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Objective: Effectiveness of antipsychotic drugs is inferred from relatively small randomized clinical trials conducted with carefully selected and monitored participants. This evidence is not necessarily generalizable to individuals treated in daily clinical practice. The authors compared the clinical effectiveness between all oral and long-acting injectable (LAI) antipsychotic medications used in the treatment of schizophrenia in the U.S. Department of Veterans Affairs (VA) health care system.Methods: This was an observational study utilizing VA pharmacy data from 37,368 outpatient veterans with schizophrenia. Outcome measures were all-cause antipsychotic discontinuation and psychiatric hospitalizations. Oral olanzapine was used as the reference group.Results: In multivariable analysis, clozapine (hazard ratio=0.43), aripiprazole long-acting injectable (LAI) (hazard ratio=0.71), paliperidone LAI (hazard ratio=0.76), antipsychotic polypharmacy (hazard ratio=0.77), and risperidone LAI (hazard ratio=0.91) were associated with reduced hazard of discontinuation compared with oral olanzapine. Oral first-generation antipsychotics (hazard ratio=1.16), oral risperidone (hazard ratio=1.15), oral aripiprazole (hazard ratio=1.14), oral ziprasidone (hazard ratio=1.13), and oral quetiapine (hazard ratio=1.11) were significantly associated with an increased risk of discontinuation compared with oral olanzapine. No treatment showed reduced risk of psychiatric hospitalization compared with oral olanzapine; quetiapine was associated with a 36% worse outcome in terms of hospitalizations compared with olanzapine.Conclusions: In a national sample of veterans with schizophrenia, those treated with clozapine, two of the LAI second-generation antipsychotics, and antipsychotic polypharmacy continued the same antipsychotic therapy for a longer period of time compared with the reference drug. This may reflect greater overall acceptability of these medications in clinical practice. [ABSTRACT FROM AUTHOR]

Aim: A growing number of studies suggest a role of neuroinflammation and oxidative stress in the pathophysiology of psychosis. Sulforaphane (SFN), a natural compound extracted from cruciferous vegetables, has shown anti‐inflammatory and anti‐oxidative effects which imply a potential effect on decreasing the risk of psychosis. However, there is no study testing the efficacy of SFN for this purpose. It's necessary to evaluate its efficacy on individuals at clinical high risk (CHR) for psychosis. Methods: This is a randomized, double‐blind, placebo‐controlled, multi‐centre trial. A total of 300 CHR subjects will be identified in the course of face‐to‐face interviews using the Structured Interview for Prodromal Syndromes. All participants will be randomly allocated to SFN group (n = 150) or placebo group (n = 150). The study duration includes an intervention for 52 consecutive weeks, and additional 1‐year follow‐up. Results: The primary outcome is 2‐year conversion rate of psychosis. Secondary outcomes include 1‐year conversion rate of psychosis, the severity and duration of prodromal symptoms, predictive risk of psychosis conversion, neurocognitive functioning and peripheral blood biomarkers of inflammation, oxidative stress and metabolism. Safety monitoring will be performed using scales for side effect, serious adverse events recording, and laboratory tests. Conclusion: This trial is expected to clarify the efficacy of SFN in improving prodromal symptoms, and its role in decreasing the risk and conversion rate of psychosis among CHR subjects. The results will also provide solid evidence about the efficacy and safety of SFN in CHR population. Potential challenges and their solutions in performing the present trial are discussed. [ABSTRACT FROM AUTHOR]

One previous small single-center clinical trial showed that a single intravenous administration of sodium nitroprusside added-on to antipsychotics improved a wide spectrum of schizophrenia (SCZ) symptoms more than placebo, and the improvement persisted for 4 weeks after infusion even though no additional drug was given. Our study attempted to replicate these data in a 4-week, add-on, double-blind, randomized, placebo-controlled trial on 20 patients performed in a site in Romania and a site in Moldova. This study's sample size and protocol were identical to the previous trial, including patients with a diagnosis of SCZ, within the first 5 years after diagnosis. Patients recruited needed to have a baseline total positive and negative syndrome scale (PANSS) score of 60 or above. Ten participants received a single dose of 0.5 µg/ kg/min intravenous sodium nitroprusside over 4 hours, and 10 participants received matching placebo infusion, added-on to antipsychotics. The primary outcomes were the PANSS total score and the PANSS negative subscale. There were no significant between-group differences in PANSS total scores or negative subscale scores during the infusion on daily evaluations for the next 7 days nor on weekly evaluations at weeks 2, 3, and 4. No significant differences were found between the 2 study groups in adverse events. Meta-analyses including all 5 published randomized controlled trials on the topic, representing 155 subjects, do not show a statistically significant benefit of sodium nitroprusside. We conclude that the current evidence does not support the efficacy of sodium nitroprusside in the treatment of SCZ. [ABSTRACT FROM AUTHOR]

Importance: Several lines of evidence suggest that estradiol influences the course of schizophrenia, and a previous randomized controlled trial demonstrated that transdermal estradiol improved symptoms in female patients of childbearing age. However, many initial positive findings in schizophrenia research are not later replicated.Objective: To independently replicate the results of the effect of estradiol on schizophrenia in women of childbearing age.Design, Setting, and Participants: An 8-week randomized, placebo-controlled trial performed in the Republic of Moldova between December 4, 2015, and July 29, 2016, among 200 premenopausal women aged 19 to 46 years with schizophrenia or schizoaffective disorder as defined by the DSM-5.Intervention: Patients were randomized to receive a 200-μg estradiol patch or placebo patch changed twice a week added to their antipsychotic treatment.Main Outcomes and Measures: The primary outcome was the positive subscale of the Positive and Negative Syndrome Scale (PANSS; lower scores indicated fewer symptoms and higher scores indicated more symptoms), analyzed with mixed models for repeated measures on an intention-to-treat basis.Results: A total of 100 women (median age, 38 years; interquartile range, 34-42 years) were randomized to receive an estradiol patch and 100 women (median age, 38 years; interquartile range, 31-41 years) were randomized to receive a placebo patch; the median age at baseline for the entire group of 200 women was 38.0 years (range, 19.5-46.0 years). At baseline, the mean positive PANSS score was 19.6 for both groups combined; at week 8, the mean positive PANSS score was 14.4 in the placebo group and 13.4 in the estradiol group. Compared with placebo, participants receiving add-on estradiol patches had statistically significant improvements in the primary outcome measure, PANSS positive subscale points (-0.94; 95% CI, -1.64 to -0.24; P = .008; effect size = 0.38). Post hoc heterogeneity analyses found that this effect occurred almost entirely in 100 participants older than 38.0 years (46 in placebo group vs 54 in estradiol group; difference, -1.98 points on the PANSS positive subscale; 95% CI, -2.94 to -1.02; P < .001). Younger participants did not benefit from estradiol (difference, 0.08 points on the PANSS positive subscale; 95% CI, -0.91 to 1.07; P = .87). Breast tenderness was more common in the estradiol group (n = 15) than in the placebo group (n = 1) as was weight gain (14 in estradiol group vs 1 in placebo group).Conclusions and Relevance: The results independently replicate the finding that transdermal estradiol is an effective add-on treatment for women of childbearing age with schizophrenia and extend it, finding improvements in negative symptoms and finding that the effect could be specific to those older than 38 years. The results should be viewed in the context of the differences in the natural course of schizophrenia between females and males.Trial Registration: ClinicalTrials.gov identifier: NCT03848234. [ABSTRACT FROM AUTHOR]

The article discusses the efficacy of robot-assisted radical prostatectomy (RARP) in treating patients with prostate cancer. It states that the robot-assisted radical prostatectomy (RARP) help limit or prevent the damage that may lead to postoperative continence and erectile function. It also cites the importance of postoperative care following a cancer operation.

