Immune responses and HIV: a little order from the chaos

HIV is evolution gone mad and bad. The virus infects a person and rapidly diversifies to become a huge swarm of viruses, each equipped differently to resist the onslaught of diverse T cells and antibodies. We can't expect to predict details of the struggle between virus and immunity, right? Wrong—maybe we can make some predictions, say two new landmark studies with potentially huge consequences for AIDS vaccine design

A Bayesian shifting method for uncertainty in the open-hole gamma-ray log around casing points

The wireline gamma-ray log is sensitive to open-hole conditions and, in particular, the diameter. This means that the log can jump at casing points. Although environmental corrections exist, they can fail at these points. We present a Bayesian method for deriving a new quantity – the shifted gamma–ray index – that takes these shifts into account by fitting a piecewise linear function to open-hole data in a depth window around the casing point. Because it is Bayesian, the method enables us to assess our uncertainty about its performance. This method requires very little knowledge of the borehole or drilling conditions but relies on the assumption that the lithology is consistent. Investigating the other wireline logs enables us to assess whether this assumption is valid. We demonstrate our method using well data from offshore mid-Norway

Suicide and suicide risk

Although recent years have seen large decreases in the overall global rate of suicide fatalities, this trend is not reflected everywhere. Suicide and suicidal behaviour continue to present key challenges for public policy and health services, with increasing suicide deaths in some countries such as the USA. The development of suicide risk is complex, involving contributions from biological (including genetics), psychological (such as certain personality traits), clinical (such as comorbid psychiatric illness), social and environmental factors. The involvement of multiple risk factors in conveying risk of suicide means that determining an individual’s risk of suicide is challenging. Improving risk assessment, for example, by using computer testing and genetic screening, is an area of ongoing research. Prevention is key to reduce the number of suicide deaths and prevention efforts include universal, selective and indicated interventions, although these interventions are often delivered in combination. These interventions, combined with psychological (such as cognitive behavioural therapy, caring contacts and safety planning) and pharmacological treatments (for example, clozapine and ketamine) along with coordinated social and public health initiatives, should continue to improve the management of individuals who are suicidal and decrease suicide-associated morbidity

A sequential dynamic Bayesian network for pore pressure estimation with uncertainty quantification

Pore-pressure estimation is an important part of oil-well drilling, since drilling into unexpected highly pressured fluids can be costly and dangerous. However, standard estimation methods rarely account for the many sources of uncertainty, or for the multivariate nature of the system. We propose the pore pressure sequential dynamic Bayesian network (PP SDBN) as an appropriate solution to both these issues. The PP SDBN models the relationships between quantities in the pore pressure system, such as pressures, porosity, lithology and wireline log data, using conditional probability distributions based on geophysical relationships to capture our uncertainty about these variables and the relationships between them. When wireline log data is given to the PP SDBN, the probability distributions are updated, providing an estimate of pore pressure along with a probabilistic measure of uncertainty that reflects the data acquired and our understanding of the system. This is the advantage of a Bayesian approach. Our model provides a coherent statistical framework for modelling the pore pressure system. The specific geophysical relationships used can be changed to better suit a particular setting, or reflect geoscientists’ knowledge. We demonstrate the PP SDBN on an offshore well from West Africa. We also perform a sensitivity analysis, demonstrating how this can be used to better understand the working of the model and which parameters are the most influential. The dynamic nature of the model makes it suitable for real time estimation during logging while drilling. The PP SDBN models shale pore pressure in shale rich formations with mechanical compaction as the overriding source of overpressure. The PP SDBN improves on existing methods since it produces a probabilistic estimate that reflects the many sources of uncertainty present

