Publications by authors named "Kim Wong"

137 Publications

RV144 vaccine imprinting constrained HIV-1 evolution following breakthrough infection.

Virus Evol 2021 9;7(2):veab057. Epub 2021 Jul 9.

US Military HIV Research Program, WRAIR, Silver Spring, MD 20910, USA.

The scale of the HIV-1 epidemic underscores the need for a vaccine. The multitude of circulating HIV-1 strains together with HIV-1's high evolvability hints that HIV-1 could adapt to a future vaccine. Here, we wanted to investigate the effect of vaccination on the evolution of the virus post-breakthrough infection. We analyzed 2,635 HIV-1 sequences sampled up to a year post-diagnosis from 110 vaccine and placebo participants who became infected in the RV144 vaccine efficacy trial. We showed that the Env signature sites that were previously identified to distinguish vaccine and placebo participants were maintained over time. In addition, fewer sites were under diversifying selection in the vaccine group than in the placebo group. These results indicate that HIV-1 would possibly adapt to a vaccine upon its roll-out.
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http://dx.doi.org/10.1093/ve/veab057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438874PMC
July 2021

Modeling Interventions to Reduce the Spread of Multidrug-Resistant Organisms Between Health Care Facilities in a Region.

JAMA Netw Open 2021 Aug 2;4(8):e2119212. Epub 2021 Aug 2.

Public Health Informatics, Computational, and Operations Research, Graduate School of Public Health and Health Policy, City University of New York, New York, New York.

Importance: Multidrug-resistant organisms (MDROs) can spread across health care facilities in a region. Because of limited resources, certain interventions can be implemented in only some facilities; thus, decision-makers need to evaluate which interventions may be best to implement.

Objective: To identify a group of target facilities and assess which MDRO intervention would be best to implement in the Shared Healthcare Intervention to Eliminate Life-threatening Dissemination of MDROs in Orange County, a large regional public health collaborative in Orange County, California.

Design, Setting, And Participants: An agent-based model of health care facilities was developed in 2016 to simulate the spread of methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Enterobacteriaceae (CRE) for 10 years starting in 2010 and to simulate the use of various MDRO interventions for 3 years starting in 2017. All health care facilities (23 hospitals, 5 long-term acute care hospitals, and 74 nursing homes) serving adult inpatients in Orange County, California, were included, and 42 target facilities were identified via network analyses.

Exposures: Increasing contact precaution effectiveness, increasing interfacility communication about patients' MDRO status, and performing decolonization using antiseptic bathing soap and a nasal product in a specific group of target facilities.

Main Outcomes And Measures: MRSA and CRE prevalence and number of new carriers (ie, transmission events).

Results: Compared with continuing infection control measures used in Orange County as of 2017, increasing contact precaution effectiveness from 40% to 64% in 42 target facilities yielded relative reductions of 0.8% (range, 0.5%-1.1%) in MRSA prevalence and 2.4% (range, 0.8%-4.6%) in CRE prevalence in health care facilities countywide after 3 years, averting 761 new MRSA transmission events (95% CI, 756-765 events) and 166 new CRE transmission events (95% CI, 158-174 events). Increasing interfacility communication of patients' MDRO status to 80% in these target facilities produced no changes in the prevalence or transmission of MRDOs. Implementing decolonization procedures (clearance probability: 39% in hospitals, 27% in long-term acute care facilities, and 3% in nursing homes) yielded a relative reduction of 23.7% (range, 23.5%-23.9%) in MRSA prevalence, averting 3515 new transmission events (95% CI, 3509-3521 events). Increasing the effectiveness of antiseptic bathing soap to 48% yielded a relative reduction of 39.9% (range, 38.5%-41.5%) in CRE prevalence, averting 1435 new transmission events (95% CI, 1427-1442 events).

Conclusions And Relevance: The findings of this study highlight the ways in which modeling can inform design of regional interventions and suggested that decolonization would be the best strategy for the Shared Healthcare Intervention to Eliminate Life-threatening Dissemination of MDROs in Orange County.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.19212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339938PMC
August 2021

Comparison of the oncogenomic landscape of canine and feline hemangiosarcoma shows novel parallels with human angiosarcoma.

Dis Model Mech 2021 Jul 23;14(7). Epub 2021 Jul 23.

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

Angiosarcoma (AS) is a highly aggressive tumor of blood and lymphatic vessels in humans that shares many similarities with spontaneously occurring hemangiosarcoma (HSA) in dogs and cats. To investigate the genetic suitability of HSA as a model for AS, we sequenced ∼1000 cancer genes in 41 cases of HSA and matched germline tissue: 15 canine visceral HSAs, 13 canine skin HSAs and 13 feline skin HSAs. Analysis of visceral HSAs from dogs presenting with concurrent splenic and cardiac neoplasms showed that the tumors were not independent primaries, consistent with the highly metastatic nature of HSA. Comparison of HSA to AS revealed that several driver genes were recurrently mutated in both species, such as TP53, PIK3CA, ATRX, GRIN2A and LRP1B. Similar to AS, a UV mutational signature was found in a subset of canine cutaneous HSAs and both species show differing mutational profiles between tissue sites. Our characterization of canine and feline HSA demonstrates many important parallels to AS and provides hope that future studies on these cancers will benefit of all three species.
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http://dx.doi.org/10.1242/dmm.049044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319545PMC
July 2021

Home before Hospital: a whole of system re-design project to improve rates of home-based dialysis therapy: Experience and outcomes over 8 years.

Int J Qual Health Care 2021 Aug;33(3)

Department of Renal Medicine, Alfred Hospital, 55 Commercial Road, Melbourne, VIC 3004, Australia.

