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An open-label extension study (NCT02873208) evaluated the long-term tolerability, safety, and efficacy of combination olanzapine/samidorphan (OLZ/SAM) treatment in patients with schizophrenia. This qualitative sub study explored perceptions of benefit, burden, and satisfaction with previous medications and OLZ/SAM.
Semi-structured interviews (60 minutes; audio-recorded) were conducted. Interviewer sensitivity training, senior interviewer oversight, and a list of common medications to aid recall supported data collection. Interview transcripts were content coded and analyzed (NVivo v11.0).
All 41 patients reported a lifetime burden with schizophrenia adversely impacting employment, relationships, emotional health, social activities, and daily tasks. Hospitalization for schizophrenia management was another reported aspect of disease burden. Although most (n=32) patients reported previous medication benefits, side effects affecting physical, emotional/behavioral, and cognitive functioning were reported by all (n=41). Following OLZ/SAM treatment, 39/41 patients (95%) reported improvements in symptoms including hallucinations, paranoia, depression, sleep, and concentration. Furthermore, patients described improvements in self-esteem, social activities, relationships, and daily activities. Twenty-three patients (56%) reported side effects attributed to OLZ/SAM; lack of energy (n=12 [29%]) and dry mouth (n= 5 [12%]) were most common. Twenty-four (59%) patients were “very satisfied” with OLZ/SAM; most (n=35 [85%]) preferred to continue OLZ/SAM vs switching to another medication. As most substudy patients (n=40; 98%) completed the extension study, satisfied patients may be overrepresented in this analysis.
This qualitative interview approach provided valuable insight into patients’ experiences with previous medications and OLZ/SAM. Overall, most patients reported treatment satisfaction and improvements in symptoms, function, and health-related quality of life with OLZ/SAM.
The randomized, controlled, phase 3b ALPINE study evaluated efficacy and safety of a 2-month formulation of aripiprazole lauroxil (AL) initiated with a 1-day regimen during hospitalization for an acute exacerbation of schizophrenia; paliperidone palmitate (PP) was included as an active control. The primary efficacy outcome, within-group change from baseline in PANSS total score at 4 weeks, was previously reported. Here we report additional exploratory PANSS subscale endpoints and patient-reported outcomes (PROs).
Adults aged 18–65 years were enrolled as inpatients and randomized to AL 1064 mg q8wk or PP 156 mg q4wk and discharged after 2 weeks of study treatment if clinically stable. Patients were followed as outpatients through week 25. Exploratory efficacy endpoints were PANSS subscale (Positive, Negative, and General) and Clinical Global Impression-Severity (CGI-S) scores. The Burden Assessment Scale was administered to patients’ nonprofessional caregivers (family member or friend). Exploratory PROs (Quality of Life Enjoyment and Satisfaction Questionnaire Short Form [Q-LES-Q-SF] and Medication Satisfaction Questionnaire) were assessed during the outpatient period. Within-group changes in PANSS subscales and CGI-S scores from baseline through week 25 were analyzed for AL and PP using mixed models with repeated measures. PROs were summarized based on observed data.
In total, 200 patients were randomized (AL, n=99; PP, n=101); 99 (AL, n=56; PP, n=43) completed the 25-week study. PANSS Positive, Negative, and General subscale scores improved with AL treatment as measured by change from baseline to week 25 (least squares [LS] mean [95% CI]: Positive, −7.0 [−8.1, −6.0]; Negative, −3.7 [−4.7, −2.8]; General, −11.1 [−12.7, −9.5]), as did CGI-S scores (LS mean [95% CI] change at week 25: –1.2 [–1.4 –1.0]). Caregiver burden decreased over the treatment period, with the largest decline noted at week 9 for AL patients’ caregivers (mean change from baseline at week 9: −8.4; week 25: −8.9). Over weeks 5, 9, and 17, 70.8%−74.7% of AL-treated patients were somewhat or very satisfied with treatment. Mean Q-LES-Q-SF total scores were stable. With PP, PANSS subscale and CGI-S scores improved from baseline to study end (LS mean [95% CI] changes at week 25: Positive, −7.1 [−8.2, −5.9]; Negative, −3.5 [−4.6, −2.5]; General, −10.4 [−12.1, −8.6]; CGI-S, −1.2 [−1.5, −1.0]). Mean caregiver burden decreased (week 9: −8.8; week 25: −9.2). Most PP patients were satisfied or very satisfied with treatment (64.7%−69.3% at weeks 5, 9, and 17), and mean Q-LES-Q-SF total scores were stable.
