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Purpose Patient-reported outcome measures (PRO) are critical tools to developing an understanding of cancer patients’ experience. This paper presents some of the lesser-understood implications of using patient-reported outcome measures in clinical research. Methods This study uses a combination of literature sources, real-world examples from supportive care studies, and statistical simulations to demonstrate the operating characteristics of patient-reported measures. Results It is demonstrated that care must be taken in the analysis of PROs as the assumptions of the most common mean-based approaches are often violated including linearity, normally distributed errors, interference with asymptotic convergence via boundary values, and more. Further, the implications of subjective discretization are shown to reduce the apparent statistical power of PRO-based studies. Conclusions PRO-based studies must be designed conscientiously as each PRO item will demonstrate a varying degree of subjectivity in a given population. Sample sizes of randomized studies using PROs must be inflated to account for this. Analyses should consider using ordinal statistical models until such time as the assumptions of mean-based models can be verified.

Purpose This review was designed to compile the currently available evidence on the prophylactic use of gabapentin in the head and neck cancer patient population. Methods A systematic search was conducted of PubMed, Web of Science, and Google Scholar to identify articles related to the use of prophylactic gabapentin in patients undergoing head and neck cancer therapy. Candidate studies were screened for inclusion and a subsequent bias assessment was conducted by multiple reviewers. Meta-analysis was conducted in cases in which the studies used compatible outcome measures. Results Ten studies were identified that met the inclusion criteria and were assessed for bias. Among the four small studies that examined pain prevention, 2 were positive and 2 were inconclusive. Three of the four studies examiniRDng opioid use noted less need for opioids in the treatment arm. Meta-analysis of the pertinent studies showed no difference in feeding tube placement (RD = 0.64%, 95%CI: (− 25.8%, 27.1%), p = 0.962) but substantially less weight loss among those in the treatment arm (p = 0.047). Conclusion Prophylactic gabapentin appears to be a promising treatment option for preventing pain, reducing opioids, and reducing weight loss in patients undergoing head and neck cancer therapy. However, the studies on the treatment to date are small and several have a substantial risk of bias.

Background Commonly used predictive models for postoperative pulmonary complications (PPCs) do not perform when applied to head and neck cases. A head and neck-specific risk prediction tool is needed. Methods Data on 794 free flap head and neck surgery cases at a single center were abstracted from the electronic medical record. Each case was reviewed for the development of PPCs. A predictive model was developed and was then compared to existing predictive models for PPCs. Results The least absolute shrinkage and selection operator procedure identified age, alcohol use, history of congestive heart failure, preoperative packed cell volume, preoperative oxygen saturation, and preoperative metabolic equivalents as predictors of PPCs in the head and neck population. The model demonstrated an area under the receiving operating characteristic curve of 0.75 (0.69-0.80) with moderately good calibration. Comparisons to the performance of existing models demonstrate superior performance. Conclusions The model for the development of PPCs developed in this article displays superior performance to existing models.

Background Radiation for patients with head and neck cancer (HNC) is associated with painful mucositis that impacts the delivery of treatment and contributes to high symptom burden. Methods This was a prospective, randomized pilot trial. Eligible patients received primary or adjuvant chemoradiation. Patients were randomized to usual care vs usual care plus gabapentin titrated to drug tolerance during radiation. Patients completed a symptom survey at baseline and weekly during therapy. Results Seventy-nine patients were enrolled in the study (38 control, 41 treatment). At interim analysis, gabapentin use resulted in a decrease in pain (P = .004), with the biggest decreases being in the latter weeks of therapy. By week 7, the median pain score in the treatment group was below the 0.25 quantile of the control group. Conclusion Prophylactic use of gabapentin during chemoradiation for HNC patients resulted in a decrease in pain, neurosensory symptoms, and general systemic symptoms.

Transfer RNAs (tRNAs) are products of RNA polymerase III (Pol III) and essential for mRNA translation and ultimately cell growth and proliferation. Whether and how individual tRNA genes are specifically regulated is not clear. Here, we report that SOX4, a well-known Pol II-dependent transcription factor that is critical for neurogenesis and reprogramming of somatic cells, also directly controls, unexpectedly, the expression of a subset of tRNA genes and therefore protein synthesis and proliferation of human glioblastoma cells. Genome-wide location analysis through chromatin immunoprecipitation-sequencing uncovers specific targeting of SOX4 to a subset of tRNA genes, including those for tRNAi Met . Mechanistically, sequence-specific SOX4-binding impedes the recruitment of TATA box binding protein and Pol III to tRNA genes and thereby represses their expression. CRISPR/Cas9-mediated down-regulation of tRNAi Met greatly inhibits growth and proliferation of human glioblastoma cells. Conversely, ectopic tRNAi Met partially rescues SOX4-mediated repression of cell proliferation. Together, these results uncover a regulatory mode of individual tRNA genes to control cell behavior. Such regulation may coordinate codon usage and translation efficiency to meet the demands of diverse tissues and cell types, including cancer cells.

