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.

Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders.

Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.

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.

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.

Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6.

Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. We ascertained eight families affected by HS and, by using a whole-exome sequencing approach, identified biallelic mutations in PEX1 or PEX6 in six of them. Loss-of-function mutations in both genes are known causes of a spectrum of autosomal-recessive peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome. PBDs are characterized by leukodystrophy, hypotonia, SNHL, retinopathy, and skeletal, craniofacial, and liver abnormalities. We demonstrate that each HS-affected family has at least one hypomorphic allele that results in extremely mild peroxisomal dysfunction. Although individuals with HS share some subtle clinical features found in PBDs, the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect PBDs. In conclusion, our findings define HS as a mild PBD, expanding the pleiotropy of mutations in PEX1 and PEX6.

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.

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.

Access to effective antimicrobials: a worldwide challenge.

Recent years have seen substantial improvements in life expectancy and access to antimicrobials, especially in low-income and lower-middle-income countries, but increasing pathogen resistance to antimicrobials threatens to roll back this progress. Resistant organisms in health-care and community settings pose a threat to survival rates from serious infections, including neonatal sepsis and health-care-associated infections, and limit the potential health benefits from surgeries, transplants, and cancer treatment. The challenge of simultaneously expanding appropriate access to antimicrobials, while restricting inappropriate access, particularly to expensive, newer generation antimicrobials, is unique in global health and requires new approaches to financing and delivering health care and a one-health perspective on the connections between pathogen transmission in animals and humans. Here, we describe the importance of effective antimicrobials. We assess the disease burden caused by limited access to antimicrobials, attributable to resistance to antimicrobials, and the potential effect of vaccines in restricting the need for antibiotics.

Provision of social norm feedback to high prescribers of antibiotics in general practice: a pragmatic national randomised controlled trial.

BACKGROUND: Unnecessary antibiotic prescribing contributes to antimicrobial resistance. In this trial, we aimed to reduce unnecessary prescriptions of antibiotics by general practitioners (GPs) in England. METHODS: In this randomised, 2 × 2 factorial trial, publicly available databases were used to identify GP practices whose prescribing rate for antibiotics was in the top 20% for their National Health Service (NHS) Local Area Team. Eligible practices were randomly assigned (1:1) into two groups by computer-generated allocation sequence, stratified by NHS Local Area Team. Participants, but not investigators, were blinded to group assignment. On Sept 29, 2014, every GP in the feedback intervention group was sent a letter from England's Chief Medical Officer and a leaflet on antibiotics for use with patients. The letter stated that the practice was prescribing antibiotics at a higher rate than 80% of practices in its NHS Local Area Team. GPs in the control group received no communication. The sample was re-randomised into two groups, and in December, 2014, GP practices were either sent patient-focused information that promoted reduced use of antibiotics or received no communication. The primary outcome measure was the rate of antibiotic items dispensed per 1000 weighted population, controlling for past prescribing. Analysis was by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN32349954, and has been completed. FINDINGS: Between Sept 8 and Sept 26, 2014, we recruited and assigned 1581 GP practices to feedback intervention (n=791) or control (n=790) groups. Letters were sent to 3227 GPs in the intervention group. Between October, 2014, and March, 2015, the rate of antibiotic items dispensed per 1000 population was 126.98 (95% CI 125.68-128.27) in the feedback intervention group and 131.25 (130.33-132.16) in the control group, a difference of 4.27 (3.3%; incidence rate ratio [IRR] 0.967 [95% CI 0.957-0.977]; p<0.0001), representing an estimated 73,406 fewer antibiotic items dispensed. In December, 2014, GP practices were re-assigned to patient-focused intervention (n=777) or control (n=804) groups. The patient-focused intervention did not significantly affect the primary outcome measure between December, 2014, and March, 2015 (antibiotic items dispensed per 1000 population: 135.00 [95% CI 133.77-136.22] in the patient-focused intervention group and 133.98 [133.06-134.90] in the control group; IRR for difference between groups 1.01, 95% CI 1.00-1.02; p=0.105). INTERPRETATION: Social norm feedback from a high-profile messenger can substantially reduce antibiotic prescribing at low cost and at national scale; this outcome makes it a worthwhile addition to antimicrobial stewardship programmes. FUNDING: Public Health England.

De Novo Truncating Mutations in the Kinetochore-Microtubules Attachment Gene CHAMP1 Cause Syndromic Intellectual Disability.

