Diagnosis in psychiatry faces familiar challenges. Validity and utility remain elusive, and confusion regarding the fluid and arbitrary border between mental health and illness is increasing. The mainstream strategy has been conservative and iterative, retaining current nosology until something better emerges. However, this has led to stagnation. New conceptual frameworks are urgently required to catalyze a genuine paradigm shift.

We outline candidate strategies that could pave the way for such a paradigm shift. These include the Research Domain Criteria (RDoC), the Hierarchical Taxonomy of Psychopathology (HiTOP), and Clinical Staging, which all promote a blend of dimensional and categorical approaches.

These alternative still heuristic transdiagnostic models provide varying levels of clinical and research utility. RDoC was intended to provide a framework to reorient research beyond the constraints of DSM. HiTOP began as a nosology derived from statistical methods and is now pursuing clinical utility. Clinical Staging aims to both expand the scope and refine the utility of diagnosis by the inclusion of the dimension of timing. None is yet fit for purpose. Yet they are relatively complementary, and it may be possible for them to operate as an ecosystem. Time will tell whether they have the capacity singly or jointly to deliver a paradigm shift.

Several heuristic models have been developed that separately or synergistically build infrastructure to enable new transdiagnostic research to define the structure, development, and mechanisms of mental disorders, to guide treatment and better meet the needs of patients, policymakers, and society.

In response to the COVID-19 pandemic, we rapidly implemented a plasma coordination center, within two months, to support transfusion for two outpatient randomized controlled trials. The center design was based on an investigational drug services model and a Food and Drug Administration-compliant database to manage blood product inventory and trial safety.

A core investigational team adapted a cloud-based platform to randomize patient assignments and track inventory distribution of control plasma and high-titer COVID-19 convalescent plasma of different blood groups from 29 donor collection centers directly to blood banks serving 26 transfusion sites.

We performed 1,351 transfusions in 16 months. The transparency of the digital inventory at each site was critical to facilitate qualification, randomization, and overnight shipments of blood group-compatible plasma for transfusions into trial participants. While inventory challenges were heightened with COVID-19 convalescent plasma, the cloud-based system, and the flexible approach of the plasma coordination center staff across the blood bank network enabled decentralized procurement and distribution of investigational products to maintain inventory thresholds and overcome local supply chain restraints at the sites.

The rapid creation of a plasma coordination center for outpatient transfusions is infrequent in the academic setting. Distributing more than 3,100 plasma units to blood banks charged with managing investigational inventory across the U.S. in a decentralized manner posed operational and regulatory challenges while providing opportunities for the plasma coordination center to contribute to research of global importance. This program can serve as a template in subsequent public health emergencies.

Operationalizing multi-site Community Engagement (CE) Studios to inform a research program is valuable for researchers. We describe the process and outcomes of hosting three CE Studios with Community Experts aged 65 years or older with chronic conditions and care partners of older adults. Experts gave feedback about processes for testing the feasibility, efficacy, effectiveness, and implementation of audio recording clinic visits and sharing recordings with patients who have multimorbidity and their care partners.

The CE Cores of the Clinical and Translational Science Awards Programs at three academic health science centers created a joint CE Studio guide. Studios were conducted iteratively by site. Following receipt of the final reports, responses were compared to find themes, similarities, and differences on four topics in addition to overall commentary: Recruitment and Retention, Study Protocol, Study Reminders and Frequency, and Recording Technology.

Eighteen older adults and care partners in three states provided valuable feedback to inform multi-site trials. Feedback influenced multiple aspects of trials in process or subsequently funded. Experts provided critique on the wording of study invitations, information sheets, and reminders to engage in study procedures. Experts were concerned for participants being disappointed by randomization to a control arm and advised how investigators should prepare to address that.

Multi-site CE Studios should be consecutive, so each team can learn from the previous teams. Using the CES Toolkit ensures that final reports were easily comparable and utilized to develop a research program that now includes three federally funded clinical trials.

Depression is an independent risk factor for cardiovascular disease (CVD), but it is unknown if successful depression treatment reduces CVD risk.

Using eIMPACT trial data, we examined the effect of modernized collaborative care for depression on indicators of CVD risk. A total of 216 primary care patients with depression and elevated CVD risk were randomized to 12 months of the eIMPACT intervention (internet cognitive-behavioral therapy [CBT], telephonic CBT, and select antidepressant medications) or usual primary care. CVD-relevant health behaviors (self-reported CVD prevention medication adherence, sedentary behavior, and sleep quality) and traditional CVD risk factors (blood pressure and lipid fractions) were assessed over 12 months. Incident CVD events were tracked over four years using a statewide health information exchange.

