Palliative whole brain radiation therapy: an international state of practice.

BACKGROUND: Improvements in radiation delivery and systemic therapies have resulted in few remaining indications for palliative whole brain radiation therapy (WBRT). Most centers preferentially use stereotactic radiotherapy (SRT) and reserve WBRT for those with >15 lesions, leptomeningeal presentation, rapidly progressive disease, or limited estimated survival. Despite regional differences among preferred dose, fractionation, and treatment technique, we predict survival post-WBRT will remain poor-indicating appropriate application of WBRT in this era of SRT and improved systemic therapies. METHODS: A multi-center, international retrospective analysis of patients receiving WBRT in 2022 was performed. Primary end point was survival after WBRT. De-identified data were analyzed centrally. Patients receiving WBRT as part of a curative regimen, prophylactically, or as bridging therapy were excluded. The collected data consisted of patient parameters including prescription dose and fractionation, use of neurocognitive sparing techniques and survival after WBRT. Survival was calculated via the Kaplan-Meier method. RESULTS: Of 29,943 international RT prescriptions written at ten participating centers in 2022, 462 (1.5%) were for palliative WBRT. Participating centers were in the United States (n=138), the United Kingdom (n=111), Hong Kong (n=72), Italy (n=49), Belgium (n=45), Germany (n=27), Ghana (n=15), and Cyprus (n=5). Twenty-six different dose regimens were used. The most common prescriptions were for 3,000 cGy over 10 fractions (45.0%) and 2,000 cGy over 5 fractions (43.5%) with significant regional preferences (P<0.001). Prior SRT was delivered in 32 patients (6.7%), hippocampal avoidance (HA) was used in 44 patients (9.5%), and memantine was prescribed in 93 patients (20.1%). Survival ranged from 0 days to still surviving at 402 days post-treatment. The global median overall survival (OS) was 84 days after WBRT [95% confidence interval (CI): 68.0-104.0]. Actuarial survival at 7 days, 1 month, 3 months, and 6 months were 95%, 78%, 48%, and 32%, respectively. Twenty-seven patients (5.8%) were unable to complete their prescribed WBRT. CONCLUSIONS: This moment-in-time analysis confirms that patients with poor expected survival are being appropriately selected for WBRT-illustrating the dwindling indications for WBRT-and demonstrates the variance in global practice. Since poor survival precludes patients from deriving benefit, memantine and HA are best suited in carefully selected cases.

Commentary: School closures, the pandemic, and pediatric mental health: Scrutinizing the evidence.

The COVID-19 pandemic arrived with significant hardship. The secondary impacts of the pandemic and our response with respect to pediatric mental health has been a subject of significant discussion in the lay public, media, and decision-maker groups. The initiatives to control SARS-CoV-2 have become politicized. A narrative emerged early that strategies to mitigate the spread of the virus were harming children's mental health. Position statements from professional organizations in Canada have been used to support this claim. The aim of this commentary is to provide a reanalysis of some of the data and research methodology used to support these position statements. Some of the direct claims such as "online learning is harmful," should be supported by a strong evidence base with significant consensus that speaks directly to causality. We find that the quality of the studies and the heterogeneity of the results does not support the strength of the unequivocal claims made by these position statements. In a sample of the current literature examining the issue, we find that outcomes range from improvements to deteriorations. Earlier studies relying on cross-sectional surveys typically have shown stronger negative effects than longitudinal cohort studies, which often have also shown groups of children experiencing no changes to measured mental health characteristics or groups that have experienced improvements. We argue it is imperative that policymakers use the highest quality evidence in making the best decisions. We as professionals must avoid discussing only one side of heterogeneous evidence.

