Effect of Rabbit ATG PK on Outcomes after TCR-αß/CD19-depleted Pediatric Haploidentical HCT for Hematologic Malignancy.

We hypothesized that inferior disease-free survival (DFS) seen in older patients undergoing αß/CD19-T-cell depleted (AB-TCD) haploidentical hematopoietic cell transplantation (HCT) for patients with hematologic malignancies was due to excessive exposure to rabbit antithymocyte globulin (rATG; Thymoglobulin®). Between 2015-2023, 163 patients with a median age of 13 years (range, 0.4-27.4) underwent AB-TCD haploidentical HCT for treatment of ALL (n=98), AML/MDS (n=49), or other malignancies (n=16) at nine centers on two prospective trials. Exposures of rATG pre- and post-HCT were predicted with a validated pharmacokinetic (PK) model. ROC curves were used to identify optimal target windows of rATG exposure related to outcomes. We identified four quadrants of rATG exposure - quadrant 1 (n=52): high pre-HCT AUC (≥50 AU*day/mL) and low post-HCT (<12 AU*day/L); quadrant 2 (n=47): both low pre-HCT and post-HCT AUCs, quadrant 3 (n=13): low pre-HCT AUC and high post-HCT, and quadrant 4 (n=51): both high pre- and post-HCT AUCs. Quadrant 1 had a 3-year DFS of 86.5% (95% CI, 76.3-96.7%), compared to quadrant 2 (64.6%; 95% CI, 49.1-80.1%), quadrant 3 (32.9%; 95% CI, 0.1-80.5%) or quadrant 4 (48.2%; 95% CI, 22.1-63.3%) (p<0.001). Adjusted regression analysis demonstrated additional factors associated with increased hazard for worse DFS: MRD-positivity (HR=2.45; 1.36-4.41; p=0.003) and CMV R+/D- serostatus (HR=3.33; 1.8-6.16; p<0.001). Non-optimal rATG exposure exhibited the strongest effect in unadjusted (HR=4.24; 1.79-10.03; p=0.001) and adjusted (MRD status or CMV serostatus) analyses (HR=3.84, 1.63-9.05; p=0.002). High exposure to rATG post-HCT is associated with inferior DFS following AB-TCD haploidentical HCT for pediatric patients with hematologic malignancies. Model-based dosing of rATG to achieve optimal exposure may improve DFS. Clinical trials: NCT02646839 & NCT04337515.

Overcoming Digital Exclusion during the COVID-19 Pandemic: Impact of Mobile Technology for Survivors of Modern Slavery and Human Trafficking - A Mixed Method Study of Survivors and Support Service Provider Views.

This collaborative, qualitative study aimed to understand the impact that smartphone technology can have for survivors of human trafficking and slavery in relation to their mental health, well-being and social connections, access to services and levels of independence and isolation. The pilot project was conceived shortly before the COVID-19 pandemic by anti-slavery charity Unseen and the telecommunications company BT, in recognition of the potential of smartphone technology to enhance survivors' recovery from trauma. BT donated smartphones and SIM cards with 6-month call and data packages that Unseen distributed to survivors they were supporting. Seventy-four survivors received a smartphone; 27 survivors were interviewed and 12 Unseen staff completed a free-text survey exploring perceptions of the intervention. A well-being capability measure (ICECAP-A) was conducted with survivors at the start and end of the project. Researchers analyzed all data, triangulating across data sources. Analysis showed support staff play a key role in the success of the intervention to increase digital inclusion. Smartphones helped survivors develop skills to assist them in their move toward independent living and navigate the systems and services in their environment. The intervention was highly valuable to survivors for support, integration and access to services. Our findings suggest that suitable technology packages should be assessed for inclusion as standard support for survivors of modern slavery within the UK Government's National Referral Mechanism (NRM). Achieving this change in NRM policy will go some way to realize the United Nations 2030 Agenda, specifically SDG 3 (Good health and wellbeing for all at all ages), SDG 8 (Decent Work-inclusive and sustained economic growth) and SDG 16 (Peace, justice and strong institutions-inclusive societies and access to justice for all).

Invasion on So Grand a Scale: Darwin, Lyell, and Invasive Species.

