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The observation of electromagnetic radiation from radio to $\gamma$-ray wavelengths has provided a wealth of information about the universe. However, at PeV (10$^{15}$ eV) energies and above, most of the universe is impenetrable to photons. New messengers, namely cosmic neutrinos, are needed to explore the most extreme environments of the universe where black holes, neutron stars, and stellar explosions transform gravitational energy into non-thermal cosmic rays. The discovery of cosmic neutrinos with IceCube has opened this new window on the universe. In this white paper, we present an overview of a next-generation instrument, IceCube-Gen2, which will sharpen our understanding of the processes and environments that govern the universe at the highest energies. IceCube-Gen2 is designed to: 1) Resolve the high-energy neutrino sky from TeV to EeV energies; 2) Investigate cosmic particle acceleration through multi-messenger observations; 3) Reveal the sources and propagation of the highest energy particles in the universe; 4) Probe fundamental physics with high-energy neutrinos. IceCube-Gen2 will increase the annual rate of observed cosmic neutrinos by a factor of ten compared to IceCube, and will be able to detect sources five times fainter than its predecessor. Furthermore, through the addition of a radio array, IceCube-Gen2 will extend the energy range by several orders of magnitude compared to IceCube. Construction will take 8 years and cost about \$350M. The goal is to have IceCube-Gen2 fully operational by 2033. IceCube-Gen2 will play an essential role in shaping the new era of multi-messenger astronomy, fundamentally advancing our knowledge of the high-energy universe. This challenging mission can be fully addressed only in concert with the new survey instruments across the electromagnetic spectrum and gravitational wave detectors which will be available in the coming years., Comment: 56 pages, 29 figures

In this paper, we study the effect of active-neutrino-sterile-neutrino mixing in the expected high-energy astrophysical neutrino flavor content. Non-unitarity in the measurement of the three-active neutrinos can be due to the existence of sterile neutrino states. We introduce the concept of the four-flavor tetrahedron in order to visualize the lack of unitarity in the astrophysical neutrino three-flavor triangle. We demonstrate that active-sterile neutrino mixings modify the allowed region of the astrophysical flavor ratio from the standard case. However, a projection of the four-flavor tetrahedron has restrictions of phase space similar to the three-flavor triangle. On the other hand, the initial presence of astrophysical sterile neutrinos drastically changes the scenario, and it allows an apparent unitarity violation in the three-flavor triangle space. Using current global fit constraints including the non-unitarity case, we also illustrate the allowed astrophysical neutrino flavor ratios. Thus, the measurement of the high-energy astrophyscal neutrino flavor content allows us to explore sterile neutrinos independently of the sterile neutrino mass scale. These are topics of investigation for current and future neutrino telescopes.

BACKGROUND Cardiovascular disease (CVD) risk assessment remains a critical step in guiding decisions to initiate primary prevention interventions in people living with HIV (PLWH). SETTING We investigated whether coronary artery calcium (CAC) scoring allowed a more accurate selection of patients who may benefit from statin therapy, compared with current risk assessment tools alone. METHODS Cross-sectional analysis of PLWH over 50 years old who underwent CAC scoring between 2009 and 2019. Framingham Risk score (FRS), QRISK2 and D:A:D scores were calculated for each participant at the time of CAC scoring and statin eligibility determined based on current European guidelines on the prevention of CVD in PLWH. RESULTS A total of 739 patients were included (mean age 56 ± 5, 92.8% male, 84% white). Among 417 (56.4%) candidates for statin therapy based on FRS ≥10%, 174 (23.5%) had no detectable calcification (CAC = 0). Conversely, 145 (19.6%) patients with detectable calcification (CAC > 0) were identified as low-risk (FRS < 10%). When compared with FRS, CAC scoring reclassified CVD risk in 43.1% of patients, 145 (19.6%) to a higher risk group that could benefit from statin therapy and 174 (23.5%) statin candidates to a lower risk group. QRISK2 and D:A:D scores performed similarly to FRS, underestimating the presence of significant coronary calcification in 21.1% and 24.9% respectively and overestimating risk in 16.9% and 18.8% patients with CAC = 0. CONCLUSIONS Establishing a decision-model based on the combination of conventional risk tools and CAC scoring improves risk assessment and the selection of PLWH who would benefit from statin therapy.

Astrophysical high-energy neutrinos observed by IceCube are sensitive to small effects in a vacuum such as those motivated from quantum-gravity theories. Here, we discuss the potential sensitivity to Lorentz violation in the diffuse astrophysical neutrino data from IceCube. The estimated sensitivity reaches the Planck-scale physics motivated region providing IceCube with real discovery potential for Lorentz violation.

In neutrino experiments, hemispherical photomultiplier tubes (PMTs) are often used to cover large surfaces or volumes to maximize the photocathode coverage with a minimum number of channels. Instrumentation is often coarse, and neutrino event reconstruction and particle identification (PID) is usually done through the morphology of PMT hits. In future neutrino experiments, it may be desirable to perform PID from a few hits, or even a single hit, by utilizing pulse shape information. In this report, we study the principle of pulse shape PID using a single 10-inch hemispherical PMT in a spherical glass housing for future neutrino telescopes. We use the Fermilab Test Beam Facility (FTBF) MTest beamline to demonstrate that with pulse shape PID, statistical separation is possible to distinguish 2 GeV electrons from 8 GeV pions, where the total charge deposition is ~20 PE in our setup. Such techniques can be applied to future neutrino telescopes focusing on low energy physics, including the IceCube-Upgrade., 27 pages, 19 figures

We have detected astrophysical neutrinos in IceCube that can be used to probe astrophysical sources at ultra high scales. Here we report a search for anomalous space time effects using astrophysical neutrino flavor data in IceCube. New effective operators are introduced to drive non-standard neutrino flavor mixing which modify the flavor ratios compared to standard cases. Using the High Energy Starting Events sample (HESE) 7.5-year data for this analysis, we found no evidence of such flavor anomalies. However, we are expecting to set limits from this new approach which goes far beyond any known techniques. Importantly, we achieve the necessary precision to probe new physics using neutrino flavor expected by Planck scale theories.

