Usual medical treatments or levonorgestrel-IUS for women with heavy menstrual bleeding:long-term randomised pragmatic trial in primary care

Background: Heavy menstrual bleeding (HMB) is a common, chronic problem affecting women and health services. However, long-term evidence on treatment in primary care is lacking. Aim: To assess the effectiveness of commencing the levonorgestrel-releasing intrauterine system (LNG-IUS) or usual medical treatments for women presenting with HMB in general practice. Design and setting: A pragmatic, multicentre, parallel, open-label, long term, randomised controlled trial in 63 primary care practices across the English Midlands. Method: In total, 571 women aged 25–50 years, with HMB were randomised to LNG-IUS or usual medical treatment (tranexamic/mefenamic acid, combined oestrogen–progestogen, or progesterone alone). The primary outcome was the patient reported Menorrhagia Multi-Attribute Scale (MMAS, measuring effect of HMB on practical difficulties, social life, psychological and physical health, and work and family life; scores from 0 to 100). Secondary outcomes included surgical intervention (endometrial ablation/hysterectomy), general quality of life, sexual activity, and safety. Results: At 5 years post-randomisation, 424 (74%) women provided data. While the difference between LNG-IUS and usual treatment groups was not significant (3.9 points; 95% confidence interval = −0.6 to 8.3; P = 0.09), MMAS scores improved significantly in both groups from baseline (mean increase, 44.9 and 43.4 points, respectively; P<0.001 for both comparisons). Rates of surgical intervention were low in both groups (surgery-free survival was 80% and 77%; hazard ratio 0.90; 95% CI = 0.62 to 1.31; P = 0.6). There was no difference in generic quality of life, sexual activity scores, or serious adverse events. Conclusion: Large improvements in symptom relief across both groups show treatment for HMB can be successfully initiated with long-term benefit and with only modest need for surgery.

Management of adult attention deficit hyperactivity disorder in UK primary care: a survey of general practitioners

Background: Compared to existing literature on childhood attention deficit hyperactivity disorder (ADHD), little published adult data are available, particularly outside of the United States. Using General Practitioner (GP) questionnaires from the United Kingdom, this study aimed to examine a number of issues related to ADHD in adults, across three cohorts of patients, adults who received ADHD drug treatment in childhood/adolescence but stopped prior to adulthood; adults who received ADHD drug treatment in childhood/adolescence and continued treatment into adulthood and adults who started ADHD drug treatment in adulthood.Methods: Patients with a diagnosis of ADHD and prescribed methylphenidate, dexamfetamine or atomoxetine were identified using data from The Health Improvement Network (THIN). Dates when these drugs started and stopped were used to classify patients into the three cohorts. From each cohort, 50 patients were randomly selected and questionnaires were sent via THIN to their GPs.GPs returned completed questionnaires to THIN who forwarded anonymised copies to the researchers. Datasets were analysed using descriptive statistics.Results: Overall response rate was 89% (133/150). GPs stated that in 19 cases, the patient did not meet the criteria of that group; the number of valid questionnaires returned was 114 (76%). The following broad trends were observed: 1) GPs were not aware of the reason for treatment cessation in 43% of cases, 2) patient choice was the most common reason for discontinuation (56%), 3) 7% of patients who stopped pharmacological treatment subsequently reported experiencing ADHD symptoms, 4) 58% of patients who started pharmacological treatment for ADHD in adulthood received pharmacological treatment for other mental health conditions prior to the ADHD being diagnosed.Conclusion: This study presents some key findings relating to ADHD; GPs were often not aware of the reason for patients stopping ADHD treatment in childhood or adolescence. Patient choice was identified as the most common reason for treatment cessation. For patients who started pharmacological treatment in adulthood, many patients received pharmacological treatment for comorbidities before a diagnosis of ADHD was made.

Diagnosing primary ciliary dyskinesia: an international patient perspective

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by progressive sinopulmonary disease, with symptoms starting soon after birth. A European Respiratory Society (ERS) Task Force aims to address disparities in diagnostics across Europe by providing evidence-based clinical practice guidelines. We aimed to identify challenges faced by patients when referred for PCD diagnostic testing. A patient survey was developed by patient representatives and healthcare specialists to capture experience. Online versions of the survey were translated into nine languages and completed in 25 countries. Of the respondents (n=365), 74% were PCD-positive, 5% PCD-negative and 21% PCD-uncertain/inconclusive. We then interviewed 20 parents/patients. Transcripts were analysed thematically. 35% of respondents visited their doctor more than 40 times with PCD-related symptoms prior to diagnostic referral. Furthermore, the most prominent theme among interviewees was a lack of PCD awareness among medical practitioners and failure to take past history into account, leading to delayed diagnosis. Patients also highlighted the need for improved reporting of results and a solution to the “inconclusive” diagnostic status. These findings will be used to advise the ERS Task Force guidelines for diagnosing PCD, and should help stakeholders responsible for improving existing services and expanding provision for diagnosis of this rare disease.

