Microsatellites used in forensics are in regions enriched for trait-associated variants.

The 20 short tandem repeat (STR) loci of the combined DNA index system (CODIS) are the basis of the vast majority of forensic genetics in the United States. One argument for permissive rules about the collection of CODIS genotypes is that the CODIS loci are thought to contain little information about ancestry or traits. However, in the past 20 years, a growing field has identified hundreds of thousands of genotype-trait associations. Here, we conduct a survey of the landscape of such associations surrounding the CODIS loci as compared with non-CODIS STRs. Although this study cannot establish or quantify associations between CODIS genotypes and phenotypes, we find that the regions around the CODIS loci are enriched for both known pathogenic variants (> 90th percentile) and for trait-associated SNPs identified in genome-wide association studies (GWAS) (≥ 95th percentile in 10kb and 100kb flanking regions), compared with other random sets of autosomal tetranucleotide-repeat STRs.

The Importance of Quality Assurance in Radiation Oncology Clinical Trials.

Clinical trials have been the center of progress in modern medicine. In oncology, we are fortunate to have a structure in place through the National Clinical Trials Network (NCTN). The NCTN provides the infrastructure and a forum for scientific discussion to develop clinical concepts for trial design. The NCTN also provides a network group structure to administer trials for successful trial management and outcome analyses. There are many important aspects to trial design and conduct. Modern trials need to ensure appropriate trial conduct and secure data management processes. Of equal importance is the quality assurance of a clinical trial. If progress is to be made in oncology clinical medicine, investigators and patient care providers of service need to feel secure that trial data is complete, accurate, and well-controlled in order to be confident in trial analysis and move trial outcome results into daily practice. As our technology has matured, so has our need to apply technology in a uniform manner for appropriate interpretation of trial outcomes. In this article, we review the importance of quality assurance in clinical trials involving radiation therapy. We will include important aspects of institution and investigator credentialing for participation as well as ongoing processes to ensure that each trial is being managed in a compliant manner. We will provide examples of the importance of complete datasets to ensure study interpretation. We will describe how successful strategies for quality assurance in the past will support new initiatives moving forward.

Microsatellites used in forensics are located in regions unusually rich in trait-associated variants.

The 20 short tandem repeat (STR) markers of the combined DNA index system (CODIS) are the basis of the vast majority of forensic genetics in the United States. One argument for permissive rules about the collection of CODIS genotypes is that the CODIS markers are thought to contain information relevant to identification only (such as a human fingerprint would), with little information about ancestry or traits. However, in the past 20 years, a quickly growing field has identified hundreds of thousands of genotype-trait associations. Here we conduct a survey of the landscape of such associations surrounding the CODIS loci as compared with non-CODIS STRs. We find that the regions around the CODIS markers are enriched for both known pathogenic variants (>90th percentile) and for SNPs identified as trait-associated in genome-wide association studies (GWAS) (≥95th percentile in 10kb and 100kb flanking regions), compared with other random sets of autosomal tetranucleotide-repeat STRs. Although it is not obvious how much phenotypic information CODIS would need to convey to strain the "DNA fingerprint" analogy, the CODIS markers, considered as a set, are in regions unusually dense with variants with known phenotypic associations.

Radiation Oncology: Future Vision for Quality Assurance and Data Management in Clinical Trials and Translational Science.

The future of radiation oncology is exceptionally strong as we are increasingly involved in nearly all oncology disease sites due to extraordinary advances in radiation oncology treatment management platforms and improvements in treatment execution. Due to our technology and consistent accuracy, compressed radiation oncology treatment strategies are becoming more commonplace secondary to our ability to successfully treat tumor targets with increased normal tissue avoidance. In many disease sites including the central nervous system, pulmonary parenchyma, liver, and other areas, our service is redefining the standards of care. Targeting of disease has improved due to advances in tumor imaging and application of integrated imaging datasets into sophisticated planning systems which can optimize volume driven plans created by talented personnel. Treatment times have significantly decreased due to volume driven arc therapy and positioning is secured by real time imaging and optical tracking. Normal tissue exclusion has permitted compressed treatment schedules making treatment more convenient for the patient. These changes require additional study to further optimize care. Because data exchange worldwide have evolved through digital platforms and prisms, images and radiation datasets worldwide can be shared/reviewed on a same day basis using established de-identification and anonymization methods. Data storage post-trial completion can co-exist with digital pathomic and radiomic information in a single database coupled with patient specific outcome information and serve to move our translational science forward with nimble query elements and artificial intelligence to ask better questions of the data we collect and collate. This will be important moving forward to validate our process improvements at an enterprise level and support our science. We have to be thorough and complete in our data acquisition processes, however if we remain disciplined in our data management plan, our field can grow further and become more successful generating new standards of care from validated datasets.