CINAMMON is a phase IV, open-label, single-arm, pilot study assessing maraviroc (MVC) in the central nervous system (CNS) when added to darunavir/ritonavir monotherapy (DRV/r) in virologically suppressed HIV-infected subjects. CCR5 tropic participants on DRV/r were recruited. Participants remained on DRV/r for 12 week (w) (control phase). MVC 150 mg qd was added w12-w36 (intervention phase). Lumbar puncture (LP) and neurocognitive function (Cogstate) examinations scheduled at baseline, w12 and w36; MRI before w12, again at w36. Primary endpoint was CSF inflammatory marker changes during intervention phase. Secondary endpoints included changes in NC function and MRI parameters. CSF/plasma DRV/r concentrations measured at w12 and w36, MVC at w36. Nineteen patients recruited, 15 completed (17M, 2F). Dropouts: headache (2), knee problem (could not attend, 1), personal reasons (1). Mean age (range) 45.4 years (27.2-65.1), 13/19 white, 10/19 MSM. No changes in selected CSF markers were seen w12-w36. Overall NC function did not improve w12-w36: total age adjusted z score improved by 0.27 (weighted paired t test; p = 0.11); for executive function only, age adjusted z score improved by 0.54 (p = 0.03). MRI brain parameters unchanged. DRV plasma:CSF concentration ratio unchanged between w12 (132) and w36 (112; p = 0.577, Wilcoxon signed-rank). MVC plasma:CSF concentration ratio was 35 at w36. No changes in neuroinflammatory markers seen. In this small study, addition of 24w MVC 150 mg qd to stable DRV/r monotherapy showed possible improvement in executive function with no global NC effect. Learning effect cannot be excluded. This effect should be further evaluated.

A case of a 37-year-old female primagravida who attended the emergency department (ED) via ambulance in hypotensive shock. She was 10 weeks pregnant, but had an inevitable miscarriage confirmed in the local Early Pregnancy Unit 3 weeks previously. She was hypotension (90/60 mm Hg), bradycardic (45 bpm) and was peripherally shut down. A provisional diagnosis of haemorrhagic shock was made, but despite intravenous fluid challenges, she appeared to be deteriorating, so a major haemorrhage protocol was activated. On examination, there was some vaginal bleeding and a protruding sac noted. The gynaecology registrar was informed and performed an Evacuation of the Retained Products of Conception in the ED. This gave instant relief to the patient and her blood pressure and heart rate became normal over a few minutes. She went on to make a full recovery. This case provides useful learning points for doctors working in the ED and other urgent care settings.

The Precision IceCube Next Generation Upgrade (PINGU) is a proposed low-energy in-fill extension to the IceCube Neutrino Observatory. With detection technology modeled closely on the successful IceCube example, PINGU will provide a 6Mton effective mass for neutrino detection with an energy threshold of a few GeV. With an unprecedented sample of over 60,000 atmospheric neutrinos per year in this energy range, PINGU will make highly competitive measurements of neutrino oscillation parameters in an energy range over an order of magnitude higher than long-baseline neutrino beam experiments. PINGU will measure the mixing parameters $\theta_{\rm 23}$ and $\Delta m^2_{\rm 32}$, including the octant of $\theta_{\rm 23}$ for a wide range of values, and determine the neutrino mass ordering at $3\sigma$ median significance within 4 years of operation. PINGU's high precision measurement of the rate of ${\nu_\tau}$ appearance will provide essential tests of the unitarity of the $3\times 3$ PMNS neutrino mixing matrix. PINGU will also improve the sensitivity of searches for low mass dark matter in the Sun, use neutrino tomography to directly probe the composition of the Earth's core, and improve IceCube's sensitivity to neutrinos from Galactic supernovae. Reoptimization of the PINGU design has permitted substantial reduction in both cost and logistical requirements while delivering performance nearly identical to configurations previously studied. This document summarizes the results of detailed studies described in a more comprehensive document to be released soon., Comment: 28 pages, 10 figures, submitted to J. Phys. G

Current and future neutrino oscillation experiments utilize information of hadronic final states to improve sensitivities on oscillation parameters measurements. Among the physics of hadronic systems in neutrino interactions, the hadronization model controls multiplicities and kinematics of final state hadrons from the primary interaction vertex. For relatively high invariant mass events, neutrino interaction generators rely on the PYTHIA6 hadronization program. Here, we show a possible improvement of this process in neutrino event generators, by utilizing expertise from the HERMES experiment. Next, we discuss the possibility to implement the PYTHIA8 program in neutrino interaction generators, including GENIE and NEUT. Finally, we show preliminary comparisons of PYTHIA8 predictions with neutrino hadron multiplicity data from bubble chamber experiments within the GENIE hadronization validation tool., Comment: 8 pages, 4 figures, proceedings of the 10th International Workshop on Neutrino-Nucleus Interactions in the Few-GeV Region (NuInt15), Osaka, Japan, 16-21 November 2015. arXiv admin note: text overlap with arXiv:1412.4301

