Rising hospital admissions for alcohol-related cirrhosis and the impact of sex and comorbidity - a data linkage study.

OBJECTIVES: International studies have shown shifting demographic data and rising hospitalizations for alcohol-related cirrhosis (ARC), with a paucity of data from Australia. We examined hospitalizations, mortality and demographic data for people admitted with ARC over the last decade in Queensland, Australia. STUDY DESIGN: Data linkage study. METHODS: A retrospective analysis of adults hospitalized with ARC during 2008-2019 was performed using state-wide admissions data. International Classification of Diseases, 10th revision, codes identified admissions with the principal diagnosis of ARC based on validated algorithms. Comorbidity was assessed using the Charlson Comorbidity Index. RESULTS: A total of 7152 individuals had 24,342 hospital admissions with ARC (16,388 were for ARC). There was a predominance of males (72.6%) and age ≥50 years (80.4%) at index admission. Females were admitted at a significantly younger age than men (59% of women and 43% of men were aged <60 years, P < 0.001). Comorbidities were common, with 45.1% of people having at least one comorbidity. More than half (54.6%) of the patients died over the study period (median follow-up time was 5.1 years; interquartile range 2.4-8.6). Women had significantly lower mortality, with 47.6% (95% confidence interval [CI] 45.0-50.2) probability of 5-year survival, compared with 40.1% (95% CI 38.5-41.6) in men. In multivariable analysis, this was attributable to significantly lower age and comorbidity burden in women. Significantly lower survival was seen in people with higher comorbidity burden. Overall, the number of admissions for ARC increased 2.2-fold from 869 admissions in 2008 to 1932 in 2019. CONCLUSIONS: Hospital admissions for ARC have risen substantially in the last decade. Females were admitted at a younger age, with fewer comorbidities and had lower mortality compared with males. The association between greater comorbidity burden and higher mortality has important clinical implications, as comorbidity-directed interventions may reduce mortality.

A discrete choice experiment to elicit preferences for a chronic disease screening programme in Queensland, Australia.

OBJECTIVE: Patient-centred care, increasingly highlighted in healthcare strategies, necessitates understanding public preferences for healthcare service attributes. We aimed to understand the preferences of the Australian population regarding the attributes of chronic disease screening programmes. STUDY DESIGN: The preferences were elicited using the discrete choice experiment (DCE) methodology. METHODS: A DCE was administered to a sample of the Australian general population. Respondents were asked to make choices, each offering two hypothetical screening scenarios defined by screening conduct, quality and accuracy of the test results, cost to the patient, wait time and source of information. Data were analysed using a panel mixed multinomial logit model. RESULTS: A strong preference for highly accurate screening tests and nurse-led screenings at local health clinics was evident. They expressed disutility for waiting time and out-of-pocket costs but were indifferent about the source of information. Their preference for a nurse-led programme was highlighted by the fact that they were willing to pay $81 and $88 to get a nurse-led programme when they were offered a general practitioner-led and a specialist-led programme, respectively. Furthermore, they were willing to pay $32 to reduce a week of waiting time and $205 for a 95% accurate test compared to a 75% accurate test. Preferences remained consistent irrespective of the respondent's place of residence. CONCLUSIONS: Our findings highlight the importance of diagnostic test accuracy and nurse-led service delivery in chronic disease screening programmes. These insights could guide the development of patient-centric services by enhancing test accuracy, reducing waiting times and promoting nurse-led care models.

The mobilisation of early mature CD56dim-CD16bright NK cells is blunted following a single bout of vigorous intensity exercise in Type 1 Diabetes.

