02602288. Registered 9 November 2015.

Integrated and Long-Term Safety Analysis of Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Background: Ibrutinib (ibr), a first-in-class, oral once-daily inhibitor of Bruton’s tyrosine kinase, is indicated by the US FDA for the treatment of pts with CLL/SLL and allows for treatment without chemotherapy. Unlike chemotherapy that is given for a finite number of cycles, ibr is continued until progressive disease (PD) or unacceptable toxicity, leading to extended ibr treatment duration in many patients. The objective was to examine safety and tolerability of ibr therapy in pts with treatment-naïve (TN) or relapsed/refractory (R/R) CLL/SLL using an integrated safety analysis approach, and conduct an analysis of long-term safety.Methods: In study PCYC-1112 (RESONATE), pts with R/R CLL/SLL received ibr 420 mg orally once-daily vs. ofatumumab (Byrd, N Engl J Med 2015). In study PCYC-1115 (RESONATE-2), pts age ≥65 years with TN CLL/SLL received ibr 420 mg orally once-daily vs. chlorambucil (Burger, N Engl J Med 2015). Progressing pts could enroll in the extension study PCYC-1116 for next line therapy (including ibr). Data from ibr-treated pts from the above randomized controlled studies were pooled for an integrated safety analysis. In study PCYC-1102, pts with TN or R/R CLL/SLL received ibr 420 mg or 840 mg orally once-daily (Byrd, N Engl J Med 2013; O’Brien, Lancet Oncol 2014). Pts could continue receiving ibr in the long-term extension study PCYC-1103 where adverse event (AE) collection was limited to grade ≥3 AEs, major hemorrhage, or AEs leading to ibr dose modification. Only data from pts treated with ibr 420 mg daily were examined herein.Results: The integrated analysis included 330 pts; 51% Rai III/IV, 54% bulky disease ≥5 cm, 28% del11q, and 37% CrCl <60 mL/min. Pts received ibr for a median of 29.0 mo (max 42.9); 280 (85%) treated for >1 year, 193 (58%) for >2-3 years, and 53 (16%) for >3 years. Concomitant medications included 50% antiplatelet agents, 28% anticoagulants, 3% granulocyte growth factors, and 2% IVIG. The most common AEs were diarrhea (53%) and fatigue (36%). Other AEs experienced by ≥25% of pts were upper respiratory tract infection (30%), nausea (29%), pyrexia (28%), and anemia (27%). Grade ≥3 AEs reported in ≥5% of pts were neutropenia (18%), pneumonia (12%), anemia (7%), and hypertension (HT, 6%). AEs of interest were primarily grade 1/2 (Table). AEs of any grade that led to dose reductions and discontinuation were reported in 13% and 19% of pts, respectively. AEs leading to discontinuation in >1 pt were pneumonia (n=4), anemia (n=3), atrial fibrillation (AFib, n=3), diarrhea (n=2), subdural hematoma (n=2), and thrombocytopenia (n=2). 29 pts died (9%), the most common causes of death were PD (n=8), and pneumonia/lung infection (n=7). In PCYC-1102/1103, 94 pts were treated with ibr for a median of 47.9 mo (max 67.4 mo). The most frequent grade ≥3 AEs were similar to those observed in PCYC-1112 or PCYC-1115/1116, and at times, reflect higher cumulative rates given the median 19 additional months of treatment and follow-up; grade ≥3 AEs reported in ≥5% of pts were hypertension (30%), pneumonia (17%), neutropenia (15%) atrial fibrillation (11%), diarrhea (9%), cellulitis (7%), thrombocytopenia (7%), hyperglycemia (7%), fatigue (6%), decrease in lymphocyte count (6%), and sepsis (5%). Most frequent malignancies included basal cell carcinoma (n=4), squamous cell carcinoma (n=4), and myelodysplastic syndromes (n=2). In 7 of 15 pts, the malignancy AE was diagnosed during the first year, while others occurred over time throughout the ongoing follow-up of >4 years. Overall survival for R/R pts was 74% at 36 mo in PCYC-1112, and 62% at 60 mo in PCYC-1102/1103. Survival of TN pts was 95% at 24 mo in PCYC-1115/1116, and 91% at 60 mo in PCYC-1102/1103 (Kaplan-Meier estimates).Conclusions: In these analyses, which included up to 5 years of follow up in TN and R/R CLL treated with single agent ibr, AEs were primarily grade 1/2 and were manageable with prolonged treatment. [Display omitted] DisclosuresCoutre:Janssen: Consultancy; Pharmacylics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding. Barr:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy. Devereux:Roche: Consultancy, Other: Travel, Accommodations, Expenses ; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; GSK: Consultancy. Robak:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Kipps:Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria. Schuh:Roche: Consultancy, Honoraria; GSK: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Furman:Genentech: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Honoraria; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau. Burger:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Roche: Other: Travel, Accommodations, Expenses; Gilead: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Portola: Consultancy. O’Dwyer:Roche: Other: Travel, accommodations, expenses; Novartis: Consultancy; Glycomimetics: Consultancy; Amgen: Consultancy, Other: Travel, Accommodations, Expenses ; BMS: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Equity Ownership, Honoraria, Research Funding; NUI Galway: Patents & Royalties. Ghia:Abbvie: Consultancy, Honoraria; Adaptive: Consultancy; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding. Valentino:Gilead: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: Travel, accommodations, and expenses; AbbVie: Equity Ownership; Corvus: Equity Ownership; Johnson and Johnson: Equity Ownership, Other: Travel, accommodations, and expenses. Suzuki:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: Leadership; Travel, Accommodations, Expenses. Ninomoto:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment; Amgen: Equity Ownership. James:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. O’Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding.

