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Objective: Improving prognostication to direct personalised therapy remains an unmet need. This study prospectively investigated promising CT, genetic, and immunohistochemical markers to improve the prediction of colorectal cancer recurrence. Material and methods: This multicentre trial (ISRCTN 95037515) recruited patients with primary colorectal cancer undergoing CT staging from 13 hospitals. Follow-up identified cancer recurrence and death. A baseline model for cancer recurrence at 3 years was developed from pre-specified clinicopathological variables (age, sex, tumour-node stage, tumour size, location, extramural venous invasion, and treatment). Then, CT perfusion (blood flow, blood volume, transit time and permeability), genetic (RAS, RAF, and DNA mismatch repair), and immunohistochemical markers of angiogenesis and hypoxia (CD105, vascular endothelial growth factor, glucose transporter protein, and hypoxia-inducible factor) were added to assess whether prediction improved over tumour-node staging alone as the main outcome measure. Results: Three hundred twenty-six of 448 participants formed the final cohort (226 male; mean 66 ± 10 years. 227 (70%) had ≥ T3 stage cancers; 151 (46%) were node-positive; 81 (25%) developed subsequent recurrence. The sensitivity and specificity of staging alone for recurrence were 0.56 [95% CI: 0.44, 0.67] and 0.58 [0.51, 0.64], respectively. The baseline clinicopathologic model improved specificity (0.74 [0.68, 0.79], with equivalent sensitivity of 0.57 [0.45, 0.68] for high vs medium/low-risk participants. The addition of prespecified CT perfusion, genetic, and immunohistochemical markers did not improve prediction over and above the clinicopathologic model (sensitivity, 0.58–0.68; specificity, 0.75–0.76). Conclusion: A multivariable clinicopathological model outperformed staging in identifying patients at high risk of recurrence. Promising CT, genetic, and immunohistochemical markers investigated did not further improve prognostication in rigorous prospective evaluation. Clinical relevance statement: A prognostic model based on clinicopathological variables including age, sex, tumour-node stage, size, location, and extramural venous invasion better identifies colorectal cancer patients at high risk of recurrence for neoadjuvant/adjuvant therapy than stage alone. Key Points: Identification of colorectal cancer patients at high risk of recurrence is an unmet need for treatment personalisation. This model for recurrence, incorporating many patient variables, had higher specificity than staging alone. Continued optimisation of risk stratification schema will help individualise treatment plans and follow-up schedules. [ABSTRACT FROM AUTHOR]

Purpose: To assess multicenter two-year patency outcomes of endovascular arteriovenous fistulas (endoAVF) created with the WavelinQ device. Materials and Methods: Patients who had fistulas created at three centers from January 2018 to December 2020 were included in this retrospective study. In total, 112 patients underwent endoAVF creation [40 females, 72 males; mean age 60 years (range 18–88)]. Data collected included patient demographics, location of fistula creation, interventions performed, and brachial artery flows pre- and post-creation. Two-year cumulative patency, functional patency, and primary patency were assessed with Kaplan–Meier methodology. Factors affecting patency and maturation were examined using the Cox proportional hazards model. Results: Technical success defined as angiographically successful endoAVF creation was 97.3% (109/112). In 11 patients the fistula did not mature for dialysis use. For 98 patients (87%) with endoAVF maturation, 12- and 24-month cumulative patency was 94.3% and 91.7%. Functional patency (two-needle cannulation) at 12 and 24 months was 95.7% and 92.7%, respectively. Median maturation time is 95 days (IQR 51–231 days). Male gender and brachial vein coiling at the time of endoAVF creation were predictive of maturation. There were 34 censored events (four patients undergoing renal transplantation; 30 patients deceased). Number of reinterventions per patient year was 0.73 where 43 were maturation procedures and 101 were maintenance procedures. One Grade 3 complication occurred of arterial access puncture site pseudoaneurysm. Conclusion: A high two-year functional and cumulative patency following endoAVF creation with the WavelinQ device was observed in this multicenter real-world experience Level of Evidence: 3 Level of Evidence III [ABSTRACT FROM AUTHOR]

We numerically compute the lowest Laplacian eigenvalues of several two-dimensional shapes with dihedral symmetry at arbitrary precision arithmetic. Our approach is based on the method of particular solutions with domain decomposition. We are particularly interested in asymptotic expansions of the eigenvalues λ (n) of shapes with n edges that are of the form λ (n) ∼ x ∑ k = 0 ∞ C k (x) n k where x is the limiting eigenvalue for n → ∞ . Expansions of this form have previously only been known for regular polygons with Dirichlet boundary conditions and (quite surprisingly) involve Riemann zeta values and single-valued multiple zeta values, which makes them interesting to study. We provide numerical evidence for closed-form expressions of higher order C k (x) and give more examples of shapes for which such expansions are possible (including regular polygons with Neumann boundary condition, regular star polygons, and star shapes with sinusoidal boundary). [ABSTRACT FROM AUTHOR]

Rapid expansion of the pulmonary microvasculature through angiogenesis drives alveolarization, the final stage of lung development that occurs postnatally and dramatically increases lung gas-exchange surface area. Disruption of pulmonary angiogenesis induces long-term structural and physiologic lung abnormalities, including bronchopulmonary dysplasia, a disease characterized by compromised alveolarization. Although endothelial cells are primary determinants of pulmonary angiogenesis, mesenchymal cells (MC) play a critical and dual role in angiogenesis and alveolarization. Therefore, we performed single cell transcriptomics and in-situ imaging of the developing lung to profile mesenchymal cells during alveolarization and in the context of lung injury. Specific mesenchymal cell subtypes were present at birth with increasing diversity during alveolarization even while expressing a distinct transcriptomic profile from more mature correlates. Hyperoxia arrested the transcriptomic progression of the MC, revealed differential cell subtype vulnerability with pericytes and myofibroblasts most affected, altered cell to cell communication, and led to the emergence of Acta1 expressing cells. These insights hold the promise of targeted treatment for neonatal lung disease, which remains a major cause of infant morbidity and mortality across the world. [ABSTRACT FROM AUTHOR]

