Circulating tumor DNA in advanced solid tumors: Clinical relevance and future directions.

The application of genomic profiling assays using plasma circulating tumor DNA (ctDNA) is rapidly evolving in the management of patients with advanced solid tumors. Diverse plasma ctDNA technologies in both commercial and academic laboratories are in routine or emerging use. The increasing integration of such testing to inform treatment decision making by oncology clinicians has complexities and challenges but holds significant potential to substantially improve patient outcomes. In this review, the authors discuss the current role of plasma ctDNA assays in oncology care and provide an overview of ongoing research that may inform real-world clinical applications in the near future.

Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation.

BACKGROUND: Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity. METHODS: In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 to 400 mg) in patients who had advanced or metastatic solid tumors that harbor a KRAS G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed. RESULTS: A total of 137 patients (60 with non-small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received divarasib. No dose-limiting toxic effects or treatment-related deaths were reported. Treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 event in 1 patient (1%). Treatment-related adverse events resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). Among patients with NSCLC, a confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), and the median progression-free survival was 13.1 months (95% CI, 8.8 to could not be estimated). Among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.2). Responses were also observed in patients with other solid tumors. Serial assessment of circulating tumor DNA showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib. CONCLUSIONS: Treatment with divarasib resulted in durable clinical responses across KRAS G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.).

Author Correction: Tumour lineage shapes BRCA-mediated phenotypes.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Tumour lineage shapes BRCA-mediated phenotypes.

Mutations in BRCA1 and BRCA2 predispose individuals to certain cancers1-3, and disease-specific screening and preventative strategies have reduced cancer mortality in affected patients4,5. These classical tumour-suppressor genes have tumorigenic effects associated with somatic biallelic inactivation, although haploinsufficiency may also promote the formation and progression of tumours6,7. Moreover, BRCA1/2-mutant tumours are often deficient in the repair of double-stranded DNA breaks by homologous recombination8-13, and consequently exhibit increased therapeutic sensitivity to platinum-containing therapy and inhibitors of poly-(ADP-ribose)-polymerase (PARP)14,15. However, the phenotypic and therapeutic relevance of mutations in BRCA1 or BRCA2 remains poorly defined in most cancer types. Here we show that in the 2.7% and 1.8% of patients with advanced-stage cancer and germline pathogenic or somatic loss-of-function alterations in BRCA1/2, respectively, selective pressure for biallelic inactivation, zygosity-dependent phenotype penetrance, and sensitivity to PARP inhibition were observed only in tumour types associated with increased heritable cancer risk in BRCA1/2 carriers (BRCA-associated cancer types). Conversely, among patients with non-BRCA-associated cancer types, most carriers of these BRCA1/2 mutation types had evidence for tumour pathogenesis that was independent of mutant BRCA1/2. Overall, mutant BRCA is an indispensable founding event for some tumours, but in a considerable proportion of other cancers, it appears to be biologically neutral-a difference predominantly conditioned by tumour lineage-with implications for disease pathogenesis, screening, design of clinical trials and therapeutic decision-making.

Development and evaluation of a text analytics algorithm for automated application of national COVID-19 shielding criteria in rheumatology patients.

INTRODUCTION: At the beginning of the COVID-19 pandemic, the UK's Scientific Committee issued extreme social distancing measures, termed 'shielding', aimed at a subpopulation deemed extremely clinically vulnerable to infection. National guidance for risk stratification was based on patients' age, comorbidities and immunosuppressive therapies, including biologics that are not captured in primary care records. This process required considerable clinician time to manually review outpatient letters. Our aim was to develop and evaluate an automated shielding algorithm by text-mining outpatient letter diagnoses and medications, reducing the need for future manual review. METHODS: Rheumatology outpatient letters from a large UK foundation trust were retrieved. Free-text diagnoses were processed using Intelligent Medical Objects software (Concept Tagger), which used interface terminology for each condition mapped to Systematized Medical Nomenclature for Medicine-Clinical Terminology (SNOMED-CT) codes. We developed the Medication Concept Recognition tool (Named Entity Recognition) to retrieve medications' type, dose, duration and status (active/past) at the time of the letter. Age, diagnosis and medication variables were then combined to calculate a shielding score based on the most recent letter. The algorithm's performance was evaluated using clinical review as the gold standard. The time taken to deploy the developed algorithm on a larger patient subset was measured. RESULTS: In total, 5942 free-text diagnoses were extracted and mapped to SNOMED-CT, with 13 665 free-text medications (n=803 patients). The automated algorithm demonstrated a sensitivity of 80% (95% CI: 75%, 85%) and specificity of 92% (95% CI: 90%, 94%). Positive likelihood ratio was 10 (95% CI: 8, 14), negative likelihood ratio was 0.21 (95% CI: 0.16, 0.28) and F1 score was 0.81. Evaluation of mismatches revealed that the algorithm performed correctly against the gold standard in most cases. The developed algorithm was then deployed on records from an additional 15 865 patients, which took 18 hours for data extraction and 1 hour to deploy. DISCUSSION: An automated algorithm for risk stratification has several advantages including reducing clinician time for manual review to allow more time for direct care, improving efficiency and increasing transparency in individual patient communication. It has the potential to be adapted for future public health initiatives that require prompt automated review of hospital outpatient letters.

