Spatially resolved whole transcriptome profiling in human and mouse tissue using Digital Spatial Profiling.

Emerging spatial profiling technology has enabled high-plex molecular profiling in biological tissues, preserving the spatial and morphological context of gene expression. Here, we describe expanding the chemistry for the Digital Spatial Profiling platform to quantify whole transcriptomes in human and mouse tissues using a wide range of spatial profiling strategies and sample types. We designed multiplexed in situ hybridization probes targeting the protein-coding genes of the human and mouse transcriptomes, referred to as the human or mouse Whole Transcriptome Atlas (WTA). Human and mouse WTAs were validated in cell lines for concordance with orthogonal gene expression profiling methods in regions ranging from ∼10-500 cells. By benchmarking against bulk RNA-seq and fluorescence in situ hybridization, we show robust transcript detection down to ∼100 transcripts per region. To assess the performance of WTA across tissue and sample types, we applied WTA to biological questions in cancer, molecular pathology, and developmental biology. Spatial profiling with WTA detected expected gene expression differences between tumor and tumor microenvironment, identified disease-specific gene expression heterogeneity in histological structures of the human kidney, and comprehensively mapped transcriptional programs in anatomical substructures of nine organs in the developing mouse embryo. Digital Spatial Profiling technology with the WTA assays provides a flexible method for spatial whole transcriptome profiling applicable to diverse tissue types and biological contexts.

Brain AVM compactness score in children with hereditary hemorrhagic telangiectasia.

OBJECTIVE: The brain arteriovenous malformation (BAVM) nidus compactness score (CS), determined on angiography, predicts BAVM recurrence after surgical resection among children with sporadic BAVMs. We measured the angiographic CS for BAVMs among children with hereditary hemorrhagic telangiectasia (HHT) to determine CS characteristics in this population. METHODS: A pediatric interventional neuroradiologist reviewed angiograms to determine the CS of BAVMs in children with HHT recruited to the BVMC. CS is based on overall nidus and perinidal anomalous vessel compactness. CS categories included 1 = diffuse nidus, 2 = intermediate nidus, and 3 = compact nidus. RESULTS: Forty-eight of 78 children (61.5%) with HHT and brain vascular malformations had a conventional angiogram; 47 (97.9%) angiograms were available. Fifty-four BAVMs were identified in 40 of these 47 children (85.1%). Of 54 BAVMs in children with HHT, CS was 1 in 7 (13%), 2 in 29 (53.7%), and 3 in 18 BAVMs (33.3%) compared with CS of 1 in six (26.1%), 2 in 15 (65.2%), and 3 in 2 BAVMs (8.7%) among 23 previously reported children with sporadic BAVMs, p = 0.045 (Fisher's exact). Seven children with HHT had intracranial hemorrhage: 4 had CS = 3, 1 had CS = 2, and 2 had CS = 1. CONCLUSIONS: A range of CSs exists across HHT BAVMs, suggesting it may be an angiographic measure of interest for future studies of BAVM recurrence and hemorrhage risk. Children with HHT may have more compact niduses compared to children with sporadic BAVMs. Additional research should determine whether CS affects hemorrhage risk or post-surgical recurrence risk in HHT-associated BAVMs, which could be used to direct BAVM treatment.

Evaluating the impact of using a wound-specific oral nutritional supplement to support wound healing in a rehabilitation setting.

