Showing papers by "Stephen J. O'Brien published in 2013"

The tiger genome and comparative analysis with lion and snow leopard genomes

Abstract: Tigers and their close relatives (Panthera) are some of the world’s most endangered species. Here we report the de novo assembly of an Amur tiger whole-genome sequence as well as the genomic sequences of a white Bengal tiger, African lion, white African lion and snow leopard. Through comparative genetic analyses of these genomes, we find genetic signatures that may reflect molecular adaptations consistent with the big cats’ hypercarnivorous diet and muscle strength. We report a snow leopard-specific genetic determinant in EGLN1 (Met394Lys39), which is likely to be associated with adaptation to high altitude. We also detect a TYR260G4 Am utation likely responsible for the white lion coat colour. Tiger and cat genomes show similar repeat composition and an appreciably conserved synteny. Genomic data from the five big cats provide an invaluable resource for resolving easily identifiable phenotypes evident in very close, but distinct, species.

A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control

Abstract: HIV-1 sequence diversity is affected by selection pressures arising from host genomic factors. Using paired human and viral data from 1071 individuals, we ran >3000 genome-wide scans, testing for associations between host DNA polymorphisms, HIV-1 sequence variation and plasma viral load (VL), while considering human and viral population structure. We observed significant human SNP associations to a total of 48 HIV-1 amino acid variants (p<2.4 × 10−12). All associated SNPs mapped to the HLA class I region. Clinical relevance of host and pathogen variation was assessed using VL results. We identified two critical advantages to the use of viral variation for identifying host factors: (1) association signals are much stronger for HIV-1 sequence variants than VL, reflecting the ‘intermediate phenotype’ nature of viral variation; (2) association testing can be run without any clinical data. The proposed genome-to-genome approach highlights sites of genomic conflict and is a strategy generally applicable to studies of host–pathogen interaction.

Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls

Abstract: Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10−11). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.

Cementless fixation in Oxford unicompartmental knee replacement: A multicentre study of 1000 knees

Abstract: The Cementless Oxford Unicompartmental Knee Replacement (OUKR) was developed to address problems related to cementation, and has been demonstrated in a randomised study to have similar clinical outcomes with fewer radiolucencies than observed with the cemented device. However, before its widespread use it is necessary to clarify contraindications and assess the complications. This requires a larger study than any previously published. We present a prospective multicentre series of 1000 cementless OUKRs in 881 patients at a minimum follow-up of one year. All patients had radiological assessment aligned to the bone–implant interfaces and clinical scores. Analysis was performed at a mean of 38.2 months (19 to 88) following surgery. A total of 17 patients died (comprising 19 knees (1.9%)), none as a result of surgery; there were no tibial or femoral loosenings. A total of 19 knees (1.9%) had significant implant-related complications or required revision. Implant survival at six years was 97.2%, and there was a partial radiolucency at the bone–implant interface in 72 knees (8.9%), with no complete radiolucencies. There was no significant increase in complication rate compared with cemented fixation (p = 0.87), and no specific contraindications to cementless fixation were identified. Cementless OUKR appears to be safe and reproducible in patients with end-stage anteromedial osteoarthritis of the knee, with radiological evidence of improved fixation compared with previous reports using cemented fixation. Cite this article: Bone Joint J 2013;95-B:181–7.

Early postoperative predictors of satisfaction following total knee arthroplasty

Abstract: Background Despite the excellent total knee arthroplasty (TKA) results reported using traditional outcome measures, dissatisfaction rates of up to 30% are reported following surgery Although several preoperative factors have been identified as possible predictors of satisfaction, there is conflicting evidence Identification of dissatisfaction in the early postoperative assessment may therefore be an alternative consideration Methods We examined the relationship between 12-month satisfaction, and early post-operative outcomes in a cohort of 486 TKA patients Preoperative, and postoperative outcome measures at 3- and 12-months (Oxford knee score, pain score, SF12, and knee motion), were analysed and compared between patients who were satisfied and dissatisfied at 12-months following TKA Mean scores, and postoperative change in scores were calculated Postoperative outcomes were examined for correlation with satisfaction, and multivariate logistic regression models used to identify potential predictors of dissatisfaction Results Overall satisfaction was 770% No preoperative differences were observed between groups Dissatisfaction was associated with worse postoperative status across all outcome measures ( p p =0052) Dissatisfied patients demonstrated minimal further improvement or even worsening of outcome scores between 3- and 12-months postoperatively ( p p p =0009) were significant predictors of subsequent 12-month satisfaction Conclusions Dissatisfaction following TKA is associated with worse outcomes as early as 3months following surgery, with minimal further improvement subsequently achieved at 12-months Early postoperative assessment following TKA should therefore be considered, including clinical assessment, to identify those patients at risk of dissatisfaction

Genome-wide and differential proteomic analysis of hepatitis B virus and aflatoxin B1 related hepatocellular carcinoma in Guangxi, China.

