The structure of EXTL3 helps to explain the different roles of bi-domain exostosins in heparan sulfate synthesis.

Heparan sulfate is a highly modified O-linked glycan that performs diverse physiological roles in animal tissues. Though quickly modified, it is initially synthesised as a polysaccharide of alternating ß-D-glucuronosyl and N-acetyl-α-D-glucosaminyl residues by exostosins. These enzymes generally possess two glycosyltransferase domains (GT47 and GT64)-each thought to add one type of monosaccharide unit to the backbone. Although previous structures of murine exostosin-like 2 (EXTL2) provide insight into the GT64 domain, the rest of the bi-domain architecture is yet to be characterised; hence, how the two domains co-operate is unknown. Here, we report the structure of human exostosin-like 3 (EXTL3) in apo and UDP-bound forms. We explain the ineffectiveness of EXTL3's GT47 domain to transfer ß-D-glucuronosyl units, and we observe that, in general, the bi-domain architecture would preclude a processive mechanism of backbone extension. We therefore propose that heparan sulfate backbone polymerisation occurs by a simple dissociative mechanism.

Asthma severity and impact on perinatal outcomes: an updated systematic review and meta-analysis.

BACKGROUND: Large-scale studies exploring the associations of asthma severity, exacerbations and medication use with adverse perinatal outcomes have been published in recent years. OBJECTIVES: To update evidence on the associations of asthma severity, exacerbations and medication use with the adverse perinatal outcomes of preterm delivery (PD), low birthweight (LBW) and small-for-gestational-age (SGA). SEARCH STRATEGY: PubMed, Embase, Wanfang, and China National Knowledge Infrastructure (CNKI) from inception to 1 January 2021. SELECTION CRITERIA: Cohort studies comparing the likelihood of adverse perinatal outcomes in groups of asthmatic women stratified by asthma severity, asthma exacerbations or medication use, or comparing the likelihood of adverse perinatal outcomes between non-asthmatic women and asthmatics of various levels of severity and exacerbation. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed risk of bias. Random-effects models were used to meta-analyse the results. MAIN RESULTS: Twenty studies met the inclusion criteria. The odds of delivering SGA babies increased with maternal asthma severity. Pregnant women with an asthma exacerbation had higher odds of delivering LBW babies and SGA babies, compared with pregnant women with asthma but without an exacerbation (pooled adjusted odds ratio [OR] 1.15, 95% CI 1.02-1.29 for LBW; number of studies with adjusted OR 3; I2 = 0%) (pooled adjusted OR 1.13, 95% CI 1.04-1.23 for SGA; number of studies with adjusted OR 4; I2 = 0%) and compared to pregnant women without asthma. Oral corticosteroids use during pregnancy was associated with increased odds of LBW, but not PD. CONCLUSIONS: The available data suggest that maternal asthma severity and exacerbations are associated with increased odds of LBW and SGA babies. TWEETABLE ABSTRACT: A systematic review and meta-analysis found that maternal asthma severity and exacerbations are associated with increased odds of delivering low birthweight and small-for-gestational-age babies.

How many melanomas might be prevented if more people applied sunscreen regularly?

BACKGROUND: Ultraviolet radiation causes cutaneous melanoma. Sunscreen prevents sunburn and protects skin cells against mutations. High-quality epidemiological studies suggest regular sunscreen use prevents melanoma. OBJECTIVES: To calculate the potential impact fraction (PIF) for melanoma in the U.S.A. and Australia assuming a range of different intervention scenarios intended to increase sunscreen use. METHODS: We calculated the PIF, the proportional difference between the observed number of melanomas arising under prevailing levels of sunscreen use compared with the number expected under counterfactual scenarios. We used published melanoma incidence projections for Australia and the white population in the U.S.A. from 2012 through to 2031 as the baseline condition, with estimates for protective effects of 'regular sunscreen use' from the literature. Sunscreen prevalence was sourced from national or state surveys. RESULTS: Under a plausible public health intervention scenario comprising incremental increases in sunscreen prevalence over a 10-year implementation programme, we estimated that cumulatively to 2031, 231 053 fewer melanomas would arise in the U.S. white population (PIF 11%) and 28 071 fewer melanomas would arise in Australia (PIF 10%). Under the theoretical maximum model of sunscreen use, almost 797 000 (PIF 38%) and approximately 96 000 (PIF 34%) melanomas would be prevented in the U.S.A. and Australia, respectively between 2012 and 2031. A sensitivity analysis using weaker effect estimates resulted in more conservative PIF estimates. CONCLUSIONS: Overall, interventions to increase use of sunscreen would result in moderate reductions in melanoma incidence, assuming no compensatory overexposure to the sun. Countries with a high incidence of melanoma should monitor levels of sunscreen use in the community.

