Publications by authors named "Sally Davies"

91 Publications

Leveraging data and new digital tools to prepare for the next pandemic.

Lancet 2021 Apr 1;397(10282):1349-1350. Epub 2021 Apr 1.

The Trinity Challenge, Cambridge CB2 1TQ, UK. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(21)00680-2DOI Listing
April 2021

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

J Dent Educ 2021 Mar 31. Epub 2021 Mar 31.

Faculty of Life Sciences & Education, University of South Wales, 9 Graig Fach, Glyntaff, Pontypridd, Wales, CF37 4BB, United Kingdom.

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.
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http://dx.doi.org/10.1002/jdd.12600DOI Listing
March 2021

The Health Index for England.

Lancet 2021 Feb;397(10275):665

Trinity College, Cambridge University, Cambridge, UK.

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http://dx.doi.org/10.1016/S0140-6736(21)00201-4DOI Listing
February 2021

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

Nat Commun 2021 02 5;12(1):833. Epub 2021 Feb 5.

Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

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.
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http://dx.doi.org/10.1038/s41467-021-21053-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864902PMC
February 2021

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

Am J Hum Genet 2021 01 26;108(1):176-185. Epub 2020 Nov 26.

Neurology and Molecular Neuroscience Research, Institute of Life Science, Swansea University Medical School, Swansea University, Swansea SA2 8PP, UK; Kids Neuroscience Centre, Kids Research, Children Hospital at Westmead, Sydney, NSW 2145, Australia; Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, NSW 2050, Australia.

Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Na) 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 Na channels. Functional characterization of mutant FHF2A co-expressed with wild-type Na1.6 (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 Na channel function.
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http://dx.doi.org/10.1016/j.ajhg.2020.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820623PMC
January 2021

Confronting antimicrobial resistance beyond the COVID-19 pandemic and the 2020 US election.

Lancet 2020 10 29;396(10257):1050-1053. Epub 2020 Sep 29.

Division of Infectious Diseases, University of Nebraska Medical Center, Omaha, NE, USA.

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http://dx.doi.org/10.1016/S0140-6736(20)32063-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524538PMC
October 2020

Protecting children's rights: why governments must be bold to tackle childhood obesity.

Lancet 2019 10 10;394(10207):1393-1395. Epub 2019 Oct 10.

Chief Medical Officer's Office, Department of Health and Social Care, London SW1H 0EU, UK.

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http://dx.doi.org/10.1016/S0140-6736(19)32274-3DOI Listing
October 2019

Global partnerships and the Chief Medical Officer's 2019 annual report.

Lancet 2019 Aug 21;394(10196):369-370. Epub 2019 Jul 21.

Department of Health and Social Care, London SW1H 0EU, UK. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(19)31666-6DOI Listing
August 2019

A new Health Index for England: the Chief Medical Officer's 2018 annual report.

Lancet 2019 01 21;393(10166):10-11. Epub 2018 Dec 21.

Department of Health and Social Care, London SW1H 0EU, UK. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(18)33210-0DOI Listing
January 2019

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

J Man Manip Ther 2018 Dec 5;26(5):301-309. Epub 2018 Sep 5.

Centre of Precision Rehabilitation for Spinal Pain, School of Sport, Exercise & Rehabilitation Sciences, University of Birmingham, Birmingham, 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. : 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. : 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% ( = 83) utilized pre-TTJM examination with 45% ( = 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.
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http://dx.doi.org/10.1080/10669817.2018.1507269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237157PMC
December 2018

Further delineation of Malan syndrome.

Hum Mutat 2018 09 25;39(9):1226-1237. Epub 2018 Jun 25.

Belfast HSC Trust, Northern Ireland Regional Genetics Service, Belfast, Northern Ireland.

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.
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http://dx.doi.org/10.1002/humu.23563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175110PMC
September 2018

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

Authors:
Sally C Davies

J Antimicrob Chemother 2018 04;73(4):833-834

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.
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http://dx.doi.org/10.1093/jac/dkx535DOI Listing
April 2018

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

Am J Hum Genet 2018 01 21;102(1):175-187. Epub 2017 Dec 21.

Manchester Centre for Genomic Medicine, Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ajhg.2017.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778085PMC
January 2018

Tackling antimicrobial resistance globally.

Med J Aust 2017 11;207(9):371-373

Department of Health, London, United Kingdom.

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http://dx.doi.org/10.5694/mja17.00865DOI Listing
November 2017

Prevention Pays-Lessons from the Chief Medical Officer's Annual Report: five years on.

Arch Dis Child 2017 10 24;102(10):885-887. Epub 2017 Jun 24.

Office of the Chief Medical Officer, Department of Health, London, UK.

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http://dx.doi.org/10.1136/archdischild-2016-311742DOI Listing
October 2017

Dr David Nabarro is the best candidate for WHO Director-General.

Authors:
Sally C Davies

Lancet 2017 05 8;389(10083):1977-1978. Epub 2017 May 8.

UK Department of Health, London SW1A 2NS, UK. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(17)31255-2DOI Listing
May 2017

Combatting antimicrobial resistance globally.

Nat Microbiol 2016 09 27;1(10):16187. Epub 2016 Sep 27.

Department of Health, Richmond House, 79 Whitehall, London SW1A 2NS, UK.

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http://dx.doi.org/10.1038/nmicrobiol.2016.187DOI Listing
September 2016

Infographic. Physical activity for early years.

Br J Sports Med 2018 May 22;52(10):631-632. Epub 2016 Sep 22.

Nuffield Department of Population Health, University of Oxford, UK.

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http://dx.doi.org/10.1136/bjsports-2016-096813DOI Listing
May 2018

Wellcome Trust: Report released on antibiotic resistance.

Nature 2016 09;537(7619):167

Department of Health, London.

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http://dx.doi.org/10.1038/537167aDOI Listing
September 2016

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

J Ment Health 2016 Jun 6;25(3):238-44. Epub 2016 Jan 6.

a Adult Department , MedNet, The Tavistock Clinic , London , UK.

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.
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http://dx.doi.org/10.3109/09638237.2015.1124386DOI Listing
June 2016

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

BMC Med Genet 2016 04 26;17(1):34. Epub 2016 Apr 26.

MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, CF24 4HQ, UK.

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.
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http://dx.doi.org/10.1186/s12881-016-0294-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845474PMC
April 2016

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

Lancet 2016 Apr 18;387(10029):1743-52. Epub 2016 Feb 18.

Department of Health, London, UK.

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.
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http://dx.doi.org/10.1016/S0140-6736(16)00215-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4842844PMC
April 2016

The future leadership of WHO.

Lancet 2016 Jan;387(10016):321-323

National Health Surveillance Agency (ANVISA), Brasilia, Brazil.

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http://dx.doi.org/10.1016/S0140-6736(16)00105-7DOI Listing
January 2016

Ebola survivors: not out of the woods yet.

BMJ 2016 Jan 22;532:i178. Epub 2016 Jan 22.

Department of Health, London, UK.

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http://dx.doi.org/10.1136/bmj.i178DOI Listing
January 2016

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

Hum Mutat 2016 Apr 4;37(4):354-8. Epub 2016 Feb 4.

Inserm, UMR 1087, l'institut du thorax, CHU Nantes, Nantes, France.

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.
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http://dx.doi.org/10.1002/humu.22952DOI Listing
April 2016

Access to effective antimicrobials: a worldwide challenge.

Lancet 2016 Jan 18;387(10014):168-75. Epub 2015 Nov 18.

Department of Health, UK.

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.
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http://dx.doi.org/10.1016/S0140-6736(15)00474-2DOI Listing
January 2016