Parkinson’s disease (PD) is a neurodegenerative disorder affecting over 10 million people worldwide. PD is characterized by both motor (e.g., tremor, rigidity, and bradykinesia) and non-motor (including cognitive impairment and neuropsychiatric symptoms such as apathy, disinhibition, executive dysfunction) symptoms. Caregiver burden is prevalent in those providing care for patients with PD and can result in negative health complications. Past work shows associations between motor symptoms, cognitive impairment, neuropsychiatric symptoms, and caregiver burden in PD. However, their relative contributions are poorly understood. This study examined these relationships, hypothesizing that while motor symptoms, cognitive impairment, and neuropsychiatric symptoms would all affect caregiver burden, neuropsychiatric symptoms would predict burden above and beyond the contribution of the other factors

Participants were 42 people living with PD who were assessed at a hospital-based tertiary movement disorders specialty clinic for deep brain stimulation (DBS) candidacy evaluation with their caregiver. Motor exam was assessed by a PD specialist using the Unified Parkinson’s Disease Rating Scale (UPDRS). The Mini Mental State Examination (MMSE) assessed global cognition. Frontal Systems Behavior Scale (FrSBe) Family Form captured caregiver ratings of neuropsychiatric symptoms under 3 subscales: apathy, disinhibition, and executive dysfunction. The Multidimensional Caregiver Strain Index (MCSI) captured caregiver burden. Linear regression analyses examined relationships between caregiver burden (MCSI) and motor symptoms (UPDRS), cognitive impairment (MMSE), and neuropsychiatric symptoms (FrSBe).

Using linear regression analyses, cognitive impairment (R2=0.08, F(1,41)=4.42, p=0.04) and neuropsychiatric symptoms (R2=0.35, F(1, 41)=21.0, p<0.01) predicted caregiver burden but motor symptoms did not (R2=0.03, F(1,41)=1.30, p=0.26). Hierarchical linear regression revealed that neuropsychiatric symptoms predicted caregiver burden above and beyond the contribution of cognitive impairment (AR2=0.28, AF(1)=12.7, p=0.001), accounting for an additional 28% of the variance in caregiver burden. Follow-up linear regression to examine the relationships between caregiver burden and the FrSBe subscales indicated that apathy (p<0.001), versus disinhibition (p=0.16) and dysexecutive behaviors (p=0.80), was the driver of the significant relationship.

Consistent with our hypothesis, results revealed that cognitive impairment and neuropsychiatric symptoms (specifically apathy) were independent predictors of caregiver burden, with neuropsychiatric symptoms predicting caregiver burden above and beyond the contribution of cognitive impairment. Somewhat surprisingly, motor symptoms were not a predictor of caregiver burden contrary to some previous research, though findings are mixed. Results highlight the importance of assessing for neuropsychiatric symptoms in PD, which may be overlooked by care providers relative to motor or cognitive symptoms, but which appear stressful to caregivers. Future directions include reexamining results in a larger more heterogenous sample including people living with PD at different disease stages (i.e., everyone in the present sample had severe enough symptoms to be considering DBS). Cognitive measures of executive functioning (which are more specific to PD than measures of global cognition) should also be included in future works. Development of supportive caregiver interventions specifically targeting apathy in PD may be useful. Longitudinal designs would be helpful to reexamine relationships following DBS surgery, as there are some reports of increased neuropsychiatric symptoms following the procedure.

Major depressive disorder (MDD) contributes to suicide risk. Treating MDD effectively is considered a key suicide prevention intervention. Yet many patients with MDD do not respond to their initial medication and require a ‘next-step’. The relationship between next-step treatments and suicidal thoughts and behaviors is uncharted.

The VA Augmentation and Switching Treatments for Depression trial randomized 1522 participants to one of three next-step treatments: Switching to Bupropion, combining with Bupropion, and augmenting with Aripiprazole. In this secondary analysis, features associated with lifetime suicidal ideation (SI) and attempts (SA) at baseline and current SI during treatment were explored.

