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Isotopes of strontium, oxygen, and carbon were analyzed in human tooth enamel from two Postclassic sites in the central Peten lakes region, Guatemala, to examine patterns of mobility and diet during a time of social unrest. Excavations at both sites, Ixlu and Zacpeten, have revealed evidence for purposeful dismemberment and interment of individuals. This study examines a possible shrine surrounded by rows of skulls at Ixlu, and a mass grave of comingled individuals interred at Zacpeten. The interments coincide with a period of conflict and warfare between two dominant polities, Itza and Kowoj. The 14 sampled individuals at Ixlu were young males, six of whom isotopically match the Maya Mountains of central Belize/southeastern Peten. At Zacpeten, isotopic signatures of adults and children (n = 68) suggested that many were either local or came from other parts of the Maya lowlands, but not the Maya Mountains. In the Late Postclassic, the Zacpeten individuals were exhumed, defiled, and deposited in a mass grave, probably by Kowojs. Although temporally and geographically related, the Ixlu and Zacpeten burials represent two distinct cases of ritual violence that reflect the tumultuous political landscape of the Postclassic period.
Patients with posttraumatic stress disorder (PTSD) exhibit smaller regional brain volumes in commonly reported regions including the amygdala and hippocampus, regions associated with fear and memory processing. In the current study, we have conducted a voxel-based morphometry (VBM) meta-analysis using whole-brain statistical maps with neuroimaging data from the ENIGMA-PGC PTSD working group.
Methods
T1-weighted structural neuroimaging scans from 36 cohorts (PTSD n = 1309; controls n = 2198) were processed using a standardized VBM pipeline (ENIGMA-VBM tool). We meta-analyzed the resulting statistical maps for voxel-wise differences in gray matter (GM) and white matter (WM) volumes between PTSD patients and controls, performed subgroup analyses considering the trauma exposure of the controls, and examined associations between regional brain volumes and clinical variables including PTSD (CAPS-4/5, PCL-5) and depression severity (BDI-II, PHQ-9).
Results
PTSD patients exhibited smaller GM volumes across the frontal and temporal lobes, and cerebellum, with the most significant effect in the left cerebellum (Hedges’ g = 0.22, pcorrected = .001), and smaller cerebellar WM volume (peak Hedges’ g = 0.14, pcorrected = .008). We observed similar regional differences when comparing patients to trauma-exposed controls, suggesting these structural abnormalities may be specific to PTSD. Regression analyses revealed PTSD severity was negatively associated with GM volumes within the cerebellum (pcorrected = .003), while depression severity was negatively associated with GM volumes within the cerebellum and superior frontal gyrus in patients (pcorrected = .001).
Conclusions
PTSD patients exhibited widespread, regional differences in brain volumes where greater regional deficits appeared to reflect more severe symptoms. Our findings add to the growing literature implicating the cerebellum in PTSD psychopathology.
On October 3–4, 2023 and September 30–October 1, 2024, the Memorial Sloan Kettering Cancer Center Department of Psychiatry and Behavioral Sciences and Supportive Care Service hosted the 4th and 5th Annual U.S. Celebration of World Hospice and Palliative Care Day (WHPCD) conferences, respectively. This article describes both events and lessons learned in anticipation of the 6th annual conference to be held October 6–7, 2025.
Methods
The 4th and 5th annual events, conference planning team reflection, and attendee evaluation responses are summarized.
Results
Since 2020, the conference has attracted attendees from around the world. Two primary aims continue to guide the event: community building and wisdom sharing at the intersection of art and science. Both the 2023 and 2024 events consisted of 13 unique interactive sessions addressing diverse hospice and palliative care topics delivered by interprofessional experts in palliative care (43 faculty in 2023 and 54 in 2024). Multidisciplinary registrants more than doubled from 764 in 43 countries (2023) to 1678 in 87 countries (2024). Complimentary registration for colleagues in low- and middle-income countries (LMIC), students and trainees, and individuals experiencing financial hardship remains a cornerstone of inclusion and equitable access to the event.
