Study of Postacute Sequelae of COVID-19 Using Digital Wearables: Protocol for a Prospective Longitudinal Observational Study.

BACKGROUND: Postacute sequelae of COVID-19 (PASC) remain understudied in nonhospitalized patients. Digital wearables allow for a continuous collection of physiological parameters such as respiratory rate and oxygen saturation that have been predictive of disease trajectories in hospitalized patients. OBJECTIVE: This protocol outlines the design and procedures of a prospective, longitudinal, observational study of PASC that aims to identify wearables-collected physiological parameters that are associated with PASC in patients with a positive diagnosis. METHODS: This is a single-arm, prospective, observational study of a cohort of 550 patients, aged 18 to 65 years, male or female, who own a smartphone or a tablet that meets predetermined Bluetooth version and operating system requirements, speak English, and provide documentation of a positive COVID-19 test issued by a health care professional within 5 days before enrollment. The primary end point is long COVID-19, defined as ≥1 symptom at 3 weeks beyond the first symptom onset or positive diagnosis, whichever comes first. The secondary end point is chronic COVID-19, defined as ≥1 symptom at 12 weeks beyond the first symptom onset or positive diagnosis. Participants must be willing and able to consent to participate in the study and adhere to study procedures for 6 months. RESULTS: The first patient was enrolled in October 2021. The estimated year for publishing the study results is 2025. CONCLUSIONS: This is a fully decentralized study investigating PASC using wearable devices to collect physiological parameters and patient-reported outcomes. The study will shed light on the duration and symptom manifestation of PASC in nonhospitalized patient subgroups and is an exemplar of the use of wearables as population-level monitoring health tools for communicable diseases. TRIAL REGISTRATION: ClinicalTrials.gov NCT04927442; https://clinicaltrials.gov/study/NCT04927442. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/57382.

Update on Pediatric Cancer Surveillance Recommendations for Patients with Neurofibromatosis Type 1, Noonan Syndrome, CBL Syndrome, Costello Syndrome, and Related RASopathies.

Neurofibromatosis type 1 (NF1), Noonan syndrome and related syndromes, grouped as the RASopathies, result from dysregulation of the RAS-MAPK pathway and demonstrate varied multisystemic clinical phenotypes. Together the RASopathies are among the more prevalent genetic cancer predisposition syndromes and require nuanced clinical management. When compared to the general population, children with RASopathies are at significantly increased risk of benign and malignant neoplasms. In the last decade, clinical trials have shown that targeted therapies can improve outcomes for low-grade and benign neoplastic lesions but have their own challenges, highlighting the multi-disciplinary care needed for such individuals, specifically those with NF1. This perspective, which originated from the 2023 AACR Childhood Cancer Predisposition Workshop, serves to update pediatric oncologists, neurologists, geneticists, counselors, and other healthcare professionals on revised diagnostic criteria, review previously published surveillance guidelines, and harmonize updated surveillance recommendations for patients with NF1 or RASopathies.

Immuno-oncologic profiling of pediatric brain tumors reveals major clinical significance of the tumor immune microenvironment.

With the success of immunotherapy in cancer, understanding the tumor immune microenvironment (TIME) has become increasingly important; however in pediatric brain tumors this remains poorly characterized. Accordingly, we developed a clinical immune-oncology gene expression assay and used it to profile a diverse range of 1382 samples with detailed clinical and molecular annotation. In low-grade gliomas we identify distinct patterns of immune activation with prognostic significance in BRAF V600E-mutant tumors. In high-grade gliomas, we observe immune activation and T-cell infiltrates in tumors that have historically been considered immune cold, as well as genomic correlates of inflammation levels. In mismatch repair deficient high-grade gliomas, we find that high tumor inflammation signature is a significant predictor of response to immune checkpoint inhibition, and demonstrate the potential for multimodal biomarkers to improve treatment stratification. Importantly, while overall patterns of immune activation are observed for histologically and genetically defined tumor types, there is significant variability within each entity, indicating that the TIME must be evaluated as an independent feature from diagnosis. In sum, in addition to the histology and molecular profile, this work underscores the importance of reporting on the TIME as an essential axis of cancer diagnosis in the era of personalized medicine.

An update on central nervous system tumors in germline replication-repair deficiency syndromes.

