PROCESS MEETS PROJECT PRIORITIZATION – A DECISION MODEL FOR DEVELOPING PROCESS IMPROVEMENT ROADMAPS

Improving business processes is a key success factor for organizations and, at the same time, a major challenge for decision makers. For process improvement to be successful, effective prioritization is essential. Despite the existence of approaches for the prioritization of process improvement projects or business processes, prescriptive research at the intersection of both research streams is missing. Existing approaches do not simultaneously prioritize business processes and improvement projects. Hence, scarce corporate funds may be misallocated. To address this research gap, we propose the PMP2, an economic decision model that assists organizations in the identification of business process improvement (BPI) roadmaps. Based on stochastic processes and simulation, the decision model maps different improvement projects to individual business processes within a process network. Thereby, it caters for process dependencies and basic interactions among projects. Drawing from the principles of value-based management, the decision model determines the process improvement roadmap with the highest contribution to the long-term firm value. To evaluate the PMP2, we instantiated it as a software prototype and performed different scenario analyses based on synthetic data. The results highlight the importance of prioritizing business processes and improvement projects in an integrated manner

Should ‘typical’, first-generation antipsychotics no longer be generally used in the treatment of schizophrenia?

Depression affects around 320 million people worldwide. Growing evidence proposes the immune system to be the core interface between psychosocial stress and the neurobiological and behavioural features of depression. Many studies have identified purinergic signalling via the P2X7 receptor (P2X7R) to be of great importance in depression genesis yet only a few have evaluated P2X7R antagonists in chronic stress-based depression models. This review summarizes their findings and analyses their methodology. The four available studies used three to nine weeks of unpredictable, chronic mild stress or unpredictable, chronic stress in male mice or rats. Stress paradigm composition varied moderately, with stimuli being primarily psychophysical rather than psychosocial. Behavioural testing was performed during or after the last week of stress application and resulted in depressive-like behaviours, immune changes (NLRP3 assembly, interleukin-1β level increase, microglia activation) and neuroplasticity impairment. During the second half of each stress paradigm, a P2X7R antagonist (Brilliant Blue G, A-438079, A-804598) was applied. Studies differed with regard to antagonist dosage and application timing. Nonetheless, all treatments attenuated the stress-induced neurobiological changes and depressive-like behaviours. The evidence at hand underpins the importance of P2X7R signalling in chronic stress and depression. However, improvements in study planning and reporting are necessary to minimize experimental bias and increase data purview. To achieve this, we propose adherence to the Research Domain Criteria and the STRANGE framework

Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-analysis.

BACKGROUND Negative symptoms are the core of schizophrenia, but whether antipsychotics are efficacious for their treatment is unclear. Moreover, there is debate whether patients in relevant trials should have predominant negative symptoms or whether prominent negative symptoms are also acceptable. METHODS We systematically reviewed randomised, blinded antipsychotic drug trials in patients with schizophrenia and either predominant or prominent negative symptoms (last search Dec 12, 2017). Separate pairwise meta-analyses were conducted in these two populations. The primary outcome was negative symptoms. Depressive, symptoms, positive symptoms, and extrapyramidal side-effects were analysed as causes of secondary negative symptoms. FINDINGS We included 21 randomized-controlled trials with 3451 participants which revealed the following significant differences in the primary outcome: in patients with predominant negative symptoms amisulpride was superior to placebo (N = 4; n = 590, SMD 0.47, CI 0.23, 0.71), olanzapine was superior to haloperidol in a small trial (n = 35) and cariprazine outperformed risperidone (N = 1, n = 456, SMD - 0.29, CI - 0.48, - 0.11). In patients with prominent negative symptoms, olanzapine and quetiapine were superior to risperidone in single trials. Overall, studies in prominent negative symptoms were potentially more confounded by improvements of secondary negative symptoms. INTERPRETATION Amisulpride is the only antipsychotic that outperformed placebo in the treatment of predominant negative symptoms, but there was a parallel reduction of depression. Cariprazine was better than risperidone in a large trial that was well-controlled for secondary negative symptoms, but the trial was sponsored by its manufacturer. Future trials should apply scientifically developed definitions such as the deficit syndrome and the persistent negative symptoms concept

Efficacy, acceptability and tolerability of all available treatments for insomnia in the elderly: a systematic review and network meta-analysis.