Structural and electronic determinants of lytic polysaccharide monooxygenase reactivity on polysaccharide substrates.

Lytic polysaccharide monooxygenases (LPMOs) are industrially important copper-dependent enzymes that oxidatively cleave polysaccharides. Here we present a functional and structural characterization of two closely related AA9-family LPMOs from Lentinus similis (LsAA9A) and Collariella virescens (CvAA9A). LsAA9A and CvAA9A cleave a range of polysaccharides, including cellulose, xyloglucan, mixed-linkage glucan and glucomannan. LsAA9A additionally cleaves isolated xylan substrates. The structures of CvAA9A and of LsAA9A bound to cellulosic and non-cellulosic oligosaccharides provide insight into the molecular determinants of their specificity. Spectroscopic measurements reveal differences in copper co-ordination upon the binding of xylan and glucans. LsAA9A activity is less sensitive to the reducing agent potential when cleaving xylan, suggesting that distinct catalytic mechanisms exist for xylan and glucan cleavage. Overall, these data show that AA9 LPMOs can display different apparent substrate specificities dependent upon both productive protein-carbohydrate interactions across a binding surface and also electronic considerations at the copper active site.

Protective effect of hormone therapy among women with hysterectomy/oophorectomy.

Study question: Does exposure to menopausal hormone therapy (MHT) in mid-aged women alter their risk of cardiovascular disease (CVD) mortality and all-cause mortality? Summary answer: MHT soon after menopause is unlikely to increase the risk of CVD mortality or all-cause mortality and may have a protective effect for women with hysterectomy/oophorectomy. What is known already: The balance of benefits and risks of MHT are currently unclear and may differ according to when treatment starts and whether women have an intact uterus. Study design size, duration: A total of 13 715 participants from the mid-aged population-based cohort (born 1946-1951) of the Australian Longitudinal Study on Women's Health (ALSWH) were followed from 1998 to 2013. Participants/materials setting methods: The measures included cardiovascular and all-cause mortality, exposure to MHT and menopausal status (based on 3-yearly self-reports). Electronic prescriptions data on MHT were also available from mid-2002 onwards. At each follow-up survey wave, participants were classified as: an existing user of MHT, an initiator of MHT or a non-initiator of MHT. Main results and the role of chance: After adjusting for confounding variables, existing users of MHT had a reduced risk (hazard ratio 0.63; 95% CI, 0.43-0.92) of CVD mortality compared with non-initiators. Insufficient evidence of an association was identified for initiators of MHT (0.66; 0.35-1.24). For all-cause mortality, risks were reduced for both initiators (0.69; 0.55-0.87) and existing users (0.80; 0.70-0.91). In a subgroup analysis, women with hysterectomy/oophorectomy had lower risks of CVD mortality for both initiators (0.14; 0.02-0.98) and existing users (0.55; 0.34-0.90), but no evidence of an association was found for women whose MHT commenced during or after menopause. Similarly for all-cause mortality, only the women with hysterectomy/oophorectomy had lower risks for both initiators (0.47; 0.31-0.70) and existing users (0.69; 0.58-0.82). Limitations, reasons for caution: Limitations include the observational nature of the study, the small number of deaths, MHT use being self-reported and the classification of menopausal status also being based on self-reported information. Wider implications of the findings: Women considering MHT soon after menopause can be reassured that the treatment is unlikely to increase their risk of CVD mortality or all-cause mortality. Study funding/competing interest(s): The Australian Longitudinal Study on Women's Health is funded by the Australian Department of Health. G.D.M. is funded by the Australian Research Council Future Fellowship. L.C. was funded by a China scholarship council (CSC) graduate scholarship. All authors report no conflict of interest. Trial registration number: N/A.

Back pain in children and adolescents.

Back pain is a common symptom in children and adolescents. Here we review the important causes, of which defects and stress reactions of the pars interarticularis are the most common identifiable problems. More serious pathology, including malignancy and infection, needs to be excluded when there is associated systemic illness. Clinical evaluation and management may be difficult and always requires a thorough history and physical examination. Diagnostic imaging is obtained when symptoms are persistent or severe. Imaging is used to reassure the patient, relatives and carers, and to guide management.

Recovery of severe motor deficit secondary to herniated lumbar disc prolapse: is surgical intervention important? A systematic review.