Background: Despite evidence that clinical outcomes for patients treated with peritoneal dialysis (PD) or home haemodialysis are better than for patients treated with conventional satellite or hospital-based haemodialysis, rates of home-based dialysis therapies world-wide remain low. Home-based dialysis care is also cost-effective and indeed the favoured dialysis option for many patients.

Methods & Objectives: Using a lean-thinking framework and established change management methodology, a project embracing a system-wide approach at making a change where a 'Home before Hospital' philosophy underpinned all approaches to dialysis care was undertaken. Three multidisciplinary working groups (pathway, outreach and hybrid) were established for re-design and implementation. The primary aim was to improve home-based dialysis therapy prevalence rates from a baseline of 14.8% by ≥2.5%/year to meet a target of 35%, whilst not only maintaining but improving the quality of care provided to patients requiring maintenance dialysis. A 'future' state pathway was developed after review of the 'current' state (Pathway Working Group) and formed the basis on which a nurse-led outreach service (Outreach Working Group) was established. With the support of the multidisciplinary team, the outreach service model focussed on early, consistent, and frequent education, patient support in decision-making, and clinician engagement.

Results: A target prevalence of >30% for home-based therapies (mainly achieved with PD) was achieved within 2 years. This prevalence rate reached 35% within 3 years and was maintained at 8 years. In addition, selected patients already on maintenance satellite-based haemodialysis (Hybrid Working Group) were educated to achieve high levels of proficiencies in self-care.

Conclusion: Having the system-wide approach to a Quality Improvement Process and using established principles and change management processes, the successful implementation of a new sustainable model of care focussed on home-based dialysis therapy was achieved. A key feature of the model (through outreach) was early nurse-led education and support of patients in decision-making and ongoing support through multidisciplinary care.
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http://dx.doi.org/10.1093/intqhc/mzab108DOI Listing
August 2021

The clinicopathologic spectrum and genomic landscape of de-/trans-differentiated melanoma.

Mod Pathol 2021 Nov 21;34(11):2009-2019. Epub 2021 Jun 21.

Experimental Cancer Genetics, Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

Dedifferentiation and transdifferentiation are rare and only poorly understood phenomena in cutaneous melanoma. To study this disease more comprehensively we have retrieved 11 primary cutaneous melanomas from our pathology archives showing biphasic features characterized by a conventional melanoma and additional areas of de-/trans-differentiation as defined by a lack of immunohistochemical expression of all conventional melanocytic markers (S-100 protein, SOX10, Melan-A, and HMB-45). The clinical, histologic, and immunohistochemical findings were recorded and follow-up was obtained. The patients were mostly elderly (median: 81 years; range: 42-86 years) without significant gender predilection, and the sun-exposed skin of the head and neck area was most commonly affected. The tumors were deeply invasive with a mean depth of 7 mm (range: 4-80 mm). The dedifferentiated component showed atypical fibroxanthoma-like features in the majority of cases (7), while additional rhabdomyosarcomatous and epithelial transdifferentiation was noted histologically and/or immunohistochemically in two tumors each. The background conventional melanoma component was of desmoplastic (4), superficial spreading (3), nodular (2), lentigo maligna (1), or spindle cell (1) types. For the seven patients with available follow-up data (median follow-up period of 25 months; range: 8-36 months), two died from their disease, and three developed metastases. Next-generation sequencing of the cohort revealed somatic mutations of established melanoma drivers including mainly NF1 mutations (5) in the conventional component, which was also detected in the corresponding de-/trans-differentiated component. In summary, the diagnosis of primary cutaneous de-/trans-differentiated melanoma is challenging and depends on the morphologic identification of conventional melanoma. Molecular analysis is diagnostically helpful as the mutated gene profile is shared between the conventional and de-/trans-differentiated components. Importantly, de-/trans-differentiation does not appear to confer a more aggressive behavior.
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http://dx.doi.org/10.1038/s41379-021-00857-zDOI Listing
November 2021

Cut-like homeobox 1 (CUX1) tumor suppressor gene haploinsufficiency induces apoptosis evasion to sustain myeloid leukemia.

Nat Commun 2021 04 30;12(1):2482. Epub 2021 Apr 30.

Experimental Cancer Genetics, Wellcome Sanger Institute, Hinxton, UK.

While oncogenes promote tumorigenesis, they also induce deleterious cellular stresses, such as apoptosis, that cancer cells must combat by coopting adaptive responses. Whether tumor suppressor gene haploinsufficiency leads to such phenomena and their mechanistic basis is unclear. Here, we demonstrate that elevated levels of the anti-apoptotic factor, CASP8 and FADD-like apoptosis regulator (CFLAR), promotes apoptosis evasion in acute myeloid leukemia (AML) cells haploinsufficient for the cut-like homeobox 1 (CUX1) transcription factor, whose loss is associated with dismal clinical prognosis. Genome-wide CRISPR/Cas9 screening identifies CFLAR as a selective, acquired vulnerability in CUX1-deficient AML, which can be mimicked therapeutically using inhibitor of apoptosis (IAP) antagonists in murine and human AML cells. Mechanistically, CUX1 deficiency directly alleviates CUX1 repression of the CFLAR promoter to drive CFLAR expression and leukemia survival. These data establish how haploinsufficiency of a tumor suppressor is sufficient to induce advantageous anti-apoptosis cell survival pathways and concurrently nominate CFLAR as potential therapeutic target in these poor-prognosis leukemias.
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http://dx.doi.org/10.1038/s41467-021-22750-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087769PMC
April 2021

The mutational landscape of melanoma brain metastases presenting as the first visceral site of recurrence.

Br J Cancer 2021 01 7;124(1):156-160. Epub 2020 Oct 7.

Experimental Cancer Genetics, The Wellcome Sanger Institute, Hinxton, Cambridgeshire, UK.