This means that doses should be reduced in a hyperbolic pattern (ie, reductions by smaller and smaller amounts) if any changes are made, because the safest course is typically to maintain a standard dose.[4] Moreover, the hyperbolic shape of the dose-response curve speaks against an average minimum effective antipsychotic dose, unless one defines the amount of efficacy by an arbitrary threshold. Standard versus reduced dose of antipsychotics for relapse prevention in multi-episode schizophrenia: a systematic review and meta-analysis of randomised controlled trials. What dose-response meta-analysis adds is the shape of the dose response curve. [Extracted from the article]

Objectives: To examine the safety and efficacy of rontalizumab, a humanised IgG1 anti-interferon α (anti-IFN-α) monoclonal antibody, in patients with moderate-to-severe systemic lupus erythematosus (SLE).Methods: Patients with active SLE were randomised (2:1) to 750 mg intravenous rontalizumab every 4 weeks or placebo (Part 1), and 300 mg subcutaneous rontalizumab every 2 weeks or placebo (Part 2).Background: Hydroxychloroquine and corticosteroids were allowed. Patients taking immunosuppressants at baseline were required per protocol to discontinue. Efficacy end points included reduction in disease activity by British Isles Lupus Disease Activity Group (BILAG)-2004 (primary), and SLE response index (SRI, secondary) at Week 24. Efficacy was also examined by an exploratory measure of IFN-regulated gene expression (interferon signature metric, ISM).Results: Patients (n=238) received rontalizumab (n=159) or placebo (n=79). At baseline, the mean Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI) score in all cohorts was ~10, and 75.6% of patients had a high ISM (ISM-High). Efficacy response rates by BILAG and SRI were similar between rontalizumab and placebo groups. However, in the exploratory subgroup of ISM-Low patients, SRI response was higher and steroid use was lower in the rontalizumab-treated patients. There was also a reduction in SELENA-SLEDAI flare index rates (HR 0.61, 0.46 to 0.81, p=0.004) in this subgroup. Adverse events were similar between placebo and rontalizumab groups.Conclusions: The primary and secondary end points of this trial were not met in all patients or in patients with high ISM scores. In an exploratory analysis, rontalizumab treatment was associated with improvements in disease activity, reduced flares and decreased steroid use in patients with SLE with low ISM scores.Trial Registration Number: NCT00962832. [ABSTRACT FROM AUTHOR]

Background: As the number of systematic reviews is growing rapidly, we systematically investigate whether meta-analyses published in leading medical journals present an outline of available evidence by referring to previous meta-analyses and systematic reviews. Methods: We searched PubMed for recent meta-analyses of pharmacological treatments published in high impact factor journals. Previous systematic reviews and meta-analyses were identified with electronic searches of keywords and by searching reference sections. We analyzed the number of meta-analyses and systematic reviews that were cited, described and discussed in each recent meta-analysis. Moreover, we investigated publication characteristics that potentially influence the referencing practices. Results: We identified 52 recent meta-analyses and 242 previous meta-analyses on the same topics. Of these, 66% of identified previous meta-analyses were cited, 36% described, and only 20% discussed by recent meta-analyses. The probability of citing a previous meta-analysis was positively associated with its publication in a journal with a higher impact factor (odds ratio, 1.49; 95% confidence interval, 1.06 to 2.10) and more recent publication year (odds ratio, 1.19; 95% confidence interval 1.03 to 1.37). Additionally, the probability of a previous study being described by the recent meta-analysis was inversely associated with the concordance of results (odds ratio, 0.38; 95% confidence interval, 0.17 to 0.88), and the probability of being discussed was increased for previous studies that employed meta-analytic methods (odds ratio, 32.36; 95% confidence interval, 2.00 to 522.85). Conclusions: Meta-analyses on pharmacological treatments do not consistently refer to and discuss findings of previous meta-analyses on the same topic. Such neglect can lead to research waste and be confusing for readers. Journals should make the discussion of related meta-analyses mandatory. [ABSTRACT FROM AUTHOR]

Importance: Antipsychotic drugs constitute the mainstay in the treatment of schizophrenia, and their efficacy is well established in hundreds of randomized clinical trials. However, it is not known whether they are effective or how effective they are across the wide range of baseline symptom severity.Objective: To examine the influence of baseline severity of schizophrenia on the efficacy of antipsychotic drugs.Design, Setting, and Participants: Meta-analysis of participant-level data from 3 pivotal randomized trials of acute schizophrenia (n = 611) and 3 pivotal trials in patients with predominantly negative symptoms of schizophrenia (n = 475).Interventions: Olanzapine or risperidone vs placebo, and amisulpride vs placebo.Main Outcomes and Measures: Change scores on the Positive and Negative Syndrome Scale (PANSS; score range, 30-210) and the Scale for the Assessment of Negative Symptoms (SANS; score range, 0-125) up to 6 weeks after baseline. The relationship between baseline and change scores for the drug and placebo groups was examined with 8 competing mixed-effects models for repeated measures.Results: The best-fitting models showed that, for both types of patients, the interactions between baseline symptom severity and treatment were statistically significant (P < .01). The greater the baseline severity was, the greater the magnitude of the differences was between active treatment and placebo. In acute treatment, the mean differences in PANSS change scores were 9.5 points for patients who were mildly ill at baseline (baseline PANSS score of 58), 13.7 for moderately ill patients (baseline PANSS score of 75), 18.8 for markedly ill patients (baseline PANSS score of 95), and 24.0 for severely ill patients (baseline PANSS score of 116). In treatment of predominantly negative symptoms, the mean differences in SANS change scores were 1.7 for those who were moderately ill (baseline SANS score of 55), 5.7 for markedly ill patients (baseline SANS score of 70), and 9.7 for severely ill patients (baseline SANS score of 85).Conclusions and Relevance: We can expect benefits of antipsychotic drugs for the full spectrum of patients likely to be treated for acute schizophrenia and for highly symptomatic patients with predominantly negative symptoms. Toward the mildest end of the spectrum, clinicians need to be aware that patients benefit less in terms of symptom improvement but may experience full adverse effects of antipsychotics. Clinicians also need to be aware that in addition to the treatment of active symptoms, which was the focus of this study, antipsychotics have another important action, namely to prevent relapses among patients in remission. [ABSTRACT FROM AUTHOR]

