Search

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.

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.

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 .

Oxidative stress promotes acute kidney injury (AKI). Higher HDL cholesterol concentrations are associated with less AKI. To test the hypothesis that HDL antioxidant activity is associated with AKI after cardiac surgery, we quantified HDL particle (HDL-P) size and number, paraoxonase-1 (PON-1) activity, and isofuran concentrations in 75 patients who developed AKI and 75 matched control patients. Higher preoperative HDL-P was associated with less AKI (OR: 0.80; 95% CI, 0.71–0.91; P = 0.001), higher PON-1 activity ( P < 0.001), and lower plasma concentrations of isofurans immediately after surgery (P = 0.02). Similarly, higher preoperative small HDL-P was associated with less AKI, higher PON-1 activity, and lower isofuran concentrations. Higher intraoperative particle losses were associated with less AKI (OR: 0.79; 95% CI 0.67–0.93; P = 0.005), and with decreased postoperative isofuran concentrations (P = 0.04) . Additionally, higher preoperative small HDL-P and increased intraoperative small particle loss were associated with improved long-term renal function (P = 0.003, 0.01, respectively). In conclusion, a higher preoperative concentration of HDL-P, particularly small particles, is associated with lower oxidative damage and less AKI. Perioperative changes in HDL-P concentrations are also associated with AKI. Small HDL-P may represent a novel modifiable risk factor for AKI.

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.

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.

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.

Postoperative pulmonary complications (PPCs) are common following major surgical procedures. Risk stratification tools have been developed to identify patients at risk for PPCs. While otolaryngology cases were included in the development of common predictive tools, they comprised small percentages in each tool. It is unclear how these tools perform in patients undergoing major head and neck surgery with free flap reconstruction. This retrospective review studied all free flap reconstructions in head and neck surgery over a 12-year period at a single institution in the southeastern US. Baseline demographic and medical information were included for each case. All cases were reviewed for development of major PPCs, including pneumonia and respiratory failure. The cohort underwent risk stratification using the ARISCAT and Gupta pulmonary risk indices. Performance of these predictive models for head and neck surgery was determined through receiver-operator curve comparison. 794 patients were identified with a median age of 62 years (IQR 41–83). Sixty-five percent were male. Forty-three (5.4%) developed pneumonia, 23 patients developed respiratory failure (2.9%), and 38 patients developed both (4.8%), resulting in a total PPC proportion of 13.1% (n = 104). Both ARISCAT and Gupta pulmonary risk indices demonstrated low discrimination to predict PPCs in head and neck free flap reconstruction, with areas under the curve of 0.60 and 0.65, respectively. Two major indices for prediction of postoperative pulmonary complications do not accurately identify risk in patients undergoing major head and neck surgery. Further studies are needed to develop predictive tools for PPCs in this high-risk population.

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.

Summary The cellular origin of sporadic pancreatic neuroendocrine tumors (PNETs) is obscure. Hormone expression suggests that these tumors arise from glucagon-producing alpha cells or insulin-producing β cells, but instability in hormone expression prevents linage determination. We utilize loss of hepatic glucagon receptor (GCGR) signaling to drive alpha cell hyperproliferation and tumor formation to identify a cell of origin and dissect mechanisms that drive progression. Using a combination of genetically engineered Gcgr knockout mice and GCGR-inhibiting antibodies, we show that elevated plasma amino acids drive the appearance of a proliferative population of SLC38A5+ embryonic progenitor-like alpha cells in mice. Further, we characterize tumors from patients with rare bi-allelic germline GCGR loss-of-function variants and find prominent tumor-cell-associated expression of the SLC38A5 paralog SLC7A8 as well as markers of active mTOR signaling. Thus, progenitor cells arise from adult alpha cells in response to metabolic signals and, when inductive signals are chronically present, drive tumor initiation., Graphical Abstract, Highlights GCGR inhibition induces an SLC38A5+ alpha cell population in aged mice An SLC38A5+ alpha cell subpopulation initiates pancreatic tumors in aged Gcgr−/− mice Tumors exhibit low mutational burden and response to mTOR inhibition by rapamycin Tumors in GCGR loss-of-function models lack immune cell infiltration, Smith et al. demonstrate that chronic mTOR signaling, driven by elevated serum amino acids, in Gcgr knockout mice promotes tumor initiation from an SLC38A5+ alpha cell subpopulation and supports tumor maintenance. Furthermore, they provide evidence that an SLC7A8+ alpha cell population contains the progenitors for human tumors in GCGR-mutant patients.

