Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism.

ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder.

Establishment and initial implementation of the Australasian Pelvic Floor Procedure Registry.

INTRODUCTION AND HYPOTHESIS: Stress urinary incontinence (SUI) and pelvic organ prolapse (POP) are common pelvic floor disorders (PFDs). Owing to significant adverse events associated with mesh-related pelvic floor procedures (PFPs) in a proportion of the surgically treated population, and deficits in collection and reporting of these events, the Australian Government identified an urgent need for a tracking mechanism to improve safety and quality of care. The Australasian Pelvic Floor Procedure Registry (APFPR) was recently established following the 2018 Senate Committee Inquiry with the aim of tracking outcomes of PFP involving the use of devices and/or prostheses, with the objective of improving the health outcomes of women who undergo these procedures. This paper will describe the APFPR's aims, development, implementation and possible challenges on the way to its establishment. METHODS: The APFPR has been developed and implemented in accordance with the national operating principles of clinical quality registries (CQRs). The minimum datasets (MDS) for the registry's database have been developed using a modified Delphi process, and data are primarily being collected from participating surgeons. Patient recruitment is based on an opt-out approach or a waiver of consent. Patient-reported outcome measures (PROMs) providing additional health and outcome information will be obtained from participating women to support safety monitoring of mesh-related adverse events. RESULTS: Currently in the Australasian Pelvic Floor Procedure Registry (APFPR) there are 32 sites from various jurisdictions across Australia, that have obtained relevant ethics and governance approvals to start patient recruitment and data collection as of January 2023. Additionally, there are two sites that are awaiting governance review and five sites that are having documentation compiled for submission. Seventeen sites have commenced patient registration and have entered data into the database. Thus far, we have 308 patients registered in the APFPR database. The registry also published its first status report and a consumer-friendly public report in 2022. CONCLUSIONS: The registry will act as a systematic tracking mechanism by collecting outcomes on PFP, especially those involving devices and/or prostheses to improve safety and quality of care.

Innate Intracellular Antiviral Responses Restrict the Amplification of Defective Virus Genomes of Parainfluenza Virus 5.

During the replication of parainfluenza virus 5 (PIV5), copyback defective virus genomes (DVGs) are erroneously produced and are packaged into "infectious" virus particles. Copyback DVGs are the primary inducers of innate intracellular responses, including the interferon (IFN) response. While DVGs can interfere with the replication of nondefective (ND) virus genomes and activate the IFN-induction cascade before ND PIV5 can block the production of IFN, we demonstrate that the converse is also true, i.e., high levels of ND virus can block the ability of DVGs to activate the IFN-induction cascade. By following the replication and amplification of DVGs in A549 cells that are deficient in a variety of innate intracellular antiviral responses, we show that DVGs induce an uncharacterized IFN-independent innate response(s) that limits their replication. High-throughput sequencing was used to characterize the molecular structure of copyback DVGs. While there appears to be no sequence-specific break or rejoining points for the generation of copyback DVGs, our findings suggest there are region, size, and/or structural preferences selected for during for their amplification.IMPORTANCE Copyback defective virus genomes (DVGs) are powerful inducers of innate immune responses both in vitro and in vivo They impact the outcome of natural infections, may help drive virus-host coevolution, and promote virus persistence. Due to their potent interfering and immunostimulatory properties, DVGs may also be used therapeutically as antivirals and vaccine adjuvants. However, little is known of the host cell restrictions which limit their amplification. We show here that the generation of copyback DVGs readily occurs during parainfluenza virus 5 (PIV5) replication, but that their subsequent amplification is restricted by the induction of innate intracellular responses. Molecular characterization of PIV5 copyback DVGs suggests that while there are no genome sequence-specific breaks or rejoin points for the generation of copyback DVGs, genome region, size, and structural preferences are selected for during their evolution and amplification.

ZTTK syndrome: Clinical and molecular findings of 15 cases and a review of the literature.