Onartuzumab is a unique, humanized, monovalent (one-armed) monoclonal antibody (mAb) against the MET receptor. The intravenous (IV) pharmacokinetics (PK) of onartuzumab were investigated in a phase I study and a phase II study in recurrent non-small cell lung cancer (NSCLC) patients. The potential for drug-drug interaction (DDI) was assessed during co-administration of IV onartuzumab with oral erlotinib, by measuring the PK of both drugs. The concentration-time profiles of onartuzumab were adequately described using a two-compartment model with linear clearance (CL) at doses between 4 and 30 mg/kg. The estimates for CL, central compartment volume (V1), and median terminal half-life were 0.439 L/day, 2.77 L, and 13.4 days, respectively. Statistically significant covariates included creatinine clearance (CrCL) on clearance, weight and gender on V1, and weight on peripheral compartment volume (V2), but the clinical relevance of these covariates needs to be further evaluated. The current analysis did not indicate obvious DDI between onartuzumab and erlotinib. MET diagnostic status did not impact the exposure of either agent. Despite the slightly faster clearance compared with typical bivalent mAbs, the PK of onartuzumab support dosing regimens of 15 mg/kg every 3 weeks or doses equivalent to achieve the target minimum tumoristatic concentration in patients. [ABSTRACT FROM AUTHOR]

The article discusses a research study on examining differences in the efficacy of long-term and mid-term use of antipsychotic medications for the treatment of schizophrenia. Selected studies were used for the data-driven study in a clinical approach where Phase 1 Clinical Antipsychotic Trials of Intervention Effectiveness results are similar to European First-Episode Schizophrenia Trial short-term efficacy studies. Conclusions indicated the importance of second-generation antipsychotics.

We reply to the Ioannidis's paper "Effectiveness of antidepressants; an evidence based myth constructed from a thousand controlled trials." We disagree that antidepressants have no greater efficacy than placebo. We present the efficacy from hundreds of trials in terms of the percentage of patients with a substantial clinical response (a 50% improvement or more symptomatic reduction). This meta-analysis finds that 42-70% of depressed patients improve with drug and 21%-39% improve with placebo. The response benefit of antidepressant treatment is 33%-11% greater than placebo. Ioannidis argues that it would be vanishingly smaller because systematic biasing in these clinical trials would reduce the drug-placebo difference to zero. Ioannidis' argument that antidepressants have no benefit is eroded by his failures of logic because he does not present any evidence that there are a large number of studies where placebo is substantially more effective than drug. (To reduce to zero, one would also have to show that some of the unpublished studies find placebo better than drug and have substantial systematic or methodological bias). We also present the empirical evidence showing that these methodological concerns generally have the opposite effect of what Ioannidis argues, supporting our contention that the measured efficacy of antidepressants likely underestimates true efficacy. Our most important criticism is Ioannidis' basic underlying argument about antidepressants that if the existing evidence is imperfect and methods can be criticized, then this proves that antidepressant are not efficacious. He presents no credible evidence that antidepressants have zero effect size. Valid arguments can point out difficulties with the data but do not prove that a given drug had no efficacy. Indeed better evidence might prove it was more efficacious that originally found. We find no empirical or ethical reason why psychiatrists should not try to help depressed patients with drugs and/ or with psychotherapeutic/behavioral treatments given evidence of efficacy even though our treatment knowledge has limitations. The immense suffering of patients with major depression leads to ethical, moral, professional and legal obligations to treat patients with the best available tools at our disposal, while diligently and actively monitoring for adverse effects and actively revising treatment components as necessary. [ABSTRACT FROM AUTHOR]

At the 2008 annual meeting of the American College of Neuropsychopharmacology (ACNP), a symposium was devoted to the following question: 'what have we learned about the design of pragmatic clinical trials (PCTs) from the recent costly long-term, large-scale trials of psychiatric treatments?' in order to inform the design of future trials. In all, 10 recommendations were generated placing emphasis on (1) appropriate conduct of pragmatic trials; (2) clinical, rather than, merely statistical significance; (3) sampling from the population clinicians are called upon to treat; (4) clinical outcomes of patients, rather than, on outcome measures; (5) use of stratification, controlling, or adjusting when necessary and not otherwise; (6) appropriate consideration of site differences in multisite studies; (7) encouragement of 'post hoc' exploration to generate (not test) hypotheses; (8) precise articulation of the treatment strategy to be tested and use of the corresponding appropriate design; (9) expanded opportunity for training of researchers and reviewers in RCT principles; and (10) greater emphasis on data sharing. [ABSTRACT FROM AUTHOR]

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The article discusses a study on the effects of glucocorticoids (GC) on weight change during the treatment of Wegener's granulomatosis based on data from the Wegener's Granulomatosis Etanercept Trial. The study concludes that disease control was associated with lower cumulative GC doses but greater weight gain. According to the study, more than one-fifth of patients involved in the trial gained >10 kilograms (kg) in the first year of treatment.

Scale-derived cutoff points are frequently used to define ‘response’ in antipsychotic drug trials. This procedure is useful, because responder rates can be understood more intuitively than a difference in means of rating scales. As various definitions of response have been used, we examined original participant data to assess whether the choice of the Brief Psychiatric Rating Scale-based response cutoff had an impact on the results of seven (n=1870) antipsychotic drug trials in schizophrenia. We also analyzed whether the chronicity of the illness has an impact on the question of which cutoff is most sensitive in detecting differences between drugs. The results in terms of p-values and response rate differences varied substantially in dependence on the cutoff chosen. The use of response rate ratios attenuated the variability. In contrast to a widely held belief, low response cutoffs were not more sensitive in detecting differences between drugs than higher cutoffs. In more chronic, less responsive participants, there was a trend for higher cutoffs to be less sensitive in detecting differences between drugs than lower ones. The results of clinical trials depend considerably on the response cutoff chosen. Therefore, the cutoff should never be chosen post hoc, a large range of cutoffs should be presented and the a priori choice of the primary cutoff should be based on clinical relevance. The use of ratios rather than differences attenuates the variability. Cutoffs need to be calculated on the basis of 0–6 rather than on 1–7 scoring systems. We suggest a table presenting responder rates in 25 percent steps covering the whole range up to 100% reduction from baseline, which could be displayed together with recently presented criteria for remission.Neuropsychopharmacology (2007) 32, 1903–1910; doi:10.1038/sj.npp.1301325; published online 7 February 2007 [ABSTRACT FROM AUTHOR]