La pandémie de la COVID-19 est arrivée avec des difficultés importantes. Les effets secondaires de la pandémie et notre réponse à l'égard de la santé mentale pédiatrique ont constitué un sujet de discussion significatif dans le public profane, les médias et les groupes de décideurs. Les initiatives de contrôle du SRAS-CoV-2 sont devenues politisées. Une histoire a émergé tôt disant que les stratégies pour atténuer la propagation du virus nuisaient à la santé mentale des enfants. Des énoncés de position des organisations professionnelles du Canada ont été utilisés pour soutenir cette revendication. Le présent commentaire vise à offrir une ré-analyse de certaines données et méthodologies de recherche utilisées pour soutenir ces énoncés de position. Certaines revendications directes comme « l'apprentissage en ligne est nuisible ¼ devraient être appuyées par une forte base de données probantes et un consensus significatif qui s'adresse directement à la causalité. Nous croyons que la qualité des études et l'hétérogénéité des résultats ne soutiennent pas la force des revendications sans équivoque faites par ces énoncés de position. Dans un échantillon de la littérature actuelle qui examine la question, nous constatons que les résultats vont des améliorations aux détériorations. Des études précédentes s'appuyant sur des sondages transversaux ont typiquement montré des effets négatifs plus forts que les études de cohorte longitudinales, qui ont aussi souvent montré des groupes d'enfants qui ne connaissent aucun changement des caractéristiques mesurées de la santé mentale ou des groupes qui ont connu des améliorations. Nous défendons qu'il est impératif que les décideurs utilisent les données probantes de la plus grande qualité en prenant les meilleures décisions. Nous, comme professionnels, devons éviter de ne discuter que d'un côté des données probantes hétérogènes.

Evaluating the psychosocial status of BC children and youth during the COVID-19 pandemic: A MyHEARTSMAP cross-sectional study.

BACKGROUND: Understanding the psychosocial status of children and adolescents during the COVID-19 pandemic is vital to the appropriate and adequate allocation of social supports and mental health resources. This study evaluates the burden of mental health concerns and the impact of demographic factors while tracking mental health service recommendations to inform community service needs. METHODS: MyHEARTSMAP is a digital self-assessment mental health evaluation completed by children and their guardian throughout British Columbia between August 2020 to July 2021. Severity of mental health concerns was evaluated across psychiatric, social, functioning, and youth health domains. Proportional odds modelling evaluated the impact of demographic factors on severity. Recommendations for support services were provided based on the evaluation. RESULTS: We recruited 541 families who completed 424 psychosocial assessments on individual children. Some degree of difficulty across the psychiatric, social, or functional domains was reported for more than half of children and adolescents. Older youth and those not attending any formal school or education program were more likely to report greater psychiatric difficulty. Girls experienced greater social concerns, and children attending full-time school at-home were more likely to identify difficulty within the youth health domain but were not more likely to have psychiatric difficulties. Considerations to access community mental health service were triggered in the majority (74%) of cases. CONCLUSIONS: Psychosocial concerns are highly prevalent amongst children and adolescents during the COVID-19 pandemic. Based on identified needs of this cohort, additional community health supports are required, particularly for higher risk groups.

Differential age-associated brain atrophy and white matter changes among homeless and precariously housed individuals compared with the general population.

Background: Homeless or precariously housed individuals live with poor health and experience premature mortality compared with the general population, yet little is known about age-related brain changes among these individuals. We evaluated whether MRI measures of brain structure are differentially associated with age and selected risk factors among individuals who are homeless or precariously housed compared with a general population sample. Methods: We compared T1-weighted and diffusion tensor imaging measures of brain macrostructure and white matter microstructure in a well-characterised sample of 312 precariously housed participants with a publicly available dataset of 382 participants recruited from the general population. We used piecewise and multiple linear regression to examine differential associations between MRI measures and between the samples, and to explore associations with risk factors in the precariously housed sample. Results: Compared with the general population sample, older age in the precariously housed sample was associated with more whole-brain atrophy (ß=-0.20, p=0.0029), lower whole-brain fractional anisotropy (ß=-0.32, p<0.0001) and higher whole-brain mean diffusivity (ß=0.69, p<0.0001). Several MRI measures had non-linear associations with age, with further adverse changes after age 35-40 in the precariously housed sample. History of traumatic brain injury, stimulant dependence and heroin dependence was associated with more atrophy or alterations in white matter diffusivity in the precariously housed sample. Conclusions: Older age is associated with adverse MRI measures of brain structure among homeless and precariously housed individuals compared with the general population. Education, improvements in care provision and policy may help to reduce the health disparities experienced by these individuals.

Traumatic brain injury in precariously housed persons: Incidence and risks.