Analytical propagation model for underwater free-space optical communication through realistic levels of oceanic absorption and scattering.

Optical communications (OC) through water bodies is an attractive technology for a variety of applications. Thanks to current single-photon detection capabilities, OC receiver systems can reliably decode very weak transmitted signals. This is the regime where pulse position modulation is an ideal scheme. However, there has to be at least one photon that goes through the pupil of the fore optics and lands in the assigned time bin. We estimate the detectable photon budget as a function of range for propagation through ocean water, both open and coastal. We make realistic assumptions about the water's inherent optical properties, specifically, absorption and scattering coefficients, as well as the strong directionality of the scattering phase function for typical hydrosol populations. We adopt an analytical (hence very fast) path-integral small-angle solution of the radiative transfer equation for multiple forward-peaked scattering across intermediate to large optical distances. Integrals are performed both along the directly transmitted beam (whether or not it is still populated) and radially away from it. We use this modeling framework to estimate transmission of a 1 J pulse of 532 nm light through open ocean and coastal waters. Thresholds for single-photon detection per time bin are a few km and a few 100 m. These are indicative estimates that will be reduced in practice due to sensor noise, background light, turbulence, bubbles, and so on, to be included in future work.

The use of evidence to guide decision-making during the COVID-19 pandemic: divergent perspectives from a qualitative case study in British Columbia, Canada.

BACKGROUND: The challenges of evidence-informed decision-making in a public health emergency have never been so notable as during the COVID-19 pandemic. Questions about the decision-making process, including what forms of evidence were used, and how evidence informed-or did not inform-policy have been debated. METHODS: We examined decision-makers' observations on evidence-use in early COVID-19 policy-making in British Columbia (BC), Canada through a qualitative case study. From July 2021- January 2022, we conducted 18 semi-structured key informant interviews with BC elected officials, provincial and regional-level health officials, and civil society actors involved in the public health response. The questions focused on: (1) the use of evidence in policy-making; (2) the interface between researchers and policy-makers; and (3) key challenges perceived by respondents as barriers to applying evidence to COVID-19 policy decisions. Data were analyzed thematically, using a constant comparative method. Framework analysis was also employed to generate analytic insights across stakeholder perspectives. RESULTS: Overall, while many actors' impressions were that BC's early COVID-19 policy response was evidence-informed, an overarching theme was a lack of clarity and uncertainty as to what evidence was used and how it flowed into decision-making processes. Perspectives diverged on the relationship between 'government' and public health expertise, and whether or not public health actors had an independent voice in articulating evidence to inform pandemic governance. Respondents perceived a lack of coordination and continuity across data sources, and a lack of explicit guidelines on evidence-use in the decision-making process, which resulted in a sense of fragmentation. The tension between the processes involved in research and the need for rapid decision-making was perceived as a barrier to using evidence to inform policy. CONCLUSIONS: Areas to be considered in planning for future emergencies include: information flow between policy-makers and researchers, coordination of data collection and use, and transparency as to how decisions are made-all of which reflect a need to improve communication. Based on our findings, clear mechanisms and processes for channeling varied forms of evidence into decision-making need to be identified, and doing so will strengthen preparedness for future public health crises.

Gene Regulatory Networks in Coronary Artery Disease.

