News event memory in amnestic and non-amnestic MCI, heritable risk for dementia, and subjective memory complaints.

Robust and sensitive clinical measures are needed for more accurate and earlier detection of Alzheimer's disease (AD), for staging preclinical AD, and for gauging the efficacy of treatments. Mild impairment on episodic memory tests is thought to indicate a cognitive risk of developing AD and mild cognitive impairment (MCI), considered to be a transitional stage between normal aging and AD. Novel tests of semantic memory, such as memory for news events, are also impaired early on but have received little clinical attention even though they may provide a novel way to assess cognitive risk for AD. We examined memory for news events in older adults with normal cognition (NC, N = 34), amnestic MCI (aMCI, N = 27), or non-aMCI (N = 10) using the Retrograde Memory News Events Test (RM-NET). We asked if news event memory was sensitive to 1) aMCI and also non-aMCI, which has rarely been examined, 2) genetic risk for dementia (positive family history of any type of dementia, presence of an APOE-4 allele, or polygenic risk for AD), and 3) subjective memory functioning judgments about the past. We found that both MCI subgroups exhibited impaired RM-NET Lifespan accuracy scores together with temporally-limited retrograde amnesia. For the aMCI group amnesia extended back 45 years prior to testing, but not beyond that time frame. The extent of retrograde amnesia could not be reliably estimated in the small non-aMCI group. The effect sizes of having MCI on the RM-NET were medium for the non-aMCI group and large for the aMCI group, whereas the effect sizes of participant characteristics on RM-NET accuracy scores were small. For the combined MCI group (N = 37), news event memory was significantly related to positive family history of dementia but was not related to the more specific genetic markers of AD risk. For the NC group, news event memory was not related to any measure of genetic risk. Objective measures of past memory from the RM-NET were not related to subjective memory judgements about the present or the recent past in either group. By contrast, when individuals subjectively compared their present versus past memory abilities, there was a significant association between this judgment and objective measures of the past from the RM-NET (direct association for the NC group and inverse for the MCI group). The RM-NET holds significant promise for early identification of those with cognitive and genetic risk factors for AD and non-AD dementias.

An evaluation of treatment response and remission definitions in adult obsessive-compulsive disorder: A systematic review and individual-patient data meta-analysis.

INTRODUCTION: Expert consensus operationalized treatment response and remission in obsessive-compulsive disorder (OCD) as a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) reduction ≥35% and score ≤12 with ≤2 on Clinical Global Impressions Improvement (CGI-I) and Severity (CGI-S) scales, respectively. However, there has been scant empirical evidence supporting these definitions. METHODS: We conducted a systematic review and an individual participant data meta-analysis of randomized-controlled trials (RCTs) in adults with OCD to determine optimal Y-BOCS thresholds for response and remission. We estimated pooled sensitivity/specificity for each percent reduction threshold (response) or posttreatment score (remission) to determine response and remission defined by a CGI-I and CGI-S ≤ 2, respectively. RESULTS: Individual participant data from 25 of 94 eligible RCTs (1235 participants) were included. The optimal threshold for response was ≥30% Y-BOCS reduction and for remission was ≤15 posttreatment Y-BOCS. However, differences in sensitivity and specificity between the optimal and nearby thresholds for response and remission were small with some uncertainty demonstrated by the confidence ellipses. CONCLUSION: While the empirically derived Y-BOCS thresholds in our meta-analysis differ from expert consensus, given the predominance of data from more recent trials of OCD, which involved more refractory participants and novel treatment modalities as opposed to first-line therapies, we recommend the continued use of the consensus definitions.

Consent for Research Involving Spanish- and English-Speaking Latinx Adults With Schizophrenia.