Brain metastases are a major cause of melanoma-related mortality and morbidity. We undertook whole-exome sequencing of 50 tumours from patients undergoing surgical resection of brain metastases presenting as the first site of visceral disease spread and validated our findings in an independent dataset of 18 patients. Brain metastases had a similar driver mutational landscape to cutaneous melanomas in TCGA. However, KRAS was the most significantly enriched driver gene, with 4/50 (8%) of brain metastases harbouring non-synonymous mutations. Hotspot KRAS mutations were mutually exclusive from BRAF, NRAS and HRAS mutations and were associated with a reduced overall survival from the resection of brain metastases (HR 10.01, p = 0.001). Mutations in KRAS were clonal and concordant with extracranial disease, suggesting that these mutations are likely present within the primary. Our analyses suggest that KRAS mutations could help identify patients with primary melanoma at higher risk of brain metastases who may benefit from more intensive, protracted surveillance.
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http://dx.doi.org/10.1038/s41416-020-01090-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782512PMC
January 2021

Multi-site clonality analysis uncovers pervasive heterogeneity across melanoma metastases.

Nat Commun 2020 08 27;11(1):4306. Epub 2020 Aug 27.

Experimental Cancer Genetics, The Wellcome Sanger Institute, Hinxton, Cambridgeshire, UK.

Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal evidence of diversification among metastatic lineages. UV-induced mutations dominate the trunk, whereas APOBEC-associated mutations are found in the branches of the evolutionary tree. Multi-sample analyses from a further seven patients confirmed that lineage diversification was pervasive, representing an important mode of melanoma dissemination. Our analyses demonstrate that joint analysis of cancer cell fraction estimates across multiple metastases can uncover previously unrecognised levels of tumour heterogeneity and highlight the limitations of inferring heterogeneity from a single biopsy.
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http://dx.doi.org/10.1038/s41467-020-18060-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453196PMC
August 2020

Dissecting the early steps of MLL induced leukaemogenic transformation using a mouse model of AML.

Nat Commun 2020 03 16;11(1):1407. Epub 2020 Mar 16.

Wellcome and MRC Cambridge Stem Cell Institute and University of Cambridge Department of Haematology, Jeffrey Cheah Biomedical Centre, Puddicombe Way, Cambridge, CB2 0AW, UK.

Leukaemogenic mutations commonly disrupt cellular differentiation and/or enhance proliferation, thus perturbing the regulatory programs that control self-renewal and differentiation of stem and progenitor cells. Translocations involving the Mll1 (Kmt2a) gene generate powerful oncogenic fusion proteins, predominantly affecting infant and paediatric AML and ALL patients. The early stages of leukaemogenic transformation are typically inaccessible from human patients and conventional mouse models. Here, we take advantage of cells conditionally blocked at the multipotent haematopoietic progenitor stage to develop a MLL-r model capturing early cellular and molecular consequences of MLL-ENL expression based on a clear clonal relationship between parental and leukaemic cells. Through a combination of scRNA-seq, ATAC-seq and genome-scale CRISPR-Cas9 screening, we identify pathways and genes likely to drive the early phases of leukaemogenesis. Finally, we demonstrate the broad utility of using matched parental and transformed cells for small molecule inhibitor studies by validating both previously known and other potential therapeutic targets.
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http://dx.doi.org/10.1038/s41467-020-15220-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075888PMC
March 2020

In situ CRISPR-Cas9 base editing for the development of genetically engineered mouse models of breast cancer.

EMBO J 2020 03 13;39(5):e102169. Epub 2020 Jan 13.

Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Genetically engineered mouse models (GEMMs) of cancer have proven to be of great value for basic and translational research. Although CRISPR-based gene disruption offers a fast-track approach for perturbing gene function and circumvents certain limitations of standard GEMM development, it does not provide a flexible platform for recapitulating clinically relevant missense mutations in vivo. To this end, we generated knock-in mice with Cre-conditional expression of a cytidine base editor and tested their utility for precise somatic engineering of missense mutations in key cancer drivers. Upon intraductal delivery of sgRNA-encoding vectors, we could install point mutations with high efficiency in one or multiple endogenous genes in situ and assess the effect of defined allelic variants on mammary tumorigenesis. While the system also produces bystander insertions and deletions that can stochastically be selected for when targeting a tumor suppressor gene, we could effectively recapitulate oncogenic nonsense mutations. We successfully applied this system in a model of triple-negative breast cancer, providing the proof of concept for extending this flexible somatic base editing platform to other tissues and tumor types.
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http://dx.doi.org/10.15252/embj.2019102169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049816PMC
March 2020

Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets.

Nat Commun 2019 07 18;10(1):3163. Epub 2019 Jul 18.

Department of Pathology, University of California, San Francisco, CA, 94143, USA.

Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.
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http://dx.doi.org/10.1038/s41467-019-11107-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639323PMC
July 2019

Knowing More of the Iceberg: How Detecting a Greater Proportion of Carbapenem-Resistant Enterobacteriaceae Carriers Influences Transmission.

J Infect Dis 2020 05;221(11):1782-1794

Public Health Computational and Operations Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Background: Clinical testing detects a fraction of carbapenem-resistant Enterobacteriaceae (CRE) carriers. Detecting a greater proportion could lead to increased use of infection prevention and control measures but requires resources. Therefore, it is important to understand the impact of detecting increasing proportions of CRE carriers.

Methods: We used our Regional Healthcare Ecosystem Analyst-generated agent-based model of adult inpatient healthcare facilities in Orange County, California, to explore the impact that detecting greater proportions of carriers has on the spread of CRE.

Results: Detecting and placing 1 in 9 carriers on contact precautions increased the prevalence of CRE from 0% to 8.0% countywide over 10 years. Increasing the proportion of detected carriers from 1 in 9 up to 1 in 5 yielded linear reductions in transmission; at proportions >1 in 5, reductions were greater than linear. Transmission reductions did not occur for 1, 4, or 5 years, varying by facility type. With a contact precautions effectiveness of ≤70%, the detection level yielding nonlinear reductions remained unchanged; with an effectiveness of >80%, detecting only 1 in 5 carriers garnered large reductions in the number of new CRE carriers. Trends held when CRE was already present in the region.

