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In difficult-to-treat depression (DTD) the outcome metrics historically used to evaluate treatment effectiveness may be suboptimal. Metrics based on remission status and on single end-point (SEP) assessment may be problematic given infrequent symptom remission, temporal instability, and poor durability of benefit in DTD.
Self-report and clinician assessment of depression symptom severity were regularly obtained over a 2-year period in a chronic and highly treatment-resistant registry sample (N = 406) receiving treatment as usual, with or without vagus nerve stimulation. Twenty alternative metrics for characterizing symptomatic improvement were evaluated, contrasting SEP metrics with integrative (INT) metrics that aggregated information over time. Metrics were compared in effect size and discriminating power when contrasting groups that did (N = 153) and did not (N = 253) achieve a threshold level of improvement in end-point quality-of-life (QoL) scores, and in their association with continuous QoL scores.
Metrics based on remission status had smaller effect size and poorer discrimination of the binary QoL outcome and weaker associations with the continuous end-point QoL scores than metrics based on partial response or response. The metrics with the strongest performance characteristics were the SEP measure of percentage change in symptom severity and the INT metric quantifying the proportion of the observation period in partial response or better. Both metrics contributed independent variance when predicting end-point QoL scores.
Revision is needed in the metrics used to quantify symptomatic change in DTD with consideration of INT time-based measures as primary or secondary outcomes. Metrics based on remission status may not be useful.
The causal impacts of recreational cannabis legalization are not well understood due to the number of potential confounds. We sought to quantify possible causal effects of recreational cannabis legalization on substance use, substance use disorder, and psychosocial functioning, and whether vulnerable individuals are more susceptible to the effects of cannabis legalization than others.
We used a longitudinal, co-twin control design in 4043 twins (N = 240 pairs discordant on residence), first assessed in adolescence and now age 24–49, currently residing in states with different cannabis policies (40% resided in a recreationally legal state). We tested the effect of legalization on outcomes of interest and whether legalization interacts with established vulnerability factors (age, sex, or externalizing psychopathology).
In the co-twin control design accounting for earlier cannabis frequency and alcohol use disorder (AUD) symptoms respectively, the twin living in a recreational state used cannabis on average more often (βw = 0.11, p = 1.3 × 10−3), and had fewer AUD symptoms (βw = −0.11, p = 6.7 × 10−3) than their co-twin living in an non-recreational state. Cannabis legalization was associated with no other adverse outcome in the co-twin design, including cannabis use disorder. No risk factor significantly interacted with legalization status to predict any outcome.
Recreational legalization was associated with increased cannabis use and decreased AUD symptoms but was not associated with other maladaptations. These effects were maintained within twin pairs discordant for residence. Moreover, vulnerabilities to cannabis use were not exacerbated by the legal cannabis environment. Future research may investigate causal links between cannabis consumption and outcomes.
The introduction of new fuels into the market is a unique opportunity to take advantage of new fuel compositions to improve the efficiency and emissions of internal combustion reciprocating engines and alternative fuel feedstocks. However, there are numerous challenges that introductions of new fuels face before they can become first legal, then ubiquitous. This chapter reviews four different case studies related to changing fuel composition. In some circumstances, the fuel formulation was changed in seemingly minor ways, and resulted in the unanticipated consequences. In other cases, a fuel change was desired, but an unexpected barrier slowed the introduction of the fuel change. These case studies should be viewed as opportunities to understand the interdependencies that exist and factors that need to be considered when trying to change the fuel in the marketplace.
Structural racism in the USA has roots that extend deep into healthcare and medical research, and it remains a key driver of illness and early death for Black, Indigenous, People of Color (BIPOC). Furthermore, the persistence of racism within academic medicine compels an interrogation of education and research within this context. In the spirit of this interrogation, this article highlights a unique model of community-engaged education that integrates cultural humility. As an individual and institutional stance, cultural humility denotes lifelong learning and self-critique, the mitigation of power imbalances, and accountability. The integration of cultural humility emphasizes that when space is created for BIPOC communities to lead the way, education regarding healthcare and research can be effectively reimagined. Demonstrating this effectiveness, six community partners led the development and implementation of a five-module Structural Racism in Healthcare and Research course. Using a cohort model approach, the pilot course enrolled 12 community members and 12 researchers. The curriculum covered topics such as history of racism in healthcare and research, and introduced participants to a cultural resilience framework. Evaluation results demonstrated a significant increase in participants’ knowledge and ability to identify and take action to address inequities related to racism in healthcare and research.
