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.

To quantify the impact of patient- and unit-level risk adjustment on infant hospital-onset bacteremia (HOB) standardized infection ratio (SIR) ranking.

A retrospective, multicenter cohort study.

Infants admitted to 284 neonatal intensive care units (NICUs) in the United States between 2016 and 2021.

Expected HOB rates and SIRs were calculated using four adjustment strategies: birthweight (model 1), birthweight and postnatal age (model 2), birthweight and NICU complexity (model 3), and birthweight, postnatal age, and NICU complexity (model 4). Sites were ranked according to the unadjusted HOB rate, and these rankings were compared to rankings based on the four adjusted SIR models.

Compared to unadjusted HOB rate ranking (smallest to largest), the number and proportion of NICUs that left the fourth quartile (worst-performing) following adjustments were as follows: adjusted for birthweight (16, 22.5%), birthweight and postnatal age (19, 26.8%), birthweight and NICU complexity (22, 31.0%), birthweight, postnatal age and NICU complexity (23, 32.4%). Comparing NICUs that moved into the better-performing quartiles after birthweight adjustment to those that remained in the better-performing quartiles regardless of adjustment, the median percentage of low birthweight infants was 17.1% (Interquartile Range (IQR): 15.8, 19.2) vs 8.7% (IQR: 4.8, 12.6); and the median percentage of infants who died was 2.2% (IQR: 1.8, 3.1) vs 0.5% (IQR: 0.01, 12.0), respectively.

Adjusting for patient and unit-level complexity moved one-third of NICUs in the worst-performing quartile into a better-performing quartile. Risk adjustment may allow for a more accurate comparison across units with varying levels of patient acuity and complexity.

COVID-19 changed the epidemiology of community-acquired respiratory viruses. We explored patterns of respiratory viral testing to understand which tests are most clinically useful in the postpandemic era.

We conducted a retrospective observational study of discharge data from PINC-AI (formerly Premier), a large administrative database. Use of multiplex nucleic acid amplification respiratory panels in acute care, including small (2–5 targets), medium (6–11), and large panels (>11), were compared between the early pandemic (03/2020–10/2020), late pandemic (11/2020–4/2021), and prepandemic respiratory season (11/2019 - 02/2020) using ANOVA.

A median of 160.5 facilities contributed testing data per quarter (IQR 155.5–169.5). Prepandemic, facilities averaged 103 respiratory panels monthly (sd 138), including 79 large (sd 126), 7 medium (sd 31), and 16 small panels (sd 73). Relative to prepandemic, utilization decreased during the early pandemic (62 panels monthly/facility; sd 112) but returned to the prepandemic baseline by the late pandemic (107 panels monthly/facility; sd 211). Relative to prepandemic, late pandemic testing involved more small panel use (58 monthly/facility, sd 156) and less large panel use (47 monthly/facility, sd 116). Comparisons among periods demonstrated significant differences in overall testing (P < 0.0001), large panel use (P < 0.0001), and small panel use (P < 0.0001).

Postpandemic, clinical use of respiratory panel testing shifted from predominantly large panels to predominantly small panels. Factors driving this change may include resource availability, costs, and the clinical utility of targeting important pathogenic viruses instead of testing “for everything.”

Major depressive disorder (MDD) is a tremendous global disease burden and the leading cause of disability worldwide. Unfortunately, individuals diagnosed with MDD typically experience a delayed response to traditional antidepressants and many do not adequately respond to pharmacotherapy, even after multiple trials. The critical need for novel antidepressant treatments has led to a recent resurgence in the clinical application of psychedelics, and intravenous ketamine, which has been investigated as a rapid-acting treatment for treatment resistant depression (TRD) as well acute suicidal ideation and behavior. However, variations in the type and quality of experimental design as well as a range of treatment outcomes in clinical trials of ketamine make interpretation of this large body of literature challenging.

This umbrella review aims to advance our understanding of the effectiveness of intravenous ketamine as a pharmacotherapy for TRD by providing a systematic, quantitative, large-scale synthesis of the empirical literature.

We performed a comprehensive PubMed search for peer-reviewed meta-analyses of primary studies of intravenous ketamine used in the treatment of TRD. Meta-analysis and primary studies were then screened by two independent coding teams according to pre-established inclusion criteria as well as PRISMA and METRICS guidelines. We then employed metaumbrella, a statistical package developed in R, to perform effect size calculations and conversions as well as statistical tests.

In a large-scale analysis of 1,182 participants across 51 primary studies, repeated-dose administration of intravenous ketamine demonstrated statistically significant effects (p<0.05) compared to placebo-controlled as well as other experimental conditions in patients with TRD, as measured by standardized clinician-administered and self-report depression symptom severity scales.