DNA replication-repair deficiency (RRD) arises from pathogenic variants in the mismatch repair and/or polymerase-proofreading genes. Multiple germline cancer predisposition syndromes in children and young adults, including constitutional mismatch repair deficiency (CMMRD), Lynch, polymerase-proofreading deficiency, and rare digenic syndromes can lead to RRD cancers. The most frequent brain tumors in these children are high-grade gliomas. Embryonal tumors like medulloblastoma have also been described. Lower-grade tumors are reported from cancer surveillance initiatives. The latter has an extremely high rate of malignant transformation. Novel functional assays quantifying the genomic microsatellite indel load have been demonstrated to be highly sensitive and specific for the diagnosis of RRD cancers and children with germline CMMRD. Importantly, RRD brain tumors uniformly harbor high mutation and microsatellite burden. High T-cell infiltration makes these aggressive cancers amenable to immune checkpoint inhibition, irrespective of their germline genetic background. Synergistic combinations are reported to be successful in patients failing checkpoint inhibitor monotherapy. Future directions include the development of innovative approaches to improve immune surveillance for RRD brain cancers. Additionally, the use of novel tools including circulating tumor DNA and quantifying microsatellite indel load over time can be useful to monitor disease burden and treatment responses in patients.

Brain-state mediated modulation of inter-laminar dependencies in visual cortex.

Spatial attention is critical for recognizing behaviorally relevant objects in a cluttered environment. How the deployment of spatial attention aids the hierarchical computations of object recognition remains unclear. We investigated this in the laminar cortical network of visual area V4, an area strongly modulated by attention. We found that deployment of attention strengthened unique dependencies in neural activity across cortical layers. On the other hand, shared dependencies were reduced within the excitatory population of a layer. Surprisingly, attention strengthened unique dependencies within a laminar population. Crucially, these modulation patterns were also observed during successful behavioral outcomes that are thought to be mediated by internal brain state fluctuations. Successful behavioral outcomes were also associated with phases of reduced neural excitability, suggesting a mechanism for enhanced information transfer during optimal states. Our results suggest common computation goals of optimal sensory states that are attained by either task demands or internal fluctuations.

Clinical Updates and Surveillance Recommendations for DNA Replication Repair Deficiency Syndromes in Children and Young Adults.

Replication repair deficiency (RRD) is a pan-cancer mechanism characterized by abnormalities in the DNA mismatch repair (MMR) system due to pathogenic variants in the PMS2, MSH6, MSH2, or MLH1 genes, and/or in the polymerase-proofreading genes POLE and POLD1. RRD predisposition syndromes (constitutional MMR deficiency, Lynch, and polymerase proofreading-associated polyposis) share overlapping phenotypic and biological characteristics. Moreover, cancers stemming from germline defects of one mechanism can acquire somatic defects in another, leading to complete RRD. Here we describe the recent advances in the diagnostics, surveillance, and clinical management for children with RRD syndromes. For patients with constitutional MMR deficiency, new data combining clinical insights and cancer genomics have revealed genotype-phenotype associations and helped in the development of novel functional assays, diagnostic guidelines, and surveillance recommendations. Recognition of non-gastrointestinal/genitourinary malignancies, particularly aggressive brain tumors, in select children with Lynch and polymerase proofreading-associated polyposis syndromes harboring an RRD biology have led to new management considerations. Additionally, universal hypermutation and microsatellite instability have allowed immunotherapy to be a paradigm shift in the treatment of RRD cancers independent of their germline etiology. These advances have also stimulated a need for expert recommendations about genetic counseling for these patients and their families. Future collaborative work will focus on newer technologies such as quantitative measurement of circulating tumor DNA and functional genomics to tailor surveillance and clinical care, improving immune surveillance; develop prevention strategies; and deliver these novel discoveries to resource-limited settings to maximize benefits for patients globally.

Precision immuno-oncology approach for four malignant tumors in siblings with constitutional mismatch repair deficiency syndrome.

Constitutional mismatch repair deficiency (CMMRD) is a rare syndrome characterized by an increased incidence of cancer. It is caused by biallelic germline mutations in one of the four mismatch repair genes (MMR) genes: MLH1, MSH2, MSH6, or PMS2. Accurate diagnosis accompanied by a proper molecular genetic examination plays a crucial role in cancer management and also has implications for other family members. In this report, we share the impact of the diagnosis and challenges during the clinical management of two brothers with CMMRD from a non-consanguineous family harbouring compound heterozygous variants in the PMS2 gene. Both brothers presented with different phenotypic manifestations and cancer spectrum. Treatment involving immune checkpoint inhibitors significantly contributed to prolonged survival in both patients affected by lethal gliomas. The uniform hypermutation also allowed immune-directed treatment using nivolumab for the B-cell lymphoma, thereby limiting the intensive chemotherapy exposure in this young patient who remains at risk for subsequent malignancies.

