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IntroductionDespite the development of many successful pharmaceutical interventions, a significant subset of patients experience treatment-resistant depression (TRD). Ketamine and its derivatives constitute a novel therapeutic approach to treat TRD; however, standard tools, such as the Montgomery–Åsberg Depression Rating Scale (MADRS) are still being used to measure symptoms and track changes.MethodsThe aim of this study was to review item-level differences between rate of data change (MADRS score) and rater-weighted perception of the most useful items for assessing change in symptoms while remotely conducting the 10-item version of the MADRS in TRD in a clinical trial of rapid-acting antidepressants. Two studies of rapid-acting antidepressants in the treatment of TRD were used to identify item-scoring trends when MADRS is administered remotely and repeatedly (733 subjects across 10 visits). Scoring trends were evaluated in tandem to a rater survey completed by 75 raters. This was completed to gain insight on MADRS items’ perceived level of helpfulness when assessing change of symptoms in rapid-acting antidepressant trials.ResultsMADRS items ‘Reduced sleep’, ‘Apparent sadness’, and ‘Pessimistic thoughts’ were found to have the greatest average data change by visit, while raters ranked ‘Reported sadness’, ‘Lassitude’ and ‘Apparent sadness’ as the most helpful items when assessing symptom change.DiscussionThe diversion between rate of data-change ranking and rater perception of helpfulness could be related to difficulty in assessing specific items, to the novel treatment itself, and/or to the sensitivity to symptom change to which raters are accustomed in traditional antidepressant treatments.

Abstract Ratings on the Positive and Negative Syndrome Scale (PANSS) are ideally based on both a patient interview and an informant questionnaire. In research and clinical settings, however, the informant questionnaire is often omitted. This study investigated the consequences of omitting informant information by comparing PANSS ratings of patients with schizophrenia (n = 49 patients, 77 ratings) conducted with and without informant information, respectively. Additionally, changes in symptom severity over time based on ratings with and without informant information were also compared for the full PANSS and the six-item version of the PANSS (PANSS-6). PANSS ratings including informant information were higher than those without, both at the total score and individual item level. Additionally, the full PANSS appeared less “responsive” to baseline-to-endpoint changes for ratings without informant information compared to ratings including informant information, while no differences were found for the PANSS-6.

Abstract Background Major depressive disorder (MDD) is a recurrent psychiatric condition that presents challenges in responding to treatment and achieving long-term remission. To improve outcomes, a shared decision-making treatment approach with patient and healthcare practitioner (HCP) engagement is vital. PatientsLikeMe (PLM), a peer community of patients, provides information on MDD, symptoms, and treatment through forums and resources, helping patients stay engaged in their treatment journey. Data on PLM can be harnessed to gain insights into patient perspectives on MDD symptom management, medication switches, and treatment goals and measures. Methods This ongoing, decentralized, longitudinal, observational, prospective study is being conducted using the PLM platform in two parts, enrolling up to 500 patients with MDD in the United States aged ≥ 18 years to compare vortioxetine with other monotherapy antidepressants. The first qualitative component consists of a webinar and discussion forum with PLM community members with MDD, followed by a pilot for functionality testing to improve the study flow and questions in the quantitative survey. The quantitative component follows on the PLM platform, utilizing patient-reported assessments, over a 24-week period. Three surveys will be conducted at baseline and weeks 12 and 24 to collect data on patient global impression of improvement, depression severity, cognitive function, quality of life (QoL) and well-being, medication satisfaction, emotional blunting, symptoms of anhedonia and resilience, as well as goal attainment. Quantitative results will be compared between groups. The qualitative component is complete; patient recruitment is underway for the quantitative component, with results expected in late 2023. Discussion These results will help HCPs understand patient perspectives on the effectiveness of vortioxetine versus other monotherapy antidepressants in alleviating symptoms of MDD and improvements in QoL. Data from the PLM platform will support a patient goal-based treatment approach, as results can be shared by patients with their HCPs, providing them with insights on patient-centric goals, treatment management and adherence, as well as allowing them to observe changes in patient-related outcomes scores. Findings from the study will also help to optimize the PLM platform to build scalable solutions and connectivity within the community to better serve patients with MDD.