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is caused by de novo loss-of-function variants in the SON gene (MIM #617140). This multisystemic disorder is characterized by intellectual disability, seizures, abnormal brain imaging, variable dysmorphic features, and various congenital anomalies. The wide application and increasing accessibility of whole exome sequencing (WES) has helped to identify new cases of ZTTK syndrome over the last few years. To date, there have been approximately 45 cases reported in the literature. Here, we describe 15 additional individuals with variants in the SON gene, including those with missense variants bringing the total number of known cases to 60. We have reviewed the clinical and molecular data of these new cases and all previously reported cases to further delineate the most common as well as emerging clinical findings related to this syndrome. Furthermore, we aim to delineate any genotype-phenotype correlations specifically for a recurring pathogenic four base pair deletion (c.5753_5756del) along with discussing the impact of missense variants seen in the SON gene.

Characterization of Macrophage Polarization States Using Combined Measurement of 2-Deoxyglucose and Glutamine Accumulation: Implications for Imaging of Atherosclerosis.

OBJECTIVE: Despite the early promising results of 18F-fluorodeoxyglucose positron emission tomography for assessment of vessel wall inflammation, its accuracy in prospective identification of vulnerable plaques has remained limited. Additionally, previous studies have indicated that 18F-fluorodeoxyglucose uptake alone may not allow for accurate identification of specific macrophage activation states. We aimed to determine whether combined measurement of glucose and glutamine accumulation-the 2 most important bioenergetic substrates for macrophages-improves the distinction of macrophage inflammatory states and can be utilized to image atherosclerosis. APPROACH AND RESULTS: Murine peritoneal macrophages (MΦ) were activated ex vivo into proinflammatory states with either lipopolysaccharide (MΦLPS) or interferon-γ+tumor necrosis factor-α (MΦIFN-γ+TNF-α). An alternative polarization phenotype was induced with interleukin-4 (MΦIL-4). The pronounced increase in 2-deoxyglucose uptake distinguishes MΦLPS from MΦIFN-γ+TNF-α, MΦIL-4, and unstimulated macrophages (MΦ0). Despite having comparable levels of 2-deoxyglucose accumulation, MΦIL-4 can be distinguished from both MΦIFN-γ+TNF-α and MΦ0 based on the enhanced glutamine accumulation, which was associated with increased expression of a glutamine transporter, Slc1a5. Ex vivo autoradiography experiments demonstrated distinct and heterogenous patterns of 18F-fluorodeoxyglucose and 14C-glutamine accumulation in atherosclerotic lesions of low-density lipoprotein receptor-null mice fed a high-fat diet. CONCLUSIONS: Combined assessment of glutamine and 2-deoxyglucose accumulation improves the ex vivo identification of macrophage activation states. Combined ex vivo metabolic imaging demonstrates heterogenous and distinct patterns of substrate accumulation in atherosclerotic lesions. Further studies are required to define the in vivo significance of glutamine uptake in atherosclerosis and its potential application in identification of vulnerable plaques.

Characterization of minority HIV-1 drug resistant variants in the United Kingdom following the verification of a deep sequencing-based HIV-1 genotyping and tropism assay.