Update on Cancer Predisposition Syndromes and Surveillance Guidelines for Childhood Brain Tumors.

Tumors of the central nervous system (CNS) comprise the second most common group of neoplasms in childhood. The incidence of germline predisposition among children with brain tumors continues to grow as our knowledge on disease etiology increases. Some children with brain tumors may present with nonmalignant phenotypic features of specific syndromes (e.g., nevoid basal cell carcinoma syndrome, neurofibromatosis type 1 and type 2, DICER1 syndrome, and constitutional mismatch-repair deficiency), while others may present with a strong family history of cancer (e.g., Li-Fraumeni syndrome) or with a rare tumor commonly found in the context of germline predisposition (e.g., rhabdoid tumor predisposition syndrome). Approximately 50% of patients with a brain tumor may be the first in a family identified to have a predisposition. The past decade has witnessed a rapid expansion in our molecular understanding of CNS tumors. A significant proportion of CNS tumors are now well characterized and known to harbor specific genetic changes that can be found in the germline. Additional novel predisposition syndromes are also being described. Identification of these germline syndromes in individual patients has not only enabled cascade testing of family members and early tumor surveillance but also increasingly affected cancer management in those patients. Therefore, the AACR Cancer Predisposition Working Group chose to highlight these advances in CNS tumor predisposition and summarize and/or generate surveillance recommendations for established and more recently emerging pediatric brain tumor predisposition syndromes.

Effects of PNA Sequence and Target Site Selection on Function of a 4.5S Non-Coding RNA.

Peptide nucleic acid (PNA) based antisense strategy is a promising therapeutic approach to specifically inhibit target gene expression. However, unlike protein coding genes, identification of an ideal PNA binding site for non-coding RNA is not straightforward. Here, we compare the inhibitory activities of PNA molecules that bind a non-coding 4.5S RNA called SRP RNA, a key component of the bacterial signal recognition particle (SRP). A 9-mer PNA (PNA9) complementary to the tetraloop region of the RNA was more potent in inhibiting its interaction with the SRP protein, compared to an 8-mer PNA (PNA8) targeting a stem-loop. PNA9, which contained a homo-pyrimidine sequence could form a triplex with the complementary stretch of RNA in vitro as confirmed using a fluorescent derivative of PNA9 (F-PNA13). The RNA-PNA complex formation resulted in inhibition of SRP function with PNA9 and F-PNA13, but not PNA8 highlighting the importance of target site selection. Surprisingly, F-PNA13 which was more potent in inhibiting SRP function in vitro, showed weaker antibacterial activity compared to PNA9 likely due to poor cell penetration of the longer PNA. Our results underscore the importance of suitable target site selection and optimum PNA length to develop better antisense molecules against non-coding RNA.

A fluorescent MOF and its synthesized MOF@cotton composite: Ratiometric sensing of vitamin B2 and antibiotic drug molecule.

Here, we demonstrated the synthesis of a zinc based luminescent MOF, 1 (NDC = 2,6- naphthalenedicarboxylate) for the ratiometric detection of biomarker riboflavin (RBF; vitamin B2) in water dispersed medium. Further, this MOF detected two other antibiotic drug molecules, nitrofurantoin (NFT) and nitrofurazone (NZF). The detection of these analytes is very quick (∼seconds), and the limit of detection (LOD) for RBF, NZF and NFT are calculated as 16.58 ppm, 47.63 ppb and 56.96 ppb, respectively. The detection of these analytes was also comprehended by solid, solution, cost-effective paper strip method i.e., triphasic identification capabilities. The sensor is reusable without losing its detection efficacy. The sensor further showed the recognition abilities of these antibiotics in real field samples (river water, urine and tablet) and RBF in vitamin B2 pills and food samples (milk and cold drinks). The sensing merit of 1 urged us to fabricate of 1@cotton fabric composite, which exhibited the colorimetric detection of these analytes. In-depth experimental analysis suggested that the occurrence of photo-induced electron transfer (PET), fluorescence resonance energy transfer (FRET), and the inner filter effect (IFE) are the possible sensing mechanisms for the recognition of the antibiotics drug. The FRET mechanism is responsible for the recognition of RBF. The sensing mechanism is further supported by the theoretical analysis and the excited lifetime measurement.

Dark Matter Induced Power in Quantum Devices.

