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Australia's National Lung Cancer Screening Program will commence in July 2025, targeted at individuals aged 50-70 years with a 30 pack-year smoking history (equivalent to 20 cigarettes per day for 30 years), who either currently smoke or have quit within the past 10 years. We forecasted the number of screening-eligible individuals over the first 5 years of the program using data from the 2019 National Drug Strategy Household Survey and the 2022 Australian Bureau of Statistics population projections. Multiple imputation integrated with predictive modelling of future or unmeasured smoking characteristics was used to address missing data and, simultaneously, to project individuals' smoking histories to 2030. In 2025, 930 500 (95% prediction interval 852 200-1 019 000) individuals were estimated to be eligible, with the number meeting the criteria declining slightly during the years 2025-2030 in all Australian jurisdictions. Overall, 26-30% of those eligible will have quit smoking, and 70-74% will currently smoke. These estimates can be used in resource planning and as an indicative denominator to track participation rates for the program over time., Competing Interests: None declared

Background: The management of neonates with long-gap esophageal atresia (LGEA) combined with distal congenital esophageal strictures (CES) is challenging. We sought to review our approach for this rare set of anomalies., Methods: We reviewed children with LGEA + CES surgically treated at two institutions (2018-2024). LGEA repair was performed using the Foker technique (traction-induced esophageal lengthening). A CES strategy was chosen based on preoperative evaluations and intraoperative findings. The configuration and length of the CES were assessed using retrograde flexible esophagoscopy via gastrostomy with contrast fluoroscopy., Results: Eight patients (75% male) with LGEA + CES were treated: Four had type A and four had type B EA. Median gap length was 3.5 cm. Three underwent thoracoscopic esophageal lengthening. After a median follow-up of 18 months (IQR: 9-25), all retained their native esophagus. However, those who had CES resection concurrent with the lengthening process or at the time of EA anastomosis had more challenging perioperative courses: one required additional time on traction and another required esophageal anastomotic stricture resection., Conclusions: Our experience with LGEA and distal CES emphasizes tailoring surgical approaches to each patient's unique condition, avoiding a one-size-fits-all strategy. However, if the esophageal tissue above the distal CES is in good condition, our preference has shifted towards retaining the CES during traction, performing gentle dilation at anastomosis time, and conducting definitive endoscopic management subsequently. We would caution against making the assumption that salvage of the native esophagus is not possible or that resection of the CES is always needed., Level of Evidence: Level III., Competing Interests: Conflict of interest The authors have no sources of financial support or conflicts of interest that are relevant to this work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Tricuspid valve disease in carcinoid heart syndrome is usually diagnosed via screening echocardiography in patients with known carcinoid syndrome. Vasoactive intestinal peptide tumour (VIPoma) is a rare tumour with an incidence of 0.05%-2% that typically presents with symptoms related to the release of vasoactive intestinal peptide: flushing, diarrhoea and electrolyte abnormalities like hypokalaemia and hypochlorhydria. Historically, the cardiac valves are unaffected. We present a case where a finding of tricuspid regurgitation and stenosis on echocardiography prompted an expedited workup for malignancy ultimately leading to a diagnosis of VIPoma., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We consider a Markovian model for the kinetics of RNA Polymerase (RNAP) which provides a physical explanation for the phenomenon of cooperative pushing during transcription elongation observed in biochemical experiments on Escherichia coli and yeast RNAP. To study how backtracking of RNAP affects cooperative pushing we incorporate into this model backward (upstream) RNAP moves. With a rigorous mathematical treatment of the model we derive conditions on the mutual static and kinetic interactions between RNAP under which backtracking preserves cooperative pushing. This is achieved by exact computation of several key properties in the steady state of this model, including the distribution of headway between two RNAP along the DNA template and the average RNAP velocity and flux., (Creative Commons Attribution license.)

Background: Children with left aortic arch and aberrant right subclavian artery may present with either respiratory or swallowing symptoms beyond the classically described solid-food dysphagia. We describe the clinical features and outcomes of children undergoing surgical repair of an aberrant right subclavian artery., Materials and Methods: This was a retrospective review of children undergoing repair of an aberrant right subclavian artery between 2017 and 2022. Primary outcome was symptom improvement. Pre- and post-operative questionnaires were used to assess dysphagia (PEDI-EAT-10) and respiratory symptoms (PEDI-TBM-7). Paired t -test and Fisher's exact test were used to analyse symptom resolution. Secondary outcomes included perioperative outcomes, complications, and length of stay., Results: Twenty children, median age 2 years (IQR 1-11), were included. All presented with swallowing symptoms, and 14 (70%) also experienced respiratory symptoms. Statistically significant improvements in symptoms were reported for both respiratory and swallowing symptoms. Paired (pre- and post-op) PEDI-EAT-10 and PEDI-TBM-7 scores were obtained for nine patients, resulting in mean (± SD) scores decreasing (improvement in symptoms) from 19.9 (± 9.3) to 2.4 (± 2.5) p = 0.001, and 8.7 (± 4.7) to 2.8 (± 4.0) p = 0.006, respectively. Reoperation was required in one patient due to persistent dysphagia from an oesophageal stricture. Other complications included lymphatic drainage ( n = 4) and transient left vocal cord hypomobility ( n = 1)., Conclusion: Children with a left aortic arch with aberrant right subclavian artery can present with oesophageal and respiratory symptoms beyond solid food dysphagia. A thorough multidisciplinary evaluation is imperative to identify patients who can benefit from surgical repair, which appears to be safe and effective.

Objective: To compare 50-year forecasts of Australian tobacco smoking rates in relation to trends in smoking initiation and cessation and in relation to a national target of ≤5% adult daily prevalence by 2030., Methods: A compartmental model of Australian population daily smoking, calibrated to the observed smoking status of 229 523 participants aged 20-99 years in 26 surveys (1962-2016) by age, sex and birth year (1910-1996), estimated smoking prevalence to 2066 using Australian Bureau of Statistics 50-year population predictions. Prevalence forecasts were compared across scenarios in which smoking initiation and cessation trends from 2017 were continued, kept constant or reversed., Results: At the end of the observation period in 2016, model-estimated daily smoking prevalence was 13.7% (90% equal-tailed interval (EI) 13.4%-14.0%). When smoking initiation and cessation rates were held constant, daily smoking prevalence reached 5.2% (90% EI 4.9%-5.5%) after 50 years, in 2066. When initiation and cessation rates continued their trajectory downwards and upwards, respectively, daily smoking prevalence reached 5% by 2039 (90% EI 2037-2041). The greatest progress towards the 5% goal came from eliminating initiation among younger cohorts, with the target met by 2037 (90% EI 2036-2038) in the most optimistic scenario. Conversely, if initiation and cessation rates reversed to 2007 levels, estimated prevalence was 9.1% (90% EI 8.8%-9.4%) in 2066., Conclusion: A 5% adult daily smoking prevalence target cannot be achieved by the year 2030 based on current trends. Urgent investment in concerted strategies that prevent smoking initiation and facilitate cessation is necessary to achieve 5% prevalence by 2030., Competing Interests: Competing interests: Although not relevant to the current project, KC declares she receives salaray support from the National Health and Medical Research Council Australia (APP1194679). She is also co-PI of an investigator-initiated trial of cervical screening, "Compass", run by the Australian Centre for Prevention of Cervical Cancer (ACPCC), which is a government-funded not-for-profit charity. Compass receives infrastructure support from the Australian government and the ACPCC has received equipment and a funding contribution from Roche Molecular Diagnostics, USA. KC is also co-PI on a major implementation program Elimination of Cervical Cancer in the Western Pacific which has received support from the Minderoo Foundation and the Frazer Family Foundation and equipment donations from Cepheid Inc., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Genetic variation in APOE is associated with altered lipid metabolism, as well as cardiovascular and neurodegenerative disease risk. However, prior studies are largely limited to European ancestry populations and differential risk by sex and ancestry has not been widely evaluated. We utilized a phenome-wide association study (PheWAS) approach to explore APOE -associated phenotypes in the All of Us Research Program., Methods: We determined APOE alleles for 181,880 All of Us participants with whole genome sequencing and electronic health record (EHR) data, representing seven gnomAD ancestry groups. We tested association of APOE variants, ordered based on Alzheimer's disease risk hierarchy (ε2/ε2<ε2/ε3<ε3/ε3<ε2/ε4<ε3/ε4<ε4/ε4), with 2,318 EHR-derived phenotypes. Bonferroni-adjusted analyses were performed overall, by ancestry, by sex, and with adjustment for social determinants of health (SDOH)., Findings: In the overall cohort, PheWAS identified 17 significant associations, including an increased odds of hyperlipidemia (OR 1.15 [1.14-1.16] per APOE genotype group; P =1.8×10 -129 ), dementia, and Alzheimer's disease (OR 1.55 [1.40-1.70]; P =5×10 -19 ), and a reduced odds of fatty liver disease (OR 0.93 [0.90-0.95]; P =1.6×10 -9 ) and chronic liver disease. ORs were similar after SDOH adjustment and by sex, except for an increased number of cardiovascular associations in males, and decreased odds of noninflammatory disorders of vulva and perineum in females (OR 0.89 [0.84-0.94]; P =1.1×10 -5 ). Significant heterogeneity was observed for hyperlipidemia and mild cognitive impairment across ancestry. Unique associations by ancestry included transient retinal arterial occlusion in the European ancestry group, and first-degree atrioventricular block in the American Admixed/Latino ancestry group., Interpretation: We replicate extensive phenotypic associations with APOE alleles in a large, diverse cohort, despite limitations in accuracy for EHR-derived phenotypes. We provide a comprehensive catalog of APOE -associated phenotypes and present evidence of unique phenotypic associations by sex and ancestry, as well as heterogeneity in effect size across ancestry.