PURPOSE OF REVIEW: Coronary artery disease is a complex disorder and the leading cause of mortality worldwide. As technologies for the generation of high-throughput multiomics data have advanced, gene regulatory network modeling has become an increasingly powerful tool in understanding coronary artery disease. This review summarizes recent and novel gene regulatory network tools for bulk tissue and single cell data, existing databases for network construction, and applications of gene regulatory networks in coronary artery disease. RECENT FINDINGS: New gene regulatory network tools can integrate multiomics data to elucidate complex disease mechanisms at unprecedented cellular and spatial resolutions. At the same time, updates to coronary artery disease expression data in existing databases have enabled researchers to build gene regulatory networks to study novel disease mechanisms. Gene regulatory networks have proven extremely useful in understanding CAD heritability beyond what is explained by GWAS loci and in identifying mechanisms and key driver genes underlying disease onset and progression. Gene regulatory networks can holistically and comprehensively address the complex nature of coronary artery disease. In this review, we discuss key algorithmic approaches to construct gene regulatory networks and highlight state-of-the-art methods that model specific modes of gene regulation. We also explore recent applications of these tools in coronary artery disease patient data repositories to understand disease heritability and shared and distinct disease mechanisms and key driver genes across tissues, between sexes, and between species.

A genetically defined disease model reveals that urothelial cells can initiate divergent bladder cancer phenotypes.

Small cell carcinoma of the bladder (SCCB) is a rare and lethal phenotype of bladder cancer. The pathogenesis and molecular features are unknown. Here, we established a genetically engineered SCCB model and a cohort of patient SCCB and urothelial carcinoma samples to characterize molecular similarities and differences between bladder cancer phenotypes. We demonstrate that SCCB shares a urothelial origin with other bladder cancer phenotypes by showing that urothelial cells driven by a set of defined oncogenic factors give rise to a mixture of tumor phenotypes, including small cell carcinoma, urothelial carcinoma, and squamous cell carcinoma. Tumor-derived single-cell clones also give rise to both SCCB and urothelial carcinoma in xenografts. Despite this shared urothelial origin, clinical SCCB samples have a distinct transcriptional profile and a unique transcriptional regulatory network. Using the transcriptional profile from our cohort, we identified cell surface proteins (CSPs) associated with the SCCB phenotype. We found that the majority of SCCB samples have PD-L1 expression in both tumor cells and tumor-infiltrating lymphocytes, suggesting that immune checkpoint inhibitors could be a treatment option for SCCB. We further demonstrate that our genetically engineered tumor model is a representative tool for investigating CSPs in SCCB by showing that it shares a similar a CSP profile with clinical samples and expresses SCCB-up-regulated CSPs at both the mRNA and protein levels. Our findings reveal distinct molecular features of SCCB and provide a transcriptional dataset and a preclinical model for further investigating SCCB biology.

Patient-Reported Symptoms Demonstrating an Association with Severity of Visual Field Damage in Glaucoma.

PURPOSE: To determine which patient-reported symptoms best distinguish patients with and without glaucoma and explain the most variance in visual field (VF) damage and to compare the amount of variance that can be explained by symptoms versus retinal nerve fiber layer (RNFL) thickness. DESIGN: Cross-sectional study. PARTICIPANTS: Adults diagnosed with glaucoma or suspicion of glaucoma (controls). METHODS: Worse-eye VF damage was defined on the basis of perimetric testing. Thickness of RNFL was defined by OCT imaging. Patients rated their visual symptoms on questions collated from several published questionnaires, rating the frequency and severity of 28 symptoms on a scale of 1 (never/not at all) to 4 (very often/severe). Multivariable regression models identified patient-reported symptoms that contributed the highest variance in VF damage. MAIN OUTCOME MEASURES: Patient-reported symptoms that explained the most variance in VF damage and amount of variance in VF damage explained by patient-reported symptoms and RNFL. RESULTS: A total of 170 patients (mean age: 64 years; 58% female; 47% employed) completed testing, including 95 glaucoma suspects and 75 glaucoma patients. In glaucoma patients, median mean deviation of VF damage in the worse eye was -19.3 and ranged from -5.3 to -34.7 decibels. Symptoms more common among glaucoma patients compared with glaucoma suspects included better vision in 1 eye, blurry vision, glare, sensitivity to light, cloudy vision, missing patches of vision, and little peripheral vision. Worse severity ratings for the symptom "little peripheral vision" explained the most variance in VF damage (43%). A multivariable model including the frequency of cloudy vision, severity of having little peripheral vision, missing patches, 1 eye having better vision, and vision worsening, plus sociodemographic features, explained 62% of the variance in VF damage. Comparatively, a multivariable model of worse-eye RNFL thickness and sociodemographic features explained 42% of the variance in VF damage, whereas a model including only sociodemographic features explained 8% of the variance in VF damage. CONCLUSIONS: Five patient-reported symptoms explain a significant amount of the variance in VF damage. Asking patients about their symptoms may optimize patient-physician communication and be a useful adjunct to clinical testing in some patients to estimate disease severity.