Background Patients prefer fewer pills and once-daily (qd) dosing without food restrictions. We assessed the impact on adherence [by Medication Event Monitoring System (MEMS) cap monitoring] of switching from abacavir (ABC) and lamivudine (3TC) twice daily (bid) to ABC/3TC fixed-dose formulation (FDC, Kivexa®) qd to achieve a qd regimen. Methods A randomized, open-label, 8-week study comparing adherence, efficacy and safety of immediate vs. delayed switching from ABC/3TC to FDC qd. Results Ninety-four patients were dosed. Significantly improved adherence was observed at week 4 with qd ABC/3TC across all three adherence variables: taking compliance 99.2% (90.7–100%) vs. 96.6% (60.0–100%) (P=0.017); dosing compliance 97.1% (64.3–100%) vs. 91.9% (33.3–100%) (P=0.016); and timing compliance 95.5% (53.8–100%) vs. 86.3% (4.3–100%) (P=0.006). Treatment satisfaction increased significantly at week 4 with ABC/3TC qd [92% (82–99%) vs. 85% (75–93%) (P=0.004)]. Two patients were withdrawn from the study because of intolerance to ABC/3TC. Conclusions Switching from ABC and 3TC bid to ABC/3TC FDC qd significantly improved adherence by MEMS cap monitoring at week 4 and improved patient satisfaction with therapy. The results remain to be confirmed over a longer follow-up. Use of qd regimens supports adherence and improves treatment satisfaction relative to bid regimens.

For certain genetic conditions DNA testing identifies carriers and determines the risk status of foetuses, thus helping parents to make more informed prenatal decisions. Data, collected from three genetic centres in England and Wales from August 1986 to July 1990, are used to describe trends in demand for DNA testing, the impact of DNA tests on carrier risk assessment, and the use of DNA tests in relation to pregnancy outcome. Altogether the data include 23,388 subjects and 681 pregnancies in 8738 families divided into five cohorts by year of entry and referral. The most frequent gene disorders referred to the genetic centres are currently being tested or will soon be tested. For these disorders the initial high level of activity has declined and may have reached steady state. Demand for DNA services is high for cystic fibrosis and Duchenne muscular dystrophy, intermediate for Huntington's disease, and low for adult polycystic kidney disease, phenylketonuria and tuberous sclerosis. Based on these findings we suggest that demand for DNA tests will be high in serious, untreatable and slow progressing conditions with early onset; intermediate for conditions affecting intellect and neurological integrity with later onset; and low for treatable, late-onset conditions, or those for which there is evidence of heterogeneity, and variable penetrance. It would be helpful to assess the extent to which this view of demand is confirmed when the new disorders being DNA tested are considered and for the pattern of activity of DNA testing for some types of cancer. Since no DNA centre could offer a fully comprehensive testing service, it is recommended that a structure is created to audit overall activity, assist in policy formulation, and influence supraregional service organisation, in order that the spread of DNA services be planned as effectively as possible. This structure would facilitate monitoring of the evolution of contract specifications agreed by commissioners and providers on a regional basis.

Background The use of highly active antiretroviral therapy (HAART) has profoundly altered the life expectancy of individuals infected with HIV. Metabolic abnormalities associated with antiretrovirals and cumulative exposure to combination antiretroviral therapy, including dyslipidaemia and insulin resistance, have been linked to an increased risk of myocardial infarction. Methods Longitudinal data from a large prospectively collected clinical database were analysed. All patients who commenced first antiretroviral therapy (ART) [two nucleoside reverse transcriptase inhibitors (NRTIs)+one nonnucleoside reverse transcriptase inhibitor (NNRTI) or one active protease inhibitor (PI)] since 1996 were identified. Patients with elevated cholesterol levels [>5.5 mmol/L (215 mg/dL)] prior to therapy initiation were excluded. Quantitative data were categorized into quartiles and presented stratified by individuals developing abnormal levels of cholesterol during first-line HAART. Event time was defined as time from commencing first-line ART to either development of cholesterol level >6.5 mmol/L (254 mg/dL) or switch of first-line therapy. The Kaplan–Meier product limit survival method was used to estimate time to abnormal cholesterol level, and the χ2 test was used for comparisons between drug classes. Cox's proportional hazards regression analysis was used to identify factors predicting a likelihood of raised cholesterol level. Results A total of 1664 patients were included in the study: 57.1% on two NRTIs+one NNRTI, 38.4% on two NRTIs+one PI, and 4.4% on two NRTIs+a boosted PI regimen. Regimens containing stavudine or PIs were associated with a significantly higher event risk and earlier time to event. No differences between efavirenz and nevirapine or between didanosine and lamivudine were observed. In 28 patients exposed to the combination of tenofovir+lamivudine+efavirenz, there were no episodes of elevated cholesterol level. Conclusion Dyslipidaemia has emerged as an important issue in HIV-infected individuals receiving antiretroviral therapy. This study demonstrates that age at start of therapy, baseline cholesterol level, stavudine use and PI use are all associated with increased risk of hypercholesterolemia on initial therapy. Both NRTI and NNRTI/PI choice influence risk of hypercholesterolaemia.

Background Murine data indicate that angiogenesis is central to the aetiopathogenesis of Kaposi’s sarcoma (KS). Therefore, we measured angiogenic cytokines and growth factors in patients with AIDS-related KS during treatment with both antiretrovirals and second-line paclitaxel chemotherapy. Cytokines measured included tumour necrosis factor-α (TNF-α), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and the interleukins IL-2, -6 and -12. Patients and methods Enzyme-linked immunosorbent assays (ELISAs) were carried out to measure plasma cytokine levels in 17 patients with AIDS-related KS who had progressed within 6 months of receiving liposomal anthracyclines and were treated with paclitaxel 100 mg/m2 every 2 weeks. Measurements were carried out before progression, at commencement and at the completion of paclitaxel. Results The objective response rate to paclitaxel was 71% (95% confidence interval 60% to 81%). In 17 patients with AIDS-related KS, we observed eight partial responses and four complete responses. Patients with AIDS Clinical Trial Group stage T1 disease had higher plasma VEGF (P = 0.05) and lower plasma TNF-α levels (P = 0.05) than patients with earlier stage T0 KS. There were no correlations between plasma cytokines (bFGF, VEGF, TNF-α, and IL-2,-6 and -12) and the CD4 and CD8 cell counts or HIV-1 RNA viral load. Response to paclitaxel was associated with a fall in plasma IL-6 levels (P = 0.04) but no change in other cytokines. There were no significant changes in CD4, CD8, CD16/56, CD19 cell counts and HIV-1 viral loads during chemotherapy. Conclusions Angiogenic cytokines may correlate with KS disease extent but not with cellular immune function or HIV viraemia. Response to paclitaxel therapy correlates with a fall in plasma IL-6 levels and recent data indicate this may be a surrogate marker of KS-associated herpesvirus viral load. Overall, clinical response in KS correlates poorly with known angiogenic cytokines.

