Challenging immunodominance of influenza-specific CD8+ T cell responses restricted by the risk-associated HLA-A*68:01 allomorph.

Although influenza viruses lead to severe illness in high-risk populations, host genetic factors associated with severe disease are largely unknown. As the HLA-A*68:01 allele can be linked to severe pandemic 2009-H1N1 disease, we investigate a potential impairment of HLA-A*68:01-restricted CD8+ T cells to mount robust responses. We elucidate the HLA-A*68:01+CD8+ T cell response directed toward an extended influenza-derived nucleoprotein (NP) peptide and show that only ~35% individuals have immunodominant A68/NP145+CD8+ T cell responses. Dissecting A68/NP145+CD8+ T cells in low vs. medium/high responders reveals that high responding donors have A68/NP145+CD8+ memory T cells with clonally expanded TCRαßs, while low-responders display A68/NP145+CD8+ T cells with predominantly naïve phenotypes and non-expanded TCRαßs. Single-cell index sorting and TCRαß analyses link expansion of A68/NP145+CD8+ T cells to their memory potential. Our study demonstrates the immunodominance potential of influenza-specific CD8+ T cells presented by a risk HLA-A*68:01 molecule and advocates for priming CD8+ T cell compartments in HLA-A*68:01-expressing individuals for establishment of pre-existing protective memory T cell pools.

Carbapenemase-producing Enterobacteriaceae in Australian hospitals: outcome of point-prevalence screening in high-risk wards.

Carbapenemase-producing Enterobacteriaceae (CPE) infections are increasingly reported in Australian hospitals, but prevalence is unknown. In 2016, Victorian hospitals conducted CPE point-prevalence surveys in high-risk wards (intensive care, haematology, transplant). Forty-three hospitals performed 134 surveys, with 1839/2342 (79%) high-risk patients screened. Twenty-four surveys were also performed in other wards. Inability to obtain patient consent was the leading reason for non-participation. In high-risk wards, no CPE cases were detected; three cases were identified in other wards. Since there is low prevalence in high-risk wards, continuous screening is not recommended. Targeted screening may be enhanced by review of patient consent processes.

Differential protein stability and clinical responses of EML4-ALK fusion variants to various ALK inhibitors in advanced ALK-rearranged non-small cell lung cancer.

Background: Anaplastic lymphoma kinase (ALK) inhibition using crizotinib has become the standard of care in advanced ALK-rearranged non-small cell lung cancer (NSCLC), but the treatment outcomes and duration of response vary widely. Echinoderm microtubule-associated protein-like 4 (EML4)-ALK is the most common translocation, and the fusion variants show different sensitivity to crizotinib in vitro. However, there are only limited data on the specific EML4-ALK variants and clinical responses of patients to various ALK inhibitors. Patients and methods: By multiplex reverse-transcriptase PCR, which detects 12 variants of known EML4-ALK rearrangements, we retrospectively determined ALK fusion variants in 54 advanced ALK rearrangement-positive NSCLCs. We subdivided the patients into two groups (variants 1/2/others and variants 3a/b) by protein stability and evaluated correlations of the variant status with clinical responses to crizotinib, alectinib, or ceritinib. Moreover, we established the EML4-ALK variant-expressing system and analyzed patterns of sensitivity of the variants to ALK inhibitors. Results: Of the 54 tumors analyzed, EML4-ALK variants 3a/b (44.4%) was the most common type, followed by variants 1 (33.3%) and 2 (11.1%). The 2-year progression-free survival (PFS) rate was 76.0% [95% confidence interval (CI) 56.8-100] in group EML4-ALK variants 1/2/others versus 26.4% (95% CI 10.5-66.6) in group variants 3a/b (P = 0.034) among crizotinib-treated patients. Meanwhile, the 2-year PFS rate was 69.0% (95% CI 49.9-95.4) in group variants 1/2/others versus 32.7% (95% CI 15.6-68.4) in group variants 3a/b (P = 0.108) among all crizotinib-, alectinib-, and ceritinib-treated patients. Variant 3a- or 5a-harboring cells were resistant to ALK inhibitors with >10-fold higher half maximal inhibitory concentration in vitro. Conclusion: Our findings show that group EML4-ALK variants 3a/b may be a major source of ALK inhibitor resistance in the clinic. The variant-specific genotype of the EML4-ALK fusion allows for more precise stratification of patients with advanced NSCLC.

