Search

Abstract Audio-visual media possesses a remarkable ability to synchronise audiences’ neural, behavioural, and physiological responses. This synchronisation is considered to reflect some dimension of collective attention or engagement with the stimulus. But what is it about these stimuli that drives such strong engagement? There are several properties of media stimuli which may lead to synchronous audience response: from low-level audio-visual features, to the story itself. Here, we present a study which separates low-level features from narrative by presenting participants with the same content but in separate modalities. In this way, the presentations shared no low-level features, but participants experienced the same narrative. We show that synchrony in participants’ heart rate can be driven by the narrative information alone. We computed both visual and auditory perceptual saliency for the content and found that narrative was approximately 10 times as predictive of heart rate as low-level saliency, but that low-level audio-visual saliency has a small additive effect towards heart rate. Further, heart rate synchrony was related to a separate cohorts’ continuous ratings of immersion, and that synchrony is likely to be higher at moments of increased narrative importance. Our findings demonstrate that high-level narrative dominates in the alignment of physiology across viewers.

BackgroundDelivering prescription digital therapeutics (ie, evidence-based interventions designed to treat, manage, or prevent disorders via websites or smartphone apps) in primary care could increase patient access to substance use disorder (SUD) treatments. However, the optimal approach to implementing prescription digital therapeutics in primary care remains unknown. ObjectiveThis pilot study is a precursor to a larger trial designed to test whether implementation strategies (practice facilitation [PF] and health coaching [HC]) improve the delivery of prescription digital therapeutics for SUDs in primary care. This mixed methods study describes outcomes among patients in the 2 pilot clinics and presents qualitative findings on implementation. MethodsFrom February 10 to August 6, 2021, a total of 3 mental health specialists embedded in 2 primary care practices of the same integrated health system were tasked with offering app-based prescription digital therapeutics to patients with SUD. In the first half of the pilot, implementation activities included training and supportive tools. PF (at 1 clinic) and HC (at 2 clinics) were added in the second half. All study analyses relied on secondary data, including electronic health records and digital therapeutic vendor data. Primary outcomes were the proportion of patients reached by the prescription digital therapeutics and fidelity related to ideal use. We used qualitative methods to assess the adherence to planned activities and the barriers and facilitators to implementing prescription digital therapeutics. ResultsOf all 18 patients prescribed the apps, 10 (56%) downloaded the app and activated their prescription, and 8 (44%) completed at least 1 module of content. Patients who activated the app completed 1 module per week on average. Ideal use (fidelity) was defined as completing 4 modules per week and having a monthly SUD-related visit; 1 (6%) patient met these criteria for 10 weeks (of the 12-week prescription period). A total of 5 (28%) patients had prescriptions while HC was available, 2 (11%) were successfully contacted, and both declined coaching. Clinicians reported competing clinical priorities, technical challenges, and logistically complex workflows in part because the apps required a prescription. Some pilot activities were impacted by staff turnover that coincided with the COVID-19 pandemic. The facilitators to implementation were high engagement and the perception that the apps could meet patient needs. ConclusionsThe pilot study encountered the barriers to implementing prescription digital therapeutics in a real-world primary care setting, especially staffing shortages, turnover, and competing priorities for clinic teams. The larger randomized trial will clarify the extent to which PF and HC improve the implementation of digital therapeutics. Trial RegistrationClinicalTrials.gov NCT04907045; https://clinicaltrials.gov/study/NCT04907045

IntroductionHealth systems like the Veterans Health Administration (VA) face challenges in recruiting and retaining a primary care physician workforce. This cross-sectional study of recent or current VA medical residents sought to identify determinants of intent to pursue primary care practice in VA after residency training.MethodsResidents were identified from administrative data between 2020 and 2021 and recruited via an emailed self-administered survey. Multivariable logistic regression, accounting for survey non-response, was applied to examine the association between intent to pursue VA practice and two sets of measures: VA training experiences and individual preferences for work conditions.ResultsOf 268 responses received, 141 (56%) of the sample reported inclination to consider VA employment post-residency. Experiences with training in VA were rated more positively in the VA-inclined group compared to the not-inclined group. In the multivariable model, intent to practice primary care was the strongest predictor (OR 4.04, p

Abstract Dementia with Lewy bodies (DLB) is a common form of dementia in the elderly population. We performed genome-wide DNA methylation mapping of cerebellar tissue from pathologically confirmed DLB cases and controls to study the epigenetic profile of this understudied disease. After quality control filtering, 728,197 CpG-sites in 278 cases and 172 controls were available for the analysis. We undertook an epigenome-wide association study, which found a differential methylation signature in DLB cases. Our analysis identified seven differentially methylated probes and three regions associated with DLB. The most significant CpGs were located in ARSB (cg16086807), LINC00173 (cg18800161), and MGRN1 (cg16250093). Functional enrichment evaluations found widespread epigenetic dysregulation in genes associated with neuron-to-neuron synapse, postsynaptic specialization, postsynaptic density, and CTCF-mediated synaptic plasticity. In conclusion, our study highlights the potential importance of epigenetic alterations in the pathogenesis of DLB and provides insights into the modified genes, regions and pathways that may guide therapeutic developments.

The patient–physician relationship is a critical determinant of patient health outcomes. Verbal and non-verbal communication, such as eye gaze, are vital aspects of this bond. Neurobiological studies indicate that oxytocin may serve as a link between increased eye gaze and social bonding. Therefore, oxytocin signaling could serve as a key factor influencing eye gaze as well as the patient–physician relationsh ip. We aimed to test the effects of oxytocin on gaze to the eyes of the physician and the patient–physician relationship by conducting a randomized placebo-controlled crossover trial in healthy volunteers with intranasally administered oxytocin (with a prev iously effective single dose of 24 IU, EudraCT number 2018-004081-34). The eye gaze of 68 male volunteers was studied using eye tracking during a simulated video call consultation with a physician, who provided information about vaccination against the human papillomavirus. Relationship outcomes, including trust, satisfaction, and perceived physician communication style, were measured using questionnaires and corrected for possible confounds (social anxiety and attachment orientation). Additional secondary outcome measures for the effect of oxytocin were recall of information and pupil diameter and exploratory outcomes included mood and anxiety measures. Oxytocin did not affect the eye-tracking p arameters of volunteers’ gaze toward the eyes of the physician. Moreover, oxytocin did n ot affect the parameters of bonding between volunteers and the physician nor other secondary and exploratory outcomes in this setting. Bayesian hypothesis testing provided evidence for the absence of effects. These results contradict the notion that oxy tocin affects eye gaze patterns or bonding.

