Oral IBGard™ Before Colonoscopy: A Single-Center Double-Blinded, Randomized, Placebo-Controlled Trial.

BACKGROUND: Peppermint oil is well known to inhibit smooth muscle contractions, and its topical administration during colonoscopy is reported to reduce colonic spasms. AIMS: We aimed to assess whether oral administration of IBGard™, a sustained-release peppermint oil formulation, before colonoscopy reduces spasms and improves adenoma detection rate (ADR).  METHODS: We performed a single-center randomized, double-blinded, placebo-controlled trial. Patients undergoing screening or surveillance colonoscopies were randomized to receive IBGard™ or placebo. The endoscopist graded spasms during insertion, inspection, and polypectomy. Bowel preparation, procedure time, and time of drug administration were documented. Statistical analysis was performed using the Student's t test and Wilcoxon rank-sum test. RESULTS: There was no significant difference in baseline characteristics or dose-timing distribution between IBGard™ and placebo groups. Similarly, there was no difference in ADR (IBGard™ = 47.8%, placebo = 43.1%, p = 0.51), intubation spasm score (1.23 vs 1.2, p = 0.9), withdrawal spasm score (1.3 vs 1.23, p = 0.72), or polypectomy spasm score (0.52 vs 0.46, p = 0.69). Limiting the analysis to patients who received the drug more than 60 min prior to the start of the procedure did not produce any significant differences in these endpoints. CONCLUSIONS: This randomized controlled trial failed to show benefit of orally administered IBGard™ prior to colonoscopy on the presence of colonic spasms or ADR. Because of its low barrier to widespread adoption, the use of appropriately formulated and timed oral peppermint oil warrants further study to determine its efficacy in reducing colonic spasms and improving colonoscopy quality.

Performance of computational methods for the evaluation of pericentriolar material 1 missense variants in CAGI-5.

The CAGI-5 pericentriolar material 1 (PCM1) challenge aimed to predict the effect of 38 transgenic human missense mutations in the PCM1 protein implicated in schizophrenia. Participants were provided with 16 benign variants (negative controls), 10 hypomorphic, and 12 loss of function variants. Six groups participated and were asked to predict the probability of effect and standard deviation associated to each mutation. Here, we present the challenge assessment. Prediction performance was evaluated using different measures to conclude in a final ranking which highlights the strengths and weaknesses of each group. The results show a great variety of predictions where some methods performed significantly better than others. Benign variants played an important role as negative controls, highlighting predictors biased to identify disease phenotypes. The best predictor, Bromberg lab, used a neural-network-based method able to discriminate between neutral and non-neutral single nucleotide polymorphisms. The CAGI-5 PCM1 challenge allowed us to evaluate the state of the art techniques for interpreting the effect of novel variants for a difficult target protein.

Hemobilia: Historical overview, clinical update, and current practices.

Hemobilia refers to macroscopic blood in the lumen of the biliary tree. It represents an uncommon, but important, cause of gastrointestinal bleeding and can have potentially lethal sequelae if not promptly recognized and treated. The earliest known reports of hemobilia date to the 17th century, but due to the relative rarity and challenges in diagnosis of hemobilia, it has historically not been well-studied. Until recently, most cases of hemobilia were due to trauma, but the majority now occur as a sequela of invasive procedures involving the hepatopancreatobiliary system. A triad (Quincke's) of right upper quadrant pain, jaundice and overt gastrointestinal bleeding has been classically described in hemobilia, but it is present in only a minority of patients. Therefore, prompt diagnosis depends critically on a high index of suspicion based on a patient's clinical presentation and a history of recently undergoing hepatopancreatobiliary intervention or having other predisposing factors. Treatment of hemobilia depends on the suspected source and clinical severity and thus ranges from supportive medical care to urgent advanced endoscopic, interventional radiologic, or surgical intervention. In the present review, we provide a historical perspective, clinical update and overview of current trends and practices pertaining to hemobilia.

Dose rate response of Digital Megavolt Imager detector for flattening filter-free beams.