In ALPINE, patients who initiated AL or PP in the hospital and continued treatment during outpatient care experienced improvement in schizophrenia symptoms and reported satisfaction with medication, decreased caregiver burden, and stable quality of life.
Animal-derived dietary protein ingestion and physical activity stimulate myofibrillar protein synthesis rates in older adults. We determined whether a non-animal-derived diet can support daily myofibrillar protein synthesis rates to the same extent as an omnivorous diet. Nineteen healthy older adults (aged 66 (sem 1) years; BMI 24 (sem 1) kg/m2; twelve males, seven females) participated in a randomised, parallel-group, controlled trial during which they consumed a 3-d isoenergetic high-protein (1·8 g/kg body mass per d) diet, where the protein was provided from predominantly (71 %) animal (OMNI; n 9; six males, three females) or exclusively vegan (VEG; n 10; six males, four females; mycoprotein providing 57 % of daily protein intake) sources. During the dietary control period, participants conducted a daily bout of unilateral resistance-type leg extension exercise. Before the dietary control period, participants ingested 400 ml of deuterated water, with 50-ml doses consumed daily thereafter. Saliva samples were collected throughout to determine body water 2H enrichments, and muscle samples were collected from rested and exercised muscle to determine daily myofibrillar protein synthesis rates. Deuterated water dosing resulted in body water 2H enrichments of approximately 0·78 (sem 0·03) %. Daily myofibrillar protein synthesis rates were 13 (sem 8) (P = 0·169) and 12 (sem 4) % (P = 0·016) greater in the exercised compared with rested leg (1·59 (sem 0·12) v. 1·77 (sem 0·12) and 1·76 (sem 0·14) v. 1·93 (sem 0·12) %/d) in OMNI and VEG groups, respectively. Daily myofibrillar protein synthesis rates did not differ between OMNI and VEG in either rested or exercised muscle (P > 0·05). Over the course of a 3-d intervention, omnivorous- or vegan-derived dietary protein sources can support equivalent rested and exercised daily myofibrillar protein synthesis rates in healthy older adults consuming a high-protein diet.
Acute cannabis administration can produce transient psychotic-like effects in healthy individuals. However, the mechanisms through which this occurs and which factors predict vulnerability remain unclear. We investigate whether cannabis inhalation leads to psychotic-like symptoms and speech illusion; and whether cannabidiol (CBD) blunts such effects (study 1) and adolescence heightens such effects (study 2).
Two double-blind placebo-controlled studies, assessing speech illusion in a white noise task, and psychotic-like symptoms on the Psychotomimetic States Inventory (PSI). Study 1 compared effects of Cann-CBD (cannabis containing Δ-9-tetrahydrocannabinol (THC) and negligible levels of CBD) with Cann+CBD (cannabis containing THC and CBD) in 17 adults. Study 2 compared effects of Cann-CBD in 20 adolescents and 20 adults. All participants were healthy individuals who currently used cannabis.
In study 1, relative to placebo, both Cann-CBD and Cann+CBD increased PSI scores but not speech illusion. No differences between Cann-CBD and Cann+CBD emerged. In study 2, relative to placebo, Cann-CBD increased PSI scores and incidence of speech illusion, with the odds of experiencing speech illusion 3.1 (95% CIs 1.3–7.2) times higher after Cann-CBD. No age group differences were found for speech illusion, but adults showed heightened effects on the PSI.
Inhalation of cannabis reliably increases psychotic-like symptoms in healthy cannabis users and may increase the incidence of speech illusion. CBD did not influence psychotic-like effects of cannabis. Adolescents may be less vulnerable to acute psychotic-like effects of cannabis than adults.
