CD8+ T cell targeting of tumor antigens presented by HLA-E.

The nonpolymorphic major histocompatibility complex E (MHC-E) molecule is up-regulated on many cancer cells, thus contributing to immune evasion by engaging inhibitory NKG2A/CD94 receptors on NK cells and tumor-infiltrating T cells. To investigate whether MHC-E expression by cancer cells can be targeted for MHC-E-restricted T cell control, we immunized rhesus macaques (RM) with rhesus cytomegalovirus (RhCMV) vectors genetically programmed to elicit MHC-E-restricted CD8+ T cells and to express established tumor-associated antigens (TAAs) including prostatic acidic phosphatase (PAP), Wilms tumor-1 protein, or Mesothelin. T cell responses to all three tumor antigens were comparable to viral antigen-specific responses with respect to frequency, duration, phenotype, epitope density, and MHC restriction. Thus, CMV-vectored cancer vaccines can bypass central tolerance by eliciting T cells to noncanonical epitopes. We further demonstrate that PAP-specific, MHC-E-restricted CD8+ T cells from RhCMV/PAP-immunized RM respond to PAP-expressing HLA-E+ prostate cancer cells, suggesting that the HLA-E/NKG2A immune checkpoint can be exploited for CD8+ T cell-based immunotherapies.

Late gene expression-deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIV.

Rhesus cytomegalovirus-based (RhCMV-based) vaccine vectors induce immune responses that protect ~60% of rhesus macaques (RMs) from SIVmac239 challenge. This efficacy depends on induction of effector memory-based (EM-biased) CD8+ T cells recognizing SIV peptides presented by major histocompatibility complex-E (MHC-E) instead of MHC-Ia. The phenotype, durability, and efficacy of RhCMV/SIV-elicited cellular immune responses were maintained when vector spread was severely reduced by deleting the antihost intrinsic immunity factor phosphoprotein 71 (pp71). Here, we examined the impact of an even more stringent attenuation strategy on vector-induced immune protection against SIV. Fusion of the FK506-binding protein (FKBP) degradation domain to Rh108, the orthologue of the essential human CMV (HCMV) late gene transcription factor UL79, generated RhCMV/SIV vectors that conditionally replicate only when the FK506 analog Shield-1 is present. Despite lacking in vivo dissemination and reduced innate and B cell responses to vaccination, Rh108-deficient 68-1 RhCMV/SIV vectors elicited high-frequency, durable, EM-biased, SIV-specific T cell responses in RhCMV-seropositive RMs at doses of ≥ 1 × 106 PFU. Strikingly, elicited CD8+ T cells exclusively targeted MHC-Ia-restricted epitopes and failed to protect against SIVmac239 challenge. Thus, Rh108-dependent late gene expression is required for both induction of MHC-E-restricted T cells and protection against SIV.

Using Vocal Characteristics To Classify Psychological Distress in Adult Helpline Callers: Retrospective Observational Study.