In this study we investigated the dose rate response characteristics of the Digital Megavolt Imager (DMI) detector, including panel saturation, linearity, and imager ghosting effects for flattening filter-free (FFF) beams. The DMI detector dose rate response characteristics were measured as a function of dose rate on a Varian TrueBeam machine. Images were acquired at dose rates ranging from 400 to 1400 MU/min for 6XFFF and 400 to 2400 MU/min for 10XFFF. Line profiles and central portal doses derived from the images were analyzed and compared. The linearity was verified by acquiring images with incremental Monitor Unit (MU) ranging from 5 to 500 MU. Ghosting effects were studied at different dose rates. Finally, for validation, test plans with optimal fluence were created and measured with different dose rates. All test plans were analyzed with a Gamma criteria of 3%-3 mm and 10% dose threshold. Our study showed that there was no panel saturation observed from the profile comparison even at the maximum dose rate of 2400 MU/min. The central portal doses showed a slight decrease (1.013-1.008 cGy/MU for 6XFFF, and 1.020-1.009 cGy/MU for 10XFFF) when dose rate increased (400-1400 MU/min for 6XFFF, and 400-2400 MU/min for 10XFFF). The linearity of the DMI detector response was better than 0.5% in the range of 20-500 MU for all energies. The residual image was extremely small and statistically undetectable. The Gamma index measured with the test plans decreased from 100% to 97.8% for 6XFFF when dose rate increased from 400 to 1400 MU/min. For 10XFFF, the Gamma index decreased from 99.9% to 91.5% when dose rate increased from 400 to 2400 MU/min. We concluded that the Portal Dosimetry system for the TrueBeam using DMI detector can be reliably used for IMRT and VMAT QA for FFF energies.

Effective experimental validation of miRNA targets using an improved linker reporter assay.

miRNAs are small, non-coding RNAs that play critical roles in various cellular processes. Although there are several algorithms that can predict the potential candidate genes that are regulated by a miRNA, these algorithms require further experimental validation in order to demonstrate genuine targets of miRNAs. Moreover, most algorithms predict hundreds to thousands of putative target genes for each miRNA, and it is difficult to validate all candidates using the whole 3'-untranslated region (UTR) reporter assay. We report a fast, simple and efficient experimental approach to screening miRNA candidate targets using a 3'-UTR linker assay. Critically, the linker has only a short miRNA regulatory element sequence of approximately 22 base pairs in length and can provide a benefit for screening strong miRNA candidates for further validation using the whole 3'-UTR sequence. Our technique will provide a simplified platform for the high-throughput screening of miRNA target gene validation.

Frequency of symptomatic vertebral body compression fractures requiring intervention following single-fraction stereotactic radiosurgery for spinal metastases.

OBJECTIVE The purpose of this study was to determine the rate of symptomatic vertebral body compression fractures (VCFs) requiring kyphoplasty or surgery in patients treated with 24-Gy single-fraction stereotactic radiosurgery (SRS). METHODS This retrospective analysis included all patients who had been treated with 24-Gy, single-fraction, image-guided intensity-modulated radiation therapy for histologically confirmed solid tumor metastases over an 8-year period (2005-2013) at Memorial Sloan Kettering Cancer Center. Charts and imaging studies were reviewed for post-SRS kyphoplasty or surgery for mechanical instability. A Spinal Instability Neoplastic Score (SINS) was calculated for each patient both at the time of SRS and at the time of intervention for VCF. RESULTS Three hundred twenty-three patients who had undergone single-fraction SRS between C-1 and L-5 were included in this analysis. The cumulative incidence of VCF 5 years after SRS was 7.2% (95% CI 4.1-10.2), whereas that of death following SRS at the same time point was 82.5% (95% CI 77.5-87.4). Twenty-six patients with 36 SRS-treated levels progressed to symptomatic VCF requiring treatment with kyphoplasty (6 patients), surgery (10 patients), or both (10 patients). The median time to symptomatic VCF was 13 months. Seven patients developed VCF at 11 levels adjacent to the SRS-treated level. Fractured levels had no evidence of tumor progression. The median SINS changed from 6.5 at SRS (interquartile range [IQR] 4.3-8.8) to 11.5 at stabilization (IQR 9-13). In patients without prior stabilization at the level of SRS, there was an association between the SINS and the time to fracture. CONCLUSIONS Five years after ablative single-fraction SRS to spinal lesions, the cumulative incidence of symptomatic VCF at the treated level without tumor recurrence was 7.2%. Higher SINSs at the time of SRS correlated with earlier fractures.

