Experimental testing of a prototype cantilevered liquid-nitrogen-cooled silicon mirror.

This report presents testing of a prototype cantilevered liquid-nitrogen-cooled silicon mirror. This mirror was designed to be the first mirror for the new soft X-ray beamlines to be built as part of the Advanced Light Source Upgrade. Test activities focused on fracture, heat transfer, modal response and distortion, and indicated that the mirror functions as intended.

ORE identifies extreme expression effects enriched for rare variants.

MOTIVATION: Non-coding rare variants (RVs) may contribute to Mendelian disorders but have been challenging to study due to small sample sizes, genetic heterogeneity and uncertainty about relevant non-coding features. Previous studies identified RVs associated with expression outliers, but varying outlier definitions were employed and no comprehensive open-source software was developed. RESULTS: We developed Outlier-RV Enrichment (ORE) to identify biologically-meaningful non-coding RVs. We implemented ORE combining whole-genome sequencing and cardiac RNAseq from congenital heart defect patients from the Pediatric Cardiac Genomics Consortium and deceased adults from Genotype-Tissue Expression. Use of rank-based outliers maximized sensitivity while a most extreme outlier approach maximized specificity. Rarer variants had stronger associations, suggesting they are under negative selective pressure and providing a basis for investigating their contribution to Mendelian disorders. AVAILABILITY AND IMPLEMENTATION: ORE, source code, and documentation are available at https://pypi.python.org/pypi/ore under the MIT license. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Health and sustainable development: an analysis of 20 European voluntary national reviews.

OBJECTIVES: United Nations member states agreed Agenda 2030 and the Sustainable Development Goals (SDGs) in 2015. Countries report their progress through Voluntary National Reviews. In this paper, we look at the extent to which the World Health Organisation (WHO) Europe SDG Roadmap (the Roadmap) on Agenda 2030 implementation is reflected in the first 20 Voluntary National Reviews (VNRs) submitted from the WHO European region. In particular, we wanted to look at how integrated the three dimensions of sustainable development were, the identification of health co-benefits and potential-added value from the health sector. STUDY DESIGN: This was a semi-quantitative analysis of 20 VNRs using an ordinal scale (no evidence, limited evidence, good evidence). Results are presented as frequency tables by criteria and by country. METHODS: We devised an assessment template consisting of 41 criteria based on the nine key areas and a selection of the proposed areas for action in the Roadmap. Each VNR was then assessed and scored against these criteria to produce country-specific and average scores for each of the nine key areas and the 25 measures we selected. RESULTS: Countries generally have good evidence on key areas such as governance, monitoring, leaving no-one behind and multipartner cooperation. They have less evidence on the key areas of health determinants, healthy settings, health literacy and investing for health. Many countries link the economic and environmental dimensions of sustainable development but not the interplay with the social (health and well-being) dimension. Some countries specifically highlighted commitments to support developing nations but few recognised the impact of domestic policies on planetary boundaries or the health of future generations. CONCLUSIONS: We found little evidence that the health sector has had a major strategic influence on actions which affect wider determinants (or health co-benefits). The WHO Europe SDG Roadmap offers a means and an opportunity for redressing this weakness, but this may require health professionals to work within their communities across all three dimensions of sustainable development.

The sustainable development goals provide an important framework for addressing dangerous climate change and achieving wider public health benefits.

OBJECTIVES: To suggest how public health systems and the health sector can utilise the United Nation (UN) sustainable development goals (SDGs) to address climate change and other threats to future health and deliver immediate public health benefits. STUDY DESIGN AND METHODS: We examined UN and World Health Organisation guidance on SDGs and other published texts on systems thinking, integration, universality and co-benefits. RESULTS AND CONCLUSIONS: The UN SDGs are a set of globally agreed objectives to end poverty, protect all that makes the planet habitable and ensure that all people enjoy peace and prosperity. The SDGs integrate the three dimensions of sustainable development (economic, environmental and social), they apply to high-income countries as well as developing countries and there are mechanisms to hold countries to account. There are three crucial issues for public health. First, a systems approach to future proof health and social justice. Second, an evidence-based approach to aid communication, framing and engagement. And, third, the importance of interventions that deliver health co-benefits (i.e. both immediate and long-term benefits to health, equity and prosperity). The SDGs present public health professionals with an important opportunity to create the right conditions for a better future through the organised efforts of society.