BACKGROUND: Homeless and precarious housed persons are particularly prone to traumatic brain injuries (TBIs), but existent incidence rates are hampered by poor case acquisition. We rigorously documented TBIs in precariously housed persons transitioning in and out of homelessness. METHODS: Between December 2016 and May 2018, 326 precariously housed participants enrolled in a longitudinal study in Vancouver, Canada were assessed monthly for TBI occurrences after education on sequelae. Over one participant-year, 2433 TBI screenings were acquired for 326 person-years and variables associated with odds of incident TBI were evaluated. FINDINGS: One hundred participants acquired 175 TBIs, yielding an observed incidence proportion of 30·7% and event proportion of 53·7%. Of the injured, 61% reported one TBI and 39% reported multiple injuries. Acute intoxication was present for more than half of the TBI events assessed. Additionally, 9·7% of TBI events occurred in the context of a drug overdose. Common injury mechanisms were falls (45·1%), assaults (25·1%), and hitting one's head on an object (13·1%). In this community-based but non-randomly recruited sample, exploratory analyses identified factors associated with odds of an incident TBI over one year of follow-up, including: schizophrenia disorders (odds ratio (OR) = 0·43, 95% confidence interval (CI) 0·19, 0·94), role functioning (OR = 0·69, 95% CI 0·52, 0·91), opioid dependence (OR = 2·17, 95% CI 1·27, 3·72) and those reporting past TBIs (OR = 1·99, 95% CI 1·13, 3·52). INTERPRETATION: Given the ubiquity of TBIs revealed in this precariously housed sample, we identify an underappreciated and urgent healthcare priority. Several factors modified the odds of incident TBI, which can facilitate investigations into targeted prevention efforts. FUNDING: Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, William and Ada Isabelle Steel Research Fund, Simon Fraser University Vice-President Research Undergraduate Student Research Award and Simon Fraser University Psychology Department Research Grant.

Dynamic networks of psychotic symptoms in adults living in precarious housing or homelessness.

BACKGROUND: People living in precarious housing or homelessness have higher than expected rates of psychotic disorders, persistent psychotic symptoms, and premature mortality. Psychotic symptoms can be modeled as a complex dynamic system, allowing assessment of roles for risk factors in symptom development, persistence, and contribution to premature mortality. METHOD: The severity of delusions, conceptual disorganization, hallucinations, suspiciousness, and unusual thought content was rated monthly over 5 years in a community sample of precariously housed/homeless adults (n = 375) in Vancouver, Canada. Multilevel vector auto-regression analysis was used to construct temporal, contemporaneous, and between-person symptom networks. Network measures were compared between participants with (n = 219) or without (n = 156) history of psychotic disorder using bootstrap and permutation analyses. Relationships between network connectivity and risk factors including homelessness, trauma, and substance dependence were estimated by multiple linear regression. The contribution of network measures to premature mortality was estimated by Cox proportional hazard models. RESULTS: Delusions and unusual thought content were central symptoms in the multilevel network. Each psychotic symptom was positively reinforcing over time, an effect most pronounced in participants with a history of psychotic disorder. Global connectivity was similar between those with and without such a history. Greater connectivity between symptoms was associated with methamphetamine dependence and past trauma exposure. Auto-regressive connectivity was associated with premature mortality in participants under age 55. CONCLUSIONS: Past and current experiences contribute to the severity and dynamic relationships between psychotic symptoms. Interrupting the self-perpetuating severity of psychotic symptoms in a vulnerable group of people could contribute to reducing premature mortality.

The Air that we Breathe: Neutral and volatile PFAS in Indoor Air.

Sources of exposure to per- and polyfluorinated alkyl substances (PFAS) include food, water, and given that humans spend typically 90% of our time indoors, air and dust. Quantifying PFAS prevalent indoors, such as neutral, volatile PFAS, and estimating their exposure risk to humans is thus important. To accurately measure these compounds indoors, polyethylene (PE) sheets were employed and validated as passive detection tools, and analyzed by gas chromatography-mass spectrometry. Air concentrations were compared to dust and carpet concentrations reported elsewhere. Partitioning between PE sheets of different thicknesses suggested that interactions of the PEs with the compounds are occurring by absorption. Volatile PFAS, specifically fluorotelomer alcohols (FTOHs), were ubiquitous in indoor environments. For example, in carpeted Californian kindergarten classrooms, 6:2 FTOH dominated with concentrations ranging from 9-600 ng m-3, followed by 8:2 FTOH. Concentrations of volatile PFAS from air, carpet and dust were closely related to each other, indicating that carpets and dust are major sources of FTOHs in air. Nonetheless, air posed the largest exposure risk of FTOHs and biotransformed perfluorinated alkyl acids (PFAA) in young children. This research highlights inhalation of indoor air as an important exposure pathway and the need for further reduction of precursors to PFAA.