Bustards comprise a highly threatened family of birds and, being relatively fast, heavy fliers with very limited frontal visual fields, are particularly susceptible to mortality at powerlines. These infrastructures can also displace them from immediately adjacent habitat and act as barriers, fragmenting their ranges. With geographically ever wider energy transmission and distribution grids, the powerline threat to bustards is constantly growing. Reviewing the published and unpublished literature up to January 2021, we found 2,774 records of bustard collision with powerlines, involving 14 species. Some studies associate powerline collisions with population declines. To avoid mortalities, the most effective solution is to bury the lines; otherwise they should be either routed away from bustard-frequented areas, or made redundant by local energy generation. When possible, new lines should run parallel to existing structures and wires should preferably be as low and thick as possible, with minimal conductor obstruction of vertical airspace, although it should be noted that these measures require additional testing. A review of studies finds limited evidence that ‘bird flight diverters’ (BFDs; devices fitted to wires to induce evasive action) achieve significant reductions in mortality for some bustard species. Nevertheless, dynamic BFDs are preferable to static ones as they are thought to perform more effectively. Rigorous evaluation of powerline mortalities, and effectiveness of mitigation measures, need systematic carcass surveys and bias corrections. Whenever feasible, assessments of displacement and barrier effects should be undertaken. Following best practice guidelines proposed with this review paper to monitor impacts and mitigation could help build a reliable body of evidence on best ways to prevent bustard mortality at powerlines. Research should focus on validating mitigation measures and quantifying, particularly for threatened bustards, the population effects of powerline grids at the national scale, to account for cumulative impacts on bustards and establish an equitable basis for compensation measures.
Variation exists in the timing of surgery for balanced complete atrioventricular septal defect repair. We sought to explore associations between timing of repair and resource utilisation and clinical outcomes in the first year of life.
In this retrospective single-centre cohort study, we included patients who underwent complete atrioventricular septal defect repair between 2005 and 2019. Patients with left or right ventricular outflow tract obstruction and major non-cardiac comorbidities (except trisomy 21) were excluded. The primary outcome was days alive and out of the hospital in the first year of life.
Included were 79 infants, divided into tertiles based on age at surgery (1st = 46 to 137 days, 2nd = 140 – 176 days, 3rd = 178 – 316 days). There were no significant differences among age tertiles for days alive and out of the hospital in the first year of life by univariable analysis (tertile 1, median 351 days; tertile 2, 348 days; tertile 3, 354 days; p = 0.22). No patients died. Fewer post-operative ICU days were used in the oldest tertile relative to the youngest, but days of mechanical ventilation and hospitalisation were similar. Clinical outcomes after repair and resource utilisation in the first year of life were similar for unplanned cardiac reinterventions, outpatient cardiology clinic visits, and weight-for-age z-score at 1 year.
Age at complete atrioventricular septal defect repair is not associated with important differences in clinical outcomes or resource utilisation in the first year of life.
We compared experiences with The Multifaceted Intervention to Improve Prescribing for Acute Respiratory Infection for Adult and Children in Emergency Department and Urgent Care Settings versus Choosing Wisely to evaluate inappropriate antimicrobial prescribing in ambulatory care. Both identified the same clinics, diagnoses, and antibiotics for high-yield antibiotic stewardship interventions.
We investigated the efficacy and complication profile of intranasal dexmedetomidine for transthoracic echocardiography sedation in patients with single ventricle physiology and shunt-dependent pulmonary blood flow during the high-risk interstage period.
A single-centre, retrospective review identified interstage infants who received dexmedetomidine for echocardiography sedation. Baseline and procedural vitals were reported. Significant adverse events related to sedation were defined as an escalation in care or need for any additional/increased inotropic support to maintain pre-procedural haemodynamics. Minor adverse events were defined as changes from baseline haemodynamics that resolved without intervention. To assess whether sedation was adequate, echocardiogram reports were reviewed for completeness.
From September to December 2020, five interstage patients (age 29–69 days) were sedated with 3 mcg/kg intranasal dexmedetomidine. The median sedation onset time and duration time was 24 minutes (range 12–43 minutes) and 60 minutes (range 33–60 minutes), respectively. Sedation was deemed adequate in all patients as complete echocardiograms were accomplished without a rescue dose. When compared to baseline, three (60%) patients had a >10% reduction in heart rate, one (20%) patient had a >10% reduction in oxygen saturations, and one (20%) patient had a >30% decrease in blood pressure. Amongst all patients, no significant complications occurred and haemodynamic changes from baseline did not result in need for intervention or interruption of study.
Intranasal dexmedetomidine may be a reasonable option for echocardiography sedation in infants with shunt-dependent single ventricle heart disease, and further investigation is warranted to ensure efficacy and safety in an outpatient setting.
Heart attacks (HAs) present clinically with varying symptoms, which are not always described by patients as chest pain (CP) or chest discomfort (CD). Emergency Medical Dispatchers (EMDs) select the CP/CD dispatch protocol for non-chest pain HA symptoms or classic HA complaint of CP/CD. Nevertheless, it is still unknown how often callers report HA symptoms other than CP/CD.
The objective of this study was to characterize the caller’s descriptions of the primary HA symptoms, descriptions of the other HA symptoms, and the use of a case entry (CE) question clarifier.