Widespread prevalence of a CREBRF variant amongst Maori and Pacific children is associated with weight and height in early childhood.

OBJECTIVE: Investigating a large and ethnically diverse cohort from the Pacific region, we aimed to replicate and extend the recently reported findings that a CREBRF genetic variant is strongly associated with body mass index in Samoans. METHODS: A birth cohort of more than six thousand children was utilised. In this study, genotyping of two markers (rs12513649 and rs373863828) was undertaken in Maori, Pacific, European and Asian individuals in the cohort. RESULTS: We report that these CREBRF genetic variants are not confined to Samoans but are prevalent in all other Pacific populations sampled, including Maori. We found that the rs373863828 variant was significantly associated with growth at 4 years of age. On average, we observed allele-specific increases in weight (P=0·004, +455 g, s.e. 0.158), height (P=0·007, +0·70 cm, s.e. 0.26) and waist circumference (P=0·004, +0·70 cm, s.e. 0.24) at 4 years of age. The rs373863828 variant was not associated with birth weight (P=0·129). CONCLUSIONS: We replicated the finding that a CREBRF variant is associated with increased body mass. We then built on the original findings by demonstrating the prevalence of the rs12513649 and rs373863828 variants in multiple Pacific population groups and by demonstrating that the rs373863828 variant is associated with growth in early childhood. Pacific population groups experience a disproportionately high burden of obesity, starting in early childhood. This new knowledge offers potential for evidence-based interventions aimed at establishing healthy growth trajectories from the earliest possible age.

Discordance of patient and physician health status concerns in systemic lupus erythematosus.

Objectives To compare the health status concerns of patients with systemic lupus erythematosus (SLE) and of their physicians. Methods Cross-sectional questionnaire study of SLE patients and their treating physicians at a tertiary disease-specific outpatient clinic. Patients and physicians completed a questionnaire regarding their concern about specific disease manifestations and impact on quality of life. For each item, degree of concern was rated on a five-point Likert scale and summarized as median (interquartile range). Ratings between patients and physicians were compared using Mann-Whitney U tests. Results A total of 84 patients and 21 physicians participated. Patients' predominant concerns centred on function and fatigue, whereas physicians' concerns focused on SLE-related organ complications. Of the 10 highest ranked patient concerns, only two were common to the 10 highest ranked physician concerns, while physicians rated seven significantly differently; all 10 highest ranked physician concerns were rated significantly lower by patients. The three highest ranked patient concerns (fatigue, pain and feeling worn out) were routinely assessed by 47.6%, 42.9% and 9.5% of physicians, respectively. Conclusion There was significant discordance between SLE patient and physician health status concerns. Items which were ranked highly by patients were not assessed consistently by physicians, highlighting a significant gap in healthcare communication.

Use of granulocyte transfusions among haematology units in England and North Wales.