Alcohol Affects the P3 Component of an Adaptive Stop Signal Task ERP

BACKGROUND The P3 component of the event-related potential (ERP) has been particularly useful in alcohol research for identifying endophenotypes of alcohol use disorder (AUD) risk in sober subjects. However, practice and/or fatigue reduces P3 amplitude, limiting the ability to ascertain acute and adaptive effects of alcohol exposure. Here, we report acute alcohol effects on P3 amplitude and latency using an adaptive stop signal task (aSST). METHODS One hundred and forty eight nondependent moderate to heavy social drinkers, age 21 to 27, participated in 2 single-blind, alcohol or placebo, counterbalanced sessions approximately one week apart. During each session, subjects performed an adaptive stop signal task (aSST) at (1) baseline, (2) upon reaching the target 60 mg/dL breath alcohol concentration or at the equivalent time during the placebo session, and (3) approximately 135 minutes later while the breath alcohol concentration was clamped. Here, we report on differences between baseline and first subsequent measurements across the experimental sessions. During each aSST run, the stop signal delay (SSD, the time between stop and go signals) adjusted trial-by-trial based on the subject’s performance. RESULTS The aSST reliably generated a STOP P3 component that did not change significantly with repeated task performance. The pre-infusion SSD distribution was bimodal, with mean values several hundred msec apart (FAST: 153 msec and SLOW: 390 msec). This suggested different response strategies: FAST SSD favoring “going” over “stopping,” and SLOW SSD favoring “stopping” over “going”. Exposure to alcohol at 60 mg/dL differentially affected the amplitude and latency of the STOP P3 according to SSD group. Alcohol significantly reduced P3 amplitude in the SLOW SSD compared to FAST SSD group, but significantly increased P3 latency in the FAST SSD compared to SLOW SSD group. CONCLUSIONS The aSST is a robust and sensitive task for detecting alcohol induced changes in inhibition behavior as measured by the P3 component in a within subject design. Alcohol was associated with P3 component changes which varied by SSD group, suggesting a differential effect as a function of task strategy. Overall, the data support the potential utility of the aSST in the detection of alcohol response related AUD risk

Decline of meticillin-resistant Staphylococcus aureus in Oxfordshire hospitals is strain-specific and preceded infection-control intensification

Background In the past, strains of Staphylococcus aureus have evolved, expanded, made a marked clinical impact and then disappeared over several years. Faced with rising meticillin-resistant S aureus (MRSA) rates, UK government-supported infection control interventions were rolled out in Oxford Radcliffe Hospitals NHS Trust from 2006 onwards. Methods Using an electronic Database, the authors identified isolation of MRS among 611 434 hospital inpatients admitted to acute hospitals in Oxford, UK, 1 April 1998 to 30 June 2010. Isolation rates were modelled using segmented negative binomial regression for three groups of isolates: from blood cultures, from samples suggesting invasion (eg, cerebrospinal fluid, joint fluid, pus samples) and from surface swabs (eg, from wounds). Findings MRSA isolation rates rose rapidly from 1998 to the end of 2003 (annual increase from blood cultures 23%, 95% CI 16% to 30%), and then declined. The decline accelerated from mid-2006 onwards (annual decrease post-2006 38% from blood cultures, 95% CI 29% to 45%, p=0.003 vs previous decline). Rates of meticillin-sensitive S aureus changed little by comparison, with no evidence for declines 2006 onward (p=0.40); by 2010, sensitive S aureus was far more common than MRSA (blood cultures: 2.9 vs 0.25; invasive samples 14.7 vs 2.0 per 10 000 bedstays). Interestingly, trends in isolation of erythromycin-sensitive and resistant MRSA differed. Erythromycin-sensitive strains rose significantly faster (eg, from blood cultures p=0.002), and declined significantly more slowly (p=0.002), than erythromycin-resistant strains (global p<0.0001). Bacterial typing suggests this reflects differential spread of two major UK MRSA strains (ST22/36), ST36 having declined markedly 2006-2010, with ST22 becoming the dominant MRSA strain. Conclusions MRSA isolation rates were falling before recent intensification of infection-control measures. This, together with strain-specific changes in MRSA isolation, strongly suggests that incompletely understood biological factors are responsible for the much recent variation in MRSA isolation. A major, mainly meticillin-sensitive, S aureus burden remains

Disease prevention strategies for QX disease (Marteilia sydneyi) of Sydney rock oysters (Saccostrea glomerata)

