A therapeutic small molecule enhances γ-oscillations and improves cognition/memory in Alzheimer's disease model mice.

Brain rhythms provide the timing for recruitment of brain activity required for linking together neuronal ensembles engaged in specific tasks. The γ-oscillations (30 to 120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. These oscillations are reduced in numerous neurological and psychiatric disorders, including early cognitive decline in Alzheimer's disease (AD). Here, we report on a potent brain-permeable small molecule, DDL-920 that increases γ-oscillations and improves cognition/memory in a mouse model of AD, thus showing promise as a class of therapeutics for AD. We employed anatomical, in vitro and in vivo electrophysiological, and behavioral methods to examine the effects of our lead therapeutic candidate small molecule. As a novel in central nervous system pharmacotherapy, our lead molecule acts as a potent, efficacious, and selective negative allosteric modulator of the γ-aminobutyric acid type A receptors most likely assembled from α1ß2δ subunits. These receptors, identified through anatomical and pharmacological means, underlie the tonic inhibition of parvalbumin (PV) expressing interneurons (PV+INs) critically involved in the generation of γ-oscillations. When orally administered twice daily for 2 wk, DDL-920 restored the cognitive/memory impairments of 3- to 4-mo-old AD model mice as measured by their performance in the Barnes maze. Our approach is unique as it is meant to enhance cognitive performance and working memory in a state-dependent manner by engaging and amplifying the brain's endogenous γ-oscillations through enhancing the function of PV+INs.

Dying of mesothelioma: A qualitative exploration of caregiver experiences.

OBJECTIVE: To explore the experience of family caregivers of people with mesothelioma with focus on end-of-life issues. METHODS: A qualitative sub-study using semi-structured interviews and thematic analysis. RESULTS: Fourteen caregivers were interviewed; 11 were bereaved. The overarching theme was the impact of patients' diagnosis, treatment and death on caregivers and families. Three main themes were identified: (i) information provision and decision-making; (ii) grief and bereavement; and (iii) involvement and timing of palliative care. Caregivers initially had minimal knowledge of mesothelioma and wanted more information. Prognostic uncertainty caused distress. Grief and bereavement sub-themes were (i) coping and personal priorities; (ii) reflections on dying; and (iii) reflections on care. Caregivers highlighted the importance of creating meaningful events, having hope, 'doing something' and support from family and external sources. Reflections on dying contrasted regret after a 'bad', often unexpected death, with 'good' deaths. Care was made difficult by challenges navigating the health system and perceived gaps. Caregivers reported late referral to palliative care. CONCLUSION: Lack of information caused challenges for caregivers. Grief and bereavement outcomes varied and may have been adversely impacted by lack of engagement with palliative care. Integrated care with lung cancer coordinators and improved palliative care access may reduce caregiver burden.

"SQiD, the Single Question in Delirium; can a single question help clinicians to detect delirium in hospitalised cancer patients?" running heading Single Question in Delirium" (Bcan-D-20-01665).

AIM: A serious syndrome for cancer in-patients, delirium risk increases with age and medical acuity. Screening tools exist but detection is frequently delayed or missed. We test the 'Single Question in Delirium' (SQiD), in comparison to psychiatrist clinical interview. METHODS: Inpatients in two comprehensive cancer centres were prospectively screened. Clinical staff asked informants to respond to the SQiD: "Do you feel that [patient's name] has been more confused lately?". The primary endpoint was negative predictive value (NPV) of the SQiD versus psychiatrist diagnosis (Diagnostic and Statistics Manual criteria). Secondary endpoints included: NPV of the Confusion Assessment Method (CAM), sensitivity, specificity and Cohen's Kappa coefficient. RESULTS: Between May 2012 and July 2015, the SQiD plus CAM was applied to 122 patients; 73 had the SQiD and psychiatrist interview. Median age was 65 yrs. (interquartile range 54-74), 46% were female; median length of hospital stay was 12 days (5-18 days). Major cancer types were lung (19%), gastric or other upper GI (15%) and breast (14%). 70% of participants had stage 4 cancer. Diagnostic values were similar between the SQiD (NPV = 74, 95% CI 67-81; kappa = 0.32) and CAM (NPV = 72, 95% CI 67-77, kappa = 0.32), compared with psychiatrist interview. Overall the CAM identified only a small number of delirious cases but all were true positives. The specificity of the SQiD was 87% (74-95) The SQiD had higher sensitivity than CAM (44% [95% CI 41-80] vs 26% [10-48]). CONCLUSION: The SQiD, administered by bedside clinical staff, was feasible and its psychometric properties are now better understood. The SQiD can contribute to delirium detection and clinical care for hospitalised cancer patients.

Pneumonia is not just pneumonia: Differences in utilization and costs with common comorbidities.