The VA augmentation and switching treatments for improving depression outcomes (VAST-D) study: Rationale and design considerations

Because two-thirds of patients with Major Depressive Disorder do not achieve remission with their first antidepressant, we designed a trial of three “next-step” strategies: switching to another antidepressant (bupropion-SR) or augmenting the current antidepressant with either another antidepressant (bupropion-SR) or with an atypical antipsychotic (aripiprazole). The study will compare 12-week remission rates and, among those who have at least a partial response, relapse rates for up to 6 months of additional treatment. We review seven key efficacy/effectiveness design decisions in this mixed “efficacy-effectiveness” trial.

P-107 Health-Related Quality of Life in Patients with Ulcerative Colitis Receiving Short- And Long-Term Treatment with Multimatrix Mesalamine

The frequency and severity of ulcerative colitis (UC) symptoms are inversely related to patients' health-related quality of life (HRQL). Thus, treatment that reduces UC symptoms should produce HRQL improvements. This analysis estimated changes in HRQL for patients with UC who received short-term (8 weeks) and long-term (12 months) multimatrix mesalamine treatment. Data were from a completed, open-label, prospective, multi-country trial of adult patients with mild-to-moderate UC (ClinicalTrials.gov ID: NCT01124149). In the acute phase, patients with active UC received 4.8 g/d multimatrix mesalamine once-daily for 8 weeks. Patients in complete or partial remission at Week 8 (with remission status defined using a modified UC-Disease Activity Index) subsequently received 2.4 g/d multimatrix mesalamine once-daily for 12 months. HRQL was assessed at 3 visits: baseline, acute endpoint (Week 8 or early withdrawal visit), and maintenance endpoint (Month 12 or early withdrawal visit). Generic HRQL was measured by the 12-item Short Form health survey (SF-12v2), which captures 8 domains and physical and mental summary scores of HRQL for the preceding 4 weeks. Disease-specific HRQL was measured by the Short Inflammatory Bowel Disease Questionnaire (SIBDQ), which captures 4 domains and an overall summary score of HRQL for the preceding 2 weeks. For both instruments, higher scores indicate better HRQL. Changes in scores from baseline to acute endpoint were examined using paired-samples t-tests and Cohen's effect sizes. Changes in scores across all 3 visits were examined using repeated-measures analysis of variance (ANOVA) models. A post-hoc, exploratory subgroups analysis used mixed-factors ANOVA models to compare changes in scores from acute endpoint to maintenance endpoint between patients still in remission versus those not in remission at maintenance endpoint. All pairwise comparisons tested within ANOVA models used Bonferroni-adjusted P-values. Patients showed statistically significant improvements from baseline to acute endpoint in all SF-12v2 (sample size range [SSR]: 550–562) and SIBDQ (SSR: 462–496) scores (all P < 0.001). Effect sizes for change ranged from 0.41 (physical functioning) to 0.74 (pain) for SF-12v2 domains, and from 0.68 (systemic symptoms) to 1.00 (bowel symptoms) for SIBDQ domains. From acute endpoint to maintenance endpoint, improvements in SF-12v2 scores (SSR: 309–316) were maintained for 6 of 8 domains (all but pain and social functioning) and both summary scores. For SIBDQ scores (SSR: 246–273), improvement in systemic symptoms was maintained, but significant decreases were observed for all other domains, and overall score (P < 0.05). Post-hoc subgroup analyses found that improvements in all SF-12v2 and SIBDQ scores were sustained for patients in remission at maintenance endpoint, while patients not in remission showed significant declines in all scores (all P < 0.001). Patients with active mild-to-moderate UC treated with multimatrix mesalamine for 8 weeks showed significant improvements in all measured aspects of HRQL. Patients who had achieved partial or complete remission at acute endpoint and received 12 additional months of treatment maintained these improvements for most generic HRQL domains but not most disease-specific HRQL domains. Post-hoc analyses found that improvements in HRQL were not maintained for patients who were no longer in remission.

