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Background: Elective egg freezing decisions are complex. We developed a Decision Aid for elective egg freezing and conducted a phase 1 study to evaluate its acceptability and utility for decision-making., Methods: The online Decision Aid was developed according to International Patient Decision Aid Standards and evaluated using a pre/post survey design. Twenty-six Australian women aged 18-45 years, interested in receiving elective egg freezing information, proficient in English, and with access to the internet were recruited using social media and university newsletters. Main outcomes were: acceptability of the Decision Aid; feedback on the Decision Aid design and content; concern raised by the Decision Aid, and; utility of the Decision Aid as measured by scores on the Decisional Conflict Scale and on a study-specific scale assessing knowledge about egg freezing and age-related infertility., Results: Most participants found the Decision Aid acceptable (23/25), balanced (21/26), useful for explaining their options (23/26), and for reaching a decision (18/26). Almost all reported satisfaction with the Decision Aid (25/26) and the level of guidance  it provided (25/26). No participant reported serious concerns about the Decision Aid, and most would recommend it to other women considering elective egg freezing (22/26). Median Decisional Conflict Scale score decreased from 65/100 (Interquartile range: 45-80) pre-Decision Aid to 7.5/100 (Interquartile range: 0-37.5) post-Decision Aid review (p < 0.001). Median knowledge score increased from 8.5/14 (Interquartile range: 7-11) pre-Decision Aid to 11/14 (Interquartile range: 10-12) post-Decision Aid review (p = 0.01)., Conclusion: This elective egg freezing Decision Aid appears acceptable and useful for decision-making. It improved knowledge, reduced decisional conflict and did not raise serious concerns. The Decision Aid will be further evaluated using a prospective randomised control trial., Study Registration: ACTRN12618001685202 (retrospectively registered: 12 October 2018)., (© 2023. The Author(s).)

Schizophrenia is a chronic, heterogeneous, severe psychiatric disorder characterized by a spectrum of symptomology and is associated with substantial morbidity and mortality. For the last 70 years, available treatments have shared blockade of dopamine D2 receptors as their primary mechanism of action (MOA), the efficacy of which has been limited by incomplete resolution of all symptoms as well as treatment non-response in a select subset of patients. In addition, antipsychotics are associated with class-related side effects attributed to this primary MOA, including extrapyramidal symptoms (EPS). The need for non-D2 treatment options for patients which offer a novel risk/benefit profile is therefore apparent. There has been substantial investment in the research and development of non-D2 drug candidates. However, none of these programs have received successful regulatory approval by the FDA (as of Oct 2022). In this article, the scale of industry-sponsored clinical trials for D2-based investigational pharmacological treatments in schizophrenia was quantified and compared with investigational compounds with non-D2 MOAs. In a dataset of 545 clinical trials identified in ClinicalTrials.gov from January 2002 to July 2022, total enrollments in trials of non-D2-based compounds for the treatment of schizophrenia summed to approximately 34,000 patients, compared with 27,144 patients for D2-based compounds. These data indicate that there remains substantial and ongoing investment in the development of novel non-D2 options for schizophrenia, with a success rate measured by regulatory approval that is well-below recent benchmarks for the broader category of CNS drugs. Improved trial design, conduct, endpoints, and analyses/methods may influence signal detection and reliability to support development and registration of non-D2 compounds.

Inhibitors of dopamine transporters (DAT), norepinephrine transporters (NET) and serotonin transporters (SERT) are effective treatments for neuropsychiatric diseases. Dasotraline [(1R,4 S)- 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-1-naphthalenamine, also known as SEP-225289) was evaluated for its inhibitory potency at DAT, NET and SERT using in vitro and in vivo assays. In vitro radiometric functional uptake studies showed preferential inhibition by dasotraline of hDAT (IC 50 =3 nM) and hNET (IC 50 =4 nM relative to hSERT(IC 50 =15 nM). In mouse ex vivo occupancy studies, dasotraline demonstrated total plasma concentration-dependent occupancy at DAT, NET and SERT. Determination of the TO 50 (50% transporter occupancy) were 32, 109 and 276 ng/ml, respectively. In SPECT imaging studies in baboons, dasotraline (0.2 mg/kg iv) displaced radiotracer binding to DAT by 87% but only 20% at NET and SERT. Rat microdialysis studies were performed in prefrontal cortex and striatum. Dasotraline produced sustained (>4 h) increases in dopamine and norepinephrine concentrations. Dasotraline was also more potent at increasing synaptic dopamine in the striatum, and norepinephrine in the prefrontal cortex than serotonin in these regions. In summary, dasotraline preferentially inhibits DAT and NET relative to SERT. Together, the occupancy and neurochemical profile of dasotraline provide a mechanistic basis for the treatment of diseases that have an underlying causality involving dopamine and norepinephrine dysfunction., Competing Interests: Conflict of interest statement All authors of this article were employees of Sepracor Inc. (which subsequently became Sunovion Pharmaceuticals) when the research studies described herein were conducted., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: High levels of inflammation pre- and post-percutaneous coronary intervention (PCI) are associated with worse outcomes. Recent trials have suggested a benefit from treating inflammation with colchicine in coronary artery disease. In this randomised pilot COPE-PCI sub-study, we aimed to determine if administration of colchicine pre-PCI, would attenuate the inflammatory effect of PCI., Methods: PCI patients were randomised to colchicine or placebo, 6 to 24-hours pre-procedure. Study blood samples were taken immediately pre-PCI, and 24-hours post-procedure. Samples were tested for a broad array of inflammatory biomarkers including high-sensitive(hs)-CRP, leucocyte counts, and hs-troponin-. Periprocedural Myocardial Injury (PM-Injury) was defined as per the ESC Third Universal Definitions of Myocardial Infarction., Results: Thirty-six were randomised to colchicine and 39 to placebo. Treatment groups were similar for baseline variables. The median time from drug administration to pre-PCI blood sampling was 18-hours. Overall inflammation was low across the patient population, pre- & post-PCI hsCRP was <1.4 mg/L. Colchicine patients had numerically lower levels of pre-PCI cytokines: IL-1β (p = 0.01), IL-6 (p = 0.02), IL-10 (p = 0.01), IFNγ (p = 0.01), TNFα (p = 0.02) and WBC-count (p = 0.04). Post-PCI (38-hours post-drug) measures of inflammation were similar between treatment arms. Absolute troponin change (post-PCI - pre-PCI levels) was less in colchicine patients (p = 0.02)., Conclusion: The reduction in PCI-related myocardial injury that resulted from colchicine given on median 18 h pre-PCI, was associated with numerically lower levels of inflammation pre-PCI but no difference one day post-PCI in the colchicine vs placebo groups., Clinical Trial Registration: The trial was publicly registered at www.anzctr.org.au, Trial ID: ACTRN12615000485538., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: In this randomized pilot trial, we aimed to assess the anti-inflammatory effect of preprocedural colchicine on coronary microvascular physiology measurements before and after PCI., Methods: Patients undergoing PCI for stable angina (SA) or non-ST-elevation myocardial infarction (NSTEMI) were randomized to oral colchicine or placebo, 6- to 24-hours before the procedure. Strict prespecified inclusion/exclusion criteria were set to ensure all patients were given the study medication, had a PCI, and had pre- and post-PCI culprit vessel invasive coronary physiology measurements. Fractional flow reserve (FFR), Index of Microvascular Resistance (IMR), Coronary Flow Reserve (CFR), and Resistive Reserve Ratio (RRR) were measured immediately before and after PCI. CMVD was defined as any one of post-PCI IMR >32 or CFR <2 or RRR <2. High-sensitive-(hs)-troponin-I, hsCRP, and leucocyte count were measured before and 24 hours after PCI., Results: A total of 50 patients were randomized and met the strict prespecified inclusion/exclusion criteria: 24-colchicine and 26-placebo. Pre-PCI coronary physiology measurements, hs-troponin-I, and hsCRP were similar between groups. Although numerically lower in patients given colchicine, the proportion of patients who developed CMVD was not significantly different between groups (colchicine: 10 (42%) vs placebo: 16 (62%), p =0.16). Colchicine patients had higher post-PCI CFR and RRR vs placebo (respectively: 3.25 vs 2.00, p =0.03 & 4.25 vs 2.75, p < 0.01). Neutrophil count was lower after PCI in the colchicine arm ( p =0.02), and hsCRP post-PCI remained low in both treatment arms (1.0 mg/L vs 1.7 mg/L, p =0.97). Patients randomized to colchicine had significantly less PCI-related absolute hs-troponin-I change (46 ng/L vs 152 ng/L, p =0.01)., Conclusion: In this pilot randomized substudy, colchicine given 6 to 24 hours before PCI did not statistically impact the post-PCI CMVD definition used in this study, yet it did improve post-PCI RRR and CFR measurements, with less procedure-related troponin release and less inflammation., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Justin Cole et al.)

