Mortality and AIDS-defining events among young people following transition from paediatric to adult HIV care in the UK.

OBJECTIVES: To investigate risk of AIDS and mortality after transition from paediatric to adult care in a UK cohort of young people with perinatally acquired HIV. METHODS: Records of people aged ≥ 13 years on 31 December 2015 in the UK paediatric HIV cohort (Collaborative HIV Paediatric Study) were linked to those of adults in the UK Collaborative HIV Cohort (CHIC) cohort. We calculated time from transition to a new AIDS event/death, with follow-up censored at the last visit or 31 December 2015, whichever was the earliest. Cumulative incidence of and risk factors for AIDS/mortality were assessed using Kaplan-Meier and Cox regression. RESULTS: At the final paediatric visit, the 474 participants [51% female, 80% black, 60% born outside the UK, median (interquartile range) age at antiretroviral therapy (ART) initiation = 9 (5-13) years] had a median age of 18 (17-19) years and CD4 count of 471 (280-663) cell/µL; 89% were prescribed ART and 60% overall had a viral load ≤ 400 copies/mL. Over median follow-up in adult care of 3 (2-6) years, 35 (8%) experienced a new AIDS event (n = 25) or death (n = 14) (incidence = 1.8/100 person-years). In multivariable analyses, lower CD4 count at the last paediatric visit [adjusted hazard ratio = 0.8 (95% confidence interval: 0.7-1.0)/100 cells/µL increment] and AIDS diagnosis in paediatric care [2.7 (1.4-5.5)] were associated with a new AIDS event/mortality in adult care. CONCLUSIONS: Young people with perinatally acquired HIV transitioning to adult care with markers of disease progression in paediatric care experienced poorer outcomes in adult care. Increased investment in multidisciplinary specialized services is required to support this population at high risk of morbidity and mortality.

Investigation of the efficacy of the short regimen for rifampicin-resistant TB from the STREAM trial.

BACKGROUND: The STREAM trial demonstrated that a 9-11-month "short" regimen had non-inferior efficacy and comparable safety to a 20+ month "long" regimen for the treatment of rifampicin-resistant tuberculosis. Imbalance in the components of the composite primary outcome merited further investigation. METHODS: Firstly, the STREAM primary outcomes were mapped to alternatives in current use, including WHO programmatic outcome definitions and other recently proposed modifications for programmatic or research purposes. Secondly, the outcomes were re-classified according to the likelihood that it was a Failure or Relapse (FoR) event on a 5-point Likert scale: Definite, Probable, Possible, Unlikely, and Highly Unlikely. Sensitivity analyses were employed to explore the impact of informative censoring. The protocol-defined modified intention-to-treat (MITT) analysis population was used for all analyses. RESULTS: Cure on the short regimen ranged from 75.1 to 84.2% across five alternative outcomes. However, between-regimens results did not exceed 1.3% in favor of the long regimen (95% CI upper bound 10.1%), similar to the primary efficacy results from the trial. Considering only Definite or Probable FoR events, there was weak evidence of a higher risk of FoR in the short regimen, HR 2.19 (95%CI 0.90, 5.35), p = 0.076; considering only Definite FoR events, the evidence was stronger, HR 3.53 (95%CI 1.05, 11.87), p = 0.030. Cumulative number of grade 3-4 AEs was the strongest predictor of censoring. Considering a larger effect of informative censoring attenuated treatment differences, although 95% CI were very wide. CONCLUSION: Five alternative outcome definitions gave similar overall results. The risk of failure or relapse (FoR) may be higher in the short regimen than in the long regimen, highlighting the importance of how loss to follow-up and other censoring is accounted for in analyses. The outcome of time to FoR should be considered as a primary outcome for future drug-sensitive and drug-resistant TB treatment trials, provided sensitivity analyses exploring the impact of departures from independent censoring are also included.

Mortality from abdominal aortic aneurysm: trends in European Union 15+ countries from 1990 to 2017.

