Climate Change and Cardiovascular Health: A Systematic Review.

Importance: Climate change may increase the risk of adverse cardiovascular outcomes by causing direct physiologic changes, psychological distress, and disruption of health-related infrastructure. Yet, the association between numerous climate change-related environmental stressors and the incidence of adverse cardiovascular events has not been systematically reviewed. Objective: To review the current evidence on the association between climate change-related environmental stressors and adverse cardiovascular outcomes. Evidence Review: PubMed, Embase, Web of Science, and Cochrane Library were searched to identify peer-reviewed publications from January 1, 1970, through November 15, 2023, that evaluated associations between environmental exposures and cardiovascular mortality, acute cardiovascular events, and related health care utilization. Studies that examined only nonwildfire-sourced particulate air pollution were excluded. Two investigators independently screened 20 798 articles and selected 2564 for full-text review. Study quality was assessed using the Navigation Guide framework. Findings were qualitatively synthesized as substantial differences in study design precluded quantitative meta-analysis. Findings: Of 492 observational studies that met inclusion criteria, 182 examined extreme temperature, 210 ground-level ozone, 45 wildfire smoke, and 63 extreme weather events, such as hurricanes, dust storms, and droughts. These studies presented findings from 30 high-income countries, 17 middle-income countries, and 1 low-income country. The strength of evidence was rated as sufficient for extreme temperature; ground-level ozone; tropical storms, hurricanes, and cyclones; and dust storms. Evidence was limited for wildfire smoke and inadequate for drought and mudslides. Exposure to extreme temperature was associated with increased cardiovascular mortality and morbidity, but the magnitude varied with temperature and duration of exposure. Ground-level ozone amplified the risk associated with higher temperatures and vice versa. Extreme weather events, such as hurricanes, were associated with increased cardiovascular risk that persisted for many months after the initial event. Some studies noted a small increase in cardiovascular mortality, out-of-hospital cardiac arrests, and hospitalizations for ischemic heart disease after exposure to wildfire smoke, while others found no association. Older adults, racial and ethnic minoritized populations, and lower-wealth communities were disproportionately affected. Conclusions and Relevance: Several environmental stressors that are predicted to increase in frequency and intensity with climate change are associated with increased cardiovascular risk, but data on outcomes in low-income countries are lacking. Urgent action is needed to mitigate climate change-associated cardiovascular risk, particularly in vulnerable populations.

Informed Inclusion Model: Medical Student Wheelchair User in an Obstetrics and Gynecology Clerkship.

ABSTRACT: Students with physical disabilities are underrepresented in medicine, driven in part by ableist beliefs about the ability of individuals with disabilities to complete procedure-based or surgically oriented clerkships, including obstetrics and gynecology (Ob/Gyn). There is a dearth of literature on this topic; however, there is also a growing commitment to disability inclusion by medical and specialty training associations. Nevertheless, published case studies and accommodation protocols for medical student wheelchair users navigating an Ob/Gyn clerkship are absent in the literature. This article describes successful disability inclusion for an Ob/Gyn clerkship, including accommodations for medical student wheelchair users. The authors share mechanisms to address and combat ableist assumptions and facilitate access for future medical students by working collaboratively with student and key stakeholders to develop an inclusive and accessible training experience.These recommendations are shared through the story of a third-year medical student who rotated through the longitudinal clerkships at the Cleveland Clinic Lerner College of Medicine. The student, an individual with osteogenesis imperfecta who uses a power wheelchair with a seat elevator, completed third-year rotations and thrived in her clinical experiences. The authors describe her journey through a robust 4-week Ob/Gyn clerkship, in which she fulfilled the required clinical core conditions and observation skills with reasonable accommodation. Given the high acuity, surgery, and outpatient demands in Ob/Gyn-and the transferrable skills to other clerkships-the student's experience is an excellent exemplar for demonstrating disability inclusion and reasonable accommodation.Ob/Gyn clerkship directors and clinical faculty can broadly use the recommended timelines and communication protocols to create accessible training environments. With student input, minor scheduling adjustments, ongoing communication, reasonable accommodations, and an open mind, medical students on the clinical wards who are wheelchair users can successfully navigate the required expectations of medical training.