OBJECTIVES: To establish the current use of granulocyte transfusions in haematology patients and explore interest in further research. BACKGROUND: Granulocytes may be used for the treatment of severe infection in neutropenic patients or for primary or secondary prophylaxis. Clinical utility of granulocyte transfusions is unclear, and recent studies have demonstrated equivocal outcomes. Pooled granulocytes are the main granulocyte product used in England and Wales, but there are no data on the patterns of use and little consensus on accepted indications. METHODS: A survey was distributed to UK hospitals delivering intensive chemotherapy. Clinical scenarios were posed, with further questions on clinician experience of using granulocytes, availability of the product, barriers to use and interest in further research. RESULTS: The response rate was 57%; 34·9% of all responses were from allogeneic stem cell transplant centres. Paediatric centres comprised 9·5% respondents, and 19% centres had access to apheresis granulocytes. Of respondents, 58·7% had used granulocytes in the last 3 years, 89·2% of whom used granulocytes to treat refractory infection. There was little consensus on use of granulocytes in the given clinical scenarios even when patients clearly met national guideline criteria. Paediatric centres were overall more likely to recommend granulocyte use. The most frequently identified barrier to use of granulocytes was lack of evidence of effect. Of the respondents, 75% indicated a willingness to participate in further research. CONCLUSION: There remains a lack of consistency about use of granulocytes, which is unsurprising given the lack of clinical data to support their efficacy. We did, however, demonstrate a willingness to participate in further research.

Provision of cellular blood components to CMV-seronegative patients undergoing allogeneic stem cell transplantation in the UK: survey of UK transplant centres.

OBJECTIVES: To identify current UK practice with regards to provision of blood components for cytomegalovirus (CMV)-seronegative, potential, allogeneic stem cell recipients of seronegative grafts. BACKGROUND: Infection with CMV remains a major cause of morbidity and mortality after allogeneic stem cell transplantation (aSCT). CMV transmission has been a risk associated with the transfusion of blood components from previously exposed donors, but leucocyte reduction has been demonstrated to minimise this risk. In 2012, the UK Advisory Committee for the Safety of Tissues and Organs (SaBTO) recommended that CMV-unselected components could be safely transfused without increased risk of CMV transmission. METHODS: We surveyed UK aSCT centres to establish current practice. RESULTS: Fifteen adult and seven paediatric centres (75%) responded; 22·7% continue to provide components from CMV-seronegative donors. Reasons cited include the continued perceived risk of CMV transmission by blood transfusion, its associated morbidity and concerns regarding potential for ambiguous CMV serostatus in seronegative potential transplant recipients due to passive antibody transfer from CMV-seropositive blood donors, leading to erroneous donor/recipient CMV matching at transplant. CONCLUSIONS: The survey demonstrated a surprisingly high rate (22.7%) of centres continuing to provide blood components from CMV-seronegative donors despite SaBTO guidance.

Association between DPYD c.1129-5923 C>G/hapB3 and severe toxicity to 5-fluorouracil-based chemotherapy in stage III colon cancer patients: NCCTG N0147 (Alliance).

Severe (grade≥3) adverse events (AEs) to 5-fluorouracil (5-FU)-based chemotherapy regimens can result in treatment delays or cessation, and, in extreme cases, life-threatening complications. Current genetic biomarkers for 5-FU toxicity prediction, however, account for only a small proportion of toxic cases. In the current study, we assessed DPYD variants suggested to correlate with 5-FU toxicity, a deep intronic variant (c.1129-5923 C>G), and four variants within a haplotype (hapB3) in 1953 stage III colon cancer patients who received adjuvant FOLFOX±cetuximab. Logistic regression was used to assess multivariable associations between DPYD variant status and AEs common to 5-FU (5FU-AEs). In our study cohort, 1228 patients (62.9%) reported any grade≥3 AE (overall AE), with 638 patients (32.7%) reporting any grade≥3 5FU-AE. Only 32 of 78 (41.0%) patients carrying DPYD c.1129-5923 C>G and the completely linked hapB3 variants c.1236 C>G and c.959-51 T>C showed at least one grade≥3 5FU-AE, resulting in no statistically significant association (adjusted odds ratio=1.47, 95% confidence interval=0.90-2.43, P=0.1267). No significant associations were identified between c.1129-5923 C>G/hapB3 and overall grade≥3 AE rate. Our results suggest that c.1129-5923 C>G/hapB3 have limited predictive value for severe toxicity to 5-FU-based combination chemotherapy.

Relationship Between Metformin Use and Recurrence and Survival in Patients With Resected Stage III Colon Cancer Receiving Adjuvant Chemotherapy: Results From North Central Cancer Treatment Group N0147 (Alliance).