Background: Endoscopic balloon dilatation (EBD) of the sphincter of Oddi has been proposed as an alternative therapy with possible advantages, as compared with endoscopic sphincterotomy (ES), for removal of bile duct stones. Patients and methods: In a randomised study, we compared the efficacy and complication rate of the two techniques in 202 patients with common bile duct stones. Patients were followed up for 12 months. Results: A total of 103 patients were randomised to the EBD group and 99 to the ES group. Overall duct clearance was 87.1% and did not differ between the two groups (EBD 87.4%; ES 86.9%). The complication rate at 24 hours was 6.8% in the EBD group and 3.0% in the ES group (NS). Complications during follow up were 11.7% and 15.2% respectively (NS). A multivariate logistic regression analysis showed only the size of the largest stone to be predictive of success for either technique. Conclusion: Endoscopic balloon dilatation offers no significant advantage over the well established technique of endoscopic sphincterotomy for the removal of bile duct stones.

The effect of altering antiretroviral therapy (ART) on responses to viral, recall and human immunodeficiency virus (HIV)-1-specific recombinant antigens and interleukin-2 (IL-2) in HIV-1-infected patients was assessed. A longitudinal cohort study in eight HIV-1 infected individuals following a clinically indicated therapy change (seven for drug intolerance and one for virological failure) from protease inhibitor (PI) to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral regimens was performed. CD4 T-cell counts, viral loads, lymphoproliferative responses, cytokine production and latent proviral deoxyribonucleic acid (DNA) were measured at baseline and at weeks 12 and 24 after therapy substitution. Following therapy-switch there was a 33% proportional increase in mitogen response (95% confidence interval (CI), 3-33%) and a 31% increase (95% CI, 15-48%) in viral and recall-antigen responses. Six patients developed proliferative responses to low concentration IL-2 stimulation. All patients demonstrated an increase in median HIV-1-specific responses, as three had detectable virus at baseline (two being viral rebound); this may reflect an autovaccination effect. Proviral DNA changes largely reflected plasma HIV-1 ribonucleic acid (RNA). In conclusion, NNRTI substitution for a PI may favour immune reconstitution with an improvement in HIV-1-specific responses, which may reflect differential effects on antigen processing and presentation, an autovaccination effect or alternatively a potential suppressive effect of the PI.

Next generation neutrino oscillation experiments utilize details of hadronic final states to improve the precision of neutrino interaction measurements. The hadronic system was often neglected or poorly modeled in the past, but they have significant effects on high precision neutrino oscillation and cross-section measurements. Among the physics of hadronic systems in neutrino interactions, the hadronization model controls multiplicities and kinematics of final state hadrons from the primary interaction vertex. For relatively high invariant mass events, many neutrino experiments rely on the PYTHIA program. Here, we show a possible improvement of this process in neutrino event generators, by utilizing expertise from the HERMES experiment. Finally, we estimate the impact on the systematics of hadronization models for neutrino mass hierarchy analysis using atmospheric neutrinos such as the PINGU experiment., Comment: v1: 9 pages, 7 figures, proceedings of the CETUP*-Workshop on Neutrino Interactions, July 22-31, 2014 at Lead/Dead Wood, South Dakota, USA. v2: 15 pages, 8 figures, 1 table, will be published by Journal of Physics G: Nuclear and Particle Physics (IoP)