Background: Venous thrombotic events (VTEs) have been observed in Wegener granulomatosis, but the incidence rate is not known.Objective: To measure the incidence of VTEs in patients with Wegener granulomatosis.Design: Prospective, observational cohort study.Setting: A multicenter, randomized, double-blind, placebo-controlled treatment trial for Wegener granulomatosis.Patients: 180 patients with Wegener granulomatosis enrolled during periods of active disease.Measurements: Venous thrombotic events (deep venous thromboses or pulmonary emboli) were documented and confirmed prospectively. Incidence rates were calculated on the basis of time to first VTE.Results: Thirteen patients had VTEs before enrollment. During 228 person-years of prospective follow-up, 16 VTEs occurred in 167 patients with no history of VTE. Median time from enrollment to VTE for patients with an event was 2.1 months. The incidence of VTE among patients with Wegener granulomatosis was 7.0 per 100 person-years (95% CI, 4.0 to 11.4).Limitations: Although prospectively recorded, screening for VTEs did not occur.Conclusions: The incidence rate of VTEs in Wegener granulomatosis is high when compared with available rates in the general population, patients with lupus, and patients with rheumatoid arthritis. These results have important implications for clinical care of patients with Wegener granulomatosis.*For a list of members of The Wegener's Granulomatosis Etanercept Trial Research Group, see the Appendix. [ABSTRACT FROM AUTHOR]

Background: Breast pain and tenderness affects 70% of women at some time. These symptoms have been attributed to stretching of the nerves with increase in breast size, but tissue mechanisms are poorly understood. Methods: Eighteen patients (n = 12 breast reduction and n = 6 breast reconstruction) were recruited and assessed for breast pain by clinical questionnaire. Breast skin biopsies from each patient were examined using immunohistological methods with specific antibodies to the capsaicin receptor TRPV1, related vanilloid thermoreceptors TRPV3 and TRPV4, and nerve growth factor (NGF). Results: TRPV1-positive intra-epidermal nerve fibres were significantly increased in patients with breast pain and tenderness (TRPV1 fibres / mm epidermis, median [range] - no pain group, n = 8, 0.69 [0-1.27]; pain group, n = 10, 2.15 [0.77-4.38]; p = 0.0009). Nerve Growth Factor, which upregulates TRPV1 and induces nerve sprouting, was present basal keratinocytes: some breast pain specimens also showed NGF staining in supra-basal keratinocytes. TRPV4-immunoreactive fibres were present in sub-epidermis but not significantly changed in painful breast tissue. Both TRPV3 and TRPV4 were significantly increased in keratinocytes in breast pain tissues; TRPV3, median [range] - no pain group, n = 6, 0.75 [0-2]; pain group, n = 11, 2 [1-3], p = 0.008; TRPV4, median [range] - no pain group, n = 6, [0-1]; pain group, n = 11, 1 [0.5-2], p = 0.014). Conclusion: Increased TRPV1 intra-epidermal nerve fibres could represent collateral sprouts, or re-innervation following nerve stretch and damage by polymodal nociceptors. Selective TRPV1- blockers may provide new therapy in breast pain. The role of TRPV3 and TRPV4 changes in keratinocytes deserve further study. [ABSTRACT FROM AUTHOR]

This study is an analysis of findings of a follow-up study of 105 patients with functional psychotic illness who had participated in a random and blind 4-week trial of pimozide, lithium, both and placebo. The intention was to examine the question of whether a 4-week delay in initiating antipsychotic treatment has a detrimental effect 2.5 years later. Detailed follow-up measures included need for care over the 2.5 years, treatments required, occupational decline, police contact, substance misuse, psychopathology and cognitive function. There was no evidence at all that those initially randomized to placebo had a poorer outcome in terms of any of these variables. It is concluded that a 4-week delay in initiating active treatment in patients with functional psychosis has no long-term adverse effects. [ABSTRACT FROM AUTHOR]

This study describes the procedures used to establish videotaped inter-rater reliability in a multi center study investigating the clinical efficacy of divalproex sodium for the treatment of acute mania. A total of 46 raters from 10 centers viewed and rated five videotaped diagnostic patient interviews using a modified SADS and SADS-C. Raters also viewed a fallow-up videotaped interview at the midpoint of the study. Raters rated the quality of each interview for its teaching potential. Agreement among raters within study sites was estimated by the intraclass correlation coefficient. Results demonstrated significant agreement among raters within study centers at baseline and follow-up for both the SADS and SADS-C. [ABSTRACT FROM AUTHOR]

The therapeutic efficacy of thiothixene in the treatment of behaviorally agitated dementia nursing home patients was studied in a double-blind, randomized, placebo-controlled clinical trial. Thirty-three subjects were randomized for thiothixene (dose range: 0.25–18 mg) or placebo treatment over an 11-week period, followed by a 6-week crossover period to assess for return of symptoms in the group crossed over to placebo and further improvement in the group crossed over to thiothixene. Thiothixene was significantly more effective than placebo in the reduction of agitation at the end of 11 weeks of treatment. Symptoms tended to return after discontinuation. There were no significant changes in the Mini-Mental State Examination (MMSE) or Activities of Daily Living (ADLs) and no significant differences in side-effects. Two placebo-treated patients died, and two patients died after being crossed over from thiothixene to placebo. The results suggest the efficacy of low doses of thiothixene for well-defined agitation in specifically selected demented nursing home patients. [ABSTRACT FROM AUTHOR]

The article highlights the findings of a study concerning the use of national registers in analyzing the outcomes of psychotropic drug. Topics discussed include limitations of randomized clinical trials (RCTs); comparison between the efficacy of classic mood stabilizers and antipsychotics for the prevention of rehospitalization; and mentions that the use of lithium was not associated with increased frequency of hospitalization for cardiac reasons.