The continued emergence of vaccine-resistant SARS-CoV-2 variants of concern (VOC) requires specific identification of each VOC as it arises. Here, we report an expanded version of our previously described sloppy molecular beacon (SMB) melting temperature (Tm) signature-based assay for VOCs, now modified to include detection of Delta (B.1.617.2) and Omicron (B.1.1.529) sub-variants. The SMB-VOC assay targets the signature codons 501, 484 and 452 in the SARS-CoV-2 spike protein which we show can specifically detect and differentiate all known VOCs including the Omicron subvariants (BA.1, BA.2, BA.2.12.1, BA.4/BA.5). The limit of detection (LOD) of the assay was 20, 22 and 36 genomic equivalents (GE) per reaction with the Delta, Omicron BA.1 and BA.2 respectively. Clinical validation of the 3-codon assay in the LC480 instrument showed the assay detected 94% (81/86) of the specimens as WT or VOCs and 6% (5/86) of the tests producing indeterminate results compared to sequencing. Sanger sequencing also failed for four samples. None of the specimens were incorrectly identified as WT or as a different VOC by our assay. Thus, excluding specimens with indeterminant results, the assay was 100% sensitive and 100% specific compared to Sanger sequencing for variant identification. This new assay concept can be easily expanded to add newer variants and can serve as a robust diagnostic tool for selecting appropriate monoclonal antibody therapy and rapid VOC surveillance. [ABSTRACT FROM AUTHOR]

Background: This multicentre, open-label, Phase Ib/II trial evaluated the insulin-like growth factor (IGF) 1/2 neutralising antibody xentuzumab plus enzalutamide in metastatic castrate-resistant prostate cancer (mCRPC). Methods: The trial included Phase Ib escalation and expansion parts and a randomised Phase II part versus enzalutamide alone. Primary endpoints in the Phase Ib escalation, Phase Ib expansion and Phase II parts were maximum tolerated dose (MTD), prostate-specific antigen response and investigator-assessed progression-free survival (PFS), respectively. Patients in the Phase Ib escalation and Phase II parts had progressed on/after docetaxel/abiraterone. Results: In the Phase Ib escalation (n = 10), no dose-limiting toxicities were reported, and xentuzumab 1000 mg weekly plus enzalutamide 160 mg daily (Xe1000 + En160) was defined as the MTD and recommended Phase 2 dose. In the Phase Ib expansion (n = 24), median PFS was 8.2 months, and one patient had a confirmed, long-term response. In Phase II (n = 86), median PFS for the Xe1000 + En160 and En160 arms was 7.4 and 6.2 months, respectively. Subgroup analysis suggested trends towards benefit with Xe1000 + En160 in patients whose tumours had high levels of IGF1 mRNA or PTEN protein. Overall, the combination was well tolerated. Conclusions: Xentuzumab plus enzalutamide was tolerable but lacked antitumour activity in unselected patients with mCRPC. Clinical trial registration: EudraCT number 2013-004011-41. [ABSTRACT FROM AUTHOR]

Background: Health systems are screening patients for health-related social needs (HRSN) but the optimal approach is unknown. Objective: To describe the variation in responding to an HRSN questionnaire delivered via patient portal, and whether referral to and resources provided by social workers differed by response status. Design: Retrospective observational study. Participants: Primary care patients with a visit between June 2020 and January 2022. Intervention: HRSN questionnaire Main Measures: We identified each patient's index visit (e.g., date of their first questionnaire response for responders or their first visit within the study period for non-responders). Through the EHR, we identified patients' demographic characteristics. We linked the area deprivation index (ADI) to each patient and grouped patients into quintiles. We used multilevel logistic regressions to identify characteristics associated with responding to the questionnaire and, for responders, reporting a need. We also determined if responder status was associated with receiving a social worker referral or receiving a resource. We included patient demographics and ADI quintile as fixed variables and practice site as a random variable. Key Results: Our study included 386,997 patients, of which 51% completed at least one HRSN questionnaire question. Patients with Medicaid insurance (AOR: 0.62, 95%CI: 0.61, 0.64) and those who lived in higher ADI neighborhoods had lower adjusted odds of responding (AOR: 0.76, 95% CI: 0.75, 0.78 comparing quintile 5 to quintile 1). Of responders, having Medicaid insurance (versus private) increased the adjusted odds of reporting each of the HRSN needs by two- to eightfold (p < 0.01). Patients who completed a questionnaire (versus non-responders) had similar adjusted odds of receiving a referral (AOR: 0.91, 95% CI: 0.80, 1.02) and receiving a resource from a SW (AOR: AOR: 1.18, 95%CI: 0.79, 1.77). Conclusion: HRSN questionnaire responses may not accurately represent the needs of patients, especially when delivered solely via patient portal. [ABSTRACT FROM AUTHOR]

Background: This was a first-in-human Phase 1/2 open-label dose-escalation study of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737. Methods: Patients with advanced solid tumours enrolled in dose-escalation cohorts and received SRA737 monotherapy orally on a continuous daily (QD) dosing schedule in 28-day cycles. Expansion cohorts included up to 20 patients with prospectively selected, pre-specified response predictive biomarkers. Results: In total, 107 patients were treated at dose levels from 20–1300 mg. The maximum tolerated dose (MTD) of SRA737 was 1000 mg QD, the recommended Phase 2 dose (RP2D) was 800 mg QD. Common toxicities of diarrhoea, nausea and vomiting were generally mild to moderate. Dose-limiting toxicity at daily doses of 1000 and 1300 mg QD SRA737 included gastrointestinal events, neutropenia and thrombocytopenia. Pharmacokinetic analysis at the 800 mg QD dose showed a mean Cmin of 312 ng/mL (546 nM), exceeding levels required to cause growth delay in xenograft models. No partial or complete responses were seen. Conclusions: SRA737 was well tolerated at doses that achieved preclinically relevant drug concentrations but single agent activity did not warrant further development as monotherapy. Given its mechanism of action resulting in abrogating DNA damage repair, further clinical development of SRA737 should be as combination therapy. Clinical trial registration: Clinicaltrials.gov NCT02797964. [ABSTRACT FROM AUTHOR]

Peri-hilar cholangiocarcinoma (pCCA) is chemorefractory and limited genomic analyses have been undertaken in Western idiopathic disease. We undertook comprehensive genomic analyses of a U.K. idiopathic pCCA cohort to characterize its mutational profile and identify new targets. Whole exome and targeted DNA sequencing was performed on forty-two resected pCCA tumors and normal bile ducts, with Gene Set Enrichment Analysis (GSEA) using one-tailed testing to generate false discovery rates (FDR). 60% of patients harbored one cancer-associated mutation, with two mutations in 20%. High frequency somatic mutations in genes not typically associated with cholangiocarcinoma included mTOR, ABL1 and NOTCH1. We identified non-synonymous mutation (p.Glu38del) in MAP3K9 in ten tumors, associated with increased peri-vascular invasion (Fisher's exact, p < 0.018). Mutation-enriched pathways were primarily immunological, including innate Dectin-2 (FDR 0.001) and adaptive T-cell receptor pathways including PD-1 (FDR 0.007), CD4 phosphorylation (FDR 0.009) and ZAP70 translocation (FDR 0.009), with overlapping HLA genes. We observed cancer-associated mutations in over half of our patients. Many of these mutations are not typically associated with cholangiocarcinoma yet may increase eligibility for contemporary targeted trials. We also identified a targetable MAP3K9 mutation, in addition to oncogenic and immunological pathways hitherto not described in any cholangiocarcinoma subtype. [ABSTRACT FROM AUTHOR]