The WEPPcloud interface is a new online decision-support tool for the Water Erosion Prediction Project (WEPP) model that facilitates data preparation and model runs, and summarizes model outputs into tables and maps that are easily interpretable by users. The interface can be used by land and water managers in United States, Europe, and Australia interested in simulating streamflow, sediment and pollutant loads from both undisturbed and disturbed (e.g. post-wildfire or post-treatment such as thinning or prescribed fires) forested watersheds. This article contains full hydrologic model runs for 28 forested watersheds in the U.S. Pacific Northwest with the WEPPcloud online interface. It also includes links to repositories with the individual model runs, a table containing default model parameters for disturbed conditions, and figures with model outputs as compared to observed data. The data in the repositories include all the raw data input and output from the model as well as the processed data, which can be accessed through tables and shapefiles to provide additional insights into the model outputs. Lastly, the article describes how the data are organized and the content of each folder containing the data. These model runs are useful for anyone interested in modeling forested watersheds with the WEPPcloud interface., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Objective: Improved biomarkers of current disease activity and prediction of relapse are needed in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). For clinical relevance, biomarkers must perform well longitudinally in patients on treatment and in patients with nonsevere flares., Methods: Twenty-two proteins were measured in 347 serum samples from 74 patients with AAV enrolled in a clinical trial. Samples were collected at Month 6 after remission induction, then every 3 months until Month 18, or at the time of flare. Associations of protein concentrations with concurrent disease activity and with future flare were analyzed using mixed-effects models, Cox proportional hazards models, and conditional logistic regression., Results: Forty-two patients had flares during the 12-month follow-up period, and 32 remained in remission. Twenty-two patients had severe flares. Six experimental markers (CXCL13, IL-6, IL-8, IL-15, IL-18BP, and matrix metalloproteinase-3 [MMP-3]) and ESR were associated with disease activity using all three methods (P < 0.05, with P < 0.01 in at least one method). A rise in IL-8, IL-15, or IL-18BP was associated temporally with flare. Combining C-reactive protein (CRP), IL-18BP, neutrophil gelatinase-associated lipocalin (NGAL), and sIL-2Rα improved association with active AAV. CXCL13 and MMP-3 were increased during treatment with prednisone, independent of disease activity. Marker concentrations during remission were not predictive of future flare., Conclusion: Serum biomarkers of inflammation and tissue damage and repair have been previously shown to be strongly associated with severe active AAV were less strongly associated with active AAV in a longitudinal study that included mild flares and varying treatment. Markers rising contemporaneously with flare or with an improved association in combination merit further study., (© 2021 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: To address the US opioid epidemic, there is an urgent clinical need to provide persons with opioid use disorder (OUD) with effective medication treatments for OUD (MOUD). Formulations of sublingual buprenorphine/naloxone (SL-BUP/NLX) are considered the standard of care for OUD including within the Veterans Healthcare Administration (VHA). However, poor retention on MOUD undermines its effectiveness. Long-acting injectable monthly buprenorphine (INJ-BUP) (e.g., Sublocade®) has the potential to improve retention and therefore reduce opioid use and overdose. Designing and conducting studies for OUD pose unique challenges. The strategies and solutions to some of these considerations in designing Cooperative Studies Program (CSP) 2014, Buprenorphine for Treating Opioid Use Disorder in Veterans (VA-BRAVE), a randomized, 20-site, clinical effectiveness trial comparing INJ-BUP to SL-BUP/NLX conducted within the VHA may provide valuable guidance for others confronted with similar investigation challenges., Methods: This 52-week, parallel group, open-label, randomized controlled trial (RCT) evaluates the comparative effectiveness of two current FDA-approved formulations of buprenorphine: (1) daily SL-BUP/NLX vs. (2) monthly (28-day) INJ-BUP for Veterans with moderate to severe OUD (n = 952). The primary outcomes are (1) retention in MOUD and (2) opioid abstinence. Secondary outcomes include measures of other drug use, psychiatric symptoms, medical outcomes including prevalence rates of HIV, hepatitis B and C as well as social outcomes (housing instability, criminal justice involvement), service utilization and cost-effectiveness. Special considerations in conducting a comparative effectiveness trial with this population and during COVID-19 pandemic were also included., Discussion: The evaluation of the extended-release formulation of buprenorphine compared to the standard sublingual formulation in real-world VHA settings is of paramount importance in addressing the opioid epidemic. The extent to which this new treatment facilitates retention, decreases opioid use, and prevents severe sequelae of OUD has not been studied in any long-term trial to date. Positive findings in this trial could lead to widespread adoption of MOUD, and, if proven superior INJ-BUP, by clinicians throughout the VHA and beyond. This treatment has the potential to reduce opioid use among Veterans, improve medical, psychological, and social outcomes, and save lives at justifiable cost. Trial registration Registered at Clinicaltrials.gov NCT04375033., (© 2022. The Author(s).)

Importance: Suicide and suicide attempts are persistent and increasing public health problems. Observational studies and meta-analyses of randomized clinical trials have suggested that lithium may prevent suicide in patients with bipolar disorder or depression., Objective: To assess whether lithium augmentation of usual care reduces the rate of repeated episodes of suicide-related events (repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event., Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial assessed lithium vs placebo augmentation of usual care in veterans with bipolar disorder or depression who had survived a recent suicide-related event. Veterans at 29 VA medical centers who had an episode of suicidal behavior or an inpatient admission to prevent suicide within 6 months were screened between July 1, 2015, and March 31, 2019., Interventions: Participants were randomized to receive extended-release lithium carbonate beginning at 600 mg/d or placebo., Main Outcomes and Measures: Time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide., Results: The trial was stopped for futility after 519 veterans (mean [SD] age, 42.8 [12.4] years; 437 [84.2%] male) were randomized: 255 to lithium and 264 to placebo. Mean lithium concentrations at 3 months were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depressive disorder. No overall difference in repeated suicide-related events between treatments was found (hazard ratio, 1.10; 95% CI, 0.77-1.55). No unanticipated safety concerns were observed. A total of 127 participants (24.5%) had suicide-related outcomes: 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and 3 in the placebo group., Conclusions and Relevance: In this randomized clinical trial, the addition of lithium to usual Veterans Affairs mental health care did not reduce the incidence of suicide-related events in veterans with major depression or bipolar disorders who experienced a recent suicide event. Therefore, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events in patients who are actively being treated for mood disorders and substantial comorbidities., Trial Registration: ClinicalTrials.gov Identifier: NCT01928446.

Objectives: To identify barriers and enablers to motherhood experienced by female doctors in Australia., Methods: Semi-structured telephone interviews were conducted with 18 female physician-mothers in Australia, during March and May 2020. Interview data were examined using thematic analysis to extract key themes., Results: Six key barriers and seven key enablers were identified. Barriers (B1-6) largely reflected structural and cultural issues operating within health services and the wider medical profession. Barriers were the experience of working in medicine (B1); demands of postgraduate specialty training (B2); attitudes towards mothers in medicine (B3); gender inequality (B4); insufficient entitlements and support (B5); and competing priorities, conflicting roles (B6). Enablers were supportive partnerships (E1); break from traditional gender roles (E2); capacity to delegate/outsource (E3); doctors supporting doctors (E4); flexible work arrangements (E5); increasing acceptance and support (E6); and capacity to combine career and family (E7)., Conclusion: This was the first qualitative study to explore motherhood experiences among female doctors in Australia. Participants reported structural and cultural barriers during all stages of motherhood. The mismatch between identified barriers and available supports reveals opportunities for improving the experience of physician-mothers.

Background: Uptake of elective egg freezing has increased globally. The decision to freeze eggs is complex, and detailed, unbiased information is needed. To address this, we developed an online Decision Aid for women considering elective egg freezing. Decision Aids are the standard of care to support complex health decisions., Objectives: This study will measure the impact of the Decision Aid on decision-making (e.g. decisional conflict, engagement in decision-making, distress, and decision delay) and decision quality (e.g. knowledge, level of informed choice, and regret)., Methods and Analysis: A single-blinded two-arm parallel-group randomized controlled trial. Women considering elective egg freezing will be recruited using social media, newsletters, and fertility clinics. Data will be collected at baseline (recruitment), 6-month, and 12-month post-randomization. The primary hypothesis is that the intervention (Decision Aid plus Victorian Assisted Reproductive Technology Authority website) will reduce decisional conflict (measured using the Decisional Conflict Scale) at 12 months more than control (Victorian Assisted Reproductive Technology Authority website only). Secondary outcomes include engagement in decision-making (Perceived Involvement in Care Scale), distress (Depression, Anxiety, and Stress Scale), decision delay, knowledge, informed choice (Multi-dimensional Measure of Informed Choice), and decisional regret (Decisional Regret Scale)., Ethics: The study was approved by the University of Melbourne Human Research Ethics Committee (Ethics ID: 2056457). Informed consent will be obtained from all participants prior to enrolment., Discussion: This is the first international randomized controlled trial that aims to investigate the effect of an elective egg freezing Decision Aid on decision-related outcomes (e.g. decisional conflict, informed choice, and regret). It is anticipated that participants who receive the Decision Aid will have better decision and health outcomes., Registration Details: ACTRN12620001032943: Comparing different information resources on the process and quality of decision-making in women considering elective egg freezing.