Telbivudine and adefovir combination therapy for patients with chronic lamivudine-resistant hepatitis B virus infections

We evaluated second-line salvage therapy with adefovir + telbivudine (group 1), adefovir followed by adefovir + telbivudine (group 2), or lamivudine + adefovir followed by adefovir + telbivudine (group 3) in hepatitis B patients with an inadequate virologic response to lamivudine treatment. Simple linear regression analysis showed that for each additional month of treatment, the most significant reduction in viral load occurred in group 1 (HBV DNA [Log10 IU/mL]: group 1, −0.149; group 2, -0.081; group 3, −0.123). Generalized estimating equation analysis revealed that compared to group 1, hepatitis B virus (HBV) DNA levels were 1.203 and 0.443 Log10 IU/mL higher in groups 2 and 3, respectively. Overall, a significant reduction in viral load (−0.060 Log10 IU/mL) was observed for each additional month of treatment. Adefovir + telbivudine treatment resulted in a significant reduction in HBV DNA levels. Moreover, telbivudine treatment resulted in a significant reduction in viral load (−0.050 Log10 IU/mL) compared to lamivudine treatment after the emergence of lamivudine resistance.Electronic supplementary materialThe online version of this article (doi:10.1007/s00705-013-1786-4) contains supplementary material, which is available to authorized users.

Glucagon-Like Peptide 1, Insulin, Sensory Neurons, and Diabetic Neuropathy

Like insulin, glucagon-like peptide 1 (GLP-1) may have direct trophic actions on the nervous system, but its potential role in supporting diabetic sensory neurons is uncertain. We identified wide expression of GLP-1 receptors on dorsal root ganglia sensory neurons of diabetic and nondiabetic mice. Exendin-4, a GLP-1 agonist, increased neurite outgrowth of adult sensory neurons in vitro. To determine the effects ofexendin-4 in comparison with continuous low- or high-dose insulin in vivo, we evaluated parallel cohorts of type 1 (streptozotocin-induced) and type 2 (db/db) mice of 2 months' diabetes duration with established neuropathy during an additional month of treatment. High-dose insulin alone reversed hyperglycemia in type 1 diabetic mice, partly reversed thermal sensory loss, improved epidermal innervation but failed to reverse electrophysiological abnormalities. Exendin-4 improved both sensory electrophysiology and behavioral sensory loss. Low-dose insulin was ineffective. In type 2 diabetes, hyperglycemia was uncorrected, and neither insulin nor exendin-4 reversed sensory electrophysiology, sensory behavior, or loss of epidermal axons. However, exendin-4 alone improved motor electrophysiology. Receptor for advanced glycosylated end products and nuclear factor-κB neuronal expression were not significantly altered by diabetes or treatment. Taken together, these results suggest that although GLP-1 agonists and insulin alone are insufficient to reverse all features of diabetic neuropathy, in combination, they might benefit some aspects of established diabetic neuropathy.

Early treatment with, and time receiving, first disease-modifying antirheumatic drug predicts long-term function in patients with inflammatory polyarthritis

ObjectivesTo investigate the influence of early disease-modifying antirheumatic drug (DMARD) treatment on long-term functional outcome in patients with recent-onset inflammatory polyarthritis (IP), and the impact of the duration of first...

