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Blood pressure measurement is a marker of antenatal care quality. In well resourced settings, lower blood pressure cutoffs for hypertension are associated with adverse pregnancy outcomes. We aimed to study the associations between blood pressure thresholds and adverse outcomes and the diagnostic test properties of these blood pressure cutoffs in low-resource settings.We did a secondary analysis of data from 22 intervention clusters in the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials (NCT01911494) in India (n=6), Mozambique (n=6), and Pakistan (n=10). We included pregnant women aged 15-49 years (12-49 years in Mozambique), identified in their community by trained community health workers, who had data on blood pressure measurements and outcomes. The trial was unmasked. Maximum blood pressure was categorised as: normal blood pressure (systolic blood pressure [sBP]120 mm Hg and diastolic blood pressure [dBP]80 mm Hg), elevated blood pressure (sBP 120-129 mm Hg and dBP80 mm Hg), stage 1 hypertension (sBP 130-139 mm Hg or dBP 80-89 mm Hg, or both), non-severe stage 2 hypertension (sBP 140-159 mm Hg or dBP 90-109 mm Hg, or both), or severe stage 2 hypertension (sBP ≥160 mm Hg or dBP ≥110 mm Hg, or both). We classified women according to the maximum blood pressure category reached across all visits for the primary analyses. The primary outcome was a maternal, fetal, or neonatal mortality or morbidity composite. We estimated dose-response relationships between blood pressure category and adverse outcomes, as well as diagnostic test properties.Between Nov 1, 2014, and Feb 28, 2017, 21 069 women (6067 in India, 4163 in Mozambique, and 10 839 in Pakistan) contributed 103 679 blood pressure measurements across the three CLIP trials. Only women with non-severe or severe stage 2 hypertension, as discrete diagnostic categories, experienced more adverse outcomes than women with normal blood pressure (risk ratios 1·29-5·88). Using blood pressure categories as diagnostic thresholds (women with blood pressure within the category or any higher category vs those with blood pressure in any lower category), dose-response relationships were observed between increasing thresholds and adverse outcomes, but likelihood ratios were informative only for severe stage 2 hypertension and maternal CNS events (likelihood ratio 6·36 [95% CI 3·65-11·07]) and perinatal death (5·07 [3·64-7·07]), particularly stillbirth (8·53 [5·63-12·92]).In low-resource settings, neither elevated blood pressure nor stage 1 hypertension were associated with maternal, fetal, or neonatal mortality or morbidity adverse composite outcomes. Only the threshold for severe stage 2 hypertension met diagnostic test performance standards. Current diagnostic thresholds for hypertension in pregnancy should be retained.University of British Columbia, the BillMelinda Gates Foundation.

Summary Background To overcome the three delays in triage, transport and treatment that underlie adverse pregnancy outcomes, we aimed to reduce all-cause adverse outcomes with community-level interventions targeting women with pregnancy hypertension in three low-income countries. Methods In this individual participant-level meta-analysis, we de-identified and pooled data from the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised controlled trials in Mozambique, Pakistan, and India, which were run in 2014–17. Consenting pregnant women, aged 12–49 years, were recruited in their homes. Clusters, defined by local administrative units, were randomly assigned (1:1) to intervention or control groups. The control groups continued local standard of care. The intervention comprised community engagement and existing community health worker-led mobile health-supported early detection, initial treatment, and hospital referral of women with hypertension. For this meta-analysis, as for the original studies, the primary outcome was a composite of maternal or perinatal outcome (either maternal, fetal, or neonatal death, or severe morbidity for the mother or baby), assessed by unmasked trial surveillance personnel. For this analysis, we included all consenting participants who were followed up with completed pregnancies at trial end. We analysed the outcome data with multilevel modelling and present data with the summary statistic of adjusted odds ratios (ORs) with 95% CIs (fixed effects for maternal age, parity, maternal education, and random effects for country and cluster). This meta-analysis is registered with PROSPERO, CRD42018102564. Findings Overall, 44 clusters (69 330 pregnant women) were randomly assigned to intervention (22 clusters [36 008 pregnancies]) or control (22 clusters [33 322 pregnancies]) groups. 32 290 (89·7%) pregnancies in the intervention group and 29 698 (89·1%) in the control group were followed up successfully. Median maternal age of included women was 26 years (IQR 22–30). In the intervention clusters, 6990 group and 16 691 home-based community engagement sessions and 138 347 community health worker-led visits to 20 819 (57·8%) of 36 008 women (of whom 11 095 [53·3%] had a visit every 4 weeks) occurred. Blood pressure and dipstick proteinuria were assessed per protocol. Few women were eligible for methyldopa for severe hypertension (181 [1%] of 20 819) or intramuscular magnesium sulfate for pre-eclampsia (198 [1%]), of whom most accepted treatment (162 [89·5%] of 181 for severe hypertension and 133 [67·2%] of 198 for pre-eclampsia). 1255 (6%) were referred to a comprehensive emergency obstetric care facility, of whom 864 (82%) accepted the referral. The primary outcome was similar in the intervention (7871 [24%] of 32 290 pregnancies) and control clusters (6516 [22%] of 29 698; adjusted OR 1·17, 95% CI 0·90–1·51; p=0·24). No intervention-related serious adverse events occurred, and few adverse effects occurred after in-community treatment with methyldopa (one [2%] of 51; India only) and none occurred after in-community treatment with magnesium sulfate or during transport to facility. Interpretation The CLIP intervention did not reduce adverse pregnancy outcomes. Future community-level interventions should expand the community health worker workforce, assess general (rather than condition-specific) messaging, and include health system strengthening. Funding University of British Columbia, a grantee of the Bill & Melinda Gates Foundation.