Significance of results
The U.S. WHPCD Conference provides a virtual platform to disseminate high-quality science, honor both clinician and patient and caregiver experiences, and celebrate hospice and palliative care delivery during substantial local and global change across practice and policy domains. We remain committed to ensuring an internationally relevant, culturally diverse, and multidisciplinary and interprofessional agenda that will draw increased participation worldwide during future annual events.
Posttraumatic stress disorder (PTSD) has been associated with advanced epigenetic age cross-sectionally, but the association between these variables over time is unclear. This study conducted meta-analyses to test whether new-onset PTSD diagnosis and changes in PTSD symptom severity over time were associated with changes in two metrics of epigenetic aging over two time points.
Methods
We conducted meta-analyses of the association between change in PTSD diagnosis and symptom severity and change in epigenetic age acceleration/deceleration (age-adjusted DNA methylation age residuals as per the Horvath and GrimAge metrics) using data from 7 military and civilian cohorts participating in the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (total N = 1,367).
Results
Meta-analysis revealed that the interaction between Time 1 (T1) Horvath age residuals and new-onset PTSD over time was significantly associated with Horvath age residuals at T2 (meta β = 0.16, meta p = 0.02, p-adj = 0.03). The interaction between T1 Horvath age residuals and changes in PTSD symptom severity over time was significantly related to Horvath age residuals at T2 (meta β = 0.24, meta p = 0.05). No associations were observed for GrimAge residuals.
Conclusions
Results indicated that individuals who developed new-onset PTSD or showed increased PTSD symptom severity over time evidenced greater epigenetic age acceleration at follow-up than would be expected based on baseline age acceleration. This suggests that PTSD may accelerate biological aging over time and highlights the need for intervention studies to determine if PTSD treatment has a beneficial effect on the aging methylome.
Recent increases in homophobic and transphobic harassment, hate crimes, anti-lesbian, gay, bisexual, transgender, gender nonconforming, and queer (LGBTQ+) legislation, and discrimination in healthcare toward LGBTQ+ persons require urgent attention.
This study describes seriously ill LGBTQ+ patients’ and partners’ experiences of discriminatory care delivered by healthcare providers.
Methods
Qualitative data from a mixed-methods study using an online survey were analyzed using a grounded theory approach. Seriously ill LGBTQ+ persons, their spouses/partners and widows were recruited from a wide range of organizations serving the LGBTQ+ community. Respondents were asked to describe instances where they felt they received poor care from a healthcare provider because they were LGBTQ+.
Results
Six main themes emerged: (1) disrespectful care; (2) inadequate care; (3) abusive care; (4) discriminatory care toward persons who identify as transgender; (5) discriminatory behaviors toward partners; and (6) intersectional discrimination. The findings provide evidence that some LGBTQ+ patients receive poor care at a vulnerable time in their lives. Transgender patients experience unique forms of discrimination that disregard or belittle their identity.
Significance of Results
Professional associations, accrediting bodies, and healthcare organizations should set standards for nondiscriminatory, respectful, competent, safe and affirming care for LGBTQ+ patients. Healthcare organizations should implement mechanisms for identifying problems and ensuring nondiscrimination in services and employment; safety for patients and staff; strategies for outreach and marketing to the LGBTQ+ community, and ongoing staff training to ensure high quality care for LGBTQ+ patients, partners, families, and friends. Policy actions are needed to combat discrimination and disparities in healthcare, including passage of the Equality Act by Congress.
The Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH) trial demonstrated that minimally invasive surgery to treat spontaneous lobar intracerebral hemorrhage (ICH) improved functional outcomes. We aimed to explore current management trends for spontaneous lobar ICH in Canada to assess practice patterns and determine whether further randomized controlled trials are needed to clarify the role of surgical intervention.