Abstract Precise, scalable, and quantitative evaluation of whole slide images is crucial in neuropathology. We release a deep learning model for rapid object detection and precise information on the identification, locality, and counts of cored plaques and cerebral amyloid angiopathy (CAA). We trained this object detector using a repurposed image-tile dataset without any human-drawn bounding boxes. We evaluated the detector on a new manually-annotated dataset of whole slide images (WSIs) from three institutions, four staining procedures, and four human experts. The detector matched the cohort of neuropathology experts, achieving 0.64 (model) vs. 0.64 (cohort) average precision (AP) for cored plaques and 0.75 vs. 0.51 AP for CAAs at a 0.5 IOU threshold. It provided count and locality predictions that approximately correlated with gold-standard human CERAD-like WSI scoring (p = 0.07 ± 0.10). The openly-available model can quickly score WSIs in minutes without a GPU on a standard workstation.

A primary science goal for JWST is to detect and characterize the atmospheres of terrestrial planets orbiting M dwarfs (M-Earths). The existence of atmospheres on M-Earths is highly uncertain because their host stars’ extended history of high X-ray and ultraviolet irradiation may act to completely remove their atmospheres. We present two JWST secondary eclipse observations of the M-Earth Gl 486b (also known as GJ 486b) between 5 and 12 μ m. We combined these observations with a precise analysis of the host star parameters to derive a planetary dayside temperature of T _p = 865 ± 14 K. We compared this temperature to the maximum expected temperature for a zero albedo, zero heat redistribution bare rock and derived a temperature ratio of ${ \mathcal R }=\frac{{T}_{{\rm{p}},{\rm{dayside}}}}{{T}_{{\rm{p}},{\rm{\max }}}}=0.97\pm 0.01$ . This value is consistent with an airless body with a slight nonzero albedo or a thin atmosphere with

Abstract Understanding surface temperature is important for habitability. Recent work on Mars has found that the dependence of surface temperature on elevation (surface lapse rate) converges to zero in the limit of a thin CO2 atmosphere. However, the mechanisms that control the surface lapse rate are still not fully understood. It remains unclear how the surface lapse rate depends on both greenhouse effect and surface pressure. Here, we use climate models to study when and why “mountaintops are cold.” We find the tropical surface lapse rate increases with the greenhouse effect and with surface pressure. The greenhouse effect dominates the surface lapse rate transition and is robust across latitudes. The pressure effect is important at low latitudes in moderately opaque (τ ∼ 0.1) atmospheres. A simple model provides insights into the mechanisms of the transition. Our results suggest that topographic cold‐trapping may be important for the climate of arid planets.

Abstract Background Understanding how SARS-CoV-2 infection impacts long-term patient outcomes requires identification of comparable persons with and without infection. We report the design and implementation of a matching strategy employed by the Department of Veterans Affairs’ (VA) COVID-19 Observational Research Collaboratory (CORC) to develop comparable cohorts of SARS-CoV-2 infected and uninfected persons for the purpose of inferring potential causative long-term adverse effects of SARS-CoV-2 infection in the Veteran population. Methods In a retrospective cohort study, we identified VA health care system patients who were and were not infected with SARS-CoV-2 on a rolling monthly basis. We generated matched cohorts within each month utilizing a combination of exact and time-varying propensity score matching based on electronic health record (EHR)-derived covariates that can be confounders or risk factors across a range of outcomes. Results From an initial pool of 126,689,864 person-months of observation, we generated final matched cohorts of 208,536 Veterans infected between March 2020-April 2021 and 3,014,091 uninfected Veterans. Matched cohorts were well-balanced on all 37 covariates used in matching after excluding patients for: no VA health care utilization; implausible age, weight, or height; living outside of the 50 states or Washington, D.C.; prior SARS-CoV-2 diagnosis per Medicare claims; or lack of a suitable match. Most Veterans in the matched cohort were male (88.3%), non-Hispanic (87.1%), white (67.2%), and living in urban areas (71.5%), with a mean age of 60.6, BMI of 31.3, Gagne comorbidity score of 1.4 and a mean of 2.3 CDC high-risk conditions. The most common diagnoses were hypertension (61.4%), diabetes (34.3%), major depression (32.2%), coronary heart disease (28.5%), PTSD (25.5%), anxiety (22.5%), and chronic kidney disease (22.5%). Conclusion This successful creation of matched SARS-CoV-2 infected and uninfected patient cohorts from the largest integrated health system in the United States will support cohort studies of outcomes derived from EHRs and sample selection for qualitative interviews and patient surveys. These studies will increase our understanding of the long-term outcomes of Veterans who were infected with SARS-CoV-2.

Background: Left atrial volume (LAV) has prognostic value. Guidelines propose indexation to body surface area (BSA), however studies demonstrate this can overcorrect for body size. Limited studies investigate indexation across different ethnicities. We sought to evaluate the effect of ethnicity on indexation. Methods: Using data from the World Alliance of Societies of Echocardiography (WASE) cohort, healthy subjects were classified by race as White, Black, Asian, or Other. Biplane LAV was indexed to traditional isometric measurements (BSA, height, weight, ideal body weight (IBW) and IBW derived BSA (IBSA)), as well as previously-derived allometric height exponents (2.7 and 1.72). Additionally, an allometric height exponent for our cohort was derived (linear regression of the logarithmic transformation of LAV = a(height)b) as 1.87. All indices were then assessed using Spearman correlation, with a good index retaining correlation of LAV/index to raw LAV (r∼1), while avoiding overcorrection by the index (r∼0). Results: There were 1366 subjects (White: 524, Black: 149, Asian: 523, Other: 170; median age 44 years, 653 females (47.8%)). In the entire group, BSA, IBSA, height1.87 and height1.72 performed well with retaining correlation to raw LAV (r > 0.9 for all), and minimising overcorrection to body size (r

Antecedentes: Durante la pandemia de COVID-19 se ha reportado incremento de casos de síndrome de Guillain-Barré (SGB). Objetivo: Describir características clínicas y pronóstico de pacientes con SGB antes y durante la pandemia de COVID-19. Material y métodos: Cohorte prospectiva de pacientes con SGB estratificados en dos subgrupos: antes (2018-2019) y durante (2020-2021) la pandemia de COVID-19. Se registraron características clínicas, paraclínicas y defunciones. Se definió como buen pronóstico a la recuperación de la marcha independiente a los tres meses. Resultados: Se incluyeron 201 pacientes (123 durante la pandemia y 78 antes), 69 % del sexo masculino, edad de 45 ± 16 años, 2.5 % de muertes intrahospitalarias. Durante la pandemia se observó mayor frecuencia de la variante desmielinizante (50 %), afección de nervios craneales bulbares (44 % versus 28 %), antecedente de vacunación (16 % versus 0 %) y menor puntuación en la escala MRC (30 ± 16.7 versus 34.3 ± 17.7); se observó aumento de casos de julio a septiembre (38 versus 13). No existieron diferencias significativas en la recuperación de la marcha independiente y número de defunciones. Conclusiones: Durante la pandemia se atendió mayor número de casos de SGB, 16 % asociado a la vacuna contra SARS-CoV-2; los pacientes no presentaron peor pronóstico.