The importance of naturalization-the establishment of species introduced into foreign places-to the early development of Darwin's theory of evolution deserves historical attention. Introduced and invasive European species presented Darwin with interpretive challenges during his service as naturalist on the HMS Beagle. Species naturalization and invasive species strained the geologist Charles Lyell's creationist view of the organic world, a view which Darwin adopted during the voyage of the Beagle but came to question afterward. I suggest that these phenomena primed Darwin to question the "stability of species." I then examine the role of introduced and invasive species in Darwin's early theorizing and negotiation with Lyell's ideas, recorded in his post-voyage "transmutation notebooks." Therein, the subject was an inflection point in his contention with Lyell's views and moreover, his theorizing on invasive species occasioned some of his earliest inklings of natural selection. Finally, I examine how naturalization was crucial to Lyell's own eventual conversion to evolutionism. I conclude with brief reflections on the implications of this narrative for our understanding of Darwin's reasoning, his intellectual relationship to Lyell, and the historical context that shaped his theory.

Genetic parentage reveals the (un)natural history of Central Valley hatchery steelhead.

Populations composed of individuals descended from multiple distinct genetic lineages often feature significant differences in phenotypic frequencies. We considered hatchery production of steelhead, the migratory anadromous form of the salmonid species Oncorhynchus mykiss, and investigated how differences among genetic lineages and environmental variation impacted life history traits. We genotyped 23,670 steelhead returning to the four California Central Valley hatcheries over 9 years from 2011 to 2019, confidently assigning parentage to 13,576 individuals to determine age and date of spawning and rates of iteroparity and repeat spawning within each year. We found steelhead from different genetic lineages showed significant differences in adult life history traits despite inhabiting similar environments. Differences between coastal and Central Valley steelhead lineages contributed to significant differences in age at return, timing of spawning, and rates of iteroparity among programs. In addition, adaptive genomic variation associated with life history development in this species varied among hatchery programs and was associated with the age of steelhead spawners only in the coastal lineage population. Environmental variation likely contributed to variations in phenotypic patterns observed over time, as our study period spanned both a marine heatwave and a serious drought in California. Our results highlight evidence of a strong genetic component underlying known phenotypic differences in life history traits between two steelhead lineages.

Genome-matched treatments and patient outcomes in the Maine Cancer Genomics Initiative (MCGI).

Genomic tumor testing (GTT) is an emerging technology aimed at identifying variants in tumors that can be targeted with genomically matched drugs. Due to limited resources, rural patients receiving care in community oncology settings may be less likely to benefit from GTT. We analyzed GTT results and observational clinical outcomes data from patients enrolled in the Maine Cancer Genomics Initiative (MCGI), which provided access to GTTs; clinician educational resources; and genomic tumor boards in community practices in a predominantly rural state. 1603 adult cancer patients completed enrollment; 1258 had at least one potentially actionable variant identified. 206 (16.4%) patients received a total of 240 genome matched treatments, of those treatments, 64% were FDA-approved in the tumor type, 27% FDA-approved in a different tumor type and 9% were given on a clinical trial. Using Inverse Probability of Treatment Weighting to adjust for baseline characteristics, a Cox proportional hazards model demonstrated that patients who received genome matched treatment were 31% less likely to die within 1 year compared to those who did not receive genome matched treatment (HR: 0.69; 95% CI: 0.52-0.90; p-value: 0.006). Overall, GTT through this initiative resulted in levels of genome matched treatment that were similar to other initiatives, however, clinical trials represented a smaller share of treatments than previously reported, and "off-label" treatments represented a greater share. Although this was an observational study, we found evidence for a potential 1-year survival benefit for patients who received genome matched treatments. These findings suggest that when disseminated and implemented with a supportive infrastructure, GTT may benefit cancer patients in rural community oncology settings, with further work remaining on providing genome-matched clinical trials.

HuD (ELAVL4) gain-of-function impairs neuromuscular junctions and induces apoptosis in in vitro and in vivo models of amyotrophic lateral sclerosis.

Early defects at the neuromuscular junction (NMJ) are among the first hallmarks of the progressive neurodegenerative disease amyotrophic lateral sclerosis (ALS). According to the "dying back" hypothesis, disruption of the NMJ not only precedes, but is also a trigger for the subsequent degeneration of the motoneuron in both sporadic and familial ALS, including ALS caused by the severe FUS pathogenic variant P525L. However, the mechanisms linking genetic and environmental factors to NMJ defects remain elusive. By taking advantage of co-cultures of motoneurons and skeletal muscle derived from human induced pluripotent stem cells (iPSCs), we show that the neural RNA binding protein HuD (ELAVL4) may underlie NMJ defects and apoptosis in FUS-ALS. HuD overexpression in motoneurons phenocopies the severe FUSP525L mutation, while HuD knockdown in FUSP525L co-cultures produces phenotypic rescue. We validated these findings in vivo in a Drosophila FUS-ALS model. Neuronal-restricted overexpression of the HuD-related gene, elav, produces per se a motor phenotype, while neuronal-restricted elav knockdown significantly rescues motor dysfunction caused by FUS. Finally, we show that HuD levels increase upon oxidative stress in human motoneurons and in sporadic ALS patients with an oxidative stress signature. On these bases, we propose HuD as an important player downstream of FUS mutation in familial ALS, with potential implications for sporadic ALS related to oxidative stress.