Operationalising resilience in longitudinal studies: a systematic review of methodological approaches.

Over the life course, we are invariably faced with some form of adversity. The process of positively adapting to adverse events is known as 'resilience'. Despite the acknowledgement of 2 common components of resilience, that is, adversity and positive adaptation, no consensus operational definition has been agreed. Resilience operationalisations have been reviewed in a cross-sectional context; however, a review of longitudinal methods of operationalising resilience has not been conducted. The present study conducts a systematic review across Scopus and Web of Science capturing studies of ageing that posited operational definitions of resilience in longitudinal studies of ageing. Thirty-six studies met inclusion criteria. Non-acute events, for example, cancer, were the most common form of adversity identified and psychological components, for example, the absence of depression, the most common forms of positive adaptation. Of the included studies, 4 used psychometrically driven methods, that is, repeated administration of established resilience metrics, 9 used definition-driven methods, that is, a priori establishment of resilience components and criteria, and 23 used data-driven methods, that is, techniques that identify resilient individuals using latent variable models. Acknowledging the strengths and limitations of each operationalisation is integral to the appropriate application of these methods to life course and longitudinal resilience research.

Epidemiology of Clostridium difficile infections in Australia: enhanced surveillance to evaluate time trends and severity of illness in Victoria, 2010-2014.

BACKGROUND: With epidemic strains of Clostridium difficile posing a substantial healthcare burden internationally, there is a need for longitudinal evaluation of Clostridium difficile infection (CDI) events in Australia. AIM: To evaluate time trends and severity of illness for CDI events in Australian healthcare facilities. METHODS: All CDI events in patients admitted to Victorian public hospitals between 1(st) October 2010 and 31(st) December 2014 were reported to the Victorian Healthcare Associated Infection Surveillance System. CDI was defined as the isolation of a toxin-producing C. difficile organism in a diarrhoeal specimen, and classified as community-associated (CA-CDI) or healthcare-associated (HA-CDI). Severe disease was defined as admission to an intensive care unit, requirement for surgery and/or death due to infection. Time trends were examined using a mixed-effects Poisson regression model, and the Walter and Edward test of seasonality was applied to evaluate potential cyclical patterns. FINDINGS: In total, 6736 CDI events were reported across 89 healthcare facilities. Of these, 4826 (71.6%) were HA-CDI, corresponding to a rate of 2.49/10,000 occupied bed days (OBDs). The incidence of HA-CDI was highest in the fifth quarter of surveillance (3.6/10,000 OBDs), followed by a reduction. Severe disease was reported in 1.66% of events, with the proportion being significantly higher for CA-CDI compared with HA-CDI (2.21 vs 1.45%, P = 0.03). The highest and lowest incidence of HA-CDI occurred in March and October, respectively. CONCLUSIONS: A low incidence of HA-CDI was reported in Victoria compared with US/European surveillance reports. Seasonality was evident, together with diminishing HA-CDI rates in 2012-2014. Severe infections were more common in CA-CDI, supporting future enhanced surveillance in community settings.

Management of paediatric otogenic cerebral venous sinus thrombosis: a systematic review.

