Physiological, hyaluronan-selected intracytoplasmic sperm injection for infertility treatment (HABSelect): a parallel, two-group, randomised trial

Background Sperm selection strategies aimed at improving success rates of intracytoplasmic sperm injection (ICSI) include binding to hyaluronic acid (herein termed hyaluronan). Hyaluronan-selected sperm have reduced levels of DNA damage and aneuploidy. Use of hyaluronan-based sperm selection for ICSI (so-called physiological ICSI [PICSI]) is reported to reduce the proportion of pregnancies that end in miscarriage. However, the effect of PICSI on livebirth rates is uncertain. We aimed to investigate the efficacy of PICSI versus standard ICSI for improving livebirth rates among couples undergoing fertility treatment. Methods This parallel, two-group, randomised trial included couples undergoing an ICSI procedure with fresh embryo transfer at 16 assisted conception units in the UK. Eligible women (aged 18–43 years) had a body-mass index of 19–35 kg/m2 and a follicle-stimulating hormone (FSH) concentration of 3·0–20·0 mIU/mL or, if no FSH measurement was available, an anti-müllerian hormone concentration of at least 1·5 pmol/L. Eligible men (aged 18–55 years) had not had a vasovasostomy or been treated for cancer in the 24 months before recruitment and were able, after at least 3 days of sexual abstinence, to produce freshly ejaculated sperm for the treatment cycle. Couples were randomly assigned (1:1) with an online system to receive either PICSI or a standard ICSI procedure. The primary outcome was full-term (?37 weeks' gestational age) livebirth, which was assessed in all eligible couples who completed follow-up. This trial is registered, number ISRCTN99214271. Findings Between Feb 1, 2014, and Aug 31, 2016, 2772 couples were randomly assigned to receive PICSI (n=1387) or ICSI (n=1385), of whom 2752 (1381 in the PICSI group and 1371 in the ICSI group) were included in the primary analysis. The term livebirth rate did not differ significantly between PICSI (27·4% [379/1381]) and ICSI (25·2% [346/1371]) groups (odds ratio 1·12, 95% CI 0·95–1·34; p=0·18). There were 56 serious adverse events in total, including 31 in the PICSI group and 25 in the ICSI group; most were congenital abnormalities and none were attributed to treatment. Interpretation Compared with ICSI, PICSI does not significantly improve term livebirth rates. The wider use of PICSI, therefore, is not recommended at present

Mechanisms of translational regulation by a human eIF5-mimic protein

The translation factor eIF5 is an important partner of eIF2, directly modulating its function in several critical steps. First, eIF5 binds eIF2/GTP/Met-tRNAiMet ternary complex (TC), promoting its recruitment to 40S ribosomal subunits. Secondly, its GTPase activating function promotes eIF2 dissociation for ribosomal subunit joining. Finally, eIF5 GDP dissociation inhibition (GDI) activity can antagonize eIF2 reactivation by competing with the eIF2 guanine exchange factor (GEF), eIF2B. The C-terminal domain (CTD) of eIF5, a W2-type HEAT domain, mediates its interaction with eIF2. Here, we characterize a related human protein containing MA3- and W2-type HEAT domains, previously termed BZW2 and renamed here as eIF5-mimic protein 1 (5MP1). Human 5MP1 interacts with eIF2 and eIF3 and inhibits general and gene-specific translation in mammalian systems. We further test whether 5MP1 is a mimic or competitor of the GEF catalytic subunit eIF2Bε or eIF5, using yeast as a model. Our results suggest that 5MP1 interacts with yeast eIF2 and promotes TC formation, but inhibits TC binding to the ribosome. Moreover, 5MP1 is not a GEF but a weak GDI for yeast eIF2. We propose that 5MP1 is a partial mimic and competitor of eIF5, interfering with the key steps by which eIF5 regulates eIF2 function

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Background Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. Findings In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. Interpretation Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. Funding UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology

Abstracts from the NIHR INVOLVE Conference 2017

n/

Clinician- and patient-factors influencing treatment decisions: Ethnographic study of antibiotic prescribing and operative procedures in out-of-hours and general dental practices

Operative treatment is indicated for most toothache/dental abscesses, yet antibiotics instead of procedures are often prescribed. This ethnographic study aimed to identify clinician and patient factors influencing urgent dental care for adults during actual appointments; and to identify elements sensitive to context. Appointments were observed in out-of-hours and general dental practices. Follow-up interviews took place with dentists, dental nurses, and patients. Dentist and patient factors were identified through thematic analysis of observation records and appointment/interview transcripts. Dentist factors were based on a published list of factors influencing antibiotic prescribing for adults with acute conditions across primary health care and presented within the Capability-Opportunity-Motivation-Behaviour model. Contextually sensitive elements were revealed by comparing the factors between settings. In total, thirty-one dentist factors and nineteen patient factors were identified. Beliefs about antibiotics, goals for the appointment and access to dental services were important for both dentists and patients. Dentist factors included beliefs about the lifetime impact of urgent dental procedures on patients. Patient factors included their communication and negotiation skills. Contextual elements included dentists’ concerns about inflicting pain on regular patients in general dental practice; and patients’ difficulties accessing care to complete temporary treatment provided out of hours. This improved understanding of factors influencing shared decisions about treatments presents significant opportunity for new, evidence-based, contextually sensitive antibiotic stewardship interventions

Bone density measurements in intra-oral radiographs.

