This study introduces the prostate cancer linear energy transfer sensitivity index (PCLSI) as a novel method to predict relative biological effectiveness (RBE) in prostate cancer using linear energy transfer (LET) in proton therapy based on screening for DNA repair mutations.

Five prostate cancer cell lines with DNA repair mutations known to cause sensitivity to LET and DNA repair inhibitors were examined using published data. Relative Du145 LET sensitivity data were leveraged to deduce the LET equivalent of olaparib doses. The PCLSI model was built using three of the prostate cancer cell lines (LNCaP, 22Rv1 and Du145) with DNA mutation frequency from patient cohorts. The PCLSI model was compared against two established RBE models, McNamara and McMahon, for LET-optimized prostate cancer treatment plans.

The PCLSI model relies on the presence of eight DNA repair mutations: AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53, which are most likely to predict increased LET sensitivity and RBE in proton therapy. In the LET-optimized plan, the PCLSI model indicates that prostate cancer cells with these DNA repair mutations are more sensitive to increased LET than the McNamara and McMahon RBE models, with expected RBE increases ranging from 11%–33% at 2keV/µm.

The PCLSI model predicts increasing RBE as a function of LET in the presence of certain genetic mutations. The integration of LET-optimized proton therapy and genetic mutation profiling could be a significant step toward the use of individualized medicine to improve outcomes using RBE escalation without the potential toxicity of physical dose escalation.

Increasing daylight exposure might be a simple way to improve mental health. However, little is known about daylight-symptom associations in depressive disorders.

In a subset of the Australian Genetics of Depression Study (N = 13,480; 75% female), we explored associations between self-reported number of hours spent in daylight on a typical workday and free day and seven symptom dimensions: depressive (overall, somatic, psychological); hypo-manic-like; psychotic-like; insomnia; and daytime sleepiness. Polygenic scores for major depressive disorder (MDD); bipolar disorder (BD); and schizophrenia (SCZ) were calculated. Models were adjusted for age, sex, shift work status, employment status, season, and educational attainment. Exploratory analyses examined age-stratified associations (18–24 years; 25–34 years; 35–64 years; 65 and older). Bonferroni-corrected associations (p < 0.004) are discussed.

Adults with depression reported spending a median of one hour in daylight on workdays and three hours on free days. More daylight exposure on workdays and free days was associated with lower depressive (overall, psychological, somatic) and insomnia symptoms (p’s<0.001), but higher hypo-manic-like symptoms (p’s<0.002). Genetic loading for MDD and SCZ were associated with less daylight exposure in unadjusted correlational analyses (effect sizes were not meaningful). Exploratory analyses revealed age-related heterogeneity. Among 18–24-year-olds, no symptom dimensions were associated with daylight. By contrast, for the older age groups, there was a pattern of more daylight exposure and lower insomnia symptoms (p < 0.003) (except for 25–34-year-olds on free days, p = 0.019); and lower depressive symptoms with more daylight on free days, and to some extent workdays (depending on the age-group).

Exploration of the causal status of daylight in depression is warranted.

Transcranial direct current stimulation (tDCS) is a promising treatment for major depressive disorder (MDD). This study evaluated its antidepressant and cognitive effects as a safe, effective, home-based therapy for MDD.

This double-blind, sham-controlled, randomized trial divided participants into low-intensity (1 mA, n = 47), high-intensity (2 mA, n = 49), and sham (n = 45) groups, receiving 42 daily tDCS sessions, including weekends and holidays, targeting the dorsolateral prefrontal cortex for 30 minutes. Assessments were conducted at baseline and weeks 2, 4, and 6. The primary outcome was cognitive improvement assessed by changes in total accuracy on the 2-back test from baseline to week 6. Secondary outcomes included changes in depressive symptoms (HAM-D), anxiety (HAM-A), and quality of life (QLES). Adverse events were monitored. This trial was registered with ClinicalTrials.gov (NCT04709952).