BACKGROUND: Otogenic paediatric cerebral venous sinus thrombosis (CVST) is rare but has potential clinical sequelae. Its management has long been debated mainly concerning the role of surgery and the use of anticoagulant therapy. OBJECTIVE OF REVIEW: To review the current literature and examine the medical and surgical management of paediatric otogenic CVST and its clinical and radiological outcome. TYPE OF REVIEW: Systematic review. SEARCH STRATEGY: The electronic databases (MEDLINE, EMBASE, Cochrane) were searched from inception to November 2014 using text words 'cerebral venous sinus thrombosis OR cerebral venous thrombosis OR lateral sinus thrombosis OR sigmoid sinus thrombosis' AND 'otogenic OR mastoiditis OR otitis media' AND 'children OR paediatric OR pediatric'. EVALUATION METHOD: Inclusion criteria were applied by two reviewers and data extraction was carried out. The type of otological surgery (conservative versus extensive) and the use of anticoagulants with their clinical and radiological outcomes were tabulated. RESULTS: Thirty-six studies (15 case reports and 21 case series) were included with a total of 190 patients. A total of 92.1% of patients underwent otological surgery, and 69.5% had conservative surgery and 30.5% extensive otological surgery. Anticoagulants were used in 59%. A total of 79.2% of patients were reported to have had a good clinical outcome. Within this group, 56% had conservative surgery and anticoagulants. Follow-up scans were documented in 61.6% of patients and complete recanalisation was observed in 51%. Complete recanalisation was observed in 47% of those who had been anticoagulated and 55% of those who received no anticoagulation. CONCLUSIONS: Conservative otological surgery with the combination of anticoagulation was the most common treatment modality found in the group of patients with good clinical outcome. However, given the current low level of evidence, a multicentre collaborative study is needed to help establish the optimum surgical approach and the role of anticoagulation in managing paediatric otogenic CVST.

Risk factors for delay in symptomatic presentation: a survey of cancer patients.

BACKGROUND: Delay in symptomatic presentation leading to advanced stage at diagnosis may contribute to poor cancer survival. To inform public health approaches to promoting early symptomatic presentation, we aimed to identify risk factors for delay in presentation across several cancers. METHODS: We surveyed 2371 patients with 15 cancers about nature and duration of symptoms using a postal questionnaire. We calculated relative risks for delay in presentation (time from symptom onset to first presentation >3 months) by cancer, symptoms leading to diagnosis and reasons for putting off going to the doctor, controlling for age, sex and deprivation group. RESULTS: Among 1999 cancer patients reporting symptoms, 21% delayed presentation for >3 months. Delay was associated with greater socioeconomic deprivation but not age or sex. Patients with prostate (44%) and rectal cancer (37%) were most likely to delay and patients with breast cancer least likely to delay (8%). Urinary difficulties, change of bowel habit, systemic symptoms (fatigue, weight loss and loss of appetite) and skin symptoms were all common and associated with delay. Overall, patients with bleeding symptoms were no more likely to delay presentation than patients who did not have bleeding symptoms. However, within the group of patients with bleeding symptoms, there were significant differences in risk of delay by source of bleeding: 35% of patients with rectal bleeding delayed presentation, but only 9% of patients with urinary bleeding. A lump was a common symptom but not associated with delay in presentation. Twenty-eight percent had not recognised their symptoms as serious and this was associated with a doubling in risk of delay. Embarrassment, worry about what the doctor might find, being too busy to go to the doctor and worry about wasting the doctor's time were also strong risk factors for delay, but were much less commonly reported (<6%). INTERPRETATION: Approaches to promote early presentation should aim to increase awareness of the significance of cancer symptoms and should be designed to work for people of the lowest socioeconomic status. In particular, awareness that rectal bleeding is a possible symptom of cancer should be raised.

Pediatric endocrine surgery: a 20-year experience at the Mayo Clinic.