Glaucoma presents an epidemiological burden as the leading cause of irreversible blindness globally and the most common cause of preventable blindness. While elevated intraocular pressure is the strongest modifiable risk factor, the exact mechanisms of retinal ganglion cell damage leading to progressive vision loss are not entirely understood. Studies of other neurodegenerative diseases show a potential for human gut microbiome dysbiosis to play a pathogenic role. An investigation into whether the microbiome, a potential modifiable risk factor, has significance in glaucoma enables exploration of prophylactic or additive treatments. Elevated population levels of specific bacterial species have been noted in glaucoma patients, particularly Prevotellaceae, Enterobacteriaceae and Escherichia coli , while Megomonas is speculated to be protective. Evidence also points to systemic neuro-inflammation and disruption of autoimmune processes as a result of imbalances in both human and animal models, where heat shock proteins may contribute to pathogenesis. Further research into the influence of gut microbiome on pathogenesis offers a chance to minimise irreversible vision loss in glaucoma., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Weighting can improve study estimate representativeness. We examined the impact of weighting on associations between participants' characteristics and cancer, cardiovascular and all-cause mortality in the Australian 45 and Up Study cohort., Methods: Raking weighted cohort data to the 2006 Australian population for seven sociodemographic characteristics. Deaths were ascertained via linkage to routinely collected data. Cox's proportional hazards regression quantified associations between 11 sociodemographic and health characteristics and cancer, cardiovascular and all-cause mortality. The ratios of hazard ratios (RHRs) compared unweighted and weighted estimates., Results: Among 195,052 included participants (median follow-up 11.4 years), there were 7200 cancer, 5912 cardiovascular and 21,840 all-cause deaths. Overall, 102/111 (91.9%) weighted HRs did not differ significantly from unweighted HRs (100%, 86.5% and 89.2% of 37 HRs for cancer, cardiovascular and all-cause mortality, respectively). Significant differences included a somewhat stronger association between single/widowed/divorced (versus married/de-facto) and cardiovascular mortality (unweighted HR=1.25 (95%CI:1.18-1.32), weighted HR=1.33 (95%CI:1.24-1.42), RHR=1.06 (95%CI:1.02-1.11)); and between no school certificate/qualification (versus university degree) and all-cause mortality (unweighted HR=1.21 (95%CI:1.15-1.27), weighted HR=1.28 (95%CI:1.19-1.38), RHR=1.06 (95%CI:1.03-1.10))., Conclusion: Our results support the generalisability of most estimates of associations in the 45 and Up Study, particularly in relation to cancer mortality. Slight distortion of a few associations with cardiovascular or all-cause mortality were observed., Competing Interests: Declaration of Competing Interest Sarsha Yap, Qingwei Luo, Stephen Wade, Preston Ngo, David Goldsbury, Peter Sarich, Emily Banks, Marianne Weber, Michael David, Julia Steinberg have no competing interests to declare. Karen Canfell is co-principal investigator (PI) of an investigator-initiated trial of cervical screening, “Compass”, run by the Australian Centre for Prevention of Cervical Cancer (ACPCC), which is a government-funded not-for-profit charity. Compass receives infrastructure support from the Australian government and the ACPCC has received equipment and a funding contribution from Roche Molecular Diagnostics, USA. KC is also co-PI on a major implementation program Elimination of Cervical Cancer in the Western Pacific (ECCWP) which has received support from the Minderoo Foundation and equipment donations from Cepheid Inc. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: To reduce the incidence of seromas, we have adapted the quilting procedure used in open abdominoplasty to the endoscopic-assisted repair of concomitant ventral hernia (VH) and diastasis recti (DR). The aim of this study was to describe the technique and assess its efficacy by comparing two groups of patients operated on with the same repair technique before and after introducing the quilting., Methods: This retrospective study included data prospectively registered in the French Club Hernie database from 176 consecutive patients who underwent surgery for concomitant VH and DR via the double-layer suturing technique. Patients were categorized into two groups: Group 1 comprised 102 patients operated before introducing the quilting procedure and Group 2 comprised 74 operated after introducing the quilting. To carry out comparisons between groups, seromas were classified into two types: type A included spontaneously resorbable seromas and seromas drained by a single puncture and type B included seromas requiring two or more punctures and complicated cases requiring reoperation., Results: The global percentage of seromas was 24.4%. The percentage of seromas of any type was greater in Group 1 (27.5%) than in Group 2 (20.3%). The percentage of Type B seromas was greater in Group 1 (19.6%) than in Group 2 (5.4%), when the percentage of Type A seromas was greater in Group 2 (14.9) than in Group 1 (7.9%). Differences were significant (p = 0.014). The operation duration was longer in Group 2 (83.9 min) than in Group 1 (69.9 min). Four complications requiring reoperation were observed in Group 1: three persistent seromas requiring surgical drainage under general anesthesia and one encapsulated seroma., Conclusion: Adapting the quilting technique to the endoscopic-assisted bilayer suturing technique for combined VH and DR repair can significantly reduce the incidence and severity of postoperative seromas., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Odorants interact with receptors expressed in specialized olfactory neurons, and neurons of the same class send their axons to distinct glomeruli in the brain. The stereotypic spatial glomerular activity map generates recognition and the behavioral response for the odorant. The valence of an odorant changes with concentration, typically becoming aversive at higher concentrations. Interestingly, in Drosophila larvae, the odorant (E)-2-hexenal is aversive at low concentrations and attractive at higher concentrations. We investigated the molecular and neural basis of this phenomenon, focusing on how activities of different olfactory neurons conveying opposing effects dictate behaviors. We identified the repellant neuron in the larvae as one expressing the olfactory receptor Or7a, whose activation alone at low concentrations of (E)-2-hexenal elicits an avoidance response in an Or7a-dependent manner. We demonstrate that avoidance can be overcome at higher concentrations by activation of additional neurons that are known to be attractive, most notably odorants that are known activators of Or42a and Or85c. These findings suggest that in the larval stage, the attraction-conveying neurons can overcome the aversion-conveying channels for (E)-2-hexenal., Competing Interests: Competing interests A.R. is founder and President of Sensorygen Inc., a startup company identifying insect control methods and new flavors and fragrances, and Remote Epigenetics Inc., a startup company identifying volatile compounds that have applications in agriculture. The remaining authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

With the recent advances in natural language processing and deep learning, the development of tools that can assist medical coders in ICD-10 diagnosis coding and increase their efficiency in coding discharge summaries is significantly more viable than before. To that end, one important component in the development of these models is the datasets used to train them. In this study, such datasets are presented, and it is shown that one of them can be used to develop a BERT-based language model that can consistently perform well in assigning ICD-10 codes to discharge summaries written in Swedish. Most importantly, it can be used in a coding support setup where a tool can recommend potential codes to the coders. This reduces the range of potential codes to consider and, in turn, reduces the workload of the coder. Moreover, the de-identified and pseudonymised dataset is open to use for academic users., (©2023 AMIA - All rights reserved.)

Background and Objective: Since 2016, new therapies have transformed the standard of care for lung cancer, creating a need for up-to-date evidence for health economic modelling. We developed a discrete event simulation of advanced lung cancer treatment to provide estimates of survival outcomes and healthcare costs in the Australian setting that can be updated as new therapies are introduced., Methods: Treatment for advanced lung cancer was modelled under a clinician-specified treatment algorithm for Australia in 2022. Prevalence of lung cancer subpopulations was extracted from cBioPortal and the Sax Institute's 45 and Up Study, a large prospective cohort linked to cancer registrations. All costs were from the health system perspective for the year 2020. Pharmaceutical and molecular diagnostic costs were obtained from public reimbursement fees, while other healthcare costs were obtained from health system costs in the 45 and Up Study. Treatment efficacy was obtained from clinical trials and observational study data. Costs and survival were modelled over a 10-year horizon. Uncertainty intervals were generated with probabilistic sensitivity analyses. Overall survival predictions were validated against real-world studies., Results: Under the 2022 treatment algorithm, estimated mean survival and costs for advanced lung cancer 10 years post-diagnosis were 16.4 months (95% uncertainty interval [UI]: 14.7-18.1) and AU$116,069 (95% UI: $107,378-$124,933). Survival and costs were higher assuming optimal treatment utilisation rates (20.5 months, 95% UI: 19.1-22.5; $154,299, 95% UI: $146,499-$161,591). The model performed well in validation, with good agreement between predicted and observed survival in real-world studies., Conclusions: Survival improvements for advanced lung cancer have been accompanied by growing treatment costs. The estimates reported here can be used for budget planning and economic evaluations of interventions across the spectrum of cancer control., (© 2023. The Author(s).)