The adaptor proteins NCK1 and NCK2 are well-established signalling nodes that regulate diverse biological processes including cell proliferation and actin dynamics in many tissue types. Here we have investigated the distribution and function of Nck1 and Nck2 in the developing mouse mammary gland. Using publicly available single-cell RNA sequencing data, we uncovered distinct expression profiles between the two paralogs. Nck1 showed widespread expression in luminal, basal, stromal and endothelial cells, while Nck2 was restricted to luminal and basal cells, with prominent enrichment in hormone-sensing luminal subtypes. Next, using mice with global knockout of Nck1 or Nck2, we assessed mammary gland development during and after puberty (5, 8 and 12 weeks of age). Mice lacking Nck1 or Nck2 displayed significant defects in ductal outgrowth and branching at 5 weeks compared to controls, and the defects persisted in Nck2 knockout mice at 8 weeks before normalizing at 12 weeks. These defects were accompanied by an increase in epithelial cell proliferation at 5 weeks and a decrease at 8 weeks in both Nck1 and Nck2 knockout mice. We also profiled expression of several key genes associated with mammary gland development at these timepoints and detected temporal changes in transcript levels of hormone receptors as well as effectors of cell proliferation and migration in Nck1 and Nck2 knockout mice, in line with the distinct phenotypes observed at 5 and 8 weeks. Together these studies reveal a requirement for NCK proteins in mammary gland morphogenesis, and suggest that deregulation of Nck expression could drive breast cancer progression and metastasis. [ABSTRACT FROM AUTHOR]

Background: There is still debate regarding the principal role and ideal timing of perioperative chemotherapy (CTx) for patients with upfront resectable colorectal liver metastases (CRLM). This study assesses long-term oncological outcomes in patients receiving neoadjuvant CTx only versus those receiving neoadjuvant combined with adjuvant therapy (perioperative CTx). Methods: International multicentre retrospective analysis of patients with CRLM undergoing liver resection between 2010 and 2015. Characteristics and outcomes were compared before and after propensity score matching (PSM). Primary endpoints were long-term oncological outcomes, such as recurrence-free survival (RFS) and overall survival (OS). Furthermore, stratification by the tumour burden score (TBS) was applied. Results: Of 967 patients undergoing hepatectomy, 252 were analysed, with a median follow-up of 45 months. The unmatched comparison revealed a bias towards patients with neoadjuvant CTx presenting with more high-risk patients (p = 0.045) and experiencing increased postoperative complications ≥Clavien-Dindo III (20.9% vs. 8%, p = 0.003). Multivariable analysis showed that perioperative CTx was associated with significantly improved RFS (hazard ratio [HR] 0.579, 95% confidence interval [CI] 0.420–0.800, p = 0.001) and OS (HR 0.579, 95% CI 0.403–0.834, p = 0.003). After PSM (n = 180 patients), the two groups were comparable regarding baseline characteristics. The perioperative CTx group presented with a significantly prolonged RFS (HR 0.53, 95% CI 0.37–0.76, p = 0.007) and OS (HR 0.58, 95% CI 0.38–0.87, p = 0.010) in both low and high TBS patients. Conclusions: When patients after resection of CRLM are able to tolerate additional postoperative CTx, a perioperative strategy demonstrates increased RFS and OS in comparison with neoadjuvant CTx only in both low and high-risk situations. [ABSTRACT FROM AUTHOR]

Spatial biases commonly occur in biodiversity conservation efforts, and bobcats in Mexico exemplify this issue. Bobcats are one of the most well-studied felids worldwide. However, in Mexico bobcat studies are limited despite a wide distributional range. The objective of our study was to review the scientific literature published on bobcats in Mexico from 1988 to 2019 and to identify potential sampling biases. For each study, we identified the year, location, taxonomic focus, topic studied, and georeferenced each research location that included data collection in Mexico. We compared the spatial distribution of bobcat studies to random locations with a generalized linear model with binomial error structure using three variables and their interactions (degree of biome transformation, distance to protected lands, and distance to capital cities). We reviewed 210 publications (including research articles and undergraduate and postgraduate theses). Only in 37 publications were bobcats the single species studied. Bobcat studies have increased in Mexico since 2004 with most (78.57%) published within the 2004–2019 period. The main topic studied was diet, followed by species interactions. All but three states within the bobcat distribution in Mexico have at least one research study. We found that study locations are biased towards the less transformed biomes and protected lands. Bobcats can persist in urbanized landscapes although a threshold of disturbance for the species in Mexico remains unknown. Thus, we suggest bobcat research efforts to be strategically directed to fill knowledge gaps and with greater emphasis on highly transformed landscapes where the species may be at risk. [ABSTRACT FROM AUTHOR]

Inductively coupled plasma mass spectrometry (ICP-MS) has proven to be an excellent analytical technique with high sensitivity for detecting low levels of long-lived radionuclides, such as thorium. However, the high-sensitivity technique increases the memory effect of thorium. This study developed a rapid, high-throughput, simple method for measuring thorium in urine using quadrupole inductively coupled plasma mass spectrometry (Q-ICP-MS). Replacing the commonly used hazardous hydrofluoric acid with a rinse solution of 0.025 mol/L oxalic acid and 5% (v/v) nitric acid eliminated the memory effect of thorium. 233U was used as internal standard in this study. The limit of detection (LOD) for thorium in this study is 0.77 ng/L, which is comparable to those of reported methods using more sophisticated and expensive sector field inductively coupled plasma mass spectrometry (SF-ICP-MS). This proposed method can determine thorium concentrations in urine in both occupationally exposed workers and populations that live in areas with high background levels of thorium. [ABSTRACT FROM AUTHOR]