Valproate, risperidone, and paliperidone: A case of valproate-induced hyperammonemic encephalopathy.

Hyperammonemia is a well-known adverse effect of valproate that can progress to a potentially fatal condition known as valproate-induced hyperammonemic encephalopathy (VHE). VHE is more common when valproate is used in combination therapy with other antiepileptic medications. A growing number of case reports have pointed to a possible interaction with the antipsychotic risperidone leading to an increased risk of VHE. We present a case of VHE in which a 20-year-old male patient with bipolar affective disorder developed VHE when on concomitant valproate, risperidone, and paliperidone palmitate. On the seventh day of treatment with oral risperidone, oral divalproex sodium was added. Intramuscular paliperidone palmitate was initiated on day 13, and oral risperidone was discontinued after the second loading dose on day 16. The following day, the patient displayed worsening psychomotor retardation, swaying gait, drowsiness, and vomiting. The patient was found to have hyperammonemia and transferred to the emergency department for treatment of suspected VHE.

gPKPDviz: A flexible R shiny tool for pharmacokinetic/pharmacodynamic simulations using mrgsolve.

GPKPDviz is a Shiny application (app) dedicated to real-time simulation, visualization, and assessment of the pharmacokinetic/pharmacodynamic (PK/PD) models. Within the app, gPKPDviz is capable of generating virtual populations and complex dosing and sampling scenarios, which, together with the streamlined workflow, is designed to efficiently assess the impact of covariates and dosing regimens on PK/PD end points. The actual population data from clinical trials can be loaded into the app for simulation if desired. The app-generated dosing regimens include single or multiple dosing, and more complex regimens, such as loading doses or intermittent dosing. When necessary, the dosing regimens can be defined externally and loaded to the app for simulation. Using mrgsolve as the simulation engine, gPKPDviz is typically used for population simulation, however, with a slight modification of the mrgsolve model, gPKPDviz is capable of performing individual simulations with individual post hoc parameters, individual dosing logs, and individual sampling timepoints through an external dataset. A built-in text editor has a debugging feature for the mrgsolve model, providing the same error messages as model compilation in R. GPKPDviz has had stringent validation by comparing simulation results between the app and using mrgsolve in R. GPKPDviz is a member of the suite of Modeling and Simulation Shiny apps developed at Genentech to facilitate the typical modeling work in Clinical Pharmacology. For broader access to the Pharmacometric community, gPKPDviz has been published as an open-source application in GitHub under the terms of GNU General Public License.

Genetic and environmental drivers of migratory behavior in western burrowing owls and implications for conservation and management.

Migration is driven by a combination of environmental and genetic factors, but many questions remain about those drivers. Potential interactions between genetic and environmental variants associated with different migratory phenotypes are rarely the focus of study. We pair low coverage whole genome resequencing with a de novo genome assembly to examine population structure, inbreeding, and the environmental factors associated with genetic differentiation between migratory and resident breeding phenotypes in a species of conservation concern, the western burrowing owl (Athene cunicularia hypugaea). Our analyses reveal a dichotomy in gene flow depending on whether the population is resident or migratory, with the former being genetically structured and the latter exhibiting no signs of structure. Among resident populations, we observed significantly higher genetic differentiation, significant isolation-by-distance, and significantly elevated inbreeding. Among migratory breeding groups, on the other hand, we observed lower genetic differentiation, no isolation-by-distance, and substantially lower inbreeding. Using genotype-environment association analysis, we find significant evidence for relationships between migratory phenotypes (i.e., migrant versus resident) and environmental variation associated with cold temperatures during the winter and barren, open habitats. In the regions of the genome most differentiated between migrants and residents, we find significant enrichment for genes associated with the metabolism of fats. This may be linked to the increased pressure on migrants to process and store fats more efficiently in preparation for and during migration. Our results provide a significant contribution toward understanding the evolution of migratory behavior and vital insight into ongoing conservation and management efforts for the western burrowing owl.