We point out that power measurements of single quasiparticle devices open a new avenue to detect dark matter (DM). The threshold of these devices is set by the Cooper pair binding energy, and is therefore so low that they can detect DM as light as about an MeV incoming from the Galactic halo, as well as the low-velocity thermalized DM component potentially present in the Earth. Using existing power measurements with these new devices, as well as power measurements with SuperCDMS-CPD, we set new constraints on the spin-independent DM scattering cross section for DM masses from about 10 MeV to 10 GeV. We outline future directions to improve sensitivity to both halo DM and a thermalized DM population in the Earth using power deposition in quantum devices.

Actively Driven Light-Addressable Sensor/Actuator System for Automated pH Control for the Integration in Lab-On-A-Chip (LoC) Platforms.

The miniaturization of microfluidic systems usually comes at the cost of more difficult integration of sensors and actuators inside the channel. As an alternative, this work demonstrates the embedding of semiconductor-based sensor and actuator technologies that can be spatially and temporally controlled from outside the channel using light. The first element is a light-addressable potentiometric sensor, consisting of an Al/Si/SiO2/Si3N4 structure, that can measure pH changes at the Si3N4/electrolyte interface. The pH value is a crucial factor in biological and chemical systems, and besides measuring, it is often important to bring the system out of equilibrium or to adjust and control precisely the surrounding medium. This can be done photoelectrocatalytically by utilizing light-addressable electrodes. These consist of a glass/SnO2:F/TiO2 structure, whereby direct charge transfer between the TiO2 and the electrolyte leads to a pH change upon irradiation. To complement the advantages of both, we integrated a light-addressable sensor with a pH sensitivity of 41.5 mV·pH-1 and a light-addressable electrode into a microfluidic setup. Here, we demonstrated a simultaneous operation with the ability to generate and record pH gradients inside a channel under static and dynamic flow conditions. The results show that dependent on the light-addressable electrode (LAE)-illumination conditions, pH changes up to ΔpH of 2.75 and of 3.52 under static and dynamic conditions, respectively, were spatially monitored by the light-addressable potentiometric sensor. After flushing with fresh buffer solution, the pH returned to its initial value. Depending on the LAE illumination, pH gradients with a maximum pH change of ΔpH of 1.42 were tailored perpendicular to the flow direction. In a final experiment, synchronous LAE illumination led to a stepwise increase in the pH inside the channel.

Spatiotemporal variations, sources, pollution status and health risk assessment of dissolved trace elements in a major Arabian Sea draining river: insights from multivariate statistical and machine learning approaches.

River Mahi drains through semi-arid regions (Western India) and is a major Arabian Sea draining river. As the principal surface water source, its water quality is important to the regional population. Therefore, the river water was sampled extensively (n = 64, 16 locations, 4 seasons and 2 years) and analyzed for 11 trace elements (TEs; Sr, V, Cu, Ni, Zn, Cd, Ba, Cr, Mn, Fe, and Co). Machine learning (ML) and multivariate statistical analysis (MVSA) were applied to investigate their possible sources, spatial-temporal-annual variations, evaluate multiple water quality parameters [heavy metal pollution index (HPI), heavy metal evaluation index (HEI)], and health indices [hazard quotient (HQ), and hazard index (THI)] associated with TEs. TE levels were higher than their corresponding world average values in 100% (Sr, V and Zn), 78%(Cu), 41%(Ni), 27%(Cr), 9%(Cd), 8%(Ba), 8%(Co), 6%(Fe), and 0%(Mn), of the samples. Three principal components (PCs) accounted for 74.5% of the TE variance: PC-1 (Fe, Co, Mn and Cu) and PC-2 (Sr and Ba) are contributed from geogenic sources, while PC-3 (Cr, Ni and Zn) are derived from geogenic and anthropogenic sources. HPI, HEI, HQ and THI all indicate that water quality is good for domestic purposes and poses little hazard. ML identified Random forest as the most suitable model for predicting HEI class (accuracy: 92%, recall: 92% and precision: 94%). Even with a limited dataset, the study underscores the potential application of ML to predictive classification modeling.