Methods:
Neurologists, neurosurgeons, physiatrists and trainees in these specialties were invited to complete a 16-question survey exploring three areas: (1) current management for spontaneous lobar ICH at their institution, (2) perceived influence of ENRICH on their practice and (3) perceived need for additional clinical trial data. Standard descriptive statistics were used to report categorical variables. The χ2 test was used to compare responses across specialties and career stages.
Results:
The survey was sent to 433 physicians, and 101 (23.3%) responded. Sixty-eight percent of participants reported that prior to publication of the ENRICH trial, spontaneous lobar ICH was primarily managed conservatively, with surgery reserved for life-threatening situations. Forty-three percent of participants did not foresee a significant increase in surgical intervention at their institution. Of neurosurgical respondents, 33% remained hesitant to offer surgical intervention beyond lifesaving operations. Only 5% reported routinely using specifically designed technologies to evacuate ICH. Seventy percent reported that another randomized controlled trial comparing nonsurgical to surgical management for spontaneous lobar ICH is needed.
Conclusions:
There is significant practice variability in the management of spontaneous lobar ICH across Canadian institutions, stressing the need for additional clinical trial data to determine the role of surgical intervention.
The recommended first-line treatment for insomnia is cognitive behavioral therapy for insomnia (CBTi), but access is limited. Telehealth- or internet-delivered CBTi are alternative ways to increase access. To date, these intervention modalities have never been compared within a single study. Further, few studies have examined (a) predictors of response to the different modalities, (b) whether successfully treating insomnia can result in improvement of health-related biomarkers, and (c) mechanisms of change in CBTi. This protocol was designed to compare the three CBTi modalities to each other and a waitlist control for adults aged 50–65 years (N = 100). Participants are randomly assigned to one of four study arms: in-person- (n = 30), telehealth- (n = 30) internet-delivered (n = 30) CBTi, or 12-week waitlist control (n = 10). Outcomes include self-reported insomnia symptom severity, polysomnography, circadian rhythms of activity and core body temperature, blood- and sweat-based biomarkers, cognitive functioning and magnetic resonance imaging.
Cancer is associated with physical, social, spiritual, and psychological changes in patients and their caregivers. However, in sub-Saharan Africa, there is lack of evidence on the impact of gender, social norms, and relationship dynamics in the face of terminal illness. The aim of this paper is to explore how gender identity, social norms, and power relations are impacted when a person is living in Uganda with advanced cancer.
Methods
Focus groups with adult men and women living with advanced cancer in Uganda were conducted. Interviews explored the social effects of cancer and common challenges, including how both disease and treatment affect the patient and marital relationships within their families. Participants’ recommendations were sought to improve the social well-being of patients and their families. Data were analyzed using inductive thematic analysis.
Results
Men and women experienced negative changes in their roles and identities, often feeling unable to fulfill their marital duties in terms of intimacy, their social roles and responsibilities based on societal expectations. Men expressed loss of a “masculine” identity when unable to provide economically for the household. This led to tension in the familial power dynamics, contributing to relationship breakdown and gender-based violence (GBV) against spouses. Women noted challenges with parenting, relationship breakdowns, and increased GBV.
Significance of results
Gender impacts the patient and the family dynamic throughout the life course, including during advanced cancer. Patients and caregivers experience a change in their roles and identities while coping with existential distress and end-of-life tasks. Given these results, gender considerations and dynamics should be incorporated into overall palliative care provision. In addition, there is a need to integrate GBV screening and support in cancer services to address social health and safety needs in the context of serious illness.