BACKGROUND: The widespread global access to antiretroviral drugs has led to considerable reductions in morbidity and mortality but, unfortunately, the risk of virologic failure increases with the emergence, and potential transmission, of drug resistant viruses. Detecting and quantifying HIV-1 drug resistance has therefore become the standard of care when designing new antiretroviral regimens. The sensitivity of Sanger sequencing-based HIV-1 genotypic assays is limited by its inability to identify minority members of the quasispecies, i.e., it only detects variants present above ~ 20% of the viral population, thus, failing to detect minority variants below this threshold. It is clear that deep sequencing-based HIV-1 genotyping assays are an important step change towards accurately monitoring HIV-infected individuals. METHODS: We implemented and verified a clinically validated HIV-1 genotyping assay based on deep sequencing (DEEPGEN™) in two clinical laboratories in the United Kingdom: St. George's University Hospitals Healthcare NHS Foundation Trust (London) and at NHS Lothian (Edinburgh), to characterize minority HIV-1 variants in 109 plasma samples from ART-naïve or -experienced individuals. RESULTS: Although subtype B HIV-1 strains were highly prevalent (44%, 48/109), most individuals were infected with non-B subtype viruses (i.e., A1, A2, C, D, F1, G, CRF02_AG, and CRF01_AE). DEEPGEN™ was able to accurately detect drug resistance-associated mutations not identified using standard Sanger sequencing-based tests, which correlated significantly with patient's antiretroviral treatment histories. A higher proportion of minority PI-, NRTI-, and NNRTI-resistance mutations was detected in NHS Lothian patients compared to individuals from St. George's, mainly M46I/L and I50 V (associated with PIs), D67 N, K65R, L74I, M184 V/I, and K219Q (NRTIs), and L100I (NNRTIs). Interestingly, we observed an inverse correlation between intra-patient HIV-1 diversity and CD4+ T cell counts in the NHS Lothian patients. CONCLUSIONS: This is the first study evaluating the transition, training, and implementation of DEEPGEN™ between three clinical laboratories in two different countries. More importantly, we were able to characterize the HIV-1 drug resistance profile (including minority variants), coreceptor tropism, subtyping, and intra-patient viral diversity in patients from the United Kingdom, providing a rigorous foundation for basing clinical decisions on highly sensitive and cost-effective deep sequencing-based HIV-1 genotyping assays in the country.

Differential Regulation of Macrophage Glucose Metabolism by Macrophage Colony-stimulating Factor and Granulocyte-Macrophage Colony-stimulating Factor: Implications for 18F FDG PET Imaging of Vessel Wall Inflammation.

Purpose To determine the divergence of immunometabolic phenotypes of macrophages stimulated with macrophage colony-stimulating factor (M-CSF) and granulocyte-M-CSF (GM-CSF) and its implications for fluorine 18 (18F) fluorodeoxyglucose (FDG) imaging of atherosclerosis. Materials and Methods This study was approved by the animal care committee. Uptake of 2-deoxyglucose and various indexes of oxidative and glycolytic metabolism were evaluated in nonactivated murine peritoneal macrophages (MΦ0) and macrophages stimulated with M-CSF (MΦM-CSF) or GM-CSF (MΦGM-CSF). Intracellular glucose flux was measured by using stable isotope tracing of glycolytic and tricyclic acid intermediary metabolites. 18F-FDG uptake was evaluated in murine atherosclerotic aortas after stimulation with M-CSF or GM-CSF by using quantitative autoradiography. Results Despite inducing distinct activation states, GM-CSF and M-CSF stimulated progressive but similar levels of increased 2-deoxyglucose uptake in macrophages that reached up to sixfold compared with MΦ0. The expression of glucose transporters, oxidative metabolism, and mitochondrial biogenesis were induced to similar levels in MΦM-CSF and MΦGM-CSF. Unexpectedly, there was a 1.7-fold increase in extracellular acidification rate, a 1.4-fold increase in lactate production, and overexpression of several critical glycolytic enzymes in MΦM-CSF compared with MΦGM-CSF with associated increased glucose flux through glycolytic pathway. Quantitative autoradiography demonstrated a 1.6-fold induction of 18F-FDG uptake in murine atherosclerotic plaques by both M-CSF and GM-CSF. Conclusion The proinflammatory and inflammation-resolving activation states of macrophages induced by GM-CSF and M-CSF in either cell culture or atherosclerotic plaques may not be distinguishable by the assessment of glucose uptake. © RSNA, 2016 Online supplemental material is available for this article.

Yeast dynamin interaction with ESCRT proteins at the endosome.