Receptive Vocabulary of CLIL and Non-CLIL Primary and Secondary School Learners

CLIL instruction has been reported to be beneficial for foreign language vocabulary learning since CLIL students show higher vocabulary profiles than students of their same age in traditional EFL contexts. However, to our knowledge, the receptive vocabulary knowledge of CLIL and non-CLIL learners at the end of primary and secondary education has not been examined yet. Hence, this study aims at comparing the receptive vocabulary size 79 CLIL primary learners with the receptive vocabulary knowledge of 331 non-CLIL learners at the end of primary and secondary school. Sex-based differences were also analysed. The 2k Vocabulary Levels Test (VLT) was used for the purposes of the study. Results revealed that learners’ receptive vocabulary sizes lie within the most frequent 1000 words, non-CLIL secondary school students throw better results than primary students but the differences between the secondary group and the CLIL group are not statistically significant. As for sex-based differences, we found no significant differences among the groups. These findings led us to believe that the CLIL approach offers a benefit for vocabulary acquisition since CLIL learners have been exposed to the foreign language for a shorter period of time and the results are quite similar to their non-CLIL secondary school partners.

Investigating high-achieving sixth grade students' erroneous answers on the angle concept in Yozgat

The angle concept is a multifaceted concept having static and dynamic definitions. The static definition of the angle refers to “the space between two rays” or “the intersection of two rays at the same end point” (Mitchelmore & White, 1998), whereas the dynamic definition of the angle concept highlights that the size of angle is the amount of rotation in direction (Fyhn, 2006). Since both definitions represent two diverse situations and have unique limitations (Henderson & Taimina, 2005), students may hold misconceptions about the angle concept. In this regard, the aim of this research was to explore high achievers’ knowledge regarding the definition of the angle concept as well as to investigate their erroneous answers on the angle concept.

104 grade 6 students drawn from four well-established elementary schools of Yozgat, Turkey were participated in this research. All participants were selected via a purposive sampling method and their mathematics grades were 4 or 5 out of 5, and. Data were collected through four questions prepared by considering the learning competencies set out in the grade 6 curriculum in Turkey and the findings of previous studies whose purposes were to identify students’ misconceptions of the angle concept. The findings were analyzed by two researchers, and their inter-rater agreement was calculated as 0.91, or almost perfect. Thereafter, coding discrepancies were resolved, and consensus was established.

The angle concept is a multifaceted concept having static and dynamic definitions.The static definition of the angle refers to “the space between two rays” or“the intersection of two rays at the same end point” (Mitchelmore & White, 1998), whereas the dynamicdefinition of the angle concept highlights that the size of angle is the amountof rotation in direction (Fyhn, 2006). Since both definitionsrepresent two diverse situations and have unique limitations (Henderson & Taimina, 2005), students may holdmisconceptions about the angle concept. In this regard, the aim of thisresearch was to explore high achievers’ knowledge regarding the definition ofthe angle concept as well as to investigate their erroneous answers on theangle concept.

Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.

BACKGROUND: EGFR overexpression occurs in 27-55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. METHODS: In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m(2) and oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1250 mg/m(2) per day on days 1-21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m(2) and oxaliplatin 100 mg/m(2) on day 1, capecitabine 1000 mg/m(2) per day on days 1-21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785. FINDINGS: Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11.3 months (95% CI 9.6-13.0) compared with 8.8 months (7.7-9.8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1.37, 95% CI 1.07-1.76; p=0.013). mEOC+P was associated with increased incidence of grade 3-4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥ 3 neutropenia 35 [13%] vs 74 [28%]). INTERPRETATION: Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma. FUNDING: Amgen, UK National Institute for Health Research Biomedical Research Centre.

Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial

BACKGROUND: In the previously reported ALSYMPCA trial in patients with castration-resistant prostate cancer and symptomatic bone metastases, overall survival was significantly longer in patients treated with radium-223 dichloride (radium-223) than in patients treated with placebo. In this study, we investigated safety and overall survival in radium-223 treated patients in an early access programme done after the ALSYMPCA study and before regulatory approval of radium-223.

METHODS: We did an international, prospective, interventional, open-label, single-arm, phase 3b study. Enrolled patients were aged 18 years or older with histologically or cytologically confirmed progressive bone-predominant metastatic castration-resistant prostate cancer with two or more skeletal metastases on imaging (with no restriction as to whether they were symptomatic or asymptomatic; without visceral disease but lymph node metastases were allowed). Patients received intravenous injections of radium-223, 50 kBq/kg (current recommendation 55 kBq/kg after implementation of National Institute of Standards and Technology update on April 18, 2016) every 4 weeks for up to six injections. Other concomitant anticancer therapies were allowed. Primary endpoints were safety and overall survival. The safety and efficacy analyses were done on all patients who received at least one dose of the study drug. The study has been completed, and we report the final analysis here. This study is registered with ClinicalTrials.gov, number NCT01618370, and the European Union Clinical Trials Register, EudraCT number 2012-000075-16.

FINDINGS: Between July 22, 2012, and Dec 19, 2013, 839 patients were enrolled from 113 sites in 14 countries. 696 patients received one or more doses of radium-223; 403 (58%) of these patients had all six planned injections. Any-grade treatment-emergent adverse events occurred in 523 (75%) of 696 patients; any-grade treatment-emergent adverse events deemed to be related to treatment were reported in 281 (40%) patients. The most common grade 3 or worse treatment-related treatment-emergent adverse events were anaemia in 32 (5%) patients, thrombocytopenia in 15 (2%) patients, neutropenia in ten (1%) patients, and leucopenia in nine (1%) patients. Any grade of serious adverse events were reported in 243 (35%) patients. Median follow-up was 7·5 months (IQR 5-11) and 210 deaths were reported; median overall survival was 16 months (95% CI 13-not available [NA]). In an exploratory analysis of overall survival with predefined factors, median overall survival was longer for: patients with baseline alkaline phosphatase concentration less than the upper limit of normal (ULN; median NA, 95% CI 16 months-NA) than for patients with an alkaline phosphatase concentration equal to or greater than the ULN (median 12 months, 11-15); patients with baseline haemoglobin levels 10 g/dL or greater (median 17 months, 14-NA) than for patients with haemoglobin levels less than 10 g/dL (median 10 months, 8-14); patients with a baseline Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (median NA, 17 months-NA) than for patients with an ECOG PS of 1 (median 13 months, 11-NA) or an ECOG PS of 2 or more (median 7 months, 5-11); and for patients with no reported baseline pain (median NA, 16 months-NA) than for those with mild pain (median 14 months, 13-NA) or moderate-severe pain (median 11 months, 9-13). Median overall survival was also longer in patients who received radium-223 plus abiraterone, enzalutamide, or both (median NA, 95% CI 16 months-NA) than in those who did not receive these agents (median 13 months, 12-16), and in patients who received radium-223 plus denosumab (median NA, 15 months-NA) than in patients who received radium-223 without denosumab (median 13 months, 12-NA).

INTERPRETATION: Our findings show that radium-223 can be safely combined with abiraterone or enzalutamide, which are now both part of the standard of care for patients with metastatic castration-resistant prostate cancer. Furthermore, our findings extend to patients who were asymptomatic at baseline, unlike those enrolled in the pivotal ALSYMPCA study. The findings of prolonged survival in patients treated with concomitant abiraterone, enzalutamide, or denosumab require confirmation in prospective randomised trials.

FUNDING: Pharmaceutical Division of Bayer.

PIPc study: development of indicators of potentially inappropriate prescribing in children (PIPc) in primary care using a modified Delphi technique

Objective There is limited evidence regarding the quality of prescribing for children in primary care. Several prescribing criteria (indicators) have been developed to assess the appropriateness of prescribing in older and middle-aged adults but few are relevant to children. The objective of this study was to develop a set of prescribing indicators that can be applied to prescribing or dispensing data sets to determine the prevalence of potentially inappropriate prescribing in children (PIPc) in primary care settings.


Design Two-round modified Delphi consensus method.


Setting Irish and UK general practice.


Participants A project steering group consisting of academic and clinical general practitioners (GPs) and pharmacists was formed to develop a list of indicators from literature review and clinical expertise. 15 experts consisting of GPs, pharmacists and paediatricians from the Republic of Ireland and the UK formed the Delphi panel.