The intervention group exhibited greater improvement in depressive symptoms (p < 0.01) and sleep quality (p < 0.01) than the usual care group, but there was no intervention effect on systolic blood pressure (p = 0.36), low-density lipoprotein cholesterol (p = 0.38), high-density lipoprotein cholesterol (p = 0.79), triglycerides (p = 0.76), CVD prevention medication adherence (p = 0.64), or sedentary behavior (p = 0.57). There was an intervention effect on diastolic blood pressure that favored the usual care group (p = 0.02). The likelihood of an incident CVD event did not differ between the intervention (13/107, 12.1%) and usual care (9/109, 8.3%) groups (p = 0.39).

Successful depression treatment alone is not sufficient to lower the heightened CVD risk of people with depression. Alternative approaches are needed.

ClinicalTrials.gov Identifier: NCT02458690

Knowledge of sex differences in risk factors for posttraumatic stress disorder (PTSD) can contribute to the development of refined preventive interventions. Therefore, the aim of this study was to examine if women and men differ in their vulnerability to risk factors for PTSD.

As part of the longitudinal AURORA study, 2924 patients seeking emergency department (ED) treatment in the acute aftermath of trauma provided self-report assessments of pre- peri- and post-traumatic risk factors, as well as 3-month PTSD severity. We systematically examined sex-dependent effects of 16 risk factors that have previously been hypothesized to show different associations with PTSD severity in women and men.

Women reported higher PTSD severity at 3-months post-trauma. Z-score comparisons indicated that for five of the 16 examined risk factors the association with 3-month PTSD severity was stronger in men than in women. In multivariable models, interaction effects with sex were observed for pre-traumatic anxiety symptoms, and acute dissociative symptoms; both showed stronger associations with PTSD in men than in women. Subgroup analyses suggested trauma type-conditional effects.

Our findings indicate mechanisms to which men might be particularly vulnerable, demonstrating that known PTSD risk factors might behave differently in women and men. Analyses did not identify any risk factors to which women were more vulnerable than men, pointing toward further mechanisms to explain women's higher PTSD risk. Our study illustrates the need for a more systematic examination of sex differences in contributors to PTSD severity after trauma, which may inform refined preventive interventions.

Nursing home residents may be particularly vulnerable to coronavirus disease 2019 (COVID-19). Therefore, a question is when and how often nursing homes should test staff for COVID-19 and how this may change as severe acute respiratory coronavirus virus 2 (SARS-CoV-2) evolves.

We developed an agent-based model representing a typical nursing home, COVID-19 spread, and its health and economic outcomes to determine the clinical and economic value of various screening and isolation strategies and how it may change under various circumstances.

Under winter 2023–2024 SARS-CoV-2 omicron variant conditions, symptom-based antigen testing averted 4.5 COVID-19 cases compared to no testing, saving $191 in direct medical costs. Testing implementation costs far outweighed these savings, resulting in net costs of $990 from the Centers for Medicare & Medicaid Services perspective, $1,545 from the third-party payer perspective, and $57,155 from the societal perspective. Testing did not return sufficient positive health effects to make it cost-effective [$50,000 per quality-adjusted life-year (QALY) threshold], but it exceeded this threshold in ≥59% of simulation trials. Testing remained cost-ineffective when routinely testing staff and varying face mask compliance, vaccine efficacy, and booster coverage. However, all antigen testing strategies became cost-effective (≤$31,906 per QALY) or cost saving (saving ≤$18,372) when the severe outcome risk was ≥3 times higher than that of current omicron variants.

SARS-CoV-2 testing costs outweighed benefits under winter 2023–2024 conditions; however, testing became cost-effective with increasingly severe clinical outcomes. Cost-effectiveness can change as the epidemic evolves because it depends on clinical severity and other intervention use. Thus, nursing home administrators and policy makers should monitor and evaluate viral virulence and other interventions over time.

Parkinsonism and Parkinson's disease (PD) have been described as consequences of repetitive head impacts (RHI) from boxing, since 1928. Autopsy studies have shown that RHI from other contact sports can also increase risk for neurodegenerative diseases, including chronic traumatic encephalopathy (CTE) and Lewy bodies. In vivo research on the relationship between American football play and PD is scarce, with small samples, and equivocal findings. This study leveraged the Fox Insight study to evaluate the association between American football and parkinsonism and/or PD Diagnosis and related clinical outcomes.