Abstract: Both hepatitis B virus (HBV) and aflatoxin B1 (AFB1) exposure can cause liver damage as well as increase the probability of hepatocellular carcinoma (HCC). To investigate the underlying genetic changes that may influence development of HCC associated with HBV infection and AFB1 exposure, HCC patients were subdivided into 4 groups depending upon HBV and AFB1 exposure status: (HBV(+)/AFB1(+), HBV(+)/AFB1(-), HBV(-)/AFB1(+), HBV(-)/AFB1(-)). Genetic abnormalities and protein expression profiles were analyzed by array-based comparative genomic hybridization and isobaric tagging for quantitation. A total of 573 chromosomal aberrations (CNAs) including 184 increased and 389 decreased were detected in our study population. Twenty-five recurrently altered regions (RARs; chromosomal alterations observed in ≥10 patients) in chromosomes were identified. Loss of 4q13.3-q35.2, 13q12.1-q21.2 and gain of 7q11.2-q35 were observed with a higher frequency in the HBV(+)/AFB1(+), HBV(+)/AFB1(-) and HBV(-)/AFB1(+) groups compared to the HBV(-)/AFB(-) group. Loss of 8p12-p23.2 was associated with high TNM stage tumors (P = 0.038) and was an unfavorable prognostic factor for tumor-free survival (P =0.045). A total of 133 differentially expressed proteins were identified in iTRAQ proteomics analysis, 69 (51.8%) of which mapped within identified RARs. The most common biological processes affected by HBV and AFB1 status in HCC tumorigenesis were detoxification and drug metabolism pathways, antigen processing and anti-apoptosis pathways. Expression of AKR1B10 was increased significantly in the HBV(+)/AFB1(+) and HBV(-)/AFB1(+) groups. A significant correlation between the expression of AKR1B10 mRNA and protein levels as well as AKR1B10 copy number was observered, which suggest that AKR1B10 may play a role in AFB1-related hepatocarcinogenesis. In summary, a number of genetic and gene expression alterations were found to be associated with HBV and AFB1- related HCC. The possible synergistic effects of HBV and AFB1 in hepatocarcinogenesis warrant further investigations.

Modifiable factors delaying early discharge following primary joint arthroplasty.

Abstract: Recent NHS reforms have incentivised reduction in length of stay, with the UK department of health expecting health trusts to reduce bed days and ultimately reduce overall costs. The aim of this study was to identify avoidable causes for protracted hospital admission following total hip arthroplasty (THA) or total knee arthroplasty (TKA) within a fast-track unit. During a 6-month period, 535 consecutive patients underwent primary THA or TKA under the care of a single surgeon. All patients with a post-operative stay of greater than 72 h were identified, and reasons for delayed discharge were determined. The majority of arthroplasty patients were discharged within 3 days post-operatively. Twenty-one per cent of THA patients and 25 % of TKA patients remained as inpatients for greater than 72 h. For the THA population, this equates to 43 % of bed days used by 21 % of patients, and for the TKA population, 44 % of bed days were used by 25 % of patients. The major factor within both groups for delayed discharge was attributed to inadequate social support. Delayed discharge can never be totally prevented. This unit aims to develop improvement in social work provision, with a greater focus on pre-admission discharge planning to reduce the number of delayed discharges and ultimately reduce the cost burden of joint replacement surgery. It is not conducive with the ethos of fast-track arthroplasty to only identify social circumstances upon admission.

A common novel splice variant of SLC22A1 (OCT1) is associated with impaired responses to imatinib in patients with chronic myeloid leukaemia.

Abstract: Approximately one-third of patients with chronic myeloid leukaemia will fail to achieve or maintain responses to imatinib. Changes in solute carrier family 22 (organic cation transporter), member 1 (SLC22A1, also termed OCT1), the main transporter for imatinib, have been proposed as a possible predictive factor. We analysed SLC22A1 mRNA levels and single nucleotide polymorphisms (SNPs) located in exon 7 in 153 diagnostic whole blood samples from two patient cohorts. The level of SLC22A1 expression did not significantly correlate with imatinib failure or achievement of molecular remission. The SNP 408V>M (g.1222G>A) was present in 65% of patients and was associated in all cases with an eight base-pair insertion (8(+) allele) at the 3' end of exon 7. The latter generates an alternative splice site, leading to a premature stop codon. M420del was found in 33% of patients and never in cis with 8(+) (the 3(-) allele). Significantly longer times to 1% and 0·1% molecular responses (by quantitative reverse transcription polymerase chain reaction) were seen in patients with 8(+) 8(+) or 8(+) N compared to those with the remaining four genotypes (N = no insertion or deletion). Patients lacking 8(+) and 3(-) (NN, 18%) showed the best outcomes overall. Thus, while SLC22A1 expression does not appear to affect response, alterations in its splicing or amino acid sequence may do so.