Cell-free RNA from liquid biopsies can be analyzed to determine disease tissue of origin. We extend this concept to identify cell types of origin using the Tabula Sapiens transcriptomic cell atlas as well as individual tissue transcriptomic cell atlases in combination with the Human Protein Atlas RNA consensus dataset. We define cell type signature scores, which allow the inference of cell types that contribute to cell-free RNA for a variety of diseases. Cell types affected by various diseases are inferred from cell-free RNA. [ABSTRACT FROM AUTHOR]

Opinion statement: The standard of care for locally advanced rectal cancer (LARC) has included preoperative chemoradiation, total mesorectal excision surgery and post operative adjuvant chemotherapy based on histopathology. The current therapeutic landscape in LARC has many different options with different directions of travel — depending on the goal of treatment. Enthusiasm for delivering total neoadjuvant therapy (TNT) for patients with locally advanced rectal cancer (LARC) is increasing in the light of recently published randomised phase III trials — RAPIDO and PRODIGE-23. There is a wide diversity of different potential schedules and a multitude of approaches, which include induction neoadjuvant chemotherapy (NACT) with a range of chemotherapy options (CAPEOX, FOLFOX, FOLFOXIRI) and a varying duration of 6–18 weeks, or consolidation NACT. These schedules either precede or follow short-course preoperative radiation therapy (SCPRT) using 5 × 5Gy or long-course chemoradiation (LCCRT) using 45–60Gy respectively. The different strategies of induction and consolidation neoadjuvant chemotherapy have been compared and have similar long-term outcomes, but consolidation chemotherapy may facilitate organ-sparing. The results are driving novel paradigms with both intensification and de-intensification treatment strategies. The ideal combination, sequence or duration of such a TNT approach remains undefined. As yet, there are no robust clinical, genetic, molecular, immune or imaging features (alone or integrated), which either direct or aid these choices. Currently, the selection of neoadjuvant treatment is driven by the impact on avoidance or feasibility of surgery or reducing the risk of metastases rather than prevention of local recurrence. Most believe that TNT will improve overall survival, despite the present lack of evidence. Both the inherent heterogeneity in LARC and the observed range of different responses underline the need for response biomarkers to individually tailor therapy rather than 'a one size fits all' approach. [ABSTRACT FROM AUTHOR]

A Variant Surface Glycoprotein (VSG) coat protects bloodstream form Trypanosoma brucei. Prodigious amounts of VSG mRNA (~7-10% total) are generated from a single RNA polymerase I (Pol I) transcribed VSG expression site (ES), necessitating extremely high levels of localised splicing. We show that splicing is required for processive ES transcription, and describe novel ES-associated T. brucei nuclear bodies. In bloodstream form trypanosomes, the expression site body (ESB), spliced leader array body (SLAB), NUFIP body and Cajal bodies all frequently associate with the active ES. This assembly of nuclear bodies appears to facilitate the extraordinarily high levels of transcription and splicing at the active ES. In procyclic form trypanosomes, the NUFIP body and SLAB do not appear to interact with the Pol I transcribed procyclin locus. The congregation of a restricted number of nuclear bodies at a single active ES, provides an attractive mechanism for how monoallelic ES transcription is mediated. A Variant Surface Glycoprotein (VSG) coat protects bloodstream form T. brucei. Applying super-resolution microscopy Budzak et al. characterize a set of nuclear bodies, which associate with the active expression site in bloodstream form T. brucei and highlight the importance of trans-splicing for transcription of VSG. [ABSTRACT FROM AUTHOR]

Online learning has given access to education for diverse populations including students with disabilities. In our university, the ratio of students with disabilities is substantially higher in the online programmes than face-to-face. Online learning provides high accessibility though it can result in a lonely experience. Accordingly, this study aimed to appraise the first-hand experience and understanding of loneliness in online students with disabilities (OSWD), and to discuss possible solutions. Thematic analysis on semi-structured interviews attended by nine OSWD identified: 'Self-paced study can reduce stigma but cause loneliness (Theme 1)', 'Loneliness and social difficulties relate to misunderstanding of disability (Theme 2)', and 'Activities, events and staff for informal socialisation are needed (Theme 3)'. As the demand for online learning is further expanded due to the current global pandemic, our findings will be helpful for online learning institutions worldwide to establish effective strategies to reduce loneliness in OSWD. [ABSTRACT FROM AUTHOR]

Objectives: Point-of-care ultrasound (POCUS) has become increasingly integrated into medical education given the growing role of evaluative and procedural techniques in practice today. Tele-ultrasound is a new and promising venture that aims to expand medical knowledge and education to previously unreached or underserved areas. This study aimed to determine the non-inferiority of teaching ultrasound remotely using tele-ultrasound via the Philips Lumify (Philips Medical Systems, Bothell, WA) system, which utilizes video conferencing technology and real-time imaging that can be viewed by the operator and educator simultaneously. Methods: Three commonly used ultrasound exams were taught and evaluated in 56 ultrasound-naive medical participants: Focused Assessment with Sonography in Trauma (FAST), Lower Extremity Deep Venous Thrombosis (LEDVT) screening, and ultrasound-guided vascular access. The participants were randomized into either in-person traditional learning or tele-ultrasound learning with the Philips Lumify (Philips Medical Systems, Bothell, WA) units. The primary outcome of interest was the ability to perform certain tasks for each exam Results: Competency on each exam was tested across all exams and no inferiority was found between in-person and remote learning (p < 0.05). Conclusions: Our findings support the use of tele-ultrasound in beginner ultrasound education. [ABSTRACT FROM AUTHOR]

Purpose: Stenoses in mature arteriovenous fistulas (AVFs) are common and can negatively impact on the quality of haemodialysis, the longevity of the AVF and lead to debilitating symptoms. Multiple treatment options exist; however, management can vary between different centres. We aimed to establish multidisciplinary consensus on the optimal stepwise application of interventions based on evidence and consensus.Methods: A modified Delphi process was conducted with 13 participants from hospitals across the UK, all of whom have high-volume dialysis access practice.Results: The usual intervention to rectify de novo stenoses of mature AVFs is fistuloplasty, although surgery for inflow segment stenoses is also clinically acceptable. Appropriate first-line interventions include plain old balloon angioplasty or high-pressure balloon angioplasty; if these fail during the fistuloplasty, consider upsizing the balloon, prolonged balloon inflation or using alternative interventions, such as cutting or scoring balloons and ultra-high-pressure balloons. Alternative or subsequent interventions vary by anatomical site and may require additional multidisciplinary team input. For a stenoses recurring between 3 and 12 months, it is appropriate to consider interventions used de novo, but with a lower threshold for using drug-coated balloons (DCBs) in all regions and for using stent grafts in all regions but inflow segment. Recurrence after 12 months should be treated as a de novo lesion, with DCBs considered if they have been used successfully during previous interventions.Conclusions: These recommendations aim to provide a practical guide to multidisciplinary teams in order to optimise the use of multiple interventions for rectifying AVF stenoses and provide unified evidence-based practice guidelines. [ABSTRACT FROM AUTHOR]