Positive scores on the 4AT delirium assessment tool at hospital admission are linked to mortality, length of stay and home time: two-centre study of 82,770 emergency admissions.

BACKGROUND: Studies investigating outcomes of delirium using large-scale routine data are rare. We performed a two-centre study using the 4 'A's Test (4AT) delirium detection tool to analyse relationships between delirium and 30-day mortality, length of stay and home time (days at home in the year following admission). METHODS: The 4AT was performed as part of usual care. Data from emergency admissions in patients ≥65 years in Lothian, UK (n = 43,946) and Salford, UK (n = 38,824) over a period of $\sim$3 years were analysed using logistic regression models adjusted for age and sex. RESULTS: 4AT completion rates were 77% in Lothian and 49% in Salford. 4AT scores indicating delirium (≥4/12) were present in 18% of patients in Lothian, and 25% of patients in Salford. Thirty-day mortality with 4AT ≥4 was 5.5-fold greater than the 4AT 0/12 group in Lothian (adjusted odds ratio (aOR) 5.53, 95% confidence interval [CI] 4.99-6.13) and 3.4-fold greater in Salford (aOR 3.39, 95% CI 2.98-3.87). Length of stay was more than double in patients with 4AT scores of 1-3/12 (indicating cognitive impairment) or ≥ 4/12 compared with 4AT 0/12. Median home time at 1 year was reduced by 112 days (Lothian) and 61 days (Salford) in the 4AT ≥4 group (P < 0.001). CONCLUSIONS: Scores on the 4AT used at scale in practice are strongly linked with 30-day mortality, length of hospital stay and home time. The findings highlight the need for better understanding of why delirium is linked with poor outcomes and also the need to improve delirium detection and treatment.

A Single Institution 30-Year Review of Abnormal First Rib Resection for Thoracic Outlet Syndrome.

OBJECTIVES: Congenital abnormalities of the first rib (ABNFR) are a rare cause of thoracic outlet syndrome (TOS). The range of abnormalities have not been clearly documented in the literature. Surgical decompression in these patients presents with increased complexity secondary to anomalous anatomy. Our goal is to review an institutional experience of first rib resection (FRR) performed for ABNFRs, to present a novel classification system, and to analyze outcomes according to clinical presentation. METHODS: A prospectively collected database was used to identify individuals with ABNFRs who underwent FRR for TOS between 1990-2021. These individuals were identified both by preoperative imaging and intraoperative descriptions of the first rib after resection. Demographic, clinical, perioperative and pathological data were reviewed. ABNFRs were classified into 3 categories according to anatomical criteria: (I) Hypoplastic, (II) Fused, and (III) Hyperplastic. Outcomes were rated using the standardized Quick Disability of Arm Shoulder and Hand Scores (QDS), Somatic Pain Scores (SPS) and Derkash Scores (DkS). RESULTS: Among the 2200 cases of TOS, there were 19 patients (0.8%) with ABNFR who underwent FRR. Average age at surgery was 30.5 (range 11-74), including 13 men and 6 women. Presentations included 9 arterial (ATOS), 6 neurogenic (NTOS), and 4 venous (VTOS) cases. There were 6 class I, 6 class II, and 7 class III ABNFRs. Among 6 NTOS patients there were 4 abnormal nerve conduction tests and 5 positive anterior scalene muscle blocks. Among the 9 patients with ATOS, thrombolysis was attempted in 5 patients, and of these, 3 ultimately required surgical thrombectomy. Of 4 VTOS cases, 2 were managed with thrombolysis, and 2 with anticoagulation alone. The approach for FRR was transaxillary in all patients. Secondary procedures included 1 pectoralis minor tenotomy, 1 scalenectomy, and 1 contralateral rib resection. No major neurological or vascular complications occurred. There was 1 patient who required surgical evacuation of a hematoma. Intraoperative chest tube placement was required in 5 patients secondary to pleural entry during dissection. There was an overall improvement in symptoms over an average follow-up of 7.4 months. QDS reduced from 49.7 pre-op to 22.1 (P < 0.05). SPS improved from 3.4 pre-op to 1.8. DkS scores were good to excellent in 79% of patients. Residual symptoms were noted in 7, and ATOS accounted for 5 (70%) of these. All patients were able to return to work. CONCLUSIONS: Despite increased complexity, ABNFRs may be safely resected via transaxillary approach with low incidence of complications, very good symptom relief, and excellent outcomes. Congenital ABNFRs may by classified into 3 categories (hypoplastic, fused, and hyperplastic) with a variety of presentations, including ATOS, NTOS, and VTOS. Classification of ABNFRs allows concise description of abnormal anatomy which facilitates comparison between series and provides direction for surgical management to ultimately optimize patient outcomes.

