Generating Molecular Fragmentation Graphs with Autoregressive Neural Networks.

The accurate prediction of tandem mass spectra from molecular structures has the potential to unlock new metabolomic discoveries by augmenting the community's libraries of experimental reference standards. Cheminformatic spectrum prediction strategies use a "bond-breaking" framework to iteratively simulate mass spectrum fragmentations, but these methods are (a) slow due to the need to exhaustively and combinatorially break molecules and (b) inaccurate as they often rely upon heuristics to predict the intensity of each resulting fragment; neural network alternatives mitigate computational cost but are black-box and not inherently more accurate. We introduce a physically grounded neural approach that learns to predict each breakage event and score the most relevant subset of molecular fragments quickly and accurately. We evaluate our model by predicting spectra from both public and private standard libraries, demonstrating that our hybrid approach offers state-of-the-art prediction accuracy, improved metabolite identification from a database of candidates, and higher interpretability when compared to previous breakage methods and black-box neural networks. The grounding of our approach in physical fragmentation events shows especially great promise for elucidating natural product molecules with more complex scaffolds.

Hepatic cytoreduction for lung and renal neuroendocrine tumor metastases.

BACKGROUND: Patients with hepatic metastases from lung and renal neuroendocrine tumors are rare. Outcome data on treatment of hepatic metastases for these types of tumors are lacking. We report the outcomes of hepatic cytoreduction operations for these tumors. METHODS: Records of patients undergoing hepatic cytoreduction operations of at least 70 â€‹% of the hepatic tumors for well differentiated lung and renal neuroendocrine tumors were reviewed. Data collected included primary tumor type, number and size of metastases resected, tumor grade, percentage of hepatic cytoreduction, presence of extra-hepatic disease, and status at last follow up. RESULTS: Twenty-one patients were identified. Ninety percent had extrahepatic metastases. Median-time to liver progression was 66 months. The five-year survival rate was 65 â€‹%. Liver failure was the predominant cause of death. No prognostic factors for survival could be identified among the variables collected. CONCLUSION: Hepatic cytoreduction operations for lung and renal neuroendocrine tumors do not yield as good of survival rates as observed with small bowel and pancreatic neuroendocrine tumors, but are considerably better than those obtained with complete resection of colorectal metastases.

Morbidity and Outcomes of Primary Tumor Management in Patients with Widely Metastatic Well-Differentiated Small Bowel Neuroendocrine Tumors.

BACKGROUND: The benefit of primary tumor resection in distant metastatic small bowel neuroendocrine tumors (SBNETs) is controversial, with treatment-based morbidity not well-defined. We aimed to determine the impact of primary tumor resection on development of disease-specific complications in patients with metastatic well-differentiated SBNETs. PATIENTS AND METHODS: A retrospective analysis was performed of patients diagnosed with metastatic well-differentiated jejunal/ileal SBNETs at a single tertiary care cancer center from 1980 to 2016. Outcomes were compared on the basis of treatment selected at diagnosis between patients who underwent initial medical treatment or primary tumor resection. RESULTS: Among 180 patients, 71 underwent medical management and 109 primary tumor resection. Median follow-up was 116 months. Median event-free survival did not differ between treatment approaches (log-rank p = 0.2). In patients medically managed first, 16/71 (23%) required surgery due to obstruction, perforation, or bleeding. These same complications led to resection at presentation in 31/109 (28%) surgically treated patients. Development of an obstruction from the primary tumor was not associated with disease progression/recurrence (HR 1.14, 95% CI 0.75-1.75) with all patients recovering postoperatively. Ongoing tumor progression requiring secondary laparotomy was associated with worse mortality (HR 7.51, 95% CI 3.3-16.9; p < 0.001) and occurred in 20/109 (18%) primary tumor resection and 7/16 (44%) initially medically treated patients. CONCLUSIONS: Rates of event-free survival among patients with metastatic SBNETs do not differ on the basis of primary tumor management. The development of an obstruction from the primary tumor was not associated with worse outcomes with all patients salvaged. Regardless of initial treatment selected, patients with metastatic SBNET should be closely followed for early signs of primary tumor complications.

Genomic virulence features of Beauveria bassiana as a biocontrol agent for the mountain pine beetle population.