BACKGROUND: This observational study assessed trends in abdominal aortic aneurysm (AAA) death rates in European Union (EU) 15+ countries for the years 1990 to 2017. METHODS: Age-standardized death rates (ASDRs) were extracted from the Global Burden of Disease Study Global Health Data Exchange. Trends were analysed using joinpoint regression analysis. RESULTS: Between 1990 and 2017, ASDRs from AAA decreased in all 19 EU15+ countries for women, and in 18 of 19 countries for men. Increasing AAA mortality was observed only for men in Greece (+5·3 per cent). The largest relative decreases in ASDR between 1990 and 2017 were observed in Australia (men -65·6 per cent, women -50·4 per cent) and Canada (men -60·8 per cent, women -48·6 per cent). Over the 28-year interval, the smallest decreases in ASDR for women were noted in Greece (-2·3 per cent) and in Italy (-2·5 per cent). In 2017, the highest mortality rates were observed in the UK for both men and women (7·5 per 100 000 and 3·7 per 100 000 respectively). The lowest ASDR was observed in Portugal for men (2·8 per 100 000) and in Spain for women (1·0 per 100 000). ASDRs for AAA in 2017 were higher for men than women in all 19 EU15+ countries. The most recent trends demonstrated increasing AAA ASDRs in 14 of 19 countries for both sexes; the increases were relatively small compared with the improvements in the preceding years. CONCLUSION: This observational study identified decreasing mortality from AAA across EU15+ countries since 1990. The most recent trends demonstrated relatively small increases in AAA mortality across the majority of EU15+ countries since 2012.

ANTECEDENTES: Este estudio observacional evalúa las tendencias en las tasas de mortalidad del aneurisma de aorta abdominal (abdominal aortic aneurysm, AAA) en los 19 países integrantes del acrónimo conocido como EU15+ en los aóos 1990-2017. MÉTODOS: Se obtuvieron las tasas de mortalidad estandarizadas por la edad del Global Burden of Disease Study Global Health Data Exchange. Las tendencias se analizaron utilizando el análisis de regresión por puntos de inflexión (joinpoint). RESULTADOS: Entre 1990 y 2017, las tasas de muerte estandarizadas por edad (age-standardized death rates, ASDR) del AAA disminuyeron en todos los 19 EU15+ países para las mujeres, y en 18 de los 19 países para los varones. Solamente se observó un incremento de la mortalidad del AAA para los varones en Grecia (+5,3%). El mayor descenso relativo de ASDR entre 1990-2017 se observó en Australia (varones -65,6%, mujeres -50,4%) y Canadá (varones -60,8%, mujeres -48,6%). A lo largo del periodo de 28 aóos, en el caso de las mujeres, los menores descensos en ASDR se observaron en Grecia (-2,3%) y en Italia (-2,5%). En 2017, las tasas de mortalidad más elevadas se observaron en el Reino Unido tanto para varones como para mujeres (7,5/100.000 y 3,7/100.000 para varones y mujeres, respectivamente). La ASDR más baja se observó en Portugal para varones (2,8/100.000) y Espaóa para mujeres (1,0/100.000). Las ASDRs para AAA en 2017 fueron más altas para varones que para mujeres en todos los 19 países EU15+. Las tendencias más recientes demostraron aumentos de las ASDRs por AAA en 14 de 19 países para varones y mujeres; los aumentos fueron relativamente pequeóos cuando se compararon con las mejorías observadas dentro de los aóos precedentes. CONCLUSIÓN: En este estudio observacional de los países EU15+, se ha identificado una disminución en la mortalidad de los AAA entre los países integrantes de EU15+ desde 1990. Las tendencias más recientes demuestran aumentos relativamente pequeóos de la mortalidad del AAA en la mayoría de los países EU15+ desde 2012.

Cast aluminium single crystals cross the threshold from bulk to size-dependent stochastic plasticity.