In the tDCS study, of 141 participants (102 [72.3%] women; mean age 35.7 years, standard deviation 12.7), 95 completed the trial. Mean changes in the total accuracy scores from baseline to week 6 were compared across the three groups using an F-test. Linear mixed-effects models examined the interaction of group and time. Results showed no significant differences among groups in cognitive or depressive outcomes at week 6. Active groups experienced more mild adverse events compared to sham but had similar rates of severe adverse events and dropout.

Home-based tDCS for MDD demonstrated no evidence of effectiveness but was safe and well-tolerated. Further research is needed to address the technical limitations, evaluate broader cognitive functions, and extend durations to evaluate its therapeutic potential.

Successfully educating urgent care patients on appropriate use and risks of antibiotics can be challenging. We assessed the conscious and subconscious impact various educational materials (informational handout, priming poster, and commitment poster) had on urgent care patients’ knowledge and expectations regarding antibiotics.

Stratified Block Randomized Control Trial.

Urgent care centers (UCCs) in Colorado, Florida, Georgia, and New Jersey.

Urgent care patients.

We randomized 29 UCCs across six study arms to display specific educational materials (informational handout, priming poster, and commitment poster). The primary intention-to-treat (ITT) analysis evaluated whether the materials impacted patient knowledge or expectations of antibiotic prescribing by assigned study arm. The secondary as-treated analysis evaluated the same outcome comparing patients who recalled seeing the assigned educational material and patients who either did not recall seeing an assigned material or were in the control arm.

Twenty-seven centers returned 2,919 questionnaires across six study arms. Only 27.2% of participants in the intervention arms recalled seeing any educational materials. In our primary ITT analysis, no difference in knowledge or expectations of antibiotic prescribing was noted between groups. However, in the as-treated analysis, the handout and commitment poster were associated with higher antibiotic knowledge scores.

Educational materials in UCCs are associated with increased antibiotic-related knowledge among patients when they are seen and recalled; however, most patients do not recall passively displayed materials. More emphasis should be placed on creating and drawing attention to memorable patient educational materials.

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.

In South Korea, all men at the age of 18 or older are required to serve at military for a certain period as an obligation. These recruits should be able to withstand psychological stress and pressures of rapid adaptation of the unique and new environment in military. The number of military recruits facing adaptation issues has been on the rise, necessitating an evaluation for active service. In our previous study (Park et al., in press 2023), we classified the military recruits with mental issues according to latent profile analysis (LPA) and examined the treatment response during six months.

In this study, we further examined clinical characteristics over the next six months.

Ninety-two participants were analyzed with LPA using MMPI-2 clinical profiles in the previous study. The three classes were identified: mild maladjustment (Class 1, n=14), neurotic depression and anxiety (Class 2, n=36), high vulnerability and hypervigilance (Class 3, n=42). At 12 months, Clinical Global Impression-Severity and Global Assessment of Functioning were assessed to test their long-term changes.

While Class 1 and 2 significantly improved over 6 months, Class 3 showed little or no improvement even with more medications in our previous study. During the 6-month follow-up period, 50% of Class 1, 38.9% of Class 2, and 41.5% of Class 3 were dropped. It was during this period that their level of military service was decided. Class 1 and 2 which showed marked improvement up to initial 6 months, did not demonstrate substantial further improvement during follow-up period with a considerable portion stopped visiting hospital. Subjects in Class 3, who showed little or no improvement during initial 6 months, demonstrated continued improvement in this study, although their symptoms still appeared relatively severe.

This study suggests clinical implications for treatment plan and intervention of each subgroup classified based on MMPI-2 clinical profiles of military recruits who might show maladjustment to serve. The long-term continuous treatment for Class 3 patients will be needed, even after exemption from active duty.

None Declared

To determine the prevalence of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) IgG nucleocapsid (N) antibodies among healthcare personnel (HCP) with no prior history of COVID-19 and to identify factors associated with seropositivity.

Prospective cohort study.