We present a re-discovery of G278.94+1.35a as possibly one of the largest known Galactic supernova remnants (SNRs) – that we name Diprotodon. While previously established as a Galactic SNR, Diprotodon is visible in our new Evolutionary Map of the Universe (EMU) and GaLactic and Extragalactic All-sky MWA (GLEAM) radio continuum images at an angular size of $3{{{{.\!^\circ}}}}33\times3{{{{.\!^\circ}}}}23$, much larger than previously measured. At the previously suggested distance of 2.7 kpc, this implies a diameter of 157$\times$152 pc. This size would qualify Diprotodon as the largest known SNR and pushes our estimates of SNR sizes to the upper limits. We investigate the environment in which the SNR is located and examine various scenarios that might explain such a large and relatively bright SNR appearance. We find that Diprotodon is most likely at a much closer distance of $\sim$1 kpc, implying its diameter is 58$\times$56 pc and it is in the radiative evolutionary phase. We also present a new Fermi-LAT data analysis that confirms the angular extent of the SNR in gamma rays. The origin of the high-energy emission remains somewhat puzzling, and the scenarios we explore reveal new puzzles, given this unexpected and unique observation of a seemingly evolved SNR having a hard GeV spectrum with no breaks. We explore both leptonic and hadronic scenarios, as well as the possibility that the high-energy emission arises from the leftover particle population of a historic pulsar wind nebula.
The authors report on ancient DNA data from two human skeletons buried within the chancel of the 1608–1616 church at the North American colonial settlement of Jamestown, Virginia. Available archaeological, osteological and documentary evidence suggest that these individuals are Sir Ferdinando Wenman and Captain William West, kinsmen of the colony's first Governor, Thomas West, Third Baron De La Warr. Genomic analyses of the skeletons identify unexpected maternal relatedness as both carried the mitochondrial haplogroup H10e. In this unusual case, aDNA prompted further historical research that led to the discovery of illegitimacy in the West family, an aspect of identity omitted, likely intentionally, from genealogical records.
The Tulameen coal field is part of an Eocene nonmarine basin which received extensive volcaniclastic sediments due to its location within an active magmatic arc. Bentonite partings in the coal originally consisted of glassy rhyolitic tephra with phenocrysts of sanidine, biotite, and quartz. During the initial alteration, which took place within the swamp or shortly after burial, glass was transformed to either smectite-cristobalite-clinoptilolite or to smectite-kaolinite. The formation of kaolinite depended on the degree of leaching of silica and alkalies in the swamp environment. Some beds are nearly 100% kaolinite and can be designated as tonsteins. The smectite shows no evidence of interlayering; the kaolinite is well ordered. During alteration, sodium, originally a component of the glass, was lost from the system.
A later thermal event, which affected only the southern part of the basin, metamorphosed the smectite to a regularly interstratified illite/smectite with 55% illite layers and rectorite-type superlattice (IS-type). The source of potassium was dissolution of sanidine. Vitrinite reflectance measurements of the coal suggest that the smectite was stable to 145–160°C, at which temperature it transformed to K-rectorite.
The absence of randomly interstratified intermediates, even in beds rich in potassium, suggests that the transformation of smectite to K-rectorite was controlled by a steep thermal gradient possibly resulting from local magmatism or circulating geothermal fluids.
Magnetic reconnection is an important process in astrophysical environments, as it reconfigures magnetic field topology and converts magnetic energy into thermal and kinetic energy. In extreme astrophysical systems, such as black hole coronae and pulsar magnetospheres, radiative cooling modifies the energy partition by radiating away internal energy, which can lead to the radiative collapse of the reconnection layer. In this paper, we perform two- and three-dimensional simulations to model the MARZ (Magnetic Reconnection on Z) experiments, which are designed to access cooling rates in the laboratory necessary to investigate reconnection in a previously unexplored radiatively cooled regime. These simulations are performed in GORGON, an Eulerian two-temperature resistive magnetohydrodynamic code, which models the experimental geometry comprising two exploding wire arrays driven by 20 MA of current on the Z machine (Sandia National Laboratories). Radiative losses are implemented using non-local thermodynamic equilibrium tables computed using the atomic code Spk, and we probe the effects of radiation transport by implementing both a local radiation loss model and $P_{1/3}$ multi-group radiation transport. The load produces highly collisional, super-Alfvénic (Alfvén Mach number $M_A \approx 1.5$), supersonic (Sonic Mach number $M_S \approx 4-5$) strongly driven plasma flows which generate an elongated reconnection layer (Aspect Ratio $L/\delta \approx 100$, Lundquist number $S_L \approx 400$). The reconnection layer undergoes radiative collapse when the radiative losses exceed the rates of ohmic and compressional heating (cooling rate/hydrodynamic transit rate = $\tau _{\text {cool}}^{-1}/\tau _{H}^{-1}\approx 100$); this generates a cold strongly compressed current sheet, leading to an accelerated reconnection rate, consistent with theoretical predictions. Finally, the current sheet is also unstable to the plasmoid instability, but the magnetic islands are extinguished by strong radiative cooling before ejection from the layer.