As part of the Centers for Disease Control and Prevention's post-radiological/nuclear incident response mission, we developed rapid bioassay analytical methods to assess possible human exposure to radionuclides and internal contamination. Liquid scintillation counting (LSC) is a valuable analytical tool for the rapid detection and quantification of gross alpha/beta-emitting radionuclides in urine samples. A key characteristic of this type of bioassay method is its detection sensitivity for the priority threat radionuclides. We evaluated the limit of detection of selected LSC instruments to determine which instrument can be used when low-dose measurement is important. [ABSTRACT FROM AUTHOR]

This study looks at archival records and photographs from the pre-WWII Japanese occupation of the Micronesian island of Tinian to discuss the archaeological remnants of the Okinawan diaspora from the 1920s to 1940s in the Commonwealth of the Northern Mariana Islands (CNMI) today. [ABSTRACT FROM AUTHOR]

Responding to a radiological or nuclear incident may require assessing tens to hundreds of thousands of people for possible radionuclide contamination. The measurement of radioactive Sr is important because of its impact on people's health. The existing analytical method for urine Sr-90 analysis using crown ethers is laborious and involves possible exposure to concentrated acids; therefore, this work is devoted to the development of the automated Sr-90 separation process, which became possible with the prepFast pre-analytical system (Elemental Scientific, Inc). [ABSTRACT FROM AUTHOR]

Radioactive strontium is a nuclear fission decay product found in industrial products and nuclear waste and is released during nuclear accidents. Current urine radiostrontium separation methods often are based on the use of Sr resin columns or cartridges (Eichrom Technologies). Most of these analytical methods use stable Sr as a tracer, with subsequent Sr recovery. The gravimetric recovery method requires 120 times more stable Sr than does the inductively coupled plasma mass spectrometry method described here. This difference can affect cartridge performance especially with aging cartridges. [ABSTRACT FROM AUTHOR]

Here we report a new procedure to determine 239Pu in urine using a custom-made automated pre-analytical processing system (single probe) with 242Pu as a tracer followed by analysis by SF-ICP-MS. An average 242Pu recovery rate of 88% was obtained with CF-ThU-1000 columns reused > 100 times. Analytical results agree with measurements obtained using the CDC manual method with a R2 of 0.9994. Results for Oak Ridge National Laboratory reference materials align with target values with a bias range of − 3.44 to 3.05%. The limit of detection for this method is 0.63 pg/L, which is comparable to previous manual methods. [ABSTRACT FROM AUTHOR]

There is a global unmet need for rapid and cost-effective prognostic and diagnostic tools that can be used at the bedside or in the doctor's office to reduce the impact of serious disease. Many cancers are diagnosed late, leading to costly treatment and reduced life expectancy. With prostate cancer, the absence of a reliable test has inhibited the adoption of screening programs. We report a microelectronic point-of-care metabolite biomarker measurement platform and use it for prostate cancer detection. The platform, using an array of photodetectors configured to operate with targeted, multiplexed, colorimetric assays confined in monolithically integrated passive microfluidic channels, completes a combined assay of 4 metabolites in a drop of human plasma in under 2 min. A preliminary clinical study using l-amino acids, glutamate, choline, and sarcosine was used to train a cross-validated random forest algorithm. The system demonstrated sensitivity to prostate cancer of 94% with a specificity of 70% and an area under the curve of 0.78. The technology can implement many similar assay panels and hence has the potential to revolutionize low-cost, rapid, point-of-care testing. [ABSTRACT FROM AUTHOR]

Background: Resection margin status is a known prognosticator in patients who undergo resection for hilar cholangiocarcinoma. However, the influence of an isolated positive circumferential margin on clinical outcome is unclear. Methods: Patients with resected de novo hilar cholangiocarcinoma from two European hepatobiliary centres (Medical University of Vienna and Aintree University Hospital, 2006–2016) were classified according to resection margin status (negative, surgically positive, isolated circumferentially positive) and investigated with respect to overall survival (OS), recurrence-free survival (RFS) and recurrence pattern. Results: Eighty-three (48 male/35 female) patients were enrolled. The median age was 64 years (range 33–80). The median follow-up was 21.7 months (range 0.3–92.4). Forty (48%) patients had negative resection margins, 25 (30%) had an isolated positive circumferential margin and 18 (22%) had a positive surgical margin. The 5-year OS rates in patients with negative, isolated positive circumferential and positive surgical resection margins were 47%, 33% and 0%, respectively. Median OS was 45.6, 32.7 and 14.5 months, respectively (log rank, P = 0.011). Upon multivariable Cox regression analysis, resection margin status and lymph node status remained statistically significant (P < 0.05). No difference with respect to RFS and recurrence pattern was found between the groups (P > 0.05). Conclusion: Our data show that these three resection margin types were associated with different clinical outcomes. Circumferential margin status may therefore serve as a novel prognostic biomarker. [ABSTRACT FROM AUTHOR]

Mathematical models that can predict the kinetics of compounds have been increasingly adopted for drug development and risk assessment. Data for these models may be generated from in vitro experimental systems containing enzymes contributing to metabolic clearance, such as subcellular tissue fractions including microsomes and cytosol. Extrapolation from these systems is facilitated by common scaling factors, known as microsomal protein per gram (MPPG) and cytosolic protein per gram (CPPG). Historically, parameterization of MPPG and CPPG has employed the use of recovery factors, commonly benchmarked to cytochromes P450 which work well in some contexts, but could be problematic for other enzymes. Here, we propose absolute quantification of protein content and supplementary assays to evaluate microsomal/cytosolic purity that should be employed. Examples include calculation of microsomal latency by mannose-6-phosphatase activity and immunoblotting of subcellular fractions with fraction-specific markers. Further considerations include tissue source, as disease states can affect enzyme expression and activity, and the methodology used for scalar parameterization. Regional- and organ-specific expression of enzymes, in addition to differences in organ physiology, is another important consideration. Because most efforts have focused on the liver that is, for the most part, homogeneous, derived scalars may not capture the heterogeneity of other major tissues contributing to xenobiotic metabolism including the kidneys and small intestine. Better understanding of these scalars, and how to appropriately derive them from extrahepatic tissues can provide support to the inferences made with physiologically based pharmacokinetic modeling, increase its accuracy in characterizing in vivo drug pharmacokinetics, and improve confidence in go-no-go decisions for clinical trials. [ABSTRACT FROM AUTHOR]

