Börjeson-Forssman-Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families.

Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene. We ascertained 19 individuals from 15 families with likely pathogenic or pathogenic PHF6 variants (11 males and 8 females). One family had previously been reported. Six variants were novel. We analysed the clinical and genetic findings in our series and compared them with reported BFLS patients. Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity. Carrier female relatives of affected males were unaffected or had only mild symptoms. The phenotype of affected females with de novo variants overlapped with the males but included linear skin hyperpigmentation and a higher frequency of dental, retinal and cortical brain anomalies. Complications observed in our series included keloid scarring, digital fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and talipes. Our analysis highlighted sex-specific differences in PHF6 variant types and locations. Affected males often have missense variants or small in-frame deletions while affected females tend to have truncating variants or large deletions/duplications. Missense variants were found in a minority of affected females and clustered in the highly constrained PHD2 domain of PHF6. We propose recommendations for the evaluation and management of BFLS patients. These results further delineate and extend the genetic and phenotypic spectrum of BFLS.

Antimicrobial Resistance: Is Health Technology Assessment Part of the Solution or Part of the Problem?

Antimicrobial resistance is a serious challenge to the success and sustainability of our healthcare systems. There has been increasing policy attention given to antimicrobial resistance in the last few years, and increased amounts of funding have been channeled into funding for research and development of antimicrobial agents. Nevertheless, manufacturers doubt whether there will be a market for new antimicrobial technologies sufficient to enable them to recoup their investment. Health technology assessment (HTA) has a critical role in creating confidence that if valuable technologies can be developed they will be reimbursed at a level that captures their true value. We identify 3 deficiencies of current HTA processes for appraising antimicrobial agents: a methods-centric approach rather than problem-centric approach for dealing with new challenges, a lack of tools for thinking about changing patterns of infection, and the absence of an approach to epidemiological risks. We argue that, to play their role more effectively, HTA agencies need to broaden their methodological tool kit, design and communicate their analysis to a wider set of users, and incorporate long-term policy goals, such as containing resistance, as part of their evaluation criteria alongside immediate health gains.

Innovate to secure the future: the future of modern medicine.

As drug-resistant pathogens emerge and spread globally, antimicrobial (especially antibiotic) treatments are becoming less effective. As infections become more complex and costly to treat in humans and animals, antimicrobial resistance (AMR) is a global challenge of real and increasing scale and complexity. If we do not act for the long term and with sustainability in mind, the annual deaths we see currently, numbering 700,000 globally, will rise each year to 10 million by 2050. To effectively contain and mitigate AMR, we need more evidence of the drivers and impacts of AMR on human, animal and environmental health, and the links between them. We also need to turn evidence into action and tailored, sustainable approaches for countries and communities, which put clinicians and patients at the centre. Excellent research is underway across the world into innovation (including new treatments, diagnostics and vaccines), infection prevention and behavioural interventions. In this article, we explore how, where and why research should be intensified, with increased collaboration and transparency, to strengthen global health security and secure the future of modern medicine for patients globally.

A comparison of different standard-setting methods for professional qualifying dental examination.

BACKGROUND: The outcome of assessments is determined by the standard-setting method used. Standard setting is the process of deciding what is good enough. A cutoff score of 50% was commonly used in dental schools in Malaysia. This study aims to compare the conventional, norm-referenced, and modified-Angoff standard-setting methods. METHODS: The norm-referenced method of standard setting was applied to the real scores of 40 final-year dental students on a multiple-choice question (MCQ), a short answer question (SAQ), and an objective structured clinical examination (OSCE). A panel of 10 judges set the standard using the modified-Angoff method for the same paper in one sitting. One judge set the passing score of 10 OSCE questions after 2 weeks. A comparison of the grades and pass/fail rates derived from the absolute standard, norm-referenced, and modified-Angoff methods was made. The intra-rater and inter-rater reliabilities of the modified-Angoff method were assessed. RESULTS: The passing rate for the absolute standard was 100% (40/40), for the norm-referenced method it was 62.5% (25/40), and for the modified-Angoff method it was 80% (32/40). The modified-Angoff method had good inter-rater reliability of 0.876 and excellent test-retest reliability of 0.941. CONCLUSION: There were significant differences in the outcomes of these three standard-setting methods, as shown by the difference in the proportion of candidates who passed and failed the assessment. The modified-Angoff method was found to have good reliability for use with a professional qualifying dental examination.

Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine.

The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome profiles and restores expression of PPT reporters. In zebrafish, knockdown eif5a partly recapitulates the human phenotype that can be rescued with 1 µM spermidine supplementation. In summary, we uncover the role of eIF5A in human development and disease, demonstrate the mechanistic complexity of EIF5A-related disorder and raise possibilities for its treatment.

Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy.

Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Nav) channels in the brain and other tissues. FHF dysfunction has been linked to neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome sequencing identified hemi- and heterozygous variants in the N-terminal domain of the A isoform of FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants. Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental and epileptic encephalopathy and underline the critical role of the FHF2A isoform in regulating Nav channel function.

Knowledge and pre-thoracic spinal thrust manipulation examination: a survey of current practice in the UK.

OBJECTIVES: The perceived relative safety of thoracic thrust joint manipulation (TTJM) has contributed to evidence supporting its use. Yet, TTJM is not without risk, where transient side effects (SE) and severe adverse events (AE) have been documented. With evidence supporting the importance of prethrust examination in reducing AE in other spinal regions this study investigated TTJM knowledge and pre-TTJM examination. Method: An e-survey, informed by existing evidence and expertise was designed and piloted. Eligibility criteria: UK-trained physiotherapists who use TTJM. Recruitment via professional networks and social media from December 2016 to February 2017. Data analysis included descriptive analyses (means, standard deviation and frequencies/central tendencies), and content analysis (themes and frequencies) for free text data. Results: From 306 responses, the sample comprised 146 (53%) males, mean (SD) age 36.37(8.68) years, with 12.88(8.67) years in practice, 11.07(8.14) years specialization, working in National Health Service/private practice (81%) and performing 0-5 TTJM/week (86%). EXAMINATION: 40% (n = 83) utilized pre-TTJM examination with 45% (n = 139) adapting the examination for different regions. Technique selection and effect: preferred technique was prone rotational TTJM (67%). Perception of the primary underlying effect was neurophysiological (54%), biomechanical (45%) or placebo (1%). Knowledge: Levels of agreement were found for contraindications (85%), precautions (75%), and red flags (86%) with more variability for risks including AE and SE (61%). DISCUSSION: UK physiotherapists demonstrated good knowledge and agreement of contraindications, precautions, and red flags to TTJM. With <50% respondents utilizing pre-TTJM examination, variable knowledge of TTJM risks, and therapeutic effects of TTJM further research is required.

Further delineation of Malan syndrome.

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.

Reducing inappropriate prescribing of antibiotics in English primary care: evidence and outlook.

Antibiotics are indispensable for treating bacterial infections, but their effectiveness is threatened by the emergence and spread of antibacterial resistance. Antibiotics are unique among drugs since the more they are used, the less effective they become because bacterial resistance is likely to develop. In response to this threat, the UK government aims to reduce inappropriate antibiotic prescribing in humans by 50% by 2020. A team at Public Health England has found that at least 20% of antibiotic prescriptions in primary care in England were inappropriate, which, if correct, implies that antibiotic prescribing nationally needs to be reduced by 10% by 2020. These data are published in five articles in a Supplement to JAC entitled Appropriateness of antibiotic prescribing in English primary care. Inappropriate prescribing was found in every general practice included in the analyses so each one should attempt to reduce unnecessary prescriptions, not just high-prescribing practices. An ambition of 10% reduction in antibiotic prescriptions seems attainable when compared with the reduction targets of other European countries. The need for substantial improvements in data quality that are necessary to further safeguard this precious resource is also highlighted by the authors in this Supplement.