The dynamin-like protein, Vps1, is a GTPase involved in cargo sorting and membrane remodeling in multiple cellular trafficking pathways. Recently, Vps1 has been shown to genetically interact with ESCRT subunits. We tested the hypothesis that the functional connection of Vps1 with some of these subunits of ESCRT complexes occurs via a physical interaction. By utilizing the yeast two-hybrid system, we revealed that Vps1 physically interacts with the ESCRT-II subunits, Vps22 and Vps36, and the ESCRT-III subunit Vps24. We found that Vps1 and ESCRT-II components colocalize with Pep12, an endosomal marker. Additionally, loss of Vps1 or depletion of the GTPase activity of Vps1 results in a moderate defect in Cps1 targeting to the vacuole. Here, we discussed the potential implications of Vps1 and ESCRT interaction and their roles in the endosome-to-vacuole traffic. In summary, yeast dynamin interacts with ESCRT II and III complexes, and it functions in Cps1 trafficking toward the vacuole.

Anti-cancer Parasporin Toxins are Associated with Different Environments: Discovery of Two Novel Parasporin 5-like Genes.

Cry toxins are primarily a family of insecticidal toxins produced by the bacterium Bacillus thuringiensis (Bt). However, some Cry toxins, called parasporins (PSs), are non-insecticidal and have been shown to differentially kill human cancer cells. Based on amino acid homology, there are currently six different classes of parasporins (PS1-6). It is not known what role parasporins play in nature, nor if certain PSs are associated with Bt found in particular environments. Herein, we present ten parasporin-containing isolates of Bt from the Caribbean island of Trinidad. Genes coding for PS1 and PS6 were found in isolates associated mainly with artificial aquatic environments (e.g., barrels with rain water), while Bt possessing two novel PS5-like genes (ps5-1 and ps5-2), were isolated from manure collected directly from the rectum of cattle. The amino acid sequences inferred from the two PS5-like genes were 51 % homologous to each other, while being only 41 or 45 % similar to PS5Aa1/Cry64Aa, the only reported member of the parasporin five class. The low level of amino acid homology between the two PS5-like genes and PS5Aa1 indicate that the two PS5-like genes may represent a new class of parasporins, or greatly expand the level of diversity within the current parasporin 5 class.

Does the addition of saline infusion sonohysterography to transvaginal ultrasonography prevent unnecessary hysteroscopy in premenopausal women with abnormal uterine bleeding?

This observational case series in 65 premenopausal women with abnormal uterine bleeding evaluated whether transvaginal ultrasound followed by saline infusion sonohysterography (SIS) prevented unnecessary hysteroscopy. Although SIS indicated that hysteroscopy was unnecessary in eight women, this benefit was offset by the invasive nature of the scan, the number of endometrial abnormalities falsely detected by SIS and the cost of the additional investigation.

Intra-Arterial Therapy for Acute Stroke and the Effect of Technological Advances on Recanalization: Findings in a Community Hospital.

BACKGROUND: Recent randomized controlled studies have shown improvement in recanalization outcomes when physicians use the latest intra-arterial therapy devices in patients with acute, large-vessel, intracranial occlusions. The goal of this study was to explore how new procedures affected degree of and time to recanalization at a single center over the past 12 years as technology has improved. METHODS: Patients were included in the study if they had a large or medium intracranial vessel occlusion and had undergone intra-arterial therapy for acute stroke during the period 2002-2013. Therapies were categorized as intra-arterial thrombolysis with tissue plasminogen activator (IA tPA), mechanical thrombectomy using 1st-generation devices (Merci and Penumbra), or mechanical thrombectomy using 2nd-generation devices (stent-trievers). Recanalization was defined using a modified Thrombolysis in Cerebral Infarction (TICI) scale. RESULTS: Primary treatment was IA tPA in 24 (12.4%) patients, 1st-generation devices in 128 (66.0%) patients, and 2nd-generation devices in 42 (21.6%) patients. TICI 2b was achieved in 7 (29.2%) patients treated with IA tPA, in 79 (61.7%) patients treated with 1st-generation devices, and in 38 (90.5%) patients treated with 2nd-generation devices. Compared to patients treated with IA tPA, patients treated with 2nd-generation devices were more likely to reach TICI 2b recanalization (odds ratio, 11.66; 95% CI, 1.56-87.01), and they did so in shorter times. CONCLUSION: Technological advances over 12 years in endovascular stroke treatments significantly improved the chance of and reduced time to achieving TICI 2b recanalization in our community hospital. This shows the importance of adopting new technologies in a rapidly evolving field in order to provide the best-practice standard of care for the people of our region.