Background: There is little information on the incidence of AIDS-defining events which have been reported in the literature to be associated with immune reconstitution inflammatory syndrome (IRIS) after combined antiretroviral therapy (cART) initiation. These events include tuberculosis, mycobacterium avium complex (MAC), cytomegalovirus (CMV) retinitis, progressive multifocal leukoencephalopathy (PML), herpes simplex virus (HSV), Kaposi sarcoma, non-Hodgkin lymphoma (NHL), cryptococcosis and candidiasis. Methods: We identified individuals in the HIV-CAUSAL Collaboration, which includes data from six European countries and the US, who were HIV-positive between 1996 and 2013, antiretroviral therapy naive, aged at least 18 years, hadCD4+ cell count and HIV-RNA measurements and had been AIDS-free for at least 1 month between those measurements and the start of follow-up. For each AIDS-defining event, we estimated the hazard ratio for no cART versus less than 3 and at least 3 months since cART initiation, adjusting for time-varying CD4+ cell count and HIV-RNA via inverse probability weighting. Results: Out of 96 562 eligible individuals (78% men) with median (interquantile range) follow-up of 31 [13,65] months, 55 144 initiated cART. The number of cases varied between 898 for tuberculosis and 113 for PML. Compared with non-cART initiation, the hazard ratio (95% confidence intervals) up to 3 months after cART initiation were 1.21 (0.90-1.63) for tuberculosis, 2.61 (1.05-6.49) for MAC, 1.17 (0.34-4.08) for CMV retinitis, 1.18 (0.62-2.26) for PML, 1.21 (0.83-1.75) for HSV, 1.18 (0.87-1.58) for Kaposi sarcoma, 1.56 (0.82-2.95) for NHL, 1.11 (0.56-2.18) for cryptococcosis and 0.77 (0.40-1.49) for candidiasis. Conclusion: With the potential exception of mycobacterial infections, unmasking IRIS does not appear to be a common complication of cART initiation in high-income countries. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Aim\ud In the United Kingdom, diagnostic management of patients presenting to emergency department with a scaphoid injury varies. Follow-up plain radiographs, after an initial inconclusive X-ray, are common practice. We optimised the diagnostic pathway for these patients by focusing on the most appropriate diagnostic modality and on minimising the time to follow-up diagnostics.\ud \ud Materials and methods\ud A baseline audit in the period 2008–2009 involving a total of 184 patients was conducted, and after the introduction of new local guidelines for scaphoid injury diagnostics, a follow-up audit involving 79 patients was undertaken in 2010–2012.\ud \ud Results\ud In the original audit, 130 patients had only scaphoid radiographs, of which 23 underwent initial and follow-up X-rays, and 107 initial-only radiographs. Of those 23, just one single patient (4 %) displayed a scaphoid fracture. Others underwent three imaging procedures: initial radiographs, follow-up radiographs and either bone scan (41 patients) or MRI (13 patients). A further 6/41 (15 %) and 4/13 (31 %) fractures were detected by bone scan and MRI, respectively. In the re-audit, when MRI replaced follow-up X-rays and bone scans, 7 out of 77 (9 %) patients were diagnosed with scaphoid fracture. Time from initial plain radiograph to follow-up MRI was reduced from an original mean of 36 to 14 days during the re-audit period.\ud \ud Conclusion\ud The introduction of early MRI enhances scaphoid injury diagnostics and accelerates patient management. We therefore endorse the introduction of this approach on a wider scale through an update of the clinical guidelines for scaphoid injuries.

Objective: To estimate the cost effectiveness of universal, voluntary HIV screening of pregnant women in England Design: Cost effectiveness analysis. Cost estimates of caring for HIV positive children were based on the stage of HIV infection and calculated using data obtained from a London hospital between 1986 and 1996. These were combined with estimates of the health benefits and costs of antenatal screening so that the cost effectiveness of universal, voluntary antenatal screening for HIV infection in England could be estimated. Main outcome measures: Lifetime, direct costs of medical care of childhood HIV infection; life years gained as a result of the screening programme; net cost per life year gained for different pretest counselling costs; and different prevalence rates of pregnant women who were unaware that they were HIV positive. Results: Estimated direct lifetime medical and social care costs of childhood HIV infection were £178 300 using a 5% discount rate for time preference (1995-6 prices). In high prevalence areas screening pregnant women for HIV is estimated to be a cost effective intervention with a net cost of less than £4000 for each life year gained. For areas with comparatively low prevalence rates, cost effectiveness could be less than £20 000 per life year gained, depending on the number of pregnant women who are unaware that they are infected and local screening costs Conclusions: Our results confirm recent recommendations that universal, voluntary antenatal HIV screening should be implemented in the London area. Serious consideration of the policy should be given for other areas in England depending on local prevalence and screening costs.

Background The CD4 count is a dominant prognostic and predictive factor in HIV infection. This study assessed the utility of the total lymphocyte count (TLC) in place of the CD4 count to predict the development of AIDS defining opportunistic infections (ADOI). Methods The Chelsea and Westminster cohort was used to identify those people with a first episode of an ADOI. Corresponding CD4 and TLCs were recorded before diagnosis or at the time of first prescribing prophylaxis; patients without an AIDS defining opportunistic infection were defined as being at “risk” and receiver operating characteristic (ROC) curves were used to display the results of sensitivity and the false positive error rate of total lymphocyte and CD4 count groups. Results A significant linear correlation was seen between the log10 CD4 count and log10 TLC (Pearson’s correlation coefficient = 0.70, p Conclusions The TLC is minimally less reliable than the CD4 count as a predictor of ADOIs. In the absence of expensive equipment for CD4 measurement, the TLC is a useful test.

Purpose of the study : Previous investigation into antiretroviral (ARV) therapy switches in our HIV cohort suggested an annual switch rate of 20% in 2006 with 60% of switches being secondary to toxicity [1]. The purpose of this study was to investigate whether this switch rate has changed in recent years, determine reasons why patients change regimens, and identify which ARVs are most likely to be switched for toxicity concerns. Methods : The electronic patient database was reviewed to identify all patients within our HIV cohort who switched ARV therapy between 1st December 2009 and 31st May 2011. Details of which ARVs were switched and the reasons why were recorded. Any switches due to toxicity were investigated further to identify the actual or perceived adverse effect. Summary of results : Nine hundred and twenty-three regimens were switched over 18 months affecting 12% (n=722) of patients on treatment during this time. The most common reason for switching medication was due to toxicity, occurring in 452 (49%) cases. Other reasons included simplification (15%), clinical trials (8%), virological failure (8%) and drug interactions (4%). The remaining 16% switched for various reasons including pregnancy and co-morbidities. Of 452 switches for toxicity (or perceived toxicity), 122 (27%) were due to CNS side effects (89 out of a total of 122 were related to efavirenz), 64 (14%) gastrointestinal disturbances (38/64 related to protease inhibitors), 54 (12%) actual/perceived cardiovascular risk (21/54 related to abacavir and 21/54 related to saquinavir), 54 (12%) hepatotoxicity (21/54 related to atazanavir and 14/54 related to efavirenz), 42 (9%) metabolic concerns (24/42 related to protease inhibitors) and 38 (8%) renal toxicity (28/38 related to tenofovir). Other toxicities accounted for 78 (18%) switches. An observed toxicity switch rate (OTSR) per 1000 patient years (95 % CI) was calculated for each ARV. Conclusions: 12% of patients switched therapy in 18 months, predicting an annual switch rate of 8%. Toxicity remained an important reason for switching. Saquinavir and lopinavir have a significantly higher OTSR than other PIs as does zidovudine compared with other NRTIs. Nevirapine has a significantly lower OTSR than other NNRTIs. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Boyle A et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18121 http://www.jiasociety.org/index.php/jias/article/view/18121 | http://dx.doi.org/10.7448/IAS.15.6.18121