Type 1 diabetes (T1D) is a T cell mediated autoimmune disease that targets and destroys insulin-secreting pancreatic beta cells. Although T cell mediated, a number of other immune cells are also critically involved in coordinating the events leading to T1D. Specifically, innate subsets play an important role in the pathogenesis of T1D. NK cells are one of the first cell types to infiltrate the pancreas, causing damage and release of beta cell antigens. Previous work in our group has shown differential mobilisation of highly differentiated CD8+ T cells during vigorous intensity exercise in T1D compared to a control cohort. Here, we aimed to explore exercise-induced mobilisation of other cell types involved in T1D pathogenesis. In this study, we investigated the effects of a single bout of vigorous (80% predicted VO2max) intensity exercise on innate cell mobilisation in T1D and control participants. T1D (N=12, mean age 33.2yrs, predicted VO2max 32.2 ml.kg.min⁻¹, BMI 25.3 kg.m⁻²) and control (N=12, mean age 29.4yrs, predicted VO2 max 38.5 ml.kg.min⁻¹, BMI 23.7 kg.m⁻² male participants completed a 30-minute bout of cycling at 80% predicted VO2 max in a fasted state. Peripheral blood was collected at baseline, immediately post-exercise, and 1 hour post-exercise. NK cell subsets mobilised during vigorous intensity exercise in both control and T1D participants. However, mature NK cells, defined as the CD56dimCD16bright subset, displayed a lower percentage increase following vigorous intensity exercise in T1D participants (Control: 185.12%, T1D: 97.06%). This blunted mobilisation was specific to early mature NK cells (KIR+) but not later differentiated NK cells (KIR+CD57+). Myeloid lineage subsets mobilised to a similar extent in both control and T1D participants. In conclusion, vigorous exercise mobilises innate immune cells in people with T1D albeit to a different extent to those without T1D. This mobilisation of innate immune cells provides a mechanistic argument to support exercise in people with T1D where it has the potential to improve surveillance for infection and to modulate the autoimmune response to the beta cell.

Symposium review: Omics in dairy and animal science-Promise, potential, and pitfalls.

Sequencing the first genome took 15 yr and $3 billion to complete. Currently, a genome can be sequenced in a day for a few thousand dollars. Comparing the relative abundance of nearly every mRNA transcript and small RNAs from cells and tissues from different experimental conditions has become so easy that it can take longer to transfer the data between computers than to perform the experiment. Nucleotide sequencing techniques have become so sensitive that the greatest concern is not detecting a gene or transcript but rather, falsely identifying one. Better genome sequencing has led to more complete transcriptomic and proteomic databases and, combined with more sensitive instrumentation and separation techniques, is bringing us closer to detecting complete transcriptomes and proteomes. The promise of these powerful omics techniques is to lead us to new and unexpected connections between molecular processes in the context of animal health. This promise cannot be achieved without hypothesis-driven research that connects omics data with animal health experiments. Any researcher who wishes to invest the time and resources in omics experiments should be aware of the common pitfalls and limitations of these techniques so they can avoid these issues and maximize the use of these research tools. Several important questions must be asked: What is the quality of the databases and how they are annotated? Are the annotations based on experimental results or computational predictions? What assumptions are made by the analysis algorithms, and how will this affect the result? Finally, how can the research community use the vast amount of data being generated by omics experiments in ways to achieve the goals of better animal health and production (which is the promise of omics technologies)? Until the observations shown in omics data sets are used to achieve the goals of better animal health and production, the potential of omics technology will not be fully realized.

The effect of pegylated granulocyte colony-stimulating factor treatment prior to experimental mastitis in lactating Holsteins.

Neutrophils are the first-acting and most prominent cellular defense against mastitis-causing pathogens. This makes neutrophil activation and expansion obvious candidates for targeted therapeutics. The granulocyte colony-stimulating factor (G-CSF) cytokine stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream, which results in neutrophilia as well as increasing the presence of other progenitor cells in the bloodstream. A pegylated form of G-CSF (PEG-gCSF) has been shown to significantly decrease naturally occurring mastitis rates in cows postpartum. The use of PEG-gCSF had not been evaluated in response to an experimental mastitis challenge. In an effort to examine the effect and mechanism of PEG-gCSF treatment, we challenged 11 mid-lactation Holsteins with ∼400 cfu Escherichia coli P4 by intramammary infusion. Five cows received 2 PEG-gCSF injections, one at 14 d and the other at 7 d before disease challenge, and 6 cows remained untreated. To evaluate the response of cows to the PEG-gCSF treatment, we measured complete blood counts, somatic cell counts, bacterial counts, milk yield, and feed intake data. The PEG-gCSF-treated cows had significantly increased circulating levels of neutrophils and lymphocytes after each PEG-gCSF injection, as well as following mastitis challenge. The PEG-gCSF-treated cows had significantly lower bacterial counts and lower milk BSA levels at the peak of infection. In addition, control cows had significant decreases in milk yield postinfection and significantly reduced feed intake postinfection compared with PEG-gCSF-treated cows. Collectively, PEG-gCSF treatment resulted in reduced disease severity when administered before a bacterial challenge. Mechanistically, we show that G-CSF treatment increases cell surface expression of an E-selectin ligand before infection on neutrophils and monocytes found in the blood. These cells quickly disappear from the blood shortly after infection, suggesting a mechanism for the reduced mastitis severity by priming immune cells for quick targeting to the site of infection.