BACKGROUND: Elevated psychological distress has demonstrated impacts on individuals' health. Reliable and efficient ways to detect distress are key to early intervention. Artificial intelligence has the potential to detect states of emotional distress in an accurate, efficient, and timely manner. OBJECTIVE: The aim of this study was to automatically classify short segments of speech obtained from callers to national suicide prevention helpline services according to high versus low psychological distress and using a range of vocal characteristics in combination with machine learning approaches. METHODS: A total of 120 telephone call recordings were initially converted to 16-bit pulse code modulation format. Short variable-length segments of each call were rated on psychological distress using the distress thermometer by the responding counselor and a second team of psychologists (n=6) blinded to the initial ratings. Following this, 24 vocal characteristics were initially extracted from 40-ms speech frames nested within segments within calls. After highly correlated variables were eliminated, 19 remained. Of 19 vocal characteristics, 7 were identified and validated as predictors of psychological distress using a penalized generalized additive mixed effects regression model, accounting for nonlinearity, autocorrelation, and moderation by sex. Speech frames were then grouped using k-means clustering based on the selected vocal characteristics. Finally, component-wise gradient boosting incorporating these clusters was used to classify each speech frame according to high versus low psychological distress. Classification accuracy was confirmed via leave-one-caller-out cross-validation, ensuring that speech segments from individual callers were not used in both the training and test data. RESULTS: The sample comprised 87 female and 33 male callers. From an initial pool of 19 characteristics, 7 vocal characteristics were identified. After grouping speech frames into 2 separate clusters (correlation with sex of caller, Cramer's V =0.02), the component-wise gradient boosting algorithm successfully classified psychological distress to a high level of accuracy, with an area under the receiver operating characteristic curve of 97.39% (95% CI 96.20-98.45) and an area under the precision-recall curve of 97.52 (95% CI 95.71-99.12). Thus, 39,282 of 41,883 (93.39%) speech frames nested within 728 of 754 segments (96.6%) were classified as exhibiting low psychological distress, and 71455 of 75503 (94.64%) speech frames nested within 382 of 423 (90.3%) segments were classified as exhibiting high psychological distress. As the probability of high psychological distress increases, male callers spoke louder, with greater vowel articulation but with greater roughness (subharmonic depth). In contrast, female callers exhibited decreased vocal clarity (entropy), greater proportion of signal noise, higher frequencies, increased breathiness (spectral slope), and increased roughness of speech with increasing psychological distress. Individual caller random effects contributed 68% to risk reduction in the classification algorithm, followed by cluster configuration (23.4%), spectral slope (4.4%), and the 50th percentile frequency (4.2%). CONCLUSIONS: The high level of accuracy achieved suggests possibilities for real-time detection of psychological distress in helpline settings and has potential uses in pre-emptive triage and evaluations of counseling outcomes. TRIAL REGISTRATION: ANZCTR ACTRN12622000486729; https://www.anzctr.org.au/ACTRN12622000486729.aspx.

The secreted protein Cowpox Virus 14 contributes to viral virulence and immune evasion by engaging Fc-gamma-receptors.

The genome of cowpoxvirus (CPXV) could be considered prototypical for orthopoxviridae (OXPV) since it contains many open reading frames (ORFs) absent or lost in other OPXV, including vaccinia virus (VACV). These additional ORFs are non-essential for growth in vitro but are expected to contribute to the broad host range, virulence and immune evasion characteristics of CPXV. For instance, unlike VACV, CPXV encodes proteins that interfere with T cell stimulation, either directly or by preventing antigen presentation or co-stimulation. When studying the priming of naïve T cells, we discovered that CPXV, but not VACV, encodes a secreted factor that interferes with activation and proliferation of naïve CD8+ and CD4+ T cells, respectively, in response to anti-CD3 antibodies, but not to other stimuli. Deletion mapping revealed that the inhibitory protein is encoded by CPXV14, a small secreted glycoprotein belonging to the poxvirus immune evasion (PIE) family and containing a smallpoxvirus encoded chemokine receptor (SECRET) domain that mediates binding to chemokines. We demonstrate that CPXV14 inhibition of antibody-mediated T cell activation depends on the presence of Fc-gamma receptors (FcγRs) on bystander cells. In vitro, CPXV14 inhibits FcγR-activation by antigen/antibody complexes by binding to FcγRs with high affinity and immobilized CPXV14 can trigger signaling through FcγRs, particularly the inhibitory FcγRIIB. In vivo, CPXV14-deleted virus showed reduced viremia and virulence resulting in reduced weight loss and death compared to wildtype virus whereas both antibody and CD8+ T cell responses were increased in the absence of CPXV14. Furthermore, no impact of CPXV14-deletion on virulence was observed in mice lacking the inhibitory FcγRIIB. Taken together our results suggest that CPXV14 contributes to virulence and immune evasion by binding to host FcγRs.

Using Voice Biomarkers to Classify Suicide Risk in Adult Telehealth Callers: Retrospective Observational Study.