Background: Persons with spinal cord injury (SCI) are at heightened risks of developing unfavorable cardiometabolic consequences due to physical inactivity. Functional electrical stimulation (FES) and surface neuromuscular electrical stimulation (NMES)-resistance training (RT) have emerged as effective rehabilitation methods that can exercise muscles below the level of injury and attenuate cardio-metabolic risk factors. Our aims are to determine the impact of 12 weeks of NMES + 12 weeks of FES-lower extremity cycling (LEC) compared to 12 weeks of passive movement + 12 weeks of FES-LEC on: (1) oxygen uptake (VO2), insulin sensitivity, and glucose disposal in adults with SCI; (2) skeletal muscle size, intramuscular fat (IMF), and visceral adipose tissue (VAT); and (3) protein expression of energy metabolism, protein molecules involved in insulin signaling, muscle hypertrophy, and oxygen uptake and electron transport chain (ETC) activities.Methods/design: Forty-eight persons aged 18-65 years with chronic (> 1 year) SCI/D (AIS A-C) at the C5-L2 levels, equally sub-grouped by cervical or sub-cervical injury levels and time since injury, will be randomized into either the NMES + FES group or Passive + FES (control group). The NMES + FES group will undergo 12 weeks of evoked RT using twice-weekly NMES and ankle weights followed by twice-weekly progressive FES-LEC for an additional 12 weeks. The control group will undergo 12 weeks of passive movement followed by 12 weeks of progressive FES-LEC. Measurements will be performed at baseline (B; week 0), post-intervention 1 (P1; week 13), and post-intervention 2 (P2; week 25), and will include: VO2 measurements, insulin sensitivity, and glucose effectiveness using intravenous glucose tolerance test; magnetic resonance imaging to measure muscle, IMF, and VAT areas; muscle biopsy to measure protein expression and intracellular signaling; and mitochondrial ETC function.Discussion: Training through NMES + RT may evoke muscle hypertrophy and positively impact oxygen uptake, insulin sensitivity, and glucose effectiveness. This may result in beneficial outcomes on metabolic activity, body composition profile, mitochondrial ETC, and intracellular signaling related to insulin action and muscle hypertrophy. In the future, NMES-RT may be added to FES-LEC to improve the workloads achieved in the rehabilitation of persons with SCI and further decrease muscle wasting and cardio-metabolic risks.Trial Registration: ClinicalTrials.gov, NCT02660073 . Registered on 21 Jan 2016. [ABSTRACT FROM AUTHOR]

In this article, the author discusses randomized clinical trials (RCTs) which provides unbiased estimates of the effects of different treatments. Topics discussed include information on challenges faced in chemoprevention in the cases with prostate cancer; information on the papers of the periodical "New England Journal of Medicine" which deals with mortality outcome analysis; and supports provided to the clinical trials by the periodical.

A letter to the editor is presented which examines the differences between imipramine and placebo in treating depression.

Abstract: Recent analyses tried to explain the meaning of the Brief Psychiatric Rating Scale total score (BPRS) and its percentage change from baseline by equipercentile linking with the Clinical Global Impression Scale (CGI). A major limitation was that they were conducted in clinical trial populations limiting generalisability to ‘real-world’ patients. We therefore replicated the findings in a large sample covering patients admitted to a state hospital with a catchment area. BPRS and CGI ratings at admission (n=1772) and at discharge from all patients with schizophrenic disorders (ICD-10 F20.0–F20.9) admitted between 2005 and 2008 were compared using equipercentile linking. Being considered “mildly ill” according to the CGI severity score approximately corresponded to a BPRS total score of 25, “moderately ill” to a BPRS of 33–35, “markedly ill” to a BPRS of 50 and severely ill to a BPRS of 70. To be “minimally improved” according to the CGI change score was associated with a mean BPRS reduction of 13%; and “much improved” with 50% BPRS reduction. The linking functions were not identical, but overall comparable to those in previous randomised trial samples. The suggestion that a 50% BPRS reduction from baseline is a clinically meaningful definition of response in acutely ill patients was reinforced. [Copyright &y& Elsevier]

Accumulated studies have investigated pharmacological interventions for first-episode schizophrenia (FES) patients. However, studies on subsequent treatment steps, which are essential to guide clinicians, are largely missing. This Sequential Multiple-Assignment Randomized Trials comparing Antipsychotic Treatments (SMART-CAT) program intends to evaluate the effectiveness of commonly used antipsychotic drugs in FES patients. The major goals of this study are to examine: 1) what would be the optimal subsequent sequential treatment if the first antipsychotic drug failed; 2) whether clozapine could be used in those first-trial failed and have superior efficacy compared to other atypical antipsychotics. In this article we will report the detail protocol of SMART-CAT. The SMART-CAT is a randomized controlled clinical multicenter trial in which 9 institutions in China will participate. A total of 720 FES patients will be enrolled and followed up for 12 months in this study. The trial includes three treatment phases (each phase lasting for 8 weeks) and a naturalistic follow-up phase; participants who do well on an assigned treatment will remain on that treatment for the duration of the 12-month treatment period, while non-responders will move to the next phase of the study to receive a new treatment. Phase 1 is a randomized controlled trial; patients will be randomly assigned to one of the treatments with oral olanzapine, risperidone, amisulpride, aripiprazole or perphenazine. Subjects who fail to respond after 8 weeks will enter the phase 2 randomization. Phase 2 is an equipoise-stratified randomization trial, and patients will be randomly assigned to oral olanzapine, amisulpride or clozapine for 8 weeks. Subjects who fail to respond after phase 2 will enter an open label trial (phase 3); patients who receive clozapine in phase 2 and fail to respond will be assigned to an extended clozapine treatment or modified electroconvulsive therapy add-on therapy (Phase 3A). Patients who were not assigned to clozapine in phase 2 will be assigned to treatment with clozapine or another SGAs not previously used in phase 1 and 2 (Phase 3B). The primary outcome for the treatment phase is the treatment efficacy rate, which is defined as at least 40% reduction in Positive and Negative Syndrome Scale (PANSS) total score. We hypothesize that clozapine is more therapeutically effective than any other SGAs to patients who failed to meet efficacy criteria in Phase 1, and earlier treatment with clozapine can improve the functional outcomes of schizophrenia patients. As for the naturalistic follow-up phase, time to all-cause treatment failure, marked by its discontinuation is selected as the primary outcome, since it reflects both efficacy and side effects. The all-cause discontinuation is defined as discontinuing for any reasons, including poor efficacy, intolerance of adverse reactions, poor compliance and other reasons. The results of the SMART-CAT trial will provide evidence for the selection of antipsychotics in FES patients who fail to respond to the first trial of an antipsychotic drug. It will also provide evidence for the efficacy and safety of using clozapine in the early phase of schizophrenia treatment by comparing with other SGAs. The study is based on the combination of sequential therapy and dynamic therapy, which can be more suitable to assess the effectiveness of treatment options in the real-world clinical setting. As a result, we hope that this study can provide guidance for an optimal treatment algorithm in first-episode schizophrenia patients. Trial registration: ID NCT03510325 in ClinicalTrials.gov. [ABSTRACT FROM AUTHOR]