We report the discovery of a bow-shock pulsar wind nebula (PWN), named Potoroo, and the detection of a young pulsar J1638$-$4713 that powers the nebula. We present a radio continuum study of the PWN based on 20-cm observations obtained from the Australian Square Kilometre Array Pathfinder (ASKAP) and MeerKAT. PSR J1638$-$4713 was identified using Parkes radio telescope observations at frequencies above 3 GHz. The pulsar has the second-highest dispersion measure of all known radio pulsars (1 553 pc cm$^{-3}$), a spin period of 65.74 ms and a spin-down luminosity of $\dot{E}=6.1\times10^{36}$ erg s$^{-1}$. The PWN has a cometary morphology and one of the greatest projected lengths among all the observed pulsar radio tails, measuring over 21 pc for an assumed distance of 10 kpc. The remarkably long tail and atypically steep radio spectral index are attributed to the interplay of a supernova reverse shock and the PWN. The originating supernova remnant is not known so far. We estimated the pulsar kick velocity to be in the range of 1 000–2 000 km s$^{-1}$ for ages between 23 and 10 kyr. The X-ray counterpart found in Chandra data, CXOU J163802.6$-$471358, shows the same tail morphology as the radio source but is shorter by a factor of 10. The peak of the X-ray emission is offset from the peak of the radio total intensity (Stokes $\rm I$) emission by approximately 4.7$^{\prime\prime}$, but coincides well with circularly polarised (Stokes $\rm V$) emission. No infrared counterpart was found.
Deployment of law enforcement operational canines (OpK9s) risks injuries to the animals. This study’s aim was to assess the current status of states’ OpK9 (veterinary Emergency Medical Services [VEMS]) laws and care protocols within the United States.
Methods:
Cross-sectional standardized review of state laws/regulations and OpK9 VEMS treatment protocols was undertaken. For each state and for the District of Columbia (DC), the presence of OpK9 legislation and/or care protocols was ascertained. Information was obtained through governmental records and from stakeholders (eg, state EMS medical directors and state veterinary boards).
The main endpoints were proportions of states with OpK9 laws and/or treatment protocols. Proportions are reported with 95% confidence intervals (CIs). Fisher’s exact test (P <.05) assessed whether presence of an OpK9 law in a given jurisdiction was associated with presence of an OpK9 care protocol, and whether there was geographic variation (based on United States Census Bureau regions) in presence of OpK9 laws or protocols.
Results:
Of 51 jurisdictions, 20 (39.2%) had OpK9 legislation and 23 (45.1%) had state-wide protocols for EMS treatment of OpK9s. There was no association (P = .991) between presence of legislation and presence of protocols. There was no association (P = .144) between presence of legislation and region: Northeast 66.7% (95% CI, 29.9-92.5%), Midwest 50.0% (95% CI, 21.1-78.9%), South 29.4% (95% CI, 10.3-56.0%), and West 23.1% (95% CI, 5.0-53.8%). There was significant (P = .001) regional variation in presence of state-wide OpK9 treatment protocols: Northeast 100.0% (95% CI, 66.4-100.0%), Midwest 16.7% (95% CI, 2.1-48.4%), South 47.1% (95% CI, 23.0-72.2%), and West 30.8% (95% CI, 9.1-61.4%).
Conclusion:
There is substantial disparity with regard to presence of OpK9 legal and/or clinical guidance. National collaborative guidelines development is advisable to optimize and standardize care of OpK9s. Additional attention should be paid to educational and training programs to best utilize the limited available training budgets.