Patterns of service utilisation within Australian hepatology clinics: high prevalence of advanced liver disease.

BACKGROUND: Liver diseases in Australia are estimated to affect 6 million people with a societal cost of $51 billion annually. Information about utilisation of specialist hepatology care is critical in informing policy makers about the requirements for delivery of hepatology-related healthcare. AIMS: This study examined the aetiology and severity of liver disease seen in a tertiary hospital hepatology clinic, as well as the resource utilisation patterns. METHODS: A longitudinal cohort study included consecutive patients booked in hepatology outpatient clinics during a 3-month period. Subsequent outpatient appointments for these patients over the following 12 months were then recorded. RESULTS: During the initial 3-month period, 1471 appointments were scheduled with a hepatologist, 1136 of which were attended. Twenty-one per cent of patients were 'new cases'. Hepatitis B virus (HBV) was the most common disease aetiology for new cases (37%). Advanced disease at presentation varied between aetiology; only 5% of HBV cases had advanced liver disease at presentation, in contrast with HCV, NAFLD and ALD, in which advanced disease was identified at presentation in 31%, 46% and 72% of cases, respectively. Most patients (83%) attended multiple hepatology appointments, and a range of referral patterns for procedures, investigations and other specialty assessments were observed. CONCLUSIONS: There is a high prevalence of HBV in new case referrals. Patients with HCV infection, NAFLD and ALD have a high prevalence of advanced liver disease at referral, requiring ongoing surveillance for development of decompensated liver disease and liver cancer. These findings that describe the patterns of health service utilisation among patients with liver disease provide useful information for planning sustainable health service provision for this clinical population.

Clinical outcomes of elderly patients receiving neoadjuvant chemoradiation for locally advanced rectal cancer.

BACKGROUND: Studies of clinical outcomes of elderly patients treated with neoadjuvant chemoradiation (nCRT) for locally advanced rectal cancer (LARC) are limited. Our aim was to assess the impact of age on clinical outcomes in a large multi-institutional database. PATIENTS AND METHODS: Data for patients diagnosed with LARC who received nCRT and curative-intent surgery between 2005 and 2012 were collected from five major Canadian cancer centers. Age was analyzed as a continuous and dichotomous variable (< 70 versus ≥ 70 years) and correlated with disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). Cox regression models were used to adjust for important prognostic factors. RESULTS: Of 1172 patients included, 295 (25%) were ≥ 70 years, and they were less likely to receive adjuvant chemotherapy (ACT; 60% versus 79%, P < 0.0001), oxaliplatin-based ACT (12% versus 31%, P < 0.0001), less likely to complete nCT (76% versus 86%, P < 0.001), and more likely to be anemic at initiation of nCRT (42% versus 30%, P = 0.0004). In multivariate analyses, age ≥ 70 years was associated with similar DFS [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.68-1.26, P = 0.63], similar CSS (HR 0.81, 95% CI 0.46-1.41, P = 0.45), and similar OS (HR 1.28, 95% CI 0.88-1.86, P = 0.20), compared with the younger age group. As a continuous variable, increasing age was not predictive of DFS (HR 1.00, 95% CI 0.99-1.02, P = 0.49) or CSS (HR 1.002, 95% CI 0.98-1.02, P = 0.88); however, it correlated with an inferior OS (HR 1.02, 95% CI 1.00-1.03, P = 0.04). CONCLUSIONS: Elderly patients (≥ 70 years) who receive nCRT followed by surgery appear to have similar outcomes compared with younger patients. Decisions regarding eligibility for nCRT and surgery should not be based on age alone.

Burden of decompensated cirrhosis and ascites on hospital services in a tertiary care facility: time for change?

