Identifying individuals with undiagnosed post-traumatic stress disorder in a large United States civilian population - a machine learning approach.

BACKGROUND: The proportion of patients with post-traumatic stress disorder (PTSD) that remain undiagnosed may be substantial. Without an accurate diagnosis, these patients may lack PTSD-targeted treatments and experience adverse health outcomes. This study used a machine learning approach to identify and describe civilian patients likely to have undiagnosed PTSD in the US commercial population. METHODS: The IBM® MarketScan® Commercial Subset (10/01/2015-12/31/2018) was used. A random forest machine learning model was developed and trained to differentiate between patients with and without PTSD using non-trauma-based features. The model was applied to patients for whom PTSD status could not be confirmed to identify individuals likely and unlikely to have undiagnosed PTSD. Patient characteristics, symptoms and complications potentially related to PTSD, treatments received, healthcare costs, and healthcare resource utilization were described separately for patients with PTSD (Actual Positive PTSD cohort), patients likely to have PTSD (Likely PTSD cohort), and patients without PTSD (Without PTSD cohort). RESULTS: A total of 44,342 patients were classified in the Actual Positive PTSD cohort, 5683 in the Likely PTSD cohort, and 2,074,471 in the Without PTSD cohort. While several symptoms/comorbidities were similar between the Actual Positive and Likely PTSD cohorts, others, including depression and anxiety disorders, suicidal thoughts/actions, and substance use, were more common in the Likely PTSD cohort, suggesting that certain symptoms may be exacerbated among those without a formal diagnosis. Mean per-patient-per-6-month healthcare costs were similar between the Actual Positive and Likely PTSD cohorts ($11,156 and $11,723) and were higher than those of the Without PTSD cohort ($3616); however, cost drivers differed between cohorts, with the Likely PTSD cohort experiencing more inpatient admissions and less outpatient visits than the Actual Positive PTSD cohort. CONCLUSIONS: These findings suggest that the lack of a PTSD diagnosis and targeted management of PTSD may result in a greater burden among undiagnosed patients and highlights the need for increased awareness of PTSD in clinical practice and among the civilian population.

Patient-reported outcome measures for life engagement in mental health: a systematic review.

BACKGROUND: Life engagement in the context of mental health is a broad term that describes positive health aspects relating to cognition, vitality, motivation and reward, and the ability to feel pleasure-concepts that are meaningful to patients. The aim of this systematic literature review was to identify validated patient-reported outcomes (PROs) that can assess any aspect of life engagement in adults, in the field of general mental health. METHODS: This was a systematic literature review of articles in English from the MEDLINE database (date of search: September 9, 2020). The search strategy had three components: (1) terms to capture PROs; (2) terms to capture mental health; and (3) terms to capture aspects of life engagement. Articles were eligible if they included a PRO that: (1) is named; (2) can be used across mental health disorders; (3) is used to assess any aspect of life engagement; and (4) has undergone psychometric validation and/or qualitative content validation. A list of PROs was extracted. RESULTS: A total of 1585 records were screened and 233 articles were eligible for inclusion. Within these 233 articles, 49 distinct PROs were identified, two of which specifically captured their authors' interpretation of life engagement: the Engaged Living Scale (ELS) and the Life Engagement Test (LET). However, while the ELS and LET covered motivation and reward, life fulfillment, and value-based living, neither scale captured the cognitive or vitality aspects of life engagement. The remaining identified PROs generally captured single aspects of life engagement, most commonly motivation/reward/energy-apathy, pleasure-anhedonia, and mental/psychological well-being. CONCLUSION: Numerous PROs are available that may capture aspects of life engagement. However, a need remains for a new PRO that can be used in clinical trials to provide a more comprehensive description of the improvements in life engagement that patients with mental health disorders may experience with successful treatment.

Molecular architecture of a eukaryotic DNA transposase.

Mobile elements and their inactive remnants account for large proportions of most eukaryotic genomes, where they have had central roles in genome evolution. Over 50 years ago, McClintock reported a form of stress-induced genome instability in maize in which discrete DNA segments move between chromosomal locations. Our current mechanistic understanding of enzymes catalyzing transposition is largely limited to prokaryotic transposases. The Hermes transposon from the housefly is part of the eukaryotic hAT superfamily that includes hobo from Drosophila, McClintock's maize Activator and Tam3 from snapdragon. We report here the three-dimensional structure of a functionally active form of the transposase from Hermes at 2.1-A resolution. The Hermes protein has some structural features of prokaryotic transposases, including a domain with a retroviral integrase fold. However, this domain is disrupted by the insertion of an additional domain. Finally, transposition is observed only when Hermes assembles into a hexamer.

Obesity in the UK: a review and comparative analysis of policies within the devolved administrations.

In the United Kingdom obesity is a significant public problem and the formulation and implementation of policies to address it are primarily the responsibility of the devolved administrations. Containing populations which are broadly similar, albeit with regional differences, devolution allows for the exploration of the obesity policy directions the different UK countries have taken; thus providing opportunities for policy learning and comparison. A review and analysis of policy responses in the devolved administrations reveals differences in the strategic approaches to tackling obesity with England having recently introduced a population-wide strategy in contrast to the other countries. Further, policies to address obesity in England and Northern Ireland are being target driven in contrast to Scotland and Wales. In all the countries, the focus on obesity has been on addressing childhood obesity with Scotland having taken the lead on setting nutritional standards for school meals and the other countries subsequently following. While devolution has provided scope for the variation in responses to address the obesity epidemic in the UK, it is still too early to determine the impact of the different strategic approaches being used to tackling it.