Chronic wounds adversely affect patient quality of life, increase the risk of mortality, and impose high costs on healthcare systems. Since protein-energy malnutrition or specific nutrient deficiencies can delay wound healing, nutritionally focused care is a key strategy to help prevent or treat the occurrence of non-healing wounds. The objective of our study of inpatients in a rehabilitation hospital was to quantify the effect of daily wound-specific oral nutritional supplementation (WS-ONS) on healing chronic wounds. Using electronic medical records, we conducted a retrospective analysis of patients with chronic wounds. We identified records for (a) a treatment group who received standard wound care + usual hospital diet + daily WS-ONS for ≥14 days, and (b) a control group who received standard wound care + a usual hospital diet. We collected data for demographics, nutritional status, and wound-relevant health characteristics. We examined weekly measurements of wound number and sizes (surface area for superficial wounds or volume for non-superficial wounds). There were 341 patients identified, 114 with 322 wounds in the treatment group and 227 patients with 420 wounds in the control group. We found that rehabilitation inpatients who were given nutritional support had larger wounds and lower functional independence on admission. At discharge, wound area reduction (percent) was nearly two-fold better in patients who were given daily WS-ONS + usual hospital diet compared to those who consumed usual diet only (61.1% vs 34.5%). Overall, weekly wound improvement (lowered wound area or wound volume) was more likely in the WS-ONS group than in the Control group, particularly from the start of care to week 2. Inpatients with largest wounds and lowest functional independence on admission were most likely to be given WS-ONS, an indication that caregivers recognised the need for supplementation. Week-to-week improvement in wound size was more likely in patients who received WS-ONS than in those who did not. Specifically, wound areas and wound volumes were significantly lower at discharge among patients who were given specialised nutritional support. More research in this field is needed to improve care and reduce healthcare costs.

Malnutrition and Pressure Injury Risk in Vulnerable Populations: Application of the 2019 International Clinical Practice Guideline.

ABSTRACT: Nutrition plays a vital role in promoting skin integrity and supporting tissue repair in the presence of chronic wounds such as pressure injuries (PIs). Individuals who are malnourished are at greater risk of polymorbid conditions, adverse clinical outcomes, longer hospital lengths of stay, PI development, and mortality, and incur increased healthcare costs compared with patients who are adequately nourished. In addition, some patient populations tend to be more vulnerable to PI formation, such as neonates, patients with obesity, older adults, and individuals who are critically ill. Accordingly, this article aims to review the latest nutrition care recommendations for the prevention and treatment of PIs, including those recommendations tailored to special populations. A secondary objective is to translate nutrition recommendations into actionable steps for the healthcare professional to implement as part of a patient plan of care.Implementing an evidence-based plan of care built around individualized nutrition interventions is an essential step supporting skin integrity for these populations. The 2019 Prevention and Treatment of Pressure Ulcers/Injuries: Clinical Practice Guideline (CPG) affirms that meeting nutrient requirements is essential for growth, development, maintenance, and repair of body tissues. Many macronutrients and micronutrients work synergistically to heal PIs. Registered dietitian nutritionists play an important role in helping patients identify the most nutrient dense foods, protein supplements, and oral nutrition supplements to meet their unique requirements.

Baseline Characteristics of Patients With Cavernous Angiomas With Symptomatic Hemorrhage in Multisite Trial Readiness Project.

BACKGROUND AND PURPOSE: Brain cavernous angiomas with symptomatic hemorrhage (CASH) have a high risk of neurological disability from recurrent bleeding. Systematic assessment of baseline features and multisite validation of novel magnetic resonance imaging biomarkers are needed to optimize clinical trial design aimed at novel pharmacotherapies in CASH. METHODS: This prospective, multicenter, observational cohort study included adults with unresected, adjudicated brain CASH within the prior year. Six US sites screened and enrolled patients starting August 2018. Baseline demographics, clinical and imaging features, functional status (modified Rankin Scale and National Institutes of Health Stroke Scale), and patient quality of life outcomes (Patient-Reported Outcomes Measurement Information System-29 and EuroQol-5D) were summarized using descriptive statistics. Patient-Reported Outcomes Measurement Information System-29 scores were standardized against a reference population (mean 50, SD 10), and one-sample t test was performed for each domain. A subgroup underwent harmonized magnetic resonance imaging assessment of lesional iron content with quantitative susceptibility mapping and vascular permeability with dynamic contrast-enhanced quantitative perfusion. RESULTS: As of May 2020, 849 patients were screened and 110 CASH cases enrolled (13% prevalence of trial eligible cases). The average age at consent was 46±16 years, 53% were female, 41% were familial, and 43% were brainstem lesions. At enrollment, ≥90% of the cohort had independent functional outcome (modified Rankin Scale score ≤2 and National Institutes of Health Stroke Scale score <5). However, perceived health problems affecting quality of life were reported in >30% of patients (EuroQol-5D). Patients had significantly worse Patient-Reported Outcomes Measurement Information System-29 scores for anxiety (P=0.007), but better depression (P=0.002) and social satisfaction scores (P=0.012) compared with the general reference population. Mean baseline quantitative susceptibility mapping and permeability of CASH lesion were 0.45±0.17 ppm and 0.39±0.31 mL/100 g per minute, respectively, which were similar to historical CASH cases and consistent across sites. CONCLUSIONS: These baseline features will aid investigators in patient stratification and determining the most appropriate outcome measures for clinical trials of emerging pharmacotherapies in CASH.