Evaluate efficacy and safety of a 2-month dose of aripiprazole lauroxil (AL) with a 1-day initiation regimen during hospitalization for an acute exacerbation of schizophrenia.
In the phase 3b double-blind ALPINE study, adults with schizophrenia were randomized to AL (AL NanoCrystal® Dispersion + oral aripiprazole 30 mg day 1; AL 1064 mg day 8 and every 8 weeks) or paliperidone palmitate (PP 234 mg day 1; PP 156 mg day 8 and every 4 weeks). Patients were discharged after 2 weeks of hospitalization and followed through week 25. Primary endpoint was within-group changes in PANSS total score from baseline to week 4 (observed cases). Secondary analyses included within-group changes at weeks 9 and 25 (observed) and between-group comparisons at weeks 4, 9, and 25 (MMRM). Adverse events (AEs) were monitored throughout the study.
200 patients were randomized (AL, n=99; PP, n=101); 56.6% and 42.6%, respectively, completed the study. Within-group changes from baseline in PANSS were −17.4 for AL and −20.1 for PP at week 4 (both groups, P<0.001) and continued to decline at weeks 9 (AL, −19.8; PP, −22.5) and 25 (AL, −23.3; PP, −21.7). The change in PANSS over time was similar between groups. AEs occurring in ≥10% of patients in either group were injection site pain (AL, 17.2%; PP, 24.8%), akathisia (AL, 9.1%; PP, 10.9%), and weight increased (AL, 9.1%; PP, 16.8%).
AL and PP were effective and well-tolerated for initiating treatment of schizophrenia in the hospital and continuing in the outpatient setting.
Asenapine is a 2nd-generation antipsychotic currently marketed as a sublingual (SL) tablet in the US for the treatment of schizophrenia. HP-3070, asenapine transdermal system, is a patch for treatment of schizophrenia in adults. Low- and high- HP-3070 doses deliver asenapine concentrations that are similar to SL asenapine 5 mg BID and 10 mg BID, respectively, but with fewer peak and trough fluctuations.
In this Phase 3, randomized, double-blind, placebo (PBO)-controlled, 6-week inpatient study, adults with schizophrenia having baseline Positive and Negative Syndrome Scale (PANSS) total score ≥80 and Clinical Global Impression–Severity of Illness Scale (CGI-S) score ≥4 were randomized 1:1:1 to HP 3070 high-dose, HP-3070 low-dose, or PBO.
The primary efficacy objective was Week 6 PANSS score change from baseline (CFB) vs PBO.
The key secondary objective was Week 6 CGI-S CFB vs PBO. Safety assessments included treatment-emergent adverse events (TEAEs), laboratory results, vital signs, dermal safety, and extrapyramidal symptoms (EPS) assessments.
A total of 616 patients were randomized, with 486 patients completing the study. Discontinuation rates were 23.3%, 18.6%, and 21.4% for HP-3070 high-dose, HP-3070 low-dose, and PBO, respectively; withdrawal of consent and AEs were the most common reasons for discontinuation. Demographics and baseline characteristics were well-balanced among treatment groups.
For PANSS total score, least squares mean (LSM) (standard error [SE]) estimates of the treatment comparison (HP-3070 vs PBO) for CFB at Week 6 were -4.8 (1.634; 95% CI: -8.06, -1.64; p=0.003) and -6.6 (1.630; 95% CI: 9.81, 3.40; p<0.001) for HP-3070 high- and low-dose, respectively. For CGI-S CFB at Week 6, LSM (SE) for the treatment comparison were 0.4 (0.100; 95% CI: 0.55, 0.16; p<0.001) for HP 3070 high-dose and 0.4 (0.099; 95% CI: 0.64, 0.25; p<0.001) for low-dose.
No deaths or serious TEAEs related to study treatment occurred. The HP-3070 safety profile was consistent with SL asenapine. Incidence of TEAEs at the patch application site was higher for HP-3070 (14.2% high-dose, 15.2% low-dose) than for PBO (4.4%); most of these events were mild or moderate in severity. PBO patients had higher rates of psychiatric disorders (24.3% vs 15.7% and 17.6% for HP-3070 high- and low-dose, respectively), with insomnia and anxiety as most common. Study treatment discontinuations due to application site reactions or skin disorders were low (≤0.5%) across treatment groups. There was no marked mean CFB for vital signs or electrocardiogram parameters, nor treatment differences observed on EPS assessments.