BACKGROUND: Ascites, the most frequent complication of cirrhosis, is associated with poor prognosis and reduced quality of life. Recurrent hospital admissions are common and often unplanned, resulting in increased use of hospital services. AIMS: To examine use of hospital services by patients with cirrhosis and ascites requiring paracentesis, and to investigate factors associated with early unplanned readmission. METHODS: A retrospective review of the medical chart and clinical databases was performed for patients who underwent paracentesis between October 2011 and October 2012. Clinical parameters at index admission were compared between patients with and without early unplanned hospital readmissions. RESULTS: The 41 patients requiring paracentesis had 127 hospital admissions, 1164 occupied bed days and 733 medical imaging services. Most admissions (80.3%) were for management of ascites, of which 41.2% were unplanned. Of those eligible, 69.7% were readmitted and 42.4% had an early unplanned readmission. Twelve patients died and nine developed spontaneous bacterial peritonitis. Of those eligible for readmission, more patients died (P = 0.008) and/or developed spontaneous bacterial peritonitis (P = 0.027) if they had an early unplanned readmission during the study period. Markers of liver disease, as well as haemoglobin (P = 0.029), haematocrit (P = 0.024) and previous heavy alcohol use (P = 0.021) at index admission, were associated with early unplanned readmission. CONCLUSION: Patients with cirrhosis and ascites comprise a small population who account for substantial use of hospital services. Markers of disease severity may identify patients at increased risk of early readmission. Alternative models of care should be considered to reduce unplanned hospital admissions, healthcare costs and pressure on emergency services.

CCR5-Δ32 genotype does not improve predictive value of IL28B polymorphisms for treatment response in chronic HCV infection.

IL28B polymorphisms strongly predict spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. A recent study proposed a 32-base pair deletion in the CC-chemokine receptor 5 (CCR5) gene (CCR5-Δ32) interacting with the IL28B polymorphisms to influence spontaneous HCV clearance. The aim of this study was to clarify the role of CCR5-Δ32 in treatment-induced clearance of chronic hepatitis C (CHC). A cross-sectional cohort of 813 Caucasian patients with CHC genotype 1 (365 responders and 448 non-responders) who had received standard of care dual therapy with interferon (IFN)-α and ribavirin (RBV) was genotyped for the CCR5-Δ32 and IL28B polymorphisms to examine their interaction with respect to treatment response. CCR5-Δ32 did not influence treatment-induced recovery to IFN-α/RBV in CHC, and did not improve prediction of sustained virological response in the context of the IL28B polymorphisms in a multivariate model. CCR5-Δ32 homozygotes were significantly more frequent in those with CHC than healthy controls in the European cohorts (2.9% vs 0.4%, P<0.0001), but not in Australians of European ancestry. In conclusion, CCR5-Δ32 does not influence treatment response in the context of IL28B polymorphisms. Although CCR5-Δ32 may affect viral clearance within closely controlled geographical and genetic environments, we found no effect in larger cohorts treated with dual therapy.

A thiocarbamate inhibitor of endothelial lipase raises HDL cholesterol levels in mice.

By screening directed libraries of serine hydrolase inhibitors using the cell surface form of endothelial lipase (EL), we identified a series of carbamate-derived (EL) inhibitors. Compound 3 raised plasma HDL-C levels in the mouse, and a correlation was found between HDL-C and plasma compound levels. Spectroscopic and kinetic studies support a covalent mechanism of inhibition. Our findings represent the first report of EL inhibition as an effective means for increasing HDL-C in an in vivo model.

Awareness and opinions of non-alcoholic fatty liver disease by hospital specialists.

BACKGROUND/AIM: Subjects with metabolic risk factors for non-alcoholic fatty liver disease (NAFLD) are commonly seen by hospital specialists other than gastroenterologists/hepatologists. The aim of this study was to assess the awareness of NAFLD and opinions regarding management among non-hepatologists at two major tertiary hospitals in Brisbane. METHODS: A face-to-face questionnaire assessing current beliefs and practices regarding NAFLD was administered to specialists and specialists-in-training across six specialties (internal medicine, cardiology/cardiac surgery, endocrinology, thoracic medicine, rheumatology and nephrology). RESULTS: One hundred clinicians were surveyed with 99% returning completed questionnaires (>89% questions answered). The majority of respondents (75%) believe the prevalence of NAFLD in the general population to be ≤ 10%, although two-thirds feel that its incidence will rise markedly. The vast majority (>90%) appreciate that traditional cardiovascular risk factors (obesity, hypertriglyceridaemia and diabetes) are risk factors for NAFLD and acknowledge that these are common in non-hepatology patients. Despite this, most believe that NAFLD is uncommon in their own patients (89% indicated a prevalence ≤ 30%). The vast majority (93%) agree that non-alcoholic steatohepatitis (NASH) is associated with increased overall mortality, but 60% also believe that simple steatosis confers increased liver-related mortality. Most (74%) agree that a diagnosis of NASH cannot be made using liver enzymes, but 67% support 6-monthly liver function tests as the most effective way to monitor progression of NAFLD. Most respondents (71%) make no referrals to hepatology for suspected NAFLD. CONCLUSIONS: Non-hepatologists appreciate the seriousness of NAFLD but appear to underestimate its prevalence, especially among their own patients despite known risk factors. Attitudes regarding simple steatosis versus NASH and appropriate monitoring of suspected NAFLD suggest that more can be done to improve the understanding of this disease among non-hepatologists. This has implications for targeting 'at-risk' populations and appropriate referral of patients to hepatology clinics.