BACKGROUND: Preclinical and epidemiological data suggest that metformin might have antineoplastic properties against colon cancer (CC). However, the effect of metformin use on patient survival in stage III CC after curative resection is unknown. The survival outcomes were comparable regardless of the duration of metformin use. PATIENTS AND METHODS: Before randomization to FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin) with or without cetuximab, 1,958 patients with stage III CC enrolled in the N0147 study completed a questionnaire with information on diabetes mellitus (DM) and metformin use. Cox models were used to assess the association between metformin use and disease-free survival (DFS), overall survival (OS), and the time to recurrence (TTR), adjusting for clinical and/or pathological factors. RESULTS: Of the 1,958 patients, 1,691 (86%) reported no history of DM, 115 reported DM with metformin use (6%), and 152 reported DM without metformin use (8%). The adjuvant treatment arms were pooled, because metformin use showed homogeneous effects on outcomes across the two arms. Among the patients with DM (n = 267), DFS (adjusted hazard ratio [aHR], 0.90; 95% confidence interval [CI], 0.59-1.35; p = .60), OS (aHR, 0.99; 95% CI, 0.65-1.49; p = .95), and TTR (aHR, 0.87; 95% CI, 0.56-1.35; p = .53) were not different for the metformin users compared with the nonusers after adjusting for tumor and patient factors. The survival outcomes were comparable regardless of the duration of metformin use (<1, 1-5, 6-10, ≥11 years) before randomization (ptrend = .64 for DFS, ptrend = .84 for OS, and ptrend = .87 for TTR). No interaction effects were observed between metformin use and KRAS, BRAF mutation status, tumor site, T/N stage, gender, or age. CONCLUSIONS: Patients with stage III CC undergoing adjuvant chemotherapy who used metformin before the diagnosis of CC experienced DFS, OS, and TTR similar to those for non-DM patients and DM patients without metformin use. IMPLICATIONS FOR PRACTICE: The present study did not find any relationship between metformin use or its duration and disease-free survival, time to recurrence, and overall survival in a large cohort of patients with resected stage III colon cancer receiving adjuvant FOLFOX (folinic acid, fluorouracil, oxaliplatin)-based chemotherapy. This relationship was not modified by KRAS or BRAF mutation or DNA mismatch repair status. Metformin use did not increase or decrease the likelihood of chemotherapy-related grade 3 or higher adverse events.

Plasma Low-density Lipoprotein Receptor-related Protein 1 Concentration is not Associated with Human Abdominal Aortic Aneurysm Presence.

OBJECTIVE/BACKGROUND: Recent genetic data suggest that a polymorphism of LRP1 is an independent risk factor for abdominal aortic aneurysm (AAA). The aims of this study were to assess whether plasma and aortic concentrations of low-density lipoprotein receptor-related protein 1 (LRP1) are associated with AAA, and to investigate the possible relevance of LRP1 to AAA pathophysiology. METHODS: Three analyses were conducted. First, plasma LRP1 concentrations were measured in community-dwelling men with and without AAA (n = 189 and n = 309, respectively) using enzyme-linked immunosorbent assay. Second, Western blotting analyses were employed to compare the expression of LRP1 protein in aortic biopsies collected from patients with AAA and nonaneurysmal postmortem donors (n = 6/group). Finally, the effect of in vitro LRP1 blockade on matrix metalloprotease 9 (MMP9) clearance by vascular smooth muscle cells was assessed by zymography. RESULTS: Plasma LRP1 concentrations did not differ between groups of men with and without AAA (median concentration 4.56 µg/mL [interquartile range {IQR} (3.39-5.96)] and 4.43 µg/mL [IQR 3.44-5.84], respectively; p = .48), and were not associated with AAA after adjusting for other risk factors (odds ratio 1.10 [95% confidence interval: 0.91-1.32]; p = 0.35). In contrast, LRP1 expression was approximately 3.4-fold lower in aortic biopsies recovered from patients with AAA compared with controls (median [IQR] expression 1.72 [0.94-3.14] and 5.91 [4.63-6.94] relative density units, respectively; p < .01). In vitro LRP1 blockade significantly reduced the ability of vascular smooth muscle cells to internalize extracellular MMP9. CONCLUSIONS: These data suggest that aortic but not circulating LRP1 is downregulated in patients with AAA and indicates a possible role for this protein in clearing an aneurysm-relevant ligand.