PurposeA significant barrier to adoption of de-escalated treatment protocols for human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is that few predictors of poor prognosis exist. We conducted the first large whole-genome sequencing (WGS) study to characterize the genetic variation of the HPV16 genome and to evaluate its association with HPV-OPC patient survival.Patients and Methods460 OPCs from 2 large US medical centers (1980-2017) underwent HPV16 WGS. Site-specific variable positions (SNPs) across the HPV16 genome were identified. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival by HPV16 SNPs. Harrell C-index and time-dependent positive predictive value (PPV) curves and areas under the PPV curves were used to evaluate the predictive accuracy of HPV16 SNPs for overall survival.Results384 OPCs (83.48%) passed quality control filters with sufficient depth and coverage of HPV16 genome sequencing to be analyzed. 284 HPV16 SNPs with a minor allele frequency >1% were identified. Eight HPV16 SNPs were significantly associated with worse survival after false discovery rate (FDR) correction (individual prevalence:1.0%-5.5%; combined prevalence: 15.10%); E1 gene position 1053 (HR for overall survival [HRos]:3.75,95%CI:1.77-7.95;Pfdr=0.0099); L2 gene positions 4410 (HRos:5.32,95%CI:1.91-14.81;Pfdr=0.0120), 4539 (HRos:6.54,95%CI:2.03-21.08;Pfdr=0.0117); 5050 (HRos:6.53,95%CI:2.34-18.24;Pfdr=0.0030) and 5254 (HRos:7.76,95%CI:2.41-24.98;Pfdr=0.0030); and L1 gene positions 5962 (HRos:4.40,95%CI:1.88-10.31;Pfdr=0.0110) and 6025 (HRos:5.71,95%CI:2.43-13.41;Pfdr=0.0008) and position 7173 within the upstream regulatory region (HRos:9.90,95%CI:3.05-32.12;Pfdr=0.0007). Median survival time for patients with ≥1 high-risk HPV16 SNPs was 3.96 years compared to 18.67 years for patients without a high-risk SNP; log-rank test PP P =0.008).ConclusionsHPV16 genetic variation is associated with HPV-OPC prognosis and can improve prognostic accuracy.

Acute kidney injury (AKI) after endovascular aortic repair (EVAR) occurs in 20% of patients and is an independent predictor of death. Higher preoperative high-density lipoprotein (HDL) cholesterol concentration before revascularization of chronic limb ischemia is associated with a lower risk of AKI. Further, preoperative statin use has been shown to be associated with a decreased risk of AKI after EVAR. We hypothesized that both preoperative statin use and higher preoperative HDL are associated with a lower risk of AKI in patients undergoing EVAR. Charts from adult patients that underwent EVAR were selected using the ICD codes (n=251). Each chart was reviewed for demographic and medical information, preoperative and postoperative serum creatinine concentrations, and preoperative HDL concentration. One hundred and three patients had available statin medication, serum creatinine, and HDL concentrations. The associations between statin dose, HDL concentration and maximum serum creatinine change from baseline in the first 48 postoperative hours was assessed using multivariable linear regression models, adjusted for AKI risk factors. Preoperative HDL concentration was not correlated with preoperative statin dose (Pearson’s R=0.0515, p=0.57). Higher preoperative statin doses (atorvastatin equivalents) and higher preoperative HDL concentrations were associated with lower serum creatinine rise (p=0.042 and 0.002 respectively, Figure). When both preoperative statin dose and preoperative HDL concentration were included in the model, both variables lost significance, suggesting HDL may mediate the relationship between preoperative statin dose and postoperative AKI. Higher preoperative HDL concentrations and statin doses were associated with less postoperative AKI. Future work involves identifying the biological mechanism underlying these associations as a first step towards developing new therapies to prevent AKI following EVAR.

PURPOSE To provide evidence-based recommendations for prevention and management of salivary gland hypofunction and xerostomia induced by nonsurgical cancer therapies. METHODS Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and ASCO convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. PubMed, EMBASE, and Cochrane Library were searched for randomized controlled trials published between January 2009 and June 2020. The guideline also incorporated two previous systematic reviews conducted by MASCC/ISOO, which included studies published from 1990 through 2008. RESULTS A total of 58 publications were identified: 46 addressed preventive interventions and 12 addressed therapeutic interventions. A majority of the evidence focused on the setting of radiation therapy for head and neck cancer. For the prevention of salivary gland hypofunction and/or xerostomia in patients with head and neck cancer, there is high-quality evidence for tissue-sparing radiation modalities. Evidence is weaker or insufficient for other interventions. For the management of salivary gland hypofunction and/or xerostomia, intermediate-quality evidence supports the use of topical mucosal lubricants, saliva substitutes, and agents that stimulate the salivary reflex. RECOMMENDATIONS For patients who receive radiation therapy for head and neck cancer, tissue-sparing radiation modalities should be used when possible to reduce the risk of salivary gland hypofunction and xerostomia. Other risk-reducing interventions that may be offered during radiation therapy for head and neck cancer include bethanechol and acupuncture. For patients who develop salivary gland hypofunction and/or xerostomia, interventions include topical mucosal lubricants, saliva substitutes, and sugar-free lozenges or chewing gum. For patients with head and neck cancer, oral pilocarpine and oral cevimeline, acupuncture, or transcutaneous electrostimulation may be offered after radiation therapy. Additional information can be found at www.asco.org/supportive-care-guidelines .