Assessment of alcohol histories obtained from patients with liver disease: opportunities to improve early intervention.

BACKGROUND: Alcohol is an important primary and comorbid cause of liver injury in patients referred for investigation and management of liver disease. Early assessment and documentation of alcohol consumption is therefore essential, and recommended in both general practice and hospital settings. AIMS: To determine the extent and accuracy of documentation of alcohol consumption in patients referred for evaluation of liver disease. METHODS: Patients were interviewed using a structured questionnaire. The medical records of all patients interviewed were reviewed to obtain information from the referral letter and the hepatology consultations. RESULTS: Eighty-three patients were surveyed. Only 14 referrals had an informative alcohol history, despite 27 patients admitting risky alcohol consumption at the initial hepatology consultation. Ninety per cent of initial consultations had an informative alcohol history documented, whereas only 56% of patients attending a follow-up appointment had informative documentation. Assessment of alcohol consumption was comparable between the hepatology consultation and the structured questionnaire, but four subjects had substantially different alcohol histories. Alcohol Use Disorders Identification Test identified all patients reporting harmful alcohol consumption on the questionnaire. CONCLUSIONS: Hazardous alcohol use is prevalent in subjects attending hepatology clinics, but informative alcohol histories, which are crucial to patient management, are rarely documented in referrals. Screening tools improve documentation and accuracy of alcohol histories, and their use by general practitioners and hospital clinicians would improve detection rates of hazardous drinking and allow earlier intervention. Systematic use of screening tools in hepatology clinics will provide opportunities for education and reinforce recommendations to reduce hazardous or harmful alcohol consumption.

Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus.

The IDDM2 locus encoding susceptibility to type 1 diabetes was mapped previously to a 4.1-kb region spanning the insulin gene and a minisatellite or variable number of tandem repeats (VNTR) locus on human chromosome 11p15.5. By 'cross-match' haplotype analysis and linkage disequilibrium mapping, we have mapped the mutation IDDM2 to within the VNTR itself. Other polymorphisms were systematically excluded as primary disease determinants. Transmission of IDDM2 may be influenced by parent-of-origin phenomena. Although we show that the insulin gene is expressed biallelically in the adult pancreas, we present preliminary evidence that the level of transcription in vivo is correlated with allelic variation within the VNTR. Allelic variation at VNTRs may play an important general role in human disease.

Biomarker analysis in a phase III study of pemetrexed-carboplatin versus etoposide-carboplatin in chemonaive patients with extensive-stage small-cell lung cancer.

BACKGROUND: Clinical results of a randomized phase III trial comparing pemetrexed-carboplatin (PC) with etoposide-carboplatin (EC) in chemonaive patients with extensive-stage disease small-cell lung cancer (ED-SCLC) resulted in trial closure for futility; biomarker analyses using immunohistochemistry (IHC) and single-nucleotide polymorphisms (SNPs) are described herein. PATIENTS AND METHODS: Thymidylate synthase (TS), excision repair cross complementing-1 (ERCC1), glycinamide ribonucleotide formyltransferase (GARFT), and folylpolyglutamate synthetase (FPGS) were investigated using IHC (n=395). SNPs were genotyped for TS, FPGS, γ-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR), folate receptor-α FR-α, and solute carrier 19A1 (SLC19A1; n=611). RESULTS: None of the IHC biomarkers (folate pathway or ERCC1) were found to be predictive or prognostic in this setting. rs2838952 (adjacent to SLC19A1) had significant treatment-independent association with overall survival (OS; hazard ratio 0.590, P=0.01). Nine GGH-associated SNPs interacted with rs3788205 (SLC19A1) for OS on the PC arm. rs12379987 (FPGS) interacted with treatment for OS (interaction P=0.036). CONCLUSION: Potential ERCC1 and folate pathway IHC biomarkers failed to predict outcome in either study arm in ED-SCLC. SNPs in regions including FPGS and SLC19A1 and interacting SNPs in GGH and SLC19A1 were associated with differences in OS; however, none of these SNPs predicted for greater survival with PC over EC.