BACKGROUND: Latinxs are vastly underrepresented in mental health research; one of many contributing factors may be complexities in the research consent process, including language preferences. We examined determinants of comprehension of research consent procedures and tested the effects of a preconsent research schema condition among 180 adults with schizophrenia (60 Latinx-English and 60 Latinx-Spanish preference, and 60 non-Latinx White). STUDY DESIGN: Participants were randomly assigned (equal allocation) to an educational session regarding clinical research concepts and processes (schema condition) or to an attention control. Following a subsequent simulated consent procedure for a hypothetical drug trail, comprehension of consent disclosures was measured with 2 standard measures. STUDY RESULTS: One-way ANOVAs showed significant medium effect size differences between ethnicity/language groups on both measures of comprehension (η2s = 0.066-0.070). The Latinx-Spanish group showed lower comprehension than non-Latinx White participants; differences between the 2 Latinx groups did not reach statistical significance. Group differences were not statistically significant after adjusting for differences in education, or on scores from structured measures of acculturation, health literacy, or research literacy. Two-way ANOVAs showed no significant main effects for consent procedure on either comprehension measure (Ps > .369; partial η2s < 0.006) and no significant group-by-consent interactions (Ps > .554; partial η2s < 0.008). CONCLUSIONS: Although the preconsent procedure was not effective, the results suggest health and research literacy may be targets for reducing disparities in consent comprehension. The onus is on researchers to improve communication of consent information as an important step to addressing health care disparities.

Transcranial and Transcutaneous Stimulation for Pain: What Have We Learned From the COVID-19 Pandemic Shutdown?

BACKGROUND: Transcranial magnetic stimulation (TMS) and transcutaneous magnetic stimulation (tMS) offer a novel noninvasive treatment option for chronic pain. While the recent COVID-19 pandemic caused by the SARS-CoV-2 virus resulted in a temporary interruption of the treatments for patients, it provided an excellent opportunity to assess the long-term sustainability of the treatment, and the feasibility of resuming the treatments after a brief period of interruption as no such data are available in current literature. METHODS: First, a list of patients whose pain/headache conditions have been stably controlled with either treatment for at least 6 months prior to the 3-month pandemic-related shutdown was generated. Those who returned for treatments after the shutdown were identified and their underlying pain diagnoses, pre- and posttreatment Mechanical Visual Analog Scale (M-VAS) pain scores, 3-item Pain, Enjoyment, and General Activity (PEG-3), and Patient Health Questionnaire-9 scores were assessed in 3 phases: Phase I (P1) consisted of a 6-month pre-COVID-19 period in which pain conditions were stably managed with either treatment modality; Phase II (P2) consisted of the first treatment visit period immediately after COVID-19 shutdown; and Phase III (P3) consisted of a 3-4 month post-COVID-19 shutdown period patients received up to 3 sessions of either treatment modality after the P2 treatment. RESULTS: For pre- and posttreatment M-VAS pain scores, mixed-effect analyses for both treatment groups demonstrated significant (P < 0.01) time interactions across all phases. For pretreatment M-VAS pain scores, TMS (n = 27) between-phase analyses indicated a significant (F = 13.572, P = 0.002) increase from 37.7 ± 27.6 at P1 to 49.6 ± 25.9 at P2, which then decreased significantly (F = 12.752, P = 0.001) back to an average score of 37.1 ± 24.7 at P3. Similarly, tMS (n = 25) between-phase analyses indicated the mean pretreatment pain score (mean ± standard deviation [SD]) increased significantly (F = 13.383, P = 0.003) from 34.9 ± 25.1 at P1 to 56.3 ± 27.0 at P2, which then decreased significantly (F = 5.464, P = 0.027) back to an average score of 41.9 ± 26.4 at P3. For posttreatment pain scores, the TMS group between-phase analysis indicated the mean posttreatment pain score (mean ± SD) increased significantly (F = 14.206, P = 0.002) from 25.6 ± 22.9 at P1 to 36.2 ± 23.4 at P2, which then significantly decreased (F = 16.063, P < 0.001) back to an average score of 23.2 ± 21.3 at P3. The tMS group between-phase analysis indicates a significant (F = 8.324, P = 0.012) interaction between P1 and P2 only with the mean posttreatment pain score (mean ± SD) increased from 24.9 ± 25.7 at P1 to 36.9 ± 26.7 at P2. The combined PEG-3 score between-phase analyses demonstrated similar significant (P < 0.001) changes across the phases in both treatment groups. CONCLUSIONS: Both TMS and tMS treatment interruptions resulted in an increase of pain/headache severity and interference of quality of life and functions. However, the pain/headache symptoms, patients' quality of life, or function can quickly be improved once the maintenance treatments were restarted.

Characteristics of Active Duty Service Members Referred to the Navy's Weight-Management Program.