Introduction: There is increasing interest in using capitation rather than fee for service to promote primary care and population health. The goal of this study was to examine the association between practice reimbursement mix (majority fee for service versus majority capitation versus other) and receipt of common preventive screening examinations and health counseling from 2012 to 2018. Methods: Using the National Ambulatory Medical Care Survey, a retrospective cross-sectional study of 24,864 visits with primary care clinicians among patients aged 18–75 years without a cancer diagnosis was conducted. The main dependent measures were age- and sex-appropriate receipt of breast cancer screening, osteoporosis screening, cervical cancer screening, chlamydia testing, colon cancer screening, diabetes screening, and hyperlipidemia screening as well as 3 health counseling items. Multivariable logistic regression was performed to assess the association between reimbursement mix and receipt of preventive care, adjusted for patient, visit, and practice characteristics. Results: Majority capitation reimbursement was associated with a greater likelihood of receiving breast cancer screening (AOR=2.11, 95% CI=1.16, 3.84, p=0.014) and osteoporosis screening (AOR=4.34, 95% CI=1.74, 10.8, p=0.0017) than majority fee-for-service or other reimbursement mixes. Reimbursement mix was not associated with the likelihood of receiving 9 other preventive care or health counseling services. Conclusions: Larger amounts of capitation reimbursement may improve some but not all aspects of preventive care compared with fee for service.

Abstract Background Experts recommend that treatment for substance use disorder (SUD) be integrated into primary care. The Digital Therapeutics for Opioids and Other SUD (DIGITS) Trial tests strategies for implementing reSET® and reSET-O®, which are prescription digital therapeutics for SUD and opioid use disorder, respectively, that include the community reinforcement approach, contingency management, and fluency training to reinforce concept mastery. This purpose of this trial is to test whether two implementation strategies improve implementation success (Aim 1) and achieve better population-level cost effectiveness (Aim 2) over a standard implementation approach. Methods/Design The DIGITS Trial is a hybrid type III cluster-randomized trial. It examines outcomes of implementation strategies, rather than studying clinical outcomes of a digital therapeutic. It includes 22 primary care clinics from a healthcare system in Washington State and patients with unhealthy substance use who visit clinics during an active implementation period (up to one year). Primary care clinics implemented reSET and reSET-O using a multifaceted implementation strategy previously used by clinical leaders to roll-out smartphone apps (“standard implementation” including discrete strategies such as clinician training, electronic health record tools). Clinics were randomized as 21 sites in a 2x2 factorial design to receive up to two added implementation strategies: (1) practice facilitation, and/or (2) health coaching. Outcome data are derived from electronic health records and logs of digital therapeutic usage. Aim 1’s primary outcomes include reach of the digital therapeutics to patients and fidelity of patients’ use of the digital therapeutics to clinical recommendations. Substance use and engagement in SUD care are additional outcomes. In Aim 2, population-level cost effectiveness analysis will inform the economic benefit of the implementation strategies compared to standard implementation. Implementation is monitored using formative evaluation, and sustainment will be studied for up to one year using qualitative and quantitative research methods. Discussion The DIGITS Trial uses an experimental design to test whether implementation strategies increase and improve the delivery of digital therapeutics for SUDs when embedded in a large healthcare system. It will provide data on the potential benefits and cost-effectiveness of alternative implementation strategies. ClinicalTrials.gov Identifier: NCT05160233 (Submitted 12/3/2021). https://clinicaltrials.gov/ct2/show/NCT05160233

Abstract The Hydrocephalus Association (HA) workshop, Driving Common Pathways: Extending Insights from Posthemorrhagic Hydrocephalus, was held on November 4 and 5, 2019 at Washington University in St. Louis. The workshop brought together a diverse group of basic, translational, and clinical scientists conducting research on multiple hydrocephalus etiologies with select outside researchers. The main goals of the workshop were to explore areas of potential overlap between hydrocephalus etiologies and identify drug targets that could positively impact various forms of hydrocephalus. This report details the major themes of the workshop and the research presented on three cell types that are targets for new hydrocephalus interventions: choroid plexus epithelial cells, ventricular ependymal cells, and immune cells (macrophages and microglia).

Abstract BRCA1 (Breast Cancer 1, early onset) is linked to breast and ovarian cancer predisposition. Still, the risks conferred by a significant portion of BRCA1 variants identified in the population remains unknown. Most of these variants of uncertain significance are missense alterations. However, the functional implications of small in-frame deletions and/or insertions (indels) are also difficult to predict. Our group has previously evaluated the functional impact of 347 missense variants using an extensively validated transcriptional activity assay. Here we show a systematic assessment of 30 naturally occurring in-frame indels located at the C-terminal region of BRCA1. We identified positions sensitive and tolerant to alterations, expanding the knowledge of structural determinants of BRCA1 function. We further designed and assessed the impact of four single codon deletions in the tBRCT linker region and six nonsense variants at the C-terminus end of BRCA1. Amino acid substitutions, deletions or insertions in the disordered region do not significantly impact activity and are not likely to constitute pathogenic alleles. On the other hand, a sizeable fraction of in-frame indels at the BRCT domain significantly impact function. We then use a Bayesian integrative statistical model to derive the probability of pathogenicity for each variant. Our data highlights the importance of assessing the impact of small in-frame indels in BRCA1 to improve risk assessment and clinical decisions for carriers.