BACKGROUND: The mountain pine beetle, Dendroctonus ponderosae, is an irruptive bark beetle that causes extensive mortality to many pine species within the forests of western North America. Driven by climate change and wildfire suppression, a recent mountain pine beetle (MPB) outbreak has spread across more than 18 million hectares, including areas to the east of the Rocky Mountains that comprise populations and species of pines not previously affected. Despite its impacts, there are few tactics available to control MPB populations. Beauveria bassiana is an entomopathogenic fungus used as a biological agent in agriculture and forestry and has potential as a management tactic for the mountain pine beetle population. This work investigates the phenotypic and genomic variation between B. bassiana strains to identify optimal strains against a specific insect. RESULTS: Using comparative genome and transcriptome analyses of eight B. bassiana isolates, we have identified the genetic basis of virulence, which includes oosporein production. Genes unique to the more virulent strains included functions in biosynthesis of mycotoxins, membrane transporters, and transcription factors. Significant differential expression of genes related to virulence, transmembrane transport, and stress response was identified between the different strains, as well as up to nine-fold upregulation of genes involved in the biosynthesis of oosporein. Differential correlation analysis revealed transcription factors that may be involved in regulating oosporein production. CONCLUSION: This study provides a foundation for the selection and/or engineering of the most effective strain of B. bassiana for the biological control of mountain pine beetle and other insect pests populations.

The metabolic and lipidomic profiling of the effects of tracheal occlusion in a rabbit model of congenital diaphragmatic hernia.

PURPOSE: Fetal tracheal occlusion (TO) reverses the pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH), but its mechanism of action remains poorly understood. 'Omic' readouts capture metabolic and lipid processing function, which aid in understanding CDH and TO metabolic mechanisms. METHODS: CDH was created in fetal rabbits at 23 days, TO at 28 days and lung collection at 31 days (Term ∼32 days). Lung-body weight ratio (LBWR) and mean terminal bronchiole density (MTBD) were determined. In a cohort, left and right lungs were collected, weighed, and samples homogenized, and extracts collected for non-targeted metabolomic and lipidomic profiling via LC-MS and LC-MS/MS, respectively. RESULTS: LBWR was significantly lower in CDH while CDH + TO was similar to controls (p = 0.003). MTBD was significantly higher in CDH fetuses and restored to control and sham levels in CDH + TO (p < 0.001). CDH and CDH + TO resulted in significant differences in metabolome and lipidome profiles compared to sham controls. A significant number of altered metabolites and lipids between the controls and CDH groups and the CDH and CDH + TO fetuses were identified. Significant changes in the ubiquinone and other terpenoid-quinone biosynthesis pathway and the tyrosine metabolism pathway were observed in CDH + TO. CONCLUSION: CDH + TO reverses pulmonary hypoplasia in the CDH rabbit, in association with a specific metabolic and lipid signature. A synergistic untargeted 'omics' approach provides a global signature for CDH and CDH + TO, highlighting cellular mechanisms among lipids and other metabolites, enabling comprehensive network analysis to identify critical metabolic drivers in disease pathology and recovery. TYPE OF STUDY: Basic Science, Prospective. LEVEL OF EVIDENCE: II.

Past, Present, and Future Management of Localized Biliary Tract Malignancies.

Most of the patients with gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (iCCA), and peri-hilar cholangiocarcinoma (pCCA) present with advanced disease. Complete staging with multiphasic liver imaging is essential to determine the extent of disease. Operative goals should include a margin-negative resection, portal lymphadenectomy for staging, and sufficient remnant liver volume. Biliary tract malignancies have distinct mutational drivers (GBC and pCCA = ERBB2 in 20%; iCCA = fibroblast growth factor receptor 2 or isocitrate dehydrogenase 1 in 20%) amenable to therapy with inhibitors. Clinical trials assessing neoadjuvant, peri-operative, and adjuvant treatments continue to evolve and now include targeted inhibitors and the integration of hepatic arterial infusion.

Exploration and analysis of R-loop mapping data with RLBase.

R-loops are three-stranded nucleic acid structures formed from the hybridization of RNA and DNA. In 2012, Ginno et al. introduced the first R-loop mapping method. Since that time, dozens of R-loop mapping studies have been conducted, yielding hundreds of publicly available datasets. Current R-loop databases provide only limited access to these data. Moreover, no web tools for analyzing user-supplied R-loop datasets have yet been described. In our recent work, we reprocessed 810 R-loop mapping samples, building the largest R-loop data resource to date. We also defined R-loop consensus regions and developed a framework for R-loop data analysis. Now, we introduce RLBase, a user-friendly database that provides the capability to (i) explore hundreds of public R-loop mapping datasets, (ii) explore R-loop consensus regions, (iii) analyze user-supplied data and (iv) download standardized and reprocessed datasets. RLBase is directly accessible via the following URL: https://gccri.bishop-lab.uthscsa.edu/shiny/rlbase/.