Germline CBL mutation associated with a noonan-like syndrome with primary lymphedema and teratoma associated with acquired uniparental isodisomy of chromosome 11q23.

Germline mutations in the gene CBL (Casitas B-lineage lymphoma), involved in the RAS-MAPK signaling pathway, have been found as a rare cause of the neuro-cardio-facial-cutaneous syndromes. Somatically acquired homozygous CBL mutations were initially identified in association with myeloproliferative disorders, particularly juvenile myelomonocytic leukemia (JMML). We describe a girl with a Noonan-like phenotype of bilateral ptosis, lymphedema of the lower limbs and moderate intellectual disability, due to a de novo heterozygous mutation in CBL. She developed an ovarian mixed germ cell/teratoma with later occurrence of mature liver, omental, and ovarian teratomas. Copy neutral loss of heterozygosity for the CBL mutation due to acquired segmental uniparental disomy of 11q23 was observed in three teratomas, suggesting a specific association of CBL mutations in germ cell tumor predisposition.

Digital innovation for cancer risk assessment allows large-scale service redevelopment of regional cancer genetics service delivery.

Family-history assessment can identify individuals above population-risk for cancer to enable targeted Screening, Prevention and Early Detection (SPED). The online patient-facing cancer Family History Questionnaire Service (cFHQS) is a digitalised, resource efficient tool for family history data capture to facilitate this. The capturing of digital data from cFHQS allows for data interrogation of patients referred to Clinical Genetics for the purposes of service improvement. Digital data from 4,044 cFHQS respondents over a three-year period was collected and interrogated with respect to the number and type of familial tumour diagnoses to enable service improvement and streamlining of referral pathways. 81% of colorectal and 71% of breast screening assessments were population- or moderate-risk. Most patients who completed cFHQS reported more than one diagnosis of cancer/tumour/polyps in their family. 2.5% of family history assessment patients had a second indication that required assessment that would have been missed if single tumour type assessment was undertaken. Implementation of an innovative, digital family history data collection pathway has allowed large scale interrogation of referral patterns and assessment outcomes to enable service development. The high volume of inappropriate referrals to Clinical Genetics for population and moderate risk patients highlighted the need for dedicated secondary care pathway provision for these patients. The use of cFHQS streamlined family history assessment allows for redistribution of resources to improve equity and access to genetic cancer risk assessment.

FLT4/VEGFR3 and Milroy disease: novel mutations, a review of published variants and database update.

Milroy disease (MD) is an autosomal dominantly inherited primary lymphedema. In 1998, the gene locus for MD was mapped to 5q35.3 and variants in the VEGFR3 (FLT4) gene, encoding vascular endothelial growth factor receptor 3 (VEGFR3), were identified as being responsible for the majority of MD cases. Several reports have since been published detailing pathogenic FLT4 mutations. To date, a total of 58 different variants in FLT4, 20 of which are unpublished, have been observed in 95 families with MD. A review of published mutations is presented in this update. Furthermore, the unpublished variants are presented including clinical data. Comparison of clinical features in patients and their families with the same mutations reveals incomplete penetrance and variable expression, making genotype-phenotype correlations difficult. Most mutations are missense, but a few deletions and one splicing variant have also been reported. Several animal models have confirmed the role of VEGFR3 in lymphangiogenesis and studies show mutant VEGFR3 receptors are not phosphorylated. Here, an MD patient with the same p.Ile1053Phe change as seen in the Chy mouse is presented for the first time. This finding confirms that this mouse lineage is an excellent model for MD. All the data reviewed here has been submitted to a database based on the Leiden Open (source) Variation Database (LOVD) and is accessible online at www.lovd.nl/flt4.