Transfusion of CMV-unselected blood components may lead to inappropriate donor selection for patients subsequently undergoing allogeneic stem cell transplant.

OBJECTIVES: To establish whether passive transfer of cytomegalovirus (CMV) IgG via transfusion results in ambiguous serostatus in patients undergoing allogeneic stem cell transplant (SCT). BACKGROUND: CMV infection causes significant morbidity following allogeneic SCT. Leucocyte-reduced blood products from CMV-seropositive donors carry minimal risk of CMV transmission, however, may result in passive transfer of CMV IgG, leading to unintentionally CMV-mismatched recipient/donors with significant consequences. METHODS: We undertook a retrospective single-centre analysis of CMV IgG results in patients transfused with CMV-unselected (CMV-U) leucocyte-reduced components subsequently undergoing SCT. RESULTS: Of patients with >1CMV IgG measured, 8/29 (27.6%) had discordant results; all were transfused between negative and subsequent positive results and were thought to have passively acquired CMV IgG. One likely CMV naïve patient was recorded as CMV seropositive and underwent transplant with a seropositive donor, developing CMV infection which required treatment. CONCLUSIONS: Passive transfer of CMV IgG is an unanticipated consequence of transfusion of CMV-U products and has the potential to cause morbidity. Inaccurate recording of serostatus pre-transplant has wider implications for data reporting on transplant outcomes. When transfusing CMV-U components pre-transfusion CMV IgG samples must be taken and transfusion history must be considered when interpreting results.

Equivalence of online and clinician administration of a patellar tendinopathy risk factor and severity questionnaire.

The VISA-P is a questionnaire for assessing the severity of patellar tendinopathy (PT). Our study aim was to evaluate the equivalence of self-administration of the VISA-P online with the addition of risk factor questions to develop a tool suitable for high-volume remote use. A crossover study design with 107 subjects was used to determine equivalence between online and clinician administration. Three population groups were used to ensure construct validity. Online vs clinician administration revealed an intraclass correlation (ICC) of 0.79 [confidence interval (CI): 0.68-0.86] for the VISA-P with a systematic significant difference of 4.99, which is not clinically meaningful. Poor ICCs were seen for questions 7 and 8 of the VISA-P (0.37 and 0.47, respectively) in comparison with earlier questions. There were statistically significant differences between population groups for the VISA-P. The ICC for risk factor questions was excellent at 0.89 (CI: 0.84-0.93) with no mean difference (P = 1.00). The online questionnaire enables equivalent collection of VISA-P data and risk factor information and may well improve further with the suggested modifications to the instructions for questions 7 and 8. There is potential to use this questionnaire electronically to generate large databases in future research.

Presentation of a benign fibroepithelial polyp with frank haematuria: an unusual diagnosis.

INTRODUCTION: Fibroepithelial polyps are rare benign lesions which can mimic malignant disease symptomatically and radiologically. They should form part of the differential diagnosis in patients presenting with frank haematuria but they can present a diagnostic dilemma for clinicians. CASE PRESENTATION: This is a case of a 30-year-old female who initially presented with a small palpable urethral lump, thought to be a urethral caruncle by her general practitioner, obstructive voiding and intermittent frank painless haematuria. A rigid cystoscopy identified a polypoid lesion protruding out of the left ureteric orifice. This was resected and pathology showed it to be a fibroepithelial polyp. A post-operative computerized tomography scan showed no hydronephrosis on either side and no lymphadenopathy was identified but the distal left ureter could not be visualised. Further resection with a flexible ureteroscopy confirmed the presence of a benign fibroepithelial polyp and the stalk remnant was ablated with a laser. CONCLUSION: Fibroepithelial polyps mimic malignant disease symptomatically and radiologically and need to be considered in the differential diagnosis of frank haematuria.