Assessing the economic merits of managing cytomegalovirus infection in organ and stem cell transplantation.

Two preventative approaches exist to manage cytomegalovirus (CMV), a common infection in recipients of organ and stem cell transplants: prophylaxis--the prevention of viraemia--and pre-emptive therapy--the prevention of manifestation of disease in patients who have viraemia. Economic evaluation may provide a helpful framework to inform the choice between these two approaches. However, several issues arise. Direct comparisons of prophylaxis and pre-emptive therapy are rare and there are few epidemiological data that depict the full natural history of CMV infection and disease. There is a need for large, prospective randomised trials that directly compare these two strategies and are of sufficient duration to assess their overall impact on direct and indirect effects of CMV as well as patient quality of life. These methodological issues are relevant to the economic evaluation of preventative measures in other clinical settings and highlight the need for a rigorous evaluative framework to best inform decision making about the optimal strategy for patients.

Purification, crystallization and preliminary crystallographic analysis of the Hermes transposase.

DNA transposition is the movement of a defined segment of DNA from one location to another. Although the enzymes that catalyze transposition in bacterial systems have been well characterized, much less is known about the families of transposase enzymes that function in higher organisms. Active transposons have been identified in many insect species, providing tools for gene identification and offering the possibility of altering the genotypes of natural insect populations. One of these active transposons is Hermes, a 2749-base-pair element from Musca domestica that encodes its own transposase. An N-terminally deleted version of the Hermes transposase (residues 79-612) has been overexpressed and purified, and crystals that diffract to 2.1 A resolution have been obtained at 277 K by the hanging-drop method.

De-escalation from micafungin is a cost-effective alternative to traditional escalation from fluconazole in the treatment of patients with systemic Candida infections.

BACKGROUND: Systemic Candida infections (SCI) occur predominantly in intensive care unit patients and are a common cause of morbidity and mortality. Recently, changes in Candida epidemiology with an increasing prevalence of SCI caused by Candida non-albicans species have been reported. Resistance to fluconazole and azoles in general is not uncommon for non-albicans species. Despite guidelines recommending initial treatment with broad-spectrum antifungals such as echinocandins with subsequent switch to fluconazole if isolates are sensitive (de-escalation strategy), fluconazole is still the preferred first-line antifungal (escalation) in many clinical practice settings. After diagnosis of the pathogen, the initial therapy with fluconazole is switched to a broad-spectrum antifungal if a non-albicans is identified. METHODS: The cost-effectiveness of initial treatment with micafungin (de-escalation) vs fluconazole (escalation) in patients with SCI was estimated using decision analysis based on clinical and microbiological data from pertinent studies. The model horizon was 42 days, and was extrapolated to cover a lifetime horizon. All costs were analyzed from the UK NHS perspective. Several assumptions were taken to address uncertainties; the limitations of these assumptions are discussed in the article. RESULTS: In patients with fluconazole-resistant isolates, initial treatment with micafungin avoids 30% more deaths and successfully treats 23% more patients than initial treatment with fluconazole, with cost savings of £1621 per treated patient. In the overall SCI population, de-escalation results in 1.2% fewer deaths at a marginal cost of £740 per patient. Over a lifetime horizon, the incremental cost-effectiveness of de-escalation vs escalation was £15,522 per life-year and £25,673 per QALY. CONCLUSIONS: De-escalation from micafungin may improve clinical outcomes and overall survival, particularly among patients with fluconazole-resistant Candida strains. De-escalation from initial treatment with micafungin is a cost-effective alternative to escalation from a UK NHS perspective, with a differential cost per QALY below the 'willingness-to-pay' threshold of £30,000.

Interaction between the C8 alpha-gamma and C8 beta subunits of human complement C8: role of the C8 beta N-terminal thrombospondin type 1 module and membrane attack complex/perforin domain.

Human C8 is one of five complement components (C5b, C6, C7, C8, and C9) that interact to form the cytolytic membrane attack complex (MAC). It is an oligomeric protein composed of a disulfide-linked C8alpha-gamma heterodimer and a noncovalently associated C8beta chain. C8alpha and C8beta are homologous; both contain an N-terminal thrombospondin type 1 (TSP1) module, a low-density lipoprotein receptor class A (LDLRA) module, an extended central segment referred to as the membrane attack/perforin (MACPF) domain, an epidermal growth factor (EGF) module, and a second TSP1 module at the C-terminus. In this study, the segment of C8beta that confers binding specificity toward C8alpha-gamma was identified using recombinant C8beta constructs in which the N- and/or C-terminal modules were deleted or exchanged with those from C8alpha. Constructs were tested for their ability to bind C8alpha-gamma in solution and express C8 hemolytic activity. Binding to C8alpha-gamma was found to be dependent on the TSP1 + LDLRA + MACPF segment of C8beta. Within this segment, the TSP1 module and MACPF domain are principally involved and act cooperatively to mediate binding. Results from activity assays suggest that residues within this segment also mediate binding and incorporation of C8 into the MAC.