BACKGROUND: Artificial intelligence has the potential to innovate current practices used to detect the imminent risk of suicide and to address shortcomings in traditional assessment methods. OBJECTIVE: In this paper, we sought to automatically classify short segments (40 milliseconds) of speech according to low versus imminent risk of suicide in a large number (n=281) of telephone calls made to 2 telehealth counselling services in Australia. METHODS: A total of 281 help line telephone call recordings sourced from On The Line, Australia (n=266, 94.7%) and 000 Emergency services, Canberra (n=15, 5.3%) were included in this study. Imminent risk of suicide was coded for when callers affirmed intent, plan, and the availability of means; level of risk was assessed by the responding counsellor and reassessed by a team of clinical researchers using the Columbia Suicide Severity Rating Scale (=5/6). Low risk of suicide was coded for in an absence of intent, plan, and means and via Columbia suicide Severity Scale Ratings (=1/2). Preprocessing involved normalization and pre-emphasis of voice signals, while voice biometrics were extracted using the statistical language r. Candidate predictors were identified using Lasso regression. Each voice biomarker was assessed as a predictor of suicide risk using a generalized additive mixed effects model with splines to account for nonlinearity. Finally, a component-wise gradient boosting model was used to classify each call recording based on precoded suicide risk ratings. RESULTS: A total of 77 imminent-risk calls were compared with 204 low-risk calls. Moreover, 36 voice biomarkers were extracted from each speech frame. Caller sex was a significant moderating factor (ß=-.84, 95% CI -0.85, -0.84; t=6.59, P<.001). Candidate biomarkers were reduced to 11 primary markers, with distinct models developed for men and women. Using leave-one-out cross-validation, ensuring that the speech frames of no single caller featured in both training and test data sets simultaneously, an area under the precision or recall curve of 0.985 was achieved (95% CI 0.97, 1.0). The gamboost classification model correctly classified 469,332/470,032 (99.85%) speech frames. CONCLUSIONS: This study demonstrates an objective, efficient, and economical assessment of imminent suicide risk in an ecologically valid setting with potential applications to real-time assessment and response. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12622000486729; https://www.anzctr.org.au/ACTRN12622000486729.aspx.

Impact of Chorea on Self-care Activity, Employment, and Health-care Resource Use in Patients with Huntington's Disease.

Background: Chorea is recognized as a prototypic motor feature of Huntington's disease (HD), but its effect on health-related quality of life (HRQoL) has not been fully explored. This study describes the impact of chorea on HRQoL in patients with HD. Objective: To determine the impact of HD-related chorea on employment, self-care activities, activities of daily living, and health-care resource utilization (HCRU). Methods: Data were drawn from the Adelphi HD Disease Specific Programme, a real-world point-in-time survey of 144 neurologists and 427 patients in the United States between July and October 2017. HD patients with and without chorea were identified and examined for differences in employment status, reasons for employment changes, self-care activities, and modifications to cope with involuntary movements. Bivariate tests and inverse probability weighted regression adjustment methods were used to determine differences in outcomes between patients with and without chorea. Results: HD patients with (n=287) and without (n=140) chorea were identified. Patients with chorea were less likely to be employed full-time (16.7% vs 25.7%; P<0.04) and more likely to be on long-term sick leave (17.4% vs 5.0%; P<0.01). The onset of motor symptoms in HD-related chorea patients coincided with a change in employment status (42.7% vs 20.8%; P<0.01). Among those still working (n=145), more than two-fifths of patients with chorea required changes to their workplace and required these changes more frequently (45% vs 17%; P<0.001). HD patients with chorea required aid to help them get around significantly more frequently than those without chorea (55% vs 34%; P<0.001). Discussion: These results demonstrate that HD patients with chorea experienced greater negative impact to employment, self-care activities, and HCRU than patients without chorea experienced. These patients were more likely to stop working due to motor, cognitive, and behavioral symptoms; require modifications in the home and workplace; and need more assistance from caregivers than patients without chorea. Conclusions: Patients with HD-related chorea have greater detriments to emotional, interpersonal, and professional functioning that could be improved by reducing chorea.