Brain Arteriovenous Malformation Recurrence After Apparent Microsurgical Cure: Increased Risk in Children Who Present With Arteriovenous Malformation Rupture.

BACKGROUND AND PURPOSE: Do children have an increased risk for brain arteriovenous malformation (AVM) recurrence compared with adults and does this risk vary depending on initial presentation with AVM rupture? METHODS: We retrospectively studied 115 patients initially presenting with brain AVM under age 25 years who underwent complete surgical resection of the AVM as documented by digital subtraction angiography (DSA) and had delayed follow-up DSA to evaluate for AVM recurrence after apparent initial cure. RESULTS: The mean time from baseline DSA to follow-up DSA was 2.3 years, ranging from 0 to 15 years. Twelve patients (10.4% of the 115 patient cohort and 16.7% of 72 patients with hemorrhage at initial presentation) demonstrated AVM recurrence on follow-up DSA. All patients with recurrence initially presented with intracranial hemorrhage, and intracranial hemorrhage was a significant predictor of recurrence (log rank P=0.037). Among patients with initial hemorrhage, the 5-year recurrence rate was 17.8% (95% CI, 8.3%-35.7%). All recurrences occurred in patients who were children at the time of their initial presentation; the oldest was 15 years of age at the time of initial AVM surgery. The 5-year recurrence rate for children (0-18 years of age) with an initial presentation of hemorrhage was 21.4% (95% CI, 10.1%-41.9%). Using Cox regression, we found the risk of AVM recurrence decreased by 14% per each year increase in age at the time of initial surgical resection (hazard ratio=0.86 [95% CI, 0.75-0.99]; P=0.031). CONCLUSIONS: There is a high rate of recurrence of apparently cured brain AVMs in children who initially present with AVM rupture. Imaging follow-up is warranted to prevent re-rupture.

Vertebral Intraosseous Vascular Malformations in a Familial Cerebral Cavernous Malformation Population: Prevalence, Histologic Features, and Associations With CNS Disease.

OBJECTIVE. The purpose of this study was to investigate whether MRI-typical and MRI-atypical intraosseous vascular malformations are associated with familial cerebral cavernous malformation (FCCM). MATERIALS AND METHODS. In a retrospective matched case-control study, two radiologists reviewed the spinal imaging, both CT and MRI, of 22 patients with FCCM seen between 2006 and 2017 and of age- and sex-matched control subjects for MRI-typical and MRI-atypical intraosseous vascular malformations. Quantitative analysis of lesions identified included vertebral level, size, and number of lesions. Pathologic samples from two lesions were analyzed for histologic and immunohistochemical features. Whether the presence of typical, atypical, and total intraosseous vascular malformations differed between patients and control subjects was tested. For patients with complete spinal imaging, whether intraosseous vascular malformations were associated with age, sex, brain lesion count, and spinal lesion count was also tested. RESULTS. MRI-atypical intraosseous vertebral malformations were more commonly present in patients with FCCM (p = 0.003). Sixteen lesions were found in nine patients and none in the control group. The numbers of MRI-typical intraosseous vascular malformations were similar between patients and control subjects (p = 0.480). Age was associated with typical intraosseous vascular malformations (p = 0.027), though not with atypical malformations. MRI-atypical malformations were larger (mean diameter double) than MRI-typical malformations (p = 0.023). Histologic analysis of two lesions from different patients with pathologic collapse revealed the same histologic features consistent with combined capillary-venous malformations. CONCLUSION. Vertebral capillary-venous malformations (MRI-atypical intraosseous vascular malformations) are common in patients with FCCM and may have a more aggressive clinical course than MRI-typical malformations.