Distinct patterns of inheritance shape life-history traits in steelhead trout.

Life-history variation is the raw material of adaptation, and understanding its genetic and environmental underpinnings is key to designing effective conservation strategies. We used large-scale genetic pedigree reconstruction of anadromous steelhead trout (Oncorhynchus mykiss) from the Russian River, CA, USA, to elucidate sex-specific patterns of life-history traits and their heritability. SNP data from adults returning from sea over a 14-year period were used to identify 13,474 parent-offspring trios. These pedigrees were used to determine age structure, size distributions and family sizes for these fish, as well as to estimate the heritability of two key life-history traits, spawn date and age at maturity (first reproduction). Spawn date was highly heritable (h2 = 0.73) and had a cross-sex genetic correlation near unity. We provide the first estimate of heritability for age at maturity in ocean-going fish from this species and found it to be highly heritable (h2 from 0.29 to 0.62, depending on sex and method), with a much lower genetic correlation across sexes. We also evaluated genotypes at a migration-associated inversion polymorphism and found sex-specific correlations with age at maturity. The significant heritability of these two key reproductive traits in these imperiled fish, and their patterns of inheritance in the two sexes, is consistent with predictions of both natural and sexually antagonistic selection (sexes experience opposing selection pressures). This emphasizes the importance of anthropogenic factors, including hatchery practices and ecosystem modifications, in shaping the fitness of this species, thus providing important guidance for management and conservation efforts.

CLIP-Seq analysis enables the design of protective ribosomal RNA bait oligonucleotides against C9ORF72 ALS/FTD poly-GR pathophysiology.

Amyotrophic lateral sclerosis and frontotemporal dementia patients with a hexanucleotide repeat expansion in C9ORF72 (C9-HRE) accumulate poly-GR and poly-PR aggregates. The pathogenicity of these arginine-rich dipeptide repeats (R-DPRs) is thought to be driven by their propensity to bind low-complexity domains of multivalent proteins. However, the ability of R-DPRs to bind native RNA and the significance of this interaction remain unclear. Here, we used computational and experimental approaches to characterize the physicochemical properties of R-DPRs and their interaction with RNA. We find that poly-GR predominantly binds ribosomal RNA (rRNA) in cells and exhibits an interaction that is predicted to be energetically stronger than that for associated ribosomal proteins. Critically, modified rRNA "bait" oligonucleotides restore poly-GR-associated ribosomal deficits and ameliorate poly-GR toxicity in patient neurons and Drosophila models. Our work strengthens the hypothesis that ribosomal function is impaired by R-DPRs, highlights a role for direct rRNA binding in mediating ribosomal dysfunction, and presents a strategy for protecting against C9-HRE pathophysiological mechanisms.

Drosha-dependent microRNAs modulate FUS-mediated neurodegeneration in vivo.

Mutations in the Fused in Sarcoma (FUS) gene cause the familial and progressive form of amyotrophic lateral sclerosis (ALS). FUS is a nuclear RNA-binding protein involved in RNA processing and the biogenesis of a specific set of microRNAs. Here we report that Drosha and two previously uncharacterized Drosha-dependent miRNAs are strong modulators of FUS expression and prevent the cytoplasmic segregation of insoluble mutant FUS in vivo. We demonstrate that depletion of Drosha mitigates FUS-mediated degeneration, survival and motor defects in Drosophila. Mutant FUS strongly interacts with Drosha and causes its cytoplasmic mis-localization into the insoluble FUS inclusions. Reduction in Drosha levels increases the solubility of mutant FUS. Interestingly, we found two Drosha dependent microRNAs, miR-378i and miR-6832-5p, which differentially regulate the expression, solubility and cytoplasmic aggregation of mutant FUS in iPSC neurons and mammalian cells. More importantly, we report different modes of action of these miRNAs against mutant FUS. Whereas miR-378i may regulate mutant FUS inclusions by preventing G3BP-mediated stress granule formation, miR-6832-5p may affect FUS expression via other proteins or pathways. Overall, our research reveals a possible association between ALS-linked FUS mutations and the Drosha-dependent miRNA regulatory circuit, as well as a useful perspective on potential ALS treatment via microRNAs.

Low-coverage whole genome sequencing for highly accurate population assignment: Mapping migratory connectivity in the American Redstart (Setophaga ruticilla).