Pediatric hypertension screening and recognition in primary care clinics in Canada.

Objectives: Screening for hypertension in children is recommended by pediatric consensus guidelines. However, current practice is unknown. We evaluated rates of blood pressure assessment and hypertension recognition in primary care. Methods: This retrospective cohort study evaluated electronic medical record data from the Canadian Primary Care Sentinel Surveillance Network between 2011 and 2017. Children aged 3 to <18 years with at least one clinical encounter were included. Screening, follow-up, and hypertension recognition rates were evaluated. Descriptive statistics and multivariate logistical regression were used to determine patient and provider characteristics associated with increased screening and recognition of pediatric hypertension. Results: Among 378,002 children, blood pressure was documented in 33.3% of all encounters, increasing from 26.7% in 2011 to 36.2% in 2017; P=0.007. Blood pressure was documented in 76.0% of well child visits. Follow-up visits occurred within 6 months for 26.4% of children with elevated blood pressure, 57.1% of children with hypertension, and within 1 month for 7.2% of children with hypertension. Patient factors associated with increased blood pressure screening include being overweight (OR 2.15, CI 2.09 to 2.22), having diabetes (OR 1.69, CI 1.37 to 2.08), chronic kidney disease (OR 7.51, CI 6.54 to 8.62), increased social deprivation (OR 1.10, CI 1.09 to 1.11), and urban residence (OR 1.27, CI 1.15 to 1.4). Overall prevalence of hypertension was 1.9% (n=715) and of those, 5.6% (n=40) had recognized hypertension. Factors associated with increased recognition include male sex, overweight, and hyperlipidemia. Conclusions: Rates of hypertension screening and recognition are low in primary care settings in Canada, suggesting pediatric hypertension should be a priority for implementation and dissemination of interventions.

Overutilization of Helicopter Emergency Medical Services in Central Gulf Coast Region Results in Unnecessary Expenditure.

INTRODUCTION: When appropriately used, helicopter emergency medical services (HEMSs) allow for timely delivery of severely injured patients to definitive care. Inappropriate utilization of HEMSs results in increased cost to the patient and trauma system. The purpose of this study was to review current HEMS criteria in the central Gulf Coast region and evaluate for potential areas of triage refinement and cost savings. We hypothesized that a significant number of patients received potentially unwarranted HEMS transport. METHODS: A retrospective cohort study of all patients with trauma arriving to a level I trauma center by helicopter over 28 mo was performed; 381 patients with trauma and with HEMS transport from the scene were included. Data were collected from prehospital sources, as well as hospital chart review for each patient. The primary outcome was the rate of unwarranted HEMS transport. RESULTS: A total of 381 adult patients with trauma transported by the HEMS were analyzed, of which 34% were deemed potentially nonwarranted transports. The significant factors correlating with warranted HEMS transport included age, multiple long bone fractures, penetrating mechanism, and vehicle ejection. Insurance demographics did not correlate to transport modality. Many of these patients were transported from a location within the same county or the county adjacent to the trauma center. When comparing patients transported by ground and HEMSs from the same scene, no time savings were identified. Unwarranted transports at the trauma center represented an estimated health care expenditure of over $3 million. CONCLUSIONS: HEMSs may be overused in the central Gulf Coast region, creating the risk for a substantial resource and financial burden to the trauma system. Further collaboration is needed to establish HEMS triage criteria, that is, more appropriate use of resources.

Outcomes After Stereotactic Body Radiation Therapy as a Bridging Modality to Liver Transplantation for Hepatocellular Carcinoma.