Introduction: Hyponatremia occurs in 21-48% of patients with Guillain-Barre syndrome (GBS). However, little is known about the clinical implications in GBS. Materials and methods: In this observational, cross-sectional study, of patients diagnosed with GBS was conducted. Information used included: demographic clinical variables, cerebrospinal fluid (CSF) results, and nerve conduction studies. Patients with sodium levels < 135 meq/L in laboratory studies on admission and before treatment were considered to have hyponatremia. We defined good functional prognosis as the presence of independent gait (Hughes ≤ 2 points) at 3 months of follow-up. Results: Two hundred and twelve patients were initially screen and 31 (14.6%) presented hyponatremia; male gender was predominant with 72%, mean age was 45.9 ± 16 years, mean Modified Medical Research Council (MRC) score was 30.1 ± 17 points, invasive mechanical ventilation requirement was 32%, and the presence of dysautonomia 32%. One hundred and eighty-two nerve conduction studies, and 165 CSF cytochemical samples were collected. In the comparative analyses between the patients with hyponatremia versus without hyponatremia, we observed significant differences in mean age (50.4 ± 14.9 vs. 43.8 ± 16.3, p = 0.03), days of hospitalization (median) (16 [IQR = 7-51] vs. 7 [IQR = 5-12] p = 0.03), dysautonomia (54.8% vs. 28.2%, p = 0.006), protein levels (mgs/dL) in CSF (median) (105 [IQR = 59-165] vs. 39 [IQR = 28-57], p ≤ 0.001), and acute inflammatory demyelinating polyneuropathy (AIDP) variant (70.4% vs. 42%, p = 0.011). There was no significant finding in recovery of independent gait at 3 months (34.6% vs. 42.6%, p = 0.51). Conclusion: About 14% of patients with GBS presented with hyponatremia in our series and is associated with presence of dysautonomia, AIDP variant, elevated CSF protein levels and a greater number of days of hospital stay but did not impact functional prognosis.

Mars’s tadpole craters are small, young craters whose crater rims are incised by one or more exit breaches but lack visible inlets. The tadpole-forming climate records the poorly understood drying of Mars since the Early Hesperian. A third of tadpole craters have multiple breaches; therefore, the climate must have been able to generate crater rim incision in multiple locations. We use HiRISE data for four multiple-breach tadpole craters to measure their crater fill, rims, and exit breaches. We compare these measurements and other data with our calculations of liquid water supply by rain, surface melting, groundwater discharge, and basal ice sheet melting to discriminate between four proposed formation hypotheses for tadpole breaches, favoring scenarios with ice-filled craters and supraglacial melting. We conclude that multiple-breach tadpole craters record hundreds of meters of midlatitude ice and climate conditions enabling intermittent melting in the Late Hesperian and Amazonian, suggesting that liquid water on Mars has only been available in association with water ice for billions of years.

TOI-6255 b (GJ 4256) is an Earth-sized planet (1.079 ± 0.065 R _⊕ ) with an orbital period of only 5.7 hr. With the newly commissioned Keck Planet Finder and CARMENES spectrographs, we determine the planet’s mass to be 1.44 ± 0.14 M _⊕ . The planet is just outside the Roche limit, with P _orb / P _Roche = 1.13 ± 0.10. The strong tidal force likely deforms the planet into a triaxial ellipsoid with a long axis that is ∼10% longer than the short axis. Assuming a reduced stellar tidal quality factor ${Q}_{\star }^{{\prime} }\approx {10}^{7}$ , we predict that tidal orbital decay will cause TOI-6255 to reach the Roche limit in roughly 400 Myr. Such tidal disruptions may produce the possible signatures of planet engulfment that have been seen on stars with anomalously high refractory elemental abundances compared to their conatal binary companions. TOI-6255 b is also a favorable target for searching for star–planet magnetic interactions, which might cause interior melting and hasten orbital decay. TOI-6255 b is a top target (with an Emission Spectroscopy Metric of about 24) for phase-curve observations with the James Webb Space Telescope.

Abstract Loss-of-function variants in the BRCA1 and BRCA2 susceptibility genes predispose carriers to breast and/or ovarian cancer. The use of germline testing panels containing these genes has grown dramatically, but the interpretation of the results has been complicated by the identification of many sequence variants of undefined cancer relevance, termed “Variants of Uncertain Significance (VUS).” We have developed functional assays and a statistical model called VarCall for classifying BRCA1 and BRCA2 VUS. Here we describe a multifactorial extension of VarCall, called VarCall XT, that allows for co–analysis of multiple forms of genetic evidence. We evaluated the accuracy of models defined by the combinations of functional, in silico protein predictors, and family data for VUS classification. VarCall XT classified variants of known pathogenicity status with high sensitivity and specificity, with the functional assays contributing the greatest predictive power. This approach could be used to identify more patients that would benefit from personalized cancer risk assessment and management.

Abstract Background Cluster algorithms are gaining in popularity in biomedical research due to their compelling ability to identify discrete subgroups in data, and their increasing accessibility in mainstream software. While guidelines exist for algorithm selection and outcome evaluation, there are no firmly established ways of computing a priori statistical power for cluster analysis. Here, we estimated power and classification accuracy for common analysis pipelines through simulation. We systematically varied subgroup size, number, separation (effect size), and covariance structure. We then subjected generated datasets to dimensionality reduction approaches (none, multi-dimensional scaling, or uniform manifold approximation and projection) and cluster algorithms (k-means, agglomerative hierarchical clustering with Ward or average linkage and Euclidean or cosine distance, HDBSCAN). Finally, we directly compared the statistical power of discrete (k-means), “fuzzy” (c-means), and finite mixture modelling approaches (which include latent class analysis and latent profile analysis). Results We found that clustering outcomes were driven by large effect sizes or the accumulation of many smaller effects across features, and were mostly unaffected by differences in covariance structure. Sufficient statistical power was achieved with relatively small samples (N = 20 per subgroup), provided cluster separation is large (Δ = 4). Finally, we demonstrated that fuzzy clustering can provide a more parsimonious and powerful alternative for identifying separable multivariate normal distributions, particularly those with slightly lower centroid separation (Δ = 3). Conclusions Traditional intuitions about statistical power only partially apply to cluster analysis: increasing the number of participants above a sufficient sample size did not improve power, but effect size was crucial. Notably, for the popular dimensionality reduction and clustering algorithms tested here, power was only satisfactory for relatively large effect sizes (clear separation between subgroups). Fuzzy clustering provided higher power in multivariate normal distributions. Overall, we recommend that researchers (1) only apply cluster analysis when large subgroup separation is expected, (2) aim for sample sizes of N = 20 to N = 30 per expected subgroup, (3) use multi-dimensional scaling to improve cluster separation, and (4) use fuzzy clustering or mixture modelling approaches that are more powerful and more parsimonious with partially overlapping multivariate normal distributions.

