Trial of Anti-BDCA2 Antibody Litifilimab for Systemic Lupus Erythematosus.

BACKGROUND: Antibody-binding of blood dendritic cell antigen 2 (BDCA2), which is expressed exclusively on plasmacytoid dendritic cells, suppresses the production of type I interferon that is involved in the pathogenesis of systemic lupus erythematosus (SLE). The safety and efficacy of subcutaneous litifilimab, a humanized monoclonal antibody that binds to BDCA2, in patients with SLE have not been extensively studied. METHODS: We conducted a phase 2 trial of litifilimab involving participants with SLE. The initial trial design called for randomly assigning participants to receive litifilimab (at a dose of 50, 150, or 450 mg) or placebo administered subcutaneously at weeks 0, 2, 4, 8, 12, 16, and 20, with the primary end point of evaluating cutaneous lupus activity. The trial design was subsequently modified; adults with SLE, arthritis, and active skin disease were randomly assigned to receive either litifilimab at a dose of 450 mg or placebo. The revised primary end point was the change from baseline in the total number of active joints (defined as the sum of the swollen joints and the tender joints) at week 24. Secondary end points were changes in cutaneous and global disease activity. Safety was also assessed. RESULTS: A total of 334 adults were assessed for eligibility, and 132 underwent randomization (64 were assigned to receive 450-mg litifilimab, 6 to receive 150-mg litifilimab, 6 to receive 50-mg litifilimab, and 56 to receive placebo). The primary analysis was conducted in the 102 participants who had received 450-mg litifilimab or placebo and had at least four tender and at least four swollen joints. The mean (±SD) baseline number of active joints was 19.0±8.4 in the litifilimab group and 21.6±8.5 in the placebo group. The least-squares mean (±SE) change from baseline to week 24 in the total number of active joints was -15.0±1.2 with litifilimab and -11.6±1.3 with placebo (mean difference, -3.4; 95% confidence interval, -6.7 to -0.2; P = 0.04). Most of the secondary end points did not support the results of the analysis of the primary end point. Receipt of litifilimab was associated with adverse events, including two cases of herpes zoster and one case of herpes keratitis. CONCLUSIONS: In a phase 2 trial involving participants with SLE, litifilimab was associated with a greater reduction from baseline in the number of swollen and tender joints than placebo over a period of 24 weeks. Longer and larger trials are required to determine the safety and efficacy of litifilimab for the treatment of SLE. (Funded by Biogen; LILAC ClinicalTrials.gov number, NCT02847598.).

Trial of Anti-BDCA2 Antibody Litifilimab for Cutaneous Lupus Erythematosus.

BACKGROUND: Blood dendritic cell antigen 2 (BDCA2) is a receptor that is exclusively expressed on plasmacytoid dendritic cells, which are implicated in the pathogenesis of lupus erythematosus. Whether treatment with litifilimab, a humanized monoclonal antibody against BDCA2, would be efficacious in reducing disease activity in patients with cutaneous lupus erythematosus has not been extensively studied. METHODS: In this phase 2 trial, we randomly assigned adults with histologically confirmed cutaneous lupus erythematosus with or without systemic manifestations in a 1:1:1:1 ratio to receive subcutaneous litifilimab (at a dose of 50, 150, or 450 mg) or placebo at weeks 0, 2, 4, 8, and 12. We used a dose-response model to assess whether there was a response across the four groups on the basis of the primary end point, which was the percent change from baseline to 16 weeks in the Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity score (CLASI-A; scores range from 0 to 70, with higher scores indicating more widespread or severe skin involvement). Safety was also assessed. RESULTS: A total of 132 participants were enrolled; 26 were assigned to the 50-mg litifilimab group, 25 to the 150-mg litifilimab group, 48 to the 450-mg litifilimab group, and 33 to the placebo group. Mean CLASI-A scores for the groups at baseline were 15.2, 18.4, 16.5, and 16.5, respectively. The difference from placebo in the change from baseline in CLASI-A score at week 16 was -24.3 percentage points (95% confidence interval [CI] -43.7 to -4.9) in the 50-mg litifilimab group, -33.4 percentage points (95% CI, -52.7 to -14.1) in the 150-mg group, and -28.0 percentage points (95% CI, -44.6 to -11.4) in the 450-mg group. The least squares mean changes were used in the primary analysis of a best-fitting dose-response model across the three drug-dose levels and placebo, which showed a significant effect. Most of the secondary end points did not support the results of the primary analysis. Litifilimab was associated with three cases each of hypersensitivity and oral herpes infection and one case of herpes zoster infection. One case of herpes zoster meningitis occurred 4 months after the participant received the last dose of litifilimab. CONCLUSIONS: In a phase 2 trial involving participants with cutaneous lupus erythematosus, treatment with litifilimab was superior to placebo with regard to a measure of skin disease activity over a period of 16 weeks. Larger and longer trials are needed to determine the effect and safety of litifilimab for the treatment of cutaneous lupus erythematosus. (Funded by Biogen; LILAC ClinicalTrials.gov number, NCT02847598.).