INTRODUCTION: The natural history of motor deficit due to lumbar disc herniation has been thought to be favourable. However, on closer analysis of seminal articles on this topic, this is not the case for patients with severe motor deficits (MRC grade ≤3). The aim of this study is to answer the following questions: (1) Is surgical intervention beneficial in patients with severe motor weakness (defined by MRC grade of 3 or less) due to herniated lumbar nucleus pulposus? (2) Does time to surgery from onset of motor weakness influence the outcome? (3) Are there any other prognostic factors? MATERIALS AND METHODS: A comprehensive search was conducted in MEDLINE and EMBASE from 1970 upto July 2013. Inclusion criteria for studies are: (1) minimum of three patients aged 18 and older, who had symptomatic herniated lumbar disc prolapse and underwent surgery, (2) description of pre and post-operative muscle weakness utilising the Medical Research Council (MRC) muscle power grade or equivalent, such that both reviewers could confidently identify a cohort of patients with at least grade three motor weakness or worse, (3) a minimum of 6 months follow-up. RESULTS: Seven studies were identified with a total of 354 patients. Complete recovery was seen in 38.4% of patients following surgery and 32% following non-operative treatment. Age and grade of motor deficit were identified as significant prognostic factors in some of the studies. CONCLUSION: The current available evidence is not robust enough to address the questions posed. We have proposed a framework for future studies.

A simulation design for research evaluating safety innovations in anaesthesia*.

SUMMARY: It is notoriously difficult to obtain evidence from clinical randomised controlled trials for safety innovations in healthcare. We have developed a research design using simulation for the evaluation of safety initiatives in anaesthesia. We used a standard and a modified scenario in a human-patient simulator, involving a potentially life-threatening problem requiring prompt attention--either a cardiac arrest or a failure in oxygen supply. The modified scenarios involved distractions such as loud music, a demanding and uncooperative surgeon, telephone calls and frequent questions from a medical student. Twenty anaesthetics were administered by 10 anaesthetists. A mean (SD) of 11.3 (2.8) errors per anaesthetic were identified in the oxygen failure scenarios, compared with 8.0 (3.4) in the cardiac arrest scenarios (ANOVA: p = 0.04). The difference between the combined standard scenarios and the combined modified scenarios was not significant. The mean rate of errors overall was 9.7 per simulation, with a pooled SD of 4.46, so in future studies 21 subjects would provide 80% statistical power to show a reduction in error rate of 30% from baseline with p

The radiological appearances of thalassaemia.

The skeletal changes of untreated thalassaemia result from ineffective erythropoiesis and expansion of the bone marrow and affect every part of the skeleton. These changes include osteoporosis, growth retardation, platyspondyly and kyphosis. Erythropoiesis occurs at extra-medullary sites, most commonly resulting in a paraspinal mass but occasionally affecting organs containing pluripotential stem cells. Repeated transfusion unaccompanied by iron chelation causes haemosiderosis; iron is deposited at various sites causing functional impairment. Iron-chelation therapy with desferrioxamine (DFX) prevents haemosiderosis but causes a skeletal dysplasia predominantly affecting the rapidly growing long bones, in particular the distal ulna, and causing irregularity and sclerosis of the physeal-metaphyseal junction and splaying of the metaphysis. DFX also exacerbates the observed growth retardation. DFX-induced skeletal dysplasia may herald toxicity, which is associated with visual and auditory impairment. Therefore, careful balancing of the transfusion regimen and iron-chelation therapy is required. Magnetic resonance imaging (MRI) is the most sensitive technique for the detection of DFX-induced dysplasia.

L5 radiculopathy secondary to intrapelvic placement of acetabular cup fixation screw.

We report a case of L5 radiculopathy secondary to intrapelvic placement of an acetabular screw impinging on the lumbosacral trunk. A 43-year-old man underwent revision of an uncemented total hip replacement to a custom-made femoral component and uncemented cup. He subsequently developed hip pain, dysesthesia, and L5 radiculopathy. Spiral computed tomography (CT) and plain radiographs raised the possibility of an acetabular screw abutting the neurovascular bundle within the pelvis. Operative removal of the intrapelvic portion of the screw resulted in the immediate relief of the patient's radicular symptoms. This case report highlights the importance of the positioning of intrapelvic screws and the need for an anatomic awareness of the structures at risk during acetabular screw placement.

"Pig Tail" technique in intradiscal electrothermal therapy.

To describe a new method of catheter insertion in intradiscal electrothermal therapy, which eliminates the need for reinsertion of the cannula and catheter from the contralateral side in those patients in whom optimal positioning is not achieved with the standard technique. This new technique has not been described before. In those patients in whom adequate catheter position cannot be achieved with the standard technique, instead of withdrawing the cannula after the initial treatment, we recommend rotating the cannula 180 degrees through its long axis. This will allow the catheter to hit the anterior anulus and deflect backwards toward the cannula. It can then be negotiated across the midline to adequately thermally treat the whole posterior anulus. We have performed our technique in 42 consecutive patients in whom initial navigation was difficult. This new method proved to be simple and did not cause patients additional discomfort. The "pig tail" technique is safe and effective in intradiscal electrothermal therapy of those patients with difficult navigation. It avoids the need for second needle insertion, therefore avoiding the use of more local anesthesia, further discomfort for the patient, and additional radiographic exposure.