Background: According to EHS guidelines, mesh repair is recommended in case of concomitant diastasis recti (DR) and ventral hernia more than 1 cm in diameter. Since in this situation, the higher risk of hernia recurrence may be attributed to the weakness of aponeurotic layers, in our current practice, for hernias up to 3 cm, we use a bilayer suture technique. The study aimed at describing our surgical technique and evaluating the results of our current practice., Methods: The technique combines suturing repair of the hernia orifice and diastasis correction by suture, and includes an open step through periumbilical incision and an endoscopic step. The study is an observational report on 77 cases of concomitant ventral hernias and DR., Results: The median diameter of the hernia orifice was 1.5 cm (0.8-3). The median inter-rectus distance was 60 mm (30-120) at rest and 38 mm (10-85) at leg raise at tape measurement and 43 mm (25-92) and 35 mm (25-85) at CT scan respectively. Postoperative complications involved 22 seromas (28.6%), 1 hematoma (1.3%) and 1 early diastasis recurrence (1.3%). At mid-term evaluation, with 19 (12-33) months follow-up, 75 (97.4%) patients were evaluated. There were no hernia recurrences and 2 (2.6%) diastasis recurrences. The patients rated the result of their operation as excellent or good in 92% and 80% of the cases at global and esthetic evaluations, respectively. The result was rated bad at esthetic evaluation in 20% of the cases because the skin appearance was flawed, due to discrepancy between the unchanged cutaneous layer and the narrowed musculoaponeurotic layer., Conclusion: The technique provides effective repair of concomitant diastasis and ventral hernias up to 3 cm. Nevertheless, patients should be informed that the skin appearance can be flawed, because of the discrepancy between the unchanged cutaneous layer and the narrowed musculoaponeurotic layer., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Indocyanine green (ICG) is commonly used to assess perfusion, but quality defining features are lacking. We sought to establish qualitative features of esophageal ICG perfusion assessments, and develop an esophageal anastomotic scorecard to risk-stratify anastomotic outcomes., Methods: Single institution, retrospective analysis of children with an intraoperative ICG perfusion assessment of an esophageal anastomosis. Qualitative perfusion features were defined and a perfusion score developed. Associations between perfusion and clinical features with poor anastomotic outcomes (PAO, leak or refractory stricture) were evaluated with logistic and time-to-event analyses. Combining significant features, we developed and tested an esophageal anastomotic scorecard to stratify PAO risk., Results: From 2019 to 2021, 53 children (median age 7.4 months) underwent 55 esophageal anastomoses. Median (IQR) follow-up was 14 (10-19.9) months; mean (SD) perfusion score was 13.2 (3.4). Fifteen (27.3%) anastomoses experienced a PAO and had significantly lower mean perfusion scores (11.3 (3.3) vs 14.0 (3.2), p = 0.007). Unique ICG perfusion features, severe tension, and primary or rescue traction-induced esophageal lengthening [Foker] procedures were significantly associated with PAO on both logistic and Cox regression. The scorecard (range 0-7) included any Foker (+2), severe tension (+1), no arborization on either segment (+1), suture line hypoperfusion >twice expected width (+2), and segmental or global areas of hypoperfusion (+1). A scorecard cut-off >3 yielded a sensitivity of 73% and specificity of 93% (AUC 0.878 [95%CI 0.777 to 0.978]) in identifying a PAO., Conclusions: A scoring system comprised of qualitative ICG perfusion features, tissue quality, and anastomotic tension can help risk-stratify esophageal anastomotic outcomes accurately., Levels of Evidence: Diagnostic - II., Competing Interests: Declarations of Competing Interest Dr. Zendejas is a consultant for Stryker Corp. Stryker Corp. had no role in the design, conduct, interpretation, or decision to publish this study., (Copyright © 2022. Published by Elsevier Inc.)

Manufacturing autologous chimeric antigen receptor (CAR) T cell therapeutics is complex, and many patients experience treatment delays or cannot be treated at all. Although current allogeneic CAR products have the potential to overcome manufacturing bottlenecks, they are subject to immune rejection and failure to persist in the host, and thus do not provide the same level of efficacy as their autologous counterparts. Here, we aimed to develop universal allogeneic CAR T cells that evade the immune system and produce a durable response. We generated human hypoimmune (HIP) T cells with disrupted B2M, CIITA, and TRAC genes using CRISPR-Cas9 editing. In addition, CD47 and anti-CD19 CAR were expressed using lentiviral transduction. These allogeneic HIP CD19 CAR T cells were compared to allogeneic CD19 CAR T cells that only expressed the anti-CD19 CAR (allo CAR T). In vitro assays for cancer killing and exhaustion revealed no differences between allo CAR T and HIP CAR T cells, confirming that the HIP edits did not negatively affect T cell performance. Clearance of CD19 + tumors by HIP CAR T cells in immunodeficient NSG mice was comparable to that of allo CAR T cells. In fully immunocompetent humanized mice, HIP CAR T cells significantly outperformed allo CAR T cells, showed improved persistence and expansion, and provided lasting cancer clearance. Furthermore, CD47-targeting safety strategies reliably and specifically eliminated HIP CAR T cells. These findings suggest that universal allogeneic HIP CAR T cell-based therapeutics might overcome the limitations associated with poor persistence of allogeneic CAR T cells and exert durable anti-tumor responses., (© 2023. The Author(s).)

Introduction: We are conducting a multicenter study to identify classifiers predictive of disease-specific survival in patients with primary melanomas. Here we delineate the unique aspects, challenges, and best practices for optimizing a study of generally small-sized pigmented tumor samples including primary melanomas of at least 1.05mm from AJTCC TNM stage IIA-IIID patients. We also evaluated tissue-derived predictors of extracted nucleic acids' quality and success in downstream testing. This ongoing study will target 1,000 melanomas within the international InterMEL consortium., Methods: Following a pre-established protocol, participating centers ship formalin-fixed paraffin embedded (FFPE) tissue sections to Memorial Sloan Kettering Cancer Center for the centralized handling, dermatopathology review and histology-guided coextraction of RNA and DNA. Samples are distributed for evaluation of somatic mutations using next gen sequencing (NGS) with the MSK-IMPACTTM assay, methylation-profiling (Infinium MethylationEPIC arrays), and miRNA expression (Nanostring nCounter Human v3 miRNA Expression Assay)., Results: Sufficient material was obtained for screening of miRNA expression in 683/685 (99%) eligible melanomas, methylation in 467 (68%), and somatic mutations in 560 (82%). In 446/685 (65%) cases, aliquots of RNA/DNA were sufficient for testing with all three platforms. Among samples evaluated by the time of this analysis, the mean NGS coverage was 249x, 59 (18.6%) samples had coverage below 100x, and 41/414 (10%) failed methylation QC due to low intensity probes or insufficient Meta-Mixed Interquartile (BMIQ)- and single sample (ss)- Noob normalizations. Six of 683 RNAs (1%) failed Nanostring QC due to the low proportion of probes above the minimum threshold. Age of the FFPE tissue blocks (p<0.001) and time elapsed from sectioning to co-extraction (p = 0.002) were associated with methylation screening failures. Melanin reduced the ability to amplify fragments of 200bp or greater (absent/lightly pigmented vs heavily pigmented, p<0.003). Conversely, heavily pigmented tumors rendered greater amounts of RNA (p<0.001), and of RNA above 200 nucleotides (p<0.001)., Conclusion: Our experience with many archival tissues demonstrates that with careful management of tissue processing and quality control it is possible to conduct multi-omic studies in a complex multi-institutional setting for investigations involving minute quantities of FFPE tumors, as in studies of early-stage melanoma. The study describes, for the first time, the optimal strategy for obtaining archival and limited tumor tissue, the characteristics of the nucleic acids co-extracted from a unique cell lysate, and success rate in downstream applications. In addition, our findings provide an estimate of the anticipated attrition that will guide other large multicenter research and consortia., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: R.A.S. has received fees for professional services from F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, GlaxoSmithKline. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Purpose: The purpose of this study was to analyze the management and outcomes of primary button battery ingestions and their sequelae at a single high-volume center, and to propose a risk score to predict the likelihood of a severe outcome., Methods: The medical record was queried for all patients under 21 years old evaluated at our institution for button battery ingestion from 2008 to 2021. A severe outcome was defined as having at least one of the following: deep/circumferential mucosal erosion, perforation, mediastinitis, vascular or airway injury/fistula, or development of esophageal stricture. From a selection of clinically relevant factors, logistic regression determined predictors of a severe outcome, which were incorporated into a risk model., Results: 143 patients evaluated for button battery ingestion were analyzed. 24 (17%) had a severe outcome. The independent predictors of a severe outcome in multivariate analysis were location of battery in the esophagus on imaging (96%), battery size >/ = 2 cm (95%), and presence of any symptoms on presentation (96%), with P < 0.001 in all cases. Predicted probability of a severe outcome ranged from 88% when all three risk factors were observed, to 0.3% when none were present., Conclusion: We report the presentation, management, and complication profiles of a large cohort of BB ingestions treated at a single institution. A risk score to predict severe outcomes may be used by providers initially evaluating patients with button battery ingestion in order to allocate resources and expedite transfer to a center with pediatric endoscopic and surgical capabilities., Level of Evidence: Level IV., Type of Study: Clinical Research Paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Time is the greatest challenge in stroke management. This study aimed to examine factors contributing to prehospital delay and decision delay among stroke patients., Materials and Methods: A cross-sectional study involving acute stroke patients admitted to Seri Manjung Hospital was conducted between August 2019 and October 2020 via faceto- face interview. Prehospital delay was defined as more than 120 minutes taken from recognition of stroke symptoms till arrival in hospital, while decision delay was defined as more than 60 minutes taken from recognition of stroke symptoms till decision was made to seek treatment., Results: The median prehospital delay of 102 enrolled patients was 364 minutes (IQR 151.5, 1134.3) while the median for decision delay was 120 minutes (IQR 30.0, 675.0). No history of stroke (adj. OR 4.15; 95% CI 1.21, 14.25; p=0.024) and unaware of thrombolysis service (adj. OR 17.12; 95% CI 1.28, 229.17; p=0.032) were associated with higher odds of prehospital delay, while Indian ethnicity (adj. OR 0.09; 95% CI 0.02, 0.52; p=0.007) was associated with lower odds of prehospital delay as compared to Malay ethnicity. On the other hand, higher National Institutes of Health Stroke Scale (NIHSS) score (adj. OR 0.86; 95% CI 0.78, 0.95; p=0.002) was associated with lower odds of decision delay., Conclusion: Public awareness is crucial to shorten prehosital delay and decision delay for better patients' outcomes in stroke. Various public health campaigns are needed to improve the awareness for stroke.