Fox Insight is an online study of people with and without PD who are 18+ years (>50,000 enrolled). Participants complete online questionnaires on motor function, cognitive function, and general health behaviors. Participants self-reported whether they "currently have a diagnosis of Parkinson's disease, or parkinsonism, by a physician or other health care professional." In November 2020, the Boston University Head Impact Exposure Assessment was launched in Fox Insight for large-scale data collection on exposure to RHI from contact sports and other sources. Data used in this abstract were obtained from the Fox Insight database https://foxinsight-info.michaeljfox.org/insight/explore/insight.jsp on 01/06/2022. The sample includes 2018 men who endorsed playing an organized sport. Because only 1.6% of football players were women, analyses are limited to men. Responses to questions regarding history of participation in organized football were examined. Other contact and/or non-contact sports served as the referent group. Outcomes included PD status (absence/presence of parkinsonism or PD) and Penn Parkinson's Daily Activities Questionnaire-15 (PDAQ-15) for assessment of cognitive symptoms. Binary logistic regression tested associations between history and years of football play with PD status, controlling for age, education, current heart disease or diabetes, and family history of PD. Linear regressions, controlling for these variables, were used for the PDAQ-15.

Of the 2018 men (mean age=67.67, SD=9.84; 10, 0.5% Black), 788 (39%) played football (mean years of play=4.29, SD=2.88), including 122 (16.3%) who played youth football, 494 (66.0%) played high school, 128 (17.1%) played college football, and 5 (0.7%) played at the semi-professional or professional level. 1738 (86.1%) reported being diagnosed with parkinsonism/PD, and 707 of these were football players (40.7%). History of playing any level of football was associated with increased odds of having a reported parkinsonism or PD diagnosis (OR=1.52, 95% CI=1.14-2.03, p=0.004). The OR remained similar among those age <69 (sample median age) (OR=1.45, 95% CI=0.97-2.17, p=0.07) and 69+ (OR=1.45, 95% CI=0.95-2.22, p=0.09). Among the football players, there was not a significant association between years of play and PD status (OR=1.09, 95% CI=1.00-1.20, p=0.063). History of football play was not associated with PDAQ-15 scores (n=1980) (beta=-0.78, 95% CI=-1.59-0.03, p=0.059) among the entire sample.

Among 2018 men from a data set enriched for PD, playing organized football was associated with increased odds of having a reported parkinsonism/PD diagnosis. Next steps include examination of the contribution of traumatic brain injury and other sources of RHI (e.g., soccer, military service).

Former professional American football players have a high relative risk for neurodegenerative diseases like chronic traumatic encephalopathy (CTE). Interpreting low cognitive test scores in this population occasionally is complicated by performance on validity testing. Neuroimaging biomarkers may help inform whether a neurodegenerative disease is present in these situations. We report three cases of retired professional American football players who completed comprehensive neuropsychological testing, but “failed” performance validity tests, and underwent multimodal neuroimaging (structural MRI, Aß-PET, and tau-PET).

Three cases were identified from the Focused Neuroimaging for the Neurodegenerative Disease Chronic Traumatic Encephalopathy (FIND-CTE) study, an ongoing multimodal imaging study of retired National Football League players with complaints of progressive cognitive decline conducted at Boston University and the UCSF Memory and Aging Center. Participants were relatively young (age range 55-65), had 16 or more years of education, and two identified as Black/African American. Raw neuropsychological test scores were converted to demographically-adjusted z-scores. Testing included standalone (Test of Memory Malingering; TOMM) and embedded (reliable digit span, RDS) performance validity measures. Validity cutoffs were TOMM Trial 2 < 45 and RDS < 7. Structural MRIs were interpreted by trained neurologists. Aß-PET with Florbetapir was used to quantify cortical Aß deposition as global Centiloids (0 = mean cortical signal for a young, cognitively normal, Aß negative individual in their 20s, 100 = mean cortical signal for a patient with mild-to-moderate Alzheimer’s disease dementia). Tau-PET was performed with MK-6240 and first quantified as standardized uptake value ratio (SUVR) map. The SUVR map was then converted to a w-score map representing signal intensity relative to a sample of demographically-matched healthy controls.