Consider the following hat guessing game. A bear sits on each vertex of a graph $G$, and a demon puts on each bear a hat colored by one of $h$ colors. Each bear sees only the hat colors of his neighbors. Based on this information only, each bear has to guess $g$ colors and he guesses correctly if his hat color is included in his guesses. The bears win if at least one bear guesses correctly for any hat arrangement. We introduce a new parameter - fractional hat chromatic number $\hat{\mu}$, arising from the hat guessing game. The parameter $\hat{\mu}$ is related to the hat chromatic number which has been studied before. We present a surprising connection between the hat guessing game and the independence polynomial of graphs. This connection allows us to compute the fractional hat chromatic number of chordal graphs in polynomial time, to bound fractional hat chromatic number by a function of maximum degree of $G$, and to compute the exact value of $\hat{\mu}$ of cliques, paths, and cycles.

There is a need for measures to track symptom change in autism spectrum disorder (ASD). We conducted a validation study on a revised version of the Autism Behavior Inventory (ABI), and a short form (ABI-S). Caregivers of individuals (6-54 years) with confirmed diagnoses of ASD (N = 144) completed the ABI and other rating scales at 4 time points. Scale consistency for each domain, 3-5 day test-retest reliability, and construct validity, determined by comparison to pre-specified scales, were all good. Change in the ABI was congruent with changes in other instruments. Collectively, results suggest incipient suitability of the ABI as a measure of changes in core and associated symptoms of ASD.Trial Registration NCT02299700.

BackgroundPrevious studies have shown mixed results on the association between carbohydrate intake and insomnia. However, any influence that refined carbohydrates have on risk of insomnia is likely commensurate with their relative contribution to the overall diet, so studies are needed that measure overall dietary glycemic index (GI), glycemic load, and intakes of specific types of carbohydrates.ObjectiveWe hypothesized that higher GI and glycemic load would be associated with greater odds of insomnia prevalence and incidence.MethodsThis was a prospective cohort study with postmenopausal women who participated in the Women's Health Initiative Observational Study, investigating the relations of GI, glycemic load, other carbohydrate measures (added sugars, starch, total carbohydrate), dietary fiber, and specific carbohydrate-containing foods (whole grains, nonwhole/refined grains, nonjuice fruits, vegetables, dairy products) with odds of insomnia at baseline (between 1994 and 1998; n = 77,860) and after 3 y of follow-up (between 1997 and 2001; n = 53,069).ResultsIn cross-sectional and longitudinal analyses, higher dietary GI was associated with increasing odds of prevalent (fifth compared with first quintile OR: 1.11; CI: 1.05, 1.16; P-trend = 0.0014) and incident (fifth compared with first quintile OR: 1.16; CI: 1.08, 1.25; P-trend

The novel mechanisms of action (MOA) derived from some recently introduced molecular targets have led to regulatory approvals for rapid acting antidepressants (RAADs) that can generate responses within hours or days, rather than weeks or months. These novel targets include the N-methyl-D-glutamate receptor antagonist ketamine, along with its enantiomers and various derivatives, and the allosteric modulators of gamma-aminobutyric acid (GABA) receptors. There has also been a strong resurgence in interest in psychedelic compounds that impact a range of receptor sites including D1, 5-HT7, KOR, 5-HT5A, Sigma-1, NMDA, and BDNF. The RAADs developed from these novel targets have enabled successful treatment for difficult to treat depressed individuals and has generated a new wave of innovation in research and treatment. Despite the advances in the neurobiology and clinical treatment of mood disorders, we are still using rating instruments that were created decades ago for drugs from a different era (e.g., The Hamilton and Montgomery-Åsberg depression rating scales, HDRS, and MADRS) continue to be used. These rating instruments were designed to assess mood symptoms over a 7-day time frame. Consequently, the use of these rating instruments often requires modifications to address items that cannot be assessed in short time frames, such as the sleep and appetite items. This review describes the adaptative approaches that have been made with the existing scales to meet this need and examines additional domains such as daily activities, side effects, suicidal ideation and behavior, and role functioning. Recommendations for future studies are described, including the challenges related to implementation of these adapted measures and approaches to mitigation.