Cerebral Small Vessel Disease, Risk Factors, and Cognition in Tenants of Precarious Housing.

BACKGROUND AND PURPOSE: We aim to describe the burden, characteristics, and cognitive associations of cerebral small vessel disease in a Canadian sample living with multimorbidity in precarious housing. METHODS: Participants received T1, T2-fluid-attenuated inversion recovery, and susceptibility-weighted imaging 3T magnetic resonance imaging sequences and comprehensive clinical, laboratory, and cognitive assessments. Cerebral small vessel disease burden was characterized using a modified Small Vessel Disease (mSVD) score. One point each was given for moderate-severe white matter hyperintensities, ≥1 cerebral microbleeds, and ≥1 lacune. Multivariable regression explored associations between mSVD score, risk factors, and cognitive performance. RESULTS: Median age of the 228 participants (77% male) was 44.7 years (range, 23.3-63.2). In n=188 participants with consistent good quality magnetic resonance imaging sequences, mSVD scores were 0 (n=127, 68%), 1 (n=50, 27%), and 2 (n=11, 6%). Overall, one-third had an mSVD ≥1 n=61 (32%); this proportion was unchanged when adding participants with missing sequences n=72/228 (32%). The most prevalent feature was white matter hyperintensities 53/218 (24%) then cerebral microbleed 16/191 (8%) and lacunes 16/228 (7%). Older age (odds ratio, 1.10 [95% CI, 1.05-1.15], P<0.001), higher diastolic blood pressure (odds ratio, 1.05 [95% CI, 1.01-1.09], P=0.008), and a history of injection drug use (odds ratio, 3.13 [95% CI, 1.07-9.16], P=0.037) had significant independent associations with a mSVD score of ≥1 in multivariable analysis. mSVD ≥1 was associated with lower performance on tests of verbal memory, sustained attention, and decision-making, contributing 4% to 5% of the variance in each cognitive domain. CONCLUSIONS: The 32% prevalence of cerebral small vessel disease in this young, socially marginalized cohort was higher than expected for age and was associated with poorer cognitive performance.

Amygdala Nuclei Volumes Are Selectively Associated With Social Network Size in Homeless and Precariously Housed Persons.

Objective: The amygdala is a brain region comprised of a group of functionally distinct nuclei that play a central role in social behavior. In homeless and precariously housed individuals, high rates of multimorbidity, and structural aspects of the environment may dysregulate social functioning. This study examined the neurobiological substrates of social connection in homeless and precariously housed persons by examining associations between amygdala nuclei volumes and social network size. Methods: Sixty participants (mean age 43.6 years; 73.3% male) were enrolled from an ongoing study of homeless and precariously housed adults in Vancouver, Canada. Social network size was assessed using the Arizona Social Support Interview Schedule. Amygdala nuclei volumes were extracted from anatomic T1-weighted MRI data. The central and basolateral amygdala nuclei were selected as they are implicated in anxiety-related and social behaviors. The hippocampus was included as a control brain region. Multivariable regression analysis investigated the relationship between amygdala nuclei volumes and social network size. Results: After controlling for age, sex, and total brain volume, individuals with the larger amygdala and central nucleus volumes had a larger network size. This association was not observed for the basolateral amygdala complex, though subsequent analysis found the basal and accessory basal nuclei of the basolateral amygdala were significantly associated with social network size. No association was found for the lateral amygdala nucleus or hippocampus. Conclusions: These findings suggest that select amygdala nuclei may be differentially involved in the social connections of persons with multimorbid illness and social marginalization.

Medial temporal lobe cortical changes in response to exercise interventions in people with early psychosis: A randomized controlled trial.