Supplemental Digital Content is available in the text., In pregnancy in well-resourced settings, limited data suggest that higher blood pressure (BP) visit-to-visit variability may be associated with adverse pregnancy outcomes. Included were pregnant women in 22 intervention clusters of the CLIP (Community-Level Interventions for Preeclampsia) cluster randomized trials, who had received at least 2 prenatal contacts from a community health worker, including standardized BP measurement. Mixed-effects adjusted logistic regression assessed relationships between pregnancy outcomes and both BP level (median [interquartile range]) and visit-to-visit variability (SD and average real variability [ARV], adjusted for BP level), among all women and those who became hypertensive. The primary outcome was the CLIP composite of maternal and perinatal mortality and morbidity. Among 17 770 pregnancies, higher systolic and diastolic BP levels were associated with increased odds of the composite outcome per 5 mm Hg increase in BP (odds ratio [OR], 1.05 [95% CI, 1.03–1.07] and OR, 1.08 [1.06–1.11], respectively). Higher BP visit-to-visit variability was associated with increased odds, per a SD increase in BP variability measure, of (1) hypertension (systolic: OR, 2.09 [1.98–2.21] for SD and 1.52 [1.45–1.60] for ARV; diastolic: OR, 2.70 [2.54–2.87] for SD and 1.86 [1.76–1.96] for ARV); and (2) the composite outcome (systolic: OR, 1.10 [1.06–1.14] for SD and 1.06 [1.02–1.10] for ARV; diastolic: OR, 1.07 [1.03–1.11] for SD and 1.06 [1.02–1.09] for ARV). In 3 less-developed countries, higher BP level and visit-to-visit variability predicted adverse pregnancy outcomes, providing an opportunity for high-definition medicine.

Background Incomplete vital registration systems mean that causes of death during pregnancy and childbirth are poorly understood in low-income and middle-income countries. To inform global efforts to reduce maternal mortality, we compared physician review and computerised analysis of verbal autopsies (interpreting verbal autopsies [InterVA] software), to understand their agreement on maternal cause of death and circumstances of mortality categories (COMCATs) in the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials. Methods The CLIP trials took place in India, Pakistan, and Mozambique, enrolling pregnant women aged 12-49 years between Nov 1, 2014, and Feb 28, 2017. 69 330 pregnant women were enrolled in 44 clusters (36 008 in the 22 intervention clusters and 33 322 in the 22 control clusters). In this secondary analysis of maternal deaths in CLIP, we included women who died in any of the 22 intervention clusters or 22 control clusters. Trained staff administered the WHO 2012 verbal autopsy after maternal deaths. Two physicians (and a third for consensus, if needed) reviewed trial surveillance data and verbal autopsies, and, in intervention clusters, community health worker-led visit data. They determined cause of death according to the WHO International Classification of Diseases-Maternal Mortality (ICD-MM). Verbal autopsies were also analysed by InterVA computer models (versions 4 and 5) to generate cause of death. COMCAT analysis was provided by InterVA-5 and, in India, by physician review of Maternal Newborn Health Registry data. Causes of death and COMCATs assigned by physician review, Inter-VA-4, and InterVA-5 were compared, with agreement assessed with Cohen's κ coefficient. Findings Of 61 988 pregnancies with successful follow-up in the CLIP trials, 143 maternal deaths were reported (16 deaths in India, 105 in Pakistan, and 22 in Mozambique). The maternal death rate was 231 (95% CI 193-268) per 100 000 identified pregnancies. Most deaths were attributed to direct maternal causes (rather than indirect or undetermined causes as per ICD-MM classification), with fair to good agreement between physician review and InterVA-4 (κ=0·56 [95% CI 0·43-0·66]) or InterVA-5 (κ=0·44 [0·30-0·57]), and InterVA-4 and InterVA-5 (κ=0·72 [0·60-0·84]). The top three causes of death were the same by physician review, InterVA-4, and InterVA-5 (ICD-MM categories obstetric haemorrhage, non-obstetric complications, and hypertensive disorders); however, attribution of individual patient deaths to obstetric haemorrhage varied more between methods (physician review, 38 [27%] deaths; InterVA-4, 69 [48%] deaths; and InterVA-5, 82 [57%] deaths), than did attribution to non-obstetric causes (physician review, 39 [27%] deaths; InterVA-4, 37 [26%] deaths; and InterVA-5, 28 [20%] deaths) or hypertensive disorders (physician review, 23 [16%] deaths; InterVA-4, 25 [17%] deaths; and InterVA-5, 24 [17%] deaths). Agreement for all nine ICD-MM categories was fair for physician review versus InterVA-4 (κ=0·48 [0·38-0·58]), poor for physician review versus InterVA-5 (κ=0·36 [0·27-0·46]), and good for InterVA-4 versus InterVA-5 (κ=0·69 [0·59-0·79]). The most commonly assigned COMCATs by InterVA-5 were emergencies (68 [48%] of 143 deaths) and health systems (62 [43%] deaths), and by physician review (India only) were health systems (seven [44%] of 16 deaths) and inevitability (five [31%] deaths); agreement between InterVA-5 and physician review (India data only) was poor (κ=0·04 [0·00-0·15]). Interpretation Our findings indicate that InterVA-5 is less accurate than InterVA-4 at ascertaining causes and circumstances of maternal death, when compared with physician review. Our results suggest a need to improve the next iteration of InterVA, and for researchers and clinicians to preferentially use InterVA-4 when recording maternal deaths. Funding University of British Columbia (grantee of the Bill & Melinda Gates Foundation).