Metals are known to exhibit mechanical behaviour at the nanoscale different to bulk samples. This transition typically initiates at the micrometre scale, yet existing techniques to produce micrometre-sized samples often introduce artefacts that can influence deformation mechanisms. Here, we demonstrate the casting of micrometre-scale aluminium single-crystal wires by infiltration of a salt mould. Samples have millimetre lengths, smooth surfaces, a range of crystallographic orientations, and a diameter D as small as 6 µm. The wires deform in bursts, at a stress that increases with decreasing D. Bursts greater than 200 nm account for roughly 50% of wire deformation and have exponentially distributed intensities. Dislocation dynamics simulations show that single-arm sources that produce large displacement bursts halted by stochastic cross-slip and lock formation explain microcast wire behaviour. This microcasting technique may be extended to several other metals or alloys and offers the possibility of exploring mechanical behaviour spanning the micrometre scale.

Holocene changes in the trophic ecology of an apex marine predator in the South Atlantic Ocean.

Predators may modify their diets as a result of both anthropogenic and natural environmental changes. Stable isotope ratios of nitrogen and carbon in bone collagen have been used to reconstruct the foraging ecology of South American fur seals (Arctocephalus australis) in the southwestern South Atlantic Ocean since the Middle Holocene, a region inhabited by hunter-gatherers by millennia and modified by two centuries of whaling, sealing and fishing. Results suggest that the isotopic niche of fur seals from Patagonia has not changed over the last two millennia (average for the period: δ13C2200-0BP = -13.4 ± 0.5‰, δ15N2200-0BP = 20.6 ± 1.1‰). Conversely, Middle Holocene fur seals fed more pelagically than their modern conspecifics in the Río de la Plata region (δ13C7000BP = -15.9 ± 0.6‰ vs. δ13CPRESENT = -13.5 ± 0.8‰) and Tierra del Fuego (δ13C6400-4300BP = -15.4 ± 0.5‰ vs. δ13CPRESENT = -13.2 ± 0.7‰). In the latter region, Middle Holocene fur seals also fed at a higher trophic level than their modern counterparts (δ15N6400-4300BP = 20.5 ± 0.5‰ vs. δ15NPRESENT = 19.0 ± 1.6‰). Nevertheless, a major dietary shift was observed in fur seals from Tierra del Fuego during the nineteenth century (δ13C100BP = -17.2 ± 0.3‰, δ15N100BP = 18.6 ± 0.7‰), when marine primary productivity plummeted and the fur seal population was decimated by sealing. Disentangling the relative roles of natural and anthropogenic factors in explaining this dietary shift is difficult, but certainly the trophic position of fur seals has changed through the Holocene in some South Atlantic regions.

Pathology in skeletons of Peale's dolphin Lagenorhynchus australis from southern South America.

Peale's dolphin Lagenorhynchus australis is frequently seen off the coast of southern South America, where it feeds among coastal kelp beds and occasionally strands. We searched for macroscopic evidence of skeletal lesions in 78 specimens of Peale's dolphin from 2 museum collections, which contain almost all of the species' skeletons known in collections worldwide. Thirty-two specimens (41%) had some type of osteological abnormalities. In 21 cases (66%), congenital deformations were the most predominant abnormality found. Acquired lesions included (1) induced trauma: abnormal curvature (n=5 specimens) and fractures (n=2); (2) infectious diseases: spondylo-osteomyelitis (n=3); and (3) degenerative diseases: exostoses (n=8) and spondylosis deformans (n=4). It is noteworthy that all of these animals died incidentally in gillnet entanglement and were presumably healthy at the time of death. The effect that different osseous lesions may have on an animal's quality of life may depend on the area of the spine affected and the number of vertebrae involved.

Phenotypic and genotypic analyses to guide selection of reverse transcriptase inhibitors in second-line HIV therapy following extended virological failure in Uganda.