A major challenge emerging in genomic medicine is how to assess best disease risk from rare or novel variants found in disease-related genes. The expanding volume of data generated by very large phenotyping efforts coupled to DNA sequence data presents an opportunity to reinterpret genetic liability of disease risk. Here we propose a framework to estimate the probability of disease given the presence of a genetic variant conditioned on features of that variant. We refer to this as the penetrance, the fraction of all variant heterozygotes that will present with disease. We demonstrate this methodology using a well-established disease-gene pair, the cardiac sodium channel gene SCN5A and the heart arrhythmia Brugada syndrome. From a review of 756 publications, we developed a pattern mixture algorithm, based on a Bayesian Beta-Binomial model, to generate SCN5A penetrance probabilities for the Brugada syndrome conditioned on variant-specific attributes. These probabilities are determined from variant-specific features (e.g. function, structural context, and sequence conservation) and from observations of affected and unaffected heterozygotes. Variant functional perturbation and structural context prove most predictive of Brugada syndrome penetrance., Author summary The clinical implications for genetic variants, even definitively pathogenic variants, can vary strikingly across individuals. Lack of evidence to estimate the probability of disease from identified genetic variants, especially rare variants, presents a major barrier to integrating genotype information into clinical care. Here we advance an approach to estimate the penetrance, or positive predictive value of the discovery of a genetic variant, in service of advancing the use of genetic information in personalized medicine.

Rare variants in the cardiac potassium channel KV7.1 (KCNQ1) and sodium channel NaV1.5 (SCN5A) are implicated in genetic disorders of heart rhythm, including congenital long QT and Brugada syndromes (LQTS, BrS), but also occur in reference populations. We previously reported two sets of NaV1.5 (n = 356) and KV7.1 (n = 144) variants with in vitro characterized channel currents gathered from the literature. Here we investigated the ability to predict commonly reported NaV1.5 and KV7.1 variant functional perturbations by leveraging diverse features including variant classifiers PROVEAN, PolyPhen-2, and SIFT; evolutionary rate and BLAST position specific scoring matrices (PSSM); and structure-based features including “functional densities” which is a measure of the density of pathogenic variants near the residue of interest. Structure-based functional densities were the most significant features for predicting NaV1.5 peak current (adj. R2 = 0.27) and KV7.1 + KCNE1 half-maximal voltage of activation (adj. R2 = 0.29). Additionally, use of structure-based functional density values improves loss-of-function classification of SCN5A variants with an ROC-AUC of 0.78 compared with other predictive classifiers (AUC = 0.69; two-sided DeLong test p = .01). These results suggest structural data can inform predictions of the effect of uncharacterized SCN5A and KCNQ1 variants to provide a deeper understanding of their burden on carriers., Graphical abstract Unlabelled Image

Background Human papillomavirus 16 (HPV-16) E6 seropositivity is a promising early marker of human papillomavirus-driven oropharyngeal cancer (HPV-OPC), yet more sensitive imaging modalities are needed before screening is considered. The objective of this study was to determine the sensitivity of transcervical sonography (TCS) for detecting clinically apparent HPV-OPC in comparison with computed tomography (CT) and positron emission tomography (PET)/CT. Methods Fifty-one patients with known or suspected HPV-OPC without prior treatment underwent oropharyngeal TCS and blood collection (for HPV multiplex serology testing). Eight standard sonographic images were collected; primary-site tumors were measured in 3 dimensions if identified. Each patient underwent a full diagnostic workup as part of standard clinical care. The pathologic details, HPV status, final staging, and imaging findings were abstracted from the medical record. The sensitivity of each imaging modality was compared with the final clinical diagnosis (the gold standard). Results Twenty-four base of tongue cancers (47%), 22 tonsillar cancers (43%), and 2 unknown primary cancers (4%) were diagnosed; 3 patients (6%) had no tumors. All p16-tested patients were positive (n = 47). Primary-site tumors were correctly identified in 90.2% (95% confidence interval [CI], 78.6%-96.7%) with TCS, in 69.4% (95% CI, 54.6%-81.7%) with CT, and in 83.3% (95% CI, 68.6%-93.0%) with PET/CT. TCS identified tumors in 10 of 14 cases missed by CT and recognized the absence of tumors in 3 cases for which CT or PET/CT was falsely positive. The smallest sonographically identified primary-site tumor was 0.5 cm in its greatest dimension; the average size was 2.3 cm. Among p16-positive patients, 76.1% (95% CI, 61.2%-87.4%) were seropositive for HPV-16 E6. Conclusions TCS and HPV-16 E6 antibodies are sensitive for the diagnosis of HPV-OPC.

The purpose of this study was to examine patterns of oral health care among patients undergoing oral cancer therapy in order to better understand how oral care is being utilized, what types of providers are being utilized at various stages of cancer therapy, and assessing patients’ satisfaction with the care they received at these stages. An online survey was conducted via the Oral Cancer Foundation’s support group message board. Participants were asked about their oral care immediately prior to cancer therapy, during cancer therapy, and post cancer therapy. The participants were also given the opportunity to provide open response feedback on their oral care which was analyzed qualitatively. Seventy-four participants completed the survey. Participants reported being informed that they needed to receive an oral evaluation 72.6 and 53.6% of the time in the pre- and post-treatment stages, respectively. Compliance with this recommendation was 71.2% pre cancer therapy but dropped precipitously to 49.2% post cancer therapy. Pre- and post-therapy oral care was provided most commonly by the patient’s usual dentist 41.1 and 55.9%, respectively, with medical providers predominating the treatment phase, 77.7%. Patients reported dissatisfaction rates of 29.0, 20.6, and 21.0% sequentially. There is a general lack of consistency with how, when, and from whom oral cancer patients receive their oral health education. It is likely that this contributes to insufficient education resulting in high levels of patient dissatisfaction with their oral care.