Experience using a rapid assay for aneuploidy and microdeletion/microduplication detection in over 2,900 prenatal specimens.

BACKGROUND: While microarray testing can identify chromosomal abnormalities missed by karyotyping, its prenatal use is often avoided in low-risk pregnancies due to the possible identification of variants of uncertain significance (VOUS). METHODS: We tested 2,970 prenatal samples of all referral indications using a rapid BACs-on-Beads-based assay with probes for sex chromosomes, common autosomal aneuploidies, and 20 microdeletion/microduplication syndromes, designed as an alternative to microarray in low-risk pregnancies and an alternative to rapid aneuploidy testing in pregnancies also undergoing microarray analysis. RESULTS: Interpretable results were obtained in 2,940 cases (99.0%), with 89% receiving results in 1 day. Aneuploidies were detected in 7.3% and partial chromosome abnormalities in 0.45% (n = 13), including 5 referred for maternal age, abnormal maternal serum screen, or isolated ultrasound markers. The added detection above karyotype was 1 in 745 in lower-risk cases with normal ultrasounds or isolated ultrasound markers/increased nuchal measurements and 1 in 165 for fetuses with structural/growth abnormalities. Neither false negatives nor false positives were found within test limitations. Female polyploidy could not be detected, while polyploidies with Y chromosomes were suspected and confirmed through additional analysis. CONCLUSION: When combined with karyotyping, this assay provides increased interrogation of specific chromosomal regions, while limiting VOUS identification.

Epidemiologic Investigations into Outbreaks of Rift Valley Fever in Humans, South Africa, 2008-2011.

Rift Valley fever (RVF) is an emerging zoonosis posing a public health threat to humans in Africa. During sporadic RVF outbreaks in 2008-2009 and widespread epidemics in 2010-2011, 302 laboratory-confirmed human infections, including 25 deaths (case-fatality rate, 8%) were identified. Incidence peaked in late summer to early autumn each year, which coincided with incidence rate patterns in livestock. Most case-patients were adults (median age 43 years), men (262; 87%), who worked in farming, animal health or meat-related industries (83%). Most case-patients reported direct contact with animal tissues, blood, or other body fluids before onset of illness (89%); mosquitoes likely played a limited role in transmission of disease to humans. Close partnership with animal health and agriculture sectors allowed early recognition of human cases and appropriate preventive health messaging.

Five new species of the genus Leucania Ochsenheimer in Central America (Lepidoptera: Noctuidae).

Five new species of the noctuid genus Leucania in Central America are described: L. mopan Adams and McCabe, sp. nov., L. merga Adams and McCabe, sp. nov., L. championi Adams and McCabe, sp. nov., L. colorada McCabe and Adams, sp. nov., L. sororia McCabe and Adams, sp. nov. The internal genitalia are key to resolving the taxonomy in this genus; in particular, the morphology of the male everted endophallus (vesica) and the female bursa copulatrix jointly resolve taxonomic confusion among cryptic species near L. albifasciata, L. oaxacana and L. humidicola. We recognize the valvular pore plate and the "poma" (bubble-like structure at base of valvae) as generic synapomorphies for Leucania. Lappets (inflatable pouches on the outer aspect of the valvae) are newly described. Descriptions and color illustrations of the imagos, male valvae, everted endophalli, and the female bursae copulatrix are provided for all newly described species and selected congeners to aid identification. Additional nomenclatorial actions are: Leucania complicata Strecker, 1898 rest. stat.; Leucania februalis Hill, 1924 syn. nov., a junior synonym of L. humidicola; Leucania elephas Troubridge 2020 syn. nov., a junior synonym of L. humidicola.