On the use of flexible excess hazard regression models for describing long-term breast cancer survival: a case-study using population-based cancer registry data.

BACKGROUND: Breast cancer prognosis has dramatically improved over 40 years. There is, however, no proof of population 'cure'. This research aimed to examine the pattern of long-term excess mortality due to breast cancer and evaluate its determinants in the context of cancer registry data. METHODS: We used data from the Geneva Cancer Registry to identify women younger than 75 years diagnosed with invasive, localised and operated breast cancer between 1995 and 2002. Flexible modelling of excess mortality hazard, including time-dependent (TD) regression parameters, was used to estimate mortality related to breast cancer. We derived a single "final" model using a backward selection procedure and evaluated its stability through sensitivity analyses using a bootstrap technique. RESULTS: We analysed data from 1574 breast cancer women including 351 deaths (22.3%). The model building strategy retained age at diagnosis (TD), tumour size and grade (TD), chemotherapy and hormonal treatment (TD) as prognostic factors, while the sensitivity analysis on bootstrap samples identified nodes involvement and hormone receptors (TD) as additional long-term prognostic factors but did not identify chemotherapy and hormonal treatment as important prognostic factors. CONCLUSIONS: Two main issues were observed when describing the determinants of long-term survival. First, the modelling strategy presented a lack of robustness, probably due to the limited number of events observed in our study. The second was the misspecification of the model, probably due to confounding by indication. Our results highlight the need for more detailed data and the use of causal inference methods.

DNA methylation profiles correlated to striped bass sperm fertility.

BACKGROUND: Striped bass (Morone saxatilis) spermatozoa are used to fertilize in vitro the eggs of white bass (M. chrysops) to produce the preferred hybrid for the striped bass aquaculture industry. Currently, only one source of domestic striped bass juveniles is available to growers that is not obtained from wild-caught parents and is thus devoid of any genetic improvement in phenotypic traits of importance to aquaculture. Sperm epigenetic modification has been predicted to be associated with fertility, which could switch genes on and off without changing the DNA sequence itself. DNA methylation is one of the most common epigenetic modification types and changes in sperm epigenetics can be correlated to sub-fertility or infertility in male striped bass. The objective of this study was to find the differentially methylated regions (DMRs) between high-fertility and sub-fertility male striped bass, which could potentially regulate the fertility performance. RESULTS: In our present study, we performed DNA methylation analysis of high-fertility and sub-fertility striped bass spermatozoa through MBD-Seq methods. A total of 171 DMRs were discovered in striped bass sperm correlated to fertility. Based on the annotation of these DMRs, we conducted a functional classification analysis and two important groups of genes including the WDR3/UTP12 and GPCR families, were discovered to be related to fertility performance of striped bass. Proteins from the WDR3/UTP12 family are involved in forming the sperm flagella apparatus in vertebrates and GPCRs are involved in hormonal signaling and regulation of tissue development, proliferation and differentiation. CONCLUSIONS: Our results contribute insights into understanding the mechanism of fertility in striped bass, which will provide powerful tools to maximize reproductive efficiencies and to identify those males with superior gametes for this important aquaculture species.

P2Y2 R deletion ameliorates sialadenitis in IL-14α-transgenic mice.

OBJECTIVE: Interleukin-14α-transgenic (IL-14αTG) mice develop an autoimmune exocrinopathy with characteristics similar to Sjögren's syndrome, including sialadenitis and hyposalivation. The P2Y2 receptor (P2Y2 R) for extracellular ATP and UTP is upregulated during salivary gland inflammation (i.e., sialadenitis) where it regulates numerous inflammatory responses. This study investigated the role of P2Y2 Rs in autoimmune sialadenitis in the IL-14αTG mouse model of Sjögren's syndrome. MATERIALS AND METHODS: IL-14αTG mice were bred with P2Y2 R-/- mice to generate IL-14αTG × P2Y2 R-/- mice. P2Y2 R expression, lymphocytic focus scores, B- and T-cell accumulation, and lymphotoxin-α expression were evaluated in the submandibular glands (SMG) along with carbachol-stimulated saliva secretion in IL-14αTG, IL-14αTG × P2Y2 R-/- , and C57BL/6 control mice at 9 and 12 months of age. RESULTS: Genetic ablation of P2Y2 Rs in IL-14αTG mice significantly reduced B and T lymphocyte infiltration of SMGs. However, reduced sialadenitis did not restore saliva secretion in IL-14αTG × P2Y2 R-/- mice. Decreased sialadenitis in IL-14αTG × P2Y2 R-/- mice correlated with decreased lymphotoxin-α levels, a critical proinflammatory cytokine associated with autoimmune pathology in IL-14αTG mice. CONCLUSIONS: The results of this study suggest that P2Y2 Rs contribute to the development of salivary gland inflammation in IL-14αTG mice and may also contribute to autoimmune sialadenitis in humans.