The primary objective of this study is to evaluate how attendance at dental visits may change as cancer patients move through pre-diagnosis, diagnosis, and into survivorship. The Health and Retirement Study consists of longitudinal survey data collected biannually detailing financial and health information in subjects over 51 years old. We assessed a subset of 4195 patients who received a new cancer diagnosis during the study period. The odds of reporting a dental visit were examined using a mixed effects logistic regression model. A propensity score weighted analysis of the association between dental attendance and survival was also undertaken. The odds of attending a dental visit were substantially lower in the peri-diagnosis period OR = 0.784 (0.700, 0.876) and the post-diagnosis period OR = 0.734 (0.655, 0.823) compared to pre-diagnosis. This effect persisted in patients who survived for at least 2 years indicating that the decline in oral health visits was not due to low expected survival. After propensity score weighting, patients who attended a dental visit in the peri-diagnosis period demonstrated a reduced hazard of all-cause mortality HR = 0.825 (0.681, 0.979) compared with those with no attendance. Dental attendance decreases by a statistically and clinically significant amount both during and after cancer therapy despite guideline recommendations encouraging dental referral and monitoring for many types of cancer therapy. Attendance at dental appointments during cancer therapy is associated with improved survival, which is likely due to a combination of direct and indirect effects.

Routine testing for p16 immunohistochemistry (with selective HPV-specific test use) has been recommended for clinical practice in oropharyngeal squamous cell carcinoma (OPSCC). Data suggests that the E6H4 clone performs best for this purpose, yet no studies have evaluated the optimal antibody concentration for OPSCC testing. We evaluated three concentrations (undiluted, 1:5, and 1:10) of the primary antibody solution for E6H4 using tissue microarrays from a cohort of 199 OPSCC patients with a > 70% staining cutoff for positivity. Concordance was evaluated using percent agreement and Cohen’s kappa. The concentrations were evaluated for sensitivity and specificity using high risk HPV RNA in situ hybridization (RNA-ISH) and also correlated with Kaplan–Meier overall survival analysis. Inter-rater agreement was very high between p16 results at each concentration and also with RNA in situ hybridization (p

Injury to the adult brain induces activation of local astrocytes, which serves as a compensatory response that modulates tissue damage and recovery. However, the mechanism governing astrocyte activation during brain injury remains largely unknown. Here we provide in vivo evidence that SOX2, a transcription factor critical for stem cells and brain development, is also required for injury-induced activation of adult cortical astrocytes. Genome-wide chromatin immunoprecipitation-seq analysis of mouse cortical tissues reveals that SOX2 binds to regulatory regions of genes associated with signaling pathways that control glial cell activation, such as Nr2e1, Mmd2, Wnt7a, and Akt2. Astrocyte-specific deletion of Sox2 in adult mice greatly diminishes glial response to controlled cortical impact injury and, most unexpectedly, dampens injury-induced cortical loss and benefits behavioral recovery of mice after injury. Together, these results uncover an essential role of SOX2 in somatic cells under pathological conditions and indicate that SOX2-dependent astrocyte activation could be targeted for functional recovery after traumatic brain injury.

Neural cell identity reprogramming strategies aim to treat age-related neurodegenerative disorders with newly induced neurons that regenerate neural architecture and functional circuits in vivo. The isolation and neural differentiation of pluripotent embryonic stem cells provided the first in vitro models of human neurodegenerative disease. Investigation into the molecular mechanisms underlying stem cell pluripotency revealed that somatic cells could be reprogrammed to induced pluripotent stem cells (iPSCs) and these cells could be used to model Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, and Parkinson disease. Additional neural precursor and direct transdifferentiation strategies further enabled the induction of diverse neural linages and neuron subtypes both in vitro and in vivo. In this review, we highlight neural induction strategies that utilize stem cells, iPSCs, and lineage reprogramming to model or treat age-related neurodegenerative diseases, as well as, the clinical challenges related to neural transplantation and in vivo reprogramming strategies.

The cellular origin of sporadic pancreatic neuroendocrine tumors (PNETs) is obscure. Dysregulated hormone production and the absence of obvious driver mutations mask tumor origins although they presumably arise from endocrine cell lineages such as glucagon-producing alpha cells or insulin-expressing beta cells. A reciprocal feedback circuit involving pancreatic glucagon and hepatic amino acids regulates alpha cell mass such that loss of hepatic glucagon receptor (GCGR) signaling drives alpha cell hyperproliferation and tumor formation. This genetically-defined system is an ideal model for parsing the mechanisms of PNET origin and progression. Utilizing a combination of genetically engineered Gcgr knockout mice and GCGR-inhibiting antibodies, we found that elevated plasma amino acids drive reversion to a proliferative SLC38A5+ embryonic progenitor-like status. Chronic activation of this mTOR-dependent state drives tumor initiation and single cell profiling reveals tumors originate from a subpopulation of alpha cells. Profiling RNA, tumor signaling, and immune content of biopsies from rare human PNETs found in individuals with germ-line GCGR loss-of-function variants showed active mTOR and prominent tumor cell-associated expression of amino acid transporter SLC7A8. This work, for the first time, identifies metabolic control of an adult-to-progenitor alpha cell identity switch and shows that chronic maintenance of progenitor identity in the adult organ drives proliferation and tumor initiation.