A Validated Highly Sensitive Microsatellite Instability Assay Accurately Identifies Individuals Harboring Biallelic Germline PMS2 Pathogenic Variants in Constitutional Mismatch Repair Deficiency.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is a rare and extraordinarily penetrant childhood-onset cancer predisposition syndrome. Genetic diagnosis is often hampered by the identification of mismatch repair (MMR) variants of unknown significance and difficulties in PMS2 analysis, the most frequently mutated gene in CMMRD. We present the validation of a robust functional tool for CMMRD diagnosis and the characterization of microsatellite instability (MSI) patterns in blood and tumors. METHODS: The highly sensitive assessment of MSI (hs-MSI) was tested on a blinded cohort of 66 blood samples and 24 CMMRD tumor samples. Hs-MSI scores were compared with low-pass genomic instability scores (LOGIC/MMRDness). The correlation of hs-MSI scores in blood with age of cancer onset and the distribution of insertion-deletion (indel) variants in microsatellites were analyzed in a series of 169 individuals (n = 68 CMMRD, n = 124 non-CMMRD). RESULTS: Hs-MSI achieved high accuracy in the identification of CMMRD in blood (sensitivity 98.5% and specificity 100%) and detected MSI in CMMRD-associated tumors. Hs-MSI had a strong positive correlation with whole low-pass genomic instability LOGIC scores (r = 0.89, P = 2.2e-15 in blood and r = 0.82, P = 7e-3 in tumors). Indel distribution identified PMS2 pathogenic variant (PV) carriers from other biallelic MMR gene PV carriers with an accuracy of 0.997. Higher hs-MSI scores correlated with younger age at diagnosis of the first tumor (r = -0.43, P = 0.011). CONCLUSIONS: Our study confirms the accuracy of the hs-MSI assay as ancillary testing for CMMRD diagnosis, which can also characterize MSI patterns in CMMRD-associated cancers. Hs-MSI is a powerful tool to pinpoint PMS2 as the affected germline gene and thus potentially personalize cancer risk.

Spatial and Temporal Variations in Richness, Diversity and Abundance of Floral Visitors of Curry Plants (Bergera koenigii L.): Insights on Plant-Pollinator Interactions.

The reproductive success of flowering plants relates to flower-visitor communities and plant-pollinator interactions. These traits are species- and region-specific and vary across regions, pollinator groups, and plant species. However, little literature exists on the spatiotemporal variation in visitor activity, especially in India. Here, we aimed to depict the spatial and temporal variation in visitor activity on the curry plants (Bergera koenigii). Data were collected at different daytime slots from three vegetation zones (confirmed by field surveys and normalized difference vegetation index values in remote sensing)-dense, medium-density, and low-density vegetation in West Bengal, India. The visitors' richness, diversity, and abundance were higher in the area with dense vegetation. Considering daytime patterns, higher values for these parameters were obtained during 10.00-14.00 h. For most visitors, the flower handling time was shorter, and the visitation rate was higher in dense vegetation areas (at 10.00-14.00 h) than in medium- and low-density vegetation areas. The proportions of different foraging categories varied over time. Vital pollinators were Apis cerana, Apis dorsata, Appias libythea, Halictus acrocephalus, Nomia iridescens, and Tetragonula iridipennis. However, the effectiveness of pollinators remained region-specific. Therefore, it can be concluded that floral visitors' richness, diversity, abundance, and plant-visitor interactions varied spatially with their surrounding vegetation types and also changed daytime-wise.

Metastatic Neuroblastoma in the Testis: Report of a Case with Review of Literature.

Neuroblastoma is the most common extracranial malignant solid tumor in childhood. Neuroblastoma is known to metastasize in certain niche areas such as the bone, bone marrow, liver, and skin. Testicular metastasis of neuroblastoma is uncommon, and only a few cases have been reported. In this communique, we describe an infant with neuroblastoma presenting with testicular metastasis. Testicular metastasis of neuroblastoma, although uncommon, should be considered a differential of testicular masses in children.

Brain-state mediated modulation of inter-laminar dependencies in visual cortex.