An academic, tertiary-care hospital in St. Louis, Missouri.

The study included 400 HCP aged ≥18 years who potentially worked with coronavirus disease 2019 (COVID-19) patients and had no known history of COVID-19; 309 of these HCP also completed a follow-up visit 70–160 days after enrollment. Enrollment visits took place between September and December 2020. Follow-up visits took place between December 2020 and April 2021.

At each study visit, participants underwent SARS-CoV-2 IgG N-antibody testing using the Abbott SARS-CoV-2 IgG assay and completed a survey providing information about demographics, job characteristics, comorbidities, symptoms, and potential SARS-CoV-2 exposures.

Participants were predominately women (64%) and white (79%), with median age of 34.5 years (interquartile range [IQR], 30–45). Among the 400 HCP, 18 (4.5%) were seropositive for IgG N-antibodies at enrollment. Also, 34 (11.0%) of 309 were seropositive at follow-up. HCP who reported having a household contact with COVID-19 had greater likelihood of seropositivity at both enrollment and at follow-up.

In this cohort of HCP during the first wave of the COVID-19 pandemic, ∼1 in 20 had serological evidence of prior, undocumented SARS-CoV-2 infection at enrollment. Having a household contact with COVID-19 was associated with seropositivity.

In South Korea, all men at the age of 18 or older are required to serve at military for a certain period as an obligation. These recruits should be able to withstand psychological stress and pressures of rapid adaptation of the unique and new environment in military.

The current study attempted to identify distinct subgroups of patients referred for military service suitability and further to investigate whether there is a difference in clinical features such as treatment responsiveness and prognosis among those subgroups.

Subjects were male patients aged 18 to 28 years who visited the department of psychiatry at the University Hospital for evaluating mental health problems related to military service. We conducted a latent profile analysis (LPA) using 10 clinical scales of MMPI-2 as an indicator variable to investigate the subgroups of subjects. The clinical state of subjects was assessed with CGI-S and GAF scale for three time point (0, 3, and 6 month).

The results showed that the best fitting model corresponded to a three-class model: each class was named ‘Class 1: mild maladjustment’, ‘Class 2: neurotic depression and anxiety’, and ‘Class 3: highly vulnerable and hypervigilant’ respectively. Subsequent analysis was also carried out to identify changes in clinical symptoms and functional level across treatment time of each subgroup identified in LPA. We demonstrated that the three subgroups displayed differential characteristics in treatment responsiveness and clinical course evaluated by CGI-S and GAF over a treatment period of 6 months. Three subgroups indicated significant differences in the number of medications prescribed as well. Class 3 had more antidepressants and anxiolytics on use than Class 1 and 2. Antipsychotic agents and a combination of three antidepressants were prescribed more frequently in Class 3 than in Class 1 and 2.

While Class 1 and 2 significantly improved over 6 months, Class 3 showed little or no improvement in our clinical parameters even with more medications. This study has a clinical significance that it has classified qualitatively different subgroups within the sample by conducting LPA with clinical profiles of MMPI-2 and provides a basis for comprehensively understanding their differentiated clinical features. This study suggests clinical implications for treatment plan and intervention of each subgroup classified based on MMPI-2 clinical profiles of military recruits who might show maladjustment to serve.

None Declared

Three-dimensional chromatin interactions regulate gene expressions. The significance of de novo mutations (DNMs) in chromatin interactions remains poorly understood for autism spectrum disorder (ASD).

To investigate the genomic architecture of ASD in terms of non-coding de novo mutations and 3-dimensional chromatin interactions

We generated 813 whole-genome sequences from 242 Korean simplex families to detect DNMs, and identified target genes which were putatively affected by non-coding DNMs in chromatin interactions.