Nuclear industry advancements and growing concerns about environmental contamination and terrorist activity have increased interest in quantifying radioisotopes in environmental and human samples. Increased presence in the environment, ease of entry into the food chain, nuclear medicine applications, and the possibility of radiological terrorism incidents can lead to human intake of these radionuclides (Radionuclides/Radiation Protection/US EPA (2020). https://www.epa.gov/radiation/radionuclides; Radiation from the Earth (Terrestrial Radiation) (2015) Radiation and Your Health, Centers for Disease Control and Prevention. 7 December. https://www.cdc.gov/nceh/radiation/terrestrial.html). A universal method to screen for and quantify individual radionuclides as well as both levels of alpha and beta emitters would address these concerns. [ABSTRACT FROM AUTHOR]

In the case of a radiological or nuclear incident, valuable information could be obtained in a timely manner by using liquid scintillation counting (LSC) technique through fast screening of urine samples from potentially contaminated persons. This work describes the optimization of LSC parameters on PerkinElmer (PE) Tri-Carb and Quantulus GCT series instruments to develop a rapid method for screening urine in an emergency response situation. [ABSTRACT FROM AUTHOR]

Understanding how microclimate and vegetation are associated during secondary succession is of primary importance for plant conservation in the face of the increasing land cover modification. However, these patterns are still unstudied for many plant communities. This study aimed to evaluate the structure (species richness, Shannon's diversity index, Simpson´s dominance index, abundance of each species, average height of species, species cover (%), species composition, and indicator values) of a low thorn forest fragment and to analyze its relation with microclimate along a successional gradient. Four stages of succession were delimited by the analysis of Landsat images, in the state of Tamaulipas, northeast Mexico. Statistical models incorporated species richness, diversity indices, abundance, height, and cover, as variables for searching differences between stages, or to evaluate microclimate associations. A total of 70 species, 54 genera, and 27 families were determined. Height of tree layer was the most important variable for discrimination of the successional stages. Conserved areas differed floristically from other stages, associated mainly with the lowest values of wind speed originated by tree layer characteristics. A significant association between species and microclimate was found, being wind speed and relative humidity the most important variables. Some species, due to their high importance values and their patterns of association with microclimate, may be considered as key taxa for low thorn forest, which is a threatened semitropical community in northeast Mexico. Conserved and late successional areas account for climatic regulation of this plant community, and the importance of these forest patches may be considered when establishing biodiversity protection areas. [ABSTRACT FROM AUTHOR]

Following a radiological or nuclear incident, the National Response Plan has given the Department of Health and Human Services/Centers for Disease Control and Prevention the responsibility for assessing population's contamination with radionuclides. In the public health response to the incident, valuable information could be obtained in a timely and accurate manner by using liquid scintillation counting techniques to determine who has been contaminated above background for alpha and beta emitting radionuclides. The calibration plays a major role in this process therefore, knowing the effect of quench agents on calibration is essential. [ABSTRACT FROM AUTHOR]

Objectives: Mindfulness-based programs (MBPs) such as the 'Soles of the Feet' (SoF) meditation have been shown to be effective for reducing aggressive behavior in people with intellectual disabilities (ID). Research on SoF has shown promising results in the USA but there is an absence of evidence for the approach in the United Kingdom (UK). The aim of this research was to adapt SoF for the UK and to assess the feasibility and cost of implementing the SoF intervention in a UK healthcare setting (UK SoF). Methods: The UK SoF intervention consisted of a manualized protocol delivered over a six-week period by National Health Service staff to people with ID and their carers. This was a single-arm study with three measurement time points (baseline and 2- and 6-month follow-ups). Results: The UK SoF intervention was shown to be feasible, with recruitment, retention, and adherence figures exceeding the minimum cut-off of 50%. Costs were £2426 per participant, or £2766 when including set-up costs such as therapist training. Although not a primary aim, data suggest that at 6-month follow-up, there was a reduction in scores for anger and aggressive behavior, and depression and anxiety showed improvement. In addition, people with ID were able to self-report on their health-related quality of life. Conclusions: This study has indicated areas where the protocol could be further improved, and it is recommended that the research should move to a pilot trial before the development of a full randomized control trial. [ABSTRACT FROM AUTHOR]

Single-cell RNA sequencing (scRNA-seq) is the leading technique for characterizing the transcriptomes of individual cells in a sample. The latest protocols are scalable to thousands of cells and are being used to compile cell atlases of tissues, organs and organisms. However, the protocols differ substantially with respect to their RNA capture efficiency, bias, scale and costs, and their relative advantages for different applications are unclear. In the present study, we generated benchmark datasets to systematically evaluate protocols in terms of their power to comprehensively describe cell types and states. We performed a multicenter study comparing 13 commonly used scRNA-seq and single-nucleus RNA-seq protocols applied to a heterogeneous reference sample resource. Comparative analysis revealed marked differences in protocol performance. The protocols differed in library complexity and their ability to detect cell-type markers, impacting their predictive value and suitability for integration into reference cell atlases. These results provide guidance both for individual researchers and for consortium projects such as the Human Cell Atlas. A multicenter study compares 13 commonly used single-cell RNA-seq protocols. [ABSTRACT FROM AUTHOR]

Measuring 237Np and 239Pu in urine at low levels is important for both biomonitoring and radiological emergency response. Here we report a newly developed and validated analytical method used to determine 237Np and 239Pu in urine by selective retention of Np and Pu from 2 mL of urine directly onto TEVA® resin followed by SF-ICP-MS (coupled to a membrane desolvating introduction system) detection. The method provides solid phase extraction of Np/Pu with observed recovery ratios ranging from 89 to 113% and rapid results with limits of detection well below recommended detection guidelines for children and pregnant women (NCRP 161 reference). [ABSTRACT FROM AUTHOR]