INTRODUCTION: Rates of overweight and obesity have increased in the military, particularly in the U.S. Navy. While the Navy has implemented weight-management programs like ShipShape, findings on the effectiveness of these programs are mixed. Further knowledge on the characteristics of service members (SMs) who participate in these programs may help inform course curricula and improve outcomes. This study aimed to (1) examine characteristics of SMs referred to the Navy's ShipShape program at a large military treatment facility, (2) compare these characteristics among SMs who did and did not enroll in a randomized clinical trial of ShipShape (ShipShape study participants), and (3) compare demographic and health characteristics of ShipShape study participants to that of a random and similarly sized sample of Navy SMs who responded to the 2015 DoD Health-Related Behaviors Survey (HRBS). MATERIALS AND METHODS: Data from active duty Navy SMs referred to the ShipShape program at a large military treatment facility were evaluated (n = 225). A subset of these SMs enrolled in the ShipShape study (n = 187). Among enrolled SMs, data from 147 who completed all measures were compared to that of HRBS respondents. Univariate ANOVA and chi-square analyses were used to examine (1) demographic and motivational differences between SMs who did and did not enroll in the ShipShape study and (2) differences in demographics and medical and mental health conditions between ShipShape study participants and Navy HRBS respondents. RESULTS: The majority of SMs referred to ShipShape were female with an average age of 28.3 years. Compared to SMs who did not enroll in the ShipShape study (n = 38), ShipShape study participants were more likely to be female, less likely to be Hispanic, and had higher motivation and emotional eating scores. Compared to Navy HRBS respondents (n = 164), ShipShape study participants (n = 147) were younger, more likely to be female, non-Hispanic, enlisted, and obese. Further, ShipShape study participants reported significantly fewer medical health conditions but higher rates of probable depression, anxiety, and PTSD and were more likely to report receiving current mental health treatment than HRBS respondents. CONCLUSION: Overweight or obese SMs seeking weight loss in the ShipShape study were relatively young, female, non-Hispanic, motivated, but with greater emotional eating. ShipShape study participants endorsed few medical health conditions but had higher rates of probable mental health conditions compared to the HRBS sample. These findings suggest that SMs referred to Navy weight-management programs are likely experiencing comorbid mental health conditions which may interfere with the effectiveness of their weight loss efforts. The descriptive nature of this study and the focus on Navy SMs in only one ShipShape program may decrease the generalizability of our findings to participants at other locations. Nonetheless, these findings demonstrate the potential need for Navy weight-management programs that incorporate mental health treatment and address the specific needs of female and diverse SMs. A more comprehensive curriculum could improve the results of weight-management efforts, increase SM quality of life and fitness and thereby operational readiness.

Feasibility of time-restricted eating and impacts on cardiometabolic health in 24-h shift workers: The Healthy Heroes randomized control trial.

Over a quarter of the workforce in industrialized countries does shift work, which increases the risk for cardiometabolic disease. Yet shift workers are often excluded from lifestyle intervention studies to reduce this risk. In a randomized control trial with 137 firefighters who work 24-h shifts (23-59 years old, 9% female), 12 weeks of 10-h time-restricted eating (TRE) was feasible, with TRE participants decreasing their eating window (baseline, mean 14.13 h, 95% CI 13.78-14.47 h; intervention, 11.13 h, 95% CI 10.73-11.54 h, p = 3.29E-17) with no adverse effects, and improved quality of life assessed via SF-36 (ClinicalTrials.gov: NCT03533023). Compared to the standard of care (SOC) arm, TRE significantly decreased VLDL particle size. In participants with elevated cardiometabolic risks at baseline, there were significant reductions in TRE compared to SOC in glycated hemoglobin A1C and diastolic blood pressure. For individuals working a 24-h shift schedule, TRE is feasible and can improve cardiometabolic health, especially for individuals with increased risk. VIDEO ABSTRACT.

The Retrograde Memory for News Events Test (RM-NET) and the relationship between news event memory and performance on standard neuropsychological tests.