A retrospective descriptive study analyzed randomly selected EMD audios (where CD/CD protocol was used) from five accredited emergency communication centers in the United States. Several Quality Performance Review (QPR) experts reviewed the audios and recorded callers’ initial problem descriptions, the use of and responses to the CE question clarifier, including the EMD-assigned final determinant code.
A total of 1,261 audios were reviewed. The clarifier was used only 8.5% of the time. The CP/CD symptoms were mentioned alone or with other problems 87.0% of the time. Overall, CP symptom was mentioned alone 70.8%, HA alone 4.0%, and CD symptom alone 1.4% of the time.
9-1-1 callers report potential HA cases using a variety of terms and descriptions—most commonly CP. Other less-common symptoms associated with a HA may be mentioned. Therefore, EMDs must be well-trained to be prepared to probe the caller with a clarifying query to elicit more specific information when “having a heart attack” is the only complaint initially mentioned.
This study details the results of an experimental intervention designed to address the issue of price anchoring in the choice experiment framework. The intervention, which informs respondents of the tendency to anchor choices on potentially arbitrary pieces of information, is applied to a choice experiment used to examine consumers’ willingness to pay for local and/or organic tomatoes in Northern New England and develops three primary contributions. First, evidence from this study shows that anchoring effects are present. Second, providing information to consumers plays a mitigating role on these effects; price anchoring changes willing to pay estimates between 44% and 51% and exposure to anchoring-specific cheap talk is associated with a reduction in these anchoring effects between 60% and 80%. These results are explained through decreases in price sensitivity induced by increasing the mean price vector and subsequent increases in price sensitivity due to the information intervention. Finally, this study reveals that consumers are willing to pay a substantial price premium for locally grown tomatoes, from $0.96 to $1.12 per pound, offering some guidance for policy regarding growing practice and farm land use as regional coalitions support local agriculture expansion in the Northeast.
The spectrum of adverse mental health trajectories caused by sexual abuse, broadly defined as exposure to rape and unwanted physical sexual contact, is well-known. Few studies have systematically appraised the epidemiology and impact of sexual abuse among boys and men. New meta-analytic insights (k = 44; n = 45 172) reported by Zarchev and colleagues challenge assumptions that men experiencing mental ill health rarely report sexual abuse exposure. Adult-onset sexual abuse rates of 1–7% are observed in the general population, but for men experiencing mental ill health, adult lifetime prevalence was 14.1% (95% CI 7.3–22.4%), with past-year exposure 5.3% (95% CI 1.6–12.8%). We note that these rates are certainly underestimates, as childhood sexual abuse exposures were excluded. Boys and men with a sexual abuse history experience substantial disclosure and treatment barriers. We draw attention to population health gains that could be achieved via implementation of gender-sensitive assessment and intervention approaches for this at-risk population.
Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
We find that an increase in a firm’s incentives to use trade secrets to protect its intellectual property results in a more actively managed capital structure. Exploiting U.S. states’ adoption of the Uniform Trade Secrets Act as a positive “shock” in the protection afforded to trade secrets, we find that firms covered by the Act reduce debt levels while increasing investments in intangibles. Additional tests suggest that firms fund these financing and investment activities by issuing more equity. Consistent with an increase in overall intangibility magnifying contracting problems with creditors, we find that covered firms experience higher costs of debt.
Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of ‘difficult-to-treat depression’ (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.
The Scottish Medicines Consortium (SMC) conducts early health technology assessment (HTA) of new medicines on behalf of the National Health Service Scotland based on pharmaceutical company submissions. As the appraisals are conducted close to the point of marketing authorization, there is often a lack of direct head-to-head data. In 2019, assessment of relevant comparative efficacy was informed via indirect treatment comparisons (ITC) in 55 percent (36/66) of submissions. While the ITCs are essential to the decision-making process, they are frequently incomplete.
A focus group was conducted with the clinical assessment team (n = 11) to explore problems in the submission process and to identify areas for improvement. It was agreed that providing improved guidance to companies prior to submission may prevent future inconsistencies. A working group (n = 5) was tasked with identifying and implementing potential solutions. The group reviewed the focus group findings, relevant literature, and guidance from other organizations. Draft guidance was developed that was reviewed by two pharmaceutical industry representatives (SMC subcommittee members).
Findings from the focus group highlighted issues broadly related to the incomplete presentation and reporting of ITCs. The improved guidance document outlined specific requirements in a checklist format for reporting and presenting the results of different ITC data. This guidance was published in February 2020. To evaluate the impact of the updated guidance and to identify any further changes required, a follow-up focus group and survey of industry representatives is planned for March 2021.
The aim of the ITC guidance is to provide pharmaceutical companies with direction to improve the quality and transparency of reporting, which will in turn improve the quality of HTAs and thus strengthen the recommendations provided by the SMC. The follow-up focus groups and survey will assess the impact of the guidance. It is acknowledged that the results of this process may be limited by the small sample size and short duration of the assessment.