Report on the PET/CT Image-Based Radiation Dosimetry of [18F]FDHT in Women, a Validated Imaging Agent with New Applications for Evaluation of Androgen Receptor Status in Women with Metastatic Breast Cancer.

In a prospective clinical trial, [18F]fluoro-5α-dihydrotestosterone ([18F]FDHT), the radiolabeled analog of the androgen dihydrotestosterone, was used as a PET/CT imaging agent for in vivo assessment of metastatic androgen receptor-positive breast cancer in postmenopausal women. To our knowledge, this article presents the first report of PET/CT image-based radiation dosimetry of [18F]FDHT in women. Methods: [18F]FDHT PET/CT imaging was performed on a cohort of 11 women at baseline before the start of therapy and at 2 additional time points during selective androgen receptor modulator (SARM) therapy for androgen receptor-positive breast cancer. Volumes of interest (VOIs) were placed over the whole body and within source organs seen on the PET/CT images, and the time-integrated activity coefficients of [18F]FDHT were derived. The time-integrated activity coefficients for the urinary bladder were calculated using the dynamic urinary bladder model in OLINDA/EXM software, with biologic half-life for urinary excretion derived from VOI measurements of the whole body in postvoid PET/CT images. The time-integrated activity coefficients for all other organs were calculated from VOI measurements in the organs and the physical half-life of 18F. Organ dose and effective dose calculations were then performed using MIRDcalc, version 1.1. Results: At baseline before SARM therapy, the effective dose for [18F]FDHT in women was calculated as 0.020 ± 0.0005 mSv/MBq, and the urinary bladder was the organ at risk, with an average absorbed dose of 0.074 ± 0.011 mGy/MBq. Statistically significant decreases in liver SUV or uptake of [18F]FDHT were found at the 2 additional time points on SARM therapy (linear mixed model, P < 0.05). Likewise, absorbed dose to the liver also decreased by a small but statistically significant amount at the 2 additional time points (linear mixed model, P < 0.05). Neighboring abdominal organs of the gallbladder wall, stomach, pancreas, and adrenals also showed statistically significant decreases in absorbed dose (linear mixed model, P < 0.05). The urinary bladder wall remained the organ at risk at all time points. Absorbed dose to the urinary bladder wall did not show statistically significant changes from baseline at any of the time points (linear mixed model, P ≥ 0.05). Effective dose also did not show statistically significant changes from baseline (linear mixed model, P ≥ 0.05). Conclusion: Effective dose for [18F]FDHT in women before SARM therapy was calculated as 0.020 ± 0.0005 mSv/MBq. The urinary bladder wall was the organ at risk, with an absorbed dose of 0.074 ± 0.011 mGy/MBq.

The Art of Discharge Planning: Teaching Nursing Students to Address Disparities Through Simulation.

Background: Discharge planning is crucial to ensuring that patients' care and recovery needs are addressed. A new nurse graduate must be prepared to enter a clinical practice environment in which hospitals face penalties for patient readmissions. Methods: Student nurses were assigned simulated patients with a variety of health disparities and health-care diagnoses to address. A qualitative research design evaluated student perceptions of discharge planning and cultural competency. Results: Students found the simulation to be vital to their clinical experience. Students were able to develop discharge teaching that was culturally congruent for each simulated patient. Conclusions: Incorporating discharge teaching simulation into the nursing curriculum can positively impact students' ability to transition to clinical practice and build confidence in a skill that is rarely incorporated into nursing curricula.

Perceptions of COVID-19 self-testing and recommendations for implementation and scale-up among Black/African Americans: implications for the COVID-19 STEP project.