CONTEXT: Surgically managed endocrinopathies are rare in children. Most surgeons have limited experience in this field. Herein we report our operative experience with pediatric patients, performed over two decades by high-volume endocrine surgeons. SETTING: The study was conducted at the Mayo Clinic (a tertiary referral center). PATIENTS: Patients were <19 years old and underwent an endocrine operation (1993-2012). MAIN OUTCOME MEASURES: Demographics, surgical procedure, diagnoses, morbidity, and mortality were retrospectively reviewed. RESULTS: A total of 241 primary cases included 177 thyroid procedures, 13 neck dissections, 24 parathyroidectomies, 14 adrenalectomies, 7 paragangliomas, and 6 pancreatic procedures. Average age of patients was 14.2 years. There were 133 total thyroidectomies and 40 hemithyroidectomies. Fifty-three cases underwent a central or lateral neck dissection. Six-month follow-up was available for 98 total thyroidectomy patients. There were four cases of permanent hypoparathyroidism (4%) and no permanent recurrent laryngeal nerve (RLN) paralyses. Sequelae of neck dissections included temporary RLN neurapraxia and Horner's syndrome. Parathyroidectomy was performed on 24 patients: 20 with primary hyperparathyroidism (HPT), three with tertiary HPT, and one with familial hypocalciuric hypocalcemia. Three patients (16%) had recurrent HPT, all with multiglandular disease. One patient had temporary RLN neurapraxia. We performed seven bilateral and seven unilateral adrenalectomies; eight were laparoscopic. Indications included pheochromocytoma, Cushing's syndrome, adrenocortical carcinoma, congenital adrenal hyperplasia, and ganglioneuroma. One death was due to adrenocortical carcinoma. Five paraganglioma patients had succinate dehydrogenase subunit B mutations, and one recurred. Six patients with insulinoma underwent enucleation (n = 5) or distal pancreatectomy (n = 1). A single postoperative abscess was managed nonoperatively. CONCLUSION: Pediatric endocrine procedures are uncommon but can be safely performed with complication rates comparable to those of the adult population. It is imperative that these operations be performed by high-volume surgeons.

Emergency presentation of cancer and short-term mortality.

BACKGROUND: The short-term survival following a cancer diagnosis in England is lower than that in comparable countries, with the difference in excess mortality primarily occurring in the months immediately after diagnosis. We assess the impact of emergency presentation (EP) on the excess mortality in England over the course of the year following diagnosis. METHODS: All colorectal and cervical cancers presenting in England and all breast, lung, and prostate cancers in the East of England in 2006-2008 are included. The variation in the likelihood of EP with age, stage, sex, co-morbidity, and income deprivation is modelled. The excess mortality over 0-1, 1-3, 3-6, and 6-12 months after diagnosis and its dependence on these case-mix factors and presentation route is then examined. RESULTS: More advanced stage and older age are predictive of EP, as to a lesser extent are co-morbidity, higher income deprivation, and female sex. In the first month after diagnosis, we observe case-mix-adjusted excess mortality rate ratios of 7.5 (cervical), 5.9 (colorectal), 11.7 (breast ), 4.0 (lung), and 20.8 (prostate) for EP compared with non-EP. CONCLUSION: Individuals who present as an emergency experience high short-term mortality in all cancer types examined compared with non-EPs. This is partly a case-mix effect but EP remains predictive of short-term mortality even when age, stage, and co-morbidity are accounted for.

Using a birth cohort to study ageing: representativeness and response rates in the National Survey of Health and Development.

Britain's oldest birth cohort study, the MRC National Survey of Health and Development (NSHD) provides data to explore life time influences on ageing. The latest data collection was undertaken between 2006 and 2011 when study members were aged 60-64 and consisted of postal and pre-assessment questionnaires to eligible study members, followed by invitation to attend one of six clinical research facilities (CRFs) across the UK for clinical assessments, and dietary diaries and activity monitors in the days following the CRF visit. The option of a home visit for clinical assessments was provided if the study member refused or was unable to attend the CRF. We examined response and attrition, here describing rates overall and for postal and clinical assessment modes of data collection, identifying socioeconomic and health-related predictors of response, and assessing the continued representativeness of the sample. In total, 2,661 (84 % of the target sample) responded. Lower educational attainment, lower childhood cognition and lifelong smoking independently predicted lower likelihood of both overall response and CRF cooperation. At 53 years, not owning one's home and not being married predicted lower likelihood of overall response whereas manual social class and obesity predicted lower likelihood of CRF cooperation. Providing for collection of biomedical data in the home and use of assessment instruments and modes to retain study members with lower education attainment, lower cognition and poorer health behaviours should be priorities for helping reduce attrition amongst vulnerable ageing study members.

Breast cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK, 2000-2007: a population-based study.