Non-coding DNMs in chromatin interactions were significantly involved in transcriptional dysregulations related to ASD risk. Correspondingly, target genes showed spatiotemporal expressions relevant to ASD in developing brains and enrichment in biological pathways implicated in ASD, such as histone modification. Regarding clinical features of ASD, non-coding DNMs in chromatin interactions particularly contributed to low intelligence quotient levels in ASD probands. We further validated our findings using two replication cohorts, Simons Simplex Collection (SSC) and MSSNG, and showed the consistent enrichment of non-coding DNM-disrupted chromatin interactions in ASD probands. Generating human induced pluripotent stem cells in two ASD families, we were able to demonstrate that non-coding DNMs in chromatin interactions alter the expression of target genes at the stage of early neural development.

Taken together, our findings indicate that non-coding DNMs in ASD probands lead to early neurodevelopmental disruption implicated in ASD risk via chromatin interactions.

None Declared

Lamina-specific alterations of inhibitory circuitries have been considered the crucial pathogenesis of perceptual, cognitive and behavioral symptoms presented in schizophrenia and mood disorders. Especially, with emerging evidences indicating the close lamina-specific relationship between synaptic defects and γ-Aminobutyric acid (GABA)-related gene dysfunctions, it has been suggested the mRNA dysregulations of Tyrosine kinase B (TrkB) and Glutamate decarboxylase 67 (GAD67) could particularly be implicated in middle and deep layers of neocortex of patients with major psychiatric disorders.

Giving inquiries of whether defects of these mRNA levels in Orbitofrontal cortex (OFC) would be involved as lamina-specific patterns in individuals with schizophrenia and mood disorders.

We examined mRNA levels of BDNF, TrkB and GAD67 in each OFC layer I through VI. We analyzed data from postmortem brain tissue of the Stanley Neuropathology Consortium Integrative Database (SNCID). SNCID consists of 15 subjects in each of four groups (schizophrenia, bipolar disorder, major depression without psychotic features, and unaffected controls). All groups were matched for age, sex, race, brain pH and post-mortem interval.

We found TrkB mRNA levels to be significantly reduced in layer VI in both groups with schizophrenia (25.8%) and bipolar disorder (35.7%) compared with controls. GAD67 mRNA levels were also significantly reduced in layer III and IV in patients with schizophrenia (23.4% and 22.7%, respectively) and bipolar disorder (31.2% and 24.9%, respectively) compared with controls. Individuals with major depression showed only trends toward decreased mRNA levels of GAD67 in layer III and IV and of TrkB in layer VI compared with controls. TrkB mRNA levels in layer VI were significantly correlated with GAD67 mRNA levels in layer III (ρ=0.581, p=0.037) and IV (ρ=0.857, p<0.001) in subjects with bipolar disorder, but not in those with schizophrenia. When analyzed with partial correlation controlling the effects of pH and PMI, significance of correlation remained only between GAD67 mRNA in layer IV and TrkB mRNA in layer VI in individuals with bipolar disorder (ρ=0.768, p=0.006).

The resulting lamina-specific decreases in inhibitory tone across layers of OFC may contribute to the unrestrained irritability and violent behaviors in common shared by both patients with schizophrenia and bipolar disorder. Nonetheless, our findings indicate the obvious correlations between lamina-specifically altered TrkB and GAD67 mRNA levels in OFC might be a candidate for endophenotype of bipolar disorder.

None Declared

Obsessive-compulsive disorder (OCD) and schizophrenia are often reported as co-morbid conditions. However, the evidence of an association between OCD and the risk of schizophrenia is limited. This study investigated the risk of schizophrenia in patients newly diagnosed with OCD using a nationally representative sample cohort in South Korea.

Data were obtained from the 2002–2013 Korean National Health Insurance Service-National Sample Cohort of the National Health Insurance Service. Using propensity score matching, 2509 patients with OCD and a control group of 7527 patients were included in the analysis. Chi-squared tests were used to investigate and compare the general characteristics of the study population. The risk of schizophrenia was analysed using the Cox proportional hazard model.