ZusammenfassungDiese DVO Leitlinien, die in erster Linie für Allgemeinmediziner und Spezialisten für Knochenerkrankungen bestimmt sind, sollten von allen im klinischen und ambulanten Bereich tätigen medizinischen Fachkräften angewendet werden. Ziel der Leitlinie ist die Verbesserung der Diagnose, Prävention und Behandlung von Osteoporose und der Folgen der Erkrankung auf der Grundlage evidenzbasierter Medizin.Klare Empfehlungen, welche Patienten zu diagnostizieren und behandeln sind (basierend auf Risikofaktoren [einschließlich sekundärer Osteoporose]) sowie Primär-, Sekundär- oder Tertiärprävention werden dargestellt, mit dem Schwerpunkt auf der postmenopausalen Osteoporose und der Osteoporose bei Männern.Die Identifizierung von Patienten mit einem hohen Risiko für Frakturen wird hervorgehoben, und spezifische Schwellenwerte für die Intervention sind definiert (20 % Hüftfrakturrisiko innerhalb von 10 Jahren diagnostischer Schwellenwert, 30 % Hüftfrakturrisiko innerhalb von 10 Jahren therapeutische Schwelle). Die Diagnose von Osteoporose basiert auf der Anamnese des Patienten, der körperlichen Untersuchung, dem Funktionstest (z. B. Timed Up and Go Test), konventionellen Röntgenaufnahmen der Brust- und Lendenwirbelsäule und der Bestimmung der Knochenmineraldichte (BMD) durch das DXA Verfahren.Die Anamnese ist entscheidend für die Abschätzung des Frakturrisikos auf der Grundlage von 40 wissenschaftlich überprüften Risikofaktoren, die das Frakturrisiko mindestens verdoppeln (z. B. Begleiterkrankungen, Hüftfrakturen in der Familie, prävalente Frakturen an jedem Ort, Lebensstil, Anwendung von Medikamenten, körperliche Aktivität und Stürze). Röntgenaufnahmen der Brust- und Lendenwirbelsäule sind wichtig, um prävalente Wirbelkörperfrakturen zu erkennen. Beim Fehlen eines großen Traumas kann jede Fraktur bei Erwachsenen über dem Alter von 50 Jahren eine Diagnose von Osteoporose nahelegen, mit dem höchsten Risiko für eine nachfolgende Fraktur innerhalb einer kurzen Zeit nach der ersten Fraktur. BMD-Messungen mit DXA sind wichtig, um das individuelle Frakturrisiko besser abschätzen zu können. Eine grundlegende Laboruntersuchung ist obligatorisch, um verschiedene Formen der sekundären Osteoporose ausschließen zu können.Der DVO-Patientenfindungs-Algorithmus basiert auf dem Geschlecht, Alter, Knochenmineraldichte und vorbestehenden Frakturen als wichtigste Informationen. Die Indikation für eine aktive anti-osteoporotische Therapie kann durch multiple Risikofaktoren modifiziert und verfeinert werden. Dieser Algorithmus wurde seit dem Richtlinien-Update 2006 verwendet und wurde entsprechend der internationalen Literatur zu Risikofaktoren für Osteoporose und osteoporotische Frakturen aktualisiert und angepasst.Die Behandlung der Osteoporose enthält viele Therapiepfeiler. Zusammen mit Empfehlungen für Bewegung, Physiotherapie und Sturzprävention sowie Ernährung (z. B. Calcium, Vit. D), werden pharmakologische Behandlungen basierend auf evidenzbasierter Medizin empfohlen. Die aktiven Anti-Osteoporose-Medikamente müssen für die Indikation postmenopausale Osteoporose und männliche Osteoporose in Deutschland, Österreich und der Schweiz zugelassen sein. Das Management und die Vorbeugung von häufigen oder seltenen Nebenwirkungen aufgrund von Anti-Osteoporose-Behandlungen, die in der klinischen Praxis angewendet werden, werden ebenfalls detailliert behandelt.