Novel tests of semantic memory (SM)-for example, memory for news events (NE; news facts) or famous personalities-are useful for estimating the severity of retrograde amnesia. Individuals with mild cognitive impairment exhibit relatively intact SM/language on traditional neuropsychological tests but exhibit consistent impairment on novel tests of SM, suggesting novel SM tests are dissimilar from traditional SM tests. To identify the relationship between NE memory and traditional cognitive measures, older adults (N = 51) completed a traditional neuropsychological battery and the Retrograde Memory News Events Test (RM-NET; a new test that robustly measures NE memory across the adult life span with high temporal resolution), and the relationship between performance on these tests was examined. Total RM-NET scores were more closely aligned with episodic memory scores than SM scores. The strength of the association between NE scores and episodic memory scores decreased as the age of NE memory increased. Tests of news events appear to reflect performance on traditional tests of episodic memory rather than SM, especially when recent news events are tested.

Evolution of Modeled Cortisol Is Prognostic of Death in Hospitalized Patients With COVID-19 Syndrome.

Introduction: Patients hospitalized with SARS-CoV-2 have an elevated risk of mortality related to a severe inflammatory response. We hypothesized that biological modeling with a complete blood count (CBC) would be predictive of mortality. Method: In 2020, 81 patients were randomly selected from La Rochelle Hospital, France for a simple blinded retrospective study. Demographic, vital signs, CBC and CRP were obtained on admission, at days 2-3 and 3-5. From a CBC, two biological modeling indexes were resulted: the neutrophil-to-lymphocyte ratio (NLR) and cortisol index adjusted (CA). Results: By ANOVA, in survivors vs. non-survivors there was statistical different at p < 0.01 for age (66.2 vs. 80), CRP (92 vs. 179 mg/dL, normal < 10), cortisol index adjusted (323 vs. 698, normal 3-7) and genito-thyroid indexes (7.5 vs. 18.2, normal 1.5-2.5), and at p = 0.02 creatinine (1.03 vs. 1.48, normal 0.73-1.8 mg/dL). By mixed model analysis, CA and NLR improved in those who survived across all three time points, but worsened again after 3-5 days in non-survivors. CRP continued to improve over time in survivors and non-survivors. Positive vs. Negative predictive value were: CRP (91.1%, 30.4%), NLR (94.5%, 22.7%), CA (100%, 0%). Discussion: Cortisol modeling and the neutrophil-to-lymphocyte ratio were more accurate in describing the course of non-survivors than CRP. Conclusion: In patients admitted for SARS CoV-2 infection, biological modeling with a CBC predicted risk of death better than CRP. This approach is inexpensive and easily repeated.

An integrated mindfulness meditation and acceptance and commitment therapy intervention for chronic pain: Rationale, design, and methodology of a pilot randomized controlled trial of Acting with Mindfulness for Pain (AMP).

Acceptance and commitment therapy (ACT) is an evidence-based psychosocial intervention for chronic pain; however, in its present form ACT produces modest improvements in function and is no more effective than cognitive behavioral therapy (CBT), the current gold standard. This protocol paper describes the Acting with Mindfulness for Pain (AMP) protocol, which emphasizes and integrates formal mindfulness meditation practice within an ACT-based approach. This paper presents the rationale, design and methodology of an ongoing pilot randomized controlled trial (RCT) comparing AMP to CBT among Veterans with chronic pain (N = 86). Specifically, we argue that formal meditation practice is a necessary treatment component that directly targets key ACT processes which will help facilitate large treatment effects on function (e.g., general activity, social relationships, life enjoyment) among individuals with chronic pain. This study will be the first to consider formal mindfulness meditation practice as a principal treatment ingredient in the context of ACT for chronic pain. The purpose of this trial is to evaluate the feasibility of recruitment and collection of measures, and to examine preliminary treatment effects to determine the appropriateness of a subsequent full-scale RCT. This study will also explore within and between group change on primary and secondary outcomes including pain interference, pain acceptance, trait mindfulness, pain catastrophizing, values-based living, quality of life, practice adherence, and objective measures of physical activity. This study will help delineate the role of formal mindfulness practice within an ACT-based approach for chronic pain and provide preliminary data for a future fully powered RCT.

A clinical trial comparing trauma-informed guilt reduction therapy (TrIGR), a brief intervention for trauma-related guilt, to supportive care therapy.