BACKGROUND: COVID-19 self-testing (ST) is an innovative strategy with the potential to increase the access and uptake of testing and ultimately to limit the spread of the virus. To maximize the uptake and reach of this promising strategy and inform intervention development and scale up, research is needed to understand the acceptability of and willingness to use this tool. This is vital to ensure that Black/African Americans are reached by the Biden-Harris Administration's free national COVID-19 ST program. This study aimed to explore the acceptability and recommendations to promote and scale-up the uptake of COVID-19 ST among Black/African Americans. METHODS: We conducted a cross-sectional qualitative study using a semi-structured questionnaire to assess barriers and facilitators to the uptake of COVID-19 ST among a convenience sample of 28 self-identified Black/African Americans from schools, community centers, and faith-based institutions in Ohio and Maryland. Inductive content analysis was conducted to identify categories and subcategories related to acceptability and recommendations for implementing and scaling up COVID-19 ST in communities. RESULTS: Participants perceived COVID-19 self-testing as an acceptable tool that is beneficial to prevent transmission and address some of the barriers associated with health facility testing, such as transportation cost and human contact at the health facility. However, concerns were raised regarding the accurate use of the kits and costs. Recommendations for implementing and scaling up COVID-19 ST included engagement of community stakeholders to disseminate information about COVID-19 self-testing and creating culturally appropriate education tools to promote knowledge of and clear instructions about how to properly use COVID-19 ST kits. Based on these recommendations, the COVID-19 STEP (Self-Testing Education and Promotion) Project is being developed and will involve engaging community partners such as barbers, church leaders, and other community-based organizations to increase the uptake and use of free COVID-19 ST kits among Black/African Americans. CONCLUSION: Findings showed that most participants considered COVID-19 ST valuable for encouraging COVID-19 testing. However, cost and accuracy concerns may pose barriers. Future work should consider implementing interventions that leverage the benefits of COVID-19 ST and further assess the extent to which these identified facilitators and barriers may influence COVID-19 ST uptake.

Anti-KIT monoclonal antibody CDX-0159 induces profound and durable mast cell suppression in a healthy volunteer study.

BACKGROUND: Mast cells (MC) are powerful inflammatory immune sentinel cells that drive numerous allergic, inflammatory, and pruritic disorders when activated. MC-targeted therapies are approved in several disorders, yet many patients have limited benefit suggesting the need for approaches that more broadly inhibit MC activity. MCs require the KIT receptor and its ligand stem cell factor (SCF) for differentiation, maturation, and survival. Here we describe CDX-0159, an anti-KIT monoclonal antibody that potently suppresses MCs in human healthy volunteers. METHODS: CDX-0159-mediated KIT inhibition was tested in vitro using KIT-expressing immortalized cells and primary human mast cells. CDX-0159 safety and pharmacokinetics were evaluated in a 13-week good laboratory practice (GLP)-compliant cynomolgus macaque study. A single ascending dose (0.3, 1, 3, and 9 mg/kg), double-blinded placebo-controlled phase 1a human healthy volunteer study (n = 32) was conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of CDX-0159. RESULTS: CDX-0159 inhibits SCF-dependent KIT activation in vitro. Fc modifications in CDX-0159 led to elimination of effector function and reduced serum clearance. In cynomolgus macaques, multiple high doses were safely administered without a significant impact on hematology, a potential concern for KIT inhibitors. A single dose of CDX-0159 in healthy human subjects was generally well tolerated and demonstrated long antibody exposure. Importantly, CDX-0159 led to dose-dependent, profound suppression of plasma tryptase, a MC-specific protease associated with tissue MC burden, indicative of systemic MC suppression or ablation. CONCLUSION: CDX-0159 administration leads to systemic mast cell ablation and may represent a safe and novel approach to treat mast cell-driven disorders.

Perceptions of COVID-19 Self-Testing and Recommendations for Implementation and Scale up Among Black/African Americans: Implications for the COVID-19 STEP Project.