High-intensity zone, intradiscal electrothermal therapy, and magnetic resonance imaging.

Magnetic resonance imaging changes to the symptomatic intervertebral disc following intradiscal electrothermal therapy were determined in this prospective study. Magnetic resonance images before the intradiscal electrothermal therapy procedure were compared with those taken at 6 months postprocedure in 10 patients. The presence and absence of high-intensity zone, the disc height and hydration, and Modic changes were determined from the images. In six of the 10 patients, a high-intensity zone was present on the magnetic resonance images of the disc before the intradiscal electrothermal therapy procedure. In all six patients, a high-intensity zone was still present after the procedure. In all 10 patients, there were no changes to other disc parameters assessed. Our findings question the clinical relevance of the high-intensity zone. They also suggest that the main mechanism of action of intradiscal electrothermal therapy may be other than that of sealing the anular tear.

Adolescent disc protrusions. A long-term follow-up of surgery compared to chymopapain.

STUDY DESIGN: This study compared chymopapain with primary surgery in the treatment of 60 radiologically proven adolescent lumbar disc protrusions and symptoms of low back pain and sciatica; the failures of intradiscal therapy were treated by surgical discectomy. OBJECTIVES: To establish whether chymopapain is as good as primary surgery in treating adolescents with proven lumbar disc protrusions. SUMMARY OF BACKGROUND DATA: Symptomatic lumbar disc protrusions are rare in white adolescents; the reported incidence varies from 0.8% to 3.2% of all lumbar disc protrusions. This is the largest study with long-term follow-up in the world literature. METHODS: Forty-two patients between the ages of 13 and 19 years with proven lumbar disc protrusions were initially treated with chymopapain; the failures of intradiscal therapy were treated by surgical discectomy. Eighteen patients were treated with surgical discectomy. After initial review at 1, 3, 6, and 12 months, the patients were assessed using a postal questionnaire and telephone interview at a minimum of 5 years' follow-up (means: 8.5 years for chymopapain group, 7.2 years for surgery group). RESULTS: Full replies were received from 16 of 18 (89%) in the surgery group and 42 of 42 (100%) in the chymopapain group. The long-term outcome is classed as good or excellent in 81% of the surgical group and 64% in the chymopapain group. If chymopapain is used as a first-line treatment, with surgery reserved for the failures, the long-term outcome is good or excellent in 82%. The chymopapain group had a shorter hospital stay. The surgical group were more likely to be unemployed and were less able to perform manual work and less able to engage in sporting activity. CONCLUSIONS: Back pain, radicular pain, and tension signs are common, but neurologic signs are less frequent in this age group. Long-term results of surgery are no better than the results of first-line chymopapain treatment with surgery being reserved for the failures. In 60% to 70% of patients, the morbidity, cost, and hospital stay were lessened. The patient is more likely to be in satisfactory employment after chemonucleolysis than after primary surgery.

Holoprosencephaly and midline facial anomalies: redefining classification and management.

Holoprosencephaly encompasses a series of midline defects of the brain and face. Most cases are associated with severe malformations of the brain which are incompatible with life. At the other end of the spectrum, however, are patients with midline facial defects and normal or near-normal brain development. Although some are mentally retarded, others have the potential for achieving near-normal mentality and a full life expectancy. The latter patients do not fit clearly into the previously defined classification system. Proposed is a new classification focusing on those patients with normal or lobar brain morphology but with a wide range of facial anomalies. The classification aids in planning treatment. Coupled with CT scan findings of the brain and a period of observation, patients unlikely to thrive can be distinguished from those who will benefit from surgical intervention. Repair of the false median cleft lip and palate may suffice in patients with moderate mental retardation. Patients exhibiting normal or near-normal mentality with hypotelorbitism and nasomaxillary hypoplasia can be treated with a simultaneous midface advancement, facial bipartition expansion, and nasal reconstruction.

Fracture of the femoral stem of the Ring TCH hip prosthesis.

We report the clinical and operative details of seven cases of fracture of the femoral stem of the Ring TiMESH cementless hip prosthesis (two were cemented and five uncemented). Six fractures occurred in the proximal one-third of the stem and one at mid-stem. The failures are attributed mainly to two defects in stem design, the narrowness of the anteroposterior dimensions and the depth of the recess for the titanium mesh pads. Great difficulty was experienced in removing the osseo-integrated distal fragments of the broken stems.