Do pre-diagnosis primary care consultation patterns explain deprivation-specific differences in net survival among women with breast cancer? An examination of individually-linked data from the UK West Midlands cancer registry, national screening programme and Clinical Practice Research Datalink.

BACKGROUND: In England and Wales breast cancer survival is higher among more affluent women. Our aim was to investigate the potential of pre-diagnostic factors for explaining deprivation-related differences in survival. METHODS: Individually-linked data from women aged 50-70 in the West Midlands region of England, diagnosed with breast cancer 1989-2006 and continuously eligible for screening, was retrieved from the cancer registry, screening service and Clinical Practice Research Datalink. Follow-up was to the end of July 2012. Deprivation was measured at small area level, based on the quintiles of the income domain of the English indices of deprivation. Consultation rates per woman per week, time from last breast-related GP consultation to diagnosis, and from diagnosis to first surgery were calculated. We estimated net survival using the non-parametric Pohar-Perme estimator. RESULTS: The rate of primary care consultations was similar during the 18 months prior to diagnosis in each deprivation group for breast and non-breast symptoms. Survival was lower for more deprived women from 4 years after diagnosis. Lower net survival was associated with more advanced extent of disease and being non-screen-detected. There was a persistent trend of lower net survival for more deprived women, irrespective of the woman's obesity, alcohol, smoking or comorbidity status. There was no significant variation in time from last breast symptom to diagnosis by deprivation. However, women in more deprived categories experienced significantly longer periods between cancer diagnosis and first surgery (mean = 21.5 vs. 28.4 days, p = 0.03). Those whose surgery occurred more than 12 weeks following their cancer diagnosis had substantially lower net survival. CONCLUSIONS: Our data suggest that although more deprived women with breast cancer display lifestyle factors associated with poorer outcomes, their consultation frequency, comorbidities and the breast cancer symptoms they present with are similar. We found weak evidence of extended times to surgical treatment among most deprived women who were not screen-detected but who presented with symptoms in primary care, which suggests that treatment delay may play a role. Further investigation of interrelationships between these variables within a larger dataset is warranted.

Provisional epidemiological cutoff values for standard broth microdilution susceptibility testing of Flavobacterium columnare.

The gliding aquatic bacterium Flavobacterium columnare causes columnaris disease, a common problem for wild and farmed freshwater fish worldwide. Recently, a broth microdilution method was standardized to test the susceptibility of F. columnare against antimicrobials commonly used in aquaculture. We used this new method to measure the minimal inhibitory concentrations (MICs) of ten antimicrobials against 120 F. columnare isolates. The resulting MIC frequency distributions for each antimicrobial (1 MIC/isolate) were used to estimate epidemiological cut-off values (ECVs) which separate isolates with typical wild-type (WT) susceptibility from isolates with decreased non-wild-type (NWT) susceptibility. We identified 22 NWT isolates with elevated MICs relative to the ECV that covered 99.9% of the MIC distribution against one or more of the antimicrobials: ampicillin, enrofloxacin, erythromycin, florfenicol, flumequine, oxolinic acid or oxytetracycline. Ten of the NWT isolates had decreased susceptibility to a single antimicrobial class, six isolates to two antimicrobial classes and six isolates to three or more antimicrobial classes. The MIC frequency distributions and provisional cut-off values provide data needed to set epidemiological cut-off values to monitor for the development of antimicrobial resistance among F. columnare.

No 'cure' within 12 years of diagnosis among breast cancer patients who are diagnosed via mammographic screening: women diagnosed in the West Midlands region of England 1989-2011.