INTRODUCTION: Trauma-related guilt is common, associated with posttraumatic mental health problems, and can persist after posttraumatic stress disorder (PTSD) treatment. We compared the efficacy of two six-session psychotherapies, Trauma-Informed Guilt Reduction (TrIGR) and Supportive Care Therapy (SCT), for reducing trauma-related guilt. TrIGR helps patients accurately appraise their role in the trauma and re-engage in values. In SCT, patients guide session content. METHODS: A total of 184 veterans seeking VA mental health services were enrolled across two sites; 145 veterans (mean age: 39.2 [8.1]; 92.4% male; 84.8% with PTSD) who endorsed guilt related to a traumatic event that occurred during a post 9/11 Iraq or Afghanistan deployment were randomized and assessed at baseline, posttreatment, 3- and 6-month follow-up. RESULTS: Linear mixed models using intent-to-treat analyses showed guilt decreased in both conditions with a greater decrease for TrIGR (treatment × time, -0.22; F 1, 455.2 = 18.49, p = .001; d = 0.92) than supportive therapy. PTSD and depressive symptoms showed the same pattern. TrIGR had significantly higher likelihood of PTSD treatment response (67% vs. 40%), loss of PTSD diagnosis (50% vs. 14%), and meaningful change in depression (54% vs. 27%) than supportive therapy. Psychological distress and trait shame improved in both conditions. Quality of life did not change. CONCLUSIONS: Targeting guilt appears to be an effective means for reducing posttraumatic symptoms and distress.

Severities in persistent mild traumatic brain injury related headache is associated with changes in supraspinal pain modulatory functions.

Emerging evidence suggests mild traumatic brain injury related headache (MTBI-HA) is a form of neuropathic pain state. Previous supraspinal mechanistic studies indicate patients with MTBI-HA demonstrate a dissociative state with diminished levels of supraspinal prefrontal pain modulatory functions and enhanced supraspinal sensory response to pain in comparison to healthy controls. However, the relationship between supraspinal pain modulatory functional deficit and severity of MTBI-HA is largely unknown. Understanding this relationship may provide enhanced levels of insight about MTBI-HA and facilitate the development of treatments. This study assessed pain related supraspinal resting states among MTBI-HA patients with various headache intensity phenotypes with comparisons to controls via functional magnetic resonance imaging (fMRI). Resting state fMRI data was analyzed with self-organizing-group-independent-component-analysis in three MTBI-HA intensity groups (mild, moderate, and severe) and one control group (n = 16 per group) within a pre-defined supraspinal pain network based on prior studies. In the mild-headache group, significant increases in supraspinal function were observed in the right premotor cortex (T = 3.53, p < 0.001) and the left premotor cortex (T = 3.99, p < 0.0001) when compared to the control group. In the moderate-headache group, a significant (T = -3.05, p < 0.01) decrease in resting state activity was observed in the left superior parietal cortex when compared to the mild-headache group. In the severe-headache group, significant decreases in resting state supraspinal activities in the right insula (T = -3.46, p < 0.001), right premotor cortex (T = -3.30, p < 0.01), left premotor cortex (T = -3.84, p < 0.001), and left parietal cortex (T = -3.94, p < 0.0001), and an increase in activity in the right secondary somatosensory cortex (T = 4.05, p < 0.0001) were observed when compared to the moderate-headache group. The results of the study suggest that the increase in MTBI-HA severity may be associated with an imbalance in the supraspinal pain network with decline in supraspinal pain modulatory function and enhancement of sensory/pain decoding.

Protocol for a randomised controlled trial on the feasibility and effects of 10-hour time-restricted eating on cardiometabolic disease risk among career firefighters doing 24-hour shift work: the Healthy Heroes Study.