Introduction of standardized, cumulative quantitative measurement of blood loss into routine maternity care.

INTRODUCTION: Postpartum hemorrhage (PPH) is the leading cause of maternal morbidity in the UK. Visual estimation of blood loss is unreliable yet remains common practice. As part of a national quality improvement project to improve care during PPH, standardized, quantitative measurement of blood loss (QBL) for all deliveries was introduced into a tertiary obstetric unit in Cardiff, Wales. METHODS: Retrospective analysis of 875 consecutive maternities between December 2017 and February 2018 was undertaken. Of these, 372 mothers had both pre- and post-partum hemoglobin (Hb) were recorded. Regression analyses were performed to investigate the relationship between change in Hb adjusted for red cell transfusion and QBL. RESULTS: The correlation coefficient between QBL and adjusted change in Hb for all deliveries (n = 372) was 0.57. This corresponded to an estimated fall of adjusted change in Hb of 15.3 g/L (95% CI: 13.1, 17.6) per 1000 mL blood loss. DISCUSSION: QBL has been shown to be reliable across all maternity settings, with reproducible results in theater and delivery rooms (on the obstetric unit and alongside midwifery-led unit). QBL is moderately correlated with adjusted change in Hb for all volumes of bleeding and gives clinicians more accurate knowledge of blood loss than visual estimation. This low-cost, low-fidelity intervention can influence the timely escalation of clinical care and therefore patient outcome.

Comorbidity, age and overall survival in cetuximab-treated patients with advanced colorectal cancer (ACRC)--results from NCIC CTG CO.17: a phase III trial of cetuximab versus best supportive care.

BACKGROUND: the interplay between comorbidity, age and performance status (PS) as predictors of outcome in advanced colorectal cancer (ACRC) is poorly understood. We examined these factors as predictors of treatment toxicity and outcome in cetuximab-treated patients with ACRC. PATIENTS AND METHODS: comorbidity was independently evaluated using the Charlson Comorbidity Index (CCI), a validated measure of comorbidity based on the presence of medical conditions weighted according to their effect on mortality. CCI score was correlated with clinical and outcome data. RESULTS: five hundred and seventy-two patients were included; 41% were ≥ 65 years and 25% had comorbidities at randomization. In multivariate analysis (MVA) of all covariates, only older age was associated with greater comorbidity (P = 0.008). Overall survival (OS) was significantly better for patients with greater comorbidity in univariate analysis (P = 0.047). Conversely, better PS was associated with better OS in MVA (hazard ratio 1.92 for PS = 2 versus PS = 0, P < 0.0001). Age was not associated with OS (P = 0.13). Elderly patients had significantly less grade ≥ 3 vomiting (P = 0.034) but more dyspnea (P = 0.005). Patients with greater comorbidity had significantly less grade ≥ 3 vomiting (P = 0.002) but more non-neutropenic fever (P = 0.005). CONCLUSION: better PS was associated with improved OS. For patients with good PS, restricting cetuximab use in the setting of significant comorbidity does not appear justified.

SeqEM: an adaptive genotype-calling approach for next-generation sequencing studies.