Background: Diastasis recti (DR) is characterized by separation of both rectus muscles and protrusion of the median bulging, but besides median bulging DR can also entail global abdominal bulging. On other note, DR classification is based on the width of divarication, but measurement values are different at rest and at effort due to muscle contraction. Aim of the study is to provide additional features concerning the type of bulging and the width of divarication. Methods: Findings were retrospectively drawn from the data prospectively collected in the records of a continuous cohort of 105 patients (89 females, 16 males) referred for diastasis and concomitant ventral hernia repair. Results: There was a median bulging alone in 45 (42.9%) cases, a global bulging alone in 18 (17.1%) cases, both types combined in 37 (35.2%) cases and no bulging in 5 (4.8%). On 55 patients with a global bulging, 51 were females. Tape measurements values of DR width were closer to the values measured on the CT scan at leg raise than at rest. The differences were significant at rest as well as at leg raise. Though the difference at rest was highly significant ( p = 0.000), the difference at effort was not far from being not significant ( p = 0.049). Conclusion: Besides median bulging, presence or absence of the global bulging should be included in DR assessment. The difference between width of divarication at rest and on exertion raises the question of which value should be used for DR classification. The question is worth being debated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ngo, Cossa, Gueroult, Blum and Pélissier.)

Background: Breast cancer care has been affected by the COVID-19 pandemic. This systematic review aims to describe the observed pandemic-related changes in clinical and health services outcomes for breast screening and diagnosis., Methods: Seven databases (January 2020-March 2021) were searched to identify studies of breast cancer screening or diagnosis that reported observed outcomes before and related to the pandemic. Findings were presented using a descriptive and narrative approach., Results: Seventy-four studies were included in this systematic review; all compared periods before and after (or fluctuations during) the pandemic. None were assessed as being at low risk of bias. A reduction in screening volumes during the pandemic was found with over half of studies reporting reductions of ≥49%. A majority (66%) of studies reported reductions of ≥25% in the number of breast cancer diagnoses, and there was a higher proportion of symptomatic than screen-detected cancers. The distribution of cancer stage at diagnosis during the pandemic showed lower proportions of early-stage (stage 0-1/I-II, or Tis and T1) and higher proportions of relatively more advanced cases than that in the pre-pandemic period, however population rates were generally not reported., Conclusions: Evidence of substantial reductions in screening volume and number of diagnosed breast cancers, and higher proportions of advanced stage cancer at diagnosis were found during the pandemic. However, these findings reflect short term outcomes, and higher-quality research examining the long-term impact of the pandemic is needed., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

It is unclear why some melanomas aggressively metastasize while others remain indolent. Available studies employing multi-omic profiling of melanomas are based on large primary or metastatic tumors. We examine the genomic landscape of early-stage melanomas diagnosed prior to the modern era of immunological treatments. Untreated cases with Stage II/III cutaneous melanoma were identified from institutions throughout the United States, Australia and Spain. FFPE tumor sections were profiled for mutation, methylation and microRNAs. Preliminary results from mutation profiling and clinical pathologic correlates show the distribution of four driver mutation sub-types: 31% BRAF; 18% NRAS; 21% NF1; 26% Triple Wild Type. BRAF mutant tumors had younger age at diagnosis, more associated nevi, more tumor infiltrating lymphocytes, and fewer thick tumors although at generally more advanced stage. NF1 mutant tumors were frequent on the head/neck in older patients with severe solar elastosis, thicker tumors but in earlier stages. Triple Wild Type tumors were predominantly male, frequently on the leg, with more perineural invasion. Mutations in TERT, TP53, CDKN2A and ARID2 were observed often, with TP53 mutations occurring particularly frequently in the NF1 sub-type. The InterMEL study will provide the most extensive multi-omic profiling of early-stage melanoma to date. Initial results demonstrate a nuanced understanding of the mutational and clinicopathological landscape of these early-stage tumors., (© 2022 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)

Aim: Systemic therapies for lung cancer are rapidly evolving. This study aimed to describe lung cancer treatment patterns in New South Wales, Australia, prior to the introduction of immunotherapy and latest-generation targeted therapies., Methods: Systemic therapy utilization and treatment-related factors were examined for participants in the New South Wales 45 and Up Study with incident lung cancer ascertained by record linkage to the New South Wales Cancer Registry (2006-2013). Systemic therapy receipt to June 2016 was determined using medical and pharmaceutical claims data from Services Australia, and in-patient hospital records. Factors related to treatment were identified using competing risks regressions., Results: A total of 1,116 lung cancer cases were identified with a mean age at diagnosis of 72 years and median survival of 10.6 months. Systemic therapy was received by 45% of cases. Among 400 cases with metastatic non-small cell lung cancer, 51% and 28% received first- and second-line systemic therapy, respectively. Among 112 diagnosed with small-cell lung cancer, 79% and 29% received first- and second-line systemic therapy. The incidence of systemic therapy was lower for participants with indicators of poor performance status, lower educational attainment, and those who lived in areas of socioeconomic disadvantage; and was higher for participants with small-cell lung cancer histology or higher body mass index., Conclusion: This population-based Australian study identified patterns of systemic therapy use for lung cancer, particularly small-cell lung cancer. Despite a universal healthcare system, the analysis revealed socioeconomic disparities in health service utilization and relatively low utilization of systemic therapy overall., (© 2021 John Wiley & Sons Australia, Ltd.)

Molecular encoding in abiotic sequence-defined polymers (SDPs) has recently emerged as a versatile platform for information and data storage. However, the storage capacity of these sequence-defined polymers remains underwhelming compared to that of the information storing biopolymer DNA. In an effort to increase their information storage capacity, herein we describe the synthesis and simultaneous sequencing of eight sequence-defined 10-mer oligourethanes. Importantly, we demonstrate the use of different isotope labels, such as halogen tags, as a tool to deconvolute the complex sequence information found within a heterogeneous mixture of at least 96 unique molecules, with as little as four micromoles of total material. In doing so, relatively high-capacity data storage was achieved: 256 bits in this example, the most information stored in a single sample of abiotic SDPs without the use of long strands. Within the sequence information, a 256-bit cipher key was stored and retrieved. The key was used to encrypt and decrypt a plain text document containing The Wonderful Wizard of Oz . To validate this platform as a medium of molecular steganography and cryptography, the cipher key was hidden in the ink of a personal letter, mailed to a third party, extracted, sequenced, and deciphered successfully in the first try, thereby revealing the encrypted document., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