Investigating the influence of institutions, politics, organizations, and governance on the COVID-19 response in British Columbia, Canada: a jurisdictional case study protocol.

BACKGROUND: Research on public health responses to COVID-19 globally has largely focused on understanding the virus' epidemiology, identifying interventions to curb transmission, and assessing the impact of interventions on outcomes. Only recently have studies begun to situate their findings within the institutional, political, or organizational contexts of jurisdictions. Within British Columbia (BC), Canada, the COVID-19 response in early 2020 was deemed highly coordinated and effective overall; however, little is understood as to how these upstream factors influenced policy decisions. METHODS: Using a conceptual framework we developed, we are conducting a multidisciplinary jurisdictional case study to explore the influence of institutional (I), political (P), organizational (O), and governance (G) factors on BC's COVID-19 public health response in 2020-2021. A document review (e.g. policy documents, media reports) is being used to (1) characterize relevant institutional and political factors in BC, (2) identify key policy decisions in BC's epidemic progression, (3) create an organizational map of BC's public health system structure, and (4) identify key informants for interviews. Quantitative data (e.g. COVID-19 case, hospitalization, death counts) from publicly accessible sources will be used to construct BC's epidemic curve. Key informant interviews (n = 15-20) will explore governance processes in the COVID-19 response and triangulate data from prior procedures. Qualitative data will be analysed using a hybrid deductive-inductive coding approach and framework analysis. By integrating all of the data streams, our aim is to explore decision-making processes, identify how IPOG factors influenced policy decisions, and underscore implications for decision-making in public health crises in the BC context and elsewhere. Knowledge users within the jurisdiction will be consulted to construct recommendations for future planning and preparedness. DISCUSSION: As the COVID-19 pandemic evolves, governments have initiated retrospective examinations of their policies to identify lessons learned. Our conceptual framework articulates how interrelations between IPOG contextual factors might be applied to such analysis. Through this jurisdictional case study, we aim to contribute findings to strengthen governmental responses and improve preparedness for future health crises. This protocol can be adapted to and applied in other jurisdictions, across subnational jurisdictions, and internationally.

The immune niche of the liver.

The liver is an essential organ that is critical for the removal of toxins, the production of proteins, and the maintenance of metabolic homeostasis. Behind each liver functional unit, termed lobules, hides a heterogeneous, complex, and well-orchestrated system. Despite parenchymal cells being most commonly associated with the liver's primary functionality, it has become clear that it is the immune niche of the liver that plays a central role in maintaining both local and systemic homeostasis by propagating hepatic inflammation and orchestrating its resolution. As such, the immunological processes that are at play in healthy and diseased livers are being investigated thoroughly in order to understand the underpinnings of inflammation and the potential avenues for restoring homeostasis. This review highlights recent advances in our understanding of the immune niche of the liver and provides perspectives for how the implementation of new transcriptomic, multimodal, and spatial technologies can uncover the heterogeneity, plasticity, and location of hepatic immune populations. Findings from these technologies will further our understanding of liver biology and create a new framework for the identification of therapeutic targets.

Electrical stimulation as a therapeutic approach in obstructive sleep apnea - a meta-analysis.