Conclusion: Although detection of all carriers provided the most benefits for preventing new CRE carriers, if this is not feasible, it may be worthwhile to aim for detecting >1 in 5 carriers.
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http://dx.doi.org/10.1093/infdis/jiz288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213567PMC
May 2020

Cross-species genomic landscape comparison of human mucosal melanoma with canine oral and equine melanoma.

Nat Commun 2019 01 21;10(1):353. Epub 2019 Jan 21.

Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.

Mucosal melanoma is a rare and poorly characterized subtype of human melanoma. Here we perform a cross-species analysis by sequencing tumor-germline pairs from 46 primary human muscosal, 65 primary canine oral and 28 primary equine melanoma cases from mucosal sites. Analysis of these data reveals recurrently mutated driver genes shared between species such as NRAS, FAT4, PTPRJ, TP53 and PTEN, and pathogenic germline alleles of BRCA1, BRCA2 and TP53. We identify a UV mutation signature in a small number of samples, including human cases from the lip and nasal mucosa. A cross-species comparative analysis of recurrent copy number alterations identifies several candidate drivers including MDM2, B2M, KNSTRN and BUB1B. Comparison of somatic mutations in recurrences and metastases to those in the primary tumor suggests pervasive intra-tumor heterogeneity. Collectively, these studies suggest a convergence of some genetic changes in mucosal melanomas between species but also distinctly different paths to tumorigenesis.
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http://dx.doi.org/10.1038/s41467-018-08081-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341101PMC
January 2019

Association of the POT1 Germline Missense Variant p.I78T With Familial Melanoma.

JAMA Dermatol 2019 05;155(5):604-609

Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, England.

Importance: The protection of telomeres 1 protein (POT1) is a critical component of the shelterin complex, a multiple-protein machine that regulates telomere length and protects telomere ends. Germline variants in POT1 have been linked to familial melanoma, and somatic mutations are associated with a range of cancers including cutaneous T-cell lymphoma (CTCL).

Objective: To characterize pathogenic variation in POT1 in families with melanoma to inform clinical management.

Design, Setting, And Participants: In this case study and pedigree evaluation, analysis of the pedigree of 1 patient with melanoma revealed a novel germline POT1 variant (p.I78T, c.233T>C, chromosome 7, g.124870933A>G, GRCh38) that was subsequently found in 2 other pedigrees obtained from the GenoMEL Consortium.

Main Outcomes And Measures: (1) Identification of the POT1 p.I78T variant; (2) evaluation of the clinical features and characteristics of patients with this variant; (3) analysis of 3 pedigrees; (4) genomewide single-nucleotide polymorphism genotyping of germline DNA; and (5) a somatic genetic analysis of available nevi and 1 melanoma lesion.

Results: The POT1 p.I78T variant was found in 3 melanoma pedigrees, all of persons who self-reported as being of Jewish descent, and was shown to disrupt POT1-telomere binding. A UV mutation signature was associated with nevus and melanoma formation in POT1 variant carriers, and somatic mutations in driver genes such as BRAF, NRAS, and KIT were associated with lesion development in these patients.

Conclusions And Relevance: POT1 p.I78T is a newly identified, likely pathogenic, variant meriting screening for in families with melanoma after more common predisposition genes such as CDKN2A have been excluded. It could also be included as part of gene panel testing.
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http://dx.doi.org/10.1001/jamadermatol.2018.3662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506889PMC
May 2019

Sixteen diverse laboratory mouse reference genomes define strain-specific haplotypes and novel functional loci.

Nat Genet 2018 11 1;50(11):1574-1583. Epub 2018 Oct 1.

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.

We report full-length draft de novo genome assemblies for 16 widely used inbred mouse strains and find extensive strain-specific haplotype variation. We identify and characterize 2,567 regions on the current mouse reference genome exhibiting the greatest sequence diversity. These regions are enriched for genes involved in pathogen defence and immunity and exhibit enrichment of transposable elements and signatures of recent retrotransposition events. Combinations of alleles and genes unique to an individual strain are commonly observed at these loci, reflecting distinct strain phenotypes. We used these genomes to improve the mouse reference genome, resulting in the completion of 10 new gene structures. Also, 62 new coding loci were added to the reference genome annotation. These genomes identified a large, previously unannotated, gene (Efcab3-like) encoding 5,874 amino acids. Mutant Efcab3-like mice display anomalies in multiple brain regions, suggesting a possible role for this gene in the regulation of brain development.
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http://dx.doi.org/10.1038/s41588-018-0223-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205630PMC
November 2018

Results of Hairdressing Series Patch Test in Patients with Allergic Contact Dermatitis to Para-phenylenediamine; Are there any Safe Alternatives?