A rare syndromic form of intellectual disability with impaired speech was recently found associated with mutations in CHAMP1 (chromosome alignment-maintaining phosphoprotein 1), the protein product of which is directly involved in microtubule-kinetochore attachment. Through whole-exome sequencing in six unrelated nonconsanguineous families having a sporadic case of intellectual disability, we identified six novel de novo truncating mutations in CHAMP1: c.1880C>G p.(Ser627*), c.1489C>T; p.(Arg497*), c.1876_1877delAG; p.(Ser626Leufs*4), c.1043G>A; p.(Trp348*), c.1002G>A; p.(Trp334*), and c.958_959delCC; p.(Pro320*). Our clinical observations confirm the phenotypic homogeneity of the syndrome, which represents therefore a distinct clinical entity. Besides, our functional studies show that CHAMP1 protein variants are delocalized from chromatin and are unable to bind to two of its direct partners, POGZ and HP1. These data suggest a pathogenic mechanism of the CHAMP1-associated intellectual disability syndrome mediated by direct interacting partners of CHAMP1, several of which are involved in chromo/kinetochore-related disorders.

Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy.

BACKGROUND: Copy number variants (CNVs) have been linked to neurodevelopmental disorders such as intellectual disability (ID), autism, epilepsy and psychiatric disease. There are few studies of CNVs in patients with both ID and epilepsy. METHODS: We evaluated the range of rare CNVs found in 80 Welsh patients with ID or developmental delay (DD), and childhood-onset epilepsy. We performed molecular cytogenetic testing by single nucleotide polymorphism array or microarray-based comparative genome hybridisation. RESULTS: 8.8 % (7/80) of the patients had at least one rare CNVs that was considered to be pathogenic or likely pathogenic. The CNVs involved known disease genes (EHMT1, MBD5 and SCN1A) and imbalances in genomic regions associated with neurodevelopmental disorders (16p11.2, 16p13.11 and 2q13). Prompted by the observation of two deletions disrupting SCN1A we undertook further testing of this gene in selected patients. This led to the identification of four pathogenic SCN1A mutations in our cohort. CONCLUSIONS: We identified five rare de novo deletions and confirmed the clinical utility of array analysis in patients with ID/DD and childhood-onset epilepsy. This report adds to our clinical understanding of these rare genomic disorders and highlights SCN1A mutations as a cause of ID and epilepsy, which can easily be overlooked in adults.

A sea change for sick doctors - how do doctors fare after presenting to a specialist psychotherapy service?

BACKGROUND: Little is known about doctors who present to services following an episode of psychological distress. MedNet is a psycho-dynamically informed confidential self-referral service for doctors. AIMS: To examine the health and work trajectory of MedNet clients between 2002 and 2007 followed up in 2010. METHOD: We report and compare service-monitoring data for 124 doctors on engagement with health services, whether in work or not, sick leave utilised, and reported distress measured by CORE-OM at intake and at one follow-up time point. RESULTS: 95.6% of doctors continue to work and progress in their careers. 58.3% remained engaged with services. Sick leave had reduced significantly at follow-up. Distress was significantly reduced, but no differences were found with respect to social functioning and well-being. An interesting shift was observed in doctors' use of medication from treating somatic complaints towards treating mood symptoms. CONCLUSIONS: Doctors show improvements and continue to progress in their careers after a psychotherapeutically orientated intervention. A shift in doctors' perception of their difficulties is indicated from more somatic to psychological concerns. Many doctor-patients continue with ongoing professional support.

For debate: a new wave in public health improvement.

The rising burden of chronic disease poses a challenge for all public health systems and requires innovative approaches to effectively improve population health. Persisting inequalities in health are of particular concern. Disadvantage because of education, income, or social position is associated with a larger burden of disease and, in particular, multimorbidity. Although much has been achieved to enhance population health, challenges remain, and approaches need to be revisited. In this paper, we join the debate about how a new wave of public health improvement might look. We start from the premise that population health improvement is conditional on a health-promoting societal context. It is characterised by a culture in which healthy behaviours are the norm, and in which the institutional, social, and physical environment support this mindset. Achievement of this ambition will require a positive, holistic, eclectic, and collaborative effort, involving a broad range of stakeholders. We emphasise three mechanisms: maximisation of the value of health and incentives for healthy behaviour; promotion of healthy choices as default; and minimisation of factors that create a culture and environment which promote unhealthy behaviour. We give examples of how these mechanisms might be achieved.