Modulation of MHC-E transport by viral decoy ligands is required for RhCMV/SIV vaccine efficacy.

Strain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens elicit CD8+ T cells recognizing epitopes presented by major histocompatibility complex II (MHC-II) and MHC-E but not MHC-Ia. These immune responses mediate replication arrest of SIV in 50 to 60% of monkeys. We show that the peptide VMAPRTLLL (VL9) embedded within the RhCMV protein Rh67 promotes intracellular MHC-E transport and recognition of RhCMV-infected fibroblasts by MHC-E-restricted CD8+ T cells. Deletion or mutation of viral VL9 abrogated MHC-E-restricted CD8+ T cell priming, resulting in CD8+ T cell responses exclusively targeting MHC-II-restricted epitopes. These responses were comparable in magnitude and differentiation to responses elicited by 68-1 vectors but did not protect against SIV. Thus, Rh67-enabled direct priming of MHC-E-restricted T cells is crucial for RhCMV/SIV vaccine efficacy.

DNA Mismatch Repair and its Role in Huntington's Disease.

DNA mismatch repair (MMR) is a highly conserved genome stabilizing pathway that corrects DNA replication errors, limits chromosomal rearrangements, and mediates the cellular response to many types of DNA damage. Counterintuitively, MMR is also involved in the generation of mutations, as evidenced by its role in causing somatic triplet repeat expansion in Huntington's disease (HD) and other neurodegenerative disorders. In this review, we discuss the current state of mechanistic knowledge of MMR and review the roles of key enzymes in this pathway. We also present the evidence for mutagenic function of MMR in CAG repeat expansion and consider mechanistic hypotheses that have been proposed. Understanding the role of MMR in CAG expansion may shed light on potential avenues for therapeutic intervention in HD.

The Burden of Pain Associated with Osteoarthritis in the Hip or Knee from the Patient's Perspective: A Multinational Cross-Sectional Study.

INTRODUCTION: To evaluate, from the patient's perspective, the burden of pain associated with hip/knee osteoarthritis (OA) in the USA and selected European Union (EU) countries. METHODS: Data were drawn from the 2017 global Adelphi OA Disease Specific Programme™ (DSP). Patients with hip/knee OA were stratified based on pain intensity and the presence/absence of current opioid use. Outcomes included Western Ontario and McMaster Universities Osteoarthritis Index scores, functional limitations, unmet treatment needs, Charlson Comorbidity Index, relevant comorbid conditions, the 5-dimension 5-level EuroQol, and the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem. Bivariate testing compared outcomes using patients with no/mild pain without opioid use as the reference group. RESULTS: The study population comprised 2170 patients (US: n = 623 [28.7%]; EU: n = 1547 [71.3%]) with knee (54.9%), hip (24.6%), or knee/hip (20.5%) OA. Mean (SD) age was 66.4 (11.2) years. Patients had no/mild pain without opioid use (39.6%), no/mild pain with opioid use (10.2%), moderate/severe pain without opioid use (30.6%), and moderate/severe pain with opioid use (19.7%). Compared with the reference group, patients with moderate/severe pain reported significantly (p < 0.05) higher functional limitations, greater use of ≥ 3 treatments and treatment dissatisfaction, reduced quality of life, and impaired work productivity and activity. The burden was highest with moderate/severe pain with opioid use. Results were generally similar in the US and EU cohorts. CONCLUSIONS: The results from this multinational cross-sectional study indicate that the impact of OA pain is multidimensional, worsened by increasing pain intensity, and may not be adequately addressed by current treatment strategies.

A Real-World Study Using Claims Data to Evaluate Possible Failure of Opioid Treatment Regimens Among Patients with Hip and/or Knee Osteoarthritis in the US.