In recent years, immune checkpoint inhibitors (ICIs) have been approved for a growing number of cancer types. Approximately a quarter of cancer patients have a concomitant diagnosis of autoimmune disorders (AID). Activation of the immune system with ICIs poses a potential risk of AID worsening, thus, the majority of the ICI clinical trials excluded these patients from the study. There is a paucity of data regarding the benefits and risks of ICIs in cancer patients with AIDs. The primary objectives of this study were to determine the incidence of immunotherapy-related AID worsening and all immunotherapy-related adverse events (irAEs). Secondary outcomes were time to AID worsening and survival difference. All adult patients (age >=18 years) with solid malignancy who received ICIs between Jan 2016 and June 2019 were identified using the University of Louisville pharmacy database. Medical records were reviewed to include all the patients with preexisting AIDs. Descriptive statistics were used to determine the incidence of AID worsening and all irAEs. Baseline characteristics were compared between cancer patients with vs without AID worsening using Pearson chi2 and Student's t-test, where appropriate. Multivariate Cox regression analysis was used to compare survival between the 2 groups. A total of 40 patients with AIDs were identified during the study period. The cancer types were melanoma (57.5%), lung (15%), breast (5%), and others (22.5%). AIDs were rheumatological (52.5%), dermatologic (20%), gastroenterological (12.5%), neurologic (12.5%), and hematological (2.5%). The incidence of all irAEs was 60% (grade >=3 in 20%) and AID worsening was 40% (grade >=3 in 15%). The median time from ICI initiation to AID worsening was 94.5 (range 21-431) days. In multivariate Cox regression analysis, adjusted for demographics, cancer type, and stage, survival was similar for patients who had AID worsening vs those who did not (HR 0.30 (95%CI 0.06-1.40, P = 0.128). In our single-institution study, cancer patients with preexisting AID do have an increased risk of irAEs with high-grade toxicities in 20% compared to historically reported 5% in the general cancer population. About 15% of patients reported grade >=3 worsening of their AIDs. Although the risk of irAEs is numerically higher in patients with AIDs, it may be acceptable to the patients if the potential benefits of ICIs outweigh the risks., (Copyright © 2022. Published by Elsevier Inc.)

A critical step in repurposing the cellular translation machinery for the synthesis of polymeric products is the acylation of transfer RNA (tRNA) with unnatural monomers. Toward this goal, flexizymes, ribozymes capable of aminoacylation, have emerged as a uniquely adept tool for charging tRNA with ever increasingly diverse substrates. In this review, we present a library of monomer substrates that have been tested for tRNA acylation with the flexizyme system. From this mile-high view, we provide insights for understanding the chemical factors that influence flexizyme-mediated tRNA acylation. We conclude that flexizymes are primitive esterification catalysts that display a modest binding affinity to the monomer's aromatic recognition element. Together, these robust, yet flexible, flexizyme systems provide researchers with unprecedented access for preparing unnatural acyl-tRNA and the opportunity to repurpose the translation machinery for the synthesis of novel biologically derived structures beyond native proteins and peptides., Competing Interests: Declaration of interests J.N.C. and E.V.A. are co-inventors on a provisional patent (US Provisional Patent Serial No. 63/144,814) that incorporates technology described in this article., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Techniques of retromuscular repair of ventral hernias aim at avoiding complications linked to intraperitoneal patch. Aim of the study was to evaluate results of the VTEP technique., Methods: On 187 patients who underwent a VTEP, evaluation was carried out on 128 patients with a minimum follow-up of 1 year. The surgical technique consisted of creating connection between both retro-rectus spaces, by division of the medial edges of the posterior sheath and deploying the patch in the retromuscular patch without fixation. The posterior sheath was repaired in 16 cases. The patients were sent a questionnaire and invitation to have physical examination by the surgeon., Results: The mean hernia and patch size were 9 (1-50) and 225 (50-500) cm 2 , respectively. The mean follow-up was 21.2 (12-35) months; 120 (93.7%) patients were evaluated, 21 by physical examination, 41 by questionnaire, 58 by telephone and 8 (6.3%) were lost to follow-up. Hundred (83%) patients felt no pain at rest, and 88 (73%) during effort. Among patients who felt some degree of pain, the mean VAS value was 2 (1-4) at rest and 2.6 (1-7) during effort. Two recurrences occurred, 3 patients were worried about a persisting diastasis bulging at the upper border of the patch and 8 patients in which the posterior sheath was not repaired complained they felt that their upper abdomen was somewhat distended or swollen., Conclusion: The VTEP procedure provides a low level of chronic pain but can entail some drawbacks, such as the swollen abdomen, which can be attributed to the absence of repair of the posterior sheath. It may be that restoring or preserving structural integrity of the abdominal belt formed by the posterior sheath constitutes a key point in retromuscular techniques., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Anti-reflux procedures (ARP) in esophageal atresia (EA) patients can be challenging and prone to failure. These challenges become more evident with increasing complexity of EA. We sought to determine predictors of ARP failure in complex EA patients., Methods: Single-institution retrospective review of complex EA patients (e.g. long-gap EA, esophageal strictures, hiatal hernia, and reoperative ARP) who underwent an ARP from 2002 to 2019. ARP failure was defined as hiatal hernia recurrence, wrap migration/loosening, or need for reoperation. Predictors of failure were evaluated using univariate and multivariable time-to-event analysis., Results: 121 patients underwent 140 ARP at a median age of 13.5 months (IQR 7, 26.5). Nissen fundoplication (89%) was the most common ARP. Mesh (bovine pericardium) reinforcement was used in 41% of the patients. Median follow-up was 3.2 years (IQR 0.9, 5.8); 44 instances of ARP failure occurred (31%), though only 20 (14%) required reoperation. Median time to failure was 8.7 months (IQR 3.2, 25). Though fewer mesh-reinforced ARP failed (21% with vs 39% without, p = 0.02), on multivariable analysis only partial fundoplication (aHR 2.22 [95% CI 1.01-4.78]) and minimally invasive repair (aHR 2.57 [95% CI 1.12-6.01]) were significant predictors of ARP failure., Conclusion: In our practice of complex EA patients, where ARP fail in nearly one third of cases, a Nissen fundoplication performed via laparotomy provided the lowest risk of ARP failure., (Copyright © 2021. Published by Elsevier Inc.)

Background: In the VTEP series, some patients declared that their abdomen was "somewhat swollen", and the authors suggested that this might be related to disruption of the posterior sheath due to the crossing. Following this observation, we decided to evaluate the systematic repair of the posterior sheath., Methods: In 50 consecutive patients operated for ventral hernias, the VTEP procedure was modified, using the linear stapler to perform simultaneous division and closure of the posterior sheath. Perioperative data and short-term results were prospectively assessed., Results: Six (12%) complications occurred: one hematoma, one sudden death at home five days after surgery in a man with history of cardiac disease, and 4 cases of dehiscence of the staple line, which were successively reoperated by suture of the gap and posterior sheath release incision (PSR). With a mean follow-up of 7.5 months (4-12) there were no recurrences and 2 cases of "swollen abdomen", in patients who undergone PSR. The "swollen abdomen" did not occur when the posterior sheath was repaired without PSR. Preoperative diastasis bulging present in 11 cases, was totally or partially corrected in 8 and 1 cases, respectively, and unchanged in 2 cases., Conclusion: The sVTEP procedure, can contribute to prevent the swollen abdomen and to diastasis correction. The PSR can prevent staple line disruption or permit tension-free repair of the dehiscence, but then, the newly created lateral gaps can finally entail the same drawback. Search for the best solution to treat the gap in the posterior sheath requires further studies., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Paediatric spontaneous pneumothorax (PSP) management continues to lack paediatric-specific guideline recommendations. There have been increasing reports of paediatric retrospective case studies supplemented by important well designed RCT (predominantly) adult studies. Taken together, these suggest that conservative management may have an increasing role to play in the management of PSP and that aspiration may have limited utility as a first line intervention. Our local experience, as part of a multicentre retrospective analysis and subsequent audit of management since, corroborates recent published data: it highlights an increasing trend towards conservative management in spontaneous pneumothorax with similar rates of recurrence, compared to intervention, and low use of aspiration with similarly low success rates. We have therefore updated our local practice guidelines and share these with readers. Specifically, we have removed aspiration in the management of primary spontaneous pneumothorax and reserved intervention for children who are clinically unstable or show evidence of increasing air leak irrespective of pneumothorax size. Whilst the success of this change in clinical practice will need to be reviewed in the next 5-10 years, the overall low incidence of the condition, demands a multicentre, and probably multinational, collaborative approach to allow the best chance of obtaining definitive evidence to guide clinical paediatric management., (Copyright © 2021. Published by Elsevier Ltd.)