Cross-recurrence analysis for pattern matching of multidimensional physiological signals.

Cross-recurrence quantification analysis (CRQA), based on the cross-recurrence plot (CRP), is an effective method to characterize and quantify the nonlinear interrelationships between a pair of nonlinear time series. It allows the flexibility of reconstructing signals in the phase space and to identify different types of patterns at arbitrary positions between trajectories. These advantages make CRQA attractive for time series data mining tasks, which have been of recent interest in the literature. However, little has been done to exploit CRQA for pattern matching of multidimensional, especially spatiotemporal, physiological signals. In this paper, we present a novel methodology in which CRQA statistics serve as measures of dissimilarity between pairs of signals and are subsequently used to uncover clusters within the data. This methodology is evaluated on a real dataset consisting of 3D spatiotemporal vectorcardiogram (VCG) signals from healthy and diseased patients. Experimental results show that Lmax, the length of the longest diagonal line in the CRP, yields the best-performing clustering that almost exactly matches the ground truth diagnoses of patients. Results also show that our proposed measure, Rτ max, which characterizes the maximum similarity between signals over all pairwise time-delayed alignments, outperforms all other tested CRQA measures (in terms of matching the ground truth) when the VCG signals are rescaled to reduce the effects of signal amplitude.

Investigating patient engagement associations between a postdischarge texting programme and patient experience, readmission and revisit rates outcomes.

OBJECTIVES: This study aimed (1) to examine the association between patient engagement with a bidirectional, semiautomated postdischarge texting programme and Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey outcomes, readmissions and revisit rates in a large health system and (2) to describe operational and clinical flow considerations for implementing a postdischarge texting programme. SETTING: The study involved 1 main academic hospital (beds: 2500+) and 6 community hospitals (beds: 190-400, averaging 300 beds per hospital) in Houston, Texas. METHODS: Retrospective, observational cohort study between non-engaged patients (responded with 0-2 incoming text messages) and engaged patients (responded with 3+ incoming, patient-initiated text messages) between December 2022 and May 2023. We used the two-tailed t-test for continuous variables and χ2 test for categorical variables to compare the baseline characteristics between the two cohorts. For the binary outcomes, such as the revisit (1=yes, vs 0=no) and readmissions (1=yes vs 0=no), we constructed mixed effect logistic regression models with the random effects to account for repeated measurements from the hospitals. For the continuous outcome, such as the case mix index (CMI), a generalised linear quantile mixed effect model was built. All tests for significance were two tailed, using an alpha level of 0.05, and 95% CIs were provided. Significance tests were performed to evaluate the CMI and readmissions and revisit rates. RESULTS: From 78 883 patients who were contacted over the course of this pilot implementation, 49 222 (62.4%) responded, with 39 442 (50%) responded with 3+ incoming text messages. The engaged cohort had higher HCAHPS scores in all domains compared with the non-engaged cohort. The engaged cohort used significantly fewer 30-day acute care resources, experiencing 29% fewer overall readmissions and 20% fewer revisit rates (23% less likely to revisit) and were 27% less likely to be readmitted. The results were statistically significant for all but two hospitals. CONCLUSIONS: This study builds on the few postdischarge texting studies, and also builds on the patient engagement literature, finding that patient engagement with postdischarge texting can be associated with fewer acute care resources. To our knowledge, this is the only study that documented an association between a text-based postdischarge programme and HCAHPS scores, perhaps owing to the bidirectionality and ease with which patients could interact with nurses. Future research should explore the texting paradigms to evaluate their associated outcomes in a variety of postdischarge applications.