All performed in the average range on a word reading-based estimate of premorbid intellect. Contribution of Alzheimer’s disease pathology was ruled out in each case based on Centiloids quantifications < 0. All cases scored below cutoff on TOMM Trial 2 (Case #1=43, Case #2=42, Case #3=19) and Case #3 also scored well below RDS cutoff (2). Each case had multiple cognitive scores below expectations (z < -2.0) most consistently in memory, executive function, processing speed domains. For Case #1, MRI revealed mild atrophy in dorsal fronto-parietal and medial temporal lobe (MTL) regions and mild periventricular white matter disease. Tau-PET showed MTL tau burden modestly elevated relative to controls (regional w-score=0.59, 72nd%ile). For Case #2, MRI revealed cortical atrophy, mild hippocampal atrophy, and a microhemorrhage, with no evidence of meaningful tau-PET signal. For Case #3, MRI showed cortical atrophy and severe white matter disease, and tau-PET revealed significantly elevated MTL tau burden relative to controls (w-score=1.90, 97th%ile) as well as focal high signal in the dorsal frontal lobe (overall frontal region w-score=0.64, 74th%ile).

Low scores on performance validity tests complicate the interpretation of the severity of cognitive deficits, but do not negate the presence of true cognitive impairment or an underlying neurodegenerative disease. In the rapidly developing era of biomarkers, neuroimaging tools can supplement neuropsychological testing to help inform whether cognitive or behavioral changes are related to a neurodegenerative disease.

Persons with behavioral variant frontotemporal dementia (bvFTD) have been shown to exhibit altered morality, manifested as atypical utilitarian tendencies towards sacrificial moral dilemmas. This takes the form of endorsing harmful actions towards single individuals, including vulnerable or relationally close individuals (e.g. children, loved ones), in order to promote the greater good for the community or society as a whole. The dual process model of moral cognition interprets such tendencies as deriving from a lack of emotional engagement, whereas moral emotion theory views them as selective impairment in prosocial sentiments. We hypothesized that both the widespread neuropsychological practice of using sacrificial moral dilemmas to evaluate moral reasoning, and these tests' overreliance on quantitative results, inadequately represent how persons with bvFTD reason and feel while responding to moral dilemmas. To evaluate this hypothesis, we applied a mixed-methods approach to identify the reasoning, motivations, and emotional experiences of bvFTD persons during their deliberation about moral scenarios.

We conducted semi-structured interviews with 14 participants: 7 persons with bvFTD & 7 older healthy controls. Transcripts were coded in Atlas 5.0 to characterize the underlying reasoning, emotions, response processes, and values that emerged when responding to a structured set of moral dilemmas. Our dilemmas measured utilitarian reasoning holistically by incorporating both sacrificial and impartial/altruistic components, as suggested by the 2-dimensional model of utilitarianism.

Unexpectedly, bvFTD persons articulated a prosocial compass when asked about their values, stating they were organizing their choices predominantly around kindness and altruism, even when they were making choices to harm loved ones or vulnerable individuals to promote the greater good. During moral deliberation, persons with bvFTD showed significantly less metacognition (bvFTD = 10%, HC = 90%) but reported more positive emotions (joy; bvFTD = 83%, HC = 17%) than negative (frustration; bvFTD = 30 %, HC = 70 %) compared to controls. Qualitatively, this observed emotional outlook was typically coupled with a more rigid, simplistic viewpoint (e.g., "I felt great, it was a no brainer"), suggesting a moral understanding lacking emotional nuance and complexity.

Our data showed that bvFTD persons' utilitarian responses to moral dilemmas did not arise from an emotionally flat or antisocial cognitive perspective, but instead were guided by positive emotionality, simplistic reasoning, and prosocial values. These findings challenge the current understanding of the reasoning processes and experiences of persons with bvFTD and highlight the importance of incorporating mixed method approaches in dementia research that take into consideration the viewpoint of the cognitively compromised individual.

Traumatic brain injury (TBI) and concussion are associated with increased dementia risk. Accurate TBI/concussion exposure estimates are relatively unknown for less common neurodegenerative conditions like frontotemporal dementia (FTD). We evaluated lifetime TBI and concussion frequency in patients diagnosed with a range of FTD spectrum conditions and related prior head trauma to cavum septum pellucidum (CSP) characteristics observable on MRI.