Background and Aims: Anastomotic strictures following surgical repair is one of the most common complications in esophageal atresia (EA). The utility of esophageal stenting to treat anastomotic esophageal strictures in pediatrics is unclear. Our primary aim was to evaluate whether esophageal stenting, in conjunction with dilation and other endoscopic therapies, prevented surgical stricture resection (SR). Our secondary aims were to evaluate predictors of successful esophageal stenting and evaluate adverse events from stent placement., Methods: A retrospective review of pediatric patients with EA complicated by esophageal strictures was performed. The change in stricture diameter in millimeters from the time of stent removal to subsequent endoscopy was defined as delta diameter (ΔD). A receiver operating characteristic (ROC) curve analysis was performed to determine the discriminatory ability of ΔD. Youden J index was used to identify optimal cutoff-point in predicting stent success. A univariate and multivariate analysis were done to assess predictors of success., Result: Forty-nine esophageal anastomoses were stented to treat esophageal strictures. Stents prevented SR in 41% of patients. ROC curve analysis utilizing Youden J index identified ΔD of ≤4 mm (area under the curve = 0.790; 95% confidence interval: 0.655-0.924; P < 0.001) as the optimal cutoff point in differentiating stent success. The most common adverse events were erosions/ulcerations, granulation tissue formation, and vomiting/retching., Conclusion: Stent therapy in preventing SR at the site of EA repair was successful in 41% in our population with good long term follow-up. The most significant predictor of success in this study was the change in luminal diameter (≤4 mm) at initial poststent follow-up., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Esophageal growth using the Foker process (FP) for long-gap esophageal atresia (LGEA) has evolved over time., Methods: Contemporary LGEA patients treated from 2014-2020 were compared to historical controls (2005 to <2014)., Results: 102 contemporary LGEA patients (type A 50%, B 18%, C 32%; 36% prior anastomotic attempt; 20 with esophagostomy) underwent either primary repair (n=23), jejunal interposition (JI; n = 14), or Foker process (FP; n = 65; 49 primary [p], 16 rescue [r]). The contemporary p-FP cohort experienced significantly fewer leaks on traction (4% vs 22%), bone fractures (2% vs 22%), anastomotic leak (12% vs 37%), and Foker failure (FP→JI; 0% vs 15%), when compared to historical p-FP patients (n = 27), all p ≤ 0.01. Patients who underwent a completely (n = 11) or partially (n = 11) minimally invasive FP experienced fewer median days paralyzed (0 vs 8 vs 17) and intubated (9 vs 15 vs 25) compared to open FP patients, respectively (all p ≤ 0.03), with equivalent leak rates (18% vs 9% vs 26%, p = 0.47). At one-year post-FP, most patients (62%) are predominantly orally fed., Conclusion: With continued experience and technical refinements, the Foker process has evolved with improved outcomes, less morbidity and maximal esophageal preservation., (Copyright © 2021. Published by Elsevier Inc.)

Background and Aims: Children with esophageal atresia (EA) who undergo surgical repair are at risk for anastomotic stricture, which may need multiple dilations or surgical resection if the stricture proves refractory to endoscopic therapy. To date, no studies have assessed the predictive value of anastomotic diameter on long-term treatment outcomes. Our aim was to evaluate the relationship between anastomotic diameter in the early postoperative period and need for frequent dilations and stricture resection within 1 year of surgical repair. Methods: A retrospective chart review was performed of patients who had EA repair or stricture resection (SR). Medical records were reviewed to evaluate the diameter of the anastomosis at the first endoscopy after surgery, number and timing of dilations needed to treat the anastomotic stricture, and need for stricture resection. A generalized estimating equations (GEE) modeling with a logit link and binomial family was done to analyze the relationship between initial endoscopic anastomosis diameter and the outcome of needing a stricture resection. Median regression was implemented to estimate the association between number of dilations needed based on initial diameter. Results: A total of 121 patients (56 females) with a history of EA (64% long-gap EA) were identified who either underwent Foker repair at 46% or stricture resection with end-to-end esophageal anastomosis at 54%. The first endoscopy occurred a median of 22 days after surgery. Among all cases, a narrower anastomoses were more likely to need stricture resection with an OR of 12.9 (95% CI, 3.52, 47; p < 0.001) in patients with an initial diameter of <3 mm. The number of dilations that patients underwent also decreased as anastomotic diameter increased. This observation showed a significant difference when comparing all diameter categories when looking at all surgeries taken as a whole ( p < 0.008). Conclusion: Initial anastomotic diameter as assessed via endoscopy performed after high-risk EA repair predicts which patients will require more esophageal dilations as well as the likelihood for stricture resection. This data may serve to stratify patients into different endoscopic treatment plans., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Baghdadi, Clark, Ngo, Yasuda, Staffa, Zendejas, Hamilton, Jennings and Manfredi.)

Tobacco smoke is a known carcinogen, but the magnitude of smoking-related cancer risk depends on country-specific, generational smoking patterns. We quantified cancer risk in relation to smoking in a population-based cohort, the 45 and Up Study (2006-2009) in New South Wales, Australia. Cox proportional hazards regressions estimated adjusted hazard ratios (HR) by self-reported smoking history at baseline (2006-2009) for incident, primary cancers via linkage to cancer registry data to 2013 and cancer death data to 2015. Among 229 028 participants aged ≥45 years, 18 475 cancers and 5382 cancer deaths occurred. Current-smokers had increased risks of all cancers combined (HR = 1.42, 95% confidence interval [CI], 1.34-1.51), cancers of the lung (HR = 17.66, 95%CI, 14.65-21.29), larynx (HR = 11.29, 95%CI, 5.49-23.20), head-and-neck (HR = 2.53, 95%CI, 1.87-3.41), oesophagus (HR = 3.84, 95%CI, 2.33-6.35), liver (HR = 4.07, 95%CI, 2.55-6.51), bladder (HR = 3.08, 95%CI, 2.00-4.73), pancreas (HR = 2.68, 95%CI, 1.93-3.71), colorectum (HR = 1.31, 95%CI, 1.09-1.57) and unknown primary site (HR = 3.26, 95%CI, 2.19-4.84) versus never-smokers. Hazards increased with increasing smoking intensity; compared to never-smokers, lung cancer HR = 9.22 (95%CI, 5.14-16.55) for 1-5 cigarettes/day and 38.61 (95%CI, 25.65-58.13) for >35 cigarettes/day. Lung cancer risk was lower with quitting at any age but remained higher than never-smokers for quitters aged >25y. By age 80y, an estimated 48.3% of current-smokers (41.1% never-smokers) will develop cancer, and 14% will develop lung cancer, including 7.7% currently smoking 1-5 cigarettes/day and 26.4% for >35 cigarettes/day (1.0% never-smokers). Cancer risk for Australian smokers is significant, even for 'light' smokers. These contemporary estimates underpin the need for continued investment in strategies to prevent smoking uptake and facilitate cessation, which remain key to reducing cancer morbidity and mortality worldwide., (© 2021 UICC.)