Compared to those with SI only, those with lifetime SI + SA were more likely to be female, divorced, or separated, unemployed; and to have experienced more childhood adversity. They had a more severe depressive episode and were more likely to respond to ‘next-step’ treatment. The prevalence of SI decreased from 46.5% (694/1492) at baseline to 21.1% (315/1492) at end-of-treatment. SI during treatment was associated with baseline SI; low positive mental health, more anxiety, greater severity and longer duration of current MDD episode; being male and White; and treatment with S-BUP or C-BUP as compared to A-ARI.

SI declines for most patients during next-step medication treatments. But about 1 in 5 experienced emergent or worsening SI during treatment, so vigilance for suicide risk through the entire 12-week acute treatment period is necessary. Treatment selection may affect the risk of SI.

To describe the development and implementation of a novel tool designed to enhance nurse–patient communication in a major academic cancer center, which nurses can learn quickly, incorporate into their primary palliative care practice, and broadly disseminate in order to improve the patient experience.

An evidence-based empathic communication tool and educational program were designed to provide essential skills to oncology nurses in having discussions with patients about their personal values. Evaluation included nurse focus groups, pre- and post-course evaluations and interviews, and patient questionnaires.

Nurses were satisfied with the educational program and found the communication tool effective in a variety of clinical situations including discussions about personal values. Patients reported increased occurrences of these discussions when nurses utilized the framework (97% vs. 58%, p < 0.0001) and a higher quality of clinician communication (mean [SD] from 0 = very worst to 10 = very best: 7.18 [2.3] vs. 5.04 [2.9], p = 0.001).

Skilled, empathic communication is an essential component of high-quality primary palliative care. Oncology nurses are well suited to lead communication and provide this care as part of an interprofessional team. The training and tool described here are targeted and efficient, and prepare nurses to respond skillfully to emotion while facilitating important discussions about patient values.

Lumateperone (lumateperone tosylate, ITI-007) is an investigational drug for the treatment of schizophrenia, bipolar depression, and other disorders. Lumateperone has a unique mechanism of action that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission. This may provide advantages in the treatment of the broad symptoms associated with schizophrenia, including negative and depression symptoms. In 2 previous placebo-controlled trials in patients with acute schizophrenia, lumateperone 42mg (ITI-007 60mg) demonstrated statistically significant improvement in the Positive and Negative Syndrome Scale (PANSS) Total score compared with placebo. In these studies, lumateperone was well tolerated with a safety profile similar to placebo. This open-label long-term study evaluated the safety and effectiveness of lumateperone 42mg in patients with schizophrenia and stable symptoms.

Patients with stable schizophrenia were treated for up to 1 year with lumateperone 42mg. Safety assessments included adverse events (AEs), body weight, laboratory parameters, and extrapyramidal symptoms (EPS)/motor symptom assessments. Efficacy analyses included evaluation of changes in PANSS Total score and in depression symptoms, as measured by the Calgary Depression Scale for Schizophrenia (CDSS).

In the 1-year open-label study, 602 patients received at least 1 dose of lumateperone 42mg; at the time of this interim analysis, 107 patients had completed 1 year of treatment. Only 4 TEAEs occurred in ≥5% of patients (weight decrease, dry mouth, headache and diarrhea); the majority of AEs were mild or moderate in intensity. Most metabolic parameters and mean prolactin levels decreased from SOC baseline, as did mean body weight and BMI. Based on AE reporting and EPS/motor symptom scales, lumateperone treatment was associated with minimal EPS risk. Lumateperone 42mg treatment was associated with significant reductions in PANSS Total score from baseline, with continuing PANSS improvement throughout the study. In patients with moderate-to-severe depression symptoms at baseline (CDSS>5), mean CDSS scores decreased from 7.4 (baseline) to 3.1 (Day 300); 60% of patients met CDSS response criteria (50% improvement from baseline) by Day 75 and this response rate was maintained through day 300. Similar magnitude of CDSS improvement was seen regardless of concurrent antidepressant therapy.