BACKGROUND: Although opioids may be used in the management of pain in patients with osteoarthritis (OA), there is a dearth of real-world data characterizing opioid regimen failure in these patients. OBJECTIVE: Using claims data, this study explored measures that may be potentially indicative of opioid treatment failure and the association of such potential failure with health care resource utilization (HRU) and costs. PATIENTS AND METHODS: Using a national employer-sponsored insurance claims database covering the years 2011-2016, this retrospective longitudinal study identified adults with hip/knee osteoarthritis who filled ≥1 opioid prescription (index event) and had continuous health plan enrollment 6 months pre- and ≥12 months post-index. Index opioid regimen intensity was defined in the 3-month post-index period by frequency, average daily dose, and duration of action. Possible index opioid regimen failure was defined as an increase in opioid regimen intensity, addition of a non-opioid pain medication, joint surgery, or opioid-abuse-related events. One-year follow-up HRU and costs were compared between those with possible treatment failure and those without. RESULTS: Among 271,512 OA patients (61.5% knee; 11.1% hip; 27.4% both), 34.9% met the definition of possible index opioid regimen failure within a year: increased regimen intensity (16.1%), joint surgery (14.0%), addition of non-opioid pain medication (11.4%), and opioid-abuse-related events (1.9%). Rates of possible failure generally increased with higher index regimen intensity. Compared with those who did not fail, those who potentially failed their index treatment regimen had significantly higher HRU (P<0.001), and all-cause ($36,699 vs $15,114) and osteoarthritis-related costs ($17,298 vs $1,967) (both P<0.0001). CONCLUSION: Among OA patients treated with opioids, approximately one-third may fail their index opioid regimen within a year and incur significantly higher HRU and costs than those without. Further research is needed to validate these findings with clinical outcomes.

How Ambient Cues Facilitate Political Segregation.

People increasingly self-segregate into politically homogeneous communities. How they do this remains unclear. We propose that people use ambient cues correlated with political values to infer whether they would like to live in those communities. We test this hypothesis in five studies. In Studies 1 (n = 3,543) and 2 (n = 5,609), participants rated community cues; liberals and conservatives' preferences differed. In Studies 3a (n = 1,643) and 3b (n = 1,840), participants read about communities with liberal or conservative cues. Even without explicit information about the communities' politics, participants preferred communities with politically congenial cues. In Study 4 (n = 282), participants preferred politically congenial communities and wanted to leave politically uncongenial communities. In Study 5 (n = 370), people selectively navigated their communities in a politically congenial way. These studies suggest that peoples' perceptions of communities can be shaped by subtle, not necessarily political, cues that may facilitate growing political segregation.

Perceptions of the impact of chorea on health-related quality of life in Huntington disease (HD): A qualitative analysis of individuals across the HD spectrum, family members, and clinicians.

Chorea, a hallmark symptom of Huntington's disease (HD), is characterized by jerky involuntary movements affecting the whole body that can interfere with daily functioning and impact health-related quality of life (HRQOL). To characterize chorea's impact on everyday functioning and HRQOL and identify patterns of perception and experiences of chorea among patients, caregivers, and providers. Data from focus groups of individuals with manifest HD (n = 8 early-stage HD; n = 16 late-stage HD), individuals at-risk or prodromal HD (n = 16), family HD caregivers (n = 17), and HD clinicians (n = 25). Focus group recordings were transcribed verbatim and analysed via constant comparison to identify meaningful and salient themes of living with chorea. Global themes of chorea's impact identified included: watching for chorea, experiences of stigma, and constraints on independence and relationships. Themes distinct to specific respondent groups included: Vigilance (at risk, prodromal); adaptation to chorea (early-stage); loss of autonomy and social life (late-stage); monitoring engagement (family caregivers) and safety (clinical providers). Living with chorea significantly constrains daily functioning, interactions, and HRQOL across the HD disease spectrum. Addressing these impacts via appropriate management of chorea can potentially enhance functioning, HRQOL, and overall satisfaction for persons with HD and their families.

Ideological differences in the expanse of the moral circle.