Globally, breast cancer continues to be a major concern in women's health. Lifestyle related risk factors, specifically excess adipose tissue (adiposity) has reached epidemic proportions and has been identified as a major risk factor in the development of breast cancer. Dysfunctional adipose tissue has evoked research focusing on its association with metabolic-related conditions, breast cancer risk and progression. Adipose dysfunction in coordination with immune cells and inflammation, are responsible for accelerated cell growth and survival of cancer cells. Recently, evidence also implicates adiposity as a potential risk factor for chemotherapy resistance. Chemotherapeutic agents have been shown to negatively impact adipose tissue. Since adipose tissue is a major storage site for fatty acids, it is not unlikely that these negative effects may disrupt adipose tissue homeostasis. It is therefore argued that fatty acid composition may be altered due to the chemotherapeutic pharmacokinetics, which in turn could have severe health related outcomes. The underlying molecular mechanisms elucidating the effects of fatty acid composition in adiposity-linked drug resistance are still unclear and under explored. This review focuses on the potential role of adiposity in breast cancer and specifically emphasizes the role of fatty acids in cancer progression and treatment resistance.

Background People at risk of developing rheumatoid arthritis (RA) may be candidates for interventions aimed at preventing RA development [1]. The identification of such “at risk” populations includes testing for genetic and other (e.g. autoantibody) biomarkers. However, little is known about the people9s perspectives on these tests, how they react and cope when identified as being a person “at risk” and what their unmet needs are. Objectives To expore the perceptions about RA and predictive testing and to understand the various reactions and coping strategies used when identified as being at risk of developing RA from the perspective of those directly concerned. Methods As part of the EuroTEAM project, a qualitative interview study with people who were informed of being at risk of developing RA was conducted. An interview schedule was developed and pilot-tested. Interviews were audio-recorded, transcribed verbatim and analyzed using thematic analysis. Results A total of 34 individuals (with rheumatoid factor and/or ACPA positive) already informed of being at risk of developing RA participated in the study, from Austria (n=15), Germany (n=15), and the UK (n=4). In Vienna, people who had been tested within an expanded health exam participated in this study. In Birmingham and Erlangen, people with arthralgia were recruited from the outpatient clinics. Analysis of the interview data revealed five overarching themes related to predictive testing in the context of RA (Figure). There were differences between the perceptions of althralgia patients and asymptomatic individuals. People suffering from pain were much more frightened and worried when informed of being at risk of developing RA. As a consequence, they modified their lives in a larger extent and had greater knowledge about RA than those without any symptoms who were rather surprised, kept calm and hardly changed their lifestyle after being tested positive. Allmost all participants in this study would appreciate precise predictive tests in the context of RA. However, more than half of them would refuse synovial biopsy (even if this could help quantify risk more accurately) or preventive medication. Recommendations for an improved procedure of predictive testing in the field of RA were given, which could promote uptake of preventive strategies. Conclusions Participants showed large differences in views about predictive testing in the context of RA risk and offered specific suggestions that should be incorporated into service design and delivery in the context of future predictive testing programmes. These findings may also be relevant to prediction and prevention in the context of other diseases where multiple genetic risk factors interact with environmental risk factors to drive disease development. References van Steenbergen, H.W., T.W. Huizinga, and A.H. van der Helm-van Mil, The preclinical phase of rheumatoid arthritis: what is acknowledged and what needs to be assessed? Arthritis Rheum, 2013. 65(9): p. 2219–32. Disclosure of Interest None declared

Our aim was to evaluate the histological association of mandibular solid and multicystic ameloblastoma with the inferior alveolar nerve, both in situ and in segments of the nerve that had been removed separately, to assess the feasibility of preserving the nerve during resection of mandibular ameloblastomas. In this prospective histological examination of 13 resected hemimandibulectomy specimens, we studied the proximity of tumour cells to the inferior alveolar nerve. In group 1 (n=8) this association was examined with the nerve still within the mandibular segment after resection, while in group 2 (n=5) the nerve was removed from the resected tumour and examined separately. Perineural and intraneural involvement of the ameloblastoma with the nerve was confirmed in 5 cases in group 1 and 2 cases in group 2. Tumour cells abutted the nerve directly in group 1. In group 2 tumour was removed with, and found within, the nerve. On this evidence we cannot recommend preservation of the inferior alveolar nerve during operation for large, advanced, mandibular ameloblastomas.