In long-term treatment, lumateperone was associated with minimal metabolic, EPS, and cardiovascular safety issues relative to current SOC antipsychotic therapy. Lumateperone improved schizophrenia symptoms with continued long-term treatment. In patients with moderate-to-severe depression symptoms at baseline, lumateperone treatment was associated with marked improvement in CDSS scores. These data are consistent with and extend data previously reported in placebo-controlled studies in patients with acute schizophrenia treated with lumateperone.

Supported by funding from Intra-Cellular Therapies, Inc.

Lumateperone (ITI-007) is in late-phase clinical development for schizophrenia. Lumateperone has a unique mechanism of action that modulates serotonin, dopamine, and glutamate neurotransmission. This pooled analysis of lumateperone in 3 randomized, double-blind, placebo-controlled studies was conducted to evaluate the safety and tolerability of lumateperone 42mg (ITI-007 60mg).

Data were pooled from the 3 controlled late-phase studies of lumateperone 42mg in patients with acute exacerbation of schizophrenia. Safety assessments of all patients who received at least one dose of any treatment included treatment-emergent adverse events (TEAEs), changes in laboratory parameters, extrapyramidal symptoms (EPS), and vital signs.

The safety population comprised 1,073 patients (placebo [n=412], lumateperone 42mg [n=406], risperidone [n=255]). TEAEs that occurred in the lumateperone 42mg group at a rate of ≥5% and twice placebo were somnolence/sedation (24.1% vs 10.0%) and dry mouth (5.9% vs 2.2%). Rates of discontinuation due to TEAEs with lumateperone 42mg (0.5%) were similar to placebo (0.5%) and lower than risperidone (4.7%). Mean change in weight and rates of EPS-related TEAEs were less for lumateperone 42mg and placebo patients than risperidone patients. Mean change from baseline in metabolic parameters were similar or smaller for lumateperone 42mg vs placebo. Mean changes were notably higher in risperidone patients vs lumateperone 42mg and placebo for glucose, cholesterol, triglycerides, and prolactin.

In this pooled analysis, lumateperone 42mg showed good tolerability with potential benefits over risperidone for metabolic, prolactin, and EPS risks. The only TEAE that occurred in >10% of lumateperone patients was somnolence/sedation, which was impacted by morning administration; in subsequent studies that administered lumateperone in the evening, somnolence/sedation rates were markedly reduced. These results suggest that lumateperone 42mg may be a promising new treatment for schizophrenia.

Supported by funding from Intra-Cellular Therapies, Inc.

Lumateperone is a first-in-class agent in development for schizophrenia that acts synergistically through serotonergic, dopaminergic and glutamatergic systems. Lumateperone is a potent 5-HT2A antagonist, a mesolimbic/mesocortical dopamine phosphoprotein modulator (DPPM) with pre-synaptic partial agonist and post-synaptic antagonist activity at D2, a glutamate GluN2B receptor phosphoprotein modulator with D1-dependent enhancement of both NMDA and AMPA currents via the mTOR protein pathway and an inhibitor of serotonin reuptake.

Lumateperone was evaluated in 3 controlled clinical trials to evaluate efficacy in patients with acute schizophrenia. The primary endpoint was change from baseline on the PANSS total score compared to placebo. In Study ‘005, 335 patients were randomized to receive ITI-007 60mg or 120mg , risperidone 4mg (active control) or placebo QAM for 4weeks. In Study ‘301, 450 patients were randomized to receive ITI-007 60mg or 40mg , or placebo QAM for 4weeks. In Study ‘302, 696 patients were randomized to receive ITI-007 60mg or 20mg , risperidone 4mg (active control) or placebo QAM for 6weeks. Also, an open-label safety switching study was conducted in which 302 patients with stable schizophrenia were switched from standard-of-care (SOC) antipsychotics and treated for 6weeks with lumateperone QPM and then switched back to SOC.

In Studies ‘005 and ‘301, lumateperone (60mg ITI-007) met the primary endpoint with statistically significant superior efficacy over placebo at Day 28. In Study ‘302, neither dose of lumateperone separated from placebo on the primary endpoint; a high placebo response was observed in this study. Across all 3 efficacy trials, lumateperone improved symptoms of schizophrenia with the same trajectory and same magnitude of improvement from baseline to endpoint on the PANSS total score.