Development of a Visit Facilitator Role to Assist Physicians in an Ambulatory Consultative Medical Practice.

Objective: To decrease the electronic health record (EHR) clerical burden and improve patient/clinician satisfaction, allied health staff were trained as visit facilitators (VFs) to assist the physician in clinical and administrative tasks. Patients and Methods: From December 7, 2020, to October 11, 2021, patients with complex medical conditions were evaluated by an internal medicine physician in an outpatient general internal medicine (GIM) consultative practice at a tertiary care institution. A VF assisted with specific tasks before, during, and after the clinical visit. Presurvey and postsurvey assessments were performed to understand the effect of the VF on clinical tasks as perceived by the physician. Results: A total of 57 GIM physicians used a VF, and 41 (82%) physicians and 39 (79%) physicians completed the pre-VF and post-VF surveys, respectively. Physicians reported a significant reduction in time reviewing outside materials, updating pertinent information, and creating/modifying EHR orders (P<.05). Clinicians reported improved interactions with patients and on-time completion of clinical documentation. In the pre-VF survey, "too much time spent" was the most common response for reviewing outside material, placing/modifying orders, completing documentation/clinical notes, resolving in-baskets, completing dismissal letters, and completing tasks outside of work hours. In the post-VF survey, "too much time spent" was not the most common answer to any question. Satisfaction improved in all areas (P<.05). Conclusion: VFs significantly reduced the EHR clinical burden and improved GIM physician practice satisfaction. This model can potentially be used in a wide range of medical practices.

Feasibility study on elimination of all oral opioids following bariatric surgery.

BACKGROUND: The bariatric population is at increased risk for developing chronic opioid dependence. The practice of prescribing oral opioids for analgesia in postoperative ambulatory settings is a known risk factor for developing chronic opioid dependence. The use of oral opioids following minimally invasive bariatric surgery may not be necessary. OBJECTIVES: To determine whether there is any measurable impact on patient care metrics (length of stay, inpatient delta pain score, 30-day emergency department presentations, and 30-day readmissions) when eliminating the use of oral opioids for postoperative analgesia following laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (SG). SETTING: Retrospective cohort study of data collected at a single bariatric center. METHODS: A cohort of 189 consecutive patients received oral opioids in the immediate postoperative setting, in addition to a prescription for oral opioids at the time of discharge following LRYGB and SG. A second cohort of 136 consecutive patients did not receive oral opioids at any point following surgery. A descriptive bivariate analysis was performed to examine the relationships between cohort characteristics and treatment type. A multivariable linear regression analysis and a logistic regression analysis were conducted to assess the association of treatment type with clinical outcomes of interest. RESULTS: The oral opioid-free cohort received significantly fewer morphine milligram equivalents during their postoperative hospital admission (P < .001). There were no differences in lengths of stay, 30-day emergency department presentations, or 30-day readmissions. Patients in the oral opioid-free cohort reported lower average delta pain scores (P < .001). CONCLUSION: Eliminating the use of oral opioids for analgesia following LRYGB and SG does not negatively impact patient care metrics and may improve patient-reported analgesia, as reflected by a significant difference in delta pain scores averages. Elimination of oral opioids from all postoperative analgesia regimens is feasible.

The effect of pain on outcomes in a trial of duloxetine treatment of major depressive disorder.