INTRODUCTION: Career firefighters experience chronic circadian rhythm disruption, increasing their risk of cardiometabolic disease. The recent discovery that eating patterns regulate circadian rhythmicity in metabolic organs has raised the hypothesis that maintaining a consistent daily cycle of eating and fasting can support circadian rhythms and reduce disease risks. Preclinical animal studies and preliminary clinical trials have shown promising effects of time-restricted eating (TRE) to reduce disease risk without compromising physical performance. However, there is a lack of research on TRE in shift workers including firefighters. This study aims to investigate the feasibility and efficacy of 10-hour TRE on health parameters that contribute to cardiometabolic disease risks among career firefighters who work on a 24-hour shift schedule. METHODS AND ANALYSES: The Healthy Heroes Study is a randomised controlled parallel open-label clinical trial with 150 firefighters over 1 year. Firefighters are randomised with a 1:1 ratio to either the control or intervention group. The control group receives Mediterranean diet nutritional counselling (standard of care, 'SOC'). The intervention group receives the same SOC and a self-selected 10-hour TRE window. After the 2-week baseline, participants enter a 3-month monitored intervention, followed by a 9-month self-guided period with follow-up assessments. The impact of TRE on blood glucose, body weight, body composition, biomarkers (neuroendocrine, inflammatory and metabolic), sleep and mood is evaluated. These assessments occur at baseline, at the end of intervention and at 6, 9 and 12-month follow-ups. Temporal calorie intake is monitored with the smartphone application myCircadianClock throughout the study. Continuous glucose monitors, wrist-worn actigraphy device and questionnaires are used to monitor glucose levels, activity, sleep and light exposure. ETHICS AND DISSEMINATION: The study was approved by the Institutional Review Boards of the University of California San Diego and the Salk Institute for Biological Studies. Results will be disseminated through peer-reviewed manuscripts, reports and presentations. TRIAL REGISTRATION NUMBER: NCT03533023; Pre result.

fMRI findings in MTBI patients with headaches following rTMS.

Mild Traumatic Brain Injury (MTBI) patients with persistent headaches are known to have diminished supraspinal modulatory connectivity from their prefrontal cortices. Repetitive transcranial magnetic stimulation (rTMS) is able to alleviate MTBI-related headache (MTBI-HA). This functional magnetic resonance imaging (fMRI) study assessed supraspinal correlates associated with the headache analgesic effect of rTMS at left prefrontal cortex (LPFC), hypothesizing real rTMS would significantly increase modulatory functions at LPFC in comparison to sham treatment. Subjects with MTBI-HA were randomized to receive either real or sham rTMS treatments and subjected to pre- and post-treatment resting state and evoked heat-pain fMRI as described in a prior study. Real rTMS consisted of 2000 pulses delivered at 10 Hz and 80% of the resting motor threshold at left dorsolateral prefrontal cortex, whereas sham treatment was delivered with same figure-of-eight coil turned 180 degrees. Follow-up fMRI was performed one-week post-treatment. All fMRI data was processed using BrainVoyager QX Software. 14 subjects receiving real and 12 subjects receiving sham treatments completed the study. The REAL group demonstrated significant (P < 0.02) decreases in headache frequency and intensity at one week following treatment. fMRI scans in the REAL group showed increased evoked heat pain activity (P < 0.002) and resting functional connectivity (P < 0.0001) at the LPFC after rTMS. Neither this significant analgesic effect nor these fMRI findings were seen in the sham group. Sham treatment was, however, associated with a decrease in resting state activity at the LPFC (P < 0.0001). This study correlates the demonstrated analgesic effect of rTMS in the treatment of MTBI-HA with enhanced supraspinal functional connectivity in the left prefrontal cortex, which is known to be involved in "top-down" pain inhibition along the descending midbrain-thalamic-cingulate pathway. Trial Registration: This study was registered on September 24, 2013, on ClinicalTrials.gov with the identifier: NCT01948947. https://clinicaltrials.gov/ct2/show/NCT01948947 .

A prospective study to determine the clinical utility of pharmacogenetic testing of veterans with treatment-resistant depression.

BACKGROUND: Pharmacotherapies for depression are often ineffective and treatment-resistant depression (TRD) is common across bipolar disorder (BD), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). Patient genetic information can be used to predict treatment outcomes. Prospective studies indicate that pharmacogenetic (PGX) tests have utility in the treatment of depression. However, few studies have examined the utility of PGX in other diagnoses typified by depression, or in veterans, a cohort with high rates of medical comorbidity, social stress, and suicide. AIM: To determine the efficacy of genetically guided pharmacological treatment of TRD. METHODS: We conducted an 8-week, prospective, multisite, single-blind study in 182 veterans with TRD including patients with BD, MDD, and PTSD. Subjects were randomly assigned to PGX-guided treatment in which the clinician incorporated PGX information into decision-making, or treatment as usual (TAU). RESULTS: Overall, the PGX group improved marginally faster compared to TAU, but the difference was not statistically significant. Secondary analyses revealed that only PTSD patients showed a potential benefit from PGX testing. Patients predicted by PGX testing to have moderate levels of genetic risk showed a significant benefit from the PGX-guided treatment, whereas other risk groups demonstrated no benefit. Clinicians generally found the PGX test was useful, particularly in more depressed patients and/or those with more warnings for significant or serious adverse outcomes. Clinicians more often used the results to select a drug, but only rarely to adjust dosing. CONCLUSIONS: The data reveal possible group differences in the utility of PGX testing in veterans with TRD.ClinicalTrials.gov Identifier: NCT04469322.