Spatial attention is a quintessential example of adaptive information processing in the brain and is critical for recognizing behaviorally relevant objects in a cluttered environment. Object recognition is mediated by neural encoding along the ventral visual hierarchy. How the deployment of spatial attention aids these hierarchical computations is unclear. Prior studies point to two distinct mechanisms: an improvement in the efficacy of information directed from one encoding stage to another, and/or a suppression of shared information within encoding stages. To test these proposals, it is crucial to estimate the attentional modulation of unique information flow across and shared information within the encoding stages of the visual hierarchy. We investigated this in the multi-stage laminar network of visual area V4, an area strongly modulated by attention. Using network-based dependency estimation from multivariate data, we quantified the modulation of inter-layer information flow during a change detection task and found that deployment of attention indeed strengthened unique dependencies between the input and superficial layers. Using the partial information decomposition framework, we estimated the modulation of shared dependencies and found that they are reduced specifically in the putative excitatory subpopulations within a layer. Surprisingly, we found a strengthening of unique dependencies within the laminar populations, a finding not previously predicted. Crucially, these modulation patterns were also observed during successful behavioral outcomes (hits) that are thought to be mediated by endogenous brain state fluctuations, and not by experimentally imposed attentive states. Finally, phases of endogenous fluctuations that were optimal for 'hits' were associated with reduced neural excitability. A reduction in neural excitability, potentially mediated by diminished shared inputs, suggests a novel mechanism for enhancing unique information transmission during optimal states. By decomposing the modulation of multivariate information, and combined with prior theoretical work, our results suggest common computations of optimal sensory states that are attained by either task demands or endogenous fluctuations.

Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti-PD-1 Monotherapy: A Report from the International RRD Consortium.

Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy is unknown. We performed an international study on 75 patients treated with anti-PD-1; 20 are progression free (median follow-up, 3.7 years). After second progression/recurrence (n = 55), continuing ICI-based salvage prolonged survival to 11.6 months (n = 38; P < 0.001), particularly for those with extreme mutation burden (P = 0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and the immune microenvironment. Response to reirradiation was explained by an absence of deleterious postradiation indel signatures (ID8). CTLA4 expression increased over time, and subsequent CTLA4 inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to the reinvigoration of peripheral immune and radiologic responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide a mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology. SIGNIFICANCE: Hypermutant RRD-HGG are susceptible to checkpoint inhibitors beyond initial progression, leading to improved survival when reirradiation and synergistic immune/targeted agents are added. This is driven by their unique biological and immune properties, which evolve over time. Future research should focus on combinatorial regimens that increase patient survival while limiting immune toxicity. This article is featured in Selected Articles from This Issue, p. 201.

Proton Therapy Mediates Dose Reductions to Brain Structures Associated With Cognition in Children With Medulloblastoma.

PURPOSE: Emerging evidence suggests proton radiation therapy may offer cognitive sparing advantages over photon radiation therapy, yet dosimetry has not been compared previously. The purpose of this study was to examine dosimetric correlates of cognitive outcomes in children with medulloblastoma treated with proton versus photon radiation therapy. METHODS AND MATERIALS: In this retrospective, bi-institutional study, dosimetric and cognitive data from 75 patients (39 photon and 36 proton) were analyzed. Doses to brain structures were compared between treatment modalities. Linear mixed-effects models were used to create models of global IQ and cognitive domain scores. RESULTS: The mean dose and dose to 40% of the brain (D40) were 2.7 and 4.1 Gy less among proton-treated patients compared with photon-treated patients (P = .03 and .007, respectively). Mean doses to the left and right hippocampi were 11.2 Gy lower among proton-treated patients (P < .001 for both). Mean doses to the left and right temporal lobes were 6.9 and 7.1 Gy lower with proton treatment, respectively (P < .001 for both). Models of cognition found statistically significant associations between higher mean brain dose and reduced verbal comprehension, increased right temporal lobe D40 with reduced perceptual reasoning, and greater left temporal mean dose with reduced working memory. Higher brain D40 was associated with reduced processing speed and global IQ scores. CONCLUSIONS: Proton therapy reduces doses to normal brain structures compared with photon treatment. This leads to reduced cognitive decline after radiation therapy across multiple intellectual endpoints. Proton therapy should be offered to children receiving radiation for medulloblastoma.

A Gate-Tunable Ambipolar Quantum Phase Transition in a Topological Excitonic Insulator.

Coulomb interactions among electrons and holes in 2D semimetals with overlapping valence and conduction bands can give rise to a correlated insulating ground state via exciton formation and condensation. One candidate material in which such excitonic state uniquely combines with non-trivial band topology are atomic monolayers of tungsten ditelluride (WTe2 ), in which a 2D topological excitonic insulator (2D TEI) forms. However, the detailed mechanism of the 2D bulk gap formation in WTe2 , in particular with regard to the role of Coulomb interactions, has remained a subject of ongoing debate. Here, it shows that WTe2 is susceptible to a gate-tunable quantum phase transition, evident from an abrupt collapse of its 2D bulk energy gap upon ambipolar field-effect doping. Such gate tunability of a 2D TEI, into either n- and p-type semimetals, promises novel handles of control over non-trivial 2D superconductivity with excitonic pairing.