The 2019/2020 Australian bushfires (or wildfires) burned the largest forested area in Australia's recorded history, with major socio-economic and environmental consequences. Among the largest fires was the 280 000 ha Green Wattle Creek Fire, which burned large forested areas of the Warragamba catchment. This protected catchment provides critical ecosystem services for Lake Burragorang, one of Australia's largest urban supply reservoirs delivering ~85% of the water used in Greater Sydney. Water New South Wales (WaterNSW) is the utility responsible for managing water quality in Lake Burragorang. Its postfire risk assessment, done in collaboration with researchers in Australia, the UK, and United States, involved (i) identifying pyrogenic contaminants in ash and soil; (ii) quantifying ash loads and contaminant concentrations across the burned area; and (iii) estimating the probability and quantity of soil, ash, and associated contaminant entrainment for different rainfall scenarios. The work included refining the capabilities of the new WEPPcloud-WATAR-AU model (Water Erosion Prediction Project cloud-Wildfire Ash Transport And Risk-Australia) for predicting sediment, ash, and contaminant transport, aided by outcomes from previous collaborative postfire research in the catchment. Approximately two weeks after the Green Wattle Creek Fire was contained, an extreme rainfall event (~276 mm in 72 h) caused extensive ash and sediment delivery into the reservoir. The risk assessment informed on-ground monitoring and operational mitigation measures (deployment of debris-catching booms and adjustment of the water supply system configuration), ensuring the continuity of safe water supply to Sydney. WEPPcloud-WATAR-AU outputs can prioritize recovery interventions for managing water quality risks by quantifying contaminants on the hillslopes, anticipating water contamination risk, and identifying areas with high susceptibility to ash and sediment transport. This collaborative interaction among scientists and water managers, aimed also at refining model capabilities and outputs to meet managers' needs, exemplifies the successful outcomes that can be achieved at the interface of industry and science. Integr Environ Assess Manag 2021;17:1151-1161. © 2021 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC)., (© 2021 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).)

Proteins evolve through the modular rearrangement of elements known as domains. Extant, multidomain proteins are hypothesized to be the result of domain accretion, but there has been limited experimental validation of this idea. Here, we introduce a technique for genetic minimization by iterative size-exclusion and recombination (MISER) for comprehensively making all possible deletions of a protein. Using MISER, we generate a deletion landscape for the CRISPR protein Cas9. We find that the catalytically-dead Streptococcus pyogenes Cas9 can tolerate large single deletions in the REC2, REC3, HNH, and RuvC domains, while still functioning in vitro and in vivo, and that these deletions can be stacked together to engineer minimal, DNA-binding effector proteins. In total, our results demonstrate that extant proteins retain significant modularity from the accretion process and, as genetic size is a major limitation for viral delivery systems, establish a general technique to improve genome editing and gene therapy-based therapeutics., (© 2021. The Author(s).)

Background: Periprocedural myocardial infarction and injury (PM-injury) are the most common complications of percutaneous coronary intervention (PCI) and are associated with future adverse cardiac events. Inflammation plays a pivotal role in the development of PM-injury. In this randomized pilot trial, we assessed the effect of an anti-inflammatory medication colchicine on periprocedural myocardial injury., Methods: Patients undergoing PCI for stable angina or non–ST-segment–elevation myocardial infarction were randomized to oral colchicine (1 mg followed by 0.5 mg 1 hour later) or placebo, 6 to 24 hours preprocedure. Blood samples were taken immediately pre- and 24-hours post-PCI. The primary outcome, periprocedural myocardial infarction, was defined by an increase in post-PCI troponin >5×99th% upper reference limit when the pre-PCI troponin was normal, or >20% increase in post-PCI troponin when the pre-PCI troponin was raised, including supporting evidence of new myocardial ischemia. Major PM-injury was defined as per periprocedural myocardial infarction without supporting evidence of new myocardial ischemia. Minor PM-injury was defined by post-PCI troponin increase >99th% upper reference limit but ≤5×99th% upper reference limit., Results: A total of 196 patients met inclusion criteria and were randomized. One hundred twenty-one patients were excluded (no PCI, unstable troponin before PCI, or poor-quality measurements) leaving a study population of 75 patients. Thirty-six patients were randomized to colchicine and 39 to placebo preprocedure. Forty-four presented with non–ST-segment–elevation myocardial infarction and 31 with stable angina. High-sensitive (hs) troponin-I pre-PCI was similar between treatment groups (colchicine: 79 ng/L [4–1336] versus placebo: 35 [5–448], P=0.42). Absolute change in hs-troponin-I (calculated as 24-hour post-PCI minus pre-PCI measurements) was significantly lower in the colchicine group: 59 (1–221) versus placebo: 166 (53–530), P=0.02. No patients developed periprocedural myocardial infarction in either group. Significantly fewer patients developed major PM-injury: 11 (31%) versus 21 (54%), P=0.04 or minor PM-injury: 21 (58%) versus 33 (85%), P=0.01, if given colchicine pre-PCI., Conclusions: In this randomized pilot trial, colchicine given 6 to 24 hours pre-PCI reduces periprocedural myocardial injury.

Objective: Collaborative chronic care models (CCMs) were established with implementation support in nine mental health clinics. This study sought to determine whether their clinical impact was maintained after implementation support ceased., Methods: Posttrial data were analyzed from a randomized stepped-wedge CCM implementation trial in general mental health clinics in nine Department of Veterans Affairs medical centers. Sites received 1 year of implementation support, which was associated with reduced mental health hospitalization rates compared with non-CCM clinics in the same medical centers. Hospitalization rates for the year after implementation support were analyzed by using repeated measures logistic regression comparing the same clinics., Results: Hospitalization rates for the postsupport year did not differ from comparison clinics either in the population that initially showed the difference or the population active in the clinics at the end of the year of implementation support., Conclusions: Clinical effects of the CCM may wane after cessation of active implementation support.

Introduction: Approximately 25-30% of veterans deployed to Kuwait, 1990-91, report persistent multi-symptom Gulf War Illness (GWI) likely from neurotoxicant exposures. Photobiomodulation (PBM) in red/near-infrared (NIR) wavelengths is a safe, non-invasive modality shown to help repair hypoxic/stressed cells. Red/NIR wavelengths are absorbed by cytochrome C oxidase in mitochondria, releasing nitric oxide (increasing local vasodilation), and increasing adenosine tri-phosphate production. We investigated whether PBM applied transcranially could improve cognition, and health symptoms in GWI. Materials and Methods: Forty-eight (40 M) participants completed this blinded, randomized, sham-controlled trial using Sham or Real, red/NIR light-emitting diodes (LED) applied transcranially. Fifteen, half-hour transcranial LED (tLED) treatments were twice a week (7.5 weeks, in-office). Goggles worn by participant and assistant maintained blinding for visible red. Pre-/Post- testing was at Entry, 1 week and 1 month post- 15th treatment. Primary outcome measures were neuropsychological (NP) tests; secondary outcomes, Psychosocial Questionnaires, including PTSD. Results: Primary Analyses (all participants), showed improvement for Real vs. Sham, for Digit Span Forwards ( p < 0.01); and a trend for Trails 4, Number/Letter Sequencing ( p < 0.10). For secondary outcomes, Real group reported more improvement on the SF-36V Plus, Physical Component Score ( p < 0.08). Secondary Analyses included only subjects scoring below norm (50%ile) at Entry, on specific NP test/s. Real and Sham improved at 1 week after 15th treatment; however, at 1 month, only those receiving Real improved further: Digit Span Total, Forwards and Backwards; Trails 4, Number/Letter Sequencing; California Verbal Learning Test-II, long delay free recall; Continuous Performance Test-II, False Alarm Rate; and Color-Word Interference, Stroop, Trial 3, Inhibition; Sham group worsened, toward Entry values. Only those with more post-traumatic stress disorder (PTSD) symptomatology at Entry, receiving Real, continued to have additional PTSD reduction at 1 month; Sham regressed. Conclusion: This study was underpowered ( n = 48), with large heterogeneity at Entry. This likely contributed to significance or trend to significance, for only two of the NP tests (Digit Span Forwards; Trails 4, Number/Letter Sequencing) and only one general health measure, the SF-36V Plus, Physical Component Score. More subjects receiving Real, self-reported increased concentration, relaxation and sleep. Controlled studies with newer, transcranial LED home treatment devices are warranted; this is expected to increase enrollment. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT01782378., Competing Interests: MRH declares the following potential conflicts of interest: Scientific Advisory Boards: Transdermal Cap Inc, Cleveland, OH; BeWell Global Inc, Wan Chai, Hong Kong; Hologenix Inc. Santa Monica, CA; LumiThera Inc, Poulsbo, WA; Vielight, Toronto, Canada; Bright Photomedicine, São Paulo, Brazil; Quantum Dynamics LLC, Cambridge, MA; Global Photon Inc, Bee Cave, TX; Medical Coherence, Boston MA; NeuroThera, Newark DE; JOOVV Inc, Minneapolis-St. Paul MN; AIRx Medical, Pleasanton CA; FIR Industries, Inc. Ramsey, NJ; UVLRx Therapeutics, Oldsmar, FL; Ultralux UV Inc, Lansing MI; Illumiheal & Petthera, Shoreline, WA; MB Lasertherapy, Houston, TX; ARRC LED, San Clemente, CA; Varuna Biomedical Corp. Incline Village, NV; Niraxx Light Therapeutics, Inc, Boston, MA. Consulting; Lexington Int, Boca Raton, FL; USHIO Corp, Japan; Merck KGaA, Darmstadt, Germany; Philips Electronics Nederland B.V. Eindhoven, Netherlands; Johnson & Johnson Inc, Philadelphia, PA; Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany. Stockholdings: Global Photon Inc, Bee Cave, TX; Mitonix, Newark, DE. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Martin, Chao, Krengel, Ho, Yee, Lew, Knight, Hamblin and Naeser.)