Randomized Trial of Ivabradine in Patients With Hyperadrenergic Postural Orthostatic Tachycardia Syndrome.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a complex, multifaceted disorder that impairs functional status and quality of life. Current pharmacological treatments are limited. OBJECTIVES: This study investigated the effect of ivabradine (selective blocker of the Ifunny channel in the sinoatrial node) on heart rate, quality of life (QOL), and plasma norepinephrine (NE) levels in patients with hyperadrenergic POTS defined by plasma NE >600 pg/ml and abnormal tilt table test. METHODS: In total, 22 patients with hyperadrenergic POTS as the predominant subtype completed a randomized, double-blinded, placebo-controlled, crossover trial with ivabradine. Patients were randomized to start either ivabradine or placebo for 1 month, and then were crossed over to the other treatment for 1 month. Heart rate, QOL, and plasma NE levels were measured at baseline and at the end of each treatment month. RESULTS: The average age was 33.9 ± 11.7 years, 95.5% were women (n = 21), and 86.4% were White (n = 23). There was a significant reduction in heart rate between placebo and ivabradine (p < 0.001). Patients reported significant improvements in QOL with RAND 36-Item Health Survey 1.0 for physical functioning (p = 0.008) and social functioning (p = 0.021). There was a strong trend in reduction of NE levels upon standing with ivabradine (p = 0.056). Patients did not experience any significant side-effects, such as bradycardia or hypotension, with ivabradine. CONCLUSION: Ivabradine is safe and effective in significantly improving heart rate and QOL in patients with hyperadrenergic POTS as the predominant subtype.

Real-world characteristics of women with endometriosis-related pain entering a multidisciplinary endometriosis program.

BACKGROUND: Women with endometriosis are commonly treated by their sole provider. In this single-provider model of care, women frequently report long diagnostic delays, unresolved pelvic pain, multiple laparoscopic surgeries, sequential consultations with numerous providers, and an overall dissatisfaction with care. The emergence of multidisciplinary endometriosis centers aims to reduce diagnostic delays, improve pain management, and promote patient satisfaction; however, baseline data at the time of presentation to a multidisciplinary center are lacking. METHODS: A real-world, retrospective, single-site, cross-sectional study of women with surgically confirmed and/or clinically diagnosed endometriosis generated baseline data for a planned longitudinal assessment of multidisciplinary care of endometriosis. The primary objective was to determine the proportion of patients experiencing mild, moderate, or severe pain for dysmenorrhea, non-menstrual pelvic pain (NMPP), and dyspareunia at entry into a multidisciplinary endometriosis clinic. Also explored were relationships between pain scores and clinical endpoints obtained from electronic medical records. RESULTS: More than half (59%) of the study participants (n = 638) reported experiencing pelvic pain for ≥ 5 years. Pain intensity was highest for patients reporting dysmenorrhea, followed by NMPP, and dyspareunia. Significant correlations were observed between total pelvic pain and patient age (r = -0.22, p < 0.001, n = 506) and number of previous healthcare providers (r = 0.16, p = 0.006, n = 292); number of previous providers and duration of pain (r = 0.21, p = < 0.0001, n = 279); and duration of pain and years since diagnosis (r = 0.60, p < 0.001, n = 302). Mean pain scores differed significantly by age group for dysmenorrhea (p < 0.001), NMPP (p = 0.005), and total pelvic pain (p < 0.001), but not for dyspareunia (p = 0.06), with the highest mean pain scores reported among those < 30 years of age. CONCLUSION: These real-world data indicate that in the single-provider model of care, unresolved pelvic pain is common among women with endometriosis. Alternative care models, including a multidisciplinary approach, need to be evaluated for improvements in clinical outcomes. These data also highlight the importance of addressing NMPP, which may be particularly troublesome for patients.