Background: The jejunal interposition is our preferred esophageal replacement route when the native esophagus cannot be reconstructed. We report the evolution of our approach and outcomes., Methods: The study was a single-center retrospective review of children undergoing jejunal interposition for esophageal replacement. Outcomes were compared between historical (2010-2015) and contemporary cohorts (2016-2019)., Results: Fifty-five patients, 58% male, median age 4 years (interquartile range 2.4-8.3), with history of esophageal atresia (87%), caustic (9%) or peptic (4%) injury, underwent a jejunal interposition (historical cohort n = 14; contemporary cohort n = 41). Duration of intubation (11 vs 6 days; P = .01), intensive care unit (22 vs 13 days; P = .03), and hospital stay (50 vs 27 days; P = .004) were shorter in the contemporary cohort. Anastomotic leaks (7% vs 5%; P = .78), anastomotic stricture resection (7% vs 10%; P = .74), and need for reoperation (57% vs 46%; P = .48) were similar between cohorts. Most reoperations were elective conduit revisions. Microvascular augmentation, used in 70% of cases, was associated with 0% anastomotic leaks vs 18% without augmentation; P = .007. With median follow-up of 1.9 years (interquartile range 1.1, 3.8), 78% of patients are predominantly orally fed. Those with preoperative oral intake were more likely to achieve consistent postoperative oral intake (87.5% vs 64%; P = .04)., Conclusion: We have made continuous improvements in our management of patients undergoing a jejunal interposition. Of these, microvascular augmentation was associated with no anastomotic leaks. Despite its complexity and potential need for conduit revision, the jejunal interposition remains our preferred esophageal replacement, given its excellent long-term functional outcomes in these complex children who have often undergone multiple procedures before the jejunal interposition., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Non-melanoma skin cancers (NMSCs) are common and consume many healthcare resources. A health utility is a single preference-based value for assessing health-related quality of life, which can be used in economic evaluations. There are scarce data on health utilities for NMSCs., Objectives: Using a systematic review approach, we synthesized the current data on NMSC-related health utilities., Methods: A systematic review of studies of NMSC-related health utilities was conducted in Medline, Embase, and Cochrane databases. Data were extracted based on the protocol and a quality assessment was performed for each study., Results: The protocol resulted in 16 studies, involving 121 621 participants. Mean utility values across the studies ranged from 0.56 to 1 for undifferentiated NMSC, 0.84 to 1 for actinic keratosis, 0.45 to 1 for squamous cell carcinoma, and 0.67 to 1 for basal cell carcinoma. There was considerable variability in utilities by type of cancer, stage of diagnosis, time to treatment, treatment modality, and quality of life instrument or method. Utility values were predominantly based on the EuroQol 5-dimension instrument and ranged from 0.45 to 0.96, while other measurement methods produced values ranging from 0.67 to 1. Lower utility values were observed for advanced cancers and for the time period during and immediately after treatment, after which values gradually returned to pre-treatment levels., Conclusions: Most utility values clustered around relatively high values of 0.8 to 1, suggesting small decrements in quality of life associated with most NMSCs and their precursors. Variability in utilities indicates that careful characterization is required for measures to be used in economic evaluations., Competing Interests: The authors have no conflicts of interest to declare., (© 2021 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: A recurrent tracheo-esophageal fistula can complicate esophageal atresia and tracheo-esophageal fistula (TEF) repair in children. Therapeutic approaches and the rate of recurrence vary widely. Most reports are limited by small cohorts and short-term follow-up, and rates of re-recurrence are substantial, making it difficult to select the treatment of choice. We aimed to review our experience with the treatment of recurrent TEF using posterior tracheopexy, focusing on operative risks and long-term outcomes., Study Design: We conducted a retrospective review of patients with esophageal atresia TEF with recurrent TEF treated at 2 institutions from 2011 to 2020. We approach recurrent TEFs surgically. Once the TEF is divided and repaired, the membranous trachea is sutured to the anterior longitudinal ligament of the spine (posterior tracheopexy) and the esophagus is rotated into the right chest (rotational esophagoplasty), separating the suture lines widely. To detect re-recurrence, patients undergo endoscopic surveillance during follow-up., Results: Sixty-two patients with a recurrent TEF were surgically treated (posterior tracheopexy/rotational esophagoplasty) at a median age of 14 months. All had significant respiratory symptoms. On referral, 24 had earlier failed endoscopic and/or surgical attempts at repair. Twenty-nine required a concomitant esophageal anastomotic stricturoplasty or stricture resection. Postoperative morbidity included 3 esophageal leaks, and 1 transient vocal cord dysfunction. We have identified no recurrences, with a median follow-up of 2.5 years, and all symptoms have resolved., Conclusions: The surgical treatment of recurrent TEFs that incorporates a posterior tracheopexy and rotational esophagoplasty is highly effective for preventing re-recurrence with low perioperative morbidity., (Copyright © 2021 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: We describe a left-sided approach for long gap esophageal atresia (LGEA) repair in patients who have a large leftward upper pouch and no significant tracheomalacia, or as a salvage strategy after prior failed right-sided repairs., Methods: Retrospective review of patients who underwent repair via traction induced growth (Foker procedure [FP]) from 2014 to 2019 was performed. Surgical technique and post-operative outcomes were evaluated., Results: Of 47 LGEA patients, 18 (38%) were approached via the left side - 94% had a left aortic arch, and 22% had prior attempts at a right-sided anastomosis. More left-sided patients underwent minimally invasive repair (39% vs 7%, p = 0.007) and internal traction (50% vs 10%, p = 0.002) compared to right-sided patients. On multivariate analysis, internal traction was associated with a decreased length of paralysis (p<0.01); length of intubation and hospital stay were similar between groups. Anastomotic leak (17% vs 20%, p = 0.80) and stricture resection (6% vs 24%, p = 0.12) rates were similar. No left-sided FP patient required additional surgery for tracheomalacia, while six right-sided patients required intervention., Conclusion: Left-sided FP can be considered for LGEA patients with a large leftward upper pouch or as a salvage pathway after a failed right chest approach, with similar outcomes to the right-sided approach., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Molecular encoding in sequence-defined polymers shows promise as a new paradigm for data storage. Here, we report what is, to our knowledge, the first use of self-immolative oligourethanes for storing and reading encoded information. As a proof of principle, we describe how a text passage from Jane Austen's Mansfield Park was encoded in sequence-defined oligourethanes and reconstructed via self-immolative sequencing. We develop Mol.E-coder, a software tool that uses a Huffman encoding scheme to convert the character table to hexadecimal. The oligourethanes are then generated by a high-throughput parallel synthesis. Sequencing of the oligourethanes by self-immolation is done concurrently in a parallel fashion, and the liquid chromatography-mass spectrometry (LC-MS) information decoded by our Mol.E-decoder software. The passage is capable of being reproduced wholly intact by a third-party, without any purifications or the use of tandem MS (MS/MS), despite multiple rounds of compression, encoding, and synthesis., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.

Background: The repair of ventral hernias by intra-peritoneal patch (IPOM) involves a risk of pain due to stapling as well as intestinal adhesions. Extraperitoneal placement of the patch without fixation can prevent these drawbacks. Techniques of endoscopic preperitoneal repair were previously described by others. The aim of this article is to describe our technique and to evaluate the feasibility and short-term results., Methods: The totally endoscopic technique consists of dividing the median aponeurotic structures, while preserving the proper linea alba, to create a unique retro-muscular space, in which the patch is deployed without any fixation. Hundred twelve consecutive patients were operated on for ventral hernias (82 umbilical, 20 epigastric, 10 combined). Perioperative data including duration of operation, technical problems, conversions and complications, as well as postoperative pain, time to resume daily activities and time off work were prospectively assessed., Results: 98 (87.5%) patients were operated in ambulatory surgery, and 14 (12.5%) in overnight stay. The mean sizes of the hernia and the patch were 9 (1-50) cm 2 and 225 (50-500) cm 2 , respectively. The mean operation duration was 75 (30-270) min. The peritoneum was opened in 43 (38.4%) cases and closed by suture in 41 instances. There were 5 (4.5%) conversions to IPOM and 4 (3.6%) complications (1 seroma, 1 urine retention, 1 transitory ileus, and 1 intestinal obstruction) which were reoperated. The mean VAS value of postoperative pain was 2.45 (0-8), pain was scored 0 by 17 (15%) patients. The mean times to resume daily activity and work were 4 (1-15) days and 11.5 (1-30) days, respectively., Conclusion: Our results suggest that VTEP is safely feasible by surgeons skilled in laparoscopy, and might contribute to minimize pain, though this must be established by comparative studies.

Background: Gliomas represent a biologically heterogeneous group of primary brain tumors with uncontrolled cellular proliferation and diffuse infiltration that renders them almost incurable, thereby leading to a grim prognosis. Recent comprehensive genomic profiling has greatly elucidated the molecular hallmarks of gliomas, including the mutations in isocitrate dehydrogenase 1 and 2 ( IDH1 and IDH2 ), loss of chromosomes 1p and 19q (1p/19q), and epidermal growth factor receptor variant III (EGFRvIII). Detection of these molecular alterations is based on ex vivo analysis of surgically resected tissue specimen that sometimes is not adequate for testing and/or does not capture the spatial tumor heterogeneity of the neoplasm., Methods: We developed a method for noninvasive detection of radiogenomic markers of IDH both in lower-grade gliomas (WHO grade II and III tumors) and glioblastoma (WHO grade IV), 1p/19q in IDH -mutant lower-grade gliomas, and EGFRvIII in glioblastoma. Preoperative MRIs of 473 glioma patients from 3 of the studies participating in the ReSPOND consortium (collection I: Hospital of the University of Pennsylvania [HUP: n = 248], collection II: The Cancer Imaging Archive [TCIA; n = 192], and collection III: Ohio Brain Tumor Study [OBTS, n = 33]) were collected. Neuro-Cancer Imaging Phenomics Toolkit (neuro-CaPTk), a modular platform available for cancer imaging analytics and machine learning, was leveraged to extract histogram, shape, anatomical, and texture features from delineated tumor subregions and to integrate these features using support vector machine to generate models predictive of IDH , 1p/19q, and EGFRvIII. The models were validated using 3 configurations: (1) 70-30% training-testing splits or 10-fold cross-validation within individual collections, (2) 70-30% training-testing splits within merged collections, and (3) training on one collection and testing on another., Results: These models achieved a classification accuracy of 86.74% (HUP), 85.45% (TCIA), and 75.15% (TCIA) in identifying EGFRvIII, IDH , and 1p/19q, respectively, in configuration I. The model, when applied on combined data in configuration II, yielded a classification success rate of 82.50% in predicting IDH mutation (HUP + TCIA + OBTS). The model when trained on TCIA dataset yielded classification accuracy of 84.88% in predicting IDH in HUP dataset., Conclusions: Using machine learning algorithms, high accuracy was achieved in the prediction of IDH , 1p/19q, and EGFRvIII mutation. Neuro-CaPTk encompasses all the pipelines required to replicate these analyses in multi-institutional settings and could also be used for other radio(geno)mic analyses., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Despite dyslipidaemia management guidelines, many patients do not reach low-density lipoprotein cholesterol targets due to insufficiently intensive regimens or lack of adherence to their medication. This was a retrospective cohort study on the Pharmacoepidemiologic General Research eXtension (PGRx)-acute coronary syndrome (ACS) registry. Patients included were ≥ 18 years old who suffered an ACS between 2013 and 2016, and treated with lipid-lowering therapy (LLT) at hospital discharge or within 92 days. Patients were followed up to 12 months' post index ACS, a new cardiovascular event, loss to follow-up or death. Treatment intensity (high, moderate and low intensity statins ± ezetimibe) and adherence (proportion of days covered > 80%) are described. A total of 2,695 patients were included; mean age [SD] was 63.1 [12.8] years, and 77% were men. High, moderate and low intensity statins were started in 56% (1,520), 36% (971), and 3% (86) of patients, respectively. A further 2% (46) were on statin/ezetimibe combination, 2% (42) on other LLT and 1% (30) on ezetimibe alone. At follow-up, around 70% of patients were adherent to LLT, with those on moderate intensity treatments showing better adherence (76%) than those on low (63%) or high (67%) intensity treatments. Despite guideline recommendations, many patients following an ACS are not treated with high intensity statins, and adherence remains far from optimal. Effort should be made to increase the proportion of patients treated with high intensity statins following an ACS and to further improve treatment adherence., Competing Interests: EB declares having received honoraria from Amgen, MSD, Sanofi and Regeneron, Unilever, Danone, Aegerion, Chiesi, Rottapharm-MEDA, Servier, lonis-pharmaceuticals, AKCEA, Mylan and GENFIT. FS-V, GD and PN are full-time employees at Amgen and own Amgen stock options. AK and GG are full-time employees of Certara, Evidence & Access (previously - Analytica Laser), that received consulting fees from Amgen to conduct the study. EB received consulting fees from Amgen., (© 2020 Bruckert et al. Published by IMR Press.)