Cost determinants in management of brain arteriovenous malformations.

INTRODUCTION: There is little data on the cost of treating brain arteriovenous malformations (AVMs). The goal of this study then is to identify cost determinants in multimodal management of brain AVMs. METHODS: One hundred forty patients with brain AVMs prospectively enrolled in the UCSF brain AVM registry and treated between 2012 and 2015 were included in the study. Patient and AVM characteristics, treatment type, and length of stay and radiographic evidence of obliteration were collected from the registry. We then calculated the cost of all inpatient and outpatient encounters, interventions, and imaging attributable to the AVM. We used generalized linear models to test whether there was an association between patient and AVM characteristics, treatment type, and cost and length of stay. We tested whether the proportion of patients with radiographic evidence of obliteration differed between treatment modalities using Fisher's exact test. RESULTS: The overall median cost of treatment and interquartile range was $77,865 (49,566-107,448). Surgery with preoperative embolization was the costliest treatment at $91,948 (79,914-140,600), while radiosurgery was the least at $20,917 (13,915-35,583). In multi-predictor analyses, hemorrhage, Spetzler-Martin grade, and treatment type were significant predictors of cost. Patients who had surgery had significantly higher rates of obliteration compared with radiosurgery patients. CONCLUSIONS: Hemorrhage, AVM grade, and treatment modality are significant cost determinants in AVM management. Surgery with preoperative embolization was the costliest treatment and radiosurgery the least; however, surgical cases had significantly higher rates of obliteration.

Automated quality control in nuclear medicine using the structured noise index.

PURPOSE: Daily flood-field uniformity evaluation serves as the central element of nuclear medicine (NM) quality control (QC) programs. Uniformity images are traditionally analyzed using pixel value-based metrics, that is, integral uniformity (IU), which often fail to capture subtle structure and patterns caused by changes in gamma camera performance, requiring visual inspections which are subjective and time demanding. The goal of this project was to implement an advanced QC metrology for NM to effectively identify nonuniformity issues, and report issues in a timely manner for efficient correction prior to clinical use. The project involved the implementation of the program over a 2-year period at a multisite major medical institution. METHODS: Using a previously developed quantitative uniformity analysis metric, the structured noise index (SNI) [Nelson et al. (2014), \textit{J Nucl Med.}, \textbf{55}:169-174], an automated QC process was developed to analyze, archive, and report on daily NM QC uniformity images. Clinical implementation of the newly developed program ran in parallel with the manufacturer's reported IU-based QC program. The effectiveness of the SNI program was evaluated over a 21-month period using sensitivity and coefficient of variation statistics. RESULTS: A total of 7365 uniformity QC images were analyzed. Lower level SNI alerts were generated in 12.5% of images and upper level alerts in 1.7%. Intervention due to image quality issues occurred on 26 instances; the SNI metric identified 24, while the IU metric identified eight. The SNI metric reported five upper level alerts where no clinical engineering intervention was deemed necessary. CONCLUSION: An SNI-based QC program provides a robust quantification of the performance of gamma camera uniformity. It operates seamlessly across a fleet of multiple camera models and, additionally, provides effective workflow among the clinical staff. The reliability of this process could eliminate the need for visual inspection of each image, saving valuable time, while enabling quantitative analysis of inter- and intrasystem performance.

Analysis of embryonic development in the unsequenced axolotl: Waves of transcriptomic upheaval and stability.