BACKGROUND: We have previously reported that there is little evidence of population 'cure' among two populations of women diagnosed with invasive breast cancer. 'Cure' has not yet been examined in the context of screen-detection. PATIENTS AND METHODS: We examined cancer registry data on 19 800 women aged 50-70, diagnosed with a primary, invasive, non-metastatic breast cancer between 1 April 1989 and 31 March 2011 in the West Midlands region of England, linked to Hospital Episode Statistics (HES) and the National Breast Screening Service (NBSS). Follow-up was complete on all women up to 31 July 2012. Analyses were stratified by screening status, age, tumour stage, deprivation and ethnicity. We estimated net survival for the whole cohort and each subgroup. Population 'cure' was evaluated by fitting flexible parametric log-cumulative excess hazard regression models in which the excess hazard of breast cancer death was assumed to be equal to zero after a given follow-up time. RESULTS: There was an overall lack of evidence for 'cure'. Across all subgroups examined, the general pattern was that of a continuous decrease in net survival over time, with no obvious asymptotic tendency within 12 years of follow-up. Model-based analyses confirmed this observation. CONCLUSIONS: Despite dramatic improvements in survival over past decades, diagnosis with breast cancer remains associated with a small but persistent increased risk of death for all groups of women, including those whose cancer is detected asymptomatically. These findings are unlikely to be due to methodological inadequacies. Communication of these long-term consequences of breast cancer among women recently diagnosed and to those considering undergoing screening should take due consideration of these patterns.

Serum, milk, and tissue monensin concentrations in cattle with adequate and potentially toxic dietary levels of monensin: pharmacokinetics and diagnostic interpretation.

Used in both beef cattle and dairy cows, monensin can provide many health benefits but can, when unintended overexposures occur, result in adverse effects. Information on serum and tissue concentrations following overexposure and/or overt toxicosis which may aid in diagnostics and clinical outcome is lacking. The aim of this study was to determine concentrations of monensin in biological specimens following oral exposure for 10 days to an approved dose (1 mg/kg) and a higher dose (5 mg/kg) of monensin given daily on a body weight basis to 10 dairy cows. No deaths were reported; cows receiving 5 mg/kg showed early signs of toxicosis including depression, decreased feed intake, and diarrhea after 4 days of exposure. Histopathological findings were minimal in most cows. Pharmacokinetic modeling of the detected serum concentrations for the 1 and 5 mg/kg dose groups determined the Cmax , Tmax, and t1/2λ to be 0.87 and 1.68 ng/mL, 2.0 and 1.0 h, and 1.76 and 2.32 days, respectively. Mixed regression models showed that the dose level and days since last dose were significantly associated with monensin concentrations in all four tissues, and with cardiac troponin levels. The high dose resulted in a significant elevation of monensin in tissues at approximately 4.7 times compared to the monensin concentrations in the tissues of animals from the low-dose group. The cTnI concentrations in the high-dose group were 2.1 times that of cTnI in the low-dose group. Thus, the ability to diagnose monensin overexposure and/or toxicosis will improve from knowledge of biological monensin concentrations from this study.

Ethnicity, deprivation and screening: survival from breast cancer among screening-eligible women in the West Midlands diagnosed from 1989 to 2011.

BACKGROUND: Social inequalities in breast cancer survival are smaller when the cancer is screen-detected. We examined survival from screen-detected and non screen-detected breast cancer by ethnicity and deprivation. METHODS: Cancer registry data for 20 283 women aged 50-70 years, diagnosed between 1989-2011 and invited for screening, were linked with screening and ethnicity data. We examined Asian, Black and White groups, less deprived and middle/more deprived women. Net survival was estimated using ethnic- and deprivation-specific life tables. Estimates were corrected for lead-time bias and over-diagnosis. RESULTS: Net survival varied by screening history. No significant differences in survival were found by ethnicity. Five-year net survival was 90.0% (95% CI, 89.3-90.8%) in less deprived groups and 86.7% (85.9-87.4%) among middle/more deprived women. Screening benefitted all ethnic and both deprivation groups. Whether screen-detected or not, more deprived women had significantly poorer outcomes: 5-year net survival was 78.0% (76.7-79.2%) for deprived women who were not screen-detected compared with 94.0% (93.1-95.1%) for less deprived women who were screen-detected. CONCLUSIONS: The three ethnic groups differed little in their breast cancer survival. Although screening confers a survival benefit to all, there are still wide disparities in survival by deprivation. More needs to be done to determine what underlies these differences and tackle them.