Cellulose nanocrystals (CNCs) or cellulose nanofibers (CNFs) with different morphologies, chemical, mechanical and physical properties can be obtained when microcrystalline cellulose is subjected to enzymatic, chemical or mechanical treatment. With the aim of utilizing cellulose nanofibrils (CNFs) from Oryza sativa, we isolated microcrystalline cellulose using the Kraft process, followed by successive fiber fibrillation using mechanical grinding, then (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO) mediated oxidation. Analysis of pulp fibers obtained after each treatment step revealed that fiber properties such as length, crystallinity and crystal size changed when the pulp was subjected to mechanical grinding, ultrasonication and TEMPO mediated oxidation. The degree of crystallinity of the fibers increased while crystal size and fiber length decreased after each treatment. TEMPO mediated oxidation led to a decrease in fiber length and an increase in degree of crystallinity of the fibers as compared to mechanical treatment and ultrasonication. It further introduced carboxyl functional groups (COOH) on the surface of the fibrils, which implies that the nanofibers obtained in this study could be further functionalized. Hence, TEMPO mediated oxidation offers the possibility of further chemical functionalization of cellulose nanofibers isolated from agricultural residues.

Recientemente reportamos la experiencia de nuestro centro en la atención del síndrome de Guillain- Barré (SGB) en los años de la pandemia (2020 y 2021) comparándola con la de años previos (2018 y 2019).1

Habitable rocky planets around M dwarfs that have H _2 -dominated atmospheres, if they exist, would permit characterizing habitable exoplanets with detailed spectroscopy using JWST, owing to their extended atmospheres and small stars. However, the H _2 -dominated atmospheres that are consistent with habitable conditions cannot be too massive, and a moderate-sized H _2 -dominated atmosphere will lose mass to irradiation-driven atmospheric escape on rocky planets around M dwarfs. We evaluate volcanic outgassing and serpentinization as two potential ways to supply H _2 and form a steady-state H _2 -dominated atmosphere. For rocky planets of 1–7 M _⊕ and early-, mid-, and late M-type dwarfs, the expected volcanic outgassing rates from a reduced mantle fall short of the escape rates by > ∼ 1 order of magnitude, and a generous upper limit of the serpentinization rate is still less than the escape rate by a factor of a few. Special mechanisms that may sustain the steady-state H _2 -dominated atmosphere include direct interaction between liquid water and mantle, heat-pipe volcanism from a reduced mantle, and hydrodynamic escape slowed down by efficient upper-atmospheric cooling. It is thus unlikely to find moderate-size, H _2 -dominated atmospheres on rocky planets of M dwarfs that would support habitable environments.

The climate of a planet can be strongly affected by its eccentricity due to variations in the stellar flux. There are two limits for the dependence of the inner habitable zone boundary (IHZ) on eccentricity: (1) the mean stellar flux approximation ( ${S}_{{\rm{IHZ}}}\propto \sqrt{1-{e}^{2}}$ ), in which the temperature is approximately constant throughout the orbit, and (2) the maximum stellar flux approximation ( S _IHZ ∝ (1 − e ) ^2 ), in which the temperature adjusts instantaneously to the stellar flux. Which limit is appropriate is determined by the dimensionless parameter ${\rm{\Pi }}=\tfrac{C}{{BP}}$ , where C is the heat capacity of the planet, P is the orbital period, and $B=\tfrac{\partial {\rm{\Omega }}}{\partial {T}_{s}}$ , where Ω is the outgoing long-wave radiation and T _s is the surface temperature. We use the Buckingham Π theorem to derive an analytical function for the IHZ in terms of eccentricity and Π. We then build a time-dependent energy balance model to resolve the surface temperature evolution and constrain our analytical result. We find that Π must be greater than about ∼1 for the mean stellar flux approximation to be nearly exact and less than about ∼0.01 for the maximum stellar flux approximation to be nearly exact. In addition to assuming a constant heat capacity, we also consider the effective heat capacity including latent heat (evaporation and precipitation). We find that for planets with an Earthlike ocean, the IHZ should follow the mean stellar flux limit for all eccentricities. This work will aid in the prioritization of potentially habitable exoplanets with nonzero eccentricity for follow-up characterization.

Abstract Background Early evaluations of healthcare professional (HCP) COVID-19 risk occurred during insufficient personal protective equipment and disproportionate testing, contributing to perceptions of high patient-care related HCP risk. We evaluated HCP COVID-19 seropositivity after accounting for community factors and coworker outbreaks. Methods Prior to universal masking, we conducted a single-center retrospective cohort plus cross-sectional study. All HCP (1) seen by Occupational Health for COVID-like symptoms (regardless of test result) or assigned to (2) dedicated COVID-19 units, (3) units with a COVID-19 HCP outbreak, or (4) control units from 01/01/2020 to 04/15/2020 were offered serologic testing by an FDA-authorized assay plus a research assay against 67 respiratory viruses, including 11 SARS-CoV-2 antigens. Multivariable models assessed the association of demographics, job role, comorbidities, care of a COVID-19 patient, and geocoded socioeconomic status with positive serology. Results Of 654 participants, 87 (13.3%) were seropositive; among these 60.8% (N = 52) had never cared for a COVID-19 patient. Being male (OR 1.79, CI 1.05–3.04, p = 0.03), working in a unit with a HCP-outbreak unit (OR 2.21, CI 1.28–3.81, p

Abstract Background The transradial approach (TRA) to cardiac catheterization is safer than the traditional transfemoral approach (TFA), with similar clinical effectiveness. However, adoption of TRA remains low, representing less than 50% of catheterization procedures in 2015. Peer coaching is one approach to facilitate implementation; however, the costs of this strategy for cardiac procedures such as TRA are unclear. Methods We conducted an activity-based costing analysis (ABC) of a multi-center, hybrid type III implementation trial of a coaching intervention designed to increase the use of TRA. We identified the key activities of the intervention and determined the personnel, resources, and time needed to complete each activity. The personnel cost per hour and the activity duration were then used to estimate the cost of each activity and the total variable cost of the implementation. Fixed costs related to designing and running the implementation were calculated separately. All costs are reported in 2019 constant US dollars. Results The total cost of the coaching intervention implementation was $374,863. Of the total cost, $367,752 were variable costs due to travel, preparatory work, in-person coaching, post-intervention evaluation, and administrative time. We estimated fixed costs of $7112. The mean marginal cost of implementing the intervention at only one additional medical center was $52,536. Conclusions We provide granular cost estimates of a conceptually rooted implementation strategy designed to increase the uptake of TRA for cardiac catheterization. We estimate that implementation costs stemming from the coaching approach would be offset after the conversion of approximately 409 to 1363 catheterizations from TFA to TRA. Our estimates provide benchmarks of the expected costs of implementing evidence-based, but expertise-intensive, cardiac procedures. Trial registration ISRCTN, ISRCTN66341299 . Registered 7 July 2020—retrospectively registered