The incidence rate was 45.79/10 000 person-year for patients with OCD and 4.19/10 000 person-year for patients without OCD. Patients with OCD had a higher risk of schizophrenia compared to the control group after adjusting for covariates (hazard ratio = 10.46, 95% confidence interval = 6.07–18.00).

This study identified an association between the diagnosis of OCD and the risk of schizophrenia in a South Korean national representative cohort. Further research using a prospective design to clarify the causality of OCD in schizophrenia in a controlled environment should be conducted to validate these findings.

Subthreshold/attenuated syndromes are established precursors of full-threshold mood and psychotic disorders. Less is known about the individual symptoms that may precede the development of subthreshold syndromes and associated social/functional outcomes among emerging adults.

We modeled two dynamic Bayesian networks (DBN) to investigate associations among self-rated phenomenology and personal/lifestyle factors (role impairment, low social support, and alcohol and substance use) across the 19Up and 25Up waves of the Brisbane Longitudinal Twin Study. We examined whether symptoms and personal/lifestyle factors at 19Up were associated with (a) themselves or different items at 25Up, and (b) onset of a depression-like, hypo-manic-like, or psychotic-like subthreshold syndrome (STS) at 25Up.

The first DBN identified 11 items that when endorsed at 19Up were more likely to be reendorsed at 25Up (e.g., hypersomnia, impaired concentration, impaired sleep quality) and seven items that when endorsed at 19Up were associated with different items being endorsed at 25Up (e.g., earlier fatigue and later role impairment; earlier anergia and later somatic pain). In the second DBN, no arcs met our a priori threshold for inclusion. In an exploratory model with no threshold, >20 items at 19Up were associated with progression to an STS at 25Up (with lower statistical confidence); the top five arcs were: feeling threatened by others and a later psychotic-like STS; increased activity and a later hypo-manic-like STS; and anergia, impaired sleep quality, and/or hypersomnia and a later depression-like STS.

These probabilistic models identify symptoms and personal/lifestyle factors that might prove useful targets for indicated preventative strategies.

Excited delirium, which has been defined as combativeness, agitation, and altered sensorium, requires immediate treatment in prehospital or emergency department (ED) settings for the safety of both patients and caregivers. Prehospital ketamine use is prevalent, although the evidence on safety and efficacy is limited. Many patients with excited delirium are intoxicated with illicit substances. This investigation explores whether patients treated with prehospital ketamine for excited delirium with concomitant substance intoxication have higher rates of subsequent intubation in the ED compared to those without confirmed substance usage.

Over 28 months at two large community hospitals, all medical records were retrospectively searched for all patients age 18 years or greater with prehospital ketamine intramuscular (IM) administration for excited delirium and identified illicit and prescription substance co-ingestions. Trained abstractors collected demographic characteristics, history of present illness (HPI), urine drug screens (UDS), alcohol levels, and noted additional sedative administrations. Substance intoxication was determined by UDS and alcohol positivity or negativity, as well as physician HPI. Patients without toxicological testing or documentation of substance intoxication, or who may have tested positive due to ED sedation, were excluded from relevant analyses. Subsequent ED intubation was the primary pre-specified outcome. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to compare variables.

Among 86 patients given prehospital ketamine IM for excited delirium, baseline characteristics including age, ketamine dose, and body mass index were similar between those who did or did not undergo intubation. Men had higher intubation rates. Patients testing positive for alcohol, amphetamines, barbiturates, benzodiazepines, ecstasy, marijuana, opiates, and synthetic cathinones, both bath salts and flakka, had similar rates of intubation compared to those negative for these substances. Of 27 patients with excited delirium and concomitant cocaine intoxication, nine (33%) were intubated compared with four of 50 (8%) without cocaine intoxication, yielding a 5.75 OR (95%, CI 1.57 to 21.05; P = .009).

Patients treated with ketamine IM for excited delirium with concomitant cocaine intoxication had a statistically significant 5.75-fold increased rate of subsequent intubation in the ED. Amongst other substances, no other trends with intubation were noted, but further study is warranted.