Thermoelectricity in polymer composites due to fluctuation-induced tunneling.

Transport in heavily-doped polymer composites, characterized by localized charge regions, is examined in light of the recent interest in polymers for thermoelectric applications. The developed fundamental transport theory describes carrier tunneling between charged localizations by taking into account thermally induced fluctuations of the applied potential. A range of characteristic behaviors corresponding to experimental data are described. Deviations from the Wiedemann-Franz law are also identified. This novel theory enables the determination of factors dominating the transport in polymers and a comparison to tunneling without thermal fluctuations is also provided. The obtained asymptotic expressions for the conductivity, Seebeck coefficient, and carrier thermal conductivity are particularly useful for elucidating possible routes for thermoelectric transport control and optimization.

Diagnostic exercise: High mortality in a flock of chukar partridge chicks (Alectoris chukar) in California.

Mortality of 20% of a flock of 1000 chukar partridge chicks occurred over a 6-week period in Northern California from August to September 2012. Affected birds were 2 to 42 days old and died without premonitory clinical signs or after showing ruffled feathers and anorexia for 24 to 72 hours. Three carcasses were submitted for necropsy, 2 birds had hemorrhagic tracheitis grossly, and all 3 had lymphoplasmacytic and histiocytic myocarditis with myocardial necrosis microscopically. The differential diagnoses and the diagnostic workup to achieve a final diagnosis are discussed. The detection of 2 zoonotic agents in these birds makes this an interesting case from a public health perspective.

Advances in ion mobility spectrometry-mass spectrometry reveal key insights into amyloid assembly.

Interfacing ion mobility spectrometry to mass spectrometry (IMS-MS) has enabled mass spectrometric analyses to extend into an extra dimension, providing unrivalled separation and structural characterization of lowly populated species in heterogeneous mixtures. One biological system that has benefitted significantly from such advances is that of amyloid formation. Using IMS-MS, progress has been made into identifying transiently populated monomeric and oligomeric species for a number of different amyloid systems and has led to an enhanced understanding of the mechanism by which small molecules modulate amyloid formation. This review highlights recent advances in this field, which have been accelerated by the commercial availability of IMS-MS instruments. This article is part of a Special Issue entitled: Mass spectrometry in structural biology.

Fatty liver hemorrhagic syndrome in the backyard chicken: a retrospective histopathologic case series.

Fatty liver hemorrhagic syndrome, characterized by sudden death in overconditioned hens due to hepatic rupture and hemorrhage, is one of the leading noninfectious idiopathic causes of mortality in backyard chickens. Nutritional, genetic, environmental, and hormonal factors, or combinations of these, have been proposed yet not proven as the underlying cause. In an attempt to characterize the hepatic changes leading to the syndrome, this retrospective case study examined 76 backyard chickens that were diagnosed with fatty liver hemorrhagic syndrome between January 2007 and September 2012 and presented for necropsy to the diagnostic laboratory of the California Animal Health and Food Safety Laboratory System. A majority of the birds were female (99%), obese (97.5%), and in active lay (69.7%). Livers were examined histologically, and the degree of hepatocellular vacuolation (lipidosis), the reticular stromal architecture, the presence of collagenous connective tissue, and vascular wall changes were evaluated and graded using hematoxylin and eosin, Gomori's reticulin, oil red O, Masson's trichrome, and Verhoeff-Van Gieson stains. Interestingly, there was no correlation between lipidosis and reticulin grades; hepatocellular lipidosis was absent in 22% of the cases and mild in 26% of the cases. Additionally, there was evidence of repeated bouts of intraparenchymal hemorrhage before the acute "bleed-out" in 35.5% of the cases. These data are not supportive of the previously proposed causes and provide a framework for future studies to elucidate the pathogenesis of this condition. Furthermore, the data shown in this study support hemorrhagic liver syndrome as a more accurate name, as hepatic lipidosis is absent in a significant proportion of ruptured livers.

Diagnostic exercise: hemolysis and sudden death in lambs.