We administered the Ohio State University TBI Identification and Boston University Head Impact Exposure Assessment to 108 patients (age 69.5 ± 8.0, 35% female, 93% white or unknown race) diagnosed at the UCSF Memory and Aging Center with one of the following FTD or related conditions: behavioral variant frontotemporal dementia (N=39), semantic variant primary progressive aphasia (N=16), nonfluent variant PPA (N=23), corticobasal syndrome (N=14), or progressive supranuclear palsy (N=16). Data were also obtained from 217 controls (“HC”; age 76.8 ± 8.0, 53% female, 91% white or unknown race). CSP characteristics were defined based on width or “grade” (0-1 vs. 2+) and length of anterior-posterior separation (millimeters). We first describe frequency of any and multiple (2+) prior TBI based on different but commonly used definitions: TBI with loss of consciousness (LOC), TBI with LOC or posttraumatic amnesia (LOC/PTA), TBI with LOC/PTA or other symptoms like dizziness, nausea, “seeing stars,” etc. (“concussion”). TBI/concussion frequency was then compared between FTD and HC using chi-square. Associations between TBI/concussion and CSP characteristics were analyzed with chi-square (CSP grade) and Mann-Whitney U tests (CSP length). We explored sex differences due to typically higher rates of TBI among males.

History of any TBI with LOC (FTD=20.0%, HC=19.2%), TBI with LOC/PTA (FTD:32.2%, HC=31.5%), and concussion (FTD: 50.0%, HC=44.3%) was common but not different between study groups (p’s>.4). In both FTD and HC, prior TBI/concussion was nominally more frequent in males but not significantly greater than females. Frequency of repeat TBI/concussion (2+) also did not differ significantly between FTD and HC (repeat TBI with LOC: 6.7% vs. 3.3%, TBI with LOC/PTA: 12.2% vs. 10.3%, concussion: 30.2% vs. 28.7%; p’s>.2). Prior TBI/concussion was not significantly related to CSP grade or length in the total sample or within the FTD or HC groups.

TBI/concussion rates depend heavily on the symptom definition used for classifying prior injury. Lifetime symptomatic TBI/concussion is common but has an unclear impact on risk for FTD-related diagnoses. Larger samples are needed to appropriately evaluate sex differences, to evaluate whether TBI/concussion rates differ between specific FTD phenotypes, and to understand the rates and effects of more extensive repetitive head trauma (symptomatic and asymptomatic) in patients with FTD.

Participation in sports likely confers multiple benefits for children and adolescents with autism spectrum disorder (ASD). Adolescent student athletes often undergo preseason testing as part of a broader concussion management program for schools. This study compares preseason neurocognitive functioning and symptom reporting between high school athletes with and without ASD.

Participants were derived from a database of 60,751 adolescent student athletes from Maine (aged 13-18) who completed preseason testing between 2009 and 2019 and did not have missing data on the history question relating to ASD. There were 425 students (0.7%) who self-reported having been diagnosed with ASD in their health history. Cognitive functioning was measured by ImPACT, and the Post-Concussion Symptom Scale (PCSS) was used to obtain symptom ratings. Group differences between the ASD and the population control group on the five ImPACT cognitive test composite raw scores and the total symptom score from the PCSS were examined using Mann-Whitney U tests.

Compared to the population control sample, those with ASD reported much greater rates of comorbid conditions: attention deficit/hyperactivity disorder (50.1% vs. 10.3%), special education (39.2% vs. 4.4%), learning disabilities (43.8% vs. 4.4%), and prior treatment for a psychiatric condition (23.4% vs. 7.5%). Groups differed significantly across all neurocognitive composites (p values <.002). However, all differences were negligible in terms of the magnitude of the effects (r values range from 0.01-0.03). The groups also differed significantly on the PCSS total symptom score (p<.001), but the magnitude of the difference was negligible (r=.031). Among boys, the ASD group endorsed 21 of the 22 symptoms at a greater rate. Among girls, the ASD group endorsed 11 of the 22 individual baseline symptoms at a greater rate than the control group. Examples of symptoms that were endorsed at a higher rate among both boys and girls with ASD: sensitivity to noise (girls: odds ratio, OR=4.38; boys: OR=4.99), numbness or tingling (girls: OR=3.67; boys: OR=3.25), difficulty remembering (girls: OR=2.01; boys: OR=2.49), difficulty concentrating (girls: OR=1.82; boys: OR=2.40), sleeping more than usual (girls: OR=1.94; boys: OR=1.97), sensitivity to light (girls: OR=1.82; boys: OR=1.76), sadness (girls: OR=1.72; boys: OR=2.56), nervousness (girls: OR=1.80; boys: OR=2.27), and feeling more emotional (girls: OR=1.79; boys: OR=2.84).

Students with ASD participating in organized sports are likely high functioning, on average. There were small differences in their cognitive test scores compared to the population control sample. They endorsed more symptoms, however, during baseline preseason testing. If they sustain a concussion, their clinical management should be more intensive to maximize the likelihood of swift and favorable recovery.