Maternal health literacy and health numeracy conceptualizations in public health: A scoping review.

Despite unprecedented advancement in educational opportunities and access to information, maternal health literacy (MHL) and health numeracy (HN) skills remain low in North America. By enhancing MHL, the educated civic public-those who have the capacity, skills, and knowledge to apply prose and numerical health information-engages more proactively in public health practice. The purpose of this scoping review was to map the existing empirical evidence on MHL to work toward a better understanding of the practical implications for public health. We explored MHL and HN through the following research question: "How are maternal health literacy and health numeracy conceptualised in public health planning, implementation, and evaluation?" First, we employed a five-stage methodological framework for scoping reviews and used PRISMA-P to systematically identify eligible articles. Then, we used thematic analysis and an inductive approach guided by the research aims to identify themes related to how MHL and HN are conceptualised in empirical studies and developed an evidence table. Finally, two different reviewers coded articles using an inductive approach into six themes. We identified 1733 articles through a systematic search of five databases. After screening all the articles, 52 articles were included for thematic analysis. The final themes were: (i) sociocultural demographics; (ii) self-efficacy; (iii) communication; (iv) information seeking and operationalisation; (v) health status; and (vi) reasoning. The research evidence demonstrated limitations concerning the impact of sociocultural background on a mother's recognition of health problems and the extent of which patient-centred care is culturally and linguistically appropriate. The research evidence revealed an opportunity to address the sociocultural linguistic experience of mothers within public health practice. Our research team supports moving away from the biomedical model of evidence-based medicine and adopting evidence-based practice ensures healthcare providers develop a holistic understanding of the maternal health needs of socioculturally diverse mothers.

ntEdit+Sealer: Efficient Targeted Error Resolution and Automated Finishing of Long-Read Genome Assemblies.

High-quality genome assemblies are crucial to many biological studies, and utilizing long sequencing reads can help achieve higher assembly contiguity. While long reads can resolve complex and repetitive regions of a genome, their relatively high associated error rates are still a major limitation. Long reads generally produce draft genome assemblies with lower base quality, which must be corrected with a genome polishing step. Hybrid genome polishing solutions can greatly improve the quality of long-read genome assemblies by utilizing more accurate short reads to validate bases and correct errors. Currently available hybrid polishing methods rely on read alignments, and are therefore memory-intensive and do not scale well to large genomes. Here we describe ntEdit+Sealer, an alignment-free, k-mer-based genome finishing protocol that employs memory-efficient Bloom filters. The protocol includes ntEdit for correcting base errors and small indels, and for marking potentially problematic regions, then Sealer for filling both assembly gaps and problematic regions flagged by ntEdit. ntEdit+Sealer produces highly accurate, error-corrected genome assemblies, and is available as a Makefile pipeline from https://github.com/bcgsc/ntedit_sealer_protocol. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Automated long-read genome finishing with short reads Support Protocol: Selecting optimal values for k-mer lengths (k) and Bloom filter size (b).

LongStitch: high-quality genome assembly correction and scaffolding using long reads.

BACKGROUND: Generating high-quality de novo genome assemblies is foundational to the genomics study of model and non-model organisms. In recent years, long-read sequencing has greatly benefited genome assembly and scaffolding, a process by which assembled sequences are ordered and oriented through the use of long-range information. Long reads are better able to span repetitive genomic regions compared to short reads, and thus have tremendous utility for resolving problematic regions and helping generate more complete draft assemblies. Here, we present LongStitch, a scalable pipeline that corrects and scaffolds draft genome assemblies exclusively using long reads. RESULTS: LongStitch incorporates multiple tools developed by our group and runs in up to three stages, which includes initial assembly correction (Tigmint-long), followed by two incremental scaffolding stages (ntLink and ARKS-long). Tigmint-long and ARKS-long are misassembly correction and scaffolding utilities, respectively, previously developed for linked reads, that we adapted for long reads. Here, we describe the LongStitch pipeline and introduce our new long-read scaffolder, ntLink, which utilizes lightweight minimizer mappings to join contigs. LongStitch was tested on short and long-read assemblies of Caenorhabditis elegans, Oryza sativa, and three different human individuals using corresponding nanopore long-read data, and improves the contiguity of each assembly from 1.2-fold up to 304.6-fold (as measured by NGA50 length). Furthermore, LongStitch generates more contiguous and correct assemblies compared to state-of-the-art long-read scaffolder LRScaf in most tests, and consistently improves upon human assemblies in under five hours using less than 23 GB of RAM. CONCLUSIONS: Due to its effectiveness and efficiency in improving draft assemblies using long reads, we expect LongStitch to benefit a wide variety of de novo genome assembly projects. The LongStitch pipeline is freely available at https://github.com/bcgsc/longstitch .