This study was an examination of dental care utilization among survivors of early life cancers (cancer diagnosis at 20 years of age or younger) and the extent to which socio-economic factors may present a barrier to care. Data were obtained from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2016 (n = 28,640). Survey-weighted regression models were used to evaluate associations between early life cancers and subsequent frequency of dental care as adults. A mediation analysis was conducted to test education and household income as potential mediators of this association using a non-parametric bootstrap approach.Early life cancers were associated with a significant decrease in dental care utilization as adults (OR:0.459, 95%CI:(0.226, 0.935)). This diminished utilization was particularly pronounced with survivors in their 20s and 30s. Over time dental care utilization began a slow recovery. The association between early cancer and level of education was estimated to be negative but did not reach statistical significance (OR:0.739, 95%CI:(0.503, 1.086), p = 0.123). Survivors of early life cancers were less likely to be in a higher income bracket (OR:0.663, 95%CI:(0.452, 0.973), p = 0.036)). Decreases in education and household income (p

Objectives: Hypophosphatasia (HPP) is a syndrome marked by low serum alkaline phosphatase (AlkP) activity along with clinical manifestations varying from seizures to frequent fractures. Diagnosis of HPP is complicated both by its variable clinical phenotype and variable age of onset - patients are often asymptomatic well into adulthood. Although caused by variants in the ALPL gene, individual mutations are not tightly correlated with disease due to variable penetrance, expressivity, and the effect of modifier genes. In this study we sought to better understand the genotype/phenotype correlation in HPP by closely examining the clinical courses of a series of 37 patients with two rare variants in ALPL. Methods: Using BioVU, a DNA biobank that pairs patient’s genetic information with their de-identified medical record, we identified all patients that had at least one variant in ALPL. Among these patients, we chose to further study those with one of two variants. One (rs121918002) has previously been associated with disease while the other (rs148405563) was previously reported as benign. Clinical phenotypes and AlkP values were then obtained through manual review of the de-identified medical records of patients with one of these variants. Results: 20 patients with the rs121918002 (disease-associated) and 17 with the rs148405563 (benign) variant had sufficient clinical data for further analysis. None of these patients carried the diagnosis of HPP. Patients with the disease-associated variant had an average serum AlkP activity of 70.67 IU/L (SD 52.22), and 16 patients (80%) had at least one serum AlkP less than the lower limit of normal (40 IU/L). Among patients with a low AlkP, only 6 (30%) had clinical phenotypes consistent with disease. Patients with the benign variant had an average serum AlkP of 53.92 IU/L (SD 16.30) and 8 (47.1%) had at least one serum AlkP less than 40 IU/L. Among those with a low AlkP, 4 patients (23%) also had clinical phenotypes consistent with disease. Conclusions: Our study highlights the importance of clinical context to guide decisions around genetic testing in this population. In particular, genetic testing is of limited utility in those who meet clinical criteria for diagnosis. However, ALPL sequencing may be useful in younger patients with low AlkP but who do not have clinical disease. In these patients it may identify those at highest risk to go on to develop disease and assist in earlier intervention with appropriate therapy.

PurposeA major challenge in genomic medicine is how to best predict risk of disease from rare variants discovered in Mendelian disease genes but with limited phenotypic data. We have recently used Bayesian methods to show thatin vitrofunctional measurements and computational pathogenicity classification of variants in the cardiac geneSCN5Acorrelate with rare arrhythmia penetrance. We hypothesized that similar predictors could be used to impute variant-specific penetrance prior probabilities.MethodsFrom a review of 756 publications, we developed a pattern mixture algorithm, based on a Bayesian Beta-Binomial model, to generateSCN5Avariant-specific penetrance priors for the heart arrhythmia Brugada syndrome (BrS).ResultsThe resulting priors correlate with mean BrS penetrance posteriors (cross validated R2= 0.41).SCN5Avariant function and structural context provide the most information predictive of BrS penetrance. The resulting priors are interpretable as equivalent to the observation of affected and unaffected carriers.ConclusionsBayesian estimates of penetrance can efficiently integrate variant-specific data (e.g. functional, structural, and sequence) to accurately estimate disease risk attributable to individual variants. We suggest this formulation of penetrance is quantitative, probabilistic, and more precise than, but consistent with, discrete pathogenicity classification approaches.