Trauma Informed Guilt Reduction (TrIGR) therapy for guilt, shame, and moral injury resulting from trauma: Rationale, design, and methodology of a two-site randomized controlled trial.

Guilt, shame, and moral injury (MI) are common reactions following exposure to traumatic events and are associated with greater severity of several mental health problems, including posttraumatic stress disorder (PTSD), depression, increased risk of suicidal ideation and poorer psychosocial functioning. Trauma-Informed Guilt Reduction (TrIGR) is a transdiagnostic psychotherapy to address guilt, shame, and MI stemming from traumatic events. The primary goals of TrIGR are to help patients accurately appraise their trauma and to re-engage with their values in order to lead a more meaningful life. This paper presents the rationale, design, and methodology of a two-site randomized controlled trial (RCT) examining the efficacy of TrIGR compared to Supportive Care Therapy (SCT) in a sample of U.S. veterans (N = 145) who endorse guilt related to a traumatic event that occurred during military deployment. This study is the first RCT powered to investigate TrIGR's efficacy on reducing posttraumatic guilt, as measured by the Trauma Related Guilt Inventory (TRGI), in comparison to an active control condition. In addition, the study will examine a range of secondary and exploratory outcomes including shame, quality of life, suicidal ideation, substance use, and PTSD and depression symptoms. Findings from this efficacy study will be essential in informing future efficacy and effectiveness trials.

Diminished corticomotor excitability in Gulf War Illness related chronic pain symptoms; evidence from TMS study.

Chronic diffuse body pain is unequivocally highly prevalent in Veterans who served in the 1990-91 Persian Gulf War and diagnosed with Gulf War Illness (GWI). Diminished motor cortical excitability, as a measurement of increased resting motor threshold (RMT) with transcranial magnetic stimulation (TMS), is known to be associated with chronic pain conditions. This study compared RMT in Veterans with GWI related diffuse body pain including headache, muscle and joint pain with their military counterparts without GWI related diffuse body pain. Single pulse TMS was administered over the left motor cortex, using anatomical scans of each subject to guide the TMS coil, starting at 25% of maximum stimulator output (MSO) and increasing in steps of 2% until a motor response with a 50 µV peak to peak amplitude, defined as the RMT, was evoked at the contralateral flexor pollicis brevis muscle. RMT was then analyzed using Repeated Measures Analysis of Variance (RM-ANOVA). Veterans with GWI related chronic headaches and body pain (N = 20, all males) had a significantly (P < 0.001) higher average RMT (% ± SD) of 77.2% ± 16.7% compared to age and gender matched military controls (N = 20, all males), whose average was 55.6% ± 8.8%. Veterans with GWI related diffuse body pain demonstrated a state of diminished corticomotor excitability, suggesting a maladaptive supraspinal pain modulatory state. The impact of this observed supraspinal functional impairment on other GWI related symptoms and the potential use of TMS in rectifying this abnormality and providing relief for pain and co-morbid symptoms requires further investigation.Trial registration: This study was registered on January 25, 2017, on ClinicalTrials.gov with the identifier: NCT03030794. Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT03030794 .

Attitudes on pharmacogenetic testing in psychiatric patients with treatment-resistant depression.

BACKGROUND: Novel technologies make it possible to incorporate pharmacogenetic testing into the medical management of depression. However, previous studies indicate that there may be a subset of subjects who have concerns about genetic testing and may be psychologically vulnerable. If so, pharmacogenetic testing in depressed subjects could negatively impact their mental health and undermine treatment goals. METHODS: In this study, we developed a standardized instrument to assess motivations and attitudes around pharmacogenetic testing in a cohort of 170 depressed Veterans participating in a multi-center clinic trial. RESULTS: Testing reveals that subjects were largely positive about the use of genetic testing to guide pharmacological treatment and help plan their future. Most subjects showed only modest concerns about the impact on family, inability to cope with the results, and fear of discrimination. The severity of depression did not predict the concern expressed about negative outcomes. However, non-Caucasian subjects were more likely on average to endorse concerns about poor coping and fear of discrimination. CONCLUSIONS: These data indicate that while the overall risk is modest, some patients with depression may face psychosocial challenges in the context of pharmacogenetic testing. Future work should identify factors that predict distress and aim to tailor test results to different populations.