Comparative genome structure, secondary metabolite, and effector coding capacity across Cochliobolus pathogens.

The genomes of five Cochliobolus heterostrophus strains, two Cochliobolus sativus strains, three additional Cochliobolus species (Cochliobolus victoriae, Cochliobolus carbonum, Cochliobolus miyabeanus), and closely related Setosphaeria turcica were sequenced at the Joint Genome Institute (JGI). The datasets were used to identify SNPs between strains and species, unique genomic regions, core secondary metabolism genes, and small secreted protein (SSP) candidate effector encoding genes with a view towards pinpointing structural elements and gene content associated with specificity of these closely related fungi to different cereal hosts. Whole-genome alignment shows that three to five percent of each genome differs between strains of the same species, while a quarter of each genome differs between species. On average, SNP counts among field isolates of the same C. heterostrophus species are more than 25× higher than those between inbred lines and 50× lower than SNPs between Cochliobolus species. The suites of nonribosomal peptide synthetase (NRPS), polyketide synthase (PKS), and SSP-encoding genes are astoundingly diverse among species but remarkably conserved among isolates of the same species, whether inbred or field strains, except for defining examples that map to unique genomic regions. Functional analysis of several strain-unique PKSs and NRPSs reveal a strong correlation with a role in virulence.

Genome sequencing of four Aureobasidium pullulans varieties: biotechnological potential, stress tolerance, and description of new species.

BACKGROUND: Aureobasidium pullulans is a black-yeast-like fungus used for production of the polysaccharide pullulan and the antimycotic aureobasidin A, and as a biocontrol agent in agriculture. It can cause opportunistic human infections, and it inhabits various extreme environments. To promote the understanding of these traits, we performed de-novo genome sequencing of the four varieties of A. pullulans. RESULTS: The 25.43-29.62 Mb genomes of these four varieties of A. pullulans encode between 10266 and 11866 predicted proteins. Their genomes encode most of the enzyme families involved in degradation of plant material and many sugar transporters, and they have genes possibly associated with degradation of plastic and aromatic compounds. Proteins believed to be involved in the synthesis of pullulan and siderophores, but not of aureobasidin A, are predicted. Putative stress-tolerance genes include several aquaporins and aquaglyceroporins, large numbers of alkali-metal cation transporters, genes for the synthesis of compatible solutes and melanin, all of the components of the high-osmolarity glycerol pathway, and bacteriorhodopsin-like proteins. All of these genomes contain a homothallic mating-type locus. CONCLUSIONS: The differences between these four varieties of A. pullulans are large enough to justify their redefinition as separate species: A. pullulans, A. melanogenum, A. subglaciale and A. namibiae. The redundancy observed in several gene families can be linked to the nutritional versatility of these species and their particular stress tolerance. The availability of the genome sequences of the four Aureobasidium species should improve their biotechnological exploitation and promote our understanding of their stress-tolerance mechanisms, diverse lifestyles, and pathogenic potential.

Postoperative gastrointestinal bleeding in orthognathic surgery patients: its estimated prevalence and possible association to known risk factors.

PURPOSE: To assess the prevalence of gastrointestinal (GI) bleeding in patients after orthognathic surgery and its relation to known risk factors. PATIENT AND METHODS: With institutional review board approval, a single-center case series was conducted with data collected retrospectively from orthognathic surgical patients' medical records from 1990 to 2010. All patients were treated by 1 primary surgeon, were limited to 21 years or younger at the time of surgery, and had no coagulopathy. The authors' hypothesis was that patients concurrently exposed to mechanical ventilation and dual anti-inflammatory drugs in the postoperative period would be at a greater risk for clinically significant GI bleeding according to the American Society of Health-System Pharmacists guideline compared with those exposed to fewer risk factors. Its prevalence and relation to known risk factors were analyzed. RESULTS: In total 498 orthognathic cases consisting of 220 male patients (median age, 17 yr; age range, 3 to 21 yr) and 262 female patients (median age, 17 yr; age range, 10 to 21 yr) were reviewed. Of 17 patients admitted to intensive care unit level of care postoperatively, 4 patients were exposed to concomitant administration of ketorolac and steroids while being mechanically ventilated. Two of these 4 patients developed esophagogastroduodenoscopy-confirmed upper GI bleeding (UGIB). There was no incidence of UGIB in patients not exposed to all 3 risk factors concurrently. CONCLUSIONS: Postoperative GI bleeding complication is rare in orthognathic surgical patients, with an estimated prevalence of 0.4%. Based on these observations, orthognathic surgical patients who require mechanical ventilation and are receiving anti-inflammatory medications may have an increased risk of GI bleeding. In the absence of active bleeding from the surgical site, persistent decrease in hemoglobin concentration should alert one to consider the possibility of UGIB.