PURPOSE: Electrical stimulation of the upper airway dilator muscles is an emerging treatment for obstructive sleep apnea (OSA). Invasive hypoglossal nerve stimulation (HNS) has been accepted as treatment alternative to continuous positive airway pressure (CPAP) for selected patients, while transcutaneous electrical stimulation (TES) of the upper airway is being investigated as non-invasive alternative. METHODS: A meta-analysis (CRD42017074674) on the effects of both HNS and TES on the apnea-hypopnea index (AHI) and the Epworth Sleepiness Scale (ESS) in OSA was conducted including published evidence up to May 2018. Random-effects models were used. Heterogeneity and between-study variance were assessed by I2 and τ2, respectively. RESULTS: Of 41 identified clinical trials, 20 interventional trials (n = 895) could be pooled in a meta-analysis (15 HNS [n = 808], 5 TES [n = 87]). Middle-aged (mean ± SD 56.9 ± 5.5 years) and overweight (body mass index 29.1 ± 1.5 kg/m2) patients with severe OSA (AHI 37.5 ± 7.0/h) were followed-up for 6.9 ± 4.0 months (HNS) and 0.2 ± 0.4 months (TES), respectively. The AHI improved by - 24.9 h-1 [95%CI - 28.5, - 21.2] in HNS (χ2 79%, I2 82%) and by - 16.5 h-1 [95%CI - 25.1, - 7.8] in TES (χ2 7%, I2 43%; both p < 0.001). The ESS was reduced by - 5.0 (95%CI - 5.9, - 4.1) (p < 0.001). CONCLUSION: Both invasive and transcutaneous electrical stimulation reduce OSA severity by a clinically relevant margin. HNS results in a clinically relevant improvement of symptoms. While HNS represents an invasive treatment for selected patients with moderate to severe OSA, TES should be further investigated as potential non-invasive approach for OSA.

Evidence-Based Criteria for Determining Peripapillary OCT Reliability.

PURPOSE: To assess the impact of OCT signal strength (SS) and artifact on retinal nerve fiber layer (RNFL) measurement reliability and to understand whether glaucoma severity modifies this relationship. DESIGN: Retrospective, longitudinal cohort study. PARTICIPANTS: Two thousand nine hundred ninety-two OCT scans from 474 eyes of 241 patients with glaucoma or glaucoma suspect status. METHODS: We extracted mean RNFL thickness and SS and manually graded scans for artifact. To analyze the effect of SS and artifact on OCT reliability, we (1) created a multilevel linear model using measured RNFL thickness values and demographic and clinical data to estimate the true (predicted) RNFL thickness, (2) calculated model residuals (ΔRNFL) as our reliability measure, and (3) created a second multilevel linear model with splines and interaction terms that modeled overall and quadrant specific reliability (ΔRNFL) as the outcome, using SS and artifact as predictors. MAIN OUTCOME MEASURES: Impact of SS and artifact on ΔRNFL. RESULTS: For SS between 10 and 3, the impact of decreases in SS on OCT reliability is modest (-0.67 to -1.25 ΔRNFL per 1-point decrease in SS; P < 0.05). But at less than 3, changes in SS have a large impact on reliability (-15.70 to -16.34 ΔRNFL per 1-point decrease in SS; P < 0.05). At SS between 10 and 3, decreases in SS tend to have a larger impact on reliability in eyes with severe glaucoma (-1.25 per 1-point decrease in SS; P < 0.05) compared with eyes with mild or moderate glaucoma (-0.67 to -0.75 per 1-point decrease in SS; P < 0.05). The presence of artifact has a significant impact on OCT reliability independent of the effects of SS (-4.76 ΔRNFL; P < 0.05). Artifact affects reliability solely in the quadrant in which it occurs, with artifact in one quadrant showing no impact on ΔRNFL in the opposite quadrant (P > 0.05). CONCLUSIONS: Signal strength decreases down to 3 have relatively mild impacts on OCT reliability. At less than 3, the impact of further decreases in SS on reliability are substantial. The effect of SS on reliability is greater in severe glaucoma. Artifacts result in a decrease in reliability independent of the effect of SS. We propose evidence-based guidelines to guide physicians on whether to trust the results of an OCT scan.

Aortoiliac Endarterectomy: A Useful Tool in Modern Vascular Practice.

Aortoiliac endarterectomy was the standard treatment for aortoiliac occlusive disease before the availability of prosthetic graft material for aortobifemoral bypass, although the number of patients appropriate for this repair continues to diminish in the endovascular era. Patients with focal aortoiliac disease are often treated with bilateral "kissing" iliac stents through an endovascular approach. However, in patients with eccentric plaque morphology or smaller caliber vessels, the risk of distal embolization and vessel rupture is not insignificant. On the other hand, if the disease is localized to the distal aortic bifurcation, an open aortobifemoral bypass may be excessive and incur additional morbidity. Our case report reviews a 60-year-old woman who presented with lifestyle-limiting claudication from an isolated aortoiliac atherosclerotic plaque who we proceeded with an open aortoiliac endarterectomy.