Within a 24-hour period, 7 out of 200 three- to four-week-old pastured Katahdin lambs died after showing clinical signs of hemoglobinuria, red-tinged feces, weakness, and recumbency. One of the lambs that was examined clinically before natural death also had abdominal pain, trembling, tachycardia, and severe anemia with a packed cell volume of 4%. Pathologic findings included icterus, hemoglobinuric nephrosis, dark red urine, pulmonary edema, hydrothorax, splenomegaly, and acute centrilobular to midzonal hepatocellular degeneration and necrosis with cholestasis. The differential diagnoses and diagnostic workup to achieve the diagnosis are briefly discussed.

Temporal and geographic clustering of polyomavirus-associated olfactory tumors in 10 free-ranging raccoons (Procyon lotor).

Reports of primary nervous system tumors in wild raccoons are extremely rare. Olfactory tumors were diagnosed postmortem in 9 free-ranging raccoons from 4 contiguous counties in California and 1 raccoon from Oregon within a 26-month period between 2010 and 2012. We describe the geographic and temporal features of these 10 cases, including the laboratory diagnostic investigations and the neuropathologic, immunohistochemical, and ultrastructural characteristics of these tumors in the affected animals. All 9 raccoons from California were found within a localized geographic region of the San Francisco Bay Area (within a 44.13-km radius). The tight temporal and geographic clustering and consistent anatomic location in the olfactory system of tumor types not previously described in raccoons (malignant peripheral nerve sheath tumors and undifferentiated sarcomas) strongly suggest either a common cause or a precipitating factor leading to induction or potentiation of neuro-oncogenesis and so prompted an extensive diagnostic investigation to explore possible oncogenic infectious and/or toxic causes. By a consensus polymerase chain reaction strategy, a novel, recently reported polyomavirus called raccoon polyomavirus was identified in all 10 tumors but not in the normal brain tissue from the affected animals, suggesting that the virus might play a role in neuro-oncogenesis. In addition, expression of the viral protein T antigen was detected in all tumors containing the viral sequences. We discuss the potential role of raccoon polyomavirus as an oncogenic virus.

The Patient's perspective: A review of the results from a radiotherapy patient experience survey in the North-West of England.

INTRODUCTION: A patient experience survey was undertaken for patients completing radiotherapy at the three Northwest of England Radiotherapy Providers. METHODS: A previously reported National Radiotherapy Patient Experience Survey was adapted and undertaken in the Northwest of England. Quantitative data was analysed to establish trends. Frequency distribution was applied to appraise the number of participants selecting each of the pre-determined responses. Thematic analysis of free text responses was conducted. RESULTS: The questionnaire received 653 responses from the 3 providers across seven departments. Thematic analysis revealed 3 themes; logistics, information and operational. CONCLUSION: The results indicate that the majority of patients are satisfied with their treatment and care. Patients' responses indicate areas for improvements. Expectancy theory states that an individual's satisfaction is related to the difference between expected service and the service received. Consequently, when reviewing services and developing improvement it is important to understand patients' expectations. This regional survey starts to capture what people receiving radiotherapy expect from the service and the professionals delivering their treatment. IMPLICATIONS FOR PRACTICE: This survey responses make a case for reviewing the information provision pre and post radiotherapy. This includes clarifying the understanding of consent for treatment including the intended benefits and potential late effects. There is an argument to offer information sessions prior to radiotherapy to achieve more relaxed and informed patients. A recommendation from this work is for the radiotherapy community undertake a national radiotherapy patient experience survey, facilitated via the 11 Radiotherapy ODNs. A national radiotherapy survey has multiple benefits to inform improvements in practice. This includes benchmarking services against national averages. This approach is aligned with the principles of the service specification in terms of reducing variation and increasing quality.

Children and young adults with profound and multiple learning disabilities: Evidence of intelligible subvocal language.

INTRODUCTION: Literature to date describes people with Profound and Multiple Learning Disabilities (PMLD) as pre-linguistic. In contrast, this study explores the existence and use of meaningful sub vocal (SV) language by twenty PMLD participants. METHOD: The SV utterances of 20 PMLD participants were recorded and amplified. Recordings were investigated for evidence of language content and structure, listener intelligibility, and acoustic and phonetic features relative to normal speech and whisper. RESULTS: Language content and structure was identified. Listener intelligibility was demonstrated. Acoustic and phonetic features relative to normal speech and whisper were evident. CONCLUSION: Twenty PMLD participants produced meaningful SV language intelligible to listeners. This study requires further robust research to fully confirm its findings but highlights implications for clinical practice and for understanding of PMLD communication competencies. This paper is accompanied by audio samples and transcriptions of recorded utterances to demonstrate the SV language produced by the participants. The quality of the samples varies due to the difficulties in recording SV utterances and the difficulties for participants in articulating clearly. This is not normal speech, but it is normal language. The listener may need to replay samples where the quality of the recording is poor.