Auto-segmentation of neck nodal metastases using self-distilled masked image transformer on longitudinal MR images.

Objectives: Auto-segmentation promises greater speed and lower inter-reader variability than manual segmentations in radiation oncology clinical practice. This study aims to implement and evaluate the accuracy of the auto-segmentation algorithm, "Masked Image modeling using the vision Transformers (SMIT)," for neck nodal metastases on longitudinal T2-weighted (T2w) MR images in oropharyngeal squamous cell carcinoma (OPSCC) patients. Methods: This prospective clinical trial study included 123 human papillomaviruses (HPV-positive [+]) related OSPCC patients who received concurrent chemoradiotherapy. T2w MR images were acquired on 3 T at pre-treatment (Tx), week 0, and intra-Tx weeks (1-3). Manual delineations of metastatic neck nodes from 123 OPSCC patients were used for the SMIT auto-segmentation, and total tumor volumes were calculated. Standard statistical analyses compared contour volumes from SMIT vs manual segmentation (Wilcoxon signed-rank test [WSRT]), and Spearman's rank correlation coefficients (ρ) were computed. Segmentation accuracy was evaluated on the test data set using the dice similarity coefficient (DSC) metric value. P-values <0.05 were considered significant. Results: No significant difference in manual and SMIT delineated tumor volume at pre-Tx (8.68 ± 7.15 vs 8.38 ± 7.01 cm3, P = 0.26 [WSRT]), and the Bland-Altman method established the limits of agreement as -1.71 to 2.31 cm3, with a mean difference of 0.30 cm3. SMIT model and manually delineated tumor volume estimates were highly correlated (ρ = 0.84-0.96, P < 0.001). The mean DSC metric values were 0.86, 0.85, 0.77, and 0.79 at the pre-Tx and intra-Tx weeks (1-3), respectively. Conclusions: The SMIT algorithm provides sufficient segmentation accuracy for oncological applications in HPV+ OPSCC. Advances in knowledge: First evaluation of auto-segmentation with SMIT using longitudinal T2w MRI in HPV+ OPSCC.

Noise robustness and metabolic load determine the principles of central dogma regulation.

The processes of gene expression are inherently stochastic, even for essential genes required for growth. How does the cell maximize fitness in light of noise? To answer this question, we build a mathematical model to explore the trade-off between metabolic load and growth robustness. The model predicts novel principles of central dogma regulation: Optimal protein expression levels for many genes are in vast overabundance. Essential genes are transcribed above a lower limit of one message per cell cycle. Gene expression is achieved by load balancing between transcription and translation. We present evidence that each of these novel regulatory principles is observed. These results reveal that robustness and metabolic load determine the global regulatory principles that govern central dogma processes, and these principles have broad implications for cellular function.

Noise robustness and metabolic load determine the principles of central dogma regulation.

The processes of gene expression are inherently stochastic, even for essential genes required for growth. How does the cell maximize fitness in light of noise? To answer this question, we build a mathematical model to explore the trade-off between metabolic load and growth robustness. The model predicts novel principles of central dogma regulation: Optimal protein expression levels for many genes are in vast overabundance. Essential genes are transcribed above a lower limit of one message per cell cycle. Gene expression is achieved by load balancing between transcription and translation. We present evidence that each of these novel regulatory principles is observed. These results reveal that robustness and metabolic load determine the global regulatory principles that govern central dogma processes, and these principles have broad implications for cellular function.

High-Volume Hospital Had Lower Mortality of Severe Intracerebral Hemorrhage Patients.