BACKGROUND: Patients with major depressive disorder (MDD) frequently report one or more pain symptoms. To explore the relationship between improvement in pain symptoms and MDD treatment outcomes, we conducted a secondary analysis of an approximately 12-week, open label trial of duloxetine in MDD. The primary objective was to test the hypothesis that a greater reduction in pain was associated with a higher probability of MDD remission. METHODS: Adults with DSM-IV MDD were enrolled in the study if they had a Hamilton Depression Scale (HAMD-17) total score of 15 or more and a Clinical Global Impression of Severity (CGI-S) score of 4 or more. The duloxetine dose of patients could be titrated on the basis of the degree of response within the range from 60 to 120 mg given QD, with 90 mg QD as an intermediate dose. Remission of major depressive disorder was defined as a HAMD-17 total score of < or = 7. Core emotional symptoms of depression were determined by the HAMD-17 Maier subscale. Pain was assessed using a 100 mm visual analog scale (VAS) of overall pain severity over the last week (0 = no pain, 100 = pain as severe as I can imagine). For the primary analysis, mean change in VAS overall pain score over time was compared between remitters and non-remitters at endpoint using a mixed model repeated measures approach. RESULTS: Two hundred forty nine patients were included in the analysis. A greater reduction in pain was associated with a significantly higher probability of remission of MDD, after accounting for changes in the core emotional symptoms. Greater pain reduction was associated with significant improvement in MDD core emotional symptoms. A greater improvement in pain was also associated with improvements in patient and clinician-rated global assessments. CONCLUSIONS: The effective treatment of pain symptoms in patients with major depressive disorder was associated with higher remission rates. The results underscore the importance of effectively treating painful symptoms associated with depression.

The significance of treating somatic symptoms on functional outcome improvement in patients with major depressive disorder: a post hoc analysis of 2 trials.

BACKGROUND: Functional impairment is associated with major depressive disorder (MDD), and patients with MDD often present with somatic symptoms. OBJECTIVE: To examine the relationships between improved global functioning and core depressive symptoms as well as painful and nonpainful somatic symptoms in patients with MDD. METHOD: This post hoc analysis of 2 identical trials compared the efficacy of duloxetine with that of paroxetine or placebo as treatment of MDD. In the trials, patients with DSM-IV-defined MDD received duloxetine 80 mg/day (N = 188), duloxetine 120 mg/day (N = 196), paroxetine 20 mg/day (N = 183), or placebo (N = 192) for 8 weeks. The Sheehan Disability Scale (SDS), Maier subscale of the 17-item Hamilton Rating Scale for Depression, 21-item Somatic Symptom Inventory, and Visual Analog Scale for overall pain were used to measure functional impairment, core symptoms of depression, and nonpainful and painful somatic symptoms, respectively. Baseline-to-endpoint mean changes in SDS total and subdomains were measured using analysis of variance with last-observation-carried-forward Pearson partial correlations, and path analysis was used to assess the significance of associations and relative contributions of improvement in global functional impairment, depression, and somatic symptoms. The trials were conducted from November 2000 to July 2002. RESULTS: The difference between antidepressant treatment and placebo in SDS total and subdomains was significant (p < .001). At baseline and in change from baseline to endpoint, associations between global functional impairment and core depressive and somatic symptoms were all significant (p < .05). Path analysis demonstrated improvement of functional impairment attributed to treatment effect as 37.0% (core depressive symptoms), 13.0% (nonpainful somatic symptoms), and 11.0% (painful somatic symptoms). CONCLUSION: In patients with MDD, over a third of functional improvement associated with antidepressant therapy was mediated through improvement in core depressive symptoms. In addition, a significant proportion of functional improvement, although to a lesser degree, was associated with the treatment of both nonpainful and painful somatic symptoms.

Reduced suicidal ideation in bipolar I disorder mixed-episode patients in a placebo-controlled trial of olanzapine combined with lithium or divalproex.