OBJECTIVES Symptoms of insomnia are highly prevalent in the elderly. A significant number of pharmacological and non-pharmacological interventions exists, but, up-to-date, their comparative efficacy and safety has not been sufficiently assessed. METHODS We integrated the randomized evidence from every available treatment for insomnia in the elderly (>65 years) by performing a network meta-analysis. Several electronic databases were searched up to May 25, 2019. The two primary outcomes were total sleep time and sleep quality. Data for other 6 efficacy and 8 safety outcomes were also analyzed. RESULTS 53 RCTs with 6832 participants (75 years old on average) were included, 43 of which examined the efficacy of one or more drugs. Ten RCTs examined the efficacy of non-pharmacological interventions and were evaluated only with pairwise meta-analyses because they were disconnected from the network. The overall confidence in the evidence was very low primarily due to the small amount of data per comparison and their sparse connectedness. Several benzodiazepines, antidepressants and z-drugs performed better in both primary outcomes, but few comparisons had data from more than one trial. The limited evidence on non-pharmacological interventions suggested that acupressure, auricular acupuncture, mindfulness-based stress reduction program, and tart cherry juice were better than their control interventions. Regarding safety, no clear differences were detected among interventions due to large uncertainty. CONCLUSIONS Insufficient evidence exists on which intervention is more efficacious for elderly patients with insomnia. More RCTs, with longer duration, making more direct interventions among active treatments and presenting more outcomes are urgently needed

The response of head and neck squamous cell carcinoma to cetuximab treatment depends on Aurora kinase A polymorphism

Objectives: The aim of this study was to evaluate the efficiency of cetuximab-based anti-EGFR treatment and Aurora kinase A / B knockdown as a function of Aurora kinase polymorphism in HNSCC cell lines. Materials and methods: First, protein expression of Aurora kinase A / B and EGFR and Aurora kinase A polymorphism were studied in tumour samples. The survival and proliferation of Aurora kinase A homo- (Cal27) and heterozygous (HN) HNSCC cell lines was evaluated using a colony formation assay and a flow cytometric assay. Also, aneuploidy was determined. EGFR signalling pathway were visualised by western blotting. Results: Immunohistochemistry revealed the overexpression of Aurora kinase A / B in HNSCC. The knockdown of each kinase caused a significant decrease in clonogenic survival, independent of Aurora kinase A polymorphism. In contrast, cetuximab treatment impaired clonogenic survival only in the Aurora kinase A-homozygous cell line (Cal27). Conclusion: This study provides in vitro evidence for the predictive value of Aurora kinase A polymorphism in the efficiency of cetuximab treatment. Resistance to cetuximab treatment can be overcome by simultaneous Aurora kinase A/B knockdown

Reducing antipsychotic drugs in stable patients with chronic schizophrenia or schizoaffective disorder: a randomized controlled pilot trial

As the course of schizophrenic disorders is often chronic, treatment guidelines recommend continuous maintenance treatment to prevent relapses, but antipsychotic drugs can cause many side effects. It, therefore, seems reasonable to try to reduce doses in stable phases of the illness or even try to stop medication. We conducted a 26 weeks, randomized, rater blind, feasibility study to examine individualized antipsychotic dose reduction versus continuous maintenance treatment (Register Number: NCT02307396). We included chronic, adult patients with schizophrenia or schizoaffective disorder, who were treated with any antipsychotic drug except clozapine, who had not been hospitalized in the last 3 years and who were in symptomatic remission at baseline. The primary outcome was relapse of positive symptoms. Symptom severity, social functioning and side effects were also examined as secondary outcomes. 20 patients were randomized. Relapse rates in the two groups were not significantly different. No patient had to be hospitalized. One patient in the control group dropped out. The mean reduction of antipsychotic dose in the individualized dose-reduction group was 42%, however only one patient discontinued drug completely. There were no significant differences in efficacy or safety outcomes. This randomized trial provides evidence, that reduction of antipsychotic medication in chronic stable schizophrenic patients may be feasible. The results need to be confirmed in a larger trial with a longer follow-up period

60 years of placebo-controlled antipsychotic drug trials in acute schizophrenia:Meta-regression of predictors of placebo response

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

Second-generation antipsychotic drugs and short-term somatic serious adverse events: a systematic review and meta-analysis.