Background COVID-19 self-testing (ST) is an innovative strategy with the potential to increase the access and uptake of testing and ultimately to limit the spread of the virus. To maximize the uptake and reach of this promising strategy and inform intervention development and scale up, research is needed to understand the acceptability of and willingness to use this tool. This is vital to ensure that Black/African Americans are reached by the Biden-Harris Administration’s free national COVID-19 ST program. This study aimed to explore the acceptability and recommendations to promote and scale up the uptake of COVID-19 ST among Black/African Americans. Methods We conducted a cross-sectional qualitative study using a semi-structured survey to assess barriers and facilitators to the uptake of COVID-19 ST among a convenience sample of 28 self-identified Black/African Americans from schools, community centers, and faith-based institutions in Ohio and Maryland. Inductive content analysis was conducted to identify categories and subcategories related to acceptability and recommendations for implementing and scaling up COVID-19 ST in communities. Results Participants perceived COVID-19 self-testing as an acceptable tool that is beneficial to prevent transmission and address some of the barriers associated with health facility testing, such as transportation cost and human contact at the health facility. However, concerns were raised regarding the accurate use of the kits and costs. Recommendations for implementing and scaling up COVID-19 ST included engagement of community stakeholders to disseminate information about COVID-19 self-testing and creating culturally appropriate education tools to promote knowledge of and clear instructions about how to properly use COVID-19 ST kits. Based on these recommendations, the COVID-19 STEP (Self-Testing Education and Promotion) Project is being developed and will involve engaging community partners such as barbers, church leaders, and other community-based organizations to increase the uptake and use of free COVID-19 ST kits among Black/African Americans. Conclusion Findings showed that most participants considered COVID-19 ST valuable for encouraging COVID-19 testing. However, cost and accuracy concerns may pose barriers. Future work should consider implementing interventions that leverage the benefits of COVID-19 ST and further assess the extent to which these identified facilitators and barriers may influence COVID-19 ST uptake.

Imaging Androgen Receptors in Breast Cancer with 18F-Fluoro-5α-Dihydrotestosterone PET: A Pilot Study.

Most breast cancers express androgen receptors (ARs). This prospective imaging substudy explored imaging of ARs with 18F-fluoro-5α-dihydrotestosterone (18F-FDHT) PET in patients with metastatic breast cancer (MBC) receiving selective AR modulation (SARM) therapy (GTx-024). Methods: Eleven postmenopausal women with estrogen receptor-positive MBC underwent 18F-FDHT PET/CT at baseline and at 6 and 12 wk after starting SARM therapy. Abnormal tumor 18F-FDHT uptake was quantified using SUVmax AR status was determined from tumor biopsy specimens. 18F-FDHT SUVmax percentage change between scans was calculated. Best overall response was categorized as clinical benefit (nonprogressive disease) or progressive disease using RECIST 1.1. Results: The median baseline 18F-FDHT SUVmax was 4.1 (range, 1.4-5.9) for AR-positive tumors versus 2.3 (range, 1.5-3.2) for AR-negative tumors (P = 0.22). Quantitative AR expression and baseline 18F-FDHT uptake were weakly correlated (Pearson ρ = 0.39, P = 0.30). Seven participants with clinical benefit at 12 wk tended to have larger declines in 18F-FDHT uptake than did those with progressive disease both at 6 wk after starting GTx-024 (median, -26.8% [range, -42.9% to -14.1%], vs. -3.7% [range,-31% to +29%], respectively; P = 0.11) and at 12 wk after starting GTx-024 (median, -35.7% [range, -69.5% to -7.7%], vs. -20.1% [range, -26.6% to +56.5%], respectively; P = 0.17). Conclusion: These hypothesis-generating data suggest that 18F-FDHT PET/CT is worth further study as an imaging biomarker for evaluating the response of MBC to SARM therapy and reiterate the feasibility of including molecular imaging in multidisciplinary therapeutic trials.

Effect of disease duration in a randomized Phase III trial of rintatolimod, an immune modulator for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