OBJECTIVE: To identify symptoms associated with suicidality in bipolar I disorder patients, and to assess suicide risk during treatment with olan-zapine in combination with lithium or divalproex. METHOD: We used data from a study (conducted from September 1997 to October 2000) in which DSM-IV bipolar I manic or mixed-episode patients who were partially responsive to at least 2 weeks of lithium or dival-proex monotherapy prior to study entry were randomly assigned to augmentation therapy with olanzapine (5-20 mg/day) or placebo. Among mixed-episode patients with residual suicidality (Hamilton Rating Scale for Depression-item 3 [HAM-D-3] score of 1 or above) at randomization to cotherapy, we identified items in the Young Mania Rating Scale, Positive and Negative Syndrome Scale, and Barnes Akathisia Rating Scale that correlated with HAM-D-3 scores. We used factor analysis of correlated items to identify symptom domains associated with suicidality ratings and assessed changes in symptom factors and HAM-D-3 scores during 6 weeks of combination therapy with olanzapine versus placebo. RESULTS: In 58 mixed-episode patients, mean +/- SD HAM-D-3 scores averaged 1.36 +/- 0.55 after at least 2 weeks of initial mood stabilizer monotherapy prior to study entry. Factors associated with the HAM-D-3 appeared to represent somatic discomfort, agitated depression, and psychotic features. Combination therapy with olanzapine (N = 36) versus placebo (N = 22) differentially reduced HAM-D-3 scores by 58% versus 29% (p < .05) within 1 week, and all 3 associated symptom factors within 2 weeks by averages of 31% versus 12% (p < .05). CONCLUSIONS: Suicidality in adult, mixed-episode, bipolar I disorder patients was associated with somatic discomfort, agitated depression, and psychosis. Overall, these findings suggest that the addition of an atypical antipsychotic-antimanic agent in some bipolar disorder patients may help to reduce suicidal ideation.

Differential efficacy of olanzapine and lithium in preventing manic or mixed recurrence in patients with bipolar I disorder based on number of previous manic or mixed episodes.

INTRODUCTION: Bipolar disorder outcome worsens as number of manic episodes increases, suggesting that prevention of recurrent episodes early during the disorder could improve patient prognosis. We investigated treatment efficacy in prevention of mood episodes in patients subgrouped by number of prior manic episodes. METHOD: This study was a post hoc analysis of data from a multicenter, double-blind, 12-month clinical trial of relapse/recurrence in 431 initially euthymic patients with at least 2 prior manic/ mixed episodes and a DSM-IV diagnosis of bipolar I disorder randomly assigned to olanzapine (5-20 mg/day) or lithium (serum concentration 0.6 to 1.2 mEq/L). Data were collected between August 1999 and June 2002. Patients were subcategorized by illness stage according to number of prior manic/mixed episodes-early stage: 2 prior episodes (N = 53, lithium; N = 48, olanzapine), intermediate stage: 3 to 5 prior episodes (N = 80, lithium; N = 98, olanzapine), and later stage: more than 5 prior episodes (N = 81, lithium; N = 71, olanzapine)-and were evaluated for rates of relapse/recurrence. RESULTS: There were significant effects for treatment (p < .001) and illness stage (p = .006) but no significant interaction (p = .107) on rate of manic/mixed relapse/recurrence. Rates of manic/ mixed relapse/recurrence for olanzapine versus lithium were 2.1% versus 26.4% (p = .008), 13.3% versus 23.8% (p = .073), and 23.9% versus 33.3% (p = .204) for early-, intermediate-, and later-stage groups, respectively. There was no significant effect for treatment (p = .096) or illness stage (p = .731) for depressive relapse/recurrence. CONCLUSIONS: Early-stage (but not intermediate-or later-stage) patients had a significantly lower rate of relapse/recurrence of manic/mixed episodes with olanzapine compared to lithium. Thus, olanzapine maintenance therapy may be particularly effective early in the course of bipolar illness.

Wellness intervention for patients with serious and persistent mental illness.