International Society for CNS Clinical Trials and Methodology convened an expert working-group that assembled consistency/inconsistency flags for the Positive and Negative Syndrome Scale (PANSS). Twenty-four flags were identified and divided based on extent to which they represent error (Possibly, Probably, Very probably or definitely). The flags were applied to assessments derived from the NEWMEDS data repository and the CATIE clinical trial data. Almost 40% of ratings had at least one inconsistency flag raised and 10% had two. Application of flags to clinical rating can improve reliability and validity of trials.

ObjectiveAutism Behavior Inventory (ABI) is a new measure for assessing changes in core and associated symptoms of autism spectrum disorder (ASD) in participants (ages: 3 years-adulthood) diagnosed with ASD. It is a web-based tool with five domains (two ASD core domains: social communication, restrictive and repetitive behaviors; three associated domains: mental health, self-regulation, and challenging behavior). This study describes design, development, and initial psychometric properties of the ABI.MethodsABI items were generated following review of existing measures and inputs from expert clinicians. Initial ABI scale contained 161 items that were reduced to fit a factor analytic model, retaining items of adequate reliability. Two versions of the scale, ABI-full (ABI-F; 93 items) and ABI-short version (ABI-S; 36 items), were developed and evaluated for psychometric properties, including validity comparisons with commonly used measures. Both scales were administered to parents and healthcare professionals (HCPs) involved with study participants.ResultsTest-retest reliability (intraclass correlation coefficient [ICC] = 0.79) for parent ratings on ABI was robust and compared favorably to existing scales. Test-retest correlations for HCP ratings were generally lower versus parent ratings. ABI core domains and comparison measures strongly correlated (r ≥ 0.70), demonstrating good concurrent validity.ConclusionsOverall, ABI demonstrates promise as a tool for measuring change in core symptoms of autism in ASD clinical studies, with further validation required.

If treatments for cognitive impairment are to be utilized successfully, clinicians must be able to determine whether they are effective and which patients should receive them. In order to develop consensus on these issues, the International Society for CNS Clinical Trials and Methodology (ISCTM) held a meeting of experts on March 20, 2014, in Washington, DC. Consensus was reached on several important issues. Cognitive impairment and functional disability were viewed as equally important treatment targets. The group supported the notion that sufficient data are not available to exclude patients from available treatments on the basis of age, severity of cognitive impairment, severity of positive symptoms, or the potential to benefit functionally from treatment. The group reached consensus that cognitive remediation is likely to provide substantial benefits in combination with procognitive medications, although a substantial minority believed that medications can be administered without nonpharmacological therapy. There was little consensus on the best methods for assessing cognitive change in clinical practice. Some participants supported the view that performance-based measures are essential for measurement of cognitive change; others pointed to their cost and time requirements as evidence of impracticality. Interview-based measures of cognitive and functional change were viewed as more practical, but lacking validity without informant involvement or frequent contact from clinicians. The lack of consensus on assessment methods was viewed as attributable to differences in experience and education among key stakeholders and significant gaps in available empirical data. Research on the reliability, validity, sensitivity, and practicality of competing methods will facilitate consensus.

BackgroundThe Mormon Metalmark (Apodemia mormo) species complex occurs as isolated and phenotypically variable colonies in dryland areas across western North America. Lange's Metalmark, A. m. langei, one of the 17 subspecies taxonomically recognized in the complex, is federally listed under the U.S. Endangered Species Act of 1973. Metalmark taxa have traditionally been described based on phenotypic and ecological characteristics, and it is unknown how well this nomenclature reflects their genetic and evolutionary distinctiveness. Genetic variation in six microsatellite loci and mitochondrial cytochrome oxidase subunit I sequence was used to assess the population structure of the A. mormo species complex across 69 localities, and to evaluate A. m. langei's qualifications as an Evolutionarily Significant Unit.ResultsWe discovered substantial genetic divergence within the species complex, especially across the Continental Divide, with population genetic structure corresponding more closely with geographic proximity and local isolation than with taxonomic divisions originally based on wing color and pattern characters. Lange's Metalmark was as genetically divergent as several other locally isolated populations in California, and even the unique phenotype that warranted subspecific and conservation status is reminiscent of the morphological variation found in some other populations.ConclusionsThis study is the first genetic treatment of the A. mormo complex across western North America and potentially provides a foundation for reassessing the taxonomy of the group. Furthermore, these results illustrate the utility of molecular markers to aid in demarcation of biological units below the species level. From a conservation point of view, Apodemia mormo langei's diagnostic taxonomic characteristics may, by themselves, not support its evolutionary significance, which has implications for its formal listing as an Endangered Species.