PURPOSE: For patients with hepatocellular carcinoma awaiting liver transplantation (LT), stereotactic body radiation therapy (SBRT) has emerged as a bridging treatment to ensure patients maintain priority status and eligibility per Milan criteria. In this study, we aimed to determine the efficacy and safety of SBRT in such situations. METHODS AND MATERIALS: A retrospective analysis was conducted of the outcomes of 27 patients treated with SBRT who were listed for LT at 1 institution. Among these, 20 patients with 26 tumors went on to LT and were the focus of this study. Operative reports and postoperative charts were evaluated for potential radiation-related complications. The explant pathology findings were correlated with equivalent dose in 2 Gy fractions and tumor size. RESULTS: Median pretreatment tumor size was 3.05 cm. Median total dose of radiation was 50 Gy delivered in 5 fractions. Pathologic complete response (pCR) was achieved in 16 tumors (62%). Median interval from end of SBRT to transplant was 287 days. Of the 21 tumors imaged before transplant, 16 or 76% demonstrated a clinical complete response based on modified Response Evaluation Criteria in Solid Tumors criteria. There was no significant correlation between pCR rate and increasing tumor size (odds ratio [OR], 0.95; 95% confidence interval, 0.595-1.53) or pCR rate and equivalent dose in 2 Gy fractions (OR, 1.03; 95% confidence interval, 0.984-1.07.) No patients experienced radiation-related operative or postoperative complications. Of the 27 patients who were listed for transplant, the dropout rate was 22%. Two of the 5 patients with Child-Pugh score 10 died of liver failure. CONCLUSIONS: These data demonstrate that SBRT as a bridging modality is a feasible option, with a pCR rate comparable to that of other bridging modalities and no additional radiation-related operative or postoperative complications. There was no dose dependence nor size dependence for pCR rate, which may indicate that for the tumor sizes in this study, the radiation doses delivered were sufficiently high.

Stereotactic Body Radiotherapy for Palliation of Hematuria Arising From Urothelial Carcinoma of the Kidney in Unfavorable Surgical Candidates.

INTRODUCTION: Hematuria can be a distressing and debilitating complication of urothelial carcinoma (UC) of the kidney for patients who are not candidates for surgery or ureteroscopic ablation. We retrospectively assessed the efficacy, tolerability, and safety of stereotactic body radiotherapy (SBRT) for controlling gross hematuria in this patient population. MATERIALS AND METHODS: Institutional Review Board (IRB)-approved review of the records, laboratory values, pathology, and imaging of 8 consecutive patients treated with SBRT over a 5-year period for uncontrolled gross hematuria caused by UC of the renal pelvis or calyces. RESULTS: Therapy was delivered in 3 to 5 treatments over 1 to weeks. Individual treatments lasted an average of 17.2 minutes. No patient experienced treatment-related pain, vomiting, or diarrhea. All enjoyed cessation of bleeding within a week of completing therapy. Hematuria recurred in 2 patients in 4 and 22 months. Of the patients who have not re-bled, 3 expired of metastatic disease or co-morbidities, and 3 remain alive up to 6 years posttreatment. Of patients who have survived longer than a year, creatinine has changed by -0.05 to +0.35, and estimated glomerular filtration rate has fallen by an average of 22%. No patient has required dialysis. CONCLUSIONS: SBRT appears to be an effective and well-tolerated means of palliating gross hematuria secondary to UC of the renal pelvis or calyces in patients who are unfavorable candidates for nephrectomy or ureteroscopic ablation. Treatment was associated with a moderate decline in renal function.

Monitoring dialysis adequacy: history and current practice.

Dialysis adequacy for pediatric patients has largely followed the trends in adult dialysis by judging the success or adequacy of peritoneal or hemodialysis with urea kinetic modeling. While this provides a starting point to establish a dose of dialysis, it is clear that urea is only part of the picture. Many clinical parameters and interventions now have been identified that are just as impactful on mortality and morbidly as urea clearance. As such, our concept of adequacy is evolving to include non-urea parameters and assessing the impact that following an "adequate therapy" has on patient lives. As we move to a new era, we consider the impact these therapies have on patients and how it affects the quality of their lives; we must take these factors into consideration to achieve a therapy that is not just adequate, but livable.

Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Patients With Child-Pugh B or C Cirrhosis.