Rationale: Drugs that rapidly increase dopamine levels have an increased risk of abuse. Dasotraline (DAS) is a dopamine and norepinephrine reuptake inhibitor characterized by slow oral absorption with low potential for abuse. However, it remains unclear whether intravenous (i.v.) administration would facilitate the rapid elevation of dopamine levels associated with stimulant drugs., Objective: To assess the kinetics of DAS across the blood-brain barrier and time to onset of dopamine transporters (DAT) inhibition., Methods: We compared the onset of DAT occupancy and the associated elevation of synaptic dopamine levels in rhesus monkey following i.v. administration of DAS or methylphenidate (MPH) using positron emission tomography (PET). Brain entry times were estimated by reductions in [ 18 F]-FE-PE2I binding to DAT in rhesus monkeys. Elevations of synaptic dopamine were estimated by reductions in [ 11 C]-Raclopride binding to D 2 receptors., Results: Intravenous administration of DAS (0.1 and 0.2 mg/kg) resulted in striatal DAT occupancies of 54% and 68%, respectively; i.v. administered MPH (0.1 and 0.5 mg/kg) achieved occupancies of 69% and 88% respectively. Brain entry times of DAS (22 and 15 min, respectively) were longer than for MPH (3 and 2 min). Elevations in synaptic dopamine were similar for both DAS and MPH however the time for half-maximal displacement by MPH (t = 23 min) was 4-fold more rapid than for DAS (t = 88 min)., Conclusions: These results demonstrate that the pharmacodynamics effects of DAS on DAT occupancy and synaptic dopamine levels are more gradual in onset than those of MPH even with i.v. administration that is favored by recreational drug abusers.

Most people want and expect to have children but lack of awareness about the biological limits of fertility may reduce their chance of achieving their parenthood goals. We surveyed Australian university students' intentions and expectations for future parenthood, knowledge about fertility and preferred sources of fertility information. Male and female students ( n  = 1215) completed an anonymous 34-item online questionnaire. Fewer than 10% did not want children. Of those who wanted children, most (75%) wanted two or more. Although most participants wanted to have children within the biological limits of fertility they also expected to achieve many other life goals before becoming parents. Most underestimated the impact of female and male age on fertility (>75% and >95%, respectively). General practitioners and the Internet were the most preferred sources of fertility information. Almost all stated they would not feel uncomfortable if their general practitioner brought up the topic of future reproductive plans. To help women and men achieve their parenthood goals better education about fertility protection; proactive discussions with young people in primary care settings about reproductive life planning; and social policies and health promotion strategies that support becoming parents during the most fertile years are needed.

Background: One in six Australian women and couples suffer infertility. A rising proportion relates to advanced maternal age, associated with poorer oocyte quality and in vitro fertilisation (IVF) outcomes. Internationally, oocyte cryopreservation technology applied to oocytes vitrified before 35 years provides similar live-birth statistics compared to IVF treatment using fresh oocytes. Oocyte cryopreservation is accessible in Australasian settings and elective uptake is increasing. For women accessing treatment, oocyte cryopreservation may expand future family building options., Aims: To develop the first Australasian Certification in Reproductive Endocrinology and Infertility (CREI) subspecialist-led consensus guideline on oocyte cryopreservation., Methods: The ANZSREI ACCEPT (Australasian CREI Consensus Expert Panel on Trial evidence group) met in 2017 and 2018 and identified clinical aspects of care for inclusion and review. Review of the available evidence was conducted and consensus statements prepared. Areas of dissent of expert opinion and for further research were noted., Results: Consensus was reached on definition and best practice in oocyte cryopreservation for freeze method, controlled ovarian stimulation, medical risk reduction and treatment and outcomes counselling. The term 'social egg freezing' may marginalise, stigmatise or attribute social blame to women, and there is a need to revise this to a neutral and non-judgemental term such as elective or planned oocyte cryopreservation., Conclusion: Oocyte cryopreservation has the potential to improve cumulative live birth outcomes for women. Implementation of this guideline should facilitate an optimal approach for providing care., (© 2019 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

For the past 50 years, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D 2 receptors. Drug development of non-D 2 compounds, seeking to avoid the limiting side effects of dopamine receptor blockade, has failed to date to yield new medicines for patients. In this work, we report the discovery of SEP-363856 (SEP-856), a novel psychotropic agent with a unique mechanism of action. SEP-856 was discovered in a medicinal chemistry effort utilizing a high throughput, high content, mouse-behavior phenotyping platform, in combination with in vitro screening, aimed at developing non-D 2 (anti-target) compounds that could nevertheless retain efficacy across multiple animal models sensitive to D 2 -based pharmacological mechanisms. SEP-856 demonstrated broad efficacy in putative rodent models relating to aspects of schizophrenia, including phencyclidine (PCP)-induced hyperactivity, prepulse inhibition, and PCP-induced deficits in social interaction. In addition to its favorable pharmacokinetic properties, lack of D 2 receptor occupancy, and the absence of catalepsy, SEP-856's broad profile was further highlighted by its robust suppression of rapid eye movement sleep in rats. Although the mechanism of action has not been fully elucidated, in vitro and in vivo pharmacology data as well as slice and in vivo electrophysiology recordings suggest that agonism at both trace amine-associated receptor 1 and 5-HT 1A receptors is integral to its efficacy. Based on the preclinical data and its unique mechanism of action, SEP-856 is a promising new agent for the treatment of schizophrenia and represents a new pharmacological class expected to lack the side effects stemming from blockade of D 2 signaling. SIGNIFICANCE STATEMENT: Since the discovery of chlorpromazine in the 1950s, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D 2 receptors, which is associated with substantial side effects and little to no efficacy in treating the negative and cognitive symptoms of schizophrenia. In this study, we describe the discovery and pharmacology of SEP-363856, a novel psychotropic agent that does not exert its antipsychotic-like effects through direct interaction with D 2 receptors. Although the mechanism of action has not been fully elucidated, our data suggest that agonism at both trace amine-associated receptor 1 and 5-HT 1A receptors is integral to its efficacy. Based on its unique profile in preclinical species, SEP-363856 represents a promising candidate for the treatment of schizophrenia and potentially other neuropsychiatric disorders., (Copyright © 2019 by The Author(s).)

Background: Extensive evidence indicates that Collaborative Chronic Care Models (CCMs) improve outcome in chronic medical conditions and depression treated in primary care. Beginning with an evidence synthesis which indicated that CCMs are also effective for multiple mental health conditions, we describe a multistage process that translated this knowledge into evidence-based health system change in the US Department of Veterans Affairs (VA)., Evidence Synthesis: In 2010, recognizing that there had been numerous CCM trials for a wide variety of mental health conditions, we conducted an evidence synthesis compiling randomized controlled trials of CCMs for any mental health condition. The systematic review demonstrated CCM effectiveness across mental health conditions and treatment venues. Cumulative meta-analysis and meta-regression further informed our approach to subsequent CCM implementation., Policy Impact: In 2015, based on the evidence synthesis, VA Office of Mental Health and Suicide Prevention (OMHSP) adopted the CCM as the model for their outpatient mental health teams., Randomized Implementation Trial: In 2015-2018 we partnered with OMHSP to conduct a 9-site stepped wedge implementation trial, guided by insights from the evidence synthesis., Scale-Up and Spread: In 2017 OMHSP launched an effort to scale-up and spread the CCM to additional VA medical centers. Seventeen facilitators were trained and 28 facilities engaged in facilitation., Discussion: Evidence synthesis provided leverage for evidence-based policy change. This formed the foundation for a health care leadership/researcher partnership, which conducted an implementation trial and subsequent scale-up and spread effort to enhance adoption of the CCM, as informed by the evidence synthesis.