With the patent on efavirenz due to expire a potential cost-saving strategy is to switch HIV-infected patients who are stable on Atripla ® (tenofovir, emtricitabine & efavirenz) to a regimen of 2 pills once a day of generic efavirenz and co-formulated tenofovir & emtricitabine. We assessed patients' willingness to switch and whether it would be perceived to affect their adherence to their antiretroviral (ARV) regimen and quality of life (QOL). Consecutive patients who had been prescribed Atripla ® for at least 3 months were asked to anonymously complete a questionnaire detailing the number of pills they took and how many times a day they took them. They were asked about their willingness to switch for cost-saving reasons and whether they perceived their adherence and QOL would change if they were to switch to 2 pills once a day. The questions were assessed using visual analogue scales with values from 0 to 10. Univariate and multivariable logistic regression models were employed to determine statistical difference. 143 patients completed questionnaires, mean age was 42.3 years and 121 (85%) were male. 57 (40%) were taking other regular medicines and 125 (88%) took their pills once a day. Patients' willingness to switch scored a median of 2 (0=not willing at all, 5=neutral, 10=very willing). Perceived change in adherence and QOL both scored a median of 5 (0=considerably worse, 5=stay the same, 10=better). No significant associations were found between patients' willingness to switch and age, gender, in those taking other regular medicines and in those taking their pills twice or more times a day. In those taking other regular medicines an increased willingness to switch was associated with increasing number of pills taken daily (p=0.037). Willingness to switch was significantly less likely in those who perceived poorer adherence (RR 0.20, p

This is an electronic version of an article published in AIDS Care. 2007 Sep;19(8):955-65. AIDS Care is available online at informaworldTM, To establish the prevalence of sexual dysfunction amongst HIV-positive men and to determine the factors associated with dysfunction we conducted a cross-sectional study in seven European HIV treatment centres. Data on medical history, antiretroviral treatment and laboratory results were collected by interview and case record review. Sexual function was evaluated by the participant self-completion of a questionnaire based on the International Index of Erectile Function (IIEF) 711/929. Seventy-seven percent of participants returned the questionnaire. Data from 668 (72%) respondents were included. Thirty-three percent (95%CI: 29.4-36.5%) had moderate/severe erectile dysfunction (EDF) and 24% (95%CI: 20.9-27.3%) had moderate to severe impairment of sexual desire. Variables significantly associated with EDF in multivariable analysis were older age (greater than 40 years), heterosexual status, non-alcohol drinking status, depression, antidepressants, psychotropic medications and duration of ARV therapy. Low sexual desire (LSD) was associated with older age (greater than 40 years), depression and black African ethnicity. We establish that EDF and LSD are common in both ARV naïve and ARV experienced, HIV-positive individuals. Erectile dysfunction was associated with long duration of ARV treatment, with a significantly increased risk of dysfunction in the quartile with the longest period of exposure. No significant association was seen with specific classes of anti-retrovirals. Older age, and depression were the variables most consistently associated with both EDF and LSD.

Summary Immunosuppression induced by the human immunodeficiency virus (HIV-1) increases the risk of death. We measured the influence of immunological and virological factors and the type of highly active anti-retroviral therapy (HAART) on this risk. Adaptive (lymphocyte) and innate (natural killer) immune correlates and maximum HIV viral loads were assessed for association with mortality using univariate and multivariate analyses. The protective effect of HAART regimens, containing protease inhibitors (PI) and/or non-nucleoside reverse transcriptase inhibitors (NNRTI) on mortality were also examined in a prospectively recorded cohort of 9621 HIV-infected individuals. From this entire cohort, 5873 HIV infected individuals (61%) have been followed-up in the HAART era and of these 499 (8·5%) have died. In multivariate analyses, CD4 counts below the 50th centile and CD8 and CD19 counts below the 25th centile were significantly associated with mortality, as was increased age (P

To compare the immunological response to highly active antiretroviral therapy (HAART) in treatment-naive patients with a baseline CD4 count of200 cells/mm(3).We identified treatment-naive human immunodeficiency virus (HIV-1)-infected individuals who had commenced HAART since 1996 and who had a starting CD4 count of200 cells/mm(3). Immunological success was defined as achieving a CD4 count of200 cells/mm(3) and treatments were compared using univariate and multivariate Cox's proportional hazards models in order to establish whether protease inhibitor (PI)-based regimens were significantly different to regimens based on non-nucleoside reverse transcriptase inhibitors (NNRTIs). Both regimens utilize a nucleoside analogue (NA) backbone.A total of 599 patients were identified. When the variables were entered into a multivariate analysis, no significant differences between HAART regimens were found. We showed that compared with efavirenz regimens a two NA plus one PI regimen was not significantly less likely to achieve immunological success (adjusted HR: 0.65, 95% CI 0.41-1.03, P=0.07). Two NA and boosted PI (adjusted HR: 1.33, 95% CI 0.81 to 2.16) or two NA and nevirapine (adjusted HR: 0.93, 95% CI 0.67-1.29) regimens were also not significantly different from efavirenz-based regimens, based on the endpoint of immunological success.PI-, boosted PI- and NNRTI-based HAART regimens are not significantly different in achieving increased CD4 counts in individuals who commence therapy with a low CD4 count.