BACKGROUND: We investigate whether differences in breast cancer survival in six high-income countries can be explained by differences in stage at diagnosis using routine data from population-based cancer registries. METHODS: We analysed the data on 257,362 women diagnosed with breast cancer during 2000-7 and registered in 13 population-based cancer registries in Australia, Canada, Denmark, Norway, Sweden and the UK. Flexible parametric hazard models were used to estimate net survival and the excess hazard of dying from breast cancer up to 3 years after diagnosis. RESULTS: Age-standardised 3-year net survival was 87-89% in the UK and Denmark, and 91-94% in the other four countries. Stage at diagnosis was relatively advanced in Denmark: only 30% of women had Tumour, Nodes, Metastasis (TNM) stage I disease, compared with 42-45% elsewhere. Women in the UK had low survival for TNM stage III-IV disease compared with other countries. CONCLUSION: International differences in breast cancer survival are partly explained by differences in stage at diagnosis, and partly by differences in stage-specific survival. Low overall survival arises if the stage distribution is adverse (e.g. Denmark) but stage-specific survival is normal; or if the stage distribution is typical but stage-specific survival is low (e.g. UK). International differences in staging diagnostics and stage-specific cancer therapies should be investigated.

Implementing improved post-treatment care for cancer survivors in England, with reflections from Australia, Canada and the USA.

Increasing cancer incidence together with improved survival rates are contributing to the growing number of cancer survivors. Survivors may encounter a range of potential effects as a result of the cancer itself or cancer treatments. Traditionally, the major focus of follow-up care has been on detection of cancer recurrence; however, the efficacy of such strategies is questionable. Traditional follow-up frequently fails to identify or adequately address many survivors' concerns. Aftercare needs to be planned to enable better outcomes for survivors, while using scarce health-care resources efficiently. This review focuses on provision of survivorship care, rather than on research. England's National Cancer Survivorship Initiative has developed principles for improved care of those living with and beyond cancer. These include risk-stratified pathways of care, the use of treatment summaries and care plans, information and education to enable choice and the confidence to self manage, rapid re-access to specialist care, remote monitoring and well-coordinated care. Many of these principles are relevant internationally, though preferred models of care will depend on local circumstances.

Routes to diagnosis for cancer - determining the patient journey using multiple routine data sets.

BACKGROUND: Cancer survival in England is lower than the European average, which has been at least partly attributed to later stage at diagnosis in English patients. There are substantial regional and demographic variations in cancer survival across England. The majority of patients are diagnosed following symptomatic or incidental presentation. This study defines a methodology by which the route the patient follows to the point of diagnosis can be categorised to examine demographic, organisational, service and personal reasons for delayed diagnosis. METHODS: Administrative Hospital Episode Statistics data are linked with Cancer Waiting Times data, data from the cancer screening programmes and cancer registration data. Using these data sets, every case of cancer registered in England, which was diagnosed in 2006-2008, is categorised into one of eight 'Routes to Diagnosis'. RESULTS: Different cancer types show substantial differences between the proportion of cases that present by each route, in reasonable agreement with previous clinical studies. Patients presenting via Emergency routes have substantially lower 1-year relative survival. CONCLUSION: Linked cancer registration and administrative data can be used to robustly categorise the route to a cancer diagnosis for all patients. These categories can be used to enhance understanding of and explore possible reasons for delayed diagnosis.

The role of lifestyle behaviors on 20-year cognitive decline.

This study examined the association between smoking, physical activity and dietary choice at 36 and 43 years, and change in these lifestyle behaviors between these ages, and decline in verbal memory and visual search speed between 43 and 60-64 years in 1018 participants from MRC National Survey of Health and Development (NSHD, the British 1946 birth cohort). ANCOVA models were adjusted for sex, social class of origin, childhood cognition, educational attainment, adult social class, and depression; then the lifestyle behaviors were additionally mutually adjusted. Results showed that healthy dietary choice and physical activity were associated, respectively, with slower memory and visual search speed decline over 20 years, with evidence that increasing physical activity was important. Adopting positive health behaviors from early midlife may be beneficial in reducing the rate of cognitive decline and ultimately reducing the risk of dementia.