Background: The classic adductor canal block (ACB) is a regional technique that aims to introduce local anesthetic to the saphenous nerve as it traverses the adductor canal. It offers the benefit of preserved quadriceps strength, and is ideal for rehabilitation. Proximal ACB (PACB) allows the operator to place the block away from the surgical site, permitting preoperative placement. Our primary outcome was total opioid consumption; secondary outcomes included the highest numerical rating scale scores and total gait distance at the indicated time intervals., Questions/purposes: We asked: 1) Does a Continuous Proximal ACB block with Periarticular knee injection (PACB) provide better analgesia than a Continuous Epidural (CSE)?; 2) Do PACB catheter patients do better with physical therapy compared to CSE patients?; 3) Are PACB patients discharged earlier than CSE patients?, Methods: With IRB approval we performed a retrospective chart review of patients who had underwent primary total knee arthroplasty between October 2015 and September 2016. The selected patients (n = 151) were divided into two groups: CSE group, 72 patients who received a continuous epidural catheter and the PACB group, 79 patients who received at PACB with Periarticular injection. The CSE group received a single-segment combined spinal epidural (CSE) in the operating room. The epidural catheter infusion was started with 0.1% ropivacaine at 8 mL/hour to 14 mL/hour during the post-operative period. The PACB group received a proximal adductor canal catheter with 20 ml of 0.5 % ropivacaine and maintained with ropivacaine 0.2% at 8 ml to 14 ml post operatively. Total opioid consumption, highest numeric rating scores and total gait distance travelled were recorded upon discharge from the PACU and completion of postoperative day (POD) 0, 1, and 2., Results: We found that the median cumulative morphine consumption was significantly higher in the CSE group compared to the PACB group (194 (0-498) versus 126 (0-354) mg, p = 0.012), a difference that was most notable on POD 1 (84 (16-243) versus 60 (5-370) mg, p = 0.0001). Mean hospital length of stay was also shorter in the PACB group (2.6 ± 0.67 versus 3.0 ± 1.08 days, p = 0.01)., Conclusion: PACB group used significantly lower morphine consumption compared to the CSE group; they were better participants during physical therapy and achieved longer gait distances. The mean hospital length of stay was also shorter in the PACB group., Competing Interests: Conflict of interest Nothing to declare Funding Each author certifies that he or she has no commercial associations (e.g., consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article.

Importance: Collaborative chronic care models (CCMs) have extensive randomized clinical trial evidence for effectiveness in serious mental illnesses, but little evidence exists regarding their feasibility or effect in typical practice conditions., Objective: To determine the effectiveness of implementation facilitation in establishing the CCM in mental health teams and the impact on health outcomes of team-treated individuals., Design, Setting, and Participants: This quasi-experimental, randomized stepped-wedge implementation trial was conducted from February 2016 through February 2018, in partnership with the US Department of Veterans Affairs (VA) Office of Mental Health and Suicide Prevention. Nine facilities were enrolled from all VA facilities in the United States to receive CCM implementation support. All veterans (n = 5596) treated by designated outpatient general mental health teams were included for hospitalization analyses, and a randomly selected sample (n = 1050) was identified for health status interviews. Individuals with dementia were excluded. Clinicians (n = 62) at the facilities were surveyed, and site process summaries were rated for concordance with the CCM process. The CCM implementation start time was randomly assigned across 3 waves. Data analysis of this evaluable population was performed from June to September 2018., Interventions: Internal-external facilitation, combining a study-funded external facilitator and a facility-funded internal facilitator working with a designated team for 1 year., Main Outcomes and Measures: Facilitation was hypothesized to be associated with improvements in both implementation and intervention outcomes (hybrid type II trial). Implementation outcomes included the clinician Team Development Measure (TDM) and proportion of CCM-concordant team care processes. The study was powered for the primary health outcome, mental component score (MCS). Hospitalization rate was derived from administrative data., Results: The veteran population (n = 5596) included 881 women (15.7%), and the mean (SD) age was 52.2 (14.5) years. The interviewed sample (n = 1050) was similar but was oversampled for women (n = 210 [20.0%]). Facilitation was associated with improvements in TDM subscales for role clarity (53.4%-68.6%; δ = 15.3; 95% CI, 4.4-26.2; P = .01) and team primacy (50.0%-68.6%; δ = 18.6; 95% CI, 8.3-28.9; P = .001). The percentage of CCM-concordant processes achieved varied, ranging from 44% to 89%. No improvement was seen in veteran self-ratings, including the primary outcome. In post hoc analyses, MCS improved in veterans with 3 or more treated mental health diagnoses compared with others (β = 5.03; 95% CI, 2.24-7.82; P < .001). Mental health hospitalizations demonstrated a robust decrease during facilitation (β = -0.12; 95% CI, -0.16 to -0.07; P < .001); this finding withstood 4 internal validity tests., Conclusions and Relevance: Implementation facilitation that engages clinicians under typical practice conditions can enhance evidence-based team processes; its effect on self-reported overall population health status was negligible, although health status improved for individuals with complex conditions and hospitalization rate declined., Trial Registration: ClinicalTrials.gov Identifier: NCT02543840.

This chapter describes ovarian anatomy and embryology in humans. The formation of the ovarian reserve is discussed, and events of folliculogenesis are described, including description of developmental events in primordial, primary, secondary, antral and periovulatory follicles. Paracrine and autocrine factors play critical roles in oocyte maturation and follicular development, and research related to the hypothesised roles of individual factors is discussed. Gonadotrophin-dependent events relating to dominant follicle selection are discussed. The two-cell, two-gonadotrophin hypothesis of ovarian steroidogenesis is explained. The clinical role of AMH is outlined. Premature ovarian failure and known associated aetiological factors are described. In the conclusion, with an understanding of the principle events of ovarian folliculogenesis, the follicular wave theory is described, and it is explained how adaptation of ovarian stimulation regimens may achieve time-efficient fertility preservation treatment options for patients with cancer., (Copyright © 2018. Published by Elsevier Ltd.)

Objective: The objective of this study was to understand drivers of cost for carotid endarterectomy (CEA) and carotid artery stenting (CAS) and to compare variation in cost among cases performed by vascular surgery (VS) with other services (OSs)., Methods: We collected internal hospital claims data for CEA and CAS between September 2013 and August 2015 and performed a financial analysis of all hospital costs including room accommodations, medications, medical and surgical supplies, imaging, and laboratory tests. Cases were stratified by presence of symptoms and procedure type, and costs of procedures performed by VS were compared with those performed by OSs., Results: The cohort comprised 144 patients (78 asymptomatic, 66 symptomatic; 44 CAS, 100 CEA) receiving unilateral revascularization. VS (24 CAS, 70 CEA) and neurosurgery and neurointerventional radiology services (20 CAS, 30 CEA) performed all procedures. Age (71 ± 9 years vs 70 ± 11 years; P = .8) and length of stay (1.7 ± 2.1 days vs 2.2 ± 2.4 days; P = .73) were similar for VS and OSs. Symptoms were present before revascularization for 46% and were more commonly treated by OSs (78% vs 29%; P < .001). Case mix index was similar after stratifying by symptoms (asymptomatic, 1.28 ± 0.35 vs 1.39 ± 0.42 [P = .5]; symptomatic, 1.66 ± 0.73 vs 1.82 ± 0.81 [P = .9]). The largest cost components were operating room (OR)-related costs, beds, and supplies, together accounting for 76% of costs. Asymptomatic patients had 37% lower average hospital costs. For asymptomatic CAS, average index hospitalization cost was 17% less for VS compared with OSs because of 78% lower intensive care unit costs, 44% lower OR-related costs, 40% lower medication costs, and 24% lower cardiac testing costs. VS had 22% higher supply costs. For asymptomatic CEA, average index hospitalization costs were 22% lower for VS, driven by lower OR-related costs (28%), medications (28%), imaging (62%), and neurointerventional monitoring (64%). Costs were 38% higher for CAS vs CEA. For symptomatic CAS, costs were similar for both groups. For symptomatic CEA, total costs were 14% lower for VS compared with OSs, driven by 25% lower OR-related costs, 62% lower neurointerventional monitoring, 20% step-down beds, and 28% lower supply costs (and counterbalanced by 117% higher intensive care unit costs)., Conclusions: VS average hospital costs were lower for asymptomatic CAS and all CEAs compared with OSs. Drivers of higher cost appear to be attributed to variation in physicians' practice as well as patients' complexity, affording an opportunity to reduce cost by establishing standard practices when appropriate., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: Thyroid cancer is frequently difficult to diagnose due to an overlap of cytologic features between malignant and benign nodules. This overlap leads to unnecessary removal of the thyroid in patients without cancer. While providing some improvement over cytopathologic diagnostics, molecular methods frequently fail to provide a correct diagnosis for thyroid nodules. These approaches are based on the difference between cancer and adjacent thyroid tissue and assume that adjacent tissues are the same as benign nodules. However, in contrast to adjacent tissues, benign thyroid nodules can contain genetic alterations that can be found in cancer. Experimental Design: For the development of a new molecular diagnostic test for thyroid cancer, we evaluated DNA methylation in 109 thyroid tissues by using genome-wide single-base resolution DNA methylation analysis. The test was validated in a retrospective cohort containing 65 thyroid nodules., Results: By conducting reduced representation bisulfite sequencing in 109 thyroid specimens, we found significant differences between adjacent tissue, benign nodules, and cancer. These tissue-specific signatures are strongly linked to active enhancers and cancer-associated genes. Based on these signatures, we developed a new epigenetic approach for thyroid diagnostics. According to the validation cohort, our test has an estimated specificity of 97% [95% confidence interval (CI), 81-100], sensitivity of 100% (95% CI, 87-100), positive predictive value of 97% (95% CI, 83-100), and negative predictive value of 100% (95% CI, 86-100)., Conclusions: These data show that epigenetic testing can provide outstanding diagnostic accuracy for thyroid nodules. See related commentary by Mitmaker et al., p. 457 ., (©2018 American Association for Cancer Research.)