IntroductionHuman activities represent a growing threat to biodiversity, increasing species extinction and leading ecosystems to collapse. The knowledge of the spatial distribution of threats to ecosystems is fundamental to understanding their risk of collapse as defined by the Red List of Ecosystems, an International Union for Conservation of Nature (IUCN) global standard to guide conservation and management actions. Colombia is a megadiverse country; almost half of its territory is marine, and its ecosystems are subject to anthropogenic and climatic threats.MethodologyThis study provides a quantitative map assessment for a set of relevant anthropic and climatic threats and impacts on the marine and coastal areas of Colombia, intending to perform the threat description component of the Red List assessment protocol. A cumulative impact assessment was applied to analyze the threat levels (TLs) and impact levels of 12 anthropogenic and climatic pressures.ResultsThe observed TL patterns meet spatial expectations, revealing that the assessment units in the Caribbean Sea are more threatened than those in the Pacific Ocean, and continental areas are more threatened than the oceanic ones. Habitat transformation and sea warming were the threats with the most impact on coastal and marine ecosystems, respectively. Climatic threats were widely extended throughout the study area, occurring even in the most pristine zones (e.g., Malpelo Island).DiscussionClimate threats are challenging to national conservation strategies since these pressures are not completely manageable at local scales as they depend mainly on global efforts. Recommendations drawn from this work can guide actions for the conservation of the ecosystems of Colombia.

Lignin isolated from agricultural residues is a promising alternative for petroleum-based polymers as feedstocks in development of antimicrobial materials. A polymer blend based on silver nanoparticles and lignin–toluene diisocyanate film (AgNPs–Lg–TDIs) was generated from organosolv lignin and silver nanoparticles (AgNPs). Lignin was isolated from Parthenium hysterophorus using acidified methanol and used to synthesize lignin capped silver nanoparticles. Lignin–toluene diisocyanate film (Lg–TDI) was prepared by treating lignin (Lg) with toluene diisocyanate (TDI) followed by solvent casting to form films. Functional groups present and thermal properties of the films were evaluated using Fourier-transform infrared spectrophotometry (FT–IR), thermal gravimetry (TGA), and differential scanning calorimetry (DSC). Scanning electron microscopy (SEM), UV–visible spectrophotometry (UV–Vis), and Powder X-ray diffractometry (XRD) were used to assess the morphology, optical properties, and crystallinity of the films. Embedding AgNPs in the Lg–TDI films increased the thermal stability and the residual ash during thermal analysis, and the presence of powder diffraction peaks at 2θ = 20, 38, 44, 55, and 58⁰ in the films correspond to lignin and silver crystal planes (111). SEM micrographs of the films revealed the presence of AgNPs in the TDI matrix with variable sizes of between 50 to 250 nm. The doped films had a UV radiation cut-off at 400 nm as compared to that of undoped films, but they did not exhibit significant antimicrobial activity against selected microorganisms.

A modest, efficient, and sensitive chemically modified electrode was fabricated for sensing curcumin (CRC) through an electrochemically polymerized titan yellow (TY) modified carbon paste electrode (PTYMCPE) in phosphate buffer solution (pH 7.0). Cyclic voltammetry (CV) linear sweep voltammetry (LSV) and differential pulse voltammetry (DPV) approaches were used for CRC detection. PTYMCPE interaction with CRC suggests that the electrode exhibits admirable electrochemical response as compared to bare carbon paste electrode (BCPE). Under the optimized circumstances, a linear response of the electrode was observed for CRC in the concentration range 2 × 10−6 M to 10 × 10−6 M with a limit of detection (LOD) of 10.94 × 10−7 M. Moreover, the effort explains that the PTYMCPE electrode has a hopeful approach for the electrochemical resolution of biologically significant compounds. Additionally, the proposed electrode has demonstrated many advantages such as easy preparation, elevated sensitivity, stability, and enhanced catalytic activity, and can be successfully applied in real sample analysis.

Background Telemedicine outreach for posttraumatic stress disorder (TOP) is a virtual evidence-based practice (EBP) involving telephone care management and telepsychology that engages rural patients in trauma-focused psychotherapy. This evaluation examined implementation and intervention costs attributable to deploying TOP from a health system perspective. Methods Costs were ascertained as part of a stepped wedge cluster randomized trial at five sites within the Veterans Affairs (VA) Healthcare System. All sites initially received a standard implementation strategy, which included internal facilitation, dissemination of an internal facilitators operational guide, funded care manager, care managing training, and technical support. A subset of clinics that failed to meet performance metrics were subsequently randomized to enhanced implementation , which added external facilitation that focused on incorporating TOP clinical processes into existing clinic workflow. We measured site-level implementation activities using project records and structured activity logs tracking personnel-level time devoted to all implementation activities. We monetized time devoted to implementation activities by applying an opportunity cost approach. Intervention costs were measured as accounting-based costs for telepsychiatry/telepsychology and care manager visits, ascertained using VA administrative data. We conducted descriptive analyses of strategy-specific implementation costs across five sites. Descriptive analyses were conducted instead of population-level cost-effectiveness analysis because previous research found enhanced implementation was not more successful than the standard implementation in improving uptake of TOP. Results Over the 40-month study period, four of five sites received enhanced implementation. Mean site-level implementation cost per month was $919 (SD = $238) during standard implementation and increased to $1,651 (SD = $460) during enhanced implementation. Mean site-level intervention cost per patient-month was $46 (SD = $28) during standard implementation and $31 (SD = $21) during enhanced implementation. Conclusions Project findings inform the expected cost of implementing TOP, which represents one factor health systems should consider in the decision to broadly adopt this EBP. Plain Language Summary: What is already known about the topic: Trauma-focused psychotherapy delivered through telemedicine has been demonstrated as an effective approach for the treatment of post-traumatic stress disorder (PTSD). However, uptake of this evidence-based approach by integrated health systems such as the Veterans Affairs (VA) Health Care System is low. What does this paper add: This paper presents new findings on the costs of two implementation approaches designed to increase adoption telemedicine outreach for PTSD from a health system perspective. What are the implications for practice, research, and policy: Cost estimates from this paper can be used by health systems to inform the relative value of candidate implementation strategies to increase adoption of evidence-based treatments for PTSD or other mental health conditions.