Results 47 indicators were reviewed by the project steering group and 16 were presented to the Delphi panel. In the first round of this exercise, consensus was achieved on nine of these indicators. Of the remaining seven indicators, two were removed following review of expert panel comments and discussion of the project steering group. The second round of the Delphi process focused on the remaining five indicators, which were amended based on first round feedback. Three indicators were accepted following the second round of the Delphi process and the remaining two indicators were removed. The final list consisted of 12 indicators categorised by respiratory system (n=6), gastrointestinal system (n=2), neurological system (n=2) and dermatological system (n=2).


Conclusions The PIPc indicators are a set of prescribing criteria developed for use in children in primary care in the absence of clinical information. The utility of these criteria will be tested in further studies using prescribing databases.

Linking electronic journals - Lessons from the Open Journal project

The Open Journal project has completed its three year period of funding by the UK Electronic Libraries (eLib) programme (Rusbridge 1998). During that time, the number of journals that are available electronically leapt from a few tens to a few thousand. Some of these journals are now developing the sort of features the project has been advocating, in particular the use of links within journals, between different primary journals, with secondary journals data, and to non-journal sources. Assessing the achievements of the project and considering some of the difficulties it faced, we report on the different approaches to linking that the project developed, and summarise the important user responses that indicate what works and what does not. Looking ahead, there are signs of change, not just to simple linking within journals but to schemes in which links are the basis of "distributed" journals, where information may be shared and documents built from different sources. The significance has yet to be appreciated, but this would be a major change from printed journals. If projects such as this and others have provided the initial impetus, the motivation for distributed journals comes, perhaps surprisingly, from within certain parts of the industry, as the paper shows.

A SUBSET OF 3´ TO 5´ EXORIBONUCLEASES ARE THE PRIMARY ENZYMES RESPONSIBLE FOR THE DEGRADATION OF PGPG IN CYCLIC DI-GMP SIGNALING

Bis-(3´-5´)-cyclic dimeric guanosine monophosphate, or cyclic di-GMP (c-di-GMP) is a ubiquitous bacterial second messenger that regulates processes such biofilm formation, motility, and virulence. C-di-GMP is synthesized by diguanylate cyclases (DGCs), while phosphodiesterases (PDE-As) end signaling by linearizing c-di-GMP to 5ʹ-phosphoguanylyl-(3ʹ,5ʹ)-guanosine (pGpG), which is then hydrolyzed to two GMPs by previously unidentified enzymes termed PDE-Bs. To identify the PDE-B responsible for pGpG turnover, a screen for pGpG binding proteins in a Vibrio cholerae open reading frame library was conducted to identify potential pGpG binding proteins. This screen led to identification of oligoribonuclease (Orn). Purified Orn binds to pGpG and can cleave pGpG to GMP in vitro. A deletion mutant of orn in Pseudomonas aeruginosa was highly defective in pGpG turnover and accumulated pGpG. Deletion of orn also resulted in accumulation c-di-GMP, likely through pGpG-mediated inhibition of the PDE-As, causing an increase in c-di-GMP-governed auto-aggregation and biofilm. Thus, we found that Orn serves as the primary PDE-B enzyme in P. aeruginosa that removes pGpG, which is necessary to complete the final step in the c-di-GMP degradation pathway. However, not all bacteria that utilize c-di-GMP signaling also have an ortholog of orn, suggesting that other PDE-Bs must be present. Therefore, we asked whether RNases that cleave small oligoribonucleotides in other species could also act as PDE-Bs. NrnA, NrnB, and NrnC can rapidly degrade pGpG to GMP. Furthermore, they can reduce the elevated aggregation and biofilm formation in P. aeruginosa ∆orn. Together, these results indicate that rather than having a single dedicated PDE-B, different bacteria utilize distinct RNases to cleave pGpG and complete c-di-GMP signaling. The ∆orn strain also has a growth defect, indicating changes in other regulatory processes that could be due to pGpG accumulation, c-di-GMP accumulation, or another effect due to loss of Orn. We sought to investigate the genetic pathways responsible for these growth defect phenotypes by use of a transposon suppressor screen, and also investigated transcriptional changes using RNA-Seq. This work identifies that c-di-GMP degradation intersects with RNA degradation at the point of the Orn and the functionally related RNases.