Comparison of Trendelenburg Angles in Vaginal, Laparoscopic, and Robotic Uterovaginal Apical Prolapse Repairs.

STUDY OBJECTIVE: To compare the Trendelenburg angle used in laparoscopic uterovaginal apical prolapse repairs with the angles used in vaginal and robotic uterovaginal apical prolapse repairs. DESIGN: Prospective, multicenter cohort study from May 2015 to December 2016. SETTING: Two academic teaching hospitals. PATIENTS: Sixty patients who underwent vaginal high uterosacral ligament suspension, laparoscopic sacrocolpopexy, or robotic sacrocolpopexy performed by 6 surgeons board-certified in female pelvic medicine and reconstructive surgery. INTERVENTIONS: Measurement of Trendelenburg angle and time spent in Trendelenburg during surgery. MEASUREMENTS AND MAIN RESULTS: Twenty patients were enrolled in each procedure group. The median maximum angle of Trendelenburg was significantly greater in the laparoscopic group (22° [20-25]) than in the vaginal group (15° [6-19]; p <.001) and the robotic group (19° [16-21]; p = .02). The participants in the laparoscopic group spent significantly more time overall in Trendelenburg (176 minutes [143-221]) than those in the robotic group (150 minutes [127-161]; p = .01) and those in the vaginal group (120 minutes [86-128]; p <.001). The participants in the laparoscopic and robotic groups spent similar amounts of time in maximum Trendelenburg (116 minutes [52-164] and 117 minutes [61-134], respectively; p = .56), whereas the participants in the vaginal group spent significantly less time in maximum Trendelenburg (10 minutes [7-38]) than those in the laparoscopic group (p <.001). The total median operative time was highest for the laparoscopic approach (211 minutes [173-270]), followed by the robotic approach (181 minutes [165-201]) and the vaginal approach (162 minutes [128-186]; p = .008). CONCLUSION: The median maximum angle of Trendelenburg was highest in laparoscopic sacrocolpopexy-followed by robotic sacrocolpopexy-and lowest in vaginal high uterosacral ligament suspension. Patients who underwent robotic sacrocolpopexy spent less time in Trendelenburg than those who underwent the laparoscopic approach. Prolonged, steep Trendelenburg is often not required for any of the 3 surgical procedures, but a vaginal approach should be considered for those at high risk of complications from Trendelenburg position.

Narrow excision margins are appropriate for Merkel cell carcinoma when combined with adjuvant radiation: Analysis of 188 cases of localized disease and proposed management algorithm.

BACKGROUND: Merkel cell carcinoma (MCC) management typically includes surgery with or without adjuvant radiation therapy (aRT). Major challenges include determining surgical margin size and whether aRT is indicated. OBJECTIVE: To assess the association of aRT, surgical margin size, and MCC local recurrence. METHODS: Analysis of 188 MCC cases presenting without clinical nodal involvement. RESULTS: aRT-treated patients tended to have higher-risk tumors (larger diameter, positive microscopic margins, immunosuppression) yet had fewer local recurrences (LRs) than patients treated with surgery only (1% vs 15%; P = .001). For patients who underwent surgery alone, 7 of 35 (20%) treated with narrow margins (defined as ≤1.0 cm) developed LR, whereas 0 of 13 patients treated with surgical margins greater than 1.0 cm developed LR (P = .049). For aRT-treated patients, local control was excellent regardless of surgical margin size; only 1% experienced recurrence in each group (1 of 70 with narrow margins ≤1 cm and 1 of 70 with margins >1 cm; P = .56). LIMITATIONS: This was a retrospective study. CONCLUSIONS: Among patients treated with aRT, local control was superb even if significant risk factors were present and margins were narrow. We propose an algorithm for managing primary MCC that integrates risk factors and optimizes local control while minimizing morbidity.