OBJECTIVE: Hemochromatosis is an inherited disease with iron overload and joint involvement resembling osteoarthritis. To determine the rate of joint replacement surgery in patients with hemochromatosis, we performed a cross-sectional cohort study. METHODS: A total of 199 individuals with hereditary hemochromatosis were included. The prevalence of joint replacement surgery in hip, knee, and ankle joints because of secondary osteoarthritis was assessed. Data were compared with 917 healthy subjects from the population-based Bruneck study. RESULTS: A total of 32 of 199 individuals with hemochromatosis received joint replacement surgery with a total number of 52 joints replaced. Compared with expected rates in healthy individuals, patients with hemochromatosis had a significantly higher risk for joint replacement surgery (odds ratio 9.0; confidence interval, 4.6-17.4). Joint replacement occurred significantly earlier in life in patients with hemochromatosis; 21.9% of the patients with hemochromatosis and 1.7% of healthy individuals required joint replacement before the age of 50 years (P.0027). Moreover, patients with hemochromatosis were more likely to require multiple joint replacements (8.5%) than the control group (expected rate 0.3%; P.0001). CONCLUSION: Hemochromatosis is a risk factor for joint replacement surgery because of severe secondary osteoarthritis.

Objective. Cross-cultural translation of patient-reported outcome measures (PROMs) is a lengthy process, often performed professionally. Cognitive interviewing assesses patient comprehension of PROMs. The objective was to evaluate the usefulness of cognitive interviewing to assess translations and compare professional (full) with non-professional (simplified) translation processes. Methods. A full protocol used for the Bristol RA Fatigue Multi-dimensional Questionnaire and Numerical Rating Scale (BRAF-MDQ, BRAF-NRS) was compared with a simplified protocol used for the RA Impact of Disease scale (RAID). RA patients in the UK, France, the Netherlands, Germany, Spain and Sweden completed the PROMs during cognitive interviewing (BRAFs in the UK were omitted as these were performed during development). Transcripts were deductively analysed for understanding, information retrieval, judgement and response options. Usefulness of cognitive interviewing was assessed by the nature of problems identified, and translation processes by percentage of consistently problematic items (⩾40% patients per country with similar concerns). Results. Sixty patients participated (72% women). For the BRAFs (full protocol) one problematic item was identified (of 23 items × 5 languages, 1/115 = 0.9%). For the RAID (simplified protocol) two problematic items were identified (of 7 items × 6 languages, 2/42 = 4.8%), of which one was revised (Dutch). Coping questions were problematic in both PROMs. Conclusion. Conceptual and cultural challenges though rare were important, as identified by formal evaluation, demonstrating that cognitive interviewing is crucial in PROM translations. Proportionately fewer problematic items were found for the full than for the simplified translation procedure, suggesting that while both are acceptable, professional PROM translation might be preferable. Coping may be a particularly challenging notion cross-culturally.

In recent years, an increasing amount of literature is emerging on candidate urine and blood-based biomarkers associated with incidence and severity of preeclampsia (PE) in pregnant women. While enthusiasm on the usefulness of several of these markers in predicting PE is evolving, essentially all work so far has focused on the needs of high-resource settings and high-income countries, resulting primarily in multi-parameter laboratory assays based on proteomic and metabolomics analysis techniques. These highly complex methods, however, require laboratory capabilities that are rarely available or affordable in low-resource settings (LRS). The importance of quantifying maternal and perinatal risks and identifying which pregnancies can be safely prolonged is also much greater in LRS, where intensive care facilities that can rapidly respond to PE-related health threats for women and infants are limited. For these reasons, simple, low cost, sensitive, and specific point-of-care (POC) tests are needed that can be performed by antenatal health care providers in LRS and that can facilitate decisions about detection and management of PE. Our study aims to provide a comprehensive systematic review of current and emerging blood and urine biomarkers for PE, not only on the basis of their clinical performance, but also of their suitability to be used in LRS-compatible test formats, such as lateral flow and other variants of POC rapid assays.

Development of maskless lithography techniques can provide a potential solution for the photomask cost issue. Furthermore, it could open a market for small-scale manufacturing applications. Since femtosecond lasers have been found suitable for processing of a wide range of materials with sub-micrometer resolution – whereas the limit of achievable structure sizes is predicted to be below 100 nm – it is attractive to use this technique for maskless lithography. In this paper, we present the first results on super-resolution femtosecond laser lithography, which show great potential for future applications.