Objective: A recent meta-regression had shown that the degree of placebo response, which has increased over the decades, is the major predictor of drug-placebo differences in antipsychotic drug trials in acutely ill patients with schizophrenia. Drug response, however, had remained stable. In the current meta-regression we explored the factors that are associated with placebo-response.Method: We searched multiple electronic databases, ClinicalTrials.gov and the FDA website for randomized, placebo-controlled, antipsychotic drug trials in patients with acute exacerbations of schizophrenia. The outcome was the degree of placebo response measured by the BPRS or PANSS change from baseline to endpoint. 26 patient-, design-, and drug-related potential predictors of placebo response were analyzed by univariable and multivariable meta-regressions.Results: 167 double-blind randomized controlled trials with 28,102 participants were included. The mean PANSS change from baseline was 6.25 (95% CI 4.64,7.85). More recent publication year, larger study sample size, more study sites, use of the PANSS rather than the BPRS scale to measure response, shorter wash-out phases, shorter study duration, lower mean age and shorter duration of illness were associated with larger placebo response in univariable analyses. In a multivariable analysis only the number of study participants and mean participant age had an impact on placebo response.Conclusions: The degree of placebo response is moderated by a number of design and patient-related factors. These explanatory variables of placebo response are only in part identical with those that moderated drug-placebo differences. [ABSTRACT FROM AUTHOR]

Ongoing prospective studies are evaluating treatment of the primary tumor in men with de novo metastatic prostate cancer (PCa). One potential benefit is prevention of morbidity from local progression. Thus, local therapy may be best applied selectively to men with local progression once resistance to first-line therapies has occurred. Here, we gather support for the hypothesis that radical prostatectomy (RP) is safe and preserves quality of life (QOL) when applied in men with metastatic castration-resistant PCa (mCRPC). We analyzed 14 patients who underwent RP in the setting of mCRPC from 2008 to 2016. Median time from mCRPC to RP was 5.1 mo (interquartile range [IQR] 1.4–12.0). Median preoperative and <3 mo postoperative Expanded Prostate Cancer Index Composite urinary function QOL scores were 84 (IQR 70–95) and 78 (IQR 62–81), respectively. There were one Clavien Grade III, three Grade II, and one Grade I complications postoperatively. In these patients with mCRPC, RP was feasible with limited minor complications. Patient summary We report on a select group of men with metastatic castration-resistant prostate cancer who had prostatectomy. Prostatectomy is highly investigational in this setting and should not be used outside of a clinical trial other than for symptom relief. [ABSTRACT FROM AUTHOR]

Purpose: To report the efficacy, physician-reported toxicity, and patient-reported outcomes of men with intermediate-risk prostate cancer after brachytherapy in a prospective phase 2 trial.Methods and Materials: This prospective phase 2 trial involved 300 patients with previously untreated prostate cancer treated from 2006 through 2013. Eligible patients had ≤cT2b (T3 excluded according to magnetic resonance imaging), Gleason score (GS) 6 with prostate-specific antigen (PSA) level 10-15 ng/mL, or GS 7 with PSA <10 ng/mL, and were treated with prostate brachytherapy (without hormonal therapy).Results: Median patient age was 64.9 years; 3.7% had GS 6, 78.7% had GS 7 (3+4), and 17.7% had GS 7 (4+3). Median follow-up time was 5.1 years. Median PSA at 5 years was 0.01 ng/mL (range, 0-6.0 ng/mL). Ten biochemical failures occurred, for a 5-year freedom from biochemical failure rate of 97.3% (95% confidence interval [CI], 95.1-99.5), and 16 patients died, only 1 from prostate cancer, for 5-year rates of overall and biochemical progression-free survival of 94.9% (95% CI, 92.1-97.9) and 92.7% (95% CI, 89.3-96.2%). Four patients had late grade 3 genitourinary toxicity, and 2 patients had late grade 3 rectal toxicity; no grade 4 or 5 toxicity was observed. Rates of "moderate or big problems" at 4 years were 7.4% for urinary (vs 0.4% at baseline), 2.9% bowel (vs 0.4%), and 29.7% sexual function (vs 19.7%). Most men were "satisfied or extremely satisfied" (91% at 2 years after treatment and 93% at 4 years).Conclusions: Brachytherapy monotherapy is safe and effective and leads to good quality of life for some men with localized intermediate-risk prostate cancer. [ABSTRACT FROM AUTHOR]

Summary Interleukin-23 (IL-23) and IL-17 are cytokines currently being targeted in clinical trials. Although inhibition of both of these cytokines is effective for treating psoriasis, IL-12 and IL-23 p40 inhibition attenuates Crohn’s disease, whereas IL-17A or IL-17 receptor A (IL-17RA) inhibition exacerbates Crohn’s disease. This dichotomy between IL-23 and IL-17 was effectively modeled in the multidrug resistance-1a-ablated ( Abcb1a −/− ) mouse model of colitis. IL-23 inhibition attenuated disease by decreasing colonic inflammation while enhancing regulatory T (Treg) cell accumulation. Exacerbation of colitis by IL-17A or IL-17RA inhibition was associated with severe weakening of the intestinal epithelial barrier, culminating in increased colonic inflammation and accelerated mortality. These data show that IL-17A acts on intestinal epithelium to promote barrier function and provide insight into mechanisms underlying exacerbation of Crohn’s disease when IL-17A or IL-17RA is inhibited. [ABSTRACT FROM AUTHOR]

Background Dropout is a serious challenge to clinical trials in psychiatry, yet standard outcome analyses with mixed models do not account for dropout, while joint modeling uses dropout from a survival model to adjust the outcome from a mixed model, but is untested in clinical trials of schizophrenia. Aims To compare mixed and joint modeling in three acute phase pivotal placebo controlled trials of schizophrenia. Method Data were reanalyzed on 611 in-patients with acute schizophrenia who participated in three pivotal randomized controlled trials that compared placebo with olanzapine or risperidone (dropout rates placebo: 62.6% and medication: 37.4%). The outcome measures were BPRS or PANSS total change scores. Mixed-effects models for repeated measures and joint models were computed and compared to examine the time-treatment interaction. Effect size comparisons were made. Results Antipsychotic treatment was superior to placebo across analyses. Time treatment interactions were significant ( p < .05) for the mixed (beta = 2.33) and joint models (beta = 2.62). Compared with mixed modeling, joint modeling reduced the estimated change score for treatment (21.24 vs 19.74) and placebo (1.64 vs − 1.11). The effect size differences between placebo and treatment groups were greater for joint (ES = .89) than mixed modeling (ES = 0.83). Sensitivity analysis replicated this trend of results in each of the three trials. Conclusion Compared to mixed modeling, joint modeling results in a greater separation between treatment and placebo groups. This offers preliminary evidence that joint modeling may be useful in the analysis of antipsychotic placebo controlled RCTs. [ABSTRACT FROM AUTHOR]

Objective It is important to identify separate publications that report outcomes from the same underlying clinical trial, in order to avoid over-counting these as independent pieces of evidence. Methods We created positive and negative training sets (comprised of pairs of articles reporting on the same condition and intervention) that were, or were not, linked to the same clinicaltrials.gov trial registry number. Features were extracted from MEDLINE and PubMed metadata; pairwise similarity scores were modeled using logistic regression. Results Article pairs from the same trial were identified with high accuracy (F1 score = 0.843). We also created a clustering tool, Aggregator, that takes as input a PubMed user query for RCTs on a given topic, and returns article clusters predicted to arise from the same clinical trial. Discussion Although painstaking examination of full-text may be needed to be conclusive, metadata are surprisingly accurate in predicting when two articles derive from the same underlying clinical trial. [ABSTRACT FROM AUTHOR]