Review of Common Alternative Herbal "Remedies" for Skin Cancer.

BACKGROUND: Alternative herbal remedies for skin cancer are commonly found on the Internet. Many websites contain inaccurate or false information regarding side effects and efficacy. OBJECTIVE: To review the evidence behind several commonly advertised herbal remedies that claim to cure skin cancer: black salve, eggplant, frankincense, cannabis, black raspberry, milk thistle, St. John's wort, and turmeric. METHODS: A PubMed search was performed using the common and scientific names of frequently advertised herbal remedies along with the terms "nonmelanoma skin cancer," or "basal cell carcinoma" or "squamous cell carcinoma," or "melanoma." RESULTS: Some preclinical studies have shown positive evidence that these substances can induce apoptosis in skin cancer, but clinical studies proving efficacy are either insufficient, nonexistent, or show negative evidence. Botanicals that were excluded are those that do not have published studies of their efficacy as skin cancer treatments. CONCLUSION: Online advertising may tempt patients to use botanical agents while citing efficacy found in preclinical studies. However, many agents lack strong clinical evidence of efficacy. Dermatologists must be aware of common herbal alternatives for skin cancer treatment to maintain effective patient communication and education.

Fire Safety in Mohs Micrographic Surgery.

BACKGROUND: Surgical fire is a rare event, but one with potentially devastating patient outcomes. OBJECTIVE: This study was conducted to investigate the incidence, risk factors, and outcome of surgical fires experienced by members of the American College of Mohs Surgeons (ACMS). METHODS: An internet survey was developed and sent to ACMS members. Data collected included total years of experience, total number of cases, typical management of supplemental oxygen, and surgical fires experienced. RESULTS: Eighty participants contributed data on 886,200 cases of MMS. Nine surgeons (11%) reported at least 1 surgical fire, yielding an estimated incidence of 1 fire per 88,620 cases (0.001%). The most common site of involvement was the scalp (67%). Common ignition sources included monopolar electrosurgical devices (78%) and battery-powered thermal cautery (22%). Fuel sources included towels or drapes, gauze, isopropyl alcohol, aluminum chloride, hairspray, and diethyl ether. Supplemental oxygen was not involved in any of the cases. Five patients suffered singed hair while 4 patients did not suffer any injuries. None suffered any permanent functional or aesthetic deformities. CONCLUSION: The overall risk of surgical fire in MMS is minimal. However, safety measures and greater awareness of fire risks are necessary to prevent patient harm.

ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup.

The commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX, DAXX, and MEN1. We genotyped 64 PanNETs and found 58% carry ATRX, DAXX, and MEN1 mutations (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing and DNA-methylation analysis to reveal two distinct subgroups with one consisting entirely of A-D-M mutant PanNETs. Two genes differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature related to that of alpha-cells (FDR q-value < 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells.

Hydration and nutritional status in patients on home-dialysis-A single centre study.

BACKGROUND: Over-hydration (OH) and malnutrition are prevalent among patients on dialysis therapy. The prevalence of OH and malnutrition as well as the risk factors associated with OH and malnutrition in our patients on home peritoneal dialysis (PD) and home haemodialysis (HD) are examined. DESIGN AND METHODS: This was a cross-sectional study. The hydration and nutritional status of the study groups were assessed by a Body Composition Monitor. Patients who were stable on home dialysis therapy for over one year were invited to participate. Univariate and multivariate analyses were performed to identify associated factors and determine the predictors of OH and malnutrition, respectively. RESULTS: Eighty-eight patients (41 PD and 47 home HD) were recruited. A 32.95% of our patients on home dialysis therapy were in OH status. There was a significance difference in the prevalence of hydration status between patients on PD and home HD (p = 0.014), as overhydration was more common in patients on PD than home HD (46.34 vs. 21.28%). Dehydration was more common in patients on home HD than PD (29.79 vs. 9.76%). Male gender, decreasing haemoglobin level and presence of diabetes mellitus (DM) were risk factors of OH on multivariable analysis. There was no significance difference in the prevalence of malnutrition between patients on PD and home HD (p = 0.27). Increasing Fat Tissue Index (FTI), height and patients on PD therapy were at higher risk of malnutrition. CONCLUSION: OH and malnutrition were prevalent patients on home dialysis therapy.