Acta Dermatovenerol Croat 2017 Dec;25(4):307-309

Prof. Hyun-Chang Ko, MD, Department of Dermatology, School of Medicine, Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, Korea, 602-739;

Dear Editor, Exposure to hair-dye is the most frequent route of sensitization to para-phenylenediamine (PPD), a common contact allergen (1). Patients allergic to PPD often worry about the use of hairdressings and usually ask about safe alternative agents and the use of other hairdressing materials such as permanent wave agents, shampoos, and bleaching agents. However, there have been no studies on this issue. The aim of the present study was to investigate the positivity of hair-related allergens and identify safe alternatives. We conducted a prospective patch test study using the hairdressing series (Chemotechnique Diagnostics®, Vellinge, Sweden) in patients allergic to PPD and control subjects. The control group was defined as subjects who had no history of allergic contact dermatitis (ACD) to hair dye and negative reaction to PPD. Volunteers in the experimental group were recruited from patients who were previously diagnosed with PPD-induced ACD using a TRUE test® and clinical relevance, but hairdressers and barbers at high risk of being exposed to hairdressing materials were excluded. The study protocol was approved by the local ethical committee, and informed consent was obtained from all volunteers (PNUH IRB No. F2010004). We tested 24 patients allergic to PPD and 21 control group subjects; 20 of the former and 19 of the latter completed the study. A summary of the study results is shown in Table 1. Eleven patients from the experimental group (55.0%) were positive for more than one allergen other than PPD, while only 2 from the control group (11.1%) were positive (P<0.05). Para-toluenediamine sulfate (15.0%), 3-aminophenol (10.0%), and nickel-sulfate hexahydrate (10.0%) were common allergens, which is consistent with the findings of other studies that investigated hairdressing allergens (2). The rates of positive reaction for each allergen showed a higher frequency than in the control group. Previous studies reported that people allergic to PPD were also positive for other hair-related allergens (2-4). We thus suggest that people who are allergic to PPD should be cautious in using hairdressing materials and recommend performing patch tests to identify safe agents. Based on these results, although the positive rates were not statistically significant, patients in our case should also be cautiously tested with other hair-dye components. We also tentatively hypothesize that getting a permanent wave is safer than a hair-dye in patients allergic to PPD, because all study patients showed negative reaction to permanent wave components. Although our study was too small in number to generalize the results, it is a unique study on PPD-induced ACD in patients from the general population examining the positivity of each allergen in the hairdressing series. Furthermore, while most studies on the topic were of retrospective design, our study was a prospectively designed study. The patients allergic to PPD were advised to perform hairdressing series patch test and to use other hairdressing materials with care, such as bleaching agents, shampoos, and especially hair-dye components other than PPD, due to cross-reaction. Moreover, we expect this study could be an important preliminary study offering clinical data on cross-reaction with PPD and other hair-dye components.
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December 2017

Mutational Analysis Identifies Therapeutic Biomarkers in Inflammatory Bowel Disease-Associated Colorectal Cancers.

Clin Cancer Res 2018 10 27;24(20):5133-5142. Epub 2018 Jun 27.

Division of Pathology, Centre for Comparative Pathology, Edinburgh Cancer Research Centre, Institute of Genetics & Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, Scotland, United Kingdom.

Inflammatory bowel disease-associated colorectal cancers (IBD-CRC) are associated with a higher mortality than sporadic colorectal cancers. The poorly defined molecular pathogenesis of IBD-CRCs limits development of effective prevention, detection, and treatment strategies. We aimed to identify biomarkers using whole-exome sequencing of IBD-CRCs to guide individualized management. Whole-exome sequencing was performed on 34 formalin-fixed paraffin-embedded primary IBD-CRCs and 31 matched normal lymph nodes. Computational methods were used to identify somatic point mutations, small insertions and deletions, mutational signatures, and somatic copy number alterations. Mismatch repair status was examined. Hypermutation was observed in 27% of IBD-CRCs. All hypermutated cancers were from the proximal colon; all but one of the cancers with hypermutation had defective mismatch repair or somatic mutations in the proofreading domain of DNA Hypermutated IBD-CRCs had increased numbers of predicted neo-epitopes, which could be exploited using immunotherapy. We identified six distinct mutation signatures in IBD-CRCs, three of which corresponded to known mechanisms of mutagenesis. Driver genes were also identified. IBD-CRCs should be evaluated for hypermutation and defective mismatch repair to identify patients with a higher neo-epitope load who may benefit from immunotherapies. Prospective trials are required to determine whether IHC to detect loss of MLH1 expression in dysplastic colonic tissue could identify patients at increased risk of developing IBD-CRC. We identified mutations in genes in IBD-CRCs with hypermutation that might be targeted therapeutically. These approaches would complement and individualize surveillance and treatment programs. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193541PMC
October 2018

Lofexidine versus diazepam for the treatment of opioid withdrawal syndrome: A double-blind randomized clinical trial in Singapore.

J Subst Abuse Treat 2018 08 25;91:1-11. Epub 2018 Apr 25.

National Addictions Management Service, Institute of Mental Health, 10 Buangkok View, 539747, Singapore.

Background: Many individuals leave costly inpatient detoxification programs prematurely because of the severity of withdrawal symptoms experienced. In the absence of opioid-assisted detoxification in Singapore, diazepam is used to manage withdrawal. However since diazepam is addictive, there is a need to explore the effectiveness of alternative medications.

Design And Procedures: The study aimed to examine the safety and efficacy of lofexidine, a non-opiate, non-addictive, alpha 2-adrenergic agonist in assisting opioid detoxification in Singapore, using a randomized, double-blind, investigator-initiated placebo-controlled trial comparing lofexidine against diazepam. Opioid dependent patients (n = 111) were randomized to receive a 10-day course of lofexidine (n = 56) or diazepam (n = 55). The primary endpoint was the Objective Opioid Withdrawal Scale (OOWS) score on days 3 and 4 and secondary outcomes were the Short Opioid Withdrawal Scale (SOWS) score, program retention rate, and ratings of opiate craving.

Main Findings: The OOWS, SOWS and opiate craving scores were consistently lower in the lofexidine group relative to the diazepam group over the 14-day study period; however no statistically significant differences were found on days 3 and 4 (peak withdrawal). Changes in mean pupil size during peak withdrawal were significantly smaller in the lofexidine group and more participants in the lofexidine group remained in treatment and completed detoxification.