BackgroundThe consumption of sweetened beverages, refined foods, and pastries has been shown to be associated with an increased risk of depression in longitudinal studies. However, any influence that refined carbohydrates has on mood could be commensurate with their proportion in the overall diet; studies are therefore needed that measure overall intakes of carbohydrate and sugar, glycemic index (GI), and glycemic load.ObjectiveWe hypothesized that higher dietary GI and glycemic load would be associated with greater odds of the prevalence and incidence of depression.DesignThis was a prospective cohort study to investigate the relations between dietary GI, glycemic load, and other carbohydrate measures (added sugars, total sugars, glucose, sucrose, lactose, fructose, starch, carbohydrate) and depression in postmenopausal women who participated in the Women's Health Initiative Observational Study at baseline between 1994 and 1998 (n = 87,618) and at the 3-y follow-up (n = 69,954).ResultsWe found a progressively higher dietary GI to be associated with increasing odds of incident depression in fully adjusted models (OR for the fifth compared with first quintile: 1.22; 95% CI: 1.09, 1.37), with the trend being statistically significant (P = 0.0032). Progressively higher consumption of dietary added sugars was also associated with increasing odds of incident depression (OR for the fifth compared with first quintile: 1.23; 95% CI: 1.07, 1.41; P-trend = 0.0029). Higher consumption of lactose, fiber, nonjuice fruit, and vegetables was significantly associated with lower odds of incident depression, and nonwhole/refined grain consumption was associated with increased odds of depression.ConclusionsThe results from this study suggest that high-GI diets could be a risk factor for depression in postmenopausal women. Randomized trials should be undertaken to examine the question of whether diets rich in low-GI foods could serve as treatments and primary preventive measures for depression in postmenopausal women.

Two permutation classes, the X-class and subpermutations of the increasing oscillation are shown to exhibit an exponential Wilf-collapse. This means that the number of distinct enumerations of principal subclasses of each of these classes grows much more slowly than the class itself whereas a priori, based only on symmetries of the class, there is no reason to expect this. The underlying cause of the collapse in both cases is the ability to apply some form of local symmetry which, combined with a greedy algorithm for detecting patterns in these classes, yields a Wilf-collapse.

Abstract The need for patient-centered care has become a focal point of healthcare improvement initiatives. Shared decision making—in which patients and clinicians communicate about various treatment options and goals and patient input is considered when making treatment decisions—has been associated with improved health and quality of life. A method of treatment evaluation allowing incorporation of patient-specific goals and perspectives is of increasing interest to healthcare providers, payers, and patients. An approach that allows incorporation of shared goal setting is possible via use of an instrument called the Goal Attainment Scale (GAS). This scale provides the structure for measuring progress toward treatment goals set through patient–clinician collaboration. The goal attainment approach has been used as a primary outcomes measure in numerous studies but not in major depressive disorder (MDD). As MDD is a complex, multidimensional disorder affecting each patient differently, the use of GAS methodology is a relevant framework for setting personalized meaningful treatment goals. Initial research into the feasibility of using the GAS in MDD (GAS-D) to measure patient-centric outcomes that may be neglected when more traditional scales are used has been encouraging. The objective of this Commentary is to provide background and rationale for implementation of the GAS-D in clinical practice. Funding Takeda Pharmaceutical Company, Ltd., and Lundbeck LLC.