Residual Thrombosis on Ultrasonography to Guide the Duration of Anticoagulation in Patients With Deep Venous Thrombosis: A Randomized Trial

Conclusion: Rates of recurrent venous thromboembolism (VTE) in adults with proximal deep venous thrombosis (DVT) can be reduced by tailoring the duration of anticoagulation on the basis of ultrasound findings. Summary: Patients with DVT are known to have an increased risk for recurrent VTE after anticoagulation (JAMA 2005;294:706-15). Anticoagulation is generally prescribed for 3 months for patients with reversible risk factors and for a minimum of 6 months for those patients with permanent risk factors or venous thrombosis (Chest 2008;133:454-5s). An association has been suggested between residual thrombosis present by ultrasound imaging at the time warfarin therapy is discontinued and an increased risk of subsequent recurrent VTE (Ann Intern Med 2002;137:955-60). The authors performed a randomized trial to evaluate the efficacy of tailoring the duration of anticoagulation based on recanalization or persistence of residual venous thrombosis as determined by ultrasound imaging. Patients with the first episode of proximal DVT who completed 3 months of anticoagulation were assigned to receive fixed-duration anticoagulation or flexible ultrasound-guided anticoagulation. This was a randomized, multicenter, open-label trial with independent and blinded assessments of study outcomes. Patients were recruited between January 1999 and July 2003, and the study ended when the last recruited patient had 3 years of follow-up. The study was conducted at nine centers in Italy. In patients assigned to the fixed-duration of anticoagulation, those with unprovoked DVT received 3 additional months of treatment for a total of 6 months, and anticoagulation was discontinued after 3 months in those with secondary DVT. Patients assigned to a flexible-duration of anticoagulation underwent ultrasound imaging after 3 months of anticoagulation. If the veins had recanalized, anticoagulation was discontinued. If the veins had not recanalized, patients were invited to undergo further ultrasound imaging after 3 and 9 months if they had a secondary DVT and to undergo further examinations after 3, 6, 9, 15, and 20 months if they had had an unprovoked DVT. Anticoagulation was discontinued when the veins had recanalized. Patients were monitored for symptomatic recurrent VTE and major bleeding episodes. Of 538 consecutive patients who underwent a 3-month period of anticoagulation, 530 completed the trial. Overall, recurrent VTE developed in 46 of 268 patients (17.2%) allocated to fixed-duration anticoagulation and 32 of the 270 (11.9%) allocated to flexible-duration anticoagulation (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.39-0.99). If patients had unprovoked DVT, the adjusted HR was 0.61 (95% CI, 0.36-1.02). In those with secondary DVT, the HR ratio was 0.81 (95% CI, 0.32-2.06). Major bleeding occurred in 0.7% of patients in the fixed-duration group and in 1.5% in the flexible-duration group (P = .67). Comment: Tailoring the duration of oral anticoagulant therapy based on follow-up ultrasound studies reduced the risk of recurrent VTE by 35% compared with a fixed-duration administration of warfarin therapy. The data also suggest the greatest benefit of flexible-duration warfarin therapy is in those with unprovoked DVT. The major problem in extrapolating these data to clinical practice is the authors' criteria for determining recanalization of a thrombosed vein. Ultrasound criteria for quantifying residual venous thrombosis are not widely used. Their criteria for a recanalized vein were that a vein was <2 mm in diameter with probe compression or <3 mm in diameter on two consecutive examinations. These criteria differ substantially from other criteria used to determine the presence of residual thrombosis after VTE (J Thromb Haemost 2006;4:1919-24). Additional studies will be needed to determine if the authors' approach and, in particular, their method of determining recanalization of a thrombosed vein is medically sound, safe, and cost-effective in routine clinical practice.

Posttreatment Occlusal Variability Among Angle Class I Nonextraction Patients

To test the hypothesis that variability among posttreatment Angle Class I, nonextraction patients is not related to patient and treatment factors. One hundred thirty-eight subjects were randomly selected from the archives of the Department of Orthodontics, St Louis University. Patient factors evaluated included age, sex, mandibular plane angle, and ANB angle; treatment factors included active treatment time and supervising orthodontist. Objective Grading System (OGS) scores for six of the criteria (excluding interproximal contacts and root angulations) and the anterior Bolton ratio were measured on the posttreatment study casts. The partial mean overall OGS score was 24.9 +/- 8.0. Occlusal contact was the most important component contributing to the overall score, followed by alignment. Variation in the OGS scores was explained by sex, pretreatment mandibular plane and ANB angles, the posttreatment anterior Bolton ratio, and treatment duration. The partial overall OGS scores increased by approximately one point for every 4 degrees increase in the mandibular plane angle and nearly one point for every 3 additional months of treatment. Approximately 16% and 15% of the variation in alignment and buccolingual inclination, respectively, was due to the treating orthodontist. Posttreatment occlusal variability among Class I nonextraction patients can be partially explained by patient- and treatment-related factors.