Children with CHD or born very preterm are at risk for brain dysmaturation and poor neurodevelopmental outcomes. Yet, studies have primarily investigated neurodevelopmental outcomes of these groups separately.
Objective:
To compare neurodevelopmental outcomes and parent behaviour ratings of children born term with CHD to children born very preterm.
Methods:
A clinical research sample of 181 children (CHD [n = 81]; very preterm [≤32 weeks; n = 100]) was assessed at 18 months.
Results:
Children with CHD and born very preterm did not differ on Bayley-III cognitive, language, or motor composite scores, or on expressive or receptive language, or on fine motor scaled scores. Children with CHD had lower ross motor scaled scores compared to children born very preterm (p = 0.047). More children with CHD had impaired scores (<70 SS) on language composite (17%), expressive language (16%), and gross motor (14%) indices compared to children born very preterm (6%; 7%; 3%; ps < 0.05). No group differences were found on behaviours rated by parents on the Child Behaviour Checklist (1.5–5 years) or the proportion of children with scores above the clinical cutoff. English as a first language was associated with higher cognitive (p = 0.004) and language composite scores (p < 0.001). Lower median household income and English as a second language were associated with higher total behaviour problems (ps < 0.05).
Conclusions:
Children with CHD were more likely to display language and motor impairment compared to children born very preterm at 18 months. Outcomes were associated with language spoken in the home and household income.
The worldwide emergence of infectious diseases, together with the increasing incidence of antibiotic-resistant bacteria, elevate the need to properly detect, prevent, and effectively treat these infections. The overuse and misuse of common antibiotics in recent decades stimulates the need to identify new inhibitory agents. Therefore, natural products like clays, that display antibacterial properties, are of particular interest.
The absorptive properties of clay minerals are well documented for healing skin and gastrointestinal ailments. However, the antibacterial properties of clays have received less scientific attention. French green clays have recently been shown to heal Buruli ulcer, a necrotic or ‘flesh-eating’ infection caused by Mycobacterium ulcerans. Assessing the antibacterial properties of these clays could provide an inexpensive treatment for Buruli ulcer and other skin infections.
Antimicrobial testing of the two clays on a broad-spectrum of bacterial pathogens showed that one clay promotes bacterial growth (possibly provoking a response from the natural immune system), while another kills bacteria or significantly inhibits bacterial growth. This paper compares the mineralogy and chemical composition of the two French green clays used in the treatment of Buruli ulcer.
Mineralogically, the two clays are dominated by 1Md illite and Fe-smectite. Comparing the chemistry of the clay minerals and exchangeable ions, we conclude that the chemistry of the clay, and the surface properties that affect pH and oxidation state, control the chemistry of the water used to moisten the clay poultices and contribute the critical antibacterial agent(s) that ultimately debilitate the bacteria.
Radiotherapy for pediatric brain tumor has been associated with late cognitive effects. Compared to conventional photon radiotherapy (XRT), proton radiotherapy (PRT) delivers less radiation to healthy brain tissue. PRT has been associated with improved long term cognitive outcomes compared to XRT. However, there is limited research comparing the effects of XRT and PRT on verbal memory outcomes.
Participants and Methods:
Survivors of pediatric brain tumor treated with either XRT (n = 29) or PRT (n = 51) completed neuropsychological testing > 1 year following radiotherapy. XRT and PRT groups were similar with respect to sex, handedness, race, age at diagnosis, age at evaluation, tumor characteristics, and treatment history (i.e., craniospinal irradiation, craniotomy, shunting, chemotherapy, radiation dose). Verbal learning and memory were assessed using the age-appropriate version of the California Verbal Learning Test (CVLT-II/CVLT-C). Measures of intellectual functioning, executive functioning, attention and adaptive behavior were also collected. Performance on neuropsychological measures was compared between treatment groups (XRT vs. PRT) using analysis of covariance (ANCOVA). On the CVLT, each participant was classified as having an encoding deficit profile (i.e., impaired learning, recall, and recognition), retrieval deficit profile (i.e., impaired recall but intact recognition), intact profile, or other profile. Chi-squared tests of independence were used to compare the probability of each memory profile between treatment groups. Pearson correlation was used to examine associations between memory performance and strategy use, intellectual functioning, adaptive behavior, attention, and executive functioning.