Emily C McNaughton,1 Christopher Curran,1 Jamie Granskie,1 Mark Opler,2 Sara Sarkey,3 Lisa Mucha,3 Anna Eramo,4 Clement François,4 Briana Webber-Lind,5 Maggie McCue31Research Department, PatientsLikeMe,® Cambridge, MA, USA; 2MedAvante Prophase, New York, NY, USA; 3Medical Affairs, Takeda Pharmaceuticals U.S.A, Deerfield, IL, USA; 4US Clinical and Medical Affairs, Lundbeck LLC, Deerfield, IL, USA; 5Department of Clinical Science, MedAvante Prophase, Charlotte, NC, USABackground/Objectives: Major depressive disorder (MDD) is a highly prevalent disorder, frequently diagnosed and treated in a primary care setting; however, little information is available about the treatment decision-making process between MDD patients and their providers. A shared decision-making and goal attainment approach to establishing and tracking progress toward treatment goals that are meaningful to individual patients is explored in this survey study. In addition, information about patient perspectives on setting treatment goals, medication selection/switching, and engaging patients with their health care professionals was also collected and evaluated.Methods: A 50-question online survey was administered to members of the PatientsLikeMe community who indicated an MDD diagnosis and a switch in antidepressant medications within the past 2 years. Follow-up interviews were also conducted with a small subset of these participants.Results: Of the 200 participants who completed the survey, 42% reported currently having goals for MDD treatment. These goals were typically in the areas of physical health (62.7%), cognitive functioning (60.2%), and social aspects of life (57.8%). A majority of survey participants (61%) believed the goal attainment approach would be helpful to set and evaluate treatment goals.Conclusions: The data provide important insights into patient perspectives on the development of formal treatment plans and goals for MDD. In addition, the data also support the use of a patient-centric approach to shared decision-making by using a goal attainment scale to establish and track progress toward treatment goals that are meaningful to MDD patients in real-world clinical practice. The results of this study can be used to inform best practices in patient–clinician communication when developing an MDD treatment plan and goals.Keywords: goal attainment scale (GAS), PatientsLikeMe, treatment goals, depression, antidepressant, patient-centric

Introduction The six-item Positive And Negative Syndrome Scale (PANSS-6) is short psychometric valid scale quantifying the severity of core schizophrenia symptoms. Using PANSS-6 to guide treatment decision-making requires that staff members’ ratings are valid and reliable. Objectives The objective of the study was to evaluate whether such valid and reliable PANSS-6 ratings can be obtained through a video-based training program. Methods One-hundred-and-four staff members from Aarhus University Hospital - Psychiatry, Denmark participated in the training. Participants conducted baseline PANSS-6 ratings based on a video of a patient being interviewed using the Simplified Positive And Negative Symptoms interview (SNAPSI). Subsequently, a theoretical introduction video was displayed followed by five SNAPSI patient interviews. After each SNAPSI video, individual ratings were performed before a video providing the gold standard scores was displayed. The validity of ratings was estimated by calculating the proportion of participants not deviating from the gold standard scores with >2 points on individual items or >6 points on the PANSS-6 total score. Reliability was evaluated after each step in the training by means of Gwet’s Agreement Coefficient (Gwet). Results By the end of the training, 72% of the participants rated within the acceptable deviations of the gold standard, ranging from 60% (nurses) to 91% (medical doctors/psychologists). The reliability improved (Gwet baseline vs. endpoint) for all PANSS-6 items, except for Blunted affect. Conclusions The majority of the staff members conducted valid PANSS-6 ratings after a brief standardized training program, supporting the implementation of PANSS-6 in clinical settings to facilitate measurement-based care. Conflict of interest Dr. Opler is a full-time employee of MedAvante-ProPhase Inc. Dr. Correll has been a consultant and/or advisor to or have received honoraria from: Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, Gerson Lehrman Group, Indivior, IntraCellular T

Although the butterflies of North America have received considerable taxonomic attention, overlooked species and instances of hybridization continue to be revealed. The present study assembles a DNA barcode reference library for this fauna to identify groups whose patterns of sequence variation suggest the need for further taxonomic study. Based on 14,626 records from 814 species, DNA barcodes were obtained for 96% of the fauna. The maximum intraspecific distance averaged 1/4 the minimum distance to the nearest neighbor, producing a barcode gap in 76% of the species. Most species (80%) were monophyletic, the others were para- or polyphyletic. Although 15% of currently recognized species shared barcodes, the incidence of such taxa was far higher in regions exposed to Pleistocene glaciations than in those that were ice-free. Nearly 10% of species displayed high intraspecific variation (>2.5%), suggesting the need for further investigation to assess potential cryptic diversity. Aside from aiding the identification of all life stages of North American butterflies, the reference library has provided new perspectives on the incidence of both cryptic and potentially over-split species, setting the stage for future studies that can further explore the evolutionary dynamics of this group.