Background BRAF-NRS are a trio of items for fatigue severity, impact and coping. At development, patients wanted the NRS-Severity & Impact anchors to read 0=No fatigue/effect, 10=Totally exhausted/Great deal of effect, but the NRS-Coping to read 0=Not at all well, 10=Very well. 1 Construct and criterion validity of the NRS-Coping-NRS are less strong than NRS-Severity and Impact; 2 cognitive interviewing shows patient confusion over Coping anchors. 3 Objectives Test construct and criterion validity of BRAF-NRS V2, which has Revised NRS-Coping anchors of 0=Very well, 10=Not at all well (NRS-Severity and Impact unchanged), in 6 EU countries. Methods RA patients from France, Germany, Netherlands, Spain, Sweden and UK completed the BRAF-NRS V2 Revised, BRAF-NRS Original, BRAF-MDQ, RAID, SF-36. Spearman9s correlations assessed criterion and construct validity. Results Of 1276 patients 76% were female, median HAQ 1.0 (IQR 0.375–1.5). Mean BRAF-NRS-Coping Revised 4.0 (SD 2.66) vs Original 5.95 (SD 2.57), NRS-Severity 4.86 (SD 2.56), NRS-Impact 4.61 (SD 2.69). BRAF-NRS-Severity and Impact had appropriate validity with all 18 variables, overall and by country (r=0.46–0.96). Table shows BRAF-NRS-Coping Revised had better validity than NRS-Coping Original in all variables overall (stronger correlations bolded), and for 15–18/18 variables in all countrie except Spain (3/18). The difference in strength of correlations between the versions was large for the total sample, but minimal for Spain. Conclusions BRAF-NRS V2 Revised has construct and criterion validity across 6 EU countries. Whilst the BRAF-NRS-Coping Original is acceptable, the BRAF-NRS-Coping Revised has greater validity. In Spain, the validity of both versions is lower but similar to each other. Further exploration of the concept and wording of “coping” in the Spanish population is warranted. References Nicklin et al 2010a; Nicklin et al 2010b; Hewlett et al 2016 in press Acknowledgement EULAR project grant EP1009 Disclosure of Interest None declared

Background Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are rare but diagnostically challenging clinical problems. Because of the abundance of differential diagnoses, a generally accepted diagnostic guideline has not yet been established. Besides a thorough medical history, physical examination, and laboratory testing, imaging techniques are important tools in the diagnostic workup of FUO and IUO. In the last few years, 18F-FDG-PET/CT has been found to be a suitable diagnostic tool for FUO/IUO, as it is able to detect inflammatory and malignant processes with a high spatial resolution. Objectives The present study is carried out at to quantify the utility of 18F-FDG-PET/CT for the diagnosis of FUO and IUO. The study, moreover, evaluates special clinical markers, that increase the possibility of diagnosing FUO or IUO with a 18F-FDG-PET/CT. Methods All patients presenting with FUO or IUO at the University Clinic of Erlangen between 2007 and 2015 were clinically documented and subjected to 18F-FDG-PET/CT scanning. 18F-FDG-PET/CT scans were considered positive when a focal uptake of the tracer was detected additionally to the standard areas of physiological tracer uptake. 18F-FDG-PET/CT results were compared to the final diagnosis and classified as helpful or non-helpful in establishing the final diagnosis. Multivariate logistic regression was used to identify clinical parameters that correlated with a helpful 18F-FDG-PET/CT in patients with and without FUO as well as in patients with and without IUO. Results Of the 240 patients enrolled 72 presented with FUO, 142 with IUO and 26 did not fulfill FUO or IUO criteria. 235 patients were included in the multivariate logistic regression model. Final diagnosis was established in 190 patients (79.2%). In 136 (56.7% of all patients and 71.6% of the patients with a diagnosis), the 18F-FDG-PET/CT was helpful in finding the diagnosis. The chance was higher in patients without fever (p=0.003), those aged >50 years (p=0.002; p=0.005, respectively) and those with a CRP level >30 mg/dl (p=0.003; p=0.008, respectively). Conclusions Our study shows that if the standard diagnostic tests (laboratory, chest x-ray and abdominal ultrasound) did not identify the cause of FUO/IUO, 18F-FDG-PET/CT scanning should be applied in the early stage of the diagnostic process. An early use of an 18F-FDG-PET/CT is especially helpful to establish a final diagnosis in patients with an elevated C-reactive protein and age over 50 years. Disclosure of Interest None declared