Guillain-Barré syndrome (GBS) is the most frequent cause of acute flaccid paralysis and if not diagnosed and treated timely, a significant cause of long-term disability. Incidence in Latin America ranges from 0.71 to 7.63 cases/100,000 person-years. Historically, GBS has been linked to infections (mainly gastrointestinal by Campylobacter jejuni) and vaccines (including those against severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]); however, a trigger cannot be detected in most cases. Regarding SARS-CoV-2, epidemiological studies have found no association with its development. Acute motor axonal neuropathy is the most common electrophysiological variant in Mexico and Asian countries. Intravenous immunoglobulin or plasma exchanges are still the treatment cornerstones. Mortality in Mexico can be as high as 12%. Avances in understanding the drivers of nerve injury in GBS that may provide the basis for developing targeted therapies have been made during the past decade; despite them, accurate criteria for selecting patients requiring acute treatment, prognostic biomarkers, and novel therapies are still needed. The newly-developed vaccines against SARS-CoV-2 have raised concerns regarding the potential risk for developing GBS. In the midst of coronavirus disease 2019 and vaccination campaigns against SARS-CoV-2, this review discusses the epidemiology, clinical presentation, management, and outcomes of GBS in Mexico.

Summary: Aging is an intricate process characterized by multiple hallmarks including stem cell exhaustion, genome instability, epigenome alteration, impaired proteostasis, and cellular senescence. Whereas each of these traits is detrimental at the cellular level, it remains unclear how they are interconnected to cause systemic organ deterioration. Here we show that abrogating Brap, a BRCA1-associated protein essential for neurogenesis, results in persistent DNA double-strand breaks and elevation of histone H2A mono- and poly-ubiquitination (H2Aub). These defects extend to cellular senescence and proteasome-mediated histone H2A proteolysis with alterations in cells’ proteomic and epigenetic states. Brap deletion in the mouse brain causes neuroinflammation, impaired proteostasis, accelerated neurodegeneration, and substantially shortened the lifespan. We further show the elevation of H2Aub also occurs in human brain tissues with Alzheimer’s disease. These data together suggest that chromatin aberrations mediated by H2Aub may act as a nexus of multiple aging hallmarks and promote tissue-wide degeneration.

Abstract Background The Surgery As Needed for Oesophageal cancer (SANO) trial compares active surveillance with standard oesophagectomy for patients with a clinically complete response (cCR) to neoadjuvant chemoradiotherapy. The last patient with a clinically complete response is expected to be included in May 2021. The purpose of this update is to present all amendments to the SANO trial protocol as approved by the Institutional Research Board (IRB) before accrual is completed. Design The SANO trial protocol has been published ( https://doi.org/10.1186/s12885-018-4034-1 ). In this ongoing, phase-III, non-inferiority, stepped-wedge, cluster randomised controlled trial, patients with cCR (i.e. after neoadjuvant chemoradiotherapy no evidence of residual disease in two consecutive clinical response evaluations [CREs]) undergo either active surveillance or standard oesophagectomy. In the active surveillance arm, CREs are repeated every 3 months in the first year, every 4 months in the second year, every 6 months in the third year, and yearly in the fourth and fifth year. In this arm, oesophagectomy is offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant metastases. The primary endpoint is overall survival. Update Amendments to the study design involve the first cluster in the stepped-wedge design being partially randomised as well and continued accrual of patients at baseline until the predetermined number of patients with cCR is reached. Eligibility criteria have been amended, stating that patients who underwent endoscopic treatment prior to neoadjuvant chemoradiotherapy cannot be included and that patients who have highly suspected residual tumour without histological proof can be included. Amendments to the study procedures include that patients proceed to the second CRE if at the first CRE the outcome of the pathological assessment is uncertain and that patients with a non-passable stenosis at endoscopy are not considered cCR. The sample size was recalculated following new insights on response rates (34% instead of 50%) and survival (expected 2-year overall survival of 75% calculated from the moment of reaching cCR instead of 3-year overall survival of 67% calculated from diagnosis). This reduced the number of required patients with cCR from 264 to 224, but increased the required inclusions from 480 to approximately 740 patients at baseline. Conclusion Substantial amendments were made prior to closure of enrolment of the SANO trial. These amendments do not affect the outcomes of the trial compared to the original protocol. The first results are expected late 2023. If active surveillance plus surgery as needed after neoadjuvant chemoradiotherapy for oesophageal cancer leads to non-inferior overall survival compared to standard oesophagectomy, active surveillance can be implemented as a standard of care.

Abstract Background Public or patient versions of guidelines (PVGs) are derivative documents that “translate” recommendations and their rationale from clinical guidelines for health professionals into a more easily understandable and usable format for patients and the public. PVGs from different groups and organizations vary considerably in terms of quality of their reporting. In order to address this issue, we aimed to develop a reporting checklist for developers of PVGs and other potential users. Methods First, we collected a list of potential items through reviewing a sample of PVGs, existing guidance for developing and reporting PVGs or other similar evidence-based patient tools, as well as qualitative studies on original studies of patients’ needs about the content and/or reporting of information in PVGs or similar evidence-based patient tools. Second, we conducted a two-round Delphi consultation to determine the level of consensus on the items to be included in the final reporting checklist. Third, we invited two external reviewers to provide comments on the checklist. Results We generated the initial list of 45 reporting items based on a review of a sample of 30 PVGs, four PVG guidance documents, and 46 relevant studies. After the two-round Delphi consultation, we formed a checklist of 17 items grouped under 12 topics for reporting PVGs. Conclusion The RIGHT-PVG reporting checklist provides an international consensus on the important criteria for reporting PVGs.