Conclusions: Lofexidine was at least as effective as diazepam in reducing the opioid withdrawal syndrome and increased treatment retention. In addition to its non-addictive and non-abuse properties, lofexidine has several clinical advantages over diazepam. The use of lofexidine is recommended when opioid-assisted medications are not available.
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http://dx.doi.org/10.1016/j.jsat.2018.04.012DOI Listing
August 2018

Online Gambling among Treatment-Seeking Patients in Singapore: A Cross-Sectional Study.

Int J Environ Res Public Health 2018 04 23;15(4). Epub 2018 Apr 23.

National Addictions Management Service (NAMS), Institute of Mental Health, 10 Buangkok Green Medical Park, Singapore 539747, Singapore.

Given that technology has greatly facilitated easier access to gambling in previous years, it is timely to look in-depth into online gambling activities and behaviors. There have been several studies that examined online gambling. However, most of the current studies to date have focused on determining the prevalence and the epidemiology of problem gambling arising from online gambling in Western cohorts. There remains a paucity of research looking at the problem of online gambling among Asian individuals. The objectives of the current study are to elucidate the characteristics of online gambling among an Asian cohort and to explore the harm associated with online gambling and the potential mechanisms by which harm associated with online gambling could be minimized. It is hoped that the findings of the current paper will bridge the existing gaps in the research literature. A cross-sectional study design was utilized to recruit 100 participants who were attending outpatient services at the National Addictions Management Service (NAMS) from March 2014 to October 2015. The majority of the participants were male, of Chinese ethnicity and under the age of 30 years old (48%). Mobile phones and smartphones were the most commonly utilized platforms for gambling online. The median largest ever debt incurred as a result of online gambling ($20,000) was significantly more than that due to offline gambling ($500) ( = −4.17, < 0.001). As for the biggest ever loss, participants had incurred a significantly larger median loss from online gambling ($7000) ( = −2.73, < 0.01) compared to offline gambling ($2000). A total of 18.4% of participants had waited between 1 to 2 years from their first online gambling experience to seek treatment and 17.3% had waited for more than 10 years. This is perhaps one of the first Asian studies to investigate the serious harm involved in online gambling. The findings from our study are intended to guide further interventions in the treatment of online gambling related disorders; and would be of interest to governmental organizations in their planning of regulations for online gambling.
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http://dx.doi.org/10.3390/ijerph15040832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923874PMC
April 2018

The Economic Value of the Centers for Disease Control and Prevention Carbapenem-Resistant Enterobacteriaceae Toolkit.

Infect Control Hosp Epidemiol 2018 05 19;39(5):516-524. Epub 2018 Mar 19.

1Public Health Computational and Operations Research (PHICOR),Johns Hopkins Bloomberg School of Public Health,Baltimore,Maryland.

OBJECTIVEWhile previous work showed that the Centers for Disease Control and Prevention toolkit for carbapenem-resistant Enterobacteriaceae (CRE) can reduce spread regionally, these interventions are costly, and decisions makers want to know whether and when economic benefits occur.DESIGNEconomic analysisSETTINGOrange County, CaliforniaMETHODSUsing our Regional Healthcare Ecosystem Analyst (RHEA)-generated agent-based model of all inpatient healthcare facilities, we simulated the implementation of the CRE toolkit (active screening of interfacility transfers) in different ways and estimated their economic impacts under various circumstances.RESULTSCompared to routine control measures, screening generated cost savings by year 1 when hospitals implemented screening after identifying ≤20 CRE cases (saving $2,000-$9,000) and by year 7 if all hospitals implemented in a regional coordinated manner after 1 hospital identified a CRE case (hospital perspective). Cost savings was achieved only if hospitals independently screened after identifying 10 cases (year 1, third-party payer perspective). Cost savings was achieved by year 1 if hospitals independently screened after identifying 1 CRE case and by year 3 if all hospitals coordinated and screened after 1 hospital identified 1 case (societal perspective). After a few years, all strategies cost less and have positive health effects compared to routine control measures; most strategies generate a positive cost-benefit each year.CONCLUSIONSActive screening of interfacility transfers garnered cost savings in year 1 of implementation when hospitals acted independently and by year 3 if all hospitals collectively implemented the toolkit in a coordinated manner. Despite taking longer to manifest, coordinated regional control resulted in greater savings over time.Infect Control Hosp Epidemiol 2018;39:516-524.
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http://dx.doi.org/10.1017/ice.2018.49DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024255PMC
May 2018

Accuracy and Utility of Estimating Lean Body Mass and Nutritional Status in Patients with Chronic Kidney Disease on Long-Term Hemodialysis Using Anthropometric Skinfold Thickness Measurements.

Nephrol Nurs J 2018 Jan-Feb;45(1):35-40

onsultant Nephrologist, Department of Medicine, Peninsula Health, Frankston, Victoria, Australia.

Malnutrition is common in patients on hemodialysis (prevalence of 30% to 50%) and is associated with higher mortality. Lean body mass (LBM) assessment is an accurate way of assessing nutritional status. The dual-energy X-ray absorptiometry (DEXA) scan is a reliable method in assessing body compositions and LBM; however, it is expensive and largely inaccessible. Anthropometric skinfold thickness measurement (ASFM) is useful in assessing LBM. It is cheaper and accessible, but underutilized clinically. The subjective global score (SGA) is a well-established method of assessing nutritional status. All three methods of assessing nutritional status were compared. In this pilot observational study, there was a significant correlation between LBM% estimated by DEXA and ASFM (mean difference -1.46% [95% CI -4.09 to 1.18]; LOA -14.0 to 11.1). Nutritional status by SGA could only detect those severely malnourished when using LBM% by ASFM as comparison. Our study demonstrated that ASFM is a useful method of assessing LBM and nutritional status, which can be easily utilized clinically.
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August 2018

ST Spot Detector: a web-based application for automatic spot and tissue detection for spatial Transcriptomics image datasets.