Objective: This study was designed to assess the feasibility of using the Jaw Dynasplint System as an adjunct to conventional stretching exercises as a preventative measure against trismus in patients undergoing radiotherapy. Methods: Study participants (n = 40) were randomized using a permuted block design to conventional stretching or stretching plus use of the Jaw Dynasplint 3 times per day for 30 minutes. Patients were instructed to record maximum interincisal opening each day as well as logging use of the Jaw Dynasplint. Results: At 6 months after initiation of the preventative regimen, 50% of patients in the Dynasplint arm and 75% in the conventional stretching arm remained on their assigned therapy. Trismus was diagnosed in 2 patients in the control arm and in 4 patients in the Dynasplint arm. Only 25% (95% confidence interval = 11.1, 46.9) of patients in the Dynasplint arm used the device as prescribed. Conclusions: The addition of the Jaw Dynasplint decreased compliance compared with conventional stretching. It is unlikely that the prescribed regimen will prove efficacious as a preventative measure due to low compliance.

BACKGROUND Incidence of oral tongue squamous cell carcinoma (OTC) is rising among those under age 50 years. The etiology is unknown. METHODS A total of 395 cases of OTC diagnosed and/or treated at Vanderbilt University Medical Center between 2000 and 2017 were identified. Of those, 113 (28.6%) were early onset (age < 50 years). Logistic regression was used to identify factors associated with early onset OTC. Cox proportional hazards models evaluated survival and recurrence. RESULTS Compared to typical onset patients, patients with early onset OTC were more likely to receive multimodality treatment (surgery and radiation; adjusted odds ratio [aOR], 2.7; 95% confidence interval [CI], 1.2-6.3) and report a history of snuff use (aOR, 5.4; 95% CI, 1.8-15.8) and were less likely to report a history of cigarette use (aOR, 0.5; 95% CI, 0.2-0.9). Early onset patients had better overall survival (adjusted hazard ratio, 0.6). CONCLUSIONS This is the largest study to evaluate factors associated with early onset OTC and the first to report an association with snuff.

Acute kidney injury (AKI) after cardiac surgery occurs in up to 30% of patients and predicts death. We have reported that a higher preoperative HDL particle concentration is independently associated with a decreased risk of AKI after cardiac surgery. HDL has known anti-oxidant properties that may attenuate AKI. We hypothesized that HDL particle size is associated with paraoxonase-1 (PON-1) activity and with the risk of AKI after cardiac surgery. We selected 90 patients who developed mild, moderate, severe, or no AKI from a prospective trial of perioperative atorvastatin to prevent post-cardiac surgery AKI. PON-1 paraoxonase activity was measured in apoB-depleted serum with fluorescent substrate 7-diethylphospho-6,8-dixuor-4-methylumbelliferyl. HDL particle size was assessed using the NMR Lipoprofile test. Linear regression was used to assess the association between preoperative small, medium, and large HDL particle concentrations and PON-1 activity. We assessed the association between HDL particle levels and the maximum serum creatinine change from baseline in the first 48 postoperative hours using two-component latent variable mixture models adjusted for AKI risk factors. A higher preoperative small HDL particle concentration was associated with a higher preoperative PON-1 activity (p=0.003, Figure 1A). Medium and large HDL particle concentrations were not associated with PON-1 activity. Small HDL particle concentration was found to be independently associated with postoperative serum creatinine change (p=0.02, Figure 1B), while medium and large HDL particle concentrations were not. Conclusions: A higher preoperative small HDL particle concentration was associated with a higher PON-1 activity and a decreased risk of AKI after cardiac surgery. Future work will characterize HDL throughout the surgical course to identify the mechanism underlying the protective association between HDL and AKI.

Background: Accurately predicting the impact of rare nonsynonymous variants on disease risk is an important goal in precision medicine. Variants in the cardiac sodium channel SCN5A (protein Na V 1.5; voltage-dependent cardiac Na+ channel) are associated with multiple arrhythmia disorders, including Brugada syndrome and long QT syndrome. Rare SCN5A variants also occur in ≈1% of unaffected individuals. We hypothesized that in vitro electrophysiological functional parameters explain a statistically significant portion of the variability in disease penetrance. Methods: From a comprehensive literature review, we quantified the number of carriers presenting with and without disease for 1712 reported SCN5A variants. For 356 variants, data were also available for 5 Na V 1.5 electrophysiological parameters: peak current, late/persistent current, steady-state V1/2 of activation and inactivation, and recovery from inactivation. RESULTS: We found that peak and late current significantly associate with Brugada syndrome ( P P Conclusions: Na V 1.5 in vitro electrophysiological parameters are correlated with Brugada syndrome and long QT syndrome disease risk. Our data emphasize the value of in vitro electrophysiological characterization and incorporating counts of affected and unaffected carriers to aid variant classification. This quantitative analysis of the electrophysiological literature should aid the interpretation of Na V 1.5 variant electrophysiological abnormalities and help improve Na V 1.5 variant classification.

Pancreatic β cells undergo significant expansion and maturation during human and rodent postnatal development. Here, we used single-cell RNA-seq to characterize gene expression patterns at various stages of mouse islet cell development and uncovered a population of cells that is most abundant during the early postnatal period. This cell population lacks expression of FLTP and expresses PDGF receptors. Each of these conditions have previously been associated with proliferative capacity in β cells suggesting that we have identified the proliferative competent of β cell mass expansion. The subpopulation co-express many endocrine lineage-specific genes and exhibits a downregulation of genes associated with mitochondrial oxidative phosphorylation and global protein synthesis. It has upregulated activity of genes in the Wnt, Hippo, PDGF, and Notch pathways and has a significantly higher proliferation potential than the more mature β population. We show that activity of the Notch pathway is required in postnatal β cell expansion where it serves to maintain an undifferentiated endocrine state in the polyhormonal cell population. Collectively, our study identifies a proliferative, progenitor-like cell subpopulation in the postnatal islet as the source of postnatal β cell expansion.