Understanding the geographic linkages among populations across the annual cycle is an essential component for understanding the ecology and evolution of migratory species and for facilitating their effective conservation. While genetic markers have been widely applied to describe migratory connections, the rapid development of new sequencing methods, such as low-coverage whole genome sequencing (lcWGS), provides new opportunities for improved estimates of migratory connectivity. Here, we use lcWGS to identify fine-scale population structure in a widespread songbird, the American Redstart (Setophaga ruticilla), and accurately assign individuals to genetically distinct breeding populations. Assignment of individuals from the nonbreeding range reveals population-specific patterns of varying migratory connectivity. By combining migratory connectivity results with demographic analysis of population abundance and trends, we consider full annual cycle conservation strategies for preserving numbers of individuals and genetic diversity. Notably, we highlight the importance of the Northern Temperate-Greater Antilles migratory population as containing the largest proportion of individuals in the species. Finally, we highlight valuable considerations for other population assignment studies aimed at using lcWGS. Our results have broad implications for improving our understanding of the ecology and evolution of migratory species through conservation genomics approaches.

Observation of fractionally quantized anomalous Hall effect.

The integer quantum anomalous Hall (QAH) effect is a lattice analogue of the quantum Hall effect at zero magnetic field1-3. This phenomenon occurs in systems with topologically non-trivial bands and spontaneous time-reversal symmetry breaking. Discovery of its fractional counterpart in the presence of strong electron correlations, that is, the fractional QAH effect4-7, would open a new chapter in condensed matter physics. Here we report the direct observation of both integer and fractional QAH effects in electrical measurements on twisted bilayer MoTe2. At zero magnetic field, near filling factor ν = -1 (one hole per moiré unit cell), we see an integer QAH plateau in the Hall resistance Rxy quantized to h/e2 ± 0.1%, whereas the longitudinal resistance Rxx vanishes. Remarkably, at ν = -2/3 and -3/5, we see plateau features in Rxy at [Formula: see text] and [Formula: see text], respectively, whereas Rxx remains small. All features shift linearly versus applied magnetic field with slopes matching the corresponding Chern numbers -1, -2/3 and -3/5, precisely as expected for integer and fractional QAH states. Additionally, at zero magnetic field, Rxy is approximately 2h/e2 near half-filling (ν = -1/2) and varies linearly as ν is tuned. This behaviour resembles that of the composite Fermi liquid in the half-filled lowest Landau level of a two-dimensional electron gas at high magnetic field8-14. Direct observation of the fractional QAH and associated effects enables research in charge fractionalization and anyonic statistics at zero magnetic field.

Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import.

Loss-of-function variants in NIMA-related kinase 1 (NEK1) constitute a major genetic cause of amyotrophic lateral sclerosis (ALS), accounting for 2 to 3% of all cases. However, how NEK1 mutations cause motor neuron (MN) dysfunction is unknown. Using mass spectrometry analyses for NEK1 interactors and NEK1-dependent expression changes, we find functional enrichment for proteins involved in the microtubule cytoskeleton and nucleocytoplasmic transport. We show that α-tubulin and importin-ß1, two key proteins involved in these processes, are phosphorylated by NEK1 in vitro. NEK1 is essential for motor control and survival in Drosophila models in vivo, while using several induced pluripotent stem cell (iPSC)-MN models, including NEK1 knockdown, kinase inhibition, and a patient mutation, we find evidence for disruptions in microtubule homeostasis and nuclear import. Notably, stabilizing microtubules with two distinct classes of drugs restored NEK1-dependent deficits in both pathways. The capacity of NEK1 to modulate these processes that are critically involved in ALS pathophysiology renders this kinase a formidable therapeutic candidate.

Demographic Factors Predict Risk of Lymph Node Involvement in Patients with Endometrial Adenocarcinoma.

The presence of lymph node positivity (LN+) guides adjuvant treatment for endometrial adenocarcinoma (EAC) patients, but recommendations regarding LN evaluation at the time of primary surgery remain variable. Sociodemographic factors in addition to pathologic tumor characteristics may more accurately predict risk of LN+ in EAC patients. Patients diagnosed between 2004 and 2016 with pathologic T1-T2 EAC who had at least one lymph node sampled at the time of surgery in the National Cancer Data Base were included. Pathologic primary tumor predictors of LN+ were identified using logistic regression. To predict overall, pelvic only, and paraaortic and/or pelvic LN+, nomograms were generated. Among the 35,170 EAC patients included, 2864 were node positive. Using multivariable analysis, younger patient age (OR 0.98, 95% CI 0.98-0.99, p < 0.001), black versus white race (OR 1.19, 95% CI 1.01-1.40, p = 0.04), increasing pathologic tumor stage and grade, increase in tumor size, and presence of lymphovascular invasion were predictive of regional LN+. Both black versus white (OR 1.64, 95% CI 1.27-2.09, p < 0.001) and other versus white race (OR 1.54, 95% CI 1.12-2.07, p = 0.006) strongly predicted paraaortic LN+ in the multivariable analysis. Independent subset analyses of black and white women revealed that tumor grade was a stronger predictor of LN+ among black women. In addition to standard pathologic tumor features, patient age and race were associated with a higher risk of regional LN+ generally and paraaortic LN+ specifically. This information may inform adjuvant treatment decisions and guide future studies.