In this study, HP-3070 was efficacious, safe, and well-tolerated for treating schizophrenia in adults; both doses met primary and key secondary endpoints. As the first transdermal antipsychotic patch in the US, HP-3070 will provide patients a novel treatment option.
Funded by Noven Pharmaceuticals, Inc., a wholly-owned subsidiary of Hisamitsu Pharmaceutical Co.
There is a paucity of long-term prospective disaster studies of the psychological sequelae among survivors.
At 1½ and 25 years after the Spitak earthquake, 142 early adolescents from two cities were assessed: Gumri (moderate–severe exposure) and Spitak (very severe exposure). The Gumri group included treated and not-treated subjects, while the Spitak group included not-treated subjects. Instruments included: DSM-III-R PTSD-Reaction Index (PTSD-RI); DSM-5 PTSD-Checklist (PCL); Depression Self-Rating Scale (DSRS); and Center for Epidemiological Studies-Depression Scale (CES-D).
(1) Between 1½ and 25 years, PTSD rates and mean scores decreased significantly in the three groups (over 50%). However, at 25 years 9.1–22.4% met DSM-5 PTSD criteria. (2) At 1½ years, the Spitak group had higher PTSD-RI (p < 0.001) and DSRS scores (p < 0.001) compared to the Gumri-not-treated group. At 25 years, the Spitak group that had experienced fewer post-earthquake adversities (p < 0.03), had a greater decrease in PTSD-RI scores (p < 0.02), and lower CES-D scores (p < 0.01). (3) Before treatment, PTSD-RI and DSRS scores did not differ between the Gumri-treated and not-treated groups. At 25-years, the Gumri-treated group showed a greater decrease in PTSD-RI scores (p < 0.03), and lower mean PTSD-RI (p < 0.02), PCL (p < 0.02), and CES-D (p < 0.01) scores. (4) Predictors of PTSD symptom severity at 25-years included: home destruction, treatment, social support, post-earthquake adversities, and chronic medical illnesses.
Post-disaster PTSD and depressive symptoms can persist for decades. Trauma-focused treatment, alleviation of post-disaster adversities, improving the social ecology, and monitoring for chronic medical illnesses are essential components of recovery programs.
Prevention of Clostridioides difficile infection (CDI) is a national priority and may be facilitated by deployment of the Targeted Assessment for Prevention (TAP) Strategy, a quality improvement framework providing a focused approach to infection prevention. This article describes the process and outcomes of TAP Strategy implementation for CDI prevention in a healthcare system.
Hospital A was identified based on CDI surveillance data indicating an excess burden of infections above the national goal; hospitals B and C participated as part of systemwide deployment. TAP facility assessments were administered to staff to identify infection control gaps and inform CDI prevention interventions. Retrospective analysis was performed using negative-binomial, interrupted time series (ITS) regression to assess overall effect of targeted CDI prevention efforts. Analysis included hospital-onset, laboratory-identified C. difficile event data for 18 months before and after implementation of the TAP facility assessments.
The systemwide monthly CDI rate significantly decreased at the intervention (β2, −44%; P = .017), and the postintervention CDI rate trend showed a sustained decrease (β1 + β3; −12% per month; P = .008). At an individual hospital level, the CDI rate trend significantly decreased in the postintervention period at hospital A only (β1 + β3, −26% per month; P = .003).
This project demonstrates TAP Strategy implementation in a healthcare system, yielding significant decrease in the laboratory-identified C. difficile rate trend in the postintervention period at the system level and in hospital A. This project highlights the potential benefit of directing prevention efforts to facilities with the highest burden of excess infections to more efficiently reduce CDI rates.