Host genomic influences on HIV/AIDS.

Abstract: The AIDS era has seen multiple advances in the power of genetics research; scores of host genetic protective factors have been nominated and several have translated to the bedside. We discuss how genomics may inform HIV/AIDS prevention, treatment and eradication.

Glomerulopathy in the KK.Cg-Ay/J Mouse Reflects the Pathology of Diabetic Nephropathy

Abstract: The KK.Cg-Ay/J (KK-Ay) mouse strain is a previously described model of type 2 diabetes with renal impairment. In the present study, female KK-Ay mice received an elevated fat content diet (24% of calories), and a cohort was uninephrectomized (Unx) to drive renal disease severity. Compared to KK-a/a controls, 26-week-old KK-Ay mice had elevated HbA1c, insulin, leptin, triglycerides, and cholesterol, and Unx further elevated these markers of metabolic dysregulation. Unx KK-Ay mice also exhibited elevated serum BUN and reduced glomerular filtration, indicating that reduction in renal mass leads to more severe impairment in renal function. Glomerular hypertrophy and hypercellularity, mesangial matrix expansion, podocyte effacement, and basement membrane thickening were present in both binephric and uninephrectomized cohorts. Glomerular size was increased in both groups, but podocyte density was reduced only in the Unx animals. Consistent with functional and histological evidence of increased injury, fibrotic (fibronectin 1, MMP9, and TGFβ1) and inflammatory (IL-6, CD68) genes were markedly upregulated in Unx KK-Ay mice, while podocyte markers (nephrin and podocin) were significantly decreased. These data suggest podocyte injury developing into glomerulopathy in KK-Ay mice. The addition of uninephrectomy enhances renal injury in this model, resulting in a disease which more closely resembles human diabetic nephropathy.

Gender, culture and changing attitudes: experiences of HIV in Zimbabwe.

Abstract: This paper draws on a series of qualitative interviews with 60 people living in economically poor communities of Harare, the capital of Zimbabwe, to provide new insight into the cultural landscape of HIV While there has been extensive exploration of gender, sexuality, culture and HIV in Zimbabwe, there is a need to revisit these issues given the country's recent political and economic history These questions have shaped the meanings that have been created around HIV (ie, notions of HIV-as-death and as being produced by promiscuity) and the gendered mediation of cultural practices (ie, forms of sexual expression and treatment uptake) Drawing on the accounts from a group directly affected by HIV, we illustrate the persistence of gendered and spiritualised ideas about 'blame', 'transmission' and 'treatment' and the disproportionate burden that still falls on Zimbabwean women We conclude with an exploration of how everyday understandings of HIV may be shifting and the ways in which marginality, discrimination and stigma may be being challenged by openness, dialogue and attitude change

Molecular evidence for a recent demographic expansion in the puma (Puma concolor) (Mammalia, Felidae)

Abstract: The puma is an iconic predator that ranges throughout the Americas, occupying diverse habitats. Previous phylogeographic analyses have revealed that it exhibits moderate levels of genetic structure across its range, with few of the classically recognized subspecies being supported as distinct demographic units. Moreover, most of the species’ molecular diversity was found to be in South America. To further investigate the phylogeographic structure and demographic history of pumas we analyzed mtDNA sequences from 186 individuals sampled throughout their range, with emphasis on South America. Our objectives were to refine the phylogeographic assessment within South America and to investigate the demographic history of pumas using a coalescent approach. Our results extend previous phylogeographic findings, reassessing the delimitation of historical population units in South America and demonstrating that this species experienced a considerable demographic expansion in the Holocene, ca. 8,000 years ago. Our analyses indicate that this expansion occurred in South America, prior to the hypothesized re-colonization of North America, which was therefore inferred to be even more recent. The estimated demographic history supports the interpretation that pumas suffered a severe demographic decline in the Late Pleistocene throughout their distribution, followed by population expansion and re-colonization of the range, initiating from South America.