BACKGROUND: Rintatolimod is a selective TLR3 agonist, which has demonstrated clinical activity for ME/CFS in Phase II and Phase III double-blind, placebo-controlled, randomized, multi-site clinical trials. METHODS AND FINDINGS: A hypothesis-based post-hoc analysis of the Intent to Treat (ITT) population diagnosed with ME/CFS from 12 independent clinical sites of a Phase III trial was performed to evaluate the effect of rintatolimod therapy based on disease duration. The clinical activity of rintatolimod was evaluated by exercise treadmill tolerance (ETT) using a modified Bruce protocol. The ITT population (n = 208) was divided into two subsets of symptom duration. Patients with symptom duration of 2-8 years were identified as the Target Subset (n = 75); the remainder (<2 year plus >8 year) were identified as the Non-Target Subset (n = 133). Placebo-adjusted percentage improvements in exercise duration and the vertical rise for the Target Subset (n = 75) were more than twice that of the ITT population. The Non-Target Subset (n = 133) failed to show any clinically significant ETT response to rintatolimod when compared to placebo. Within the Target Subset, 51.2% of rintatolimod-treated patients improved their exercise duration by ≥25% (p = 0.003) despite reduced statistical power from division of the original ITT population into two subsets. CONCLUSION/SIGNIFICANCE: Analysis of ETT from a Phase III trial has identified within the ITT population, a subset of ME/CFS patients with ≥2 fold increased exercise response to rintatolimod. Substantial improvement in physical performance was seen for the majority (51.2%) of these severely debilitated patients who improved exercise duration by ≥25%. This magnitude of exercise improvement was associated with clinically significant enhancements in quality of life. The data indicate that ME/CFS patients have a relatively short disease duration window (<8 years) to expect a significant response to rintatolimod under the dosing conditions utilized in this Phase III clinical trial. These results may have direct relevance to the cognitive impairment and fatigue being experienced by patients clinically recovered from COVID-19 and free of detectable SARS-CoV-2. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00215800.

Outcomes following implantable cardioverter-defibrillator generator replacement in adults: A systematic review.

Randomized trials inform the use of implantable cardioverter-defibrillators (ICDs) for prevention of sudden cardiac death, yet management of patients considering ICD generator replacement procedures remains largely dependent on clinical judgment. Thus, we performed a systematic review of all studies evaluating outcomes associated with ICD generator replacement. We queried PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews for relevant studies with a prespecified search and adjudication strategy (PROSPERO registration number CRD42018100818) to evaluate outcomes including (1) survival; (2) clinical complications (eg, infection, hematoma); or (3) incidence of ICD therapy. From 1607 unique titles, 37 studies met inclusion criteria, describing outcomes for 238,949 patients. Procedural mortality was rare, but complications including reoperation (median 4.57%; range 0.38%-10.31%), infections (median 2.01%; range 0.03%-9.27%), and hematoma (median 1.22%, range 0.17%-2.53%) were observed in a small fraction of patients. Appropriate ICD therapy after generator replacement was common (median rate 23.03%; range 10.9%-31.4%), with an overall annualized event rate of 8.52% at median duration of follow-up of 32.4 months. Appropriate ICD therapy continued to occur at a significant annual rate even in patients who no longer met implantation criteria (5.27%) and in patients who never previously received ICD therapy (4.87%). This analysis of published observational data regarding ICD generator replacement procedures identifies relatively low risks of procedural complications and clinically meaningful rates of appropriate ICD therapies. These estimates may guide clinical decisions and inform the design of definitive trials.

The Nursing Doctorate: One Size Does Not Fit All.

The demand for Advanced Practice Registered Nurses, nursing faculty, and nursing leaders is driving the increase in nurses seeking doctoral degrees (Bednash, Brelin, Kirschling, & Rosseter, 2014). A variety of programs have emerged to prepare nurses for careers in health administration, research, and advanced clinical practice. Prospective graduate level nursing students can choose from doctoral programs focused on research or practice. Potential doctoral students now have several different degrees to choose from, and deciding which one is right for them can be a daunting task.

A Retrospective Look at the Experience of Parental Incarceration and Family Reentry During Adolescence.

Few studies provide firsthand experiences of parental incarceration in adolescents' own voices. Fourteen young men and women retrospectively shared their experiences of parental incarceration and family reentry during adolescence. Individual interviews focused on the following qualitative research questions: (1) What is the experience of parental incarceration and reentry for adolescents? (2) How does the child-parent relationship change from pre- to postincarceration? Relationships with incarcerated parents tended toward estrangement. Negative emotions and need for emotional support were predominant in the sample. Findings have implications for improving mental health services for children and families, trauma work, and policy interventions across services.

Psychosocial morbidity associated with bipolar disorder and borderline personality disorder in psychiatric out-patients: comparative study.