Evaluating Physician Emotion Regulation in Serious Illness Conversations Using Multimodal Assessment.

CONTEXT: Emotion regulation by the physician can influence the effectiveness of serious illness conversations. The feasibility of multimodal assessment of emotion regulation during these conversations is unknown. OBJECTIVES: To develop and assess an experimental framework for evaluating physician emotion regulation during serious illness conversations. METHODS: We developed and then assessed a multimodal assessment framework for physician emotion regulation using a cross-sectional, pilot study on physicians trained in the Serious Illness Conversation Guide (SICG) in a simulated, telehealth encounter. Development of the assessment framework included a literature review and subject matter expert consultations. Our predefined feasibility endpoints included: an enrollment rate of ≥60% of approached physicians, >90% completion rate of survey items, and <20% missing data from wearable heart rate sensors. To describe physician emotion regulation, we performed a thematic analysis of the conversation, its documentation, and physician interviews. RESULTS: Out of 12 physicians approached, 11 (92%) SICG-trained physicians enrolled in the study: five medical oncology and six palliative care physicians. All 11 completed the survey (100% completion rate). Two sensors (chest band, wrist sensor) had <20% missing data during study tasks. The forearm sensor had >20% missing data. The thematic analysis found that physicians': 1) overarching goal was to move beyond prognosis to reasonable hope; 2) tactically focused on establishing a trusting, supportive relationship; and 3) possessed incomplete awareness of their emotion regulation strategies. CONCLUSION: Our novel, multimodal assessment of physician emotion regulation was feasible in a simulated SICG encounter. Physicians exhibited an incomplete understanding of their emotion regulation strategies.

Re-examining predictors of pathologic lymph node positivity in clinically node negative oral cavity cancer.

BACKGROUND: Elective lymph node dissection (ELND) is performed for many early-stage oral cavity squamous cell carcinomas (OCSCC) with clinically negative necks (cN0), often guided by depth of invasion (DOI). However, DOI is less validated in non-tongue OC sites, and often correlates with other adverse features. We sought to evaluate the utility of DOI versus other factors for independently predicting pathologic lymph node positivity (pN+) in patients with cN0 OCSCC. METHODS: Patients with cN0 OCSCC diagnosed from 2010 to 2015 undergoing primary surgery were identified in the National Cancer Data Base. RESULTS: 5060 cN0 OCSCC patients met inclusion criteria. The presence of lymphovascular invasion (LVI) was the strongest independent predictor of pN+ (odds ratio [OR] = 4.27, 95% confidence interval [CI] 3.36-5.42, P < 0.001). High histologic grade also strongly predicted pN+ (OR 3.33, 95% CI 2.20-4.60, P < 0.001). DOI had no association with the likelihood of pN+ among all OCSCC patients, but was predictive among patients within the oral tongue subset (OR 2.01, 95% CI 1.08-3.73, P = 0.03 for DOI > 20 mm vs. DOI: 2.0-3.99 mm). CONCLUSION: LVI and grade are the strongest independent predictors of pN+ in cN0 OCSCC. Contrary to prior studies, DOI was not found to be a predictor of pN+ among patients with cN0 OCSCC. However, DOI was a predictor of pN+ or the oral tongue subset, albeit still less strongly than LVI or grade. These findings could potentially be used to better identify a subset of cN0 OCSCC patients who could be considered for omission of ELND in future studies.

Chronic active Epstein-Barr virus and hydroa vacciniforme-like lymphoproliferative disorder in a pediatric patient complicated by fatal ruptured cerebral artery aneurysm.

Hydroa vacciniforme-like lymphoproliferative disorder (HV-LPD) is a rare cutaneous form of chronic active Epstein-Barr virus (CAEBV) that presents with vesicular lesions induced by sun-exposure. Arterial aneurysm is a rare but potentially fatal complication of CAEBV and HV-LPD.