Lumateperone was well-tolerated with a favorable safety profile in all studies. In the two studies with risperidone included as an active control, lumateperone was statistically significantly better than risperidone on key safety and tolerability measures. In the open-label safety switching study statistically significant improvements from SOC were observed in body weight, cardiometabolic and endocrine parameters worsened again when switched back to SOC medication. In this study, symptoms of schizophrenia generally remained stable or improved. Greater improvements were observed in subgroups of patients with elevated symptomatology (comorbid symptoms of depression and those with prominent negative symptoms).

Lumateperone represents a novel approach to the treatment of schizophrenia with a favorable safety profile in clinical trials. The lack of cardiometabolic and motor safety issues presents a safety profile differentiated from standard-of-care antipsychotic therapy.

Funding Acknowledgements: Intra-Cellular Therapies, Inc.

Surgical site infections (SSIs) following colorectal surgery (CRS) are among the most common healthcare-associated infections (HAIs). Reduction in colorectal SSI rates is an important goal for surgical quality improvement.

To examine rates of SSI in patients with and without cancer and to identify potential predictors of SSI risk following CRS

American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) data files for 2011–2013 from a sample of 12 National Comprehensive Cancer Network (NCCN) member institutions were combined. Pooled SSI rates for colorectal procedures were calculated and risk was evaluated. The independent importance of potential risk factors was assessed using logistic regression.

Multicenter study

Of 22 invited NCCN centers, 11 participated (50%). Colorectal procedures were selected by principal procedure current procedural technology (CPT) code. Cancer was defined by International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes.

The primary outcome of interest was 30-day SSI rate.

A total of 652 SSIs (11.06%) were reported among 5,893 CRSs. Risk of SSI was similar for patients with and without cancer. Among CRS patients with underlying cancer, disseminated cancer (SSI rate, 17.5%; odds ratio [OR], 1.66; 95% confidence interval [CI], 1.23–2.26; P=.001), ASA score ≥3 (OR, 1.41; 95% CI, 1.09–1.83; P=.001), chronic obstructive pulmonary disease (COPD; OR, 1.6; 95% CI, 1.06–2.53; P=.02), and longer duration of procedure were associated with development of SSI.

Patients with disseminated cancer are at a higher risk for developing SSI. ASA score >3, COPD, and longer duration of surgery predict SSI risk. Disseminated cancer should be further evaluated by the Centers for Disease Control and Prevention (CDC) in generating risk-adjusted outcomes.

Infect Control Hosp Epidemiol 2018;39:555–562

A number of copy number variants (CNVs) have been suggested as susceptibility factors for schizophrenia. For some of these the data remain equivocal, and the frequency in individuals with schizophrenia is uncertain.

To determine the contribution of CNVs at 15 schizophrenia-associated loci (a) using a large new data-set of patients with schizophrenia (n = 6882) and controls (n = 6316), and (b) combining our results with those from previous studies.

We used Illumina microarrays to analyse our data. Analyses were restricted to 520 766 probes common to all arrays used in the different data-sets.

We found higher rates in participants with schizophrenia than in controls for 13 of the 15 previously implicated CNVs. Six were nominally significantly associated (P<0.05) in this new data-set: deletions at 1q21.1, NRXN1, 15q11.2 and 22q11.2 and duplications at 16p11.2 and the Angelman/Prader–Willi Syndrome (AS/PWS) region. All eight AS/PWS duplications in patients were of maternal origin. When combined with published data, 11 of the 15 loci showed highly significant evidence for association with schizophrenia (P<4.1×10−4).

We strengthen the support for the majority of the previously implicated CNVs in schizophrenia. About 2.5% of patients with schizophrenia and 0.9% of controls carry a large, detectable CNV at one of these loci. Routine CNV screening may be clinically appropriate given the high rate of known deleterious mutations in the disorder and the comorbidity associated with these heritable mutations.