The axolotl (Ambystoma mexicanum) has long been the subject of biological research, primarily owing to its outstanding regenerative capabilities. However, the gene expression programs governing its embryonic development are particularly underexplored, especially when compared to other amphibian model species. Therefore, we performed whole transcriptome polyA+ RNA sequencing experiments on 17 stages of embryonic development. As the axolotl genome is unsequenced and its gene annotation is incomplete, we built de novo transcriptome assemblies for each stage and garnered functional annotation by comparing expressed contigs with known genes in other organisms. In evaluating the number of differentially expressed genes over time, we identify three waves of substantial transcriptome upheaval each followed by a period of relative transcriptome stability. The first wave of upheaval is between the one and two cell stage. We show that the number of differentially expressed genes per unit time is higher between the one and two cell stage than it is across the mid-blastula transition (MBT), the period of zygotic genome activation. We use total RNA sequencing to demonstrate that the vast majority of genes with increasing polyA+ signal between the one and two cell stage result from polyadenylation rather than de novo transcription. The first stable phase begins after the two cell stage and continues until the mid-blastula transition, corresponding with the pre-MBT phase of transcriptional quiescence in amphibian development. Following this is a peak of differential gene expression corresponding with the activation of the zygotic genome and a phase of transcriptomic stability from stages 9-11. We observe a third wave of transcriptomic change between stages 11 and 14, followed by a final stable period. The last two stable phases have not been documented in amphibians previously and correspond to times of major morphogenic change in the axolotl embryo: gastrulation and neurulation. These results yield new insights into global gene expression during early stages of amphibian embryogenesis and will help to further develop the axolotl as a model species for developmental and regenerative biology.

Higher Flow Is Present in Unruptured Arteriovenous Malformations With Silent Intralesional Microhemorrhages.

BACKGROUND AND PURPOSE: Silent microhemorrhage (hemosiderin) has been observed in resected brain arteriovenous malformations (bAVM) tissue and may represent a subgroup at increased risk for clinical hemorrhage. Previous studies suggest that ruptured bAVMs have faster flow and shorter mean transit time of contrast in blood vessels than unruptured bAVMs. We hypothesized that flow would be faster in unruptured AVMs with hemosiderin compared with those without hemosiderin. METHODS: We selected unruptured, supratentorial bAVMs >3.5 cc with pathology specimens. Hemodynamic features were evaluated using color-coding angiography, including contrast mean transit time of AVM nidus, time to peak (TTP) of feeding artery (FA) and draining vein (DV), and the ratio (TTP DV/FA). Characteristics of 9 cases with hemosiderin and 16 without hemosiderin were compared using 2-sample t tests and Fisher exact tests. RESULTS: No difference in FA TTP and DV TTP was observed between groups. However, cases with hemosiderin had significantly shorter mean transit time compared with those without hemosiderin (1.11±0.28 versus 1.64±0.55 seconds; P=0.013) and a lower ratio of DV TTP/FA TTP (1.48±0.32 versus 1.94±0.61; P=0.045). Presence of venous varix was significantly associated with hemosiderin (P=0.003). No other clinical or angioarchitectural factors were associated with hemosiderin. CONCLUSIONS: Shorter mean transit time through the AVM nidus, lower DV TTP/FA TTP, and the high prevalence of venous varices suggests that high flow is an important feature of unruptured bAVMs with hemosiderin.

Soluble FLT1 Gene Therapy Alleviates Brain Arteriovenous Malformation Severity.