This study evaluated the quality of life of older adults in Vietnam. A survey was conducted on 291 old people at eight public and private nursing homes using cluster sampling. Quality of life was predicted by gender, duration of stay, center activities and community tangible support, and connection with family. Results were consistent across the four subscales of the Quality of Life Index. Quality of life of Vietnamese older adults depends not only on the quality of services provided by the nursing homes but also on family and community connections., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background: Of all cancer types, healthcare for lung cancer is the third most costly in Australia, but there is little detailed information about these costs. Our aim was to provide detailed population-based estimates of health system costs for lung cancer care, as a benchmark prior to wider availability of targeted therapies/immunotherapy and to inform cost-effectiveness analyses of lung cancer screening and other interventions in Australia., Methods: Health system costs were estimated for incident lung cancers in the Australian 45 and Up Study cohort, diagnosed between recruitment (2006-2009) and 2013. Costs to June 2016 included services reimbursed via the Medicare Benefits Schedule, medicines reimbursed via the Pharmaceutical Benefits Scheme, inpatient hospitalisations, and emergency department presentations. Costs for cases and matched, cancer-free controls were compared to derive excess costs of care. Costs were disaggregated by patient and tumour characteristics. Data for more recent cases identified in hospital records provided preliminary information on targeted therapy/immunotherapy., Results: 994 eligible cases were diagnosed with lung cancer 2006-2013; 51% and 74% died within one and three years respectively. Excess costs from one-year pre-diagnosis to three years post-diagnosis averaged ~$51,900 per case. Observed costs were higher for cases diagnosed at age 45-59 ($67,700) or 60-69 ($63,500), and lower for cases aged ≥80 ($29,500) and those with unspecified histology ($31,700) or unknown stage ($36,500). Factors associated with lower costs generally related to shorter survival: older age (p<0.0001), smoking (p<0.0001) and unknown stage (p = 0.002). There was no evidence of differences by year of diagnosis or sex (both p>0.50). For 465 cases diagnosed 2014-2015, 29% had subsidised molecular testing for targeted therapy/immunotherapy and 4% had subsidised targeted therapies., Conclusions: Lung cancer healthcare costs are strongly associated with survival-related factors. Costs appeared stable over the period 2006-2013. This study provides a framework for evaluating the health/economic impact of introducing lung cancer screening and other interventions in Australia., Competing Interests: The authors have declared that no competing interests exist.

Advanced pancreatic cancer carries a poor prognosis and has traditionally been treated with chemotherapy. However, immunotherapy has made great strides in a subset of patients depending on mismatch repair/microsatellite status. We present a patient with locally advanced pancreatic cancer treated with neoadjuvant chemotherapy followed by surgery and additional adjuvant chemotherapy whose disease progressed while on adjuvant chemotherapy. Tumour testing showed a mismatch repair mutation and high microsatellite instability, making her eligible for treatment with immunotherapy. Germline genetic testing confirmed the clinical suspicion of Lynch syndrome. She has had isolated sites of progression treated with radiation but overall has been receiving immunotherapy for more than 3 years, highlighting the importance of tumour testing as it may allow for additional treatment options and improved survival., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The primary cilium is a microtubule-based, antenna-like organelle housing several signaling pathways. It follows a cyclic pattern of assembly and deciliation (disassembly and/or shedding), as cells exit and re-enter the cell cycle, respectively. In general, primary cilia loss leads to kidney cystogenesis. However, in animal models of autosomal dominant polycystic kidney disease, a major disease caused by mutations in the polycystin genes ( Pkd1 or Pkd2 ), primary cilia ablation or acceleration of deciliation suppresses cystic growth, whereas deceleration of deciliation enhances cystogenesis. Here, we show that deciliation is delayed in the cystic epithelium of a mouse model of postnatal deletion of Pkd1 and in Pkd1 - or Pkd2 -null cells in culture. Mechanistic experiments show that PKD1 depletion activates the centrosomal integrity/mitotic surveillance pathway involving 53BP1, USP28, and p53 leading to a delay in deciliation. Reduced deciliation rate causes prolonged activation of cilia-based signaling pathways that could promote cystic growth. Our study links polycystins to cilia dynamics, identifies cellular deciliation downstream of the centrosomal integrity pathway, and helps explain pro-cystic effects of primary cilia in autosomal dominant polycystic kidney disease., (© 2020 Gerakopoulos et al.)

Familial hypocalciuric hypercalcemia (FHH) is a genetic condition associated with hypocalciuria, hypercalcemia, and, in some cases, inappropriately high levels of circulating parathyroid hormone (PTH). FHH is associated with inactivating mutations in the gene encoding the Ca2+-sensing receptor (CaSR), a GPCR, and GNA11 encoding G protein subunit α 11 (Gα11), implicating defective GPCR signaling as the root pathophysiology for FHH. However, the downstream mechanism by which CaSR activation inhibits PTH production/secretion is incompletely understood. Here, we show that mice lacking the transient receptor potential canonical channel 1 (TRPC1) develop chronic hypercalcemia, hypocalciuria, and elevated PTH levels, mimicking human FHH. Ex vivo and in vitro studies revealed that TRPC1 serves a necessary and sufficient mediator to suppress PTH secretion from parathyroid glands (PTGs) downstream of CaSR in response to high extracellular Ca2+ concentration. Gα11 physically interacted with both the N- and C-termini of TRPC1 and enhanced CaSR-induced TRPC1 activity in transfected cells. These data identify TRPC1-mediated Ca2+ signaling as an essential component of the cellular apparatus controlling PTH secretion in the PTG downstream of CaSR.

The purpose of this manuscript is to provide an overview of the technical specifications and architecture of the Ca ncer imaging P henomics T ool k it (CaPTk www.cbica.upenn.edu/captk), a cross-platform, open-source, easy-to-use, and extensible software platform for analyzing 2D and 3D images, currently focusing on radiographic scans of brain, breast, and lung cancer. The primary aim of this platform is to enable swift and efficient translation of cutting-edge academic research into clinically useful tools relating to clinical quantification, analysis, predictive modeling, decision-making, and reporting workflow. CaPTk builds upon established open-source software toolkits, such as the Insight Toolkit (ITK) and OpenCV, to bring together advanced computational functionality. This functionality describes specialized, as well as general-purpose, image analysis algorithms developed during active multi-disciplinary collaborative research studies to address real clinical requirements. The target audience of CaPTk consists of both computational scientists and clinical experts. For the former it provides i) an efficient image viewer offering the ability of integrating new algorithms, and ii) a library of readily-available clinically-relevant algorithms, allowing batch-processing of multiple subjects. For the latter it facilitates the use of complex algorithms for clinically-relevant studies through a user-friendly interface, eliminating the prerequisite of a substantial computational background. CaPTk's long-term goal is to provide widely-used technology to make use of advanced quantitative imaging analytics in cancer prediction, diagnosis and prognosis, leading toward a better understanding of the biological mechanisms of cancer development.

Inhibitors of BRAF, a gene coding a protein called B-raf, with or without inhibitors of MEK (MAPK/extracellular signal-regulated kinase) are often used as palliative treatment in BRAF-mutated metastatic melanoma. Recent data show improved progression-free survival with encorafenib with binimetinib, a newer BRAF/MEK inhibitor combination, compared with older agents, but there have been no reports of this treatment in the setting of renal and liver failure. We report a patient with disease-induced transaminitis and renal failure requiring dialysis who was successfully treated with encorafenib and binimetinib. His transaminitis improved and he was able to stop dialysis without any significant adverse effects during treatment, suggesting encorafenib with binimetinib may be used safely and effectively even in patients with end organ damage., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)