Objective: Intracerebral hemorrhage (ICH) accompanies higher mortality rates than other type of stroke. This study aimed to investigate the association between hospital volume and mortality for cases of ICH. Methods: We used nationwide data from 2013 to 2018 to compare high-volume hospitals (≥32 admissions/year) and low-volume hospitals (<32 admissions/year). We tracked patients' survival at 3-month, 1-year, 2-year, and 4-year endpoints. The survival of ICH patients was analyzed at 3-month, 1-year, 2-year, and 4-year endpoints using Kaplan-Meier survival analysis. Multivariable logistic regression analysis and Cox regression analysis were performed to determine predictive factors of poor outcomes at discharge and death. Results: Among 9,086 ICH patients who admitted to hospital during 18-month period, 6,756 (74.4%) and 2,330 (25.6%) patients were admitted to high-volume and low-volume hospitals. The mortality of total ICH patients was 18.25%, 23.87%, 27.88%, and 35.74% at the 3-month, 1-year, 2-year, and 4-year, respectively. In multivariate logistic analysis, high-volume hospitals had lower poor functional outcome at discharge than low-volume hospitals (odds ratio, 0.80; 95% confidence interval, 0.72-0.91; p < 0.001). In the Cox analysis, high-volume hospitals had significantly lower 3-month, 1-year, 2-year, and 4-year mortality than low-volume hospitals (p < 0.05). Conclusion: The poor outcome at discharge, short- and long-term mortality in ICH patients differed according to hospital volume. High-volume hospitals showed lower rates of mortality for ICH patients, particularly those with severe clinical status.

Comprehensive and accurate genome analysis at scale using DRAGEN accelerated algorithms.

Research and medical genomics require comprehensive and scalable solutions to drive the discovery of novel disease targets, evolutionary drivers, and genetic markers with clinical significance. This necessitates a framework to identify all types of variants independent of their size (e.g., SNV/SV) or location (e.g., repeats). Here we present DRAGEN that utilizes novel methods based on multigenomes, hardware acceleration, and machine learning based variant detection to provide novel insights into individual genomes with ~30min computation time (from raw reads to variant detection). DRAGEN outperforms all other state-of-the-art methods in speed and accuracy across all variant types (SNV, indel, STR, SV, CNV) and further incorporates specialized methods to obtain key insights in medically relevant genes (e.g., HLA, SMN, GBA). We showcase DRAGEN across 3,202 genomes and demonstrate its scalability, accuracy, and innovations to further advance the integration of comprehensive genomics for research and medical applications.

Hypoxia-Directed Treatment of Human Papillomavirus-Related Oropharyngeal Carcinoma.

PURPOSE: Standard curative-intent chemoradiotherapy for human papillomavirus (HPV)-related oropharyngeal carcinoma results in significant toxicity. Since hypoxic tumors are radioresistant, we posited that the aerobic state of a tumor could identify patients eligible for de-escalation of chemoradiotherapy while maintaining treatment efficacy. METHODS: We enrolled patients with HPV-related oropharyngeal carcinoma to receive de-escalated definitive chemoradiotherapy in a phase II study (ClinicalTrials.gov identifier: NCT03323463). Patients first underwent surgical removal of disease at their primary site, but not of gross disease in the neck. A baseline 18F-fluoromisonidazole positron emission tomography scan was used to measure tumor hypoxia and was repeated 1-2 weeks intratreatment. Patients with nonhypoxic tumors received 30 Gy (3 weeks) with chemotherapy, whereas those with hypoxic tumors received standard chemoradiotherapy to 70 Gy (7 weeks). The primary objective was achieving a 2-year locoregional control (LRC) of 95% with a 7% noninferiority margin. RESULTS: One hundred fifty-eight patients with T0-2/N1-N2c were enrolled, of which 152 patients were eligible for analyses. Of these, 128 patients met criteria for 30 Gy and 24 patients received 70 Gy. The 2-year LRC was 94.7% (95% CI, 89.8 to 97.7), meeting our primary objective. With a median follow-up time of 38.3 (range, 22.1-58.4) months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 94% and 100%, respectively, for the 30-Gy cohort. The 70-Gy cohort had similar 2-year PFS and OS rates at 96% and 96%, respectively. Acute grade 3-4 adverse events were more common in 70 Gy versus 30 Gy (58.3% v 32%; P = .02). Late grade 3-4 adverse events only occurred in the 70-Gy cohort, in which 4.5% complained of late dysphagia. CONCLUSION: Tumor hypoxia is a promising approach to direct dosing of curative-intent chemoradiotherapy for HPV-related carcinomas with preserved efficacy and substantially reduced toxicity that requires further investigation.

von Willebrand factor genetic variant associated with hematoma expansion after intracerebral hemorrhage.