BACKGROUND: The morbidity associated with bipolar disorder is, in part, responsible for repeated calls for improved detection and recognition. No such commentary exists for the improved detection of borderline personality disorder. Clinical experience suggests that it is as disabling as bipolar disorder, but no study has directly compared the two disorders. AIMS: To compare the levels of psychosocial morbidity in patients with bipolar disorder and borderline personality disorder. METHOD: Patients were assessed with semi-structured interviews. We compared 307 patients with DSM-IV borderline personality disorder but without bipolar disorder and 236 patients with bipolar disorder but without borderline personality disorder. RESULTS: The patients with borderline personality disorder less frequently were college graduates, were diagnosed with more comorbid disorders, more frequently had a history of substance use disorder, reported more suicidal ideation at the time of the evaluation, more frequently had attempted suicide, reported poorer social functioning and were rated lower on the Global Assessment of Functioning. There was no difference between the two patient groups in history of admission to psychiatric hospital or time missed from work during the past 5 years. CONCLUSIONS: The level of psychosocial morbidity associated with borderline personality disorder was as great as (or greater than) that experienced by patients with bipolar disorder. From a public health perspective, efforts to improve the detection and treatment of borderline personality disorder might be as important as efforts to improve the recognition and treatment of bipolar disorder.

How many different ways do patients meet the diagnostic criteria for major depressive disorder?

There are 227 possible ways to meet the symptom criteria for major depressive disorder (MDD). However, symptom occurrence is not random, and some symptoms co-occur significantly beyond chance. This raises the questions of whether all of the theoretically possible different ways of meeting the MDD criteria actually occur in patients, and whether some combinations of criteria are much more common than others. More than 1500 patients who met DSM-IV criteria for MDD at the time of the evaluation were interviewed with semi-structured interviews. The patients met the MDD symptom criteria in 170 different ways. Put another way, one-quarter (57/227) of the criteria combinations did not occur. The most frequent combination was the presence of all 9 criteria (10.1%, n=157). Nine combinations (all 9 criteria, 3 of the 8-criterion combinations, 4 of the 7-criterion combinations, and one 6-criterion combination) were present in more than 2% of the patients, together accounting for more than 40% of the diagnoses. The polythetic definition of MDD, which requires a minimum number of criteria from a list, results in significant diagnostic heterogeneity because there are many different ways to meet criteria. While there is significant heterogeneity amongst patients meeting the MDD diagnostic criteria, a relatively small number of combinations could be considered as diagnostic prototypes as they account for more than 40% of the patients diagnosed with MDD.

Does Borderline Personality Disorder Manifest Itself Differently in Patients With Bipolar Disorder and Major Depressive Disorder?

Perugi and colleagues (2013) recently reported that some features of borderline personality disorder (BPD) significantly predicted a diagnosis of bipolar disorder among depressed patients. They interpreted these findings as indicating that some BPD criteria are nonspecific and are indicators of bipolar disorder rather than BPD, whereas other criteria are more specific to BPD. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, the authors tested the hypothesis that BPD presents itself differently in psychiatric outpatients diagnosed with bipolar disorder or major depressive disorder. The authors found that the patients with bipolar disorder were significantly more likely to report impulsive behavior and transient dissociation. No criterion was significantly more common in the BPD patients with MDD. The authors therefore do not consider the BPD criteria to be nonspecific with regard to the distinction between BPD and bipolar disorder.

A brief, clinically useful, clinician-rated dimensional rating system for psychiatric diagnoses: reliability and validity in psychiatric outpatients.

BACKGROUND: In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services project, we describe the development of a dimensional rating system for Axis I disorders. METHODS: We evaluated 1,600 psychiatric outpatients with a semi-structured diagnostic interview for Axis I disorders and completed a self-report measure of psychosocial morbidity. A Standardized Clinical Outcome Rating (SCOR), a 7-point dimensional rating, was made for 17 Axis I disorders and 1 symptom construct. RESULTS: The dimensional ratings were highly reliable. After controlling for the number of Axis I disorders, each of the partial correlations between the dimensional rating and the measures of psychosocial morbidity was significant (mean partial r = 0.21). However, when the dimensional score was controlled, none of the partial correlations between the sum of the number of Axis I disorders and measures of psychosocial morbidity were significant (mean partial r = 0.03). CONCLUSIONS: The SCORs are brief standardized outcome ratings that clinicians can incorporate into routine clinical practice without incurring undue burden. These ratings could make it more feasible to conduct effectiveness studies in clinical practice and to extend measurement-based care recommendations to include clinical ratings as well as self-report assessments.