Background The BRAF-MDQ1,2 and RAID3 are patient-reported outcome measures derived from the patient perspective. The 20 item BRAF-MDQ has 4 factors (physical, cognitive, emotional fatigue, living with fatigue) and the 7 item RAID is uni-dimensional. The BRAF-MDQ properties have not been tested outside the UK, nor the validity of the new Swedish RAID examined. Objectives To test the structure, construct and criterion validity of the BRAF-MDQ and the RAID in 6 EU countries. Methods Survey of RA clinic patients in clinics in France, Germany, Netherlands, Spain, Sweden and UK (F, G, N, Sp, Sw, UK), using BRAF-MDQ, RAID and SF-36. Factor structure examined by Confirmatory Factor Analysis and internal consistency by Cronbach9s Alpha. Criterion validity for the BRAF-MDQ evaluated by internal Spearman9s correlations, and for BRAF-MDQ and RAID fatigue item by correlation with each other and SF-36 Vitality subscale. Construct validity of BRAF-MDQ and RAID evaluated by Spearman9s Correlation with each other, HAQ, and SF-36 domains. Analysis conducted overall and by individual country and for BRAF-MDQ by total and subscales. Results 1276 patients participated: F 206, G 216, N 317, Sp 157, Sw 170, UK 210. Disease duration Confirmatory factor analysis: BRAF-MDQ original UK 4 factor structure was confirmed in each country, demonstrating one factor for each set of variables, with high factor loadings (0.71–0.96). Bootstrapping (4 sets of analyses on 20 random samples of 50% of patients/country), found the structure held true in at least 19/20 sets per country. RAID single factor structure was confirmed in all countries (0.75–0.95). Internal consistency ranged from 0.75–0.96 for the BRAF-MDQ (total and subscales) and the RAID ranged from 0.93–0.96 (overall and by country). Criterion validity overall and by country: The BRAF-MDQ correlated internally and with the SF-36 Vitality and RAID fatigue items (0.6–0.93). Construct validity: BRAF-MDQ and RAID correlatied with each other, the HAQ, and remaining 8 SF36 domains (0.46–0.86). Conclusions The BRAF-MDQ and RAID demonstrate strong, consistent factor structure and internal consistency, with moderate-good criterion and construct validity across 6 EU countries, reflecting their robust methods of development. This indicates no specific country scoring is necessary, and strengthens the case for measuring both fatigue and impact in multi-country studies. References Nicklin et al, Arth Care Res 2010:62:1552–8. Nicklin et al, Arth Care Res 2010:62:1559–6. Gossec et al, Ann Rheum Dis 2009;68:1680–5 Acknowledgement EULAR project grant EP1009 Disclosure of Interest None declared

A retrospective study that involves the analysis of laboratory diagnostic data collected during the period 1996-2006 was conducted. A total of 3417 Salmonella isolations involving 183 different serotypes was recorded from 1999-2006, inclusive, at the Onderstepoort Veterinary Institute, Agricultural Research Council, South Africa. The most common serotypes were Salmonella enterica subspecies enterica serovar Typhimurium (917 incidents), Salmonella enterica subspecies enterica serovar Dublin (248 incidents), Salmonella enterica subspecies enterica serovar Enteritidis (232 incidents), Salmonella enterica subspecies enterica serovar Muenchen (164 incidents), Salmonella enterica subspecies enterica serovar Heidelberg (118 incidents) and Salmonella enterica subspecies enterica serovar Chester (113 incidents). The number of recorded Salmonella isolations over the period 1996 to 2006 varies considerably from year to year. The peak of 693 isolations was recorded in 1997, and the lowest, 108 incidents, in 2001. Of the total incidents recorded during the period of survey, 2410 (70.5 %) occurred in poultry and other birds, 641 (18.75 %) occurred in cattle, 255 (7.46) in pigs and 111 (3.24 %) in sheep. Despite the large number of serotypes isolated (183), 52% of incidents were due to only 6 serotypes in decreasing order of prevalence : S. Typhimurium, S. Dublin, S. Enteritidis, S. Muenchen, S. Heidelberg and S. Chester. Serovar Typhimurium was the most common serotype and was detected in all animal species sampled, with, 65 % (598) of the incidents occurring in poultry and 20 % (187) occurring in cattle. Of the total of 248 incidents of S. Dublin serotype, 95.6 % (237) of incidents occurred in cattle and of the 232 isolates of S. Enteritidis, 223 (96 %) originated from poultry. Serovar Choleraesuis was identified in 16 isolates from pigs. The following 4 serotypes were each recorded in more than 50 incidents : S. Hadar (102), S. Schwarzengrund (99), S. Mbandaka (94) and S. Sandiego (73). The trends of annual incidence of Salmonella infection in cattle, sheep, pigs, poultry and other birds during the 11-year period and the distribution of the main serotypes in individual species of animals from 1996-2006 are discussed.

We present the sideband phase characteristics of a fiber-coupled integrated electro-optical modulator (EOM) at a modulation frequency of 2 GHz for Fourier frequencies from 0.1 mHz to 1 Hz. The upper phase noise limit was almost an order of magnitude better than required for LISA. The EOM's phase dependencies on temperature and transmitted optical power were measured and found to be uncritical. Additionally we have investigated three optical amplifiers emitting 1 W. Their differential phase noise and optical pathlength noise as one contribution to differential phase noise were measured. The measured differential phase noise was within the requirement. The dependencies of differential phase noise on pump power were measured and requirements for the operation of the amplifier on the LISA satellite derived. DLR/50 OQ 0601 DFG/EXC/QUEST