Acute respiratory distress in an alpaca.

An alpaca was presented with a history of respiratory difficulty and death. Histology of the phrenic nerves and diaphragm revealed degenerative changes consistent with denervation atrophy, and a diagnosis of diaphragmatic paralysis was established. No gross or histological abnormalities were observed in the spinal cord or other organs. The etiology of the phrenic nerve neuropathy could not be determined. The need to examine phrenic nerves and diaphragm in camelids with respiratory distress is emphasized, as failure to examine these samples will preclude a diagnosis of diaphragmatic paralysis.

Pathology and immunohistochemical findings of west nile virus infection in psittaciformes.

West Nile virus (WNV) infection was diagnosed in 38 psittacine birds based on histology, immunohistochemistry, and reverse transcriptase polymerase chain reaction (RT-PCR). Rosellas (Platycercus spp, n = 13), conures (Enicognathus, Aratinga, and Nandayus spp, n = 6), and lorikeets (Trichoglossus spp, n = 6) represented the most commonly affected species. Clinical signs ranged from lethargy, ruffled feathers, anorexia, and weight loss in most birds to sudden death in others. Except for mild to moderate enlargement of liver and spleen, there were no significant gross lesions at necropsy. Histopathologic findings included lymphoplasmacytic and histiocytic hepatitis, interstitial nephritis, myocarditis, splenitis, enteritis, pancreatitis, and occasionally, encephalitis. Viral antigen was detected by immunohistochemistry in 34 of 35 hearts (97.1%), 29 of 32 pancreata (90.6%), 33 of 37 kidneys (89.2%), 31 of 35 intestines (88.6%), 27 of 33 gizzards (81.8%), 8 of 10 ovaries (80%), 27 of 34 spleens (79.4%), 30 of 38 livers (78.9%), 23 of 32 lungs (71.9%), 21 of 31 proventriculi (67.7%), 14 of 21 adrenals (66.7%), 10 of 16 testes (62.5%), 17 of 30 brains (56.7%), 15 of 27 skins (55.5%), 3 of 6 oviducts (50%), 15 of 34 skeletal muscles (44.1%), 11 of 27 crop or esophagus (40.7%), and 1 of 6 thymuses (16.7%). Kidney was positive for WNV by RT-PCR in all the cases tested. In conclusion, Psittaciformes are susceptible to West Nile virus infection, and WNV infections are often associated with nonspecific clinical signs and widespread viral distribution in this order of birds.

Socioeconomic inequalities in cancer survival in England after the NHS cancer plan.

BACKGROUND: Socioeconomic inequalities in survival were observed for many cancers in England during 1981-1999. The NHS Cancer Plan (2000) aimed to improve survival and reduce these inequalities. This study examines trends in the deprivation gap in cancer survival after implementation of the Plan. MATERIALS AND METHOD: We examined relative survival among adults diagnosed with 1 of 21 common cancers in England during 1996-2006, followed up to 31 December 2007. Three periods were defined: 1996-2000 (before the Cancer Plan), 2001-2003 (initialisation) and 2004-2006 (implementation). We estimated the difference in survival between the most deprived and most affluent groups (deprivation gap) at 1 and 3 years after diagnosis, and the change in the deprivation gap both within and between these periods. RESULTS: Survival improved for most cancers, but inequalities in survival were still wide for many cancers in 2006. Only the deprivation gap in 1-year survival narrowed slightly over time. A majority of the socioeconomic disparities in survival occurred soon after a cancer diagnosis, regardless of the cancer prognosis. CONCLUSION: The recently observed reduction in the deprivation gap was minor and limited to 1-year survival, suggesting that, so far, the Cancer Plan has little effect on those inequalities. Our findings highlight that earlier diagnosis and rapid access to optimal treatment should be ensured for all socioeconomic groups.