Background Research is an increasingly important aspect of higher medical training for many doctors. Studies investigating sources of stress, isolation, and workplace bullying have not previously sought information in this setting. Methods An internet based questionnaire survey of doctors undertaking research (n = 259) was conducted to examine stressors and levels of job satisfaction in this potentially vulnerable group. In order to assess overall levels of satisfaction, we asked whether doctors would recommend their research post to a colleague. Results There was a statistically significant association between those who would not recommend their post to a colleague and those who had difficulties in arranging funding and in writing up (p Conclusions Stress and bullying are common in doctors undertaking research. These findings have important implications for medical training and for doctors choosing research projects. Setting up systems of support may have important benefits.

Background Lactic acidosis is a life-threatening event during antiretroviral therapy (ART). Hyperlactataemia may be a prelude to acidosis. Our database study suggested that female gender, intercurrent illness and didanosine (ddI)-based regimens may increase risk of lactic acidosis. The aim of this matched case–control study was to identify risk factors for hyperlactataemia requiring screening. Methods Cases were defined as patients with two consecutive lactate samples ≥3.5 mmol/L taken more than 1 week apart. Cases were matched to two controls on gender, use of ddI and total duration of therapy using a 6-month window on either side. Controls never had raised lactate >2.5 mmol/L. A conditional logistic regression analysis using the PHREG procedure in SAS (SAS Institute Inc, Cary, NC) was performed with a discreet logistic model stratified by matching variables. Results Twenty-one cases were matched to 42 controls. In the univariate model, current use of stavudine (d4T), total cholesterol >5.3 mmol/L and glucose levels ≥5.2 mmol/L gave increased likelihood of persistent hyperlactataemia. The multivariate model showed current use of d4T to be a significant independent predictor of persistent hyperlactataemia. Conclusions The results of this case–control study indicate that, when controlling for ddI use, d4T use is an additional risk factor for hyperlactataemia.

Background: The mechanisms by which dyslipidemia and lipoatrophy develop during antiretroviral therapy are not clear. No treatment of lipoatrophy is currently established. Methods: This was an open-label randomized study of HIV-positive individuals on a first-line therapy containing stavudine (d4T) with either a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) and with hypercholesterolemia (defined as total cholesterol >5.2 mmol/L or >180 mg/dL) and/or lipoatrophy and with a viral load of

Background Few UK studies have systematically investigated which antiretroviral therapy (ART) combinations HIV-infected people are commenced on, when they start and reasons for stopping or changing their regimens. Objective To describe when HIV-infected ART-naive patients started first-, second- or third-line triple ART, classes of drugs prescribed and whether stopping ART was associated with virological, immunological or clinical indicators of treatment failure. Design A multicentre prospective open cohort study, employing the National Prospective Monitoring System on the use, cost and outcome of HIV service provision in UK hospitals-HIV Health-economics Collaboration (NPMS-HHC). Setting Five hundred and eighty-five ART-naive patients seen in one London and two non-London HIV clinics between 1 January 1998 and 31 December 1999. Results Of 4044 HIV-infected individuals seen, 585 (15%) were ART naive. Median time interval (interquartile range, IQR) between HIV diagnosis and starting triple ART was 800 (63–2094) days. Median CD4 count when first diagnosed with HIV infection was 278 (IQR 127–481) cells/µL which dropped to 190 (IQR 86–297) cells/µL when starting triple ART. Of these 585 patients, 162 started second-line and 46 third-line ART during the study period. Of those patients who stopped ART, 51% did not have evidence of virological, immunological or clinical indicators of therapy failure. Conclusions Reasons for the delay between diagnosis of HIV infection and starting ART are varied. The large proportion of individuals who stopped ART for reasons other than virological, immunological or clinical indicators of therapy failure, are most likely due to drug-associated toxicity. Both of these findings need to be elucidated in greater detail through prospective studies.

Changes in levels of triglycerides and cholesterol during antiretroviral therapy raise concerns regarding an increased future risk of atherogenic disease and may precede the appearance of fat redistribution. Hypotheses regarding the impact of nucleoside analogues on adipocytes provide a possible explanation for metabolic and clinical fat disturbances. It is unclear whether the choice of nucleoside analogue combination or coadministration of nonnucleoside agents influences change in lipids. We performed a cross-sectional analysis of 135 persons receiving their first nucleoside analogue plus nonnucleoside-based combination antiretroviral regimen for at least 1 month and for whom cholesterol and triglyceride values were available on therapy. Univariate and multivariate regression models were used to explore the relation between cholesterol and triglycerides, as continuous variables with other variables. Both significant and nonsignificant variables from univariate analyses were evaluated in multivariate models to limit possible confounders. No association with drug choice was observed, either when comparing thymidine analogues (stavudine or zidovudine), all nucleoside analogue combinations or choice of either efavirenz or nevirapine as nonnucleoside. Age and triglyceride levels were found in a multivariate analysis to be associated with higher cholesterol. Only higher cholesterol was associated with higher triglyceride levels. In conclusion, no differences were observed between choice of drug or combination on cholesterol or triglyceride values during therapy. Older individuals may be more likely to have elevated cholesterol values.