Background International studies necessitate validated translations and adaptations of PROMs. However, the exact technique to translate and validate a PROM is not well defined. The full procedure can be complex and costly: the Bristol Rheumatoid Arthritis Fatigue Multi-dimensional Questionnaire and Numerical Rating Scales (BRAF-MDQ; BRAF-NRS) 1 were translated by professional PROM translators using an extensive protocol. A simplified procedure can also be used as was the case for the Rheumatoid Arthritis Impact of Disease Score (RAID) - translated by the clinician developers, using a brief protocol. 2 Objectives To compare the full versus simplified procedures used for these 2 questionnaires, in 5 languages, using formal cognitive interviewing (CI). 3 Methods In each language (Dutch, English, French, German, Spanish, Swedish), 10 patients per country completed all 3 PROMS, using CI (verbalising their thoughts and audio-taped). Each item was analysed for Understanding, Retrieval (of information), Judgement and Response (options). The steering committee interpreted all the data; a cut-off for “difficult item” was set at 30% ie if >3/10 patients in a country had difficulties with an item. The number of difficult items was compared across the questionnaires. The difficult items were rephrased where appropriate. Results As planned, 60 patients participated, of whom 50 assessed all 3 questionnaires (BRAFs not assessed in English, RAID not assessed in Swedish): 72% women; 17% aged 60. (a) After the extensive translation process (BRAFs), the number of difficult items identified by CI were: BRAF-MDQ, 0 difficult items identified out of 20 questions and 5 languages (0%); and BRAF-NRS had 1 difficult item out of 3 questions and 5 languages (6.7%). Specifically, Dutch patients were confused by the BRAF-NRS Coping response option, which is reverse scored (high = good) compared to the other NRS. Overall percentage of difficult items for the BRAFs was 0.87% (1 item of 23 x 5 languages, or 1 in 115). (b) After the simplified translation process (RAID questionnaire) 2 difficult items out of 7 questions and 6 languages were identified (4.7% or 2 in 42). The difficult questions were Question 2 (functional disability) in Spanish and Q5 (physical wellbeing) in Dutch. For one item, the initial translation was widely different from the original version indicating a real translation error. Conclusions More difficult items were found for the RAID questionnaire, which had been translated using a simplified procedure, than for the BRAFs (professionally translated). The data thus suggest that while both translation methods are possible, professional PROM translation might be preferable. These problems were only identified by formal evaluation, demonstrating that cognitive interviewing is crucial in PROM translations. References Nicklin et al. Arth Care Res 2010. Gossec et al. ARD 2009. Drennen J. J Adv Nurs 2003. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2451

We studied 26 patients with severe falciparum malaria who were admitted to an ICU in Namibia. The pathophysiologic effects on various organ systems are documented and the mortality associated with organ failure is reported. Patients with three or more organ failures showed a high mortality, especially when pulmonary or renal failure occurred. Predicted mortality based on the Acute Physiology and Chronic Health Evaluation II scoring system was 34% compared to an actual mortality of 38%.

We have investigated two alternative laser systems for the Laser Interferometer Space Antenna (LISA). One consisted of the laser of LISA's technology precursor LISA Pathfinder and a fiber amplifier originally designed for a laser communication terminal onboard TerraSar-X. The other consisted of a commercial fiber distributed feedback (DFB) laser seeding a fiber amplifier. We have shown that the TerraSar-X amplifier can emit more than 1W without the onset of stimulated Brillouin scattering as required by LISA. We have measured power noise and frequency noise of the LISA Pathfinder laser (LPL) and the fiber laser. The fiber laser shows comparable or even lower power noise than the LPL. LISA will use electro-optical modulators (EOMs) between seed laser and amplifier for clock noise comparison between spacecraft. This scheme requires that the excess noise added by the amplifiers be negligible. We have investigated the phase characteristics of two fiber amplifiers emitting 1 W and found them to be compatible with the LISA requirement on amplifier differential phase noise. DLR/50 OQ 0501 DLR/50 OQ 0601

Seventy-two normal children aged between three and 12 years were assessed to establish their walking function. Speed of walking and heart rate were monitored continuously, both barefoot and in shoes, over eight consecutive lengths of a 25m walkway. Since heart rate is affected by speed, the physiological cost index (PCI)--which combines the two parameters--was calculated for each child, both barefoot and in shoes. Speed tends to increase and walking heart rate to decrease with age. However, resting heart rate also decreases with age, so the PCI has the same range for all ages. The mean PCI in shoes was 0.4 and barefoot was 0.38. The PCI for children with pathological gait is appreciably greater than that for normal children, so the PCI is a valuable quantitative indicator of the level of handicap.

Passively mode locked fiber lasers are of great interest since they are versatile light sources for many applications in frequency metrology or as seed sources for tungstate amplifiers. However, common systems are sensitive to environmental influences, e.g. vibration and thermal stress. One way for avoiding this and to obtain an environmental stable laser is the use of polarization maintaining (PM)-fibers where only light polarized along the slow axis is coupled in. In this contribution we report on experimental results of an ultra-short pulse all-PM fiber laser in linear cavity design.