OBJECTIVE: Individuals with early psychosis may have prefrontal-limbic cortical deficits, which are associated with symptom severity and cognitive impairment. This study investigated the impact of an exercise intervention on fronto-temporal cortical plasticity in female participants with early psychosis. METHODS: In a cohort of 51 female participants with early psychosis from Hong Kong, we investigated the effects of a 12-week, moderate intensity aerobic or Hatha yoga exercise trial (yoga (N = 21), aerobic (N = 18) or waitlist group (N = 12)) on cortical grey matter. Clinical assessments and structural MRI were completed pre- and post- a 12-week exercise intervention. RESULTS: Increases in cortical volume and thickness were observed in the medial temporal cortical regions, primarily in fusiform cortical thickness (F(2, 48) = 4.221, p = 0.020, η2 = 0.150) and volume (F(2, 48) = 3.521, p = 0.037, η2 = 0.128) for participants with early psychosis in the aerobic arm, but not in the yoga and waitlist arms. Increased fusiform cortical thickness (ß = 0.402, p = 0.003) was associated with increased hippocampal volume for all psychosis participants. For the aerobic group only, increases in the entorhinal and fusiform temporal gyri were associated with reduced symptom severity. CONCLUSIONS: These findings suggest exercise-induced neuroplasticity in medial temporal cortical regions occurs with aerobic exercise. These changes may be associated with improvements in psychosis symptom severity. People with early psychosis may benefit from exercise interventions, particularly aerobic exercise, as an adjunct treatment to address clinical, physical health, and neuroanatomic concerns. NIH National Library of Medicine ClinicalTrials.gov Registration #: NCT01207219https://clinicaltrials.gov/ct2/show/NCT01207219.

Cognitive Impairment in Marginally Housed Youth: Prevalence and Risk Factors.

Objective: Homeless and marginally housed youth are particularly vulnerable members of society, and are known to experience numerous health problems, including psychiatric illness, substance use, and viral infection. Despite the presence of these risk factors for cognitive compromise, there is limited research on the cognitive functioning of homeless and marginally housed youth. The present study examines the degree and pattern of cognitive impairment and associations with key risk factors in a sample of marginally housed young adults. Method: Participants (N = 101) aged 20-29 years old were recruited from single-room occupancy hotels, and underwent cognitive, psychiatric, neurological, and serological assessments. Results: Forty percent of participants were identified as mildly cognitively impaired across multiple domains, and 16% were moderately-severely impaired. Deficits in memory and attention were most prevalent, while impairments in inhibitory control/processing speed and cognitive flexibility were also present but tended to be less severe. Developmental and historical factors (premorbid intellectual functioning, neurological soft signs, earlier exposure to and longer duration of homelessness or marginal housing), as well as current health risks (stimulant dependence and hepatitis C exposure), were associated with cognitive impairment. Conclusions: The strikingly high rate of cognitive impairment in marginally housed young adults represents a major public health concern and is likely to pose a significant barrier to treatment and rehabilitation. These results suggest that the pathway to cognitive impairment involves both developmental vulnerability and modifiable risk factors. This study highlights the need for early interventions that address cognitive impairment and risk factors in marginalized young people.

Clinical and functional characteristics of young adults living in single room occupancy housing: preliminary findings from a 10-year longitudinal study.

OBJECTIVE: Young adults living in single room occupancy (SRO) hotels, a form of low-income housing, are known to have complex health and substance problems compared to their peers in the general population. The objective of this study is to comprehensively describe the mental, physical, and social health profile of young adults living in SROs. METHODS: This study reports baseline data from young adults aged 18-29 years, as part of a prospective cohort study of adults living in SROs in Vancouver, British Columbia, Canada. Baseline and follow-up data were collected from 101 young adults (median follow-up period 1.9 years [IQR 1.0-3.1]). The comprehensive assessment included laboratory tests, neuroimaging, and clinician- and patient-reported measures of mental, physical, and social health and functioning. RESULTS: Three youth died during the preliminary follow-up period, translating into a higher than average mortality rate (18.6, 95% CI 6.0, 57.2) compared to age- and sex-matched Canadians. High prevalence of interactions with the health, social, and justice systems was reported. Participants were living with median two co-occurring illnesses, including mental, neurological, and infectious diseases. Greater number of multimorbid illnesses was associated with poorer real-world functioning (ρ = - 0.373, p < 0.001). All participants reported lifetime alcohol and cannabis use, with pervasive use of stimulants and opioids. CONCLUSION: This study reports high mortality rates, multimorbid illnesses, poor functioning, poverty, and ongoing unmet mental health needs among young adults living in SROs. Frequent interactions with the health, social, and justice systems suggest important points of intervention to improve health and functional trajectories of this vulnerable population.