Survival trends of cancer amongst the south Asian and non-south Asian population under 30 years of age in Yorkshire, UK.

INTRODUCTION: Several studies have shown differences in survival trends between ethnic groups across adults with cancer in the UK. It is unclear whether these differences exist exclusively in the older adult population or whether they begin to emerge in children and young adults. METHODS: Subjects (n=3534) diagnosed with cancer under 30 years of age in Yorkshire between 1990 and 2005 were analysed. Differences in survival rates for diagnostic subgroups were estimated by ethnic group (south Asian or not) using Kaplan-Meier estimation and Cox regression. RESULTS: When compared to non-south Asians (all other ethnic groups excluding south Asians) a significant increased risk of death was seen for south Asians with leukaemia (hazard ratio (HR)=1.75; 95% confidence interval (CI)=1.11-2.76) and lymphoma (HR=2.05; 95% CI=1.09-3.87), whereas south Asians with solid tumours other than central nervous system tumours had a significantly reduced risk of death(HR=0.50; 95% CI=0.28-0.89). This was independent of socioeconomic deprivation. CONCLUSION: We found evidence of poorer survival outcomes for south Asians compared to non-south Asian children and young adults with leukaemia and lymphoma, but better outcomes for south Asian children and young adults with other solid tumours. This needs to be explained, and carefully addressed in the on-going development of cancer services.

A bundle of care to reduce colorectal surgical infections: an Australian experience.

Use of 'bundles of care' to improve patient outcomes is becoming more widespread; however, their use is more common internationally than in Australia. The objective of this study was to assess the feasibility of implementing a bundle of care for patients undergoing colorectal surgery with the aim of reducing surgical site infections. Each component of the bundle was evidence based, focusing on normothermia, normoglycaemia, oxygen delivery and use of appropriate antibiotics. Implementation required extensive consultation and education, together with a checklist to accompany patients and record whether processes were followed and outcomes achieved. Difficulties were experienced with achieving compliance with processes, although some improvements were seen. There was a link between the use of warming devices and improved maintenance of normothermia. The infection rate fell from 15% [95% confidence interval (CI) 10.4-20.2] before the project to 7% (95% CI 3.4-12.6) 12 months after the project. While the small sample size does not allow definitive conclusions to be drawn, the results are promising. Potential reasons for low compliance with individual components of the bundle of care are discussed. In conclusion, introduction of a bundle of care for patients undergoing colorectal surgery into an Australian hospital was only modestly successful. Despite this, infection rates decreased over the 12 months following introduction of the bundle.

Treatment related factors and inhibitor development in children with severe haemophilia A.

With the advent of modern factor replacement therapy the most important remaining obstacle to successful treatment in haemophilia A is the development of inhibitory antibodies against Facto VIII (FVIII). This retrospective case control study examined genetic variables and early treatment patterns in severe haemophilia A patients who subsequently developed clinically significant inhibitors to FVIII compared with matched controls who did not. Seventy eight inhibitor patients were identified from 13 UK centers over 25 years (1982-2007). For each case an age matched control was selected. Data on potential genetic and treatment related risk factors were collected for cases and controls. Treatment related data was collected for the first 50 exposure days (EDs) for controls or up to inhibitor development for cases. Risk factors were compared for significance by univariate and multivariate analysis. Of the genetic risk factors, major defects in the FVIII gene and non-caucasian ethnicity were each responsible for approximately 5-fold increases in inhibitor risk. When treatment related variables are considered, high intensity treatment increased inhibitor risk around 2.5 fold whether represented by the presence of peak treatment moments or by high overall treatment frequency. This finding was significant regardless of the timing of the high intensity treatment. Periods of intense treatment associated with surgery for porta-cath insertion were however not found to be associated with increased inhibitor risk. No association was shown between inhibitor development and age at first FVIII exposure, type of FVIII product, or the use of regular prophylaxis. This study confirms treatment-related factors as important risks for inhibitor development in Haemophilia A.