Needle assisted arthroscopic clysis of the medial collateral ligament of the knee: a simple technique to improve exposure in arthroscopic knee surgery.

Abstract: During knee arthroscopy, narrowness and tightness maybe encountered in the medial compartment that does not allow sufficient visualization or instrumentation. When this occurs, our team has found it helpful to perform a percutaneous clysis of the deep portion of the medial collateral ligament with a spinal needle. With the knee positioned in 10° to 20° of flexion and a valgus stress is applied. A spinal needle (18 Gauge) is passed percutaneously through the medial collateral ligament between the tibial plateau and undersurface of the medial meniscus. Several passes are made with the spinal needle with the bevel of the needle angled to selectively divide the fibers while keeping the medial collateral ligament under tension. Then with controlled valgus force, the medial compartment will progressively open allowing improved visualization to the posteromedial corner of the knee. This increase in space gives an enhanced visual field and further allows more room for arthroscopic instrumentation.

The effects of age and gender on the diameter of the femoral canal in patients who undergo total hip replacement

Abstract: With greater numbers of younger patients undergoing total hip replacement (THR), the effect of patient age on the diameter of the femoral canal may become more relevant. This study aimed to investigate the relationship between the diameter of the diaphysis of the femoral canal with increasing age in a large number of patients who underwent THR. A total of 1685 patients scheduled for THR had their femoral dimensions recorded from calibrated radiographs. There were 736 males and 949 females with mean ages of 67.1 years (34 to 92) and 70.2 years (29 to 92), respectively. The mean diameter of the femoral canal was 13.3 mm (8.0 to 23.0) for males and 12.7 mm (6.0 to 26.0) for females. There was a poor correlation between age and the diameter of the canal in males (r = 0.071, p = 0.05) but a stronger correlation in females (r = 0.31, p The diameter of the femoral canal diameter of a female patient undergoing THR could be predicted to increase by 3.2 mm between the ages of 40 and 80 years, in contrast a male would be expected to experience only a 0.6 mm increase during the same period. This increase in the diameter of the canal with age might affect the long-term survival of the femoral component in female patients. Cite this article: Bone Joint J 2013;95-B:339–42.

The Accurate Diagnosis of Biceps-Labral Complex Lesions with MRI and “3-Pack” Physical Examination: A Retrospective Analysis with Prospective Validation

Abstract: Objectives:Effective treatment of Biceps-Labral (B-L) Complex lesions is predicated upon accurate diagnosis. Diagnostic algorithms include both physical examination and MRI. We sought to evaluate the contribution of MRI and physical examination to the accurate diagnosis of B-L Complex lesions.Methods:A retrospective review of 273 surgical cases of lesions of the B-L Complex was performed comparing the preoperative documented clinical "Three Pack" examination to the preoperative Radiologist's MRI reading in accurately predicting lesions of the B-L Complex seen at the time of surgery, and as documented by intraoperative photos and videos. After the completion of this retrospective review, an additional 145 patients(116 symptomatic, 29 matched controls) were enrolled in a prospective validation study of the "Three Pack" examination. All patients were examined independently and separately by three examiners without contamination: the senior surgeon, the sports medicine fellow, and the senior surgeon' s PA. Re...

Warfare and society in the Ancient Eastern Mediterranean : papers arising from a colloquium held at the University of Liverpool, 13th June 2008

Abstract: Eight papers arising from a colloquium on Warfare and Society in the Ancient Eastern Mediterranean held at the University of Liverpool, 13th June 2008.

Straight talk with...Stephen O'Brien. Interviewed by Elie Dolgin.

Abstract: In December 2011, Stephen O'Brien stepped down as head of the US National Cancer Institute's Laboratory of Genomic Diversity and took up a three-year, $5 million 'megagrant' in Russia through a program started a year earlier by the Russian Ministry of Education and Science. O'Brien used his money to help launch the Theodosius Dobzhansky Center for Genome Bioinformatics at Saint Petersburg State University. On a trip back to the US, O'Brien spoke with Elie Dolgin about his new Russian center.

What are the lived experiences and perceptions of HIV among people associated with HIV support organisations in four townships of Harare, Zimbabwe?