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.

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 Surrogate outcomes are often utilized when disease outcomes are difficult to directly measure. When a biological threshold effect exists, surrogate outcomes may only represent disease in specific subpopulations. We refer to these outcomes as “partial surrogate outcomes.” We hypothesized that risk models of partial surrogate outcomes would perform poorly if they fail to account for this population heterogeneity. We developed criteria for predictive model development using partial surrogate outcomes and demonstrate their importance in model selection and evaluation within the clinical example of serum creatinine, a partial surrogate outcome for acute kidney injury. Methods Data from 4737 patients who underwent cardiac surgery at a major academic center were obtained. Linear and mixture models were fit on maximum 2-day serum creatinine change as a surrogate for estimated glomerular filtration rate at 90 days after surgery (eGFR90), adjusted for known AKI risk factors. The AUC for eGFR90 decline and Spearman’s rho were calculated to compare model discrimination between the linear model and a single component of the mixture model deemed to represent the informative subpopulation. Simulation studies based on the clinical data were conducted to further demonstrate the consistency and limitations of the procedure. Results The mixture model was highly favored over the linear model with BICs of 2131.3 and 5034.3, respectively. When model discrimination was evaluated with respect to the partial surrogate, the linear model displays superior performance (p

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.

Background Acute kidney injury (AKI) is diagnosed based on postoperative serum creatinine change, but AKI models have not consistently performed well, in part due to the omission of clinically important but practically unmeasurable variables that affect creatinine. We hypothesized that a latent variable mixture model of postoperative serum creatinine change would partially account for these unmeasured factors and therefore increase power to identify risk factors of AKI and improve predictive accuracy. Methods We constructed a two-component latent variable mixture model and a linear model using data from a prospective, 653-subject randomized clinical trial of AKI following cardiac surgery (NCT00791648) and included established AKI risk factors and covariates known to affect serum creatinine. We compared model fit, discrimination, power to detect AKI risk factors, and ability to predict AKI between the latent variable mixture model and the linear model. Results The latent variable mixture model demonstrated superior fit (likelihood ratio of 6.68 × 1071) and enhanced discrimination (permutation test of Spearman’s correlation coefficients, p

Purpose: Multiple randomized controlled trials have compared the efficacy of 2% lidocaine with 1:100,000 epinephrine to 4% articaine with 1:100,000 epinephrine. However, there is still uncertainty about expected success probabilities with various anesthetic modalities that needs to be addressed in the literature.Methods: A search of PubMed and Google yielded over 200 potential articles. 13 randomized controlled trials met the eligibility criteria for inclusion in the analysis. Analyses compared lidocaine and articaine in teeth with and without a diagnosis of pulpitis for maxillary infiltration, mandibular buccal infiltration, and inferior alveolar nerve block (IANB).Results: Articaine demonstrated superior anesthetic efficacy regardless of the type of injection administered or pulpal status. Depending on the type of injection, the estimated probability of anesthetic success with articaine was observed to be anywhere from 9.19 percentage points to 32.48 percentage points higher than lidocaine. The comparisons favoring articaine were highly significant for mandibular infiltration (p