BACKGROUND: Hematoma expansion, the leading cause of neurologic deterioration after intracerebral hemorrhage (ICH), remains one of the few modifiable risk factors for poor outcome. In the present study, we explored whether common genetic variants within the hemostasis pathway were related to hematoma expansion during the acute period after ICH. METHODS: Patients with spontaneous ICH who were admitted to the institutional Neuro-ICU between 2009 and 2011 were enrolled in the study, and clinical data were collected prospectively. Hematoma size was measured in patients admitted on or before postbleed day 2. Baseline models for hematoma growth were constructed using backwards stepwise logistic regression. Genotyping of single-nucleotide polymorphisms for 13 genes involved in hemostasis was performed, and the results were individually included in the above baseline models to test for independent association of hematoma expansion. RESULTS: During the study period, 82 patients were enrolled in the study and had complete data. The mean age was 65.9 ± 14.9 years, and 38% were female. Only von Willebrand factor was associated with absolute and relative hematoma growth in univariate analysis (P < .001 and P = .007, respectively); von Willebrand factor genotype was independently predictive of relative hematoma growth but only approached significance for absolute hematoma growth (P = .002 and P = .097, respectively). CONCLUSIONS: Our genomic analysis of various hemostatic factors identified von Willebrand factor as a potential predictor of hematoma expansion in patients with ICH. The identification of von Willebrand factor single-nucleotide polymorphisms may allow us to better identify patients who are at risk for hematoma enlargement and will benefit the most from treatment. The relationship of von Willebrand factor with regard to hematoma enlargement in a larger population warrants further study.

Concurrent carboplatin and paclitaxel definitive radiation therapy for locally advanced head and neck cancer.

BACKGROUND: We report the outcomes of cisplatin-ineligible HNSCC patients treated with definitive chemoradiation and concurrent carboplatin and paclitaxel. MATERIALS AND METHODS: We included consecutive HNSCC patients treated from 2013 to 2021 that received definitive chemoradiation with carboplatin and paclitaxel. Locoregional recurrences (LRR) and distant metastases (DM) were estimated using cumulative incidence functions. Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods. RESULTS: Sixty-five patients were identified with median age of 71 years (range 44-85). Median radiation dose was 70 Gy and the median doses of carboplatin and paclitaxel were AUC 1 and 40 mg/m2 , respectively. At a median follow-up of 29 (range 5-91) months, the 2-year rates of LRR, DM, PFS, and OS were 8.8%, 9.4%, 72.2%, and 88.7%, respectively. In total, there were 5 LRR, 7 DM, and 12 deaths. CONCLUSIONS: Chemoradiation with carboplatin and paclitaxel is an excellent option for cisplatin-ineligible HNSCC patients.

Complete genome sequence of Rahnella aquatilis CIP 78.65.

Rahnella aquatilis CIP 78.65 is a gammaproteobacterium isolated from a drinking water source in Lille, France. Here we report the complete genome sequence of Rahnella aquatilis CIP 78.65, the type strain of R. aquatilis.

Genome sequence of Amycolatopsis sp. strain ATCC 39116, a plant biomass-degrading actinomycete.

We announce the availability of a high-quality draft of the genome sequence of Amycolatopsis sp. strain 39116, one of few bacterial species that are known to consume the lignin component of plant biomass. This genome sequence will further ongoing efforts to use microorganisms for the conversion of plant biomass into fuels and high-value chemicals.

Complete genome sequence of Rahnella sp. strain Y9602, a gammaproteobacterium isolate from metal- and radionuclide-contaminated soil.

Rahnella sp. strain Y9602 is a gammaproteobacterium isolated from contaminated subsurface soils that is capable of promoting uranium phosphate mineralization as a result of constitutive phosphatase activity. Here we report the first complete genome sequence of an isolate belonging to the genus Rahnella.