Abstract Sequencing-based genetic tests to identify individuals at increased risk of hereditary breast and ovarian cancers have resulted in the identification of more than 40,000 sequence variants of BRCA1 and BRCA2. A majority of these variants are considered to be variants of uncertain significance (VUS) because their impact on disease risk remains unknown, largely due to lack of sufficient familial linkage and epidemiological data. Several assays have been developed to examine the effect of VUS on protein function, which can be used to assess their impact on cancer susceptibility. In this study, we report the functional characterization of 88 BRCA2 variants, including several previously uncharacterized variants, using a well-established mouse embryonic stem cell (mESC)-based assay. We have examined their ability to rescue the lethality of Brca2 null mESC as well as sensitivity to six DNA damaging agents including ionizing radiation and a PARP inhibitor. We have also examined the impact of BRCA2 variants on splicing. In addition, we have developed a computational model to determine the probability of impact on function of the variants that can be used for risk assessment. In contrast to the previous VarCall models that are based on a single functional assay, we have developed a new platform to analyze the data from multiple functional assays separately and in combination. We have validated our VarCall models using 12 known pathogenic and 10 neutral variants and demonstrated their usefulness in determining the pathogenicity of BRCA2 variants that are listed as VUS or as variants with conflicting functional interpretation.

Background: Bickerstaff brainstem encephalitis (BBE) presents with consciousness impairment, ataxia, ophthalmoplegia, and areflexia. Objective: We aim to describe the clinical, paraclinical, and imaging features of patients with BBE from a tertiary-referral neurological center. Methods: A case series was conducted from an ambispective cohort of patients with Guillain-Barré syndrome (GBS) from 2016 to 2021. Subjects ≥ 18 years and who met Odaka et al. BBE criteria were eligible. Data collected included: age, gender, prior infection, Guillain-Barré disability score (GDS score), time from symptom onset to diagnosis, altered mental state, time from symptom onset to altered mental state, cranial nerve involvement, deep tendon reflexes, ataxia, invasive mechanical ventilation (IMV) requirement, treatment, inpatient delirium, length of stay (days), and protein levels in CSF analysis. Nerve conduction studies (NCS) were performed, as well as neuroimaging (brain magnetic resonance imaging [MRI] and F18-fluorodeoxyglucose PET-CT). Antiganglioside antibodies panel including anti-GQ1b was solicited. Results: Four patients (1.7%) met the inclusion criteria. Two patients manifested stupor and two showed somnolence throughout the course of the disease. Three patients required IMV due to bulbar dysfunction. None of the NCS met the criteria for any GBS electrophysiological variant. One patient was positive for IgM GM2 antibodies. One patient underwent 18F-FDG PET-CT, showing generalized cortical hypometabolism. Conclusion: The frequency of BBE in our population is very low (1.7%). IgM GM2 is another anti-ganglioside antibody related to BBE. Imaging studies such as MRI frequently do not present abnormalities and [F18-FDGPET scan might be a useful study to describe a metabolism pattern to aid the diagnosis of BBE.

Fluctuations in a person's arousal accompany mental states such as drowsiness, mental effort, or motivation, and have a profound effect on task performance. Here, we investigated the link between two central instances affected by arousal levels, heart rate and eye movements. In contrast to heart rate, eye movements can be inferred remotely and unobtrusively, and there is evidence that oculomotor metrics (i.e., fixations and saccades) are indicators for aspects of arousal going hand in hand with changes in mental effort, motivation, or task type. Gaze data and heart rate of 14 participants during film viewing were used in Random Forest models, the results of which show that blink rate and duration, and the movement aspect of oculomotor metrics (i.e., velocities and amplitudes) link to heart rate-more so than the amount or duration of fixations and saccades. We discuss that eye movements are not only linked to heart rate, but they may both be similarly influenced by the common underlying arousal system. These findings provide new pathways for the remote measurement of arousal, and its link to psychophysiological features.

Globally ice-covered oceans have been found on multiple moons in the solar system and may also have been a feature of Earth’s past. However, relatively little is understood about the dynamics of these ice-covered oceans, which affect not only the physical environment but also any potential life and its detectability. A number of studies have simulated the circulation of icy-world oceans, but have come to seemingly widely different conclusions. To better understand and narrow down these diverging results, we discuss the energetic constraints for the circulation on ice-covered oceans, focusing in particular on Snowball Earth, Europa, and Enceladus. The energy input that can drive ocean circulation on ice-covered bodies can be associated with heat and salt fluxes at the boundaries as well as ocean tides and librations. We show that heating from the solid core balanced by heat loss through the ice sheet can drive an ocean circulation, but the resulting flows would be relatively weak and strongly affected by rotation. Salt fluxes associated with freezing and melting at the ice sheet boundary are unlikely to energetically drive a circulation, although they can shape the large-scale circulation when combined with turbulent mixing. Ocean tides and librations may provide an energy source for such turbulence, but the magnitude of this energy source remains highly uncertain for the icy moons, which poses a major obstacle to predicting the ocean dynamics of icy worlds and remains an important topic for future research.

TOI-561 is a galactic thick-disk star hosting an ultra-short-period (0.45-day-orbit) planet with a radius of 1.37 R _⊕ , making it one of the most metal-poor ([Fe/H] = −0.41) and oldest (≈10 Gyr) sites where an Earth-sized planet has been found. We present new simultaneous radial velocity (RV) measurements from Gemini-N/MAROON-X and Keck/HIRES, which we combined with literature RVs to derive a mass of M _b = 2.24 ± 0.20 M _⊕ . We also used two new sectors of TESS photometry to improve the radius determination, finding R _b = 1.37 ± 0.04 R _⊕ and confirming that TOI-561 b is one of the lowest-density super-Earths measured to date ( ρ _b = 4.8 ± 0.5 g cm ^−3 ). This density is consistent with an iron-poor rocky composition reflective of the host star’s iron and rock-building element abundances; however, it is also consistent with a low-density planet with a volatile envelope. The equilibrium temperature of the planet (∼2300 K) suggests that this envelope would likely be composed of high mean molecular weight species, such as water vapor, carbon dioxide, or silicate vapor, and is likely not primordial. We also demonstrate that the composition determination is sensitive to the choice of stellar parameters and that further measurements are needed to determine whether TOI-561 b is a bare rocky planet, a rocky planet with an optically thin atmosphere, or a rare example of a nonprimordial envelope on a planet with a radius smaller than 1.5 R _⊕ .

Pediatric brain tumors are the most common solid malignancies in children. Advances in the treatment of pediatric brain tumors have come in the form of imaging, biopsy, surgical techniques, and molecular profiling. This has led the way for targeted therapies and immunotherapy to be assessed in clinical trials for the most common types of pediatric brain tumors. Here we review the latest efforts and challenges in targeted molecular therapy, immunotherapy, and newer modalities such as laser interstitial thermal therapy.