Inhibition of neddylation represses lipopolysaccharide-induced proinflammatory cytokine production in macrophage cells.

Cullin-RING E3 ligases (CRLs) are a class of ubiquitin ligases that control the proteasomal degradation of numerous target proteins, including IκB, and the activity of these CRLs are positively regulated by conjugation of a Nedd8 polypeptide onto Cullin proteins in a process called neddylation. CRL-mediated degradation of IκB, which normally interacts with and retains NF-κB in the cytoplasm, permits nuclear translocation and transactivation of the NF-κB transcription factor. Neddylation occurs through a multistep enzymatic process involving Nedd8 activating enzymes, and recent studies have shown that the pharmacological agent, MLN4924, can potently inhibit Nedd8 activating enzymes, thereby preventing neddylation of Cullin proteins and preventing the degradation of CRL target proteins. In macrophages, regulation of NF-κB signaling functions as a primary pathway by which infectious agents such as lipopolysaccharides (LPSs) cause the up-regulation of proinflammatory cytokines. Here we have analyzed the effects of MLN4924, and compared the effects of MLN4924 with a known anti-inflammatory agent (dexamethasone), on certain proinflammatory cytokines (TNF-α and IL-6) and the NF-κB signaling pathway in LPS-stimulated macrophages. We also used siRNA to block neddylation to assess the role of this molecular process during LPS-induced cytokine responsiveness. Our results demonstrate that blocking neddylation, either pharmacologically or using siRNA, abrogates the increase in certain proinflammatory cytokines secreted from macrophages in response to LPS. In addition, we have shown that MLN4924 and dexamethasone inhibit LPS-induced cytokine up-regulation at the transcriptional level, albeit through different molecular mechanisms. Thus, neddylation represents a novel molecular process in macrophages that can be targeted to prevent and/or treat the LPS-induced up-regulation of proinflammatory cytokines and the disease processes associated with their up-regulation.

A novel Bacillus thuringiensis Cry-like protein from a rare filamentous strain promotes crystal localization within the exosporium.

Mutation of a novel cry-like gene (cry256) from Bacillus thuringiensis resulted in a protein crystal, normally located within the spore's exosporium, being found predominately outside the exosporium. The cry256 gene codes for a 3-domain Cry-like protein that does not correspond to any of the known Cry protein holotypes.

Medulloblastoma in a patient with the PTPN11 p.Thr468Met mutation.

Medulloblastoma is the commonest brain tumor in childhood and in a minority of patients is associated with an underlying genetic disorder such as Gorlin syndrome or familial adenomatous polyposis. Increased susceptibility to certain tumors, including neuroblastoma and some hematological malignancies, is recognized in disorders caused by mutations in genes encoding components of the RAS signaling pathway which include Noonan syndrome, Noonan syndrome with multiple lentigines (NSML; formerly called LEOPARD syndrome), Costello syndrome, Cardiofaciocutaneous syndrome, Legius syndrome, and Neurofibromatosis type 1 (NF1), collectively termed RASopathies. Although an association between medulloblastoma and NF1 has been reported, this tumor has not previously been reported in other RASopathies. We present a patient with NSML caused by the recurrent PTPN11 mutation c.1403C > T (p.Thr468Met) in whom medulloblastoma was diagnosed at age 10 years. Medulloblastoma could therefore be part of the tumor spectrum associated with this disorder.

Proactive familial cancer risk assessment: a service development study in UK primary care.