Endovascular Abdominal Aortic Aneurysm Repair: Does Anesthesia Type Matter?

BACKGROUND: Given the various types of anesthesia used for endovascular abdominal aortic aneurysm repair (EVAR), we sought to determine the effect of anesthesia type in the outcomes of elective EVAR in a large multiinstitutional healthcare maintenance organization. METHODS: A retrospective chart review was conducted on all elective EVAR conducted from August 2010 to August 2017 in 14 regional hospitals of Kaiser Permanente Southern California. Patients undergoing emergent, nonelective abdominal aortic aneurysm repairs, thoracoabdominal aneurysm repair, requiring conversion to open surgery or general anesthesia were excluded from the study. Basic demographic information, medical risk factors, anesthesia type, operative data, and postoperative morbidity and mortality data were obtained for univariate and multivariate statistical analysis. RESULTS: A total of 1,536 patients underwent EVAR, of which 1,206 met inclusion criteria. A total of 788 patients underwent general anesthesia, 164 patients underwent spinal anesthesia, 82 patients underwent epidural anesthesia, and 172 patients underwent local and monitored anesthesia care (AC). There was a significant difference in length of stay and operative time when comparing local/monitored AC to general anesthesia. No significant difference was noted in 30-day morbidity or mortality among the anesthesia groups. CONCLUSIONS: Local and regional anesthesia is a safe and effective approach for elective EVAR.

A critical review of the chest CT scans performed to detect asymptomatic synchronous metastasis in new and recurrent breast cancers.

BACKGROUND: Chest computed tomography (CTC) has now replaced chest X-ray (CXR) as the first choice of investigation to stage breast cancers in most centers in Australia. Routine staging is not recommended in early breast cancers (EBCs). This recommendation is based largely on the use of conventional tests like CXR as staging investigations (SIs). We looked at our experience with CTC in detecting asymptomatic synchronous distant metastasis (ASM) in new and recurrent breast cancers (RBCs). MATERIALS AND METHODS: Breast cancer patients from Eastern Health Breast Unit during the period from January 2012 to March 2016 were included in the study. Cases were grouped into early, advanced, and recurrent breast cancers, and outcome of CTC was assessed in each group. Relative risk of potential risk factors (tumor size, axillary nodal status, presence of lymphovascular invasion and estrogen, and HER2 receptor status) with a positive result in CTC was determined. RESULTS: Fourteen ASMs were detected from 335 CTCs giving an overall yield of 4% (95% CI 1.89-6.47). The overall false-positive rate was 10% due to 35 indeterminate findings that were found not to be metastases after further tests or observation. Even with selective use, CTCs have a low yield of 2% (95% CI - 0.19-4.19) in EBCs. Advanced breast cancers have a 9% incidence of ASMs. None of the clinically isolated locoregionally recurrent diseases were associated with detectable distant metastasis in CTC. The most common cause of indeterminate findings was small pulmonary nodules. CONCLUSION: Even with selective use, CTC has a very low yield in EBCs. Advanced breast cancers can benefit from CTC in their initial evaluation due to the higher yield. Locoregional RBCs were not usually associated with detectable metastasis on CTC. The usefulness of CTC in all stages of breast cancer is further reduced by its high rate of false-positive results.

Rapid Quantification of 4,4'-Methylenedianiline by Surface-Enhanced Raman Spectroscopy.

Methylenedianiline (MDA) is a common industrial chemical with health and product safety concerns. Common analysis methods require many steps including extraction and derivatization ending in GC/MS or HPLC analysis, which minimize its use as an on-line or at-line technique. The procedure can take hours, prohibiting its use as a real-time decision-making tool as well as using valuable resources and laboratory space. The new method presented here has been validated for MDA quantification in industrial grease samples over the concentration range of 1-40 ppm 4,4'-MDA. We present comparative results to the currently accepted method with excellent fidelity. This analytical method using surface-enhanced Raman spectroscopy reduces sample preparation and analysis time by more than an hour while preserving method accuracy, specificity, and dynamic range.