The Sydney rock oyster (Saccostrea glomerata) forms the basis of an important aquaculture industry on the east coast of Australia. During the 1970s, production of S. glomerata began to decline, in part as a result of mortalities arising from Queensland unknown (QX) disease. Histological studies implicated the paramyxean parasite Marteilia sydneyi in the disease outbreaks. Disease zoning was implemented to prevent the spread of M. sydneyi-infected oysters. This control measure hindered rock oyster farming, which historically has relied on transferring wild-caught spat between estuaries for on-growing to market size and has not prevented the subsequent occurrence of QX disease in the Georges and Hawkesbury rivers in central New South Wales. Management of QX disease has been hampered by the complicated life cycle of M. sydneyi, with outbreaks of QX disease likely to be regulated by a combination of the abundance of intermediate host of M. sydneyi, environmental stressors, and the immunocompetence of S. glomerata. The future of the Sydney rock oyster industry relies on understanding these factors and progressing the industry from relying on farming wild-caught seed to the successful commercialization of hatchery-produced QX-resistant S. glomerata

The PARP inhibitor AZD2461 provides insights into the role of PARP3 inhibition for both synthetic lethality and tolerability with chemotherapy in preclinical models

The PARP inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first PARP inhibitor approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein,so AZD2461 was developed as a poor substrate for drug transporters. Here we demonstrate the efficacy of this compound against olaparib-resistant tumors that overexpress P-glycoprotein. In addition, AZD2461 was better tolerated in combination with chemotherapy than olaparib in mice, which suggests that AZD2461 could have significant advantages over olaparib in the clinic. However, this superior toxicity profile did not extend to rats. Investigations of this difference revealed a differential PARP3 inhibitory activity for each compound and a higher level of PARP3 expression in bone marrow cells from mice as compared with rats and humans. Our findings have implications for the use of mouse models to assess bone marrow toxicity for DNA-damaging agents and inhibitors of the DNA damage response. Finally, structural modeling of the PARP3-active site with different PARP inhibitors also highlights the potential to develop compounds with different PARP family member specificity profiles for optimal antitumor activity and tolerability

Polarized QPOs from the INTEGRAL polar IGRJ14536-5522 (=Swift J1453.4-5524)

We report optical spectroscopy and high speed photometry and polarimetry of the INTEGRAL source IGRJ14536-5522 (=Swift J1453.4-5524). The photometry, polarimetry and spectroscopy are modulated on an orbital period of 3.1564(1) hours. Orbital circularly polarized modulations are seen from 0 to -18 per cent, unambiguously identifying IGRJ14536-5522 as a polar. Some of the high speed photometric data show modulations that are consistent with quasi-periodic oscillations (QPOs) on the order of 5-6 minutes. Furthermore, for the first time, we detect the (5-6) minute QPOs in the circular polarimetry. We discuss the possible origins of these QPOs. We also include details of HIPPO, a new high-speed photo-polarimeter used for some of our observations.Comment: Accepted for publication by MNRAS. The paper contains 7 figures and 1 tabl

The apéritif effect: Alcohol's effects on the brain's response to food aromas in women

OBJECTIVE: Consuming alcohol prior to a meal (an apéritif) increases food consumption. This greater food consumption may result from increased activity in brain regions that mediate reward and regulate feeding behavior. Using functional magnetic resonance imaging, we evaluated the blood oxygenation level dependent (BOLD) response to the food aromas of either roast beef or Italian meat sauce following pharmacokinetically controlled intravenous infusion of alcohol. METHODS: BOLD activation to food aromas in non-obese women (n = 35) was evaluated once during intravenous infusion of 6% v/v EtOH, clamped at a steady-state breath alcohol concentration of 50 mg%, and once during infusion of saline using matching pump rates. Ad libitum intake of roast beef with noodles or Italian meat sauce with pasta following imaging was recorded. RESULTS: BOLD activation to food relative to non-food odors in the hypothalamic area was increased during alcohol pre-load when compared to saline. Food consumption was significantly greater, and levels of ghrelin were reduced, following alcohol. CONCLUSIONS: An alcohol pre-load increased food consumption and potentiated differences between food and non-food BOLD responses in the region of the hypothalamus. The hypothalamus may mediate the interplay of alcohol and responses to food cues, thus playing a role in the apéritif phenomenon