Objective: Effective strategies to reduce costs associated with endovascular aneurysm repair (EVAR) remain elusive for many medical centers. In this study, targeted interventions to reduce inpatient EVAR costs were identified and implemented., Methods: From June 2015 to February 2016, we analyzed the EVAR practice at a high-volume academic medical center to identify, to rank, and ultimately to reduce procedure-related costs. In this analysis, per-patient direct costs to the hospital were compared before (September 2013-May 2015) and after (March 2016-January 2017) interventions were implemented. Improvement efforts concentrated on three categories that accounted for a majority of costs: implants, rooming costs, and computed tomography scans performed during the index hospitalization., Results: Costs were compared between 141 EVAR procedures before implementation (PRE period) and 47 EVAR procedures after implementation (POST period). Based on data obtained through the Society for Vascular Surgery EVAR Cost Demonstration Project, it was determined that implantable device costs were higher than those at peer institutions. New purchasing strategies were implemented, resulting in a 30.8% decrease in per-case device costs between the PRE and POST periods. Care pathways were modified to reduce use of and costs for computed tomography scans obtained during the index hospitalization. Compared with baseline, per-case imaging costs decreased by 92.9% (P < .001), including a 99.0% (P = .001) reduction in postprocessing costs. Care pathways were also implemented to reduce preprocedural rooming for patients traveling long distances the day before surgery, resulting in a 50% decrease in utilization rate (35.4% PRE to 17.0% POST; P = .021), without having a significant impact on median postprocedural length of stay (PRE, 2 days [interquartile range, 1-11 days]; POST, 2 days [1-7 days]; P = .185). Medication costs also decreased by 38.2% (P < .001) as a hospital-wide effort., Conclusions: Excessive costs associated with EVAR threaten the sustainability of these procedures in health care organizations. Targeted cost reduction efforts can effectively reduce expenses without compromising quality or limiting patients' access., (Copyright © 2018 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Although it is common for rheumatologists to initiate biologic agents after failure of methotrexate monotherapy in rheumatoid arthritis (RA), ample data support the initial use of combinations of conventional therapies in this clinical scenario. Our study explores the durability of triple therapy (methotrexate, sulfasalazine, and hydroxychloroquine) versus methotrexate-etanercept in RA., Methods: RA patients with suboptimal response to methotrexate (n = 353) were randomized to either triple therapy or methotrexate-etanercept therapy in a 48-week, double-blinded, noninferiority trial. Patients without clinical improvement at 24 weeks were switched to the alternative treatment. Of the total, 289 participated in followup. We report treatment durability, Disease Activity Score in 28 joints (DAS28), and other measures during an open-label extension for an additional period up to 72 weeks., Results: Mean ± SD duration of open-label followup was 11 ± 6 months. The likelihood of continuing conventional therapy at 1 year was 78% for triple therapy versus 63% for methotrexate-etanercept, with most treatment changes occurring at the start of followup. More patients changed from methotrexate-etanercept to triple therapy than from triple therapy to methotrexate-etanercept (P = 0.005). DAS28 scores and other disease activity measures were not different for the 2 treatments and were stable during followup., Conclusion: In RA patients with suboptimal methotrexate response randomized to receive triple therapy or methotrexate-etanercept, the former was found to be significantly more durable. Given cost differences and similar outcomes, the variable durability demonstrated provides additional evidence supporting conventional combinations over biologic agent combinations as the first choice after methotrexate inadequate response., (© 2017, American College of Rheumatology.)

Background: An objective tool quantifying the toxicity of 5-fluorouracil (5-FU) from photographs was recently reported, and its reliability was confirmed., Objective: The aim of this study was to validate the photograph-based toxicity score., Methods: Photograph-based toxicity scores of participants assigned to the 5-FU arm of a randomized placebo-controlled trial were tested for correlations with their patient-reported symptom scores and baseline characteristics., Results: Each pair of individual and overall scores of patient-reported symptoms and photograph-based toxicity was correlated at 2 and 4 weeks (correlation coefficient range, 0.34-0.95; P < .001 for all). Older age, more actinic keratoses, previous topical 5-FU use, and more keratinocyte carcinomas on the face and ears in the previous 5 years were correlated with increased 5-FU toxicity at 2 weeks (P < .05). An increase in the total number of 5-FU applications during the trial was correlated with less severe toxicity at 2 weeks (P < .001), but with increased toxicity at 4 weeks (P < .001)., Conclusion: This study provides evidence for construct validity of the photograph-based 5-FU toxicity score. The tool can be used to objectively measure 5-FU toxicity in clinical or research setting, and it can be a prototype for toxicity measurements of other topical medications., (© The Author(s) 2016.)

We examined detection and direction determination of auditory cues from a pedestrian environment among a sample of older and younger adults. Review of relevant research suggests normal aging is associated with declines in physical, cognitive, and perceptual abilities. Relatively, few studies have examined the impact of such developmental changes on pedestrian safety among older adults, and none have examined such factors in relation to use of auditory cues. Thirty-five younger and 35 older adults completed cognitive measures and a pedestrian auditory detection task. Some results by speed were similar to past research that examined younger samples. Interactions were discovered between age and speed conditions within the auditory task. Results are discussed in the context of past research and with regard to informing future injury prevention efforts., (© The Author(s) 2016.)

Background: Outcome for mental health conditions is suboptimal, and care is fragmented. Evidence from controlled trials indicates that collaborative chronic care models (CCMs) can improve outcomes in a broad array of mental health conditions. US Department of Veterans Affairs leadership launched a nationwide initiative to establish multidisciplinary teams in general mental health clinics in all medical centers. As part of this effort, leadership partnered with implementation researchers to develop a program evaluation protocol to provide rigorous scientific data to address two implementation questions: (1) Can evidence-based CCMs be successfully implemented using existing staff in general mental health clinics supported by internal and external implementation facilitation? (2) What is the impact of CCM implementation efforts on patient health status and perceptions of care?, Methods/design: Health system operation leaders and researchers partnered in an iterative process to design a protocol that balances operational priorities, scientific rigor, and feasibility. Joint design decisions addressed identification of study sites, patient population of interest, intervention design, and outcome assessment and analysis. Nine sites have been enrolled in the intervention-implementation hybrid type III stepped-wedge design. Using balanced randomization, sites have been assigned to receive implementation support in one of three waves beginning at 4-month intervals, with support lasting 12 months. Implementation support consists of US Center for Disease Control's Replicating Effective Programs strategy supplemented by external and internal implementation facilitation support and is compared to dissemination of materials plus technical assistance conference calls. Formative evaluation focuses on the recipients, context, innovation, and facilitation process. Summative evaluation combines quantitative and qualitative outcomes. Quantitative CCM fidelity measures (at the site level) plus health outcome measures (at the patient level; n = 765) are collected in a repeated measures design and analyzed with general linear modeling. Qualitative data from provider interviews at baseline and 1 year elaborate CCM fidelity data and provide insights into barriers and facilitators of implementation., Discussion: Conducting a jointly designed, highly controlled protocol in the context of health system operational priorities increases the likelihood that time-sensitive questions of operational importance will be answered rigorously and that the outcomes will result in sustainable change in the health-care system., Trial Registration: NCT02543840 ( https://www.clinicaltrials.gov/ct2/show/NCT02543840).

Importance: Topical fluorouracil was demonstrated to be effective in reducing the number of actinic keratoses (AKs) for up to 6 months, but no randomized trials studied its long-term efficacy., Objective: To evaluate the long-term efficacy of a single course of fluorouracil cream, 5%, for AK treatment., Design, Setting, and Participants: The Veterans Affairs Keratinocyte Carcinoma Chemoprevention (VAKCC) trial was a randomized, double-blinded, placebo-controlled trial with patients from dermatology clinics at 12 VA medical centers recruited from 2009 to 2011 and followed up until 2013. Our study population comprised 932 veterans with 2 or more keratinocyte carcinomas in the 5 years prior to enrollment. The mean follow-up duration was 2.6 years in both treatment and control groups., Interventions: Participants applied either topical fluorouracil cream, 5% (n = 468), or vehicle control cream (n = 464) to the face and ears twice daily for up to 4 weeks., Main Outcomes and Measures: This study reports on AK counts and treatments, which were secondary outcomes of the VAKCC trial. Actinic keratoses on the face and ears were counted by study dermatologists at enrollment and at study visits every 6 months. The number of spot treatments for AKs on the face and ears at semiannual study visits and in between study visits was recorded., Results: The number of AKs on the face and ears per participant was not different between the fluorouracil and control groups at randomization (11.1 vs 10.6, P > .10). After randomization, the fluorouracil group had fewer AKs compared with the control group at 6 months (3.0 vs 8.1, P < .001) and for the overall study duration (P < .001). The fluorouracil group also had higher complete AK clearance rates (38% vs 17% at 6 months) and fewer spot treatments at 6-month intervals, at study visits, and in between study visits during the trial (P < .01 for all). The fluorouracil group took longer to require the first spot AK treatment (6.2 months) compared with the control group (6.0 months) (hazard ratio, 0.69; 95% CI, 0.60-0.79). The number of hypertrophic AKs was not different between the 2 groups overall (P = .60), although there were fewer hypertrophic AKs in the fluorouracil group at 6 months (0.23 vs 0.41) (P = .05)., Conclusions and Relevance: Our results indicate that a single course of fluorouracil cream, 5%, effectively reduces AK counts and the need for spot treatments for longer than 2 years., Trial Registration: clinicaltrials.gov Identifier:NCT00847912.