Sulfur-bearing monazite-(Ce) occurs in silicified carbonatite at Eureka, Namibia, forming rims up to ~0.5 mm thick on earlier-formed monazite-(Ce) megacrysts. We present X-ray photoelectron spectroscopy data demonstrating that sulfur is accommodated predominantly in monazite-(Ce) as sulfate, via a clino-anhydrite-type coupled substitution mechanism. Minor sulfide and sulfite peaks in the X-ray photoelectron spectra, however, also indicate that more complex substitution mechanisms incorporating S2– and S4+ are possible. Incorporation of S6+ through clino-anhydrite-type substitution results in an excess of M2+ cations, which previous workers have suggested is accommodated by auxiliary substitution of OH– for O2–. However, Raman data show no indication of OH–, and instead we suggest charge imbalance is accommodated through F– substituting for O2–. The accommodation of S in the monazite-(Ce) results in considerable structural distortion that may account for relatively high contents of ions with radii beyond those normally found in monazite-(Ce), such as the heavy rare earth elements, Mo, Zr and V. In contrast to S-bearing monazite-(Ce) in other carbonatites, S-bearing monazite-(Ce) at Eureka formed via a dissolution–precipitation mechanism during prolonged weathering, with S derived from an aeolian source. While large S-bearing monazite-(Ce) grains are likely to be rare in the geological record, formation of secondary S-bearing monazite-(Ce) in these conditions may be a feasible mineral for dating palaeo-weathering horizons.
OBJECTIVES/SPECIFIC AIMS: Given the poor prognosis of HCC and its increasing incidence worldwide, identifying biomarkers of HCC has been an active area of research. While biomarkers are being identified at a rapid pace, many are still in early phases of clinical study and very few have proven clinical utility. The objective of this study is to identify novel biomarkers of HCC and evaluate their clinical utility as predictors of disease development and prognosis with specific emphasis on disease recurrence after liver transplantation. Biomarkers will be identified through GWAS, as well as through analysis of qualitative and quantitative liver traits by magnetic resonance imaging (MRI). These novel biomarkers will then by implemented into risk prediction models aimed to assess an individual’s risk for development of HCC and stratify their level of risk according to predicted disease prognosis. METHODS/STUDY POPULATION: This will be a case-control study, analyzing data from previously created biorepositories from four cohorts of recipients across multiple centers which have undergone liver transplant. First, a GWAS will be performed to identify genetic variant(s). Second, pre-transplant MRI’s will be evaluated using CAVASS software to assess liver quantitative and qualitative traits, including visceral adiposity. Lastly, these findings will be implemented into risk stratification models to assess each individual’s level of risk for development of HCC and for recurrence of HCC after transplant. RESULTS/ANTICIPATED RESULTS: We hypothesize that genetic variant(s) are associated with positive HCV status and the development of HCC. Additionally, we hypothesize that increased visceral adiposity measured by MRI will have an association with recurrence of HCC after transplant. Lastly, we hypothesize that possession of these aforementioned features will be associated with an increased risk of HCC development and recurrence after transplant. DISCUSSION/SIGNIFICANCE OF IMPACT: As more is learned about the nature and reliability of these biomarkers, their potential clinical applications will be revealed. Ideally these proposed risk score models will ultimately be used by clinicians to provide personalized disease management while optimizing the allocation of health care resources. For instance, this may lead to changes in the MRI screening frequency of patients considered to be at high risk for HCC. The ability to diagnose patients early and provide personalized therapies may ultimately result in fewer disease related mortalities in the future.
The Tower Hamlets Crisis House (voluntary sector), in partnership with the local home treatment team, offers a brief residential alternative to psychiatric hospital admission. Here, we review clinician-reported (Health of the Nation Outcome Scales; HoNOS) and patient-reported (DIALOG) outcome scores collected from successive admissions between June 2015 and December 2016, to assess the effectiveness of the service model. We identified 153 successive admissions, and of these, 85 (55.6%) and 91 (59.5%) patients completed both admission and discharge DIALOG and HoNOS questionnaires, respectively. We analysed ten out of twelve HoNOS domains and eight patient-reported outcome measure DIALOG domains.
We found a statistically significant improvement in nine out of ten domains of HoNOS and three out of eight domains of DIALOG.
A partnership between a home treatment team and crisis house can result in positive outcomes for patients, as determined by both clinicians and patients.