Oral Imaging Center, Department of Dentistry, Faculty of Medicine, KU Leuven, Kapucijnenvoer 7, 3000, Leuven, Belgium. Jaw bone density measurements are applicable in many clinical situations to assess bone tissue. To be able to implement research findings in clinical reality, tools must be simple and low cost. Intra-oral radiographs including a reference material perform well as a densitometric tool. However, the inclusion of a reference material, usually in the form of a metal wedge, is an additional burden for the dentist. The aim of this study was to evaluate whether a reference step wedge is required for accurate densitometric results. Dual energy X-ray absorptiometry measurements and densitometric measurements on intra-oral radiographs using a custom-made software were performed on bone samples from the premolar region of the mandible. Observer agreement of bone density expressed as grey value was high. The correlation between mandibular bone mineral density and the densitometric values on intra-oral radiographs was substantially higher when the aluminium step wedge was included. The Wilcoxon test revealed no significant difference between the density measurements using nine or three steps of the Al reference wedge. Density determination of grey value and mm Aleq thickness value both have good intra- and inter-observer agreement. However, jaw bone densitometry is far more accurate when including a reference wedge. PMID: 17668257 [PubMed - indexed for MEDLINE

Diagnosing osteoporosis by using dental panoramic radiographs: The OSTEODENT project

Measurement of cortical thickness and subjective assessment of cortical porosity on panoramic radiographs are methods previously reported for diagnosing osteoporosis. The aims of this study were to determine the relative efficacy of the mandibular cortical index and cortical width in detecting osteoporosis, both alone and in combination, and to determine the optimal cortical width threshold for referral for additional osteoporosis investigation

Osteoporosis detection using intraoral densitometry

OBJECTIVES: To determine the diagnostic accuracy of mandibular and maxillary bone density in detecting osteoporosis using receiver operating characteristic (ROC) analysis. METHODS: 671 women between 45 years and 70 years of age underwent dual energy X-ray absorptiometry (DXA) of the hip and lumbar spine. This was the gold standard for diagnosing osteoporosis. Intraoral radiography of the upper and lower right premolar region was performed, using an aluminium wedge as a densitometric reference. Jaw bone density was determined using dedicated software. Observer differences and ROC curves were analysed. RESULTS: For detecting osteoporosis using jaw bone density, the area under the ROC curve (A(z)) was 0.705. For separate analysis of mandibular and maxillary films, sensitivity varied from 33.9% to 38.7% and specificity from 83.5% to 85.3% when using a threshold of 4.3 mm Al equivalent. CONCLUSIONS: Density of the premolar region reaches a fair diagnostic accuracy, which might improve when including additional factors in the analysis and refining the densitometric tool

The relationship between the OSTEODENT index and hip fracture risk assessment using FRAX

OBJECTIVES: The OSTEODENT index is a predicted probability of osteoporosis derived from a combination of an automated analysis of a dental panoramic radiograph and clinical information. This index has been proposed as a suitable case-finding tool for identification of subjects with osteoporosis in primary dental care; however, no data exist on the relationship between OSTEODENT index and fracture risk. The aims of this study were to assess the relationship between the OSTEODENT index and hip fracture risk as determined by FRAX and to compare the performance of the OSTEODENT index and FRAX (without femoral BMD data), in determining the need for intervention as recommended in UK national treatment guidance. STUDY DESIGN: The study was a retrospective analysis of data from 339 female subjects (mean age 55.3 years), from 2 centers: Manchester (UK) and Leuven (Belgium). Clinical information and femoral neck BMD were available for FRAX, and dental panoramic radiographic data and clinical information were available to calculate the OSTEODENT index. Subjects were classified into "treat" or "lifestyle advice and reassurance" categories using the National Osteoporosis Guideline Group (NOGG) threshold. RESULTS: The OSTEODENT index result was significantly related to the 10-year probability of hip fracture derived from the reference standard FRAX tool (Rs = 0.67, P < .0001); 84 patients (24.8%) were allocated to the "treat" category on the basis of FRAX and the UK national guidance. Using this "treatment/no treatment" classification as the reference standard, ROC analysis showed no significant difference between areas under the curves for the OSTEODENT index (0.815) and the 10-year probability of hip fracture derived from the FRAX index without BMD (0.825) when used as tests for determining therapeutic intervention. CONCLUSION: The results suggest that the OSTEODENT index has value in prediction of hip fracture risk. Prospective trials are needed to confirm this finding and to examine the feasibility for its use in primary dental care