Do clashes between ideologies reflect policy differences or something more fundamental? The present research suggests they reflect core psychological differences such that liberals express compassion toward less structured and more encompassing entities (i.e., universalism), whereas conservatives express compassion toward more well-defined and less encompassing entities (i.e., parochialism). Here we report seven studies illustrating universalist versus parochial differences in compassion. Studies 1a-1c show that liberals, relative to conservatives, express greater moral concern toward friends relative to family, and the world relative to the nation. Studies 2a-2b demonstrate these universalist versus parochial preferences extend toward simple shapes depicted as proxies for loose versus tight social circles. Using stimuli devoid of political relevance demonstrates that the universalist-parochialist distinction does not simply reflect differing policy preferences. Studies 3a-3b indicate these universalist versus parochial tendencies extend to humans versus nonhumans more generally, demonstrating the breadth of these psychological differences.

Physician and patient preferences for dosing options in migraine prevention.

BACKGROUND: Adherence to a therapy, though a key factor for successful treatment, is low among patients with chronic conditions such as migraine. Dose frequency plays a major role in adherence. This study evaluated the impact of having flexible dosing options on acceptance of and adherence to a new migraine preventive therapy class among adults with migraine. METHODS: In this observational study, two 20-min online surveys were completed: one by physicians currently treating adult patients with migraine and the other by adults with migraine. Both surveys presented the participants with three scenarios: 1) only monthly, 2) only quarterly, and 3) both dosing options of the new medication are available. Physicians estimated the proportion of their migraine patients who would receive the new medication in each scenario. Patients were asked about their dosing preference when either or both options are available. Respondents were asked to rate the likelihood of their acceptance of and adherence to the therapy. RESULTS: 400 physicians and 417 US adults with migraine completed the surveys. The availability of both dosing options yielded a significant increase in the proportion of patients expected to receive the new medication. The overall proportion of patients favoring monthly dosing (35%) was similar to the proportion favoring quarterly dosing (40%). Among those who preferred monthly dosing (n = 147), a greater proportion indicated they are more likely to fill the prescription (77% vs 56%, P < 0.05) and remain adherent (80% vs 57%, P < 0.05) when only monthly is available versus when only quarterly is available. Similarly, among those who preferred quarterly dosing (n = 166), a greater proportion indicated they are likely to fill (63% vs 55%, P < 0.05) and remain adherent (62% vs 54%, P < 0.05) when only quarterly is available compared with when only monthly is available. CONCLUSIONS: Physicians anticipated that the proportion of patients to receive the new medication would increase when both dosing options are available. Patients stated that they are more likely to fill the prescription and adhere to the new therapy when their preferred dosing regimen is available.

Tetrabenazine Treatment Patterns and Outcomes for Chorea Associated with Huntington Disease: A Retrospective Chart Review.

BACKGROUND: Huntington disease (HD) is a neurodegenerative disorder characterized by motor impairments (including chorea), along with behavioral, psychiatric, and cognitive symptoms. Tetrabenazine was the first US Food and Drug Administration (FDA)-approved treatment for chorea related to HD. OBJECTIVE: To examine pharmacologic treatment patterns among patients using tetrabenazine, including reasons for treatment initiation, non-initiation, dose adjustments, and discontinuation, and to quantify the burden of chorea based on healthcare resource utilization. METHODS: In this retrospective patient chart review, neurologists were recruited from the Medefield (http://www.medefield.com) opt-in panel, and selected ≤5 medical charts based on the criteria provided and abstracted data on demographics, disease history, healthcare resource use, and treatment patterns. RESULTS: 138 neurologists participated and 512 HD patient charts were reviewed. Among these patients, 26.4% did not initiate tetrabenazine. Most HD patients (66.5%) received a tetrabenazine dose ≤50 mg. The most common reasons for stopping upward titration were optimal chorea control (55.5%), intolerability of higher doses (31.2%), and reaching the maximum recommended dosage despite suboptimal chorea control (11.4%). Chorea severity and non-persistence to tetrabenazine were associated with increased emergency room visits, hospitalizations, and days hospitalized. CONCLUSIONS: Although tetrabenazine was the sole FDA-approved treatment for HD chorea until April 2017, more than one-quarter of respondents never initiated therapy. Tetrabenazine dosing was lower than predicted, and many patients experienced adverse symptoms of intolerability at high doses. New safer and more tolerable treatment options, such as deutetrabenazine, may improve treatment outcomes and reduce healthcare resource use.