PURPOSE: Our purpose was to report outcomes in patients with Child-Pugh B or C (CP B/C) hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Patients with HCC suitable for SBRT were prospectively enrolled in the study from 2012 to 2018. Outcomes in patients with CP B/C were analyzed. Cox proportional hazard models were used to compare survival outcomes between baseline CP score and post-SBRT CP score. RESULTS: Twenty-three patients with CP B/C with a total of 29 HCC tumors were treated with SBRT. Eighty-seven percent of patients were CP B8-C10. Median tumor size was 3.1 cm (range, 1-10 cm). Median dose delivered was 40 Gy in a median of 5 fractions. Eighteen of 23 patients (78.3%) had been previously treated with transarterial chemoembolization. Median follow-up was 14.5 months. Rates of 6- and 12-month local control were 100% and 92.3%, respectively. Six- and 12-month survival rates were 73.9% and 56.5%, respectively. Median survival was 14.5 months overall and 9.2, 22.5, 14.5, and 14.4 months for patients with CP B7, B8, B9, and C10, respectively. No patients exhibited symptoms of classic radiation-induced liver disease. However, 10 patients had CP score progression, with 4 patients (17%) having a ≥2-point increase in CP score by 6 months (or time of censor). There were 7 liver-related deaths, and based on independent review by a hepatologist, 1 of these deaths may have been attributable to SBRT-related liver injury. Fifteen of 23 patients were listed for liver transplant (LT) at the time of SBRT and 9 went on to receive LT with a pathologic complete response rate of 63.6%. Median survival, excluding patients who received LT, was 7.3 months. CONCLUSIONS: SBRT is a reasonable treatment option for carefully selected patients with CP B7-C10. In our small cohort, there was no detectable difference between local control or overall survival and baseline CP score.

Concordance of genetic variation that increases risk for tourette syndrome and that influences its underlying neurocircuitry.

There have been considerable recent advances in understanding the genetic architecture of Tourette syndrome (TS) as well as its underlying neurocircuitry. However, the mechanisms by which genetic variation that increases risk for TS-and its main symptom dimensions-influence relevant brain regions are poorly understood. Here we undertook a genome-wide investigation of the overlap between TS genetic risk and genetic influences on the volume of specific subcortical brain structures that have been implicated in TS. We obtained summary statistics for the most recent TS genome-wide association study (GWAS) from the TS Psychiatric Genomics Consortium Working Group (4644 cases and 8695 controls) and GWAS of subcortical volumes from the ENIGMA consortium (30,717 individuals). We also undertook analyses using GWAS summary statistics of key symptom factors in TS, namely social disinhibition and symmetry behaviour. SNP effect concordance analysis (SECA) was used to examine genetic pleiotropy-the same SNP affecting two traits-and concordance-the agreement in single nucelotide polymorphism (SNP) effect directions across these two traits. In addition, a conditional false discovery rate (FDR) analysis was performed, conditioning the TS risk variants on each of the seven subcortical and the intracranial brain volume GWAS. Linkage disequilibrium score regression (LDSR) was used as validation of the SECA method. SECA revealed significant pleiotropy between TS and putamen (p = 2 × 10-4) and caudate (p = 4 × 10-4) volumes, independent of direction of effect, and significant concordance between TS and lower thalamic volume (p = 1 × 10-3). LDSR lent additional support for the association between TS and thalamus volume (p = 5.85 × 10-2). Furthermore, SECA revealed significant evidence of concordance between the social disinhibition symptom dimension and lower thalamus volume (p = 1 × 10-3), as well as concordance between symmetry behaviour and greater putamen volume (p = 7 × 10-4). Conditional FDR analysis further revealed novel variants significantly associated with TS (p < 8 × 10-7) when conditioning on intracranial (rs2708146, q = 0.046; and rs72853320, q = 0.035) and hippocampal (rs1922786, q = 0.001) volumes, respectively. These data indicate concordance for genetic variation involved in disorder risk and subcortical brain volumes in TS. Further work with larger samples is needed to fully delineate the genetic architecture of these disorders and their underlying neurocircuitry.

Identification of long non-coding RNA-related and -coexpressed mRNA biomarkers for hepatocellular carcinoma.