Phytoplankton versus macrophyte contribution to primary production and biogeochemical cycles of a coastal mesotidal system. A modelling approach

This study presents an assessment of the contributions of various primary producers to the global annual production and N/P cycles of a coastal system, namely the Arcachon Bay, by means of a numerical model. This 3D model fully couples hydrodynamic with ecological processes and simulates nitrogen, silicon and phosphorus cycles as well as phytoplankton, macroalgae and seagrasses. Total annual production rates for the different components were calculated for different years (2005, 2007 and 2009) during a time period of drastic reduction in seagrass beds since 2005. The total demand of nitrogen and phosphorus was also calculated and discussed with regards to the riverine inputs. Moreover, this study presents the first estimation of particulate organic carbon export to the adjacent open ocean. The calculated annual net production for the Arcachon Bay (except microphytobenthos, not included in the model) ranges between 22,850 and 35,300 tons of carbon. The main producers are seagrasses in all the years considered with a contribution ranging from 56% to 81% of global production. According to our model, the -30% reduction in seagrass bed surface between 2005 and 2007, led to an approximate 55% reduction in seagrass production, while during the same period of time, macroalgae and phytoplankton enhanced their productions by about +83% and +46% respectively. Nonetheless, the phytoplankton production remains about eightfold higher than the macroalgae production. Our results also highlight the importance of remineralisation inside the Bay, since riverine inputs only fulfill at maximum 73% nitrogen and 13% phosphorus demands during the years 2005, 2007 and 2009. Calculated advection allowed a rough estimate of the organic matter export: about 10% of the total production in the bay was exported, originating mainly from the seagrass compartment, since most of the labile organic matter was remineralised inside the bay.

A study at high energy-resolution and at low primary energies of the secondary emission from (100) tungsten

This work was supported by the Joint Services Electronics Program (U.S. Army, U.S. Navy, and U.S. Air Force) under Contract No. DA 28 043 AMC 00073(E).

Open-label placebo treatment in chronic low back pain: A randomized controlled trial

This randomized controlled trial was performed to investigate whether placebo effects in chronic low back pain could be harnessed ethically by adding open-label placebo (OLP) treatment to treatment as usual (TAU) for 3 weeks. Pain severity was assessed on three 0- to 10-point Numeric Rating Scales, scoring maximum pain, minimum pain, and usual pain, and a composite, primary outcome, total pain score. Our other primary outcome was back-related dysfunction, assessed on the Roland-Morris Disability Questionnaire. In an exploratory follow-up, participants on TAU received placebo pills for 3 additional weeks. We randomized 97 adults reporting persistent low back pain for more than 3 months' duration and diagnosed by a board-certified pain specialist. Eighty-three adults completed the trial. Compared to TAU, OLP elicited greater pain reduction on each of the three 0- to 10-point Numeric Rating Scales and on the 0- to 10-point composite pain scale (P < 0.001), with moderate to large effect sizes. Pain reduction on the composite Numeric Rating Scales was 1.5 (95% confidence interval: 1.0-2.0) in the OLP group and 0.2 (-0.3 to 0.8) in the TAU group. Open-label placebo treatment also reduced disability compared to TAU (P < 0.001), with a large effect size. Improvement in disability scores was 2.9 (1.7-4.0) in the OLP group and 0.0 (-1.1 to 1.2) in the TAU group. After being switched to OLP, the TAU group showed significant reductions in both pain (1.5, 0.8-2.3) and disability (3.4, 2.2-4.5). Our findings suggest that OLP pills presented in a positive context may be helpful in chronic low back pain.

The medico-legal importance of establishing human identity by palatal rugoscopy: evaluation of the immutability and individuality of palatal rugae under the influence of ante mortem orthodontic treatment

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Accelerating wide-angle converging waves in the near field

We show that a wide-angle converging wave may be transformed into a shape-preserving accelerating beam having a beam-width near the diffraction limit. For that purpose, we followed a strategy that is particularly conceived for the acceleration of nonparaxial laser beams, in contrast to the well-known method by Siviloglou et al (2007 Phys. Rev. Lett. 99 213901). The concept of optical near-field shaping is applied to the design of non-flat ultra-narrow diffractive optical elements. The engineered curvilinear caustic can be set up by the beam emerging from a dynamic assembly of elementary gratings, the latter enabling to modify the effective refractive index of the metamaterial as it is arranged in controlled orientations. This light shaping process, besides being of theoretical interest, is expected to open up a wide range of broadband application possibilities.