Results:
Overall, patients receiving PRT demonstrated superior verbal learning (CVLT Trials 1-5; t(76) = 2.61, p = .011), recall (CVLT Long Delay Free; t(76) = 3.57, p = .001) and strategy use (CVLT Semantic Clustering; t(76) = 2.29, p = .025) compared to those treated with XRT. Intact performance was more likely in the PRT group than the XRT group (71% PRT, 38% XRT; X2 = 8.14, p = .004). Encoding and retrieval deficits were both more common in the XRT group, with encoding problems being most prevalent (Encoding Deficits: 31% XRT, 12% PRT, X2 = 4.51, p = .034; Retrieval Deficits: 17% XRT, 4% PRT, X2 = 4.11, p = .043). Across all participants, semantic clustering predicted better encoding (r = .28, p = .011) and retrieval (r = .26, p = .022). Better encoding predicted higher intellectual (r = .56, p < .001) and adaptive functioning (r = .30, p = .011), and fewer parent-reported concerns about day-today attention (r = -.36, p = .002), and cognitive regulation (r = -.35, p = .002).
Conclusions:
Results suggest that PRT is associated with superior verbal memory outcomes compared to XRT, which may be driven by encoding skills and use of learning strategies. Moreover, encoding ability predicted general intellectual ability and day-to-day functioning. Future work may help to clarify underlying neural mechanisms associated with verbal memory decline following radiotherapy, which will better inform treatment approaches for survivors of pediatric brain tumor.
Cohort studies demonstrate that people who later develop schizophrenia, on average, present with mild cognitive deficits in childhood and endure a decline in adolescence and adulthood. Yet, tremendous heterogeneity exists during the course of psychotic disorders, including the prodromal period. Individuals identified to be in this period (known as CHR-P) are at heightened risk for developing psychosis (~35%) and begin to exhibit cognitive deficits. Cognitive impairments in CHR-P (as a singular group) appear to be relatively stable or ameliorate over time. A sizeable proportion has been described to decline on measures related to processing speed or verbal learning. The purpose of this analysis is to use data-driven approaches to identify latent subgroups among CHR-P based on cognitive trajectories. This will yield a clearer understanding of the timing and presentation of both general and domain-specific deficits.
Participants and Methods:
Participants included 684 young people at CHR-P (ages 12–35) from the second cohort of the North American Prodromal Longitudinal Study. Performance on the MATRICS Consensus Cognitive Battery (MCCB) and the Wechsler Abbreviated Scale of Intelligence (WASI-I) was assessed at baseline, 12-, and 24-months. Tested MCCB domains include verbal learning, speed of processing, working memory, and reasoning & problem-solving. Sex- and age-based norms were utilized. The Oral Reading subtest on the Wide Range Achievement Test (WRAT4) indexed pre-morbid IQ at baseline. Latent class mixture models were used to identify distinct trajectories of cognitive performance across two years. One- to 5-class solutions were compared to decide the best solution. This determination depended on goodness-of-fit metrics, interpretability of latent trajectories, and proportion of subgroup membership (>5%).
Results:
A one-class solution was found for WASI-I Full-Scale IQ, as people at CHR-P predominantly demonstrated an average IQ that increased gradually over time. For individual domains, one-class solutions also best fit the trajectories for speed of processing, verbal learning, and working memory domains. Two distinct subgroups were identified on one of the executive functioning domains, reasoning and problem-solving (NAB Mazes). The sample divided into unimpaired performance with mild improvement over time (Class I, 74%) and persistent performance two standard deviations below average (Class II, 26%). Between these classes, no significant differences were found for biological sex, age, years of education, or likelihood of conversion to psychosis (OR = 1.68, 95% CI 0.86 to 3.14). Individuals assigned to Class II did demonstrate a lower WASI-I IQ at baseline (96.3 vs. 106.3) and a lower premorbid IQ (100.8 vs. 106.2).