In this study, we report the pharmacological effects of a novel PDE10A inhibitor, SEP-39. SEP-39 is a potent (1.0nM) inhibitor of human PDE10A in vitro, with good selectivity (>16000-fold) against other PDEs. In an in vivo occupancy study, the RO50 value was determined to be 0.7mg/kg (p.o.), corresponding to plasma and brain exposures of 28ng/mL and 43ng/g, respectively. Using microdialysis, we show that 3mg/kg (p.o.) SEP-39 significantly increased rat striatal cGMP concentrations. Furthermore, SEP-39 inhibits PCP-induced hyperlocomotion at doses of 1 and 3mg/kg (p.o.) corresponding to 59-86% occupancy. At similar doses in a catalepsy study, the time on the bar was increased but the maximal effect was less than that seen with haloperidol. In an EEG study, 3 and 10mg/kg (p.o.) SEP-39 suppressed REM intensity and increased the latency to REM sleep. We also demonstrate the procognitive effects of SEP-39 in the rat novel object recognition assay. These effects appear to require less PDE10A inhibition than the reversal of PCP-induced hyperlocomotion or EEG effects, as improvements in recognition index were seen at doses of 0.3mg/kg and above. Our data demonstrate that SEP-39 is a potent, orally active PDE10A inhibitor with therapeutic potential in a number of psychiatric indications., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Until recently, in-language telephone quitline services for smokers who speak Asian languages were available only in California. In 2012, the Centers for Disease Control and Prevention (CDC) funded the national Asian Smokers' Quitline (ASQ) to expand this service to all states. The objective of this study was to examine characteristics of ASQ callers, how they heard about the quitline, and their use of the service., Methods: Characteristics of callers from August 2012 through July 2014 were examined by using descriptive statistics. We examined demographics, cigarette smoking status, time to first cigarette, how callers heard about the quitline, and service use (receipt of counseling and medication) by using ASQ intake and administrative data. We analyzed these data by language and state., Results: In 2 years, 5,771 callers from 48 states completed intake; 31% were Chinese (Cantonese or Mandarin), 38% were Korean, and 31% were Vietnamese. More than 95% of all callers who used tobacco were current daily cigarette smokers at intake. About 87% of ASQ callers were male, 57% were aged 45 to 64 years, 48% were uninsured, and educational attainment varied. Most callers (54%) were referred by newspapers or magazines. Nearly all eligible callers (99%) received nicotine patches. About 85% of smokers enrolled in counseling; counseled smokers completed an average of 4 sessions., Conclusion: ASQ reached Chinese, Korean, and Vietnamese speakers nationwide. Callers were referred by the promotional avenues employed by ASQ, and most received services (medication, counseling, or both). State quitlines and local organizations should consider transferring callers and promoting ASQ to increase access to cessation services.

Missing data pose a serious challenge to the integrity of randomized clinical trials, especially of treatments for prolonged illnesses such as schizophrenia, in which long-term impact assessment is of great importance, but the follow-up rates are often no more than 50%. Sensitivity analysis using Bayesian modeling for missing data offers a systematic approach to assessing the sensitivity of the inferences made on the basis of observed data. This paper uses data from an 18-month study of veterans with schizophrenia to demonstrate this approach. Data were obtained from a randomized clinical trial involving 369 patients diagnosed with schizophrenia that compared long-acting injectable risperidone with a psychiatrist's choice of oral treatment. Bayesian analysis utilizing a pattern-mixture modeling approach was used to validate the reported results by detecting bias due to non-random patterns of missing data. The analysis was applied to several outcomes including standard measures of schizophrenia symptoms, quality of life, alcohol use, and global mental status. The original study results for several measures were confirmed against a wide range of patterns of non-random missingness. Robustness of the conclusions was assessed using sensitivity parameters. The missing data in the trial did not likely threaten the validity of previously reported results., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background: Topical 5% 5-fluorouracil (5-FU) is known to cause toxicity, such as erythema, pain, and crusting/erosions., Objectives: We sought to develop a scale to measure this toxicity and test the scale for reliability., Methods: A scale was developed involving four parameters: erythema severity, percentage of face involved in erythema, crusting/erosions severity, and percentage of face involved in crusting/erosions. Thirteen raters graded 99 sets of photographs from the Veterans Affairs Keratinocyte Carcinoma Chemoprevention (VAKCC) Trial using these parameters., Results: Intraclass correlation overall for 13 raters was 0.82 (95% CI 0.77-0.86). There was no statistically significant trend in reliability by level of training in dermatology., Conclusions: This scale is a reliable method of evaluating the severity of toxicity from topical 5-fluorouracil and can be used by dermatologists and nondermatologists alike.

Background: Actinic keratoses (AKs) often serve as a primary endpoint for clinical studies. However, reliability of counting these lesions is poor, even among expert dermatologists., Objectives: To investigate the reliability of counting AKs before and after a yearly consensus meeting, held annually for 4 years., Methods: As part of the Veterans Affairs (VA) Keratinocyte Carcinoma Chemoprevention Trial, board-certified dermatologists convened annually for 4 years to individually count the number of actinic keratoses on three to five test subjects. The dermatologists then met as a group for a consensus discussion on what constituted an AK lesion on each subject. Afterwards, each dermatologist repeated the independent counting exercise on three to five new subjects. The intraclass correlation coefficient (ICC) was used to analyze the reliability of counting AKs among the dermatologists., Results: Eight dermatologists participated in this exercise for 4 consecutive years. Pre-consensus discussion ICCs over 4 years were 0.18, 0.34, 0.38, 0.75, respectively, showing sustained improvement with each consensus discussion. The greatest improvement in reliability of AK counts was shown during the first year of consensus discussions, when the ICC improved from 0.18 to 0.67. There was no improvement by the fourth year of consensus discussion, with pre- and post-consensus ICCs of 0.75 and 0.75, respectively., Conclusions: Annual consensus discussions can lead to improvement in reliability of AK counts. This improvement was sustained over 4 years. By the fourth year, the discussion meeting had no effect on improvement in reliability. A consensus meeting discussion may be helpful for improving reliability in other trials., (Published 2013. This article is a U.S. Government work and is in the public domain in the USA.)

Background: We investigated the effect of the respiratory motion on attenuation-corrected (AC) SPECT images for three different SPECT systems, each using a different approach in obtaining attenuation maps: scanning-line sources (SLS) acquired simultaneous with emission; slow cone-beam CT (CBCT) acquired sequentially to emission; and fast helical CT (HCT) acquired sequentially to emission., Methods: A torso phantom filled with (99m)Tc was used to model a cardiac perfusion study. Stationary baseline acquisitions were followed by the acquisitions with the phantom moving axially using a computer-controlled motion platform to simulate breathing. In addition, HCT acquisitions were made simulating breath-hold at different extents of misalignment between CT and emission. HCT images were also used to simulate the Average-CT method. Acquisitions were repeated with added breast attachments, and the heart insert in two different orientations. Visual comparison was made of AC maps, AC emission slices and polar maps. Quantitative comparisons were made of global uniformity based on the percent fractional standard deviation (%FSD) of the polar map segment values, and the ratio of the segment values in the Anterior and Inferior walls divided by that of the Lateral and Septal walls (AI/LS ratio)., Results: The AC maps for the SLS were inferior to the CT's, and most impacted by added large breast attachment. Motion artifacts seen on CBCT slices were minimized in the derived attenuation maps. AC maps obtained from HCT showed inconsistent organ sizes depending on the direction of respiration at the time of acquisition. Both visually and quantitatively CBCT resulted in the best uniformity (up to 3.4 % lower in %FSD) for all the stationary acquisitions, and for the motion acquisition of the female phantom with large breast attachment (up to 4.0 % lower). For the motion acquisition of the male phantoms, HCT resulted in slightly better uniformity (<0.5 % lower) than CBCT. Breath-hold at end-expiration slightly improved (up to 1.1 %) the uniformity over the HCT acquired during regular breathing. Further improvement was achieved with the Average-CT method. For all the systems, phantom respiratory motion reduced the AI/LS ratio compared to when the phantoms were stationary., Conclusions: The CBCT approach resulted in the best uniformity of the AC emission images. For the female phantom with larger breast attachment, HCT and SLS were truncated at some projection angles introducing artifacts into the AC emission images. The emission image artifacts observed with HCT could be mitigated by performing breath-hold acquisition at end-expiration or Average-CT type acquisitions.