This study provides large-scale, quantitative support for the effectiveness of intravenous, repeated-dose ketamine as a therapy for TRD and a report of the relative effectiveness of several treatment parameters across a large and rapidly growing literature. Future investigations should use similar analytic tools to examine evidence-stratified conditions and the comparative effectiveness of other routes of administration and treatment schedules as well as the moderating influence of other clinical and demographic variables on the effectiveness of ketamine on TRD and suicidal ideation and behavior.

None Declared

There has been rapidly growing interest in understanding the pharmaceutical and clinical properties of psychedelic and dissociative drugs, with a particular focus on ketamine. This compound, long known for its anesthetic and dissociative properties, has garnered attention due to its potential to rapidly alleviate symptoms of depression, especially in individuals with treatment-resistant depression (TRD) or acute suicidal ideation or behavior. However, while ketamine’s psychopharmacological effects are increasingly well-documented, the specific patterns of its neural impact remain a subject of exploration and basic questions remain about its effects on functional activation in both clinical and healthy populations.

This meta-analysis seeks to contribute to the evolving landscape of neuroscience research on dissociative drugs such as ketamine by comprehensively examining the effects of acute ketamine administration on neural activation, as measured by functional magnetic resonance imaging (fMRI), in healthy participants.

We conducted a meta-analysis of existing fMRI activation studies of ketamine using multilevel kernel density analysis (MKDA). Following a comprehensive PubMed search, we quantitatively synthesized all published primary fMRI whole-brain activation studies of the effects of ketamine in healthy subjects with no overlapping samples (N=18). This approach also incorporated ensemble thresholding (α=0.05-0.0001) to minimize cluster-size detection bias and Monte Carlo simulations to correct for multiple comparisons.

Our meta-analysis revealed statistically significant (p<0.05-0.0001; FWE-corrected) alterations in neural activation in multiple cortical and subcortical regions following the administration of ketamine to healthy participants (N=306).

These results offer valuable insights into the functional neuroanatomical effects caused by acute ketamine administration. These findings may also inform development of therapeutic applications of ketamine for various psychiatric and neurological conditions. Future studies should investigate the neural effects of ketamine administration, including both short-term and long-term effects, in clinical populations and their relation to clinical and functional improvements.

None Declared

Bipolar I disorder (BD-I) is a chronic and recurrent mood disorder characterized by alternating episodes of depression and mania; it is also associated with substantial morbidity and mortality and with clinically significant functional impairments. While previous studies have used functional magnetic resonance imaging (fMRI) to examine neural abnormalities associated with BD-I, they have yielded mixed findings, perhaps due to differences in sampling and experimental design, including highly variable mood states at the time of scan.

The purpose of this study is to advance our understanding of the neural basis of BD-I and mania, as measured by fMRI activation studies, and to inform the development of more effective brain-based diagnostic systems and clinical treatments.

We conducted a large-scale meta-analysis of whole-brain fMRI activation studies that compared participants with BD-I, assessed during a manic episode, to age-matched healthy controls. Following PRISMA guidelines, we conducted a comprehensive PubMed literature search using two independent coding teams to evaluate primary studies according to pre-established inclusion criteria. We then used multilevel kernel density analysis (MKDA), a well-established, voxel-wise, whole-brain, meta-analytic approach, to quantitatively synthesize all qualifying primary fMRI activation studies of mania. We used ensemble thresholding (p<0.05-0.0001) to minimize cluster size detection bias, and 10,000 Monte Carlo simulations to correct for multiple comparisons.

We found that participants with BD-I (N=2,042), during an active episode of mania and relative to age-matched healthy controls (N=1,764), exhibit a pattern of significantly (p<0.05-0.0001; FWE-corrected) different activation in multiple brain regions of the cerebral cortex and basal ganglia across a variety of experimental tasks.

This study supports the formulation of a robust neural basis for BD-I during manic episodes and advances our understanding of the pattern of abnormal activation in this disorder. These results may inform the development of novel brain-based clinical tools for bipolar disorder such as diagnostic biomarkers, non-invasive brain stimulation, and treatment-matching protocols. Future studies should compare the neural signatures of BD-I to other related disorders to facilitate the development of protocols for differential diagnosis and improve treatment outcomes in patients with BD-I.

None Declared

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent psychiatric condition that frequently originates in early development and is associated with a variety of functional impairments. Despite a large functional neuroimaging literature on ADHD, our understanding of the neural basis of this disorder remains limited, and existing primary studies on the topic include somewhat divergent results.

The present meta-analysis aims to advance our understanding of the neural basis of ADHD by identifying the most statistically robust patterns of abnormal neural activation throughout the whole-brain in individuals diagnosed with ADHD compared to age-matched healthy controls.

We conducted a meta-analysis of task-based functional magnetic resonance imaging (fMRI) activation studies of ADHD. This included, according to PRISMA guidelines, a comprehensive PubMed search and predetermined inclusion criteria as well as two independent coding teams who evaluated studies and included all task-based, whole-brain, fMRI activation studies that compared participants diagnosed with ADHD to age-matched healthy controls. We then performed multilevel kernel density analysis (MKDA) a well-established, whole-brain, voxelwise approach that quantitatively combines existing primary fMRI studies, with ensemble thresholding (p<0.05-0.0001) and multiple comparisons correction.