Multipotent neural stem cells persist in restricted regions of the adult mammalian central nervous system. These proliferative cells differentiate into diverse neuron subtypes to maintain neural homeostasis. This endogenous process can be reprogrammed as a compensatory response to physiological cues, traumatic injury, and neurodegeneration. In addition to innate neurogenesis, recent research has demonstrated that new neurons can be engineered via cell identity reprogramming in non-neurogenic regions of the adult central nervous system. A comprehensive understanding of these reprogramming mechanisms will be essential to the development of therapeutic neural regeneration strategies that aim to improve functional recovery after injury and neurodegeneration. WIREs Dev Biol 2016, 5:499–517. doi: 10.1002/wdev.234 For further resources related to this article, please visit the WIREs website

Acute kidney injury (AKI) after cardiac surgery occurs in up to 30% of patients and is an independent predictor of death. HDL may attenuate mechanisms of AKI. We hypothesized that a high preoperative HDL cholesterol concentration is protective against postoperative AKI. We analyzed data from a prospective, 393-subject trial of perioperative atorvastatin to prevent post-cardiac surgery AKI. Statin-using patients were randomized to placebo or 80mg atorvastatin the morning of surgery and 40mg on postoperative day 1. Stain-naïve patients were randomized to placebo or 80mg the day prior to surgery and 40mg daily thereafter during hospitalization. The association between HDL level and maximum serum creatinine change from baseline in the first 48 postoperative hours was assessed using a two-component latent variable mixture model and AKI risk factors. Regression analyses assessed interactions of chronic statin use, perioperative atorvastatin treatment, and HDL level on AKI risk. Postoperative AKI occurred in 99 patients (25.2%). Median (10 th , 90 th percentile) preoperative HDL was 37.6 (25.0, 54.0) mg/dL and postoperative creatinine change 0.09 (-0.11, 0.59) mg/dL. Lower HDL levels were independently associated with increased creatinine rise (p=0.02) (Figure 1A). Regression analysis showed this association was present in statin-using but not statin-naïve patients (p=0.008) (1B). The protective effect of high HDL in chronic statin users was enhanced with perioperative atorvastatin treatment (p=0.004) (1C) and with increasing chronic statin dose (p=0.003) (1D). Similar analyses using LDL found no association with AKI risk (p=0.51). Conclusions: Higher preoperative HDL was associated with less risk of AKI. Statin exposure modified this association. Specifically, subjects with higher HDL levels on chronic statin therapy had less creatinine rise and appeared to further benefit from higher chronic statin dose and perioperative atorvastatin therapy.

e18010 Background: Cancer therapy can result in lifelong detrimental changes to oral function. These changes often result in negative effects on patients' quality of life. The primary objective of this study is to evaluate attendance at dental visits among patients receiving a cancer diagnosis, and how attendance may change as patients move through pre-diagnosis, diagnosis and into survivorship. Methods: The Health and Retirement Study is a publically available dataset containing longitudinal survey data detailing financial and health information on 4195 patients, over 51 years old who received a new cancer diagnosis during the study. The odds of reporting a dental visit were examined as patients proceed through various phases of cancer therapy using a mixed-effects logistic regression model. A propensity score weighted analysis of the association between dental attendance in the survey wave in which the cancer was diagnosed and survival was also undertaken. Results: The odds of attending a dental visit were substantially lower in the diagnosis wave OR = 0.784 (0.700, 0.876) and the post-diagnosis waves OR = 0.734 (0.655, 0.823) compared to pre-diagnosis waves. This effect persisted in patients who survived for at least two years indicating that the decline in oral health visits was not due to extremely low expected survival. The decrease in oral health visits was not affected by age, race, gender, income, insurance coverage or education. After propensity score weighting, patients who attended a dental visit in their diagnosis wave demonstrated a reduced hazard of all-cause mortality HR = 0.825 (0.681, 0.979) compared with those with no attendance. Conclusions: Dental attendance decreases by a statistically and clinically significant amount both during and after cancer therapy despite indications for dental referral existing 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. The fact that the decreases in care were not modified by socioeconomic factors suggests that it is not driven by strictly financial concerns and more research is necessary to identify barriers to adequate care.