Summary The orphan nuclear receptor TLX is a master regulator of postnatal neural stem cell (NSC) self-renewal and neurogenesis; however, it remains unclear how TLX expression is precisely regulated in these tissue-specific stem cells. Here, we show that a highly conserved cis-element within the Tlx locus functions to drive gene expression in NSCs. We demonstrate that the transcription factors SOX2 and MYT1 specifically interact with this genomic element to directly regulate Tlx enhancer activity in vivo. Knockdown experiments further reveal that SOX2 dominantly controls endogenous expression of TLX, whereas MYT1 only plays a modulatory role. Importantly, TLX is essential for SOX2-mediated in vivo reprogramming of astrocytes and itself is also sufficient to induce neurogenesis in the adult striatum. Together, these findings unveil functional genetic interactions among transcription factors that are critical to NSCs and in vivo cell reprogramming., Highlights • An evolutionarily conserved enhancer drives Tlx expression in neural stem cells • SOX2 directly activates the identified enhancer and Tlx expression • SOX2-mediated in vivo reprogramming of astrocytes to neuroblasts requires TLX, In this article, Zhang and colleagues show that a genomic enhancer drives Tlx expression in neural stem cells. The transcription factors SOX2 and MYT1 directly regulate the enhancer activity and Tlx expression. Furthermore, TLX is required for SOX2-mediated in vivo reprogramming of astrocytes in the adult brain. These results may have implications in regeneration of the adult CNS.

The discovery and in vivo application of cell fate reprogramming concepts have jumpstarted new technologies aimed at the functional regeneration of damaged tissues. As most adult organ systems retain only a limited potential for self-regeneration after trauma, the production of fate-specific cells by in vivo transdifferentiation offers a targeted method for tissue bioengineering. Proof-of-principle studies have demonstrated the induction of neural precursor cells, neurons, cardiomyocytes, and insulin-producing β islet cells. Each of these induced cell types survive, mature, and integrate into the local environment in a functionally meaningful manner. Here, we briefly highlight recent advances in the in vivo reprogramming of cell identity and the current challenges that face the clinical relevance of these methods.

Objective To determine the factors associated with intra- and postoperative cerebrospinal fluid (CSF) leaks in setting of endoscopic transsphenoidal sellar surgery. Study Design Retrospective cohort. Setting Tertiary referral center. Subjects and Methods This study included 806 patients who underwent endoscopic transsphenoidal sellar surgery between 2004 and 2016. The associations between CSF leaks (intra- and postoperative) and patient demographics, medical history, tumor characteristics, and intraoperative repair techniques were analyzed. Results In sum, 205 (25.4%) patients had a CSF leak: 188 (23.3%) intraoperative leaks and 38 (4.7%) postoperative leaks. Twenty-one (2.6%) patients had postoperative leaks after having repair of an intraoperative leak; 55% of patients with a postoperative leak had an intraoperative leak repaired. On multivariate analysis, body mass index (BMI), hydrocephalus, suprasellar extension, and craniopharyngioma significantly predicted intraoperative CSF leaks, while only BMI and hydrocephalus predicted postoperative CSF leaks. Patients having septal flap repairs of CSF leaks had a higher postoperative leak rate relative to other repair techniques (odds ratio, 6.37; P = .013). Rigid reconstruction did not correlate with leaks. Conclusion For this large cohort of patients undergoing endoscopic transsphenoidal sellar surgery, BMI and hydrocephalus were identified as predictors of postoperative CSF leaks, including those occurring after repair of intraoperative leak. These variables may put stress on the surgical repair of sellar defects, and consideration of these risk factors may help counsel patients and guide perioperative decision making in regard to repair strategies and CSF diversion techniques.

Context Mutations in alkaline phosphatase (AlkP), liver/bone/kidney (ALPL), which encodes tissue-nonspecific isozyme AlkP, cause hypophosphatasia (HPP). HPP is suspected by a low-serum AlkP. We hypothesized that some patients with bone or dental disease have undiagnosed HPP, caused by ALPL variants. Objective Our objective was to discover the prevalence of these gene variants in the Vanderbilt University DNA Biobank (BioVU) and to assess phenotypic associations. Design We identified subjects in BioVU, a repository of DNA, that had at least one of three known, rare HPP disease-causing variants in ALPL: rs199669988, rs121918007, and/or rs121918002. To evaluate for phenotypic associations, we conducted a sequential phenome-wide association study of ALPL variants and then performed a de-identified manual record review to refine the phenotype. Results Out of 25,822 genotyped individuals, we identified 52 women and 53 men with HPP disease-causing variants in ALPL, 7/1000. None had a clinical diagnosis of HPP. For patients with ALPL variants, the average serum AlkP levels were in the lower range of normal or lower. Forty percent of men and 62% of women had documented bone and/or dental disease, compatible with the diagnosis of HPP. Forty percent of the female patients had ovarian pathology or other gynecological abnormalities compared with 15% seen in controls. Conclusions Variants in the ALPL gene cause bone and dental disease in patients with and without the standard biomarker, low plasma AlkP. ALPL gene variants are more prevalent than currently reported and underdiagnosed. Gynecologic disease appears to be associated with HPP-causing variants in ALPL.