Reduced cardiovascular fitness associated with exposure to clozapine in individuals with chronic schizophrenia.

Studies show that individuals with schizophrenia have impaired cardiovascular fitness (i.e., low peak aerobic power (VO2peak)). It is speculated that antipsychotics with adverse cardiovascular and metabolic profiles, in particular clozapine, have a significant impact on VO2peak. In this cross-sectional study, we examined whether exposure to clozapine was associated with further reduced VO2peak compared with non-clozapine antipsychotics. Thirty participants with chronic schizophrenia or schizoaffective disorder were divided into clozapine and non-clozapine groups. Mean daily doses of antipsychotics were standardized to chlorpromazine equivalents and haloperidol equivalents for antagonism of alpha1- and alpha2-adrenergic receptors. Participants completed an incremental-to-maximal symptom-limited exercise test on a cycle ergometer for the assessment of VO2peak. The clozapine group demonstrated significantly lower VO2peak than the non-clozapine group. Haloperidol equivalents for alpha-adrenergic receptor antagonism, but not chlorpromazine equivalents, demonstrated significant inverse associations with VO2peak. The clozapine group had a significantly higher amount of antagonistic activity at alpha-adrenergic receptors than the non-clozapine group. In conclusion, exposure to clozapine was associated with further reduced cardiovascular fitness, which may be explained by the drug's greater antagonistic activity at alpha-adrenergic receptors. Cardiovascular fitness needs to be promoted in individuals treated with antipsychotics, particularly clozapine, to prevent the risk of cardiovascular disease and mortality.

Heart-rate response to alpha2-adrenergic receptor antagonism by antipsychotics.

PURPOSE: To explore the relationship between antipsychotic-associated antagonism of alpha2-adrenergic receptors and resting heart rate in individuals with schizophrenia. METHODS: Thirty-one inpatients treated with antipsychotics were included in this exploratory analysis. Antipsychotic doses were converted to haloperidol equivalents for alpha2-adrenergic receptor antagonism. Resting heart rate was measured with the patient in the seated upright posture. RESULTS: After controlling for confounding variables, the relationship between alpha2-adrenergic receptor antagonism and resting heart rate demonstrated a positive linear effect (P = 0.002) as well as a nonlinear effect that accounted for an additional 14% of the variability in resting heart rate (P = 0.005). CONCLUSION: The observed inverted-U relationship between alpha2-adrenergic receptor antagonism and resting heart rate can possibly be attributed to an altered response of beta1-adrenergic receptors to increased norepinephrine release. Further investigations are required to confirm this exploratory finding, taking into account additional variables that include other receptors which either directly or indirectly influence heart rate. CLINICALTRIALS. GOV IDENTIFIER: NCT01392885.

Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice.

BACKGROUND: Amyloid plaques and neurofibrillary tangles (NFTs) are the defining pathological hallmarks of Alzheimer's disease (AD). Increasing the quantity of the O-linked N-acetylglucosamine (O-GlcNAc) post-translational modification of nuclear and cytoplasmic proteins slows neurodegeneration and blocks the formation of NFTs in a tauopathy mouse model. It remains unknown, however, if O-GlcNAc can influence the formation of amyloid plaques in the presence of tau pathology. RESULTS: We treated double transgenic TAPP mice, which express both mutant human tau and amyloid precursor protein (APP), with a highly selective orally bioavailable inhibitor of the enzyme responsible for removing O-GlcNAc (OGA) to increase O-GlcNAc in the brain. We find that increased O-GlcNAc levels block cognitive decline in the TAPP mice and this effect parallels decreased ß-amyloid peptide levels and decreased levels of amyloid plaques. CONCLUSIONS: This study indicates that increased O-GlcNAc can influence ß-amyloid pathology in the presence of tau pathology. The findings provide good support for OGA as a promising therapeutic target to alter disease progression in Alzheimer disease.