BACKGROUND: Family history assessment can identify individuals above population-risk for cancer to enable targeted Screening, Prevention, and Early Detection (SPED). Family History Questionnaire Service (FHQS) is a resource-efficient patient-facing online tool to facilitate this. In the UK, cancer risk assessment is usually only offered to concerned individuals proactively self-presenting to their GP, leading to inequity in accessing SPED in the community. AIM: To improve access to community cancer genetic risk assessment and explore barriers to uptake. DESIGN & SETTING: Service development project of a digital pathway using the FHQS for cancer risk assessment across four general practices within the clinical remit of the South West Thames Centre for Genomics (SWTCG). METHOD: 3100 individuals aged 38-50 years were invited to complete the FHQS through either text message or email. A random selection of 100 non-responders were contacted to determine barriers to uptake. RESULTS: In total, n = 304/3100 (10%) registered for the FHQS. Responders were more likely to be British (63% vs 47%, P<0.001), speak English as their main language (92% vs 76%, P<0.001), and not require an interpreter (99.6% vs 94.9%, P = 0.001). Of 304 responders, 158 (52%) were automatically identified as at population-risk without full family history review. Of the remaining 146 responders, 52 (36%) required either additional screening referral (n = 23), genetics referral (n = 15), and/or advice to relatives (n = 18). Of 100 non-responders contacted, eight had incorrect contact details and 53 were contactable. Reasons for not responding included not receiving invitation details (n = 26), losing the invitation (n = 5), or forgetting (n = 4). CONCLUSION: The FHQS can be used as part of a low-resource primary care pathway to identify individuals in the community above population-risk for cancer requiring action. This study highlighted barriers to uptake requiring consideration to maximise impact and minimise inequity.

Designing new UK-WHO growth charts: implications for health staff use and understanding of charts and growth monitoring.

New pre-school UK charts have been produced incorporating the new World Health Organization growth standards based on healthy breastfed infants. This paper describes the process by which the charts and evidence-based instructions were designed and evaluated, and what it revealed about professional understanding of charts and growth monitoring. A multidisciplinary expert group drew on existing literature, new data analyses and parent focus groups as well as two series of chart-plotting workshops for health staff. The first series explored possible design features and general chart understanding. The second evaluated an advanced prototype with instructions, using plotting and interpretation of three separate scenarios on the old charts, compared with the new charts. The first plotting workshops (46 participants) allowed decisions to be made about the exact chart format, but it also revealed widespread confusion about use of adjustment for gestation and the plotting of birthweight. In the second series (78 participants), high levels of plotting inaccuracy were identified on both chart formats, with 64% of respondents making at least one major mistake. Significant neonatal weight loss was poorly recognized. While most participants recognized abnormal and normal growth patterns, 13-20% did not. Many respondents had never received any formal training in chart use. Growth charts are complex clinical tools that are, at present, poorly understood and inconsistently used. The importance of clear guidelines and formal training has now been recognized and translated into supporting educational materials (free to download at http://www.growthcharts.rcpch.ac.uk).

Glutaredoxin 1 controls monocyte reprogramming during nutrient stress and protects mice against obesity and atherosclerosis in a sex-specific manner.

High-calorie diet-induced nutrient stress promotes thiol oxidative stress and the reprogramming of blood monocytes, giving rise to dysregulated, obesogenic, proatherogenic monocyte-derived macrophages. We report that in chow-fed, reproductively senescent female mice but not in age-matched male mice, deficiency in the thiol transferase glutaredoxin 1 (Grx1) promotes dysregulated macrophage phenotypes as well as rapid weight gain and atherogenesis. Grx1 deficiency derepresses distinct expression patterns of reactive oxygen species and reactive nitrogen species generators in male versus female macrophages, poising female but not male macrophages for increased peroxynitrate production. Hematopoietic Grx1 deficiency recapitulates this sexual dimorphism in high-calorie diet-fed LDLR-/- mice, whereas macrophage-restricted overexpression of Grx1 eliminates the sex differences unmasked by high-calorie diet-feeding and protects both males and females against atherogenesis. We conclude that loss of monocytic Grx1 activity disrupts the immunometabolic balance in mice and derepresses sexually dimorphic oxidative stress responses in macrophages. This mechanism may contribute to the sex differences reported in cardiovascular disease and obesity in humans.