Purpose: To retrospectively review our experience on 84 patients with squamous cell anal canal cancer (SCAC) within 12 months after combined treatment with intensity-modulated RT (IMRT), in terms of acute and early-late toxicity, overall treatment time and interruptions, colostomy-free survival (CFS), and tumor response. Methods: Acute gastrointestinal (GI), genitourinary (GU), and cutaneous (CU) toxicities were assessed according to Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03. Early-late toxicity was scored using the Radiation Therapy Oncology Group (RTOG) late radiation morbidity scoring system. Tumor response was evaluated with response evaluation criteria in solid tumors (RECIST) v1.1. Results: Acute toxicity for 84 subjects (100%): severe (≥ G3) GI and skin toxicity was observed in 4 (5%) and 19 patients (23%), respectively. Early-late toxicity for 73 subjects (87%): severe (≥ G3) GI and vulvo-vaginal toxicity was observed in 2 (3%) and 2 (3%) patients, respectively. No acute or early-late severe GU toxicity was reported. A treatment interruption occurred in 65 patients (77%). CFS was 96% (95% CI 89–99) at 6 months and 92% (95% CI 83–96) at 12 months. At 6 months complete response (CR), partial response (PR) and progressive disease (PD) was observed in 70 (83%), 3 (4%), and 7 patients (8%), respectively. At 12 months, CR was observed in 60 patients (81%); eleven patients (15%) experienced PD. Conclusion: Our study showed an excellent clinical result and very low acute toxicity rates, confirming the IMRT as standard of care for curative treatment of anal cancer patients. The current trial was registered with the number IEO N87/11 [ABSTRACT FROM AUTHOR]

Background: Barbed suture has been adopted across all surgical specialties. One of the infrequent complications seen with the use of barbed suture is small bowel obstructions (SBOs). In this study, we perform a review of the literature and the Manufacturer and User Facility Device Experience Database (MAUDE) to characterize SBOs after the use of barbed sutures in a variety of operative procedures.Methods: A review of the literature was performed by searching PubMed and Ovid. We used the search terms: "barbed," "suture," "bowel," and "obstructions." For each case report, we examined the initial surgical procedure, type of barbed suture used, the type of complication, the time to complication, the presentation, and the type of operative interventions required. We did the same with the MAUDE database.Results: Our review of the literature revealed 18 different cases of SBO secondary to the use of barbed suture. The four most common procedures, with a total of four cases each, were inguinal hernia procedures, myomectomy, hysterectomy, and pelvic floor reconstructive procedures. The average time of presentation to SBO was found to be 26.3 days post-op (1-196 days). A total of 16 patients (88.9%) presented with abdominal pain. Other common complaints included vomiting (33.3%), abdominal distension (27.8%), oral intolerance (22.2%), and constipation (16.7%). A total of 5 cases were also found to have a possible volvulus on computed tomography (CT), and 2 cases were reported to have strangulation. The MAUDE database had 14 cases reporting on obstruction.Conclusions: Surgeons should have a high index of suspicion for SBO if a patient presents with obstructive symptoms after a surgery that used barbed suture. This will often present as a mesenteric volvulus on CT. These particular SBOs require operative exploration, with laparoscopy being successful in the majority of cases. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cells mediate anti-tumour effects in a small subset of patients with cancer1–3, but dysfunction due to T cell exhaustion is an important barrier to progress4–6. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system with a tonically signaling CAR, which induces hallmark features of exhaustion6. Exhaustion was associated with a profound defect in the production of IL-2, along with increased chromatin accessibility of AP-1 transcription factor motifs and overexpression of the bZIP and IRF transcription factors that have been implicated in mediating dysfunction in exhausted T cells7–10. Here we show that CAR T cells engineered to overexpress the canonical AP-1 factor c-Jun have enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved anti-tumour potency in five different mouse tumour models in vivo. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells, and that engineering CAR T cells to overexpress c-Jun renders them resistant to exhaustion, thereby addressing a major barrier to progress for this emerging class of therapeutic agents. Chimeric antigen receptor (CAR) T cells engineered to overexpress the canonical AP-1 transcription factor c-Jun are resistant to T cell exhaustion, and provide enhanced therapeutic benefit in mouse tumour models. [ABSTRACT FROM AUTHOR]

Technology adoption literature generally focuses on behavioral and structural changes necessary for successful adoption. Little explored in that literature is the factors impacting the level of adoption which will be achieved within the organization. This healthcare industry research demonstrates that higher levels of technology adoption in organizations require the influences of both internal absorptive capabilities and external institutional pressures impacting the organization. We surveyed U.S. healthcare employees to assess top management beliefs, top management participation, absorptive capacity, institutional pressures, and level of electronic medical records (EMR) adoption in clinics and hospitals. Our results indicate no direct influence of mimetic and coercive pressures on the level of EMR adoption. Normative and mimetic pressures indirectly influence EMR adoption level through top management participation. Absorptive capacity enhances top management beliefs and participation associated with EMR adoption process, resulting in higher levels of EMR adoption in U.S. hospitals. [ABSTRACT FROM AUTHOR]

Background: Pediatric brain tumors are associated with high morbidity and mortality, in part due to insufficient understanding of tumor biology. With limited tissue allocation for research from surgical specimens, a key barrier to improving biological understanding, brain tumor autopsies have become an increasingly valuable resource. This study reviews the brain tumor autopsy practice at our institution and describes specific emerging research utilization patterns beyond the clinical autopsy report. Methods: We performed a retrospective analysis of brain tumor autopsies at Boston Children's Hospital (BCH) between 2007 and 2017 and reviewed their consents, neuropathology reports and final diagnoses. We reviewed the method of tissue triaging for research consented autopsies (bioregistry, frozen and fresh tissue) and documented their specific uses. Results: Ninety-six deaths at BCH were due to brain tumors; 56 autopsies were performed (58.3%), of which 49 (87.5%) were consented for research. Tumor mapping was performed on all cases and tissue was allocated for DNA- and RNA-based sequencing studies (published and ongoing). Three tissue allocations with a postmortem interval of 8 h or less resulted in successful cell lines. Tissue from 14 autopsies was contributed to the National DIPG Registry. Conclusion: Our institutional pediatric brain tumor autopsy clinical experience demonstrates the increased utility and wide utilization of autopsy-derived tissue for multiple types of research. These results support the increased efforts to obtain research consent for brain tumor autopsy and active collection of unfixed autopsy material in the molecular era. [ABSTRACT FROM AUTHOR]