Participants diagnosed with ADHD (N=1,550), relative to age-matched healthy controls (N=1,340), exhibited statistically significant (p<0.05-0.0001; FWE-corrected) patterns of abnormal activation in multiple brains of the cerebral cortex and basal ganglia across a variety of cognitive control tasks.

This study advances our understanding of the neural basis of ADHD and may aid in the development of new brain-based clinical interventions as well as diagnostic tools and treatment matching protocols for patients with ADHD. Future studies should also investigate the similarities and differences in neural signatures between ADHD and other highly comorbid psychiatric disorders.

None Declared

High-quality evidence is lacking for the impact on healthcare utilisation of short-stay alternatives to psychiatric inpatient services for people experiencing acute and/or complex mental health crises (known in England as psychiatric decision units [PDUs]). We assessed the extent to which changes in psychiatric hospital and emergency department (ED) activity were explained by implementation of PDUs in England using a quasi-experimental approach.

We conducted an interrupted time series (ITS) analysis of weekly aggregated data pre- and post-PDU implementation in one rural and two urban sites using segmented regression, adjusting for temporal and seasonal trends. Primary outcomes were changes in the number of voluntary inpatient admissions to (acute) adult psychiatric wards and number of ED adult mental health-related attendances in the 24 months post-PDU implementation compared to that in the 24 months pre-PDU implementation.

The two PDUs (one urban and one rural) with longer (average) stays and high staff-to-patient ratios observed post-PDU decreases in the pattern of weekly voluntary psychiatric admissions relative to pre-PDU trend (Rural: −0.45%/week, 95% confidence interval [CI] = −0.78%, −0.12%; Urban: −0.49%/week, 95% CI = −0.73%, −0.25%); PDU implementation in each was associated with an estimated 35–38% reduction in total voluntary admissions in the post-PDU period. The (urban) PDU with the highest throughput, lowest staff-to-patient ratio and shortest average stay observed a 20% (−20.4%, CI = −29.7%, −10.0%) level reduction in mental health-related ED attendances post-PDU, although there was little impact on long-term trend. Pooled analyses across sites indicated a significant reduction in the number of voluntary admissions following PDU implementation (−16.6%, 95% CI = −23.9%, −8.5%) but no significant (long-term) trend change (−0.20%/week, 95% CI = −0.74%, 0.34%) and no short- (−2.8%, 95% CI = −19.3%, 17.0%) or long-term (0.08%/week, 95% CI = −0.13, 0.28%) effects on mental health-related ED attendances. Findings were largely unchanged in secondary (ITS) analyses that considered the introduction of other service initiatives in the study period.

The introduction of PDUs was associated with an immediate reduction of voluntary psychiatric inpatient admissions. The extent to which PDUs change long-term trends of voluntary psychiatric admissions or impact on psychiatric presentations at ED may be linked to their configuration. PDUs with a large capacity, short length of stay and low staff-to-patient ratio can positively impact ED mental health presentations, while PDUs with longer length of stay and higher staff-to-patient ratios have potential to reduce voluntary psychiatric admissions over an extended period. Taken as a whole, our analyses suggest that when establishing a PDU, consideration of the primary crisis-care need that underlies the creation of the unit is key.

Transient acquisition of methicillin-resistant Staphylococcus aureus (MRSA) on healthcare personnel (HCP) gloves and gowns following patient care has been examined. However, the potential for transmission to the subsequent patient has not been studied. We explored the frequency of MRSA transmission from patient to HCP, and then in separate encounters from contaminated HCP gloves and gowns to a subsequent simulated patient as well as the factors associated with these 2 transmission pathways.

We conducted a prospective cohort study with 2 parts. In objective 1, we studied MRSA transmission from random MRSA-positive patients to HCP gloves and gowns after specific routine patient care activities. In objective 2, we simulated subsequent transmission from random HCP gloves and gowns without hand hygiene to the next patient using a manikin proxy.

For the first objective, among 98 MRSA-positive patients with 333 randomly selected individual patient–HCP interactions, HCP gloves or gowns were contaminated in 54 interactions (16.2%). In a multivariable analysis, performing endotracheal tube care had the greatest odds of glove or gown contamination (OR, 4.06; 95% CI, 1.3–12.6 relative to physical examination). For the second objective, after 147 simulated HCP–patient interactions, the subsequent transmission of MRSA to the manikin proxy occurred 15 times (10.2%).

After caring for a patient with MRSA, contamination of HCP gloves and gown and transmission to subsequent patients following HCP-patient interactions occurs frequently if contact precautions are not used. Proper infection control practices, including the use of gloves and gown, can prevent this potential subsequent transmission.