BACKGROUND: While changes in mRNA expression during tumorigenesis have been used widely as molecular biomarkers for the diagnosis of a number of cancers, the approach has limitations. For example, traditional methods do not consider the regulatory and positional relationship between mRNA and lncRNA. The latter has been largely shown to possess tumor suppressive or oncogenic properties. The combined analysis of mRNA and lncRNA is likely to facilitate the identification of biomarkers with higher confidence. RESULTS: Therefore, we have developed an lncRNA-related method to identify traditional mRNA biomarkers. First we identified mRNAs that are differentially expressed in Hepatocellular Carcinoma (HCC) by comparing cancer and matched adjacent non-tumorous liver tissues. Then, we performed mRNA-lncRNA relationship and coexpression analysis and obtained 41 lncRNA-related and -coexpressed mRNA biomarkers. Next, we performed network analysis, gene ontology analysis and pathway analysis to unravel the functional roles and molecular mechanisms of these lncRNA-related and -coexpressed mRNA biomarkers. Finally, we validated the prediction and performance of the 41 lncRNA-related and -coexpressed mRNA biomarkers using Support Vector Machine model with five-fold cross-validation in an independent HCC dataset from RNA-seq. CONCLUSIONS: Our results suggested that mRNAs expression profiles coexpressed with positionally related lncRNAs can provide important insights into early diagnosis and specific targeted gene therapy of HCC.

Phenotypes of sleep-disordered breathing symptoms to two years of age based on age of onset and duration of symptoms.

OBJECTIVE: Childhood sleep-disordered breathing (SDB) symptoms may comprise multiple phenotypes depending on craniofacial anatomy, tonsil and adenoid growth, body habitus, and rhinitis symptoms. The primary objective of this study is to identify and characterize the different SDB phenotypes to two years of age. METHODS: Data from 770 infants in the Edmonton sub-cohort of the Canadian Healthy Infant Longitudinal Study (CHILD) were analyzed to identify SDB phenotypes based on age of onset and duration of symptoms. Parents completed the 22-item sleep-related breathing disorder (SRBD) scale. Children with a SRBD ratio greater than 0.33 were considered positive for SDB at each quarterly assessment between three months and two years. The STATA Proc trajectory extension identified SDB phenotypes based on their age of onset and duration of symptoms and attributed the percentage chance of a participant being assigned to each phenotype. Multivariate linear regression identified factors associated with increased risk of being assigned to each SDB phenotype. RESULTS: Trajectory analysis identified four phenotypes: no SDB (65.7%), early-onset SDB (15.7%) with peak symptoms at nine months, late-onset SDB (14.2%) with peak symptoms at 18 months, and persistent SDB (5.3%) with symptoms from 3 to 24 months. Rhinitis was associated with all three SDB symptom trajectories (p < 0.05). Children with gastroesophageal reflux disease presented with early (p = 0.03) and late SDB (p < 0.001). Maternal obstructive sleep apnea syndrome (OSAS) was associated with persistent (p = 0.01) and late SDB (p < 0.001). Atopy (positive skin prick test at one year) was associated with persistent SDB (p = 0.04). Infants born prior to 36.5 weeks gestational age were more likely to present with late SDB (p = 0.03). CONCLUSION: Childhood SDB symptoms, rather than being a homogenous disorder, may comprise multiple overlapping phenotypes each with unique risk factors.

Long sheath use in femoral artery catheterizations in infants <15 kg is associated with a higher thrombosis rate: Proposed Protocol for Detection and Management.

OBJECTIVES: To examine the factors contributing to arterial thrombosis after catheterization, particularly the use of long vs. short introducer sheaths, and propose a new protocol to address risks. BACKGROUND: Post-procedure arterial compromise is an important concern in pediatric cardiac catheterizations. For certain interventional procedures, the use of a long sheath is necessary, however, the incidence of complications when using such sheaths has not yet been studied. METHODS: This retrospective review includes patients <15 kg who underwent femoral artery catheterization at our institution from Feb 2006 to June 2014. The study examined 29 long sheath and 40 matched interventional short sheath cases. Data collected included age, weight, time to arterial access, total sheath duration, and arterial complications. The long sheath and short sheath groups, and confounding factors, were compared for complication rate. RESULTS: The incidence of arterial compromise was 38% (11/29) in the long sheath group compared to 15% (6/40) for short sheaths (P = 0.029). Arterial thrombosis was documented by ultrasound, CT, or angiography in 71% (12/17) patients. Time to arterial access and total sheath duration were not statistically significant factors. Weight was an independent risk factor, with infants <5 kg having a higher complication rate compared to infants >5 kg at 38.2% (13/34) and 11.4% (4/35), respectively (P = 0.004). Sheath length remained statistically significant after taking weight and age into account (P = 0.011). CONCLUSION: The use of a long sheath in infants <15 kg is a significant risk factor for arterial compromise compared to short sheaths. Lower patient weight is also a contributing factor to increased incidence of complication, particularly in those <5 kg. © 2016 Wiley Periodicals, Inc.