We sought to explore the heterogeneity among patients hospitalized with pneumonia, a condition targeted in payment reform. In a retrospective cohort study of Medicare beneficiaries hospitalized for pneumonia, we compared postacute care utilization and costs of 90-day episodes of care among patients with and without comorbidities of chronic obstructive pulmonary disease (COPD) and/or heart failure. Of the 1,926,674 discharges, 28.1% had COPD, 14.3% had heart failure, and 14.6% carried both diagnoses. Patients with pneumonia were more likely to be discharged to a facility than those with pneumonia and COPD with or without heart failure, though less likely than those with pneumonia and heart failure only. Compared to patients with pneumonia only, patients with COPD and/or heart failure had higher episode payments. Acute conditions such as pneumonia may hold promise for episode-based care payment reform; however, the heterogeneity within this diagnosis indicates the need to consider other patient characteristics in interventions to improve value-based care.

Better Together: Development and Implementation of Fellow Group Evaluations of Faculty.

Background: High-quality trainee evaluations of faculty are essential for meaningful faculty development and for improving the clinical learning environment. However, concerns about anonymity can limit usefulness of trainee evaluations, particularly in smaller programs, such as subspecialty fellowships. Objective: To develop and implement a fellow-driven group evaluation process to enhance trainee confidentiality and generate high-quality feedback for pulmonary and critical care medicine faculty. Methods: A novel process was developed for faculty evaluation and feedback consisting of quarterly, structured, fellow-led group evaluation sessions focused on collecting confidential, behaviorally oriented, actionable feedback for faculty. Upper-year fellow moderators utilized a standard format to structure discussion, generating strengths and areas for growth for each faculty member while explicitly asking for input from fellows with divergent perspectives. Moderators compiled anonymized session notes for the program director, who delivered feedback to individual faculty. After the first six sessions, an electronic survey was distributed to assess fellow perceptions of the group evaluation model. Results: Thirty-seven faculty members were evaluated in 11 group sessions over 42 months. Fellows rated group-generated feedback as more confidential, more specific, more accurate, more efficient, more actionable, and less biased when compared with individual written evaluations (P < 0.01 for all categories). Conclusion: The authors successfully developed and implemented a process for fellow-led group evaluation of faculty, designed to facilitate fellow confidentiality and enrich the quality of feedback. Fellows preferred the group evaluation process and perceived group-generated feedback more favorably compared with individual written evaluations.

Phase II, double blind, placebo controlled, multi-site study to evaluate the safety, feasibility and desirability of conducting a phase III study of anamorelin for anorexia in people with small cell lung cancer: A study protocol (LUANA trial).

Anorexia is experienced by most people with lung cancer during the course of their disease and treatment. Anorexia reduces response to chemotherapy and the ability of patients to cope with, and complete their treatment leading to greater morbidity, poorer prognosis and outcomes. Despite the significant importance of cancer-related anorexia, current therapies are limited, have marginal benefits and unwarranted side effects. In this multi-site, randomised, double blind, placebo controlled, phase II trial, participants will be randomly assigned (1:1) to receive once-daily oral dosing of 100mg of anamorelin HCl or matched placebo for 12 weeks. Participants can then opt into an extension phase to receive blinded intervention for another 12 weeks (weeks 13-24) at the same dose and frequency. Adults (≥18 years) with small cell lung cancer (SCLC); newly diagnosed with planned systemic therapy OR with first recurrence of disease following a documented disease-free interval ≥6 months, AND with anorexia (i.e., ≤ 37 points on the 12-item Functional Assessment of Anorexia Cachexia Treatment (FAACT A/CS) scale) will be invited to participate. Primary outcomes are safety, desirability and feasibility outcomes related to participant recruitment, adherence to interventions, and completion of study tools to inform the design of a robust Phase III effectiveness trial. Secondary outcomes are the effects of study interventions on body weight and composition, functional status, nutritional intake, biochemistry, fatigue, harms, survival and quality of life. Primary and secondary efficacy analysis will be conducted at 12 weeks. Additional exploratory efficacy and safety analyses will also be conducted at 24 weeks to collect data over longer treatment duration. The feasibility of economic evaluations in Phase III trial will be assessed, including the indicative costs and benefits of anamorelin for SCLC to the healthcare system and society, the choice of methods for data collection and the future evaluation design. Trial registration. The trial has been registered with the Australian New Zealand Clinical Trials Registry [ACTRN12622000129785] and approved by the South Western Sydney Local Health District Human Research Ethics Committee [2021/ETH11339]. https://clin.larvol.com/trial-detail/ACTRN12622000129785.

Proportion of Racial Minority Patients and Patients With Low Socioeconomic Status Cared for by Physician Groups After Joining Accountable Care Organizations.

