Small RNA regulators (sRNAs) have been identified in a wide range of bacteria and found to play critical regulatory roles in many processes. The major families of sRNAs include true antisense RNAs, ...synthesized from the strand complementary to the mRNA they regulate, sRNAs that also act by pairing but have limited complementarity with their targets, and sRNAs that regulate proteins by binding to and affecting protein activity. The sRNAs with limited complementarity are akin to eukaryotic microRNAs in their ability to modulate the activity and stability of multiple mRNAs. In many bacterial species, the RNA chaperone Hfq is required to promote pairing between these sRNAs and their target mRNAs. Understanding the evolution of regulatory sRNAs remains a challenge; sRNA genes show evidence of duplication and horizontal transfer but also could be evolved from tRNAs, mRNAs or random transcription.
X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth ...impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia.
In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1–12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705.
Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 SE 0·1 with burosumab vs +0·8 0·1 with conventional therapy; difference 1·1, 95% CI 0·8–1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 59% of 29 patients in the burosumab group vs seven 22% of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved.
Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy.
Ultragenyx Pharmaceutical and Kyowa Kirin International.
We report the design and demonstration of a vertical external cavity surface emitting laser with intra-cavity astigmatic mode converters. Using a flexible optical pumping scheme Hermite-Gaussian ...transverse modes were excited at the gain chip and end mirror, and Laguerre-Gaussian transverse modes were observed between the two astigmatic mode converters. Adjusting the flexible pumping scheme allowed for mode order tuning while the laser was operating.
Summary
Mucopolysaccharidosis IVA (MPS IVA; Morquio A disease) is a lysosomal storage disorder caused by deficiency of N‐acetylgalactosamine‐6‐sulfate sulfatase. The natural history of this disease ...is incompletely understood. To study which variables influence the clinical outcome, we conducted a study in which MPS IVA patients were asked to fill out a questionnaire with inquiries regarding family history, diagnosis, signs and symptoms, height, weight, surgical history, physical activity, and general complaints. A total of 326 patients (172 male, 154 female) from 42 countries enrolled in the Morquio A Registry programme. The mean age of patients enrolled was 14.9 years for males and 19.1 years for females, with a wide range of 1–73 years. Sixty‐four per cent of the patients were under 18 years. Initial symptoms were recognized between 1 and 3 years of age (mean age 2.1 years) and mean age at diagnosis for the patients was 4.7 years. A progressive skeletal dysplasia was commonly observed among the MPS IVA patients. Fifty per cent of patients underwent surgical operations to improve their quality of life. The most frequent surgical sites include neck (51%), ear (33%), leg (26%) and hip (25%). The birth length for affected males and females was 52.2 ± 4.7 cm and 52.2 ± 4.5 cm, respectively. The final adult height for affected males and females was 122.5 ± 22.5 cm and 116.5 ± 20.5 cm, respectively. The results of this study provide a reference for assessment of efficacy for studies of novel therapies.
Abstract
Context
Younger age at treatment onset with conventional therapy (phosphate salts and active vitamin D; Pi/D) is associated with improved growth and skeletal outcomes in children with ...X-linked hypophosphatemia (XLH). The effect of age on burosumab efficacy and safety in XLH is unknown.
Objective
This work aimed to explore the efficacy and safety of burosumab vs Pi/D in younger (< 5 years) and older (5-12 years) children with XLH.
Methods
This post hoc analysis of a 64-week, open-label, randomized controlled study took place at 16 academic centers. Sixty-one children aged 1 to 12 years with XLH (younger, n = 26; older, n = 35) participated. Children received burosumab starting at 0.8 mg/kg every 2 weeks (younger, n = 14; older, n = 15) or continued Pi/D individually titrated per recommended guidelines (younger, n = 12; older, n = 20). The main outcome measure included the least squares means difference (LSMD) in Radiographic Global Impression of Change (RGI-C) rickets total score from baseline to week 64.
Results
The LSMD in outcomes through 64 weeks on burosumab vs conventional therapy by age group were as follows: RGI-C rickets total score (younger, +0.90; older, +1.07), total Rickets Severity Score (younger, −0.86; older, −1.44), RGI-C lower limb deformity score (younger, +1.02; older, +0.91), recumbent length or standing height Z-score (younger, +0.20; older, +0.09), and serum alkaline phosphatase (ALP) (younger, −31.15% of upper normal limit ULN; older, −52.11% of ULN). On burosumab, dental abscesses were not reported in younger children but were in 53% of older children.
Conclusion
Burosumab appears to improve outcomes both in younger and older children with XLH, including rickets, lower limb deformities, growth, and ALP, compared with Pi/D.
Summary The aim of this study was to assess the value of surveillance cultures in identifying extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL) carriers upon admission to hospital, ...and to identify risk factors for carriage. This prospective cross-sectional study included all hospital admissions over one week. Of 525 patients screened, 56 were positive for ESBLs. Half were only identified through screening. Four independent risk factors were identified: nursing home residency, hospitalization in the previous year, prior antibiotic treatment and prior ESBL carriage. Over 50% of the screened patients had at least one risk factor. By screening this targeted population, 87.5% of positive patients would have been identified.
Summary
Adaptation to the changing environment requires both the integration of external signals and the co‐ordination of internal responses. Around 50 non‐coding small RNAs (sRNAs) have been ...described in Escherichia coli; the levels of many of these vary with changing environmental conditions. This suggests that they play a role in cell adaptation. In this review, we use the regulation of RpoS (σ38) translation as a paradigm of sRNA‐mediated response to environmental conditions; rpoS is currently the only known gene regulated post‐transcriptionally by at least three sRNAs. DsrA and RprA stimulate RpoS translation in response to low temperature and cell surface stress, respectively, whereas OxyS represses RpoS translation in response to oxidative shock. However, in addition to regulating RpoS translation, DsrA represses the translation of HNS (a global regulator of gene expression), whereas OxyS represses the translation of FhlA (a transcriptional activator), allowing the cell to co‐ordinate different pathways involved in cell adaptation. Environmental cues affect the synthesis and stability of specific sRNAs, resulting in specific sRNA‐dependent translational control.
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