Background Acute kidney injury ( AKI ) after cardiac surgery is associated with increased short‐ and long‐term mortality. Inflammation, oxidative stress, and endothelial dysfunction and damage play important roles in the development of AKI . High‐density lipoproteins ( HDLs ) have anti‐inflammatory and antioxidant properties and improve endothelial function and repair. Statins enhance HDL 's anti‐inflammatory and antioxidant capacities. We hypothesized that a higher preoperative HDL cholesterol concentration is associated with decreased AKI after cardiac surgery and that perioperative statin exposure potentiates this association. Methods and Results We tested our hypothesis in 391 subjects from a randomized clinical trial of perioperative atorvastatin to reduce AKI after cardiac surgery. A 2‐component latent variable mixture model was used to assess the association between preoperative HDL cholesterol concentration and postoperative change in serum creatinine, adjusted for known AKI risk factors and suspected confounders. Interaction terms were used to examine the effects of preoperative statin use, preoperative statin dose, and perioperative atorvastatin treatment on the association between preoperative HDL and AKI . A higher preoperative HDL cholesterol concentration was independently associated with a decreased postoperative serum creatinine change ( P =0.02). The association between a high HDL concentration and an attenuated increase in serum creatinine was strongest in long‐term statin‐using patients ( P =0.008) and was further enhanced with perioperative atorvastatin treatment ( P =0.004) and increasing long‐term statin dose ( P =0.003). Conclusions A higher preoperative HDL cholesterol concentration was associated with decreased AKI after cardiac surgery. Preoperative and perioperative statin treatment enhanced this association, demonstrating that pharmacological potentiation is possible during the perioperative period. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique Identifier: NCT 00791648.

Background— An emerging standard-of-care for long-QT syndrome uses clinical genetic testing to identify genetic variants of the KCNQ1 potassium channel. However, interpreting results from genetic testing is confounded by the presence of variants of unknown significance for which there is inadequate evidence of pathogenicity. Methods and Results— In this study, we curated from the literature a high-quality set of 107 functionally characterized KCNQ1 variants. Based on this data set, we completed a detailed quantitative analysis on the sequence conservation patterns of subdomains of KCNQ1 and the distribution of pathogenic variants therein. We found that conserved subdomains generally are critical for channel function and are enriched with dysfunctional variants. Using this experimentally validated data set, we trained a neural network, designated Q1VarPred, specifically for predicting the functional impact of KCNQ1 variants of unknown significance. The estimated predictive performance of Q1VarPred in terms of Matthew’s correlation coefficient and area under the receiver operating characteristic curve were 0.581 and 0.884, respectively, superior to the performance of 8 previous methods tested in parallel. Q1VarPred is publicly available as a web server at http://meilerlab.org/q1varpred . Conclusions— Although a plethora of tools are available for making pathogenicity predictions over a genome-wide scale, previous tools fail to perform in a robust manner when applied to KCNQ1. The contrasting and favorable results for Q1VarPred suggest a promising approach, where a machine-learning algorithm is tailored to a specific protein target and trained with a functionally validated data set to calibrate informatics tools.

6059 Background: Preliminary data suggest that gabapentin (G) administered during HNC radiation may decrease treatment associated pain. To confirm this, we undertook a prospective, randomized trial in HNC patients undergoing CCR. Primary outcomes: pain severity (scale of 0-10) and opioid use. Exploratory outcomes: local and systemic symptoms measured by the Vanderbilt Head and Neck Symptom Survey version 2 plus the general symptom survey (VHNSSv2/GSS). We report results of the exploratory endpoints from the interim analysis. Methods: Measures: VHNSSv2 - 50 items, demonstrated reliability/validated, captures acute/chronic local HNC specific symptoms; GSS – 11 item checklist, demonstrated content validity, captures acute/chronic systemic symptoms. Population: HNC patients (≥ stage 2) undergoing primary or adjuvant CCR. Procedures: Randomized to standard pain management (SPM) or SPM + G dose escalated to 900mg tid. VHNSSv2/GSS completed weekly during treatment beginning week 1 and ending the last week of radiation therapy. Results were analyzed using a mixed-effects regression analysis adjusting for baseline levels of each symptom. Results: 71 patients completed a mean of 5.5 surveys. Patients on G experienced a reduction in overall systemic symptoms as measured by the GSS (11-items, p = 0.0073), fatigue (two-items, p = 0.013 ) sleep disturbance (five items, p < 0.0001) , neurosensory eating (3 items, p = 0.026), phlegm-related symptoms (4 items, p = 0.004), and trend to better smell (2 items, p = 0.055). No impact on swallow, xerostomia, voice, dental or musculoskeletal symptoms was noted. Conclusions: This exploratory analysis suggests that G may moderate neurological and neuropsychiatric toxicities in HNC patients undergoing CCR. Further studies are warranted.