Importance: The incentive structure of accountable care organizations (ACOs) may lead to participating physician groups selecting fewer vulnerable patients. Objective: To test for changes in the percentage of racial minority patients and patients with low socioeconomic status cared for by physician groups after joining the ACO. Design, Setting, and Participants: This retrospective cohort consisted of a 15% random sample of Medicare fee-for-service beneficiaries attributed to physician groups from 2010 to 2016. Medicare Shared Savings Program (MSSP) participation was determined using ACO files. Analyses were conducted between January 1, 2019, and February 25, 2020. Exposures: Using linear probability models, we conducted difference-in-differences analyses based on the year a physician group joined an ACO to estimate changes in vulnerable patients within ACO-participating groups compared with nonparticipating groups. Main Outcomes and Measures: Whether the patient was black, was dually enrolled in Medicare and Medicaid, and poverty and unemployment rates of the patient's zip code. Results: In a cohort of 76 717 physician groups caring for 7 307 130 patients, 16.1% of groups caring for 27.8% of patients participated in an MSSP ACO. Using 2010 characteristics, patients attributed to ACOs from 2012 to 2016, compared with those who were not, were less likely to be black (8.0% [n = 81 698] vs 9.3% [n = 270 924]) or dually enrolled in Medicare and Medicaid (12.8% [n = 130 957] vs 18.2% [n = 528 685]), and lived in zip codes with lower poverty rates (13.8% vs 15.5%); unemployment rates were similar (8.0% vs 8.5%). In the difference-in-differences analysis, there was no statistically significant change associated with ACO participation in the proportions of vulnerable patients attributed to ACO-participating groups compared with nonparticipating groups. After joining an ACO, ACO-participating groups had 0.0 percentage points change (95% CI, -0.1 to 0.1 percentage points; P = .59) for black patients, -0.1 percentage points (95% CI, -0.2 to 0.1 percentage points; P = .32) for patients dually enrolled in Medicare and Medicaid, 0.2 percentage points (95% CI, -3.5 to 4.0 percentage points; P = .91) in poverty rates, and -0.4 percentage points (95% CI, -2.0 to 1.2 percentage points; P = .62) in unemployment rates. Conclusions and Relevance: In this cohort study, there were no changes in the proportions of vulnerable patients cared for by ACO-participating physician groups after joining an ACO compared with changes among nonparticipating groups.

Lidocaine for Cancer Pain in Adults: A Systematic Review and Meta-Analysis.

BACKGROUND: Internationally, use of lidocaine infusions to treat cancer pain varies by center. Existing systematic reviews do not adequately inform use of lidocaine in cancer pain. OBJECTIVE: To assess the effects of systemic sodium channel blockers on cancer pain in adults, review the dose protocols for administration, and assess toxicity. DESIGN: Databases CENTRAL, MEDLINE, Embase, LILACS, CareSearch, and OpenGrey were searched from inception to 2016. Conference abstracts and reference lists were handsearched, and the lead investigators of included trials and Australian manufacturers were contacted. Included studies were randomized controlled trials evaluating one or more of lidocaine via intravenous or subcutaneous route, or mexiletine, flecainide, or tocainide via oral route; delivered at a site distant to the pain locus. The methodological quality of studies was assessed using the "risk of bias" domain-based evaluation by Jadad. Protocol is available on PROSPERO:CRD42016047092. RESULTS: One positive (n = 50) and three negative (n = 10 each) crossover trials evaluated lidocaine versus placebo, and one trial (n = 16) compared lidocaine with dexmedetomidine. Meta-analysis of pooled data in 60 patients demonstrated a significant benefit of lidocaine infusion of 4-5 mg/kg over 30-80 minutes compared with placebo for >50% reduction in cancer pain. Secondary outcomes did not show a significant difference. DISCUSSION: Based on the current available evidence, lidocaine infusion could be considered in refractory cancer pain where agents with level 1 evidence are ineffective. Further research is necessary to understand the protocol and population in which lidocaine may improve cancer pain and capitalize on the promising opportunities identified.

Analysis of Devices Authorized by the FDA for Clinical Decision Support in Critical Care.

This case series study examines the clinical evidence cited for US Food and Drug Administration­approved clinical decision support devices for use in the critical care setting.

Can pharmacoeconomics and outcomes research contribute to the empowerment of women affected by breast cancer?

Breakthroughs in genetic testing have informed patients and physicians in the treatment of breast cancer; however, they have also added to the complexity of decision-making. Genetic testing for breast cancer susceptibility not only changes treatment and screening options, but also challenges the way in which interventions are evaluated. While comparative effectiveness and cost-effective analysis methods are now standard for evaluation at the societal level, technologies such as genetic testing require us to consider the role of patient preference, especially as we move towards more personalized approaches to medicine. In this review, we discuss the changing role of pharmacoeconomics and outcomes research by highlighting how the discipline could use patient preference methods, such as conjoint analysis, to promote shared decision-making and to empower breast cancer patients. By adopting these methods we could move our focus from what is best for payers or society to one that applies scientific methods to identify what is best for patients.