Understanding How Chorea Affects Health-Related Quality of Life in Huntington Disease: An Online Survey of Patients and Caregivers in the United States.

BACKGROUND: Chorea is the hallmark motor feature of Huntington disease (HD) and can negatively impact daily functioning and health-related quality of life (HRQoL). OBJECTIVE: The objective of this study was to evaluate how chorea impacts HRQoL and overall functioning among HD patients participating on the PatientsLikeMe website ( www.PatientsLikeMe.com ). METHODS: A survey was provided to HD participants and/or their caregivers via PatientsLikeMe (9 February 2017-22 March 2017), comprising multiple-choice and open-ended questions designed to assess how chorea impacts HRQoL and overall functioning, and the importance of treating chorea. The HDQLIFE measurement system was used to evaluate patient-reported outcomes of chorea and compare Anxiety and Stigma scores in participants with high chorea versus those with low chorea [HDQLIFE Chorea scores ≥ 60 (n = 45) vs. < 60 (n = 38)]. RESULTS: A total of 115 participants (n = 35 caregivers; n = 80 individuals with HD) were included in this study. Among those experiencing chorea (n = 83, 74% of respondents), 66% indicated it was 'Very Important' to manage chorea; however, only 47% agreed that their current medication regimen helped manage their movements. In general, respondents reported that chorea negatively affected HRQoL [HDQLIFE Chorea mean score (standard deviation): 59.3 (6.1)]. Consistent with this, significantly higher Anxiety (P = 0.0423) and stigma (P < 0.0001) scores were observed among respondents with high chorea than in those with low chorea. CONCLUSIONS: These results highlight the negative impact of chorea on HRQoL and overall functioning in individuals with HD. Better chorea treatment options are needed to successfully manage symptoms and to help improve HRQoL in these individuals, and patient experiences of anxiety and stigma should be considered in treatment plans.

Physician perceptions of pharmacologic treatment options for chorea associated with Huntington disease in the United States.

OBJECTIVE: To survey neurologists and obtain clinical perceptions of tetrabenazine for the treatment of chorea in patients with Huntington disease (HD). METHODS: Board-certified/board-eligible neurologists, in practice for ≥5 years, who had treated treat ≥3 HD patients in the past 2 years, were recruited from an online physician panel to participate in a cross-sectional, web-based survey. Respondents provided information about themselves, their practice, approaches to HD chorea management and perceptions of available treatments. RESULTS: Two hundred neurologists responded to the survey. Based on clinician responses, the most common reasons to treat chorea are impairment in activities of daily living (54%) and quality of life (41%). Although tetrabenazine was the only approved treatment for chorea in HD patients at the time of this analysis, it was only prescribed to ∼50% of patients with HD-related chorea. More than half of physicians perceive tetrabenazine as having minimal or no effectiveness in improving chorea. More than 40% of physicians consider tetrabenazine to be a non-optimal treatment, and 51% of physicians agree that they are unable to titrate to efficacious doses due to adverse side effects or tolerability concerns. Physicians report that side effects leading to dose interruptions (33%) and reductions (30%) occur in their patients "often" or "almost always". The most common side effects that led to insufficient dosing and disruptions in titration were sedation and somnolence (41%), depression (24%) and anxiety (22%). CONCLUSIONS: Many physicians who treat HD-related chorea report that tolerability issues with tetrabenazine impact their ability to effectively use tetrabenazine in their clinical practice.

Retrospective Analysis of Healthcare Resource Use, Treatment Patterns, and Treatment-related Events in Patients with Huntington's Disease-associated Chorea Initiated on Tetrabenazine.