To investigate the relationship between changing morbidity patterns, the use of hospital services by HIV-infected patients and the uptake of antiretroviral therapy (ART) in England.Prospective serial cross-sectional analyses based on data collected through the National Prospective Monitoring System (NPMS), a multi-centre prospective monitoring system.HIV-infected patients seen in 10 clinics, five London and five non-London, during the three semesters, 1 January 1996 to 30 June 1997.The mean use of hospital services per patient-year, mean new HIV-related opportunistic illnesses per 1000 patient-years and percentage uptake of ART.The use of inpatient services changed particularly among AIDS patients. The mean number of inpatient days for AIDS patients decreased from 19.7 [95% confidence interval (CI) 13.7-25.7] in 1996 to 11.2 (95% CI 6.1-15.6) per patient-year in 1997. Concurrently the number of new AIDS-defining events decreased significantly from 567 (95% CI 529-607) to 203 (95% CI 183-225) per 1000 patient-years. The overall uptake of ART increased significantly from 33% (95% CI 31-35%) to 50% (95% CI 48-52%), and a switch from mono or dual to triple therapy or quadruple or more therapy was observed. However, by mid-1997 only 29% (95% CI 26-32%) of asymptomatic patients and 51% (95% CI 49-54%) of patients with symptomatic non-AIDS were on ART, compared with 69% (95% CI 66-71%) of AIDS patients.The observed reduction in new AIDS-defining events has led to a reduction in the need for inpatient hospital care and has been associated with an increased uptake of ART, including a switch to triple therapy. All of these factors are likely to have contributed to the observed reduction in mortality among English AIDS patients. As the overall uptake of ART remained relatively low in English centres further improvements can be anticipated. However, the medium to long-term effects of these treatment regimens will need to be closely monitored.

To test when patients presented with fatigue whether their beliefs about its cause was related to their frequency of attending; and to measure the association between their fatigue and psychological symptoms and their frequency of attendance during the study year.A cohort study.Primary health care.Patients presenting with fatigue as their main symptom.A fatigue questionnaire, the general health questionnaire (GHQ), an attribution scale, and measurement of consulting frequency during the 6 months before and after the patient presented.Patients who believed their fatigue was due to a physical or costly physical cause consult for any reason significantly more frequently than patients who reported that psychological as well as physical problems might have caused their fatigue. Patients' psychological distress measured with the GHQ was more closely associated with frequent attendance than their level of fatigue was.When patients present with fatigue it is important to inquire about their beliefs and psychological symptoms; these factors may be more important than the fatigue itself in explaining their help-seeking behaviour.

Traditionally an HIV viral load of over 1000 copies/ml was presumed necessary for genotypic resistance testing. We performed a retrospective analysis to assess rates of viral amplification on viral loads between 50 and 1000 copies/ml. Amplification was significantly more likely for 200-1000 copies/ml than 50-200 copies/ml; most samples amplified successfully, supporting the use of genotyping for low-level viraemia.

Stromelysin is a member of the family of metalloproteinases that degrade extracellular matrix. In situ hybridisation and histopathological studies suggest that stromelysin activity may be important in the connective tissue remodelling processes associated with atherogenesis and plaque rupture. Single strand conformation polymorphism analysis identified a common polymorphism in the stromelysin gene promoter located 1171 bp upstream from the start of transcription in which one allele has a run of six adenosines (6A) and another has five adenosines (5A). 72 men with coronary heart disease, were genotyped. They were participants in the St Thomas' Atherosclerosis Regression Study who were randomised to receive usual care (UC), dietary intervention (D), or diet plus cholestyramine (DC), with angiography at baseline and at 39 months. In these patients the frequency of the 5A allele was 0.49 (95% CI from 0.41 to 0.57) and was not significantly different from that in a sample of 354 healthy UK men. In the UC group, patients who were homozygous for the 6A allele showed greater progression of angiographic disease than those with other genotypes: the minimum absolute width of coronary segments decreased by 0.04 (SEM 0.10) mm for 5A5A, 0.20 (0.07) mm for 5A6A, and 0.67 (0.19) mm for 6A6A (P < 0.01). The findings were similar but slightly less significant for the change in mean absolute width of coronary segments (P < 0.05). No significant associations were seen in patients in the D or DC groups. In data pooled from the three treatment groups, the 6A6A genotype was significantly associated with greater progression of coronary atherosclerosis than other genotypes in patients with baseline percentage diameter stenosis less than 20% (P < 0.05), but not in those with baseline percentage diameter stenosis greater than or equal to 20%. These results provide the first evidence of a link between genetic variation in stromelysin and progression of coronary atherosclerosis and support the hypothesis that connective tissue remodeling mediated by metalloproteinases contribute to the pathogenesis of atherosclerosis.

Subjects of reproductive age at risk of having an affected child with a severe single gene disorder such as Duchenne muscular dystrophy (DMD) or cystic fibrosis (CF) were surveyed to ascertain: their views on genetic counselling and antenatal testing; their knowledge of their risk of having an affected child; and their psychological wellbeing. Questionnaires were posted to 209 individuals at 130 addresses; a 65% response rate was achieved. The majority of those surveyed were under 40 years of age (91%), half of them had received genetic counselling only once and for 47% the first encounter was after the diagnosis of their affected child. Most patients expressed their intention to use prenatal testing. However, less than 50% of those counselled knew their risk of having an affected child. Knowledge of risk was associated with the type of disease in the family (p < 0.001) (inheritance of DMD was poorly understood by relevant subjects) and was positively associated with the participant's level of education (p < 0.05). We did not detect a significant association between the number of intended children and the risk of having an affected child. In terms of family relations, genetic counselling appears to be beneficial for the nuclear family, the couple and their children, but some counselees reported a deterioration in relations with other relatives. The results indicate that couples at risk of having a child with a severe genetic disorder value the counselling provided, but many of them do not remember important facts in relation to their risk status.

Methods Prospective, cross-sectional, single-centre study of individuals stable for >6 months on ABCor TDF-based regimens (naive to TDF and ABC respectively) and

Methods Prospective, cross-sectional, single-centre study of patients stable for >6 months on ABCor TDF-based therapy (naive to TDF and ABC, respectively) and