Purpose: To provide an overview of treatment modalities for management of upper tract urothelial carcinoma (UTUC). Methods: In accordance with the standards for a scoping review, data presentation and discussion at the Consultation on UTUC in Stockholm, 6–7 September 2018, consensus was reached on the latest and most important treatment recommendations for UTUC. Using Pubmed, Web of Science, and Embase, publications were selected based on quality, clinical relevance, and level of evidence. Results: Kidney-sparing surgery should be attempted for low-grade UTUC. Radical nephroureterectomy with bladder cuff excision is first option for high-grade disease. Post-operative bladder instillation of chemotherapy should be offered after RNU to reduce intravesical recurrence rate. Identification of tumor grade and stage is crucial when selecting treatment. Ureteroscopic management of low-grade and non-invasive UTUC achieves disease-free survival similar to that offered by radical nephroureterectomy but seems to be a risk factor for intravesical recurrence. Lymphadenectomy appears important for high-risk disease, although the therapeutic benefit needs further validation. There is little evidence supporting use of Bacillus Calmette–Guérin (BCG) and mitomycin C as monotherapy and adjuvant treatment in UTUC. A randomized clinical trial has indicated that platin-based chemotherapy for invasive UTUC improves disease-free survival, suggesting that adjuvant chemotherapy should be considered standard care for ≥ T2 N0–3M0 disease. Conclusions: Risk stratification assessment is feasible and mandatory in UTUC. Identification of tumor grade and stage is essential for optimal treatment selection. Kidney-sparing surgery should be offered in low-risk disease, whereas radical nephroureterectomy and adjuvant chemotherapy should be considered in high-risk disease. [ABSTRACT FROM AUTHOR]

Purpose: To summarize current knowledge on upper urinary tract carcinoma (UTUC) regarding risk stratification, long-term results, and follow-up. Methods: A scoping review approach was applied to search literature in Pubmed, Web of Science, and Embase. Consensus was reached through discussions at Consultation on UTUC, September 2018, Stockholm. Results: To optimize oncological outcome considering both cancer-specific survival (CSS) and overall survival (OS), it is essential to identify pre- and postoperative prognostic factors. In low-risk UTUC, kidney-sparing surgery (KSS) and radical nephroureterectomy (RNU) offer equivalent CSS, whereas RNU may result in poorer OS due to nephron loss. For more aggressive tumours, undergrading can lead to insufficient treatment. The strongest prognostic factors are tumour stage and grade. Determining grade is best achieved by ureterorenoscopy (URS) with focal samples, biopsy and cytology. Staging is more difficult but can be indirectly achieved by multiphase computed tomography urography (CTU) or tumour grade determined by cytology and histopathology. Patients treated with KSS should be monitored closely with regular follow-ups (URS and CTU). Conclusion: KSS should be offered in low-risk UTUC when feasible, whereas RNU is the treatment of choice in organ-confined high-risk UTUC. Intravesical recurrence (IVR) is common after RNU, but a single postoperative dose of mitomycin instillation decreases IVR. Endourological management has high local and bladder recurrence rates; however, its effect on CSS or overall survival OS is unclear. RNU is associated with significant risk of chronic kidney disease. Careful selection of patients and risk stratification are mandatory, and patients should be followed according to strict protocols. [ABSTRACT FROM AUTHOR]

Objectives: Mindfulness-based programs have been delivered to people with intellectual disabilities (ID) and aggressive behaviour with some success. The current study is part of a wider feasibility study, which aimed to test the adaptation of the Soles of the Feet (SoF) meditation practice to a six-session, one-to-one intervention delivered within the UK National Health Service. It was designed for adults with ID to help reduce their aggressive behaviour. Methods: Eighteen stakeholders were interviewed from three groups: (1) people with ID who took part in the intervention, (2) their supporters, and (3) therapists who delivered the intervention. Thematic analysis was used to analyse the data. Results: The intervention had high acceptability among participants, although they reported mixed outcomes, these outcomes aligned closely with reports on effectiveness from supporters and therapists. Some people with ID and their supporters reported positive changes, such as reduced aggression, increased sociability, and higher quality of life. Some participants reported no change. Conclusions: Four participants and their supporters reported clear benefits from the SoF intervention. For the three that did not report benefits, this appeared to be related to whether the person with ID understood the intervention and/or were motivated to reduce their aggressive behaviour. There was also evidence of supporters needing more direct instruction on how to facilitate the SoF intervention with the person they care for. Suggestions for future research are made, and clinical implications explored. [ABSTRACT FROM AUTHOR]

Surgical fistulas were first described over 50 years ago and have revolutionized the outlook for millions of dialysis-dependent patients. Despite many developments, results remain sub-optimal with high rates of primary failure and re-intervention to maintain patency. Surgical fistulas are known to fail in part due to intimal hyperplasia leading to stenosis, and vessel manipulation during anastomosis creation can be contributory. New technology is emerging that allows the endovascular creation of fistulas with minimal vessel trauma and the initial results demonstrate encouraging outcomes with high technical success rates, low re-intervention, and failure rates and good usability for hemodialysis. Two such device systems are currently available, and here, we provide an overview of the current global status of endoAVF, patient selection criteria, trial results, technical aspects, re-interventions, and outlook for the future. [ABSTRACT FROM AUTHOR]

Introduction: This study was designed to quantify the important anatomical landmarks and the path of the inferior alveolar nerve (IAN) within the human mandibular body and ramus, in particular with reference to the bilateral sagittal split osteotomy (BSSO).Materials and methods: Four hundred and eleven CT scans were studied, 299 of these were involved in determining the position of lingula; and 230 were involved in determining the course of IAN in the mandibular molar region, namely from the mesial of the mandibular first molar to the distal of the mandibular second molar; 118 were involved with both measurements.Results: On average, the lingula was located 17.0 ± 2.2 mm from the external oblique ridge; 11.6 ± 2.0 mm from the internal oblique ridge; 17.2 ± 2.7 mm from the sigmoid notch; and 15.6 ± 1.9 mm from the posterior border of the mandible. The course of the IAN in the mandibular molar region was found to descend vertically from the distal of the mandibular second molar (7) to reach its lowest point between the first and second molars (6 and 7), and then ascend towards the mesial of the first molar (6). Horizontally, the IAN was found to traverse medially between the distal of the 7 and the middle of the 7, and then changes its path laterally towards the mesial of the 6.Conclusion: Precise knowledge of the individual’s position of the IAN will help surgical planning. [ABSTRACT FROM AUTHOR]

Surgical resection remains the only proven curative treatment for peri-hilar cholangiocarcinoma. Despite recent advances in liver surgery techniques and perioperative care, resection for peri-hilar cholangiocarcinoma remains associated with significant morbidity and mortality. Considerable variation in the perioperative management of these patients exists. Optimal perioperative management has the potential to deliver improved outcomes. This article seeks to summarize the evidence underpinning best practice in the perioperative care of patients undergoing resection of peri-hilar cholangiocarcinoma. The authors also seek to identify areas where research efforts and future clinical trials should be targeted. [ABSTRACT FROM AUTHOR]