INTRODUCTION: Weight gain and obesity that emerge during psychopharmacologic treatment are prevalent in persons with serious and persistent mental illness. Obesity is difficult to reverse, but behavioral programs involving diet and exercise are sometimes successful. METHOD: Patients with serious and persistent mental illness living in the community were enrolled voluntarily into the Solutions for Wellness Personalized Program. Participants completed an enrollment survey that provided information for the creation of an individualized management plan that included nutrition, exercise, stress management, and sleep improvement components. Weight, body mass index (BMI, kg/m(2)), behavior, and attitudes were assessed at baseline (enrollment) and monthly for 6 months. RESULTS: During the period of July 1, 2002, through June 30, 2003, 7188 patients with serious and persistent mental illness had enrolled in the program, and 83% were either overweight or obese. Follow-up survey responses taken at 6-month endpoint from finishers (N = 1422) indicated that positive changes were made in diet (91%), exercise (85%), reduced stress (93.8%), and sleep (92.9%). Significant decreases in BMI were associated with changes in diet (p = .014) and exercise (p = .035). In addition, 97% of participants reported that they were at least somewhat confident in the ability to maintain lifestyle changes, and this confidence was significantly (p < .001) associated with reaching dietary and exercise goals. CONCLUSIONS: Patients suffering from serious and persistent mental illness may benefit from participating in wellness intervention programs.

A post hoc analysis of transitioning to oral treatment with olanzapine or haloperidol after 24-hour intramuscular treatment in acutely agitated adult patients with schizophrenia.

BACKGROUND: Acutely agitated patients with schizophrenia might require treatment with IM antipsychotics, followed by a transition to oral medication. OBJECTIVE: The aim of this study was to assess the relationship between 24-hour IM and transitional oral dosages of 2 antipsychotic medications, olanzapine and haloperidol. METHODS: This post hoc analysis used data from a multinational, double-blind, randomized, placebo-controlled study comparing the efficacy of olanzapine, haloperidol, and placebo in acutely agitated inpatients aged > or =18 years with schizophrenia conducted at hospitals in 13 countries. Patients received 1 to 3 IM injections of olanzapine 10 mg or haloperidol 7.5 mg over 24 hours (IM phase), followed by 4 days of oral treatment with 5 to 20 mg/d of either antipsychotic (oral phase). Study patients were grouped according to which drug they received, and subgrouped based on whether they received a single or multiple IM injections. Rates of transition to lower (5-10 mg/d) versus higher (15-20 mg/d) dosages were compared within and between treatments. RESULTS: Data from 236 patients were analyzed (olanzapine, 121 patients [76 men, 45 women; mean (SD) age, 38.4 (12.2) years; mean (SD) weight, 74.9 (18.5) kg]; haloperidol, 115 patients [80 men, 35 women; mean (SD) age, 38.0 (10.2) years; mean (SD) weight, 75.4 (18.7) kg]). At the end of the IM phase, the rate of haloperidol patients who were transitioned to lower oral doses was significantly higher in the single-injection subgroup compared with the multiple-injection subgroup (P = 0.03); this difference was not found in the group receiving olanzapine. At day 4 of oral treatment, the rates of patients in the olanzapine and haloperidol groups who were transitioned to higher oral doses were significantly higher in the single-injection subgroups compared with the multiple-injection subgroups (P = 0.002 and =0.003, respectively). CONCLUSION: In this study, the proportion of agitated patients with schizophrenia who transitioned to higher dosages (15-20 mg) of olanzapine or haloperidol by day 4 of the oral switch was significantly greater in patients who were previously treated with a single IM injection of olanzapine (10 mg) or haloperidol (7.5 mg).right.

Microsphere lithography on hydrophobic surfaces for generating gold films that exhibit infrared localized surface plasmon resonances.

Evaporation induced self-assembly is an established method for producing close-packed two-dimensional sphere masks on hydrophilic surfaces such as glass. In sphere lithography, gold or silver is deposited over sphere masks to generate a film-over-nanospheres or a nanoprism array that can be used as a sensing surface in localized surface plasmon extinction and surface enhanced Raman spectroscopy experiments. Sphere lithography is less commonly used to prepare sphere masks on hydrophobic surfaces associated with infrared window materials, in part because it is challenging to find solvents with wetting and evaporation characteristics that are appropriate for such surfaces. This wetting challenge can be overcome with appropriate surfactants. However, surfactant residues are then left behind on the sensing surface. We report methods for depositing monolayer crystalline sphere masks onto CaF2 windows that minimize surfactant residue by either using ethanol as a volatile cosolvent that enhances wetting, or by increasing the concentration of colloid to compensate for the reduced attractions between spheres and surface. The rate of evaporation of solvents from the colloid drop is controlled by fixing the headspace partial pressure of ethanol and/or water.

Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial.

BACKGROUND: In a phase 2 study, dexpramipexole (25-150 mg twice daily) was well tolerated for up to 9 months and showed a significant benefit at the high dose in a combined assessment of function and mortality in patients with amyotrophic lateral sclerosis. We aimed to assess efficacy and safety of dexpramipexole in a phase 3 trial of patients with familial or sporadic disease. METHODS: In our randomised, double-blind, placebo-controlled phase 3 trial (EMPOWER), we enrolled participants aged 18-80 years (with first amyotrophic lateral sclerosis symptom onset 24 months or less before baseline) at 81 academic medical centres in 11 countries. We randomly allocated eligible participants (1:1) with a centralised voice-interactive online system to twice-daily dexpramipexole 150 mg or matched placebo for 12-18 months, stratified by trial site, area of disease onset (bulbar vs other areas), and previous use of riluzole. The primary endpoint was the combined assessment of function and survival (CAFS) score, based on changes in amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) total scores and time to death up to 12 months. We assessed the primary endpoint in all participants who received at least one dose and had at least one post-dose ALSFRS-R measurement or died. We monitored adverse events in all participants. This study is registered with ClinicalTrials.gov, number NCT01281189. FINDINGS: Between March 28, 2011, and Sept 30, 2011, we enrolled 943 participants (474 randomly allocated dexpramipexole, 468 randomly allocated placebo, and one withdrew). Least-square mean CAFS scores at 12 months did not differ between participants in the dexpramipexole group (score 441·76, 95% CI 415·43-468·08) and those in the placebo group (438·84, 412·81-464·88; p=0·86). At 12 months, we noted no differences in mean change from baseline in ALSFRS-R total score (-13·34 in the dexpramipexole group vs -13·42 in the placebo group; p=0·90) or time to death (74 [16%] vs 79 [17%]; hazard ratio 1·03 [0·75-1·43]; p=0·84). 37 (8%) participants in the dexpramipexole group developed neutropenia compared with eight (2%) participants in the placebo group, and incidence of other adverse events was similar between groups. INTERPRETATION: Dexpramipexole was generally well tolerated but did not differ from placebo on any prespecified efficacy endpoint measurement. Our trial can inform the design of future clinical research strategies in amyotrophic lateral sclerosis. FUNDING: Biogen Idec.

A pragmatic 12-week, randomized trial of duloxetine versus generic selective serotonin-reuptake inhibitors in the treatment of adult outpatients in a moderate-to-severe depressive episode.

Some evidence suggests that medications that modulate both serotonin and norepinephrine may be more effective than selective serotonin-reuptake inhibitors (SSRIs) in severe major depressive disorder (MDD). This prospective pragmatic trial tests this hypothesis. Patients with severe MDD were randomly assigned to either duloxetine (a serotonin and norepinephrine-reuptake inhibitor) or physicians' choice of four generic SSRIs. Nonblinded, flexibly dosed treatment was used to mimic clinical practice. To address potential investigator bias, the patient-reported Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) was used as the primary efficacy outcome measure. A total of 750 outpatients (19.2%, African descent; 14.8%, Hispanic) were randomized. The primary outcome, remission at week 12 by QIDS-SR, was numerically greater for duloxetine compared with SSRIs (36 vs. 32%), but this difference was not statistically significant. Mean changes in secondary outcomes were significantly superior in favor of duloxetine for the Hamilton Depression Scale-17 item, the Brief Pain Inventory, and the Sheehan Disability Scale. Remission superiority on the QIDS-SR was not achieved. Significantly greater benefit for duloxetine compared with SSRIs was demonstrated on measures of pain and functioning. Study demographics suggest a more generalizable racial and ethnic population than is typical in randomized clinical trials.

Altered Toll-like receptor signaling pathways in human type 1 diabetes.