Conclusions:
Youth at CHR-P demonstrate relatively homogeneous trajectories across time in terms of general cognition and most individual domains. In contrast, two distinct subgroups were observed with higher cognitive skills involving planning and foresight, and they notably exist independent of conversion outcome. Overall, these findings replicate and extend results from a recently published latent class analysis that examined 12-month trajectories among CHR-P using a different cognitive battery (Allott et al., 2022). Findings inform which individuals at CHR-P may be most likely to benefit from cognitive remediation and can inform about the substrates of deficits by establishing meaningful subtypes.
White matter hyperintensity (WMH) burden is greater, has a frontal-temporal distribution, and is associated with proxies of exposure to repetitive head impacts (RHI) in former American football players. These findings suggest that in the context of RHI, WMH might have unique etiologies that extend beyond those of vascular risk factors and normal aging processes. The objective of this study was to evaluate the correlates of WMH in former elite American football players. We examined markers of amyloid, tau, neurodegeneration, inflammation, axonal injury, and vascular health and their relationships to WMH. A group of age-matched asymptomatic men without a history of RHI was included to determine the specificity of the relationships observed in the former football players.
Participants and Methods:
240 male participants aged 45-74 (60 unexposed asymptomatic men, 60 male former college football players, 120 male former professional football players) underwent semi-structured clinical interviews, magnetic resonance imaging (structural T1, T2 FLAIR, and diffusion tensor imaging), and lumbar puncture to collect cerebrospinal fluid (CSF) biomarkers as part of the DIAGNOSE CTE Research Project. Total WMH lesion volumes (TLV) were estimated using the Lesion Prediction Algorithm from the Lesion Segmentation Toolbox. Structural equation modeling, using Full-Information Maximum Likelihood (FIML) to account for missing values, examined the associations between log-TLV and the following variables: total cortical thickness, whole-brain average fractional anisotropy (FA), CSF amyloid ß42, CSF p-tau181, CSF sTREM2 (a marker of microglial activation), CSF neurofilament light (NfL), and the modified Framingham stroke risk profile (rFSRP). Covariates included age, race, education, APOE z4 carrier status, and evaluation site. Bootstrapped 95% confidence intervals assessed statistical significance. Models were performed separately for football players (college and professional players pooled; n=180) and the unexposed men (n=60). Due to differences in sample size, estimates were compared and were considered different if the percent change in the estimates exceeded 10%.
Results:
In the former football players (mean age=57.2, 34% Black, 29% APOE e4 carrier), reduced cortical thickness (B=-0.25, 95% CI [0.45, -0.08]), lower average FA (B=-0.27, 95% CI [-0.41, -.12]), higher p-tau181 (B=0.17, 95% CI [0.02, 0.43]), and higher rFSRP score (B=0.27, 95% CI [0.08, 0.42]) were associated with greater log-TLV. Compared to the unexposed men, substantial differences in estimates were observed for rFSRP (Bcontrol=0.02, Bfootball=0.27, 994% difference), average FA (Bcontrol=-0.03, Bfootball=-0.27, 802% difference), and p-tau181 (Bcontrol=-0.31, Bfootball=0.17, -155% difference). In the former football players, rFSRP showed a stronger positive association and average FA showed a stronger negative association with WMH compared to unexposed men. The effect of WMH on cortical thickness was similar between the two groups (Bcontrol=-0.27, Bfootball=-0.25, 7% difference).
Conclusions:
These results suggest that the risk factor and biological correlates of WMH differ between former American football players and asymptomatic individuals unexposed to RHI. In addition to vascular risk factors, white matter integrity on DTI showed a stronger relationship with WMH burden in the former football players. FLAIR WMH serves as a promising measure to further investigate the late multifactorial pathologies of RHI.