BACKGROUND Antipsychotic drugs might cause acutely occurring, serious side-effects and thus contribute to the increased physical morbidity and mortality observed in patients with severe mental health disorders. We examined this hypothesis by doing a meta-analysis of International Conference on Harmonisation-Good Clinical Practice-defined serious adverse events occurring in placebo-controlled trials of antipsychotics. METHODS For this systematic review and meta-analysis, we included randomised controlled trials (RCTs) comparing second-generation antipsychotics with placebo. We searched MEDLINE, Embase, Cochrane CENTRAL, BIOSIS, PsycINFO, PubMed, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform for trials published in any language from database inception up until Jan 27, 2017. Trials were included without limitations in population (diagnostic category, age, sex, ethnicity), dosing regimen, blinding status, duration, or publication year. Only psychological studies lasting less than 1 day and trials done in mainland China were excluded. We contacted pharmaceutical companies, drug regulatory authorities, and study investigators for additional data. The primary outcome was the number of patients with at least one somatic serious adverse event. We estimated minimum and maximum numbers of patients with the outcome in each study group and synthesised the results with odds ratios (ORs) in a common-effects meta-analysis. This study is registered with PROSPERO, number CRD42016033930. FINDINGS We identified 597 RCTs, comprising 108 664 participants, that met the inclusion criteria. 314 trials (67 642 participants) with details on individual serious adverse events available constituted the main dataset for meta-analysis. 88% of these were 13 weeks (approximately 3 months) or shorter in duration (median 6 weeks, IQR 4-9). At least one somatic serious adverse event occurred in 698 (1·63%) to 862 (2·02%) of 42 600 patients on antipsychotics, and in 343 (1·37%) to 419 (1·67%) of 25 042 patients on placebo. The odds ratios (ORs) were 1·24 (95% CI 1·08-1·42) and 1·24 (1·10-1·41) based on the minimum and maximum estimate, respectively. In predefined subgroup analyses we found evidence suggesting a larger effect in older patients (>65 years; OR 1·56, 95% CI 1·22-1·98; 1·58, 1·25-1·99) as compared with adults (18-65 years; 1·09, 0·91-1·29; 1·10, 0·95-1·28); likewise in children or adolescents (<18 years) although the evidence was more uncertain (1·49, 0·81-2·75; 1·54, 0·85-2·77). Of 597 included RCTs, 30 (5%), 358 (60%), and 209 (35%) were rated at high, moderate, or low risk of bias, respectively. τ was zero for both analyses of the primary outcome (minimum estimate, maximum estimate). A Bayesian sensitivity analysis using external information on heterogeneity gave similar results. INTERPRETATION We found evidence that antipsychotics cause short-term somatic serious adverse events on top of somatic serious adverse events occurring independent of treatment. This effect appears to be mainly driven by results in older patients. Hence, clinicians should be aware that antipsychotics are potentially toxic, particularly when treating patients sharing risk factors with the older population. FUNDING German Ministry of Education and Research

Examining Side Effect Variability of Antipsychotic Treatment in Schizophrenia Spectrum Disorders: A Meta-analysis of Variance

Side effects of antipsychotic drugs play a key role in nonadherence of treatment in schizophrenia spectrum disorders (SSD). While clinical observations suggest that side effect variability between patients may be considerable, statistical evidence is required to confirm this. Here, we hypothesized to find larger side effect variability under treatment compared with control. We included double-blind, placebo-controlled, randomized controlled trials (RCTs) of adults with a diagnosis of SSD treated with 1 out of 14 antipsychotics. Standard deviations of the pre-post treatment differences of weight gain, prolactin levels, and corrected QT (QTc) times were extracted. The outcome measure was the variability ratio of treatment to control for individual antipsychotic drugs and the overall variability ratio of treatment to control across RCTs. Individual variability ratios were weighted by the inverse-variance method and entered into a random-effects model. We included N = 16 578 patients for weight gain, N = 16 633 patients for prolactin levels, and N = 10 384 patients for QTc time. Variability ratios (VR) were significantly increased for weight gain (VR = 1.08; 95% CI: 1.02-1.14; P = .004) and prolactin levels (VR = 1.38; 95% CI: 1.17-1.62; P < .001) but did not reach significance for QTc time (VR = 1.05; 95% CI: 0.98-1.12; P = 0.135). We found marked differences between individual antipsychotics and increased variability in side effects in patients under treatment with antipsychotics suggesting that subgroups of patients or individual patients may benefit from treatment allocation through stratified or personalized medicine