Abstract: Missing outcome data is a major threat in meta-analytical studies of schizophrenia. Most clinical trials in psychiatry report only continuous outcome measures and express the effect of an intervention as a difference of means. However, these results are difficult to interpret for clinicians. Converting continuous data to binary response rates is one possible solution to the problem. Based on means and standard deviations for a continuous outcome, we examined the performance of an imputation method to define a dichotomous outcome using original individual patients' data from 16 randomized trials (6276 participants) comparing antipsychotic drugs in schizophrenia. We concluded that the imputed values re-captured in a reasonable degree the observed values providing a simple and practical alternative methodological choice for imputation of missing binary data in schizophrenia trials; nevertheless, the imputation method tended to introduce biases, especially for extreme risks and large treatment differences. [Copyright &y& Elsevier]

Abstract: Objective: This comprehensive review and meta-analysis compared the effectiveness of olanzapine and other antipsychotics in schizophrenia treatment, defining effectiveness as time to all-cause medication discontinuation (primary) and as all-cause treatment discontinuation rates. This study examined randomized clinical trials (RCTs) and observational non-interventional studies. Experimental procedures: Schizophrenia studies that compared olanzapine with individual first- (FGAs) and/or second-generation antipsychotics (SGAs) were included in the meta-analyses. Hazard ratios (HR), risk ratios (RR), and their associated 95% confidence intervals were extracted for RCTs and observational studies. Sensitivity analyses assessed the impact of sources of funding, dose of olanzapine, and allocation concealment method on final results. Results: There were 60 RCTs (N=33,360) and 27 observational studies (N=202,591) included. On time to all-cause medication discontinuation, olanzapine was significantly better than aripiprazole, quetiapine, risperidone, ziprasidone and perphenazine for RCTs and better than amisulpride, risperidone, haloperidol, and perphenazine for observational studies. There were no significant differences between olanzapine and clozapine in RCTs or observational studies. All-cause discontinuation rates in RCTs were significantly lower for olanzapine compared to all comparators except amisulpride and clozapine. In observational studies, olanzapine was less effective than clozapine. Industry-sponsored studies favored olanzapine when compared to haloperidol and perphenazine; higher dose of olanzapine favored quetiapine and perphenazine when compared to olanzapine; method of allocation concealment did not generally affect the results. Conclusion: Using a global measure of medication effectiveness (time to all-cause medication discontinuation), olanzapine appears to be more effective – in both RCTs and observational studies – than most SGAs and FGAs, except for clozapine. [Copyright &y& Elsevier]

Abstract: Background: Schizophrenic patients treated with antipsychotic drugs (AP) have an increased frequency of glucose–lipid metabolic abnormalities and diabetes. Pioglitazone has been shown to be effective in the treatment of glucose and lipid abnormalities in diabetes and decreasing longer-term conversion of impaired glucose tolerance to frank diabetes. Some studies also suggest possible pro-cognitive and antidepressant effects of pioglitazone. We studied the effects of pioglitazone on potential metabolic, symptomatic and cognitive benefits in schizophrenic patients treated with AP. Methods: 54 schizophrenic patients with at least both a)impaired glucose and b) triglycerides≥120mg/dL and/or low HDL levels, participated in a double-blind placebo controlled study of 3month treatment with Pioglitazone (30–45mg/day) or matched placebo, at 5 sites (4 U.S., 1 China). Fasting glucose and lipid parameters, and psychopathology (PANSS scale) were assessed monthly, and patients had a glucose tolerance test and cognitive testing (RBANS and CPT) at baseline and at the end of study. Statistical analysis used mixed model repeated measures analysis, supplemented by completer and LOCF analysis. Results: In the total sample there was an overall effect (P''s<.05 to <.01) of pioglitazone on preventing deterioration in fasting glucose and improving HDL and PANSS depression scores; in the pioglitazone group comparison of baseline vs 3month values also showed significant (P<.05) decreases in fasting insulin, 2h glucose in GTT and insulin resistance (HOMA-IR). However there were marked differences between the responses of patients in the U.S. sites vs the China site. In the U.S. sample, patients treated with pioglitazone, when compared to placebo treated patents, had significantly lower fasting glucose (F=3.99, P=0.02), improved insulin sensitivity (lower H0MA-IR, F=6.24, P=.002), lower triglycerides (F=2.68, P=.06) and increased HDL (F=6.50, P=.001). By the end of the study 52% of the pioglitazone treated patients compared to 15% of the placebo patients had fasting glucose in the normal range (Fisher''s exact test P=.02). Pioglitazone also significantly improved PANSS depression factor scores (F=2.82, P=0.05). It did not improve cognitive performance on the RBANS or CPT tasks. Pioglitazone did not increase weight or produce any other significant side-effects. In the small mainland China site sample, pioglitazone treatment, as compared to placebo, did not show greater improvement in metabolic parameters or psychopathology ratings. Conclusions: In the sample of patients from the U.S., pioglitazone was an efficacious and safe treatment for glucose and lipid metabolic abnormalities in schizophrenic patients treated with AP, and it may also have beneficial effects on depressive symptoms. It may be particularly useful in patients whose weight gain effects from antipsychotics have plateaued and where weight loss is not the primary goal. The risk vs. benefits of longer term treatment with pioglitazone has to be carefully evaluated for individual patients. [Copyright &y& Elsevier]

Abstract: Objective: Non-adherence is a major problem in the treatment of schizophrenia. Depot antipsychotic drugs are thought to reduce relapse rates by improving adherence, but a systematic review of long-term studies in outpatients is not available. Method: We searched the Cochrane Schizophrenia Group''s register, ClinicalTrials.gov, Cochrane reviews on depot medication, and the reference sections of included studies for randomised controlled trials lasting at least 12months in outpatients that compared depot with oral antipsychotics in schizophrenia. Data on relapse (primary outcome), rehospitalisation, non-adherence, and dropout due to any reason, inefficacy of treatment and adverse events were summarised in a meta-analysis using a random-effects model. Study quality was assessed with the Cochrane collaboration''s risk of bias tool, and publication bias with funnel plots. Results: Ten studies with 1700 participants met the inclusion criteria. Depot formulations significantly reduced relapses with relative and absolute risk reductions of 30% and 10%, respectively (RR 0.70, CI 0.57–0.87, NNT 10, CI 6–25, P=0.0009), and dropout due to inefficacy (RR 0.71, CI 0.57–0.89). Limited data on non-adherence, rehospitalisation and dropout due to any reason and adverse events revealed no significant differences. There were several potential sources of bias such as limited information on randomisation methods, problems of blinding and different medications in the depot and oral groups. Other studies reduced a potential superiority of depot by excluding non-adherent patients. Discussion: Depot antipsychotic drugs significantly reduced relapse. Due to a number of methodological problems in the single trials the evidence is, nonetheless, subject to possible bias. [Copyright &y& Elsevier]