BACKGROUND AND PURPOSE: Brain arteriovenous malformation (bAVM) is an important risk factor for intracranial hemorrhage. Current therapies are associated with high morbidities. Excessive vascular endothelial growth factor has been implicated in bAVM pathophysiology. Because soluble FLT1 binds to vascular endothelial growth factor with high affinity, we tested intravenous delivery of an adeno-associated viral vector serotype-9 expressing soluble FLT1 (AAV9-sFLT1) to alleviate the bAVM phenotype. METHODS: Two mouse models were used. In model 1, bAVM was induced in R26CreER;Eng2f/2f mice through global Eng gene deletion and brain focal angiogenic stimulation; AAV2-sFLT02 (an AAV expressing a shorter form of sFLT1) was injected into the brain at the time of model induction, and AAV9-sFLT1, intravenously injected 8 weeks after. In model 2, SM22αCre;Eng2f/2f mice had a 90% occurrence of spontaneous bAVM at 5 weeks of age and 50% mortality at 6 weeks; AAV9-sFLT1 was intravenously delivered into 4- to 5-week-old mice. Tissue samples were collected 4 weeks after AAV9-sFLT1 delivery. RESULTS: AAV2-sFLT02 inhibited bAVM formation, and AAV9-sFLT1 reduced abnormal vessels in model 1 (GFP versus sFLT1: 3.66±1.58/200 vessels versus 1.98±1.29, P<0.05). AAV9-sFLT1 reduced the occurrence of bAVM (GFP versus sFLT1: 100% versus 36%) and mortality (GFP versus sFLT1: 57% [12/22 mice] versus 24% [4/19 mice], P<0.05) in model 2. Kidney and liver function did not change significantly. Minor liver inflammation was found in 56% of AAV9-sFLT1-treated model 1 mice. CONCLUSIONS: By applying a regulated mechanism to restrict sFLT1 expression to bAVM, AAV9-sFLT1 can potentially be developed into a safer therapy to reduce the bAVM severity.

Familial Cerebral Cavernous Malformations Are Associated with Adrenal Calcifications on CT Scans: An Imaging Biomarker for a Hereditary Cerebrovascular Condition.

Purpose To determine if adrenal calcifications seen at computed tomography (CT) are associated with familial cerebral cavernous malformations (fCCMs) in carriers of the CCM1 Common Hispanic Mutation. Materials and Methods This study was approved by the institutional review board. The authors retrospectively reviewed abdominal CT scans in 38 patients with fCCM, 38 unaffected age- and sex-matched control subjects, and 13 patients with sporadic, nonfamilial cerebral cavernous malformation (CCM). The size, number, and laterality of calcifications and the morphologic characteristics of the adrenal gland were recorded. Brain lesion count was recorded from brain magnetic resonance (MR) imaging in patients with fCCM. The prevalence of adrenal calcifications in patients with fCCM was compared with that in unaffected control subjects and those with sporadic CCM by using the Fisher exact test. Additional analyses were performed to determine whether age and brain lesion count were associated with adrenal findings in patients with fCCM. Results Small focal calcifications (SFCs) (≤5 mm) were seen in one or both adrenal glands in 19 of the 38 patients with fCCM (50%), compared with 0 of the 38 unaffected control subjects (P < .001) and 0 of the 13 subjects with sporadic CCM (P = .001). Adrenal calcifications in patients with fCCM were more frequently left sided, with 17 of 19 patients having more SFCs in the left adrenal gland than the right adrenal gland and 50 of the 61 observed SFCs (82%) found in the left adrenal gland. No subjects had SFCs on the right side only. In patients with fCCM, the presence of SFCs showed a positive correlation with age (P < .001) and number of brain lesions (P < .001). Conclusion Adrenal calcifications identified on CT scans are common in patients with fCCM and may be a clinically silent manifestation of disease. © RSNA, 2017.

Automated algorithm for counting microbleeds in patients with familial cerebral cavernous malformations.