This study examines the psychometric properties of the Quality of Well Being Scale (QWB), the Positive and Negative Syndrome Scale (PANSS), the Heinrich-Carpenter Quality of Life Scale (QOLS), and the Lenert PANSS-based utility measure in a cohort of patients with schizophrenia and identifies threshold values of clinically meaningful change using the Clinical Global Impressions scale (CGI), as the anchor. The correlation of these measures at baseline and change at 6 and 12 months post enrollment in a comparative effectiveness trial was evaluated in 350 veterans with schizophrenia or schizoaffective disorder. An equipercentile method was used to estimate the minimum clinically important difference (MCID) for each measure. Effect size of 0.30-0.50 for baseline quality of life associated with inpatient status supported concurrent validity. The QWB was moderately correlated with disease-specific measures. The MCID as detected by the CGI at 6 months was 0.17 for QWB, 0.15 for the Lenert utility score, 1.13 for the QOLS, and 20.2 for the PANSS. These differences were stable at 12 months. The QWB is significantly correlated with disease specific measures of health related quality of life in schizophrenia., (Published by Elsevier Ireland Ltd.)

There is growing interest in understanding individual and environmental influences on youth risk behaviors, including tobacco use. The purpose of this article is to describe the processes and findings from a study that sought to increase the capacity of Asian American and Pacific Islander (AAPI) community-based organizations to understand and address the environmental influences on tobacco use among AAPI youth. Using a multimethod approach to data collection that included GIS (geographic information system) mapping, Photovoice, and individual youth surveys, a team of community and university researchers conducted a 3-year study to assess and address the environmental influences of tobacco use among youth. Community-based participatory research principles guided the study and facilitated unique capacity building and analyses throughout the study period. Results in Long Beach from all three methods highlighted the associations between youth smoking and environmental factors: GIS mapping identified at least 77 separate locations of pro-tobacco influences, photographs captured many of these locations and provided youth leaders with opportunities to identify how other influences contributed to smoking risk, and surveys of youth indicated that perceived community safety and proximity to pro-tobacco influences were associated with smoking in the past 30 days. Subsequent community-based organization activities undertaken by study partners are also discussed, and lessons learned summarized.

Policy change is recognized for underlying much of the success of tobacco control. However, there is little evidence and attention on how Asian American and Native Hawaiian and Pacific Islander (AA and NHPI) communities may engage in policy change. Challenges for AA and NHPI communities include the racial/ethnic and geographic diversity, and tobacco data accurately representing the communities. Over the past decade, the Asian Pacific Partners for Empowerment, Advocacy and Leadership (APPEAL) has worked to develop and implement policy change for AA and NHPI communities. This article describes APPEAL's 4-prong policy change model, in the context of its overall strategic framework for policy change with communities that accounts for varying levels of readiness and leadership capacity, and targets four different levels of policy change (community, mainstream institution, legislative, and corporate). The health promotion implication of this framework for tobacco control policy engagement is for improving understanding of effective pathways to policy change, promoting innovative methods for policy analysis, and translating them into effective implementation and sustainability of policy initiatives. The APPEAL strategic framework can transcend into other communities and health topics that ultimately may contribute to the elimination of health disparities.

Tobacco remains a major risk factor for premature death and ill health among Pacific Islanders, and tobacco-related disparities persist. Eliminating these disparities requires a comprehensive approach to transform community norms about tobacco use through policy change, as contained in the World Health Organization international Framework Convention on Tobacco Control. Three of the six U.S.-affiliated Pacific Islands-the Federated States of Micronesia, Palau, and the Marshall Islands-are Parties to the Framework; the remaining three territories-American Samoa, the Commonwealth of the Northern Mariana Islands, and Guam-are excluded from the treaty by virtue of U.S. nonratification. Capacity building and leadership development are essential in achieving policy change and health equity within Pacific Islander communities. We describe promising practices from American Samoa, the Commonwealth of the Northern Mariana Islands, the Federated States of Micronesia, Guam, and Palau and highlight some of the key lessons learned in supporting and sustaining the reduction in tobacco use among Pacific Islanders as the first step toward eliminating tobacco-related disparities in these populations.

Predictive characteristics of subjects agreeing to be randomized into clinical trials for the treatment of schizophrenia and schizoaffective disorder have been little studied. In this study, we used data from the recruitment phase of a randomized trial that compared long acting injectable (LAI) risperidone to oral antipsychotic medications. Basic socio-demographic and clinical data were gathered from eligible patients and clinicians at the time of screening for trial entry. Bivariate comparisons and multivariate logistic regression were used to compare those who agreed to participate and those who refused. Altogether 446 veterans were eligible on preliminary screening, of these 382 (86 %) agreed to participate and 64 (14 %) declined. Eligible patients who agreed to be randomized were more willing to change medications without regard to their level of satisfaction with their current medication. Subjects reported as currently taking LAI medication and taking risperidone, in particular, were more likely to agree to participate. Factors that did not significantly predict participation included age, years on current medication, reported medication compliance, race, and gender. Veterans with schizophrenia or schizoaffective disorder who were actually more satisfied with their current medications and who were currently taking the experimental agent were more likely to agree to participate in this randomized clinical trial in contrast to expectations that individuals who are unsatisfied with their current treatment would be more likely to enroll in such studies.

Pedestrian safety is a significant problem in the United States, with thousands being injured each year. Multiple risk factors exist, but one poorly understood factor is pedestrians' ability to attend to vehicles using auditory cues. Auditory information in the pedestrian setting is increasing in importance with the growing number of quieter hybrid and all-electric vehicles on America's roadways that do not emit sound cues pedestrians expect from an approaching vehicle. Our study explored developmental differences in pedestrians' detection and localization of approaching vehicles. Fifty children ages 6-9 years, and 35 adults participated. Participants' performance varied significantly by age, and with increasing speed and direction of the vehicle's approach. Results underscore the importance of understanding children's and adults' use of auditory cues for pedestrian safety and highlight the need for further research., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Context: Few published evaluations documenting the results of community health leadership programs exist. Furthermore, few leadership programs specifically address cross-cultural issues or priority populations, and none have focused on the area of tobacco control., Objective: The goal of the evaluation was to determine the effectiveness of the Leadership and Advocacy Institute to Advance Minnesota's Parity for Priority Populations Institute. Institute Fellows were recruited from 5 priority populations, including African/African American, American Indian, Asian American, Chicano Latino and Lesbian, Gay, Bisexual, and Transgender. The Institute's impact on the acquisition and application of particular leadership skills was assessed, along with its impact in building priority population capacity to engage in tobacco control activities. DESIGN AND MEASURE: Findings are based on mixed methods, including Fellows' completion of paper surveys prior, during, and post-Institute, and telephone interviews conducted post-Institute., Results: Perceived skills increased in all areas assessed. Fellows reported applying specific skills acquired 16 months after the Institute. Furthermore, a high number of Fellows were more intensely involved in tobacco control work compared to baseline and reported involvement in cross-cultural collaborations or initiatives post-Institute., Conclusion: The Institute achieved both short-term and intermediate outcomes; skills were acquired during the Institute and sustained and applied in areas of tobacco control over 1 year later.

Pedestrians must use a variety of cues when making safe decisions, many of which require processing of auditory information. We examined detection and localization of approaching vehicles using auditory cues. 50 adults ages 18-49 were presented with actual sounds of vehicles approaching at 5, 12, 25, and 35 mph. Three indices were of interest: the distance at which vehicles were detected, participants' decision regarding the direction from which vehicles were approaching, and their determination of the vehicles' arrival at their location. Participants more easily detected vehicles moving at higher speeds and vehicles approaching from the right. Determination of the direction of approach reached 90% accuracy or better when vehicles were traveling at, or greater than, 12 mph, and were more approaching from the right. Determination of vehicle arrival deteriorated significantly as speeds increased. Implications of the use of auditory cues in pedestrian settings, and future directions, are discussed., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The Australasian Community Genetics Program provided a preconception screening for Tay-Sachs disease (TSD) to 4,105 Jewish high school students in Sydney and Melbourne over the 12-year period 1995-2007. By correlating the frequencies of mutant HEXA, MIM *606869 (gene map locus 15q23-q24) alleles with subjects' nominated ethnicity (Ashkenazi/Sephardi/Mixed) and grandparental birthplaces, we established that Ashkenazi ethnicity is a better predictor of TSD carrier status than grandparental ancestral origins. Screening self-identified Ashkenazi subjects detected 95% of TSD carriers (carrier frequency 1:25). Having mixed Ashkenazi and non-Ashkenazi heritage reduced the carrier frequency (1:97). South African heritage conveyed a fourfold risk of c.1421 + 1G > C mutation compared with other AJ subjects (odds ratio (OR), 4.19; 95% confidence interval (CI), 1.83-9.62, p = 0.001), but this was the only specific case of ancestral origin improving diagnostic sensitivity over that based on determining Ashkenazi ethnicity. Carriers of c.1278insTATC mutations were more likely to have heritage from Western Europe (OR, 1.65 (95% CI, 1.04-2.60), p = 0.032) and South Eastern Europe (OR, 1.77 (95% CI, 1.14-2.73), p = 0.010). However, heritage from specific European countries investigated did not significantly alter the overall odds of TSD carrier status.