Abstract: The HIV epidemic in Africa, and in Zimbabwe in particular, has taken a significant toll on individuals, families and communities. In Zimbabwe alone there have been over two million deaths since HIV emerged in the early 1980s and there are currently more than one million people living with HIV. This human tragedy has occurred in the context of an ongoing economic and political crisis that has constrained health service delivery and further complicated HIV care. It is in this complex socio-political landscape that this thesis explores the impact of HIV on people who live in the high population density areas – the lower socio-economic townships – of Harare, the capital of Zimbabwe. In order to explore the social dynamics of HIV in this particular cultural context I conducted sixty qualitative semi-structured interviews in Harare over three months in 2010 and several days in September 2011. The sixty people interviewed were either living with HIV, or the carer or partner of someone with a positive status. A variety of conceptual tools including gender, stigma, social movements and structural violence, were brought together to analyse the data obtained from interviews. This thesis first provides a micro analysis of individual experiences, in particular addressing the questions of social stigma, cultural meanings and therapeutic approach. It then adopts a more macro focus on the dynamics of structural violence and questions around human rights, which impact on the lived experience of HIV. The results of the study indicate that HIV remains a significant social, political and economic issue in Zimbabwe. They also reveal the ways in which HIV is discursively and culturally framed around the problematic nature of therapies and treatment, and the inherently gendered nature of the epidemic. Ways in which people living with HIV, and their families and communities, make sense of HIV are mapped out. This helps to uncover some of the complex intersections between cultural constructions of HIV and the embodiment of such perceptions in urban communities that are at the epicentre of the epidemic. Finally, this thesis posits that culturally derived ideas about HIV and healing can be reconfigured and gain acceptance in ways that are not incompatible with the successful uptake of biomedical technologies. It also argues that social solidarity (i.e. grassroots activism) can play a key role in ameliorating HIV-related stresses (i.e. problems of daily survival, stigma and therapies) and in challenging the structural factors that perpetuate the epidemic.

The Ultimate Player's Guide to Minecraft

Abstract: & The Ultimate Players Guide to Minecraft Second Edition Minecraft: These worlds are YOURS! Minecraft is WAY more than a game: its an alternate universe of creation, exhilaration, survival, adventure, passion! Dont enter that universe alone. Take an experienced guide wholl help you constantly as you learn the secrets of Minecraft! Stephen OBrien has been obsessing over Minecraft since its earliest betas. Hes seen it all! Now, hell take you deep inside craft and mine, cave and menagerie, farm and village. Hell reveal combat traps and tricks you need to know teach you enchantments of unimaginable power help you survive where few dare to go help you OWN the infinite worlds of Minecraft! Quick-start guide for first-night survival Customize your experience: monstrous, peaceful, and more Harvest resources, craft tools and shelterslet there be light Grab your pickaxe: mine iron, gold, diamonds, and redstone Escape (or defeat!) 14 types of hostile mobs Get friendly mobs on your side and build automated farms Brew potions to cure ills, gain superpowers, and throw at enemies Transform your shelter into a palace (or a secret underwater base) Create new worlds and master the fine art of terraforming Learn the secrets of redstone devices, and build incredible rail systems Play safely through The Nether and The End Minecraft is a trademark of Mojang Synergies / Notch Development AB. This book is not affiliated with or sponsored by Mojang Synergies /Notch Development AB. Stephen OBrien is an Australian-born writer and entrepreneur now residing in Sydney after too many years in Silicon Valley. He has written 27 books, including several best-sellers. OBrien founded Typefi, the worlds leading automated publishing system, and in his spare time invented a new type of espresso machine called mypressi. Hes a perpetual innovator who remains astounded at the unparalleled creativity Minecraft can engender.

Limerick Wave: Using flywheel technology to convert the power of the waves to electricity

Abstract: Limerick Wave Ltd. has developed an innovative wave energy converter (WEC) technology. They use a recently-patented flywheel technology to use the power from the movement of the waves (via the movement of a cylindrical floatation device) to generate electricity. The use of flywheel technology in this area is novel in that its rotation is unidirectional despite the bi-directional natural oscillation of the floatation device. In this report a mathematical description (model) of the WEC device’s operations is presented. Limerick Wave’s current experimental prototype is a 1:20 model; this model serves as a way to check the performance of a scaled-up rig. The model allows Limerick Wave to fine-tune their device’s design in order to maximise, say, the energy extracted from the ocean waves. By applying standard physical laws (conservation of angular momentum etc.) to the device’s operation, we show that such a device will demonstrate periodic behaviour regardless of its initial orientation. A crucial finding of the report concerns the power take-off mechanism. We identify two qualitatively different operational states: the first (second) state corresponds to extracting a small (large) amount of energy per cycle. Each operational state has its own benefits and shortcomings – these are examined in detail in the report. We perform a preliminary run of device-tuning; we take data from the observation buoys in Galway Bay to compute an optimum arm length for the device for harnessing power from the ocean. The data contains a strong seasonal variance and this is incorporated into the optimisation.