MOTIVATION: Next-generation sequencing presents several statistical challenges, with one of the most fundamental being determining an individual's genotype from multiple aligned short read sequences at a position. Some simple approaches for genotype calling apply fixed filters, such as calling a heterozygote if more than a specified percentage of the reads have variant nucleotide calls. Other genotype-calling methods, such as MAQ and SOAPsnp, are implementations of Bayes classifiers in that they classify genotypes using posterior genotype probabilities. RESULTS: Here, we propose a novel genotype-calling algorithm that, in contrast to the other methods, estimates parameters underlying the posterior probabilities in an adaptive way rather than arbitrarily specifying them a priori. The algorithm, which we call SeqEM, applies the well-known Expectation-Maximization algorithm to an appropriate likelihood for a sample of unrelated individuals with next-generation sequence data, leveraging information from the sample to estimate genotype probabilities and the nucleotide-read error rate. We demonstrate using analytic calculations and simulations that SeqEM results in genotype-call error rates as small as or smaller than filtering approaches and MAQ. We also apply SeqEM to exome sequence data in eight related individuals and compare the results to genotypes from an Illumina SNP array, showing that SeqEM behaves well in real data that deviates from idealized assumptions. CONCLUSION: SeqEM offers an improved, robust and flexible genotype-calling approach that can be widely applied in the next-generation sequencing studies. AVAILABILITY AND IMPLEMENTATION: Software for SeqEM is freely available from our website: www.hihg.org under Software Download.

A prospective, multicentre, observational cohort study of analgesia and outcome after pneumonectomy.

BACKGROUND: Meta-analysis and systematic reviews of epidural compared with paravertebral blockade analgesia techniques for thoracotomy conclude that although the analgesia is comparable, paravertebral blockade has a better short-term side-effect profile. However, reduction in major complications including mortality has not been proven. METHODS: The UK pneumonectomy study was a prospective observational cohort study in which all UK thoracic surgical centres were invited to participate. Data presented here relate to the mode of analgesia and outcome. Data were analysed for 312 patients having pneumonectomy at 24 UK thoracic surgical centres in 2005. The primary endpoint was a major complication. RESULTS: The most common type of analgesia used was epidural (61.1%) followed by paravertebral infusion (31%). Epidural catheter use was associated with major complications (odds ratio 2.2, 95% confidence interval 1.1-3.8; P=0.02) by stepwise logistic regression analysis. CONCLUSIONS: An increased incidence of clinically important major post-pneumonectomy complications was associated with thoracic epidural compared with paravertebral blockade analgesia. However, this study is unable to provide robust evidence to change clinical practice for a better clinical outcome. A large multicentre randomized controlled trial is now needed to compare the efficacy, complications, and cost-effectiveness of epidural and paravertebral blockade analgesia after major lung resection with the primary outcome of clinically important major morbidity.

Factors influencing surgical treatment decisions for breast cancer: a qualitative exploration of surgeon and patient perspectives.

Background: The rate of mastectomy is much higher in Newfoundland and Labrador than in any other province in Canada, even for women diagnosed at an early stage. In this paper, we present qualitative data from women who have made a decision for surgical treatment and from breast surgeons in an effort to better explicate factors influencing breast cancer (bca) surgical decision-making. Methods: The study's descriptive, qualitative design involved holding interviews with breast surgeons and holding focus groups and interviews with women who were offered the choice of breast-conserving surgery (bcs) or mastectomy (mt). Results: Participants included 35 women and 13 surgeons. High interest in mt and increasing requests for prophylactic contralateral mt were evident. A host of factors-clinical, demographic, psychosocial, education-related, and cultural-influenced the decisions. A key factor for women was fear of recurrence and a need to "just get rid of it," but the experiences of others also influenced the decisions. Life stage and family considerations also factored prominently into women's decisions. Conclusions: Women with early-stage bca more often chose mt and often demanded prophylactic removal of the healthy breast. Findings highlight the importance of ensuring that women at average risk are appropriately counselled about the low likelihood of a subsequent contralateral bca and the lack of survival benefit associated with prophylactic contralateral mt. Findings also revealed other areas of presurgical discussion that might help women think through their personal circumstances and values so as to encourage informed surgical decisions.

Eastern Canadian Gastrointestinal Cancer Consensus Conference 2018.

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference was held in Halifax, Nova Scotia, 20-22 September 2018. Experts in radiation oncology, medical oncology, surgical oncology, and pathology who are involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics in the management of pancreatic cancer, pancreatic neuroendocrine tumours, hepatocellular cancer, and rectal and colon cancer, including ■ surgical management of pancreatic adenocarcinoma,■ adjuvant and metastatic systemic therapy options in pancreatic adenocarcinoma,■ the role of radiotherapy in the management of pancreatic adenocarcinoma,■ systemic therapy in pancreatic neuroendocrine tumours,■ updates in systemic therapy for patients with advanced hepatocellular carcinoma,■ optimum duration of adjuvant systemic therapy for colorectal cancer, and■ sequence of therapy in oligometastatic colorectal cancer.