Bioinformatics 2018 06;34(11):1966-1968

Science for Life Laboratory, Division of Gene Technology, School of Biotechnology, Royal Institute of Technology (KTH), SE-106 91 Solna, Sweden.

Motiviation: Spatial Transcriptomics (ST) is a method which combines high resolution tissue imaging with high troughput transcriptome sequencing data. This data must be aligned with the images for correct visualization, a process that involves several manual steps.

Results: Here we present ST Spot Detector, a web tool that automates and facilitates this alignment through a user friendly interface.

Contact: [email protected]

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/bty030DOI Listing
June 2018

Sieve analysis of breakthrough HIV-1 sequences in HVTN 505 identifies vaccine pressure targeting the CD4 binding site of Env-gp120.

PLoS One 2017 17;12(11):e0185959. Epub 2017 Nov 17.

US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.

Although the HVTN 505 DNA/recombinant adenovirus type 5 vector HIV-1 vaccine trial showed no overall efficacy, analysis of breakthrough HIV-1 sequences in participants can help determine whether vaccine-induced immune responses impacted viruses that caused infection. We analyzed 480 HIV-1 genomes sampled from 27 vaccine and 20 placebo recipients and found that intra-host HIV-1 diversity was significantly lower in vaccine recipients (P ≤ 0.04, Q-values ≤ 0.09) in Gag, Pol, Vif and envelope glycoprotein gp120 (Env-gp120). Furthermore, Env-gp120 sequences from vaccine recipients were significantly more distant from the subtype B vaccine insert than sequences from placebo recipients (P = 0.01, Q-value = 0.12). These vaccine effects were associated with signatures mapping to CD4 binding site and CD4-induced monoclonal antibody footprints. These results suggest either (i) no vaccine efficacy to block acquisition of any viral genotype but vaccine-accelerated Env evolution post-acquisition; or (ii) vaccine efficacy against HIV-1s with Env sequences closest to the vaccine insert combined with increased acquisition due to other factors, potentially including the vaccine vector.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185959PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5693417PMC
December 2017

Patterns and rates of viral evolution in HIV-1 subtype B infected females and males.

PLoS One 2017 18;12(10):e0182443. Epub 2017 Oct 18.

Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America.

Biological sex differences affect the course of HIV infection, with untreated women having lower viral loads compared to their male counterparts but, for a given viral load, women have a higher rate of progression to AIDS. However, the vast majority of data on viral evolution, a process that is clearly impacted by host immunity and could be impacted by sex differences, has been derived from men. We conducted an intensive analysis of HIV-1 gag and env-gp120 evolution taken over the first 6-11 years of infection from 8 Women's Interagency HIV Study (WIHS) participants who had not received combination antiretroviral therapy (ART). This was compared to similar data previously collected from men, with both groups infected with HIV-1 subtype B. Early virus populations in men and women were generally homogenous with no differences in diversity between sexes. No differences in ensuing nucleotide substitution rates were found between the female and male cohorts studied herein. As previously reported for men, time to peak diversity in env-gp120 in women was positively associated with time to CD4+ cell count below 200 (P = 0.017), and the number of predicted N-linked glycosylation sites generally increased over time, followed by a plateau or decline, with the majority of changes localized to the V1-V2 region. These findings strongly suggest that the sex differences in HIV-1 disease progression attributed to immune system composition and sensitivities are not revealed by, nor do they impact, global patterns of viral evolution, the latter of which proceeds similarly in women and men.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182443PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646779PMC
October 2017

Report of the 6th International Workshop on PET in lymphoma.

Leuk Lymphoma 2017 Oct 7;58(10):2298-2303. Epub 2017 Mar 7.

m Radiology, Lysa Imaging and Haematology , Hôpitaux Universitaires Henri Mondor , Créteil , France.

Two hundred and ten nuclear medicine physicians, radiologists, and hematologists from 26 countries attended the 6th International Workshop on Positron Emission Tomography (PET) in Lymphoma and Myeloma held in Menton, France, in September 2016. The meeting was under the auspices of the European Lymphoma Institute (ELI), the European Association of Nuclear Medicine (EANM) the Lymphoma Study Association (LYSA), the Italian Foundation on Lymphoma (FIL) and the Carnot Institute for Lymphoma (CALYM). Forty scientific posters were presented. For the first time, specialists in the field of multiple myeloma (MM) were involved in the expert session. The aim was to establish from the experience of Italian and French studies new guidelines of FDG-PET/CT reporting for myeloma staging and restaging. The meeting dedicated an entire session to MM imaging followed by a session on the role of PET in Peripheral T cell Lymphoma. An entire session addressed the issues of Deauville scale particularly for end treatment assessment and the challenging consequences of immunomodulatory treatments on PET reporting. A specific session presented the potential role of baseline metabolic tumor measurement to predict outcome and identify different risk categories and the main results obtained in different lymphoma entities were described. Whether it could replace clinical staging has been extensively discussed. The more recent results obtained in the H10 trial have been presented and compared to the published data in early stage Hodgkin lymphoma. Finally, the ongoing studies using PET for guiding therapeutic strategies have been reported by the various lymphoma cooperative groups that participated to the meeting.
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http://dx.doi.org/10.1080/10428194.2017.1298752DOI Listing
October 2017

Genome-wide in vivo screen identifies novel host regulators of metastatic colonization.

Nature 2017 01 4;541(7636):233-236. Epub 2017 Jan 4.

Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.