There is compelling evidence from animal models of type 1 diabetes (T1D) that the innate immune system plays a key role in early mechanisms triggering islet destruction. Very little is known, however, about innate immune subsets and pathways potentially involved in mechanisms leading to human T1D. The present study used a comprehensive approach to analyze innate immune functions in primary monocytes and dendritic cells (DCs) from newly diagnosed patients with T1D versus age-matched healthy individuals. We observed that incubation of PBMCs in the presence of the TLR7/8 agonist R848 led to increased proportion of plasmacytoid dendritic cells (pDCs) expressing IFN-α in patients versus healthy control subjects. We also found that TLR4 activation induced a higher frequency of IL-1ß expressing monocytes and a reduction in the percentage of IL-6 expressing myeloid dendritic cells (mDCs). The altered TLR responsiveness was not due to aberrant proportions of peripheral DC subsets and monocytes in the blood and did not correlate with altered hemoglobin A1c and the expression of diabetes susceptibility genes but could potentially be associated with enhanced nuclear factor-kappa B signaling. Finally, we observed that levels of serum IFN-α2, IL-1ß, IFN-γ, and CXCL-10 were elevated in new onset patients versus the control group. Taken together, our observations provide evidence that altered innate immunity exists in mDCs and pDCs from T1D and raise the possibility that these alterations may be associated with disease mechanisms.

Early symptom change prediction of remission in depression treatment.

OBJECTIVES: This study investigated hypothesized early symptom changes as differential predictors of long-term remission for duloxetine and escitalopram. EXPERIMENTAL DESIGN: This was a post-hoc analysis from a placebo-controlled, randomized, double-blind study of patients with major depressive disorder treated for 8 weeks with duloxetine 60 mg/day (N = 273) or escitalopram 10 mg/day (N = 274), and for another 6 months with duloxetine up to 120 mg/day or escitalopram up to 20 mg/day. Odds ratios (ORs) for successful treatment (sustained remission), defined as a 17-item Hamilton Depression Rating Scale (HAMD-17) score 2.0. In a follow-up analysis, specific subscale items for psychological anxiety, motor retardation, and suicidality significantly predicted remission for duloxetine, and psychological and somatic anxiety for escitalopram. Notably, high NPVs on the Maier subscale indicated that a lack of 20% improvement on the "core" depression factor by Week 2 was highly predictive of unsuccessful treatment outcome over 8 months. CONCLUSIONS: In accord with hypotheses, early symptom changes were specific to treatment, with early response in the core depression factor (Maier subscale), anxiety, and motor activity for duloxetine, and core factor and anxiety for escitalopram. Lack of early response in depression symptom subscales was highly predictive of lack of sustained remission.

Safety and efficacy of duloxetine in the treatment of diabetic peripheral neuropathic pain in older patients.

OBJECTIVE: We present a post-hoc analysis of the safety and efficacy of duloxetine, a selective serotonin/norepinephrine reuptake inhibitor, for treatment of diabetic peripheral neuropathic pain (DPNP) in older patients. METHODS: Data from three double-blind, placebo-controlled trials in adult patients with DPNP were pooled and stratified by age (<65, >or=65 years). Patients were randomized to duloxetine (DLX) 60 mg once-daily, 60 mg twice-daily, or placebo for 12 weeks, followed by a 52-week extension phase (re-randomization to routine care or DLX 120 mg/day). Intent-to-treat analyses were used for safety and efficacy assessment. RESULTS: In the acute phase, overall TEAE rates did not differ significantly by age. A greater percentage of older patients discontinued due to TEAEs (P<0.001), regardless of treatment group. Duloxetine improved weekly mean 24-hour average pain scores versus placebo in both age groups (P<0.01). In the extension phase, a significant therapy-by-age interaction (P<0.05) was observed in overall TEAE rate; with routine care, 86.6% of older patients had >or=1 TEAE versus 74.6% of younger patients. CONCLUSIONS: Although TEAEs more frequently lead to discontinuation in older patients, duloxetine was well tolerated and efficacious for treatment of DPNP regardless of age. These data suggest duloxetine may be beneficial for treatment of DPNP in patients>or=65.