PURPOSE: Familial cerebral cavernous malformation (CCM) patients present with multiple lesions that can grow both in number and size over time and are reliably detected on susceptibility-weighted imaging (SWI). Manual counting of lesions is arduous and subject to high variability. We aimed to develop an automated algorithm for counting CCM microbleeds (lesions <5 mm in diameter) on SWI images. METHODS: Fifty-seven familial CCM type-1 patients were included in this institutional review board-approved study. Baseline SWI (n = 57) and follow-up SWI (n = 17) were performed on a 3T Siemens MR scanner with lesions counted manually by the study neuroradiologist. We modified an algorithm for detecting radiation-induced microbleeds on SWI images in brain tumor patients, using a training set of 22 manually delineated CCM microbleeds from two random scans. Manual and automated counts were compared using linear regression with robust standard errors, intra-class correlation (ICC), and paired t tests. A validation analysis comparing the automated counting algorithm and a consensus read from two neuroradiologists was used to calculate sensitivity, the proportion of microbleeds correctly identified by the automated algorithm. RESULTS: Automated and manual microbleed counts were in strong agreement in both baseline (ICC = 0.95, p < 0.001) and longitudinal (ICC = 0.88, p < 0.001) analyses, with no significant difference between average counts (baseline p = 0.11, longitudinal p = 0.29). In the validation analysis, the algorithm correctly identified 662 of 1325 microbleeds (sensitivity=50%), again with strong agreement between approaches (ICC = 0.77, p < 0.001). CONCLUSION: The automated algorithm is a consistent method for counting microbleeds in familial CCM patients that can facilitate lesion quantification and tracking.

Potential for rapid antibody detection to identify tuberculous cattle with non-reactive tuberculin skin test results.

BACKGROUND: Bovine tuberculosis (TB) control programs generally rely on the tuberculin skin test (TST) for ante-mortem detection of Mycobacterium bovis-infected cattle. RESULTS: Present findings demonstrate that a rapid antibody test based on Dual-Path Platform (DPP®) technology, when applied 1-3 weeks after TST, detected 9 of 11 and 34 of 52 TST non-reactive yet M. bovis-infected cattle from the US and GB, respectively. The specificity of the assay ranged from 98.9% (n = 92, US) to 96.0% (n = 50, GB) with samples from TB-free herds. Multi-antigen print immunoassay (MAPIA) revealed the presence of antibodies to multiple antigens of M. bovis in sera from TST non-reactors diagnosed with TB. CONCLUSIONS: Thus, use of serologic assays in series with TST can identify a significant number of TST non-reactive tuberculous cattle for more efficient removal from TB-affected herds.

Combined Endoscopic Laparoscopic Surgery Procedures for Colorectal Surgery.

Colonoscopy is the standard of care for screening and surveillance of colorectal cancers. Removal of adenomatous polyps prevents the transformation of adenomas to potential adenocarcinoma. While most polyps are amenable to simple endoscopic polypectomy, difficult polyps that are large, broad-based, or located in haustral folds or in tortuous colon segments can present a challenge for endoscopists. Traditionally, patients with endoscopically unresectable polyps have been referred for oncologic surgical resection due to the underlying risk of malignancy within the polyp; however, the majority of these polyps are benign on final pathology. Combined endoscopic laparoscopic surgery can help facilitate endoscopic removal of difficult lesions, or allow the surgeon to select the correct laparoscopic approach for polyp excision. Current literature suggests that these procedures are safe and effective and can potentially save patients from the morbidity of laparotomy and segmental colectomy.

Genome-wide association study of sporadic brain arteriovenous malformations.

BACKGROUND: The pathogenesis of sporadic brain arteriovenous malformations (BAVMs) remains unknown, but studies suggest a genetic component. We estimated the heritability of sporadic BAVM and performed a genome-wide association study (GWAS) to investigate association of common single nucleotide polymorphisms (SNPs) with risk of sporadic BAVM in the international, multicentre Genetics of Arteriovenous Malformation (GEN-AVM) consortium. METHODS: The Caucasian discovery cohort included 515 BAVM cases and 1191 controls genotyped using Affymetrix genome-wide SNP arrays. Genotype data were imputed to 1000 Genomes Project data, and well-imputed SNPs (>0.01 minor allele frequency) were analysed for association with BAVM. 57 top BAVM-associated SNPs (51 SNPs with p<10(-05) or p<10(-04) in candidate pathway genes, and 6 candidate BAVM SNPs) were tested in a replication cohort including 608 BAVM cases and 744 controls. RESULTS: The estimated heritability of BAVM was 17.6% (SE 8.9%, age and sex-adjusted p=0.015). None of the SNPs were significantly associated with BAVM in the replication cohort after correction for multiple testing. 6 SNPs had a nominal p<0.1 in the replication cohort and map to introns in EGFEM1P, SP4 and CDKAL1 or near JAG1 and BNC2. Of the 6 candidate SNPs, 2 in ACVRL1 and MMP3 had a nominal p<0.05 in the replication cohort. CONCLUSIONS: We performed the first GWAS of sporadic BAVM in the largest BAVM cohort assembled to date. No GWAS SNPs were replicated, suggesting that common SNPs do not contribute strongly to BAVM susceptibility. However, heritability estimates suggest a modest but significant genetic contribution.