Metastasis is the leading cause of death for cancer patients. This multi-stage process requires tumour cells to survive in the circulation, extravasate at distant sites, then proliferate; it involves contributions from both the tumour cell and tumour microenvironment ('host', which includes stromal cells and the immune system). Studies suggest the early steps of the metastatic process are relatively efficient, with the post-extravasation regulation of tumour growth ('colonization') being critical in determining metastatic outcome. Here we show the results of screening 810 mutant mouse lines using an in vivo assay to identify microenvironmental regulators of metastatic colonization. We identify 23 genes that, when disrupted in mouse, modify the ability of tumour cells to establish metastatic foci, with 19 of these genes not previously demonstrated to play a role in host control of metastasis. The largest reduction in pulmonary metastasis was observed in sphingosine-1-phosphate (S1P) transporter spinster homologue 2 (Spns2)-deficient mice. We demonstrate a novel outcome of S1P-mediated regulation of lymphocyte trafficking, whereby deletion of Spns2, either globally or in a lymphatic endothelial-specific manner, creates a circulating lymphopenia and a higher percentage of effector T cells and natural killer (NK) cells present in the lung. This allows for potent tumour cell killing, and an overall decreased metastatic burden.
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http://dx.doi.org/10.1038/nature20792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603286PMC
January 2017

TCGA Expedition: A Data Acquisition and Management System for TCGA Data.

PLoS One 2016 27;11(10):e0165395. Epub 2016 Oct 27.

Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.

Background: The Cancer Genome Atlas Project (TCGA) is a National Cancer Institute effort to profile at least 500 cases of 20 different tumor types using genomic platforms and to make these data, both raw and processed, available to all researchers. TCGA data are currently over 1.2 Petabyte in size and include whole genome sequence (WGS), whole exome sequence, methylation, RNA expression, proteomic, and clinical datasets. Publicly accessible TCGA data are released through public portals, but many challenges exist in navigating and using data obtained from these sites. We developed TCGA Expedition to support the research community focused on computational methods for cancer research. Data obtained, versioned, and archived using TCGA Expedition supports command line access at high-performance computing facilities as well as some functionality with third party tools. For a subset of TCGA data collected at University of Pittsburgh, we also re-associate TCGA data with de-identified data from the electronic health records. Here we describe the software as well as the architecture of our repository, methods for loading of TCGA data to multiple platforms, and security and regulatory controls that conform to federal best practices.

Results: TCGA Expedition software consists of a set of scripts written in Bash, Python and Java that download, extract, harmonize, version and store all TCGA data and metadata. The software generates a versioned, participant- and sample-centered, local TCGA data directory with metadata structures that directly reference the local data files as well as the original data files. The software supports flexible searches of the data via a web portal, user-centric data tracking tools, and data provenance tools. Using this software, we created a collaborative repository, the Pittsburgh Genome Resource Repository (PGRR) that enabled investigators at our institution to work with all TCGA data formats, and to interrogate these data with analysis pipelines, and associated tools. WGS data are especially challenging for individual investigators to use, due to issues with downloading, storage, and processing; having locally accessible WGS BAM files has proven invaluable.

Conclusion: Our open-source, freely available TCGA Expedition software can be used to create a local collaborative infrastructure for acquiring, managing, and analyzing TCGA data and other large public datasets.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165395PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082933PMC
June 2017

Impact of Delays between Clinical and Laboratory Standards Institute and Food and Drug Administration Revisions of Interpretive Criteria for Carbapenem-Resistant Enterobacteriaceae.

J Clin Microbiol 2016 11 31;54(11):2757-2762. Epub 2016 Aug 31.

Public Health Computational and Operations Research (PHICOR), Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

Delays often occur between CLSI and FDA revisions of antimicrobial interpretive criteria. Using our Regional Healthcare Ecosystem Analyst (RHEA) simulation model, we found that the 32-month delay in changing carbapenem-resistant Enterobacteriaceae (CRE) breakpoints might have resulted in 1,821 additional carriers in Orange County, CA, an outcome that could have been avoided by identifying CRE and initiating contact precautions. Policy makers should aim to minimize the delay in the adoption of new breakpoints for antimicrobials against emerging pathogens when containment of spread is paramount; delays of <1.5 years are ideal.
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http://dx.doi.org/10.1128/JCM.00635-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078554PMC
November 2016

Deep genome sequencing and variation analysis of 13 inbred mouse strains defines candidate phenotypic alleles, private variation and homozygous truncating mutations.

Genome Biol 2016 08 1;17(1):167. Epub 2016 Aug 1.

Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1HH, UK.

Background: The Mouse Genomes Project is an ongoing collaborative effort to sequence the genomes of the common laboratory mouse strains. In 2011, the initial analysis of sequence variation across 17 strains found 56.7 M unique single nucleotide polymorphisms (SNPs) and 8.8 M indels. We carry out deep sequencing of 13 additional inbred strains (BUB/BnJ, C57BL/10J, C57BR/cdJ, C58/J, DBA/1J, I/LnJ, KK/HiJ, MOLF/EiJ, NZB/B1NJ, NZW/LacJ, RF/J, SEA/GnJ and ST/bJ), cataloguing molecular variation within and across the strains. These strains include important models for immune response, leukaemia, age-related hearing loss and rheumatoid arthritis. We now have several examples of fully sequenced closely related strains that are divergent for several disease phenotypes.

Results: Approximately 27.4 M unique SNPs and 5 M indels are identified across these strains compared to the C57BL/6 J reference genome (GRCm38). The amount of variation found in the inbred laboratory mouse genome has increased to 71 M SNPs and 12 M indels. We investigate the genetic basis of highly penetrant cancer susceptibility in RF/J finding private novel missense mutations in DNA damage repair and highly cancer associated genes. We use two highly related strains (DBA/1J and DBA/2J) to investigate the genetic basis of collagen-induced arthritis susceptibility.

Conclusions: This paper significantly expands the catalogue of fully sequenced laboratory mouse strains and now contains several examples of highly genetically similar strains with divergent phenotypes. We show how studying private missense mutations can lead to insights into the genetic mechanism for a highly penetrant phenotype.
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http://dx.doi.org/10.1186/s13059-016-1024-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968449PMC
August 2016
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