A clinically useful self-report measure of the DSM-5 mixed features specifier of major depressive disorder.

BACKGROUND: To acknowledge the clinical significance of manic features in depressed patients, DSM-5 included criteria for a mixed features specifier for major depressive disorder (MDD). In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project we modified our previously published depression scale to include a subscale assessing the DSM-5 mixed features specifier. METHODS: More than 1100 psychiatric outpatients with MDD or bipolar disorder completed the Clinically Useful Depression Outcome Scale (CUDOS) supplemented with questions for the DSM-5 mixed features specifier (CUDOS-M). To examine discriminant and convergent validity the patients were rated on clinician severity indices of depression, anxiety, agitation, and irritability. Discriminant and convergent validity was further examined in a subset of patients who completed other self-report symptom severity scales. Test-retest reliability was examined in a subset who completed the CUDOS-M twice. We compared CUDOS-M scores in patients with MDD, bipolar depression, and hypomania. RESULTS: The CUDOS-M subscale had high internal consistency and test-retest reliability, was more highly correlated with another self-report measure of mania than with measures of depression, anxiety, substance use problems, eating disorders, and anger, and was more highly correlated with clinician severity ratings of agitation and irritability than anxiety and depression. CUDOS-M scores were significantly higher in hypomanic patients than depressed patients, and patients with bipolar depression than patients with MDD. LIMITATIONS: The study was cross-sectional, thus we did not examine whether the CUDOS-M detects emerging mixed symptoms when depressed patients are followed over time. Also, while we examined the correlation between the CUDOS-M and clinician ratings of agitation and irritability, we did not examine the association with a clinician measure of manic symptomatology such as the Young Mania Rating Scale CONCLUSIONS: In the present study of a large sample of psychiatric outpatients, the CUDOS-M was a reliable and valid measure of the DSM-5 mixed features specifier for MDD.

Intranasal seasonal influenza vaccine and a TLR-3 agonist, rintatolimod, induced cross-reactive IgA antibody formation against avian H5N1 and H7N9 influenza HA in humans.

The intranasal use of rintatolimod, a specific TLR-3 agonist, combined with trivalent seasonal influenza vaccine generated cross-protection against highly pathogenic H5N1 avian influenza in mice. The purpose of this clinical trial is to assess the safety and impact of rintatolimod on intranasal influenza vaccine in healthy adults. During Stage I of this Phase I/II clinical trial, 12 volunteers were immunized intranasally with 3 doses of FluMist seasonal influenza vaccine on Days 0, 28, and 56 followed by intranasal rintatolimod (50 µg, 200 µg, or 500 µg) 3 days later. Parotid saliva and nasal wash samples were collected at baseline and on Days 25, 53, 84, and 417. The samples were tested for IgA and IgG specific antibodies (Ab) directed against the homologous FluMist viral hemagglutinins (HAs). In addition, viral specific responses against influenza A HAs were tested for IgA Ab cross-reactivity against 3 H5 clades: HA (H5N1) A/Indonesia/5/2005, HA (H5N1) A/Hong Kong/483/97 and HA (H5N1) A/Vietnam/1194/2004, as well as, two H7 strains, HA (H7N9) A/Shanghai/2/2013 and HA (H7N3) A/chicken/Jalisco/CPA1. The combination of the intranasal FluMist along with the rintatolimod generated specific secretory IgA responses of at least 4-fold over baseline against at least one of the homologous vaccine strains included in the vaccine in 92% of the vaccinees. Additionally, this vaccination strategy induced cross-reactive secretory IgA against highly pathogenic avian influenza virus strains H5N1, H7N9, and H7N3 with pandemic potential for humans. The combination of rintatolimod and FluMist was well-tolerated.