Prognostic value of the cadmium-zinc-telluride camera: A comparison with a conventional (Anger) camera.

BACKGROUND: New multipinhole cadmium-zinc-telluride (CZT) cameras allow for faster imaging and lower radiation doses for single photon emission computed tomography (SPECT) studies, but assessment of prognostic ability is necessary. METHODS AND RESULTS: We collected data from all myocardial SPECT perfusion studies performed over 15 months at our institution, using either a CZT or conventional Anger camera. A Cox proportional hazards model was used to assess the relationship between camera type, imaging results, and either death or myocardial infarction (MI). Clinical variables including age, sex, body mass index (BMI), and historical risk factors were used for population description and model adjustments. We had 2,088 patients with a total of 69 deaths and 65 MIs (122 events altogether). A 3% increase in DDB (difference defect burden) represented a 12% increase in the risk of death or MI, whereas a 3% increase in rest defect burden or stress defect burden represented an 8% increase; these risks were the same for both cameras (P > .24, interaction tests). CONCLUSIONS: The CZT camera has similar prognostic values for death and MI to conventional Anger cameras. This suggests that it may successfully be used to decrease patient dose.

Morphometric characterization of brain arteriovenous malformations for clinical and radiological studies to identify silent intralesional microhemorrhages.

Brain arteriovenous malformations (bAVMs) are vascular lesions that can cause significant morbidity and mortality, particularly when they bleed, i.e., rupture. Determining the risk of rupture for bAVMs is a crucial task to determine the most appropriate approach to patients with bAVM. Furthermore, patients who present with a hemorrhagic event also have a higher risk of subsequent hemorrhage. Determination of the hemorrhage risk and management strategy for incidentally discovered bAVMs still remains a controversial subject. In recent years, we have identified silent intralesional microhemorrhages (SIMs) as a possible risk factor for subsequent hemorrhage in patients with bAVMs. The principal aim of this study was to determine critical histological features that can be correlated with preoperative radioimaging findings, and allow better identification of patients with greater risk of adverse outcome. Here we provide a detailed descriptive analysis of the morphometric assessment of bAVMs in order to provide reproducible methodology that will aid in correlating preoperative radioimaging findings with histological features that may be significantly associated with increased risk of hemorrhage/rupture.

Single-Stage Reconstruction of Achilles Tendon and Overlying Tissue With the Extended Temporoparietal Fasciagaleal Flap--23-Year Follow-Up and the Review of the Literature.

In the absence of an established "gold standard" for complex Achilles tendon and regional soft tissue defect reconstruction, many techniques have been advocated. Two cases describing a novel technique of successful repair with the review of literature are presented. The underlying problem consisted of Achilles tendon necrosis with local inflammation in the first case and tendon contracture with foot malposition due to a burn injury in the other. Each patient, upon debridement, had a 6-cm Achilles tendon defect with associated overlying soft tissue deficits reconstructed with an extended temporoparietal fasciagaleal flap and a split thickness skin graft. Both cases highlight the successful functional and aesthetic quality as well as the durability of concurrent vascularized tendon and soft tissue replacement and coverage in 2 distinct clinical scenarios.