BACKGROUND: Huntington's disease (HD) is a multifaceted neurodegenerative disorder characterized by involuntary movements, specifically chorea, as well as behavioral and psychiatric disturbance, and cognitive dysfunction. Tetrabenazine was the first approved treatment for chorea, although tolerability concerns exist. OBJECTIVES: To characterize demographic and clinical characteristics of HD patients with chorea based on tetrabenazine use and examine treatment persistence with tetrabenazine in a real-world setting. METHODS: Patients with a claim for HD-associated chorea (ICD-9-CM code 333.4) between 1/1/08 and 9/30/15 were selected from the MarketScan® Commercial and Medicare Supplemental databases. The first diagnosis date during the study period was considered the index date, with ≥6 months of continuous medical and prescription coverage before and after the index date. Treatment persistence was defined as the number of days from initiation to discontinuation or end of follow-up period. Discontinuation was defined as a gap in therapy of ≥60 days. RESULTS: 1644 patients met selection criteria (mean age ± standard deviation: 54.5 ± 15.5), of which 151 (9.2%) were treated with tetrabenazine during the study period. The average (median) daily dose of tetrabenazine during the treatment period was 45.5 (42.3) mg/day. A total of 41.8% (59/141) of HD patients who initiated tetrabenazine experienced a ≥60-day gap in tetrabenazine therapy, with a median time to discontinuation of 293.5 days. During the 6-month post-index period after HD diagnosis, HD patients incurred higher all-cause healthcare costs ($20 204) vs the 6-month pre-index period ($6057), driven by higher hospitalization and pharmacy costs. CONCLUSIONS: A small percentage of HD patients with chorea were treated with tetrabenazine and discontinuation rates were high among those receiving treatment, with a median time to discontinuation of 9 months.

The influence of gender on the relationship between psychopathy and five moral foundations.

Previous research has demonstrated that individuals higher in psychopathy are less concerned about preventing harm and preserving fairness than individuals lower in psychopathy, yet it is unclear whether this is true for both genders. Females have been shown to be more concerned about moral issues related to preventing harm, being fair and maintaining purity, and males are more concerned about in-group loyalty and respecting authority. In addition, females on average are more empathic, less willing to cause harm and may be less sensitive to fairness. The goal of this study was to examine gender's influence on the relationship between psychopathy and five moral foundations. In a large online sample, we found that although gender moderated the relationship between psychopathy and harm and fairness, the magnitude of these interactions was small. The main effects of gender and of psychopathy support previous research. Overall, females were more concerned than males about preventing harm. Both males and females scoring higher in psychopathy were less concerned about harm and fairness than those lower in psychopathy. Copyright © 2017 John Wiley & Sons, Ltd.

Interaction of proliferating cell nuclear antigen with PMS2 is required for MutLα activation and function in mismatch repair.

Eukaryotic MutLα (mammalian MLH1-PMS2 heterodimer; MLH1-PMS1 in yeast) functions in early steps of mismatch repair as a latent endonuclease that requires a mismatch, MutSα/ß, and DNA-loaded proliferating cell nuclear antigen (PCNA) for activation. We show here that human PCNA and MutLα interact specifically but weakly in solution to form a complex of approximately 1:1 stoichiometry that depends on PCNA interaction with the C-terminal endonuclease domain of the MutLα PMS2 subunit. Amino acid substitution mutations within a PMS2 C-terminal 721QRLIAP motif attenuate or abolish human MutLα interaction with PCNA, as well as PCNA-dependent activation of MutLα endonuclease, PCNA- and DNA-dependent activation of MutLα ATPase, and MutLα function in in vitro mismatch repair. Amino acid substitution mutations within the corresponding yeast PMS1 motif (723QKLIIP) reduce or abolish mismatch repair in vivo. Coupling of a weak allele within this motif (723AKLIIP) with an exo1Δ null mutation, which individually confer only weak mutator phenotypes, inactivates mismatch repair in the yeast cell.