Pseudo-continuous arterial spin labeling quantifies cerebral blood flow in patients with acute ischemic stroke and chronic lacunar stroke.

OBJECTIVE: We employed non-invasive pseudo-continuous arterial spin labeling (pCASL) to quantify cerebral blood flow (CBF) in infarcted and nearby neural regions in patients with acute ischemic stroke (AIS) and chronic lacunar stroke (CLS). The results were compared with CBF in healthy individuals. METHODS: AIS and CLS patients were imaged with ASL, diffusion-weighted imaging (DWI) and conventional MRI. CBF maps were created with 3DASL software. Two expert readers identified AIS and CLS lesions on conventional images, DWI images and CBF maps. A senior radiologist calculated CBF values for lesions and nearby regions. Lesion, nearby regions and normal corresponding region values were analyzed using a two-sample t-test. RESULTS: Fifty-six stroke patients (21 with AIS and 35 with CLS) and 30 healthy subjects participated in this study. In the AIS group, AIS lesions appeared in the cortex/white matter, external/internal capsule (EC/IC), and basal ganglia. AIS lesions had lower CBF values than the normal corresponding regions (p<0.05). The mean CBF values in AIS nearby regions were significantly higher than those in normal corresponding regions (p<0.05). In the CLS group, the CBF values in white matter and EC/IC were lower than the CBF values in normal corresponding regions (p=0.063 and 0.052, respectively). The CBF values in CLS nearby regions and normal corresponding regions were not significantly different (p>0.05). CONCLUSION: In some regions of the brain, CLS lesions, AIS lesions, and their nearby regions have different perfusion statuses. In particular, the AIS nearby regions perfusion in our subjects was significantly higher than that previously reported. pCASL can be a robust imaging technique for diagnosing strokes in clinical practices.

Target delineation for radiosurgery of a small brain arteriovenous malformation using high-resolution contrast-enhanced cone beam CT.

Three years following endovascular embolization of a 3 mm ruptured arteriovenous malformation (AVM) of the left superior colliculus in a 42-year-old man, digital subtraction angiography showed continuous regrowth of the lesion. Thin-slice MRI acquired for treatment planning did not show the AVM nidus. The patient was brought back to the angiography suite for high-resolution contrast-enhanced cone beam CT (VasoCT) acquired using an angiographic c-arm system. The lesion and nidus were visualized with VasoCT. MRI, CT and VasoCT data were transferred to radiation planning software and mutually co-registered. The nidus was annotated for radiation on VasoCT data by an experienced neurointerventional radiologist and a dose/treatment plan was completed. Due to image registration, the treatment area could be directly adopted into the MRI and CT data. The AVM was completely obliterated 10 months following completion of the radiosurgery treatment.

Target delineation for radiosurgery of a small brain arteriovenous malformation using high-resolution contrast-enhanced cone beam CT.

Three years following endovascular embolization of a 3 mm ruptured arteriovenous malformation (AVM) of the left superior colliculus in a 42-year-old man, digital subtraction angiography showed continuous regrowth of the lesion. Thin-slice MRI acquired for treatment planning did not show the AVM nidus. The patient was brought back to the angiography suite for high-resolution contrast-enhanced cone beam CT (VasoCT) acquired using an angiographic c-arm system. The lesion and nidus were visualized with VasoCT. MRI, CT and VasoCT data were transferred to radiation planning software and mutually co-registered. The nidus was annotated for radiation on VasoCT data by an experienced neurointerventional radiologist and a dose/treatment plan was completed. Due to image registration, the treatment area could be directly adopted into the MRI and CT data. The AVM was completely obliterated 10 months following completion of the radiosurgery treatment.