Abstract: Signal detection methods were used to identify values of metabolic variables that predict development of prediabetes or diabetes before (moderators) or associated with treatment (mediators), utilizing data from two multi-center clinical trials of patients with schizophrenia, treated for 6 months with olanzapine (OLZ) or ziprasidone (ZIP). At baseline, participants were often overweight/obese (63% with a body mass index ⩾25.0kg/m2), dyslipidemic [more than one-third had elevated triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentrations], and prediabetic (20%). Weight gain was significantly greater in OLZ-treated patients, as was accentuation of dyslipidemia. However, there were no significant correlations between weight gain and lipid changes from baseline to weeks 2, 4, 8 or to last observation. Type 2 diabetes developed in 4% and prediabetes in 18% of the population. Significant baseline predictors of diabetes were a HDL-C concentration <28mg/dL, or being ⩾58-years-old if HDL-C concentration was ⩾28mg/dL. Baseline plasma glucose concentration ⩾92mg/dL was the only significant predictor of developing prediabetes, accounting for 60% of cases. Post-treatment increments in plasma TG concentrations ⩾145mg/dL or ⩾59mg/dL were significant predictors of diabetes (23%) or prediabetes (27%), respectively. If the increase in TG was <145mg/dL, rapid weight gain ⩾6.1kg in 2weeks predicted development of diabetes (18%). These findings provide a quantitative approach to identify those at greatest treatment-associated risk to develop glucose intolerance, and emphasize the need to address co-morbid medical disorders in these patients. [Copyright &y& Elsevier]

Background Mucopolysaccharidosis type IH (MPS1/Hurler Syndrome), cerebral adrenoleukodystrophy (cALD), metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (GLD) are fatal IMDs affecting the central nervous system treatable through allogeneic hematopoietic stem cell transplantation (HSCT). In the absence of a non-carrier HLA matched related donor, cord blood (CB) is the preferred source of cells in IMDs due to rapid availability and flexibility in matching. However, prolonged neutropenia and high graft failure rates present a challenge, particularly with reduced intensity conditioning regimens. MGTA-456 is produced from a single CB unit using an aryl hydrocarbon receptor antagonist in a 15-day expansion culture of CD34+ cells. In previous phase 1/2 studies, hematologic malignancy patients treated with myeloablative conditioning and MGTA-456, with median 324-fold CD34+ expansion, showed 100% engraftment with a 9 day reduction in time to neutrophil recovery. As higher CD34+ doses have been correlated with improved engraftment in IMD transplant patients, we hypothesize MGTA-456 may reduce duration of neutropenia and risk of graft failure and more rapidly correct the metabolic deficiency in IMD patients. Patients and Methods A Phase 2, open-label trial (NCT03406962) initiated in Feb 2018 is enrolling up to 12 patients <16 yo with a diagnosis of MPS1, cALD, MLD, or GLD. Eligible CB units are matched at ≥ 6 of 8 HLA loci. The reduced toxicity conditioning regimen consists of anti-thymocyte globulin (days -9 to -6), fludarabine (40 mg/m2 x4 days) and busulfan (total exposure 21,000 to 22,000 μM/min/L−1 x4 days). Immunoprophylaxis consists of cyclosporin and methylprednisolone. Results Five patients have been treated per protocol to date (Figure 1). MGTA-456 contained a median 561-fold expansion of CD34+ cells after culture with a median infused CD34+ cell dose of 110 × 106 cells/kg and median total nucleated cell dose of 26.4 × 107 (Figure 2). The median duration of neutropenia was 1 day (range 0-9), in contrast to a median of 8 days for a historical cohort (Figure 3). Myeloid chimerism was ≥98% donor by day +14 in evaluable patients. Two patients developed autoimmune cytopenia, a known complication in IMD patients after HSCT, unrelated to MGTA-456. Time to discharge after transplant was a median of 19.5 days at time of reporting. Preliminary data from MPS1 patients demonstrated normalization of blood alpha-L-iduronidase enzyme activity and decreased urinary glycosoaminoglycan levels after transplant. Conclusions Treatment of IMD patients with MGTA-456 showed early and robust engraftment in all patients with marked reduction in days of neutropenia compared to a historical cohort. These preliminary data, in combination with the previous hematologic malignancy patients treated, suggest MGTA-456 substantially enhances engraftment and rate of neutrophil recovery. [ABSTRACT FROM AUTHOR]

Background: The appropriate treatment for patients in whom reperfusion fails to occur after thrombolytic therapy for acute myocardial infarction remains unclear. There are few data comparing emergency percutaneous coronary intervention (rescue PCI) with conservative care in such patients, and none comparing rescue PCI with repeated thrombolysis. Methods: We conducted a multicenter trial in the United Kingdom involving 427 patients with ST-segment elevation myocardial infarction in whom reperfusion failed to occur (less than 50 percent ST-segment resolution) within 90 minutes after thrombolytic treatment. The patients were randomly assigned to repeated thrombolysis (142 patients), conservative treatment (141 patients), or rescue PCI (144 patients). The primary end point was a composite of death, reinfarction, stroke, or severe heart failure within six months. Results: The rate of event-free survival among patients treated with rescue PCI was 84.6 percent, as compared with 70.1 percent among those receiving conservative therapy and 68.7 percent among those undergoing repeated thrombolysis (overall P=0.004). The adjusted hazard ratio for the occurrence of the primary end point for repeated thrombolysis versus conservative therapy was 1.09 (95 percent confidence interval, 0.71 to 1.67; P=0.69), as compared with adjusted hazard ratios of 0.43 (95 percent confidence interval, 0.26 to 0.72; P=0.001) for rescue PCI versus repeated thrombolysis and 0.47 (95 percent confidence interval, 0.28 to 0.79; P=0.004) for rescue PCI versus conservative therapy. There were no significant differences in mortality from all causes. Nonfatal bleeding, mostly at the sheath-insertion site, was more common with rescue PCI. At six months, 86.2 percent of the rescue-PCI group were free from revascularization, as compared with 77.6 percent of the conservative-therapy group and 74.4 percent of the repeated-thrombolysis group (overall P=0.05). Conclusions: Event-free survival after failed thrombolytic therapy was significantly higher with rescue PCI than with repeated thrombolysis or conservative treatment. Rescue PCI should be considered for patients in whom reperfusion fails to occur after thrombolytic therapy. N Engl J Med 2005;353:2758-68. [ABSTRACT FROM AUTHOR]