Background: Clinical practice guidelines support efforts to improve functioning in patients with schizophrenia. Discrepancies in the perception of cognitive status between clinicians, patients with schizophrenia, and their caregivers have been associated with impaired functional abilities in patients; medication side effects might worsen both cognition and daily functioning. We assessed daily/social functioning and cognition in stable patients with schizophrenia who switched to the long-acting injectable (LAI) antipsychotic aripiprazole lauroxil (AL). Methods: Clinically stable adults with residual symptoms of schizophrenia or intolerance following three or more doses of paliperidone palmitate or risperidone LAI were switched to flexibly dosed open-label AL treatment (441mg, 662mg, or 882mg every 4 weeks or 882mg every 6 weeks) for six months (ClinicalTrials.gov identifier: NCT02634320). Daily/social functioning was assessed using the Personal and Social Performance Scale (PSP); total and subscale scores were summarized using descriptive statistics. The cognitive status of patients was assessed using the New York Assessment of Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT) at baseline and Month 6 or early termination, providing patient, caregiver, and clinician perspectives. A post hoc analysis assessed level of agreement in ratings of cognitive status among respondents, evaluated at baseline and last assessment, using weighted kappa coefficients (0.01-0.20, slight agreement; 0.21-0.40, fair agreement; 0.41-0.60, moderate agreement; 0.61-0.80, substantial agreement.). Results: All 51 enrolled patients received one or more AL doses; 35 completed the study, and 45 contributed data at last assessment. Mean age was 40.6 years; 72.5 percent of patients were male. Based on PSP total score, functioning was maintained from baseline (mean [standard deviation (SD)]: 55.1 [10.5]) through six months of AL treatment (mean [SD]: 57.7 [13.2]). Proportions of patients rating personal and social functioning issues as "not present" or "mild" remained stable between baseline and Month 6 for each PSP subscale. At baseline (n=50), cognitive difficulties were most commonly rated "not present" or "mild" in all NY-AACENT domains by patients (58-86% across domains), clinicians (62-94%), and caregivers (50-92%), and these rates were maintained or increased at last assessment for all reporters. Weighted kappa coefficients indicated fair-to-substantial agreement between patients and clinicians across domains at last assessment (0.32-0.64; baseline: 0.14-0.55); patient--caregiver agreement ranged from 0.07 to 0.50 at last assessment (baseline: 0.25-0.60). Conclusion: In clinically stable patients with schizophrenia who initiated AL, self-reported functioning was maintained over six months of treatment. Clinician-, caregiver-, and patient-reported cognitive function was stable at baseline and maintained in all NY-AACENT domains; patient--clinician agreement on level of cognitive impairment increased over six months of treatment with AL. [ABSTRACT FROM AUTHOR]

This paper investigates the determinants of leveraged buyout (LBO)activity by comparing firms that have implemented LBOs to those that have not. The analysis considers sources of gains from LBOs as well as the costs that can arise from the large amount of debt included in their financial strutures. Consitent with the free cash flowe theory we find that firms that initiate LBOs can be characterized as having a combination of unfavorable investment opportunities (low Tobin's q) and relatively high cash flow. In addion, firms likely to have high costs of financial distress (e.g. firms with high R&D expenditures), are less likely to do LBOs.

A permutation class $C$ is splittable if it is contained in a merge of two of its proper subclasses, and it is 1-amalgamable if given two permutations $\sigma$ and $\tau$ in $C$, each with a marked element, we can find a permutation $\pi$ in $C$ containing both $\sigma$ and $\tau$ such that the two marked elements coincide. It was previously shown that unsplittability implies 1-amalgamability. We prove that unsplittability and 1-amalgamability are not equivalent properties of permutation classes by showing that the class $Av(1423, 1342)$ is both splittable and 1-amalgamable. Our construction is based on the concept of LR-inflations, which we introduce here and which may be of independent interest.