OBJECTIVES: We investigated phenotypic and genotypic resistance after 2 years of first-line therapy with two HIV treatment regimens in the absence of virological monitoring. METHODS: NORA [Nevirapine OR Abacavir study, a sub-study of the Development of AntiRetroviral Therapy in Africa (DART) trial] randomized 600 symptomatic HIV-infected Ugandan adults (CD4 cell count <200 cells/mm(3)) to receive zidovudine/lamivudine plus abacavir (cABC arm) or nevirapine (cNVP arm). All virological tests were performed retrospectively, including resistance tests on week 96 plasma samples with HIV RNA levels ≥1000 copies/mL. Phenotypic resistance was expressed as fold-change in IC(50) (FC) relative to wild-type virus. RESULTS: HIV-1 RNA viral load ≥1000 copies/mL at week 96 was seen in 58/204 (28.4%) cABC participants and 21/159 (13.2%) cNVP participants. Resistance results were available in 35 cABC and 17 cNVP participants; 31 (89%) cABC and 16 (94%) cNVP isolates had a week 96 FC below the biological cut-off for tenofovir (2.2). In the cNVP arm, 16/17 participants had resistance mutations synonymous with high-level resistance to nevirapine and efavirenz; FC values for etravirine were above the biological cut-off in 9 (53%) isolates. In multivariate regression models, K65R, Y115F and the presence of thymidine analogue-associated mutations were associated with increased susceptibility to etravirine in the cABC arm. CONCLUSIONS: Our data support the use of tenofovir following failure of a first-line zidovudine-containing regimen and shed further light on non-nucleoside reverse transcriptase inhibitor hypersusceptibility.

Digital papillary adenocarcinoma: An important differential diagnosis for digital soft tissue masses.

Digital papillary adenocarcinoma (DPAC) is a rare, aggressive cancer with significant metastatic potential which arises from digital sweat glands. We present a case of a DPAC managed with surgical excision and reconstruction with a reversed homodigital island flap. Level of evidence: V.

Heavy metals and essential elements in Commerson's dolphins (Cephalorhynchus c. commersonii) from the southwestern South Atlantic Ocean.

A survey of the elemental contents of K, Mg, Mn, Na, Cl, Br, Cs, Co, Rb, Fe, Zn, Al, Ti, V, As, Ag, Au and Cd in liver, kidney and muscle was performed in specimens of Commerson's dolphins (Cephalorhynchus c. commersonii) from subantarctic waters. The concentrations were determined by Instrumental Neutron Activation Analysis and the specimens derives from animals incidentally caught in artisanal fishing nets. Liver had the highest concentrations of Fe, 897(79) µg g(-1) DW (dry weight) (average; standard deviation in parenthesis), kidney had the highest Cd, 35 (24) µg g(-1) DW; Cl, 9,200 (1,700) µg g(-1) DW; Na, 6,800 (1,100) µg g(-1) DW and Br, 73(12) µg g(-1) DW; and muscle the highest Mg 954 (71) µg g(-1) DW. Potassium and Cs concentrations in muscle and kidney ranged in 12,510-13,020 and 0.230-0.252 µg g(-1) DW, respectively; Zn and Mn concentrations were similar in liver and kidney (117-122.1 and 3.66-16.5 µg g(-1) DW, respectively). Silver was high in liver 5.4(5.0) µg g(-1) DW and kidney 1.2(2.7) µg g(-1) DW. Gold, Rb, Co and As had no differences among tissues. Likewise, as in other odontocete species, the concentrations of essential elements showed little variation between the specimens analyzed, since they are regulated biochemically; however, heavy metals showed high variability. This study constitutes the first large description of the elemental composition in Commerson's dolphins from subantarctic waters of the South Atlantic Ocean.

Outcomes of skin cancer excision in frail patients: A retrospective cohort study.

BACKGROUND: Non-melanoma skin cancer (NMSC) is the most common cancer type and incidence increases with age. As a consequence, an increasing number of frail patients are being referred for consideration of skin cancer surgery. However, some of these patients may not live long enough to experience benefit from surgery, while being at risk of postoperative complications. OBJECTIVES: To investigate the treatment burden of surgical excision of skin cancers in frail individuals. METHODS: We conducted a single-center retrospective cohort study analyzing outcomes of skin cancer excision in frail versus non-frail patients. RESULTS: Eighty-eight patients were included. The complication rate was higher in frail versus non-frail patients: 12 (27.9%) versus 9 (18.8%), with 5 unplanned postoperative hospital attendances leading to 3 hospital admissions in the frail cohort. Nine patients in the frail group (21%) died within 6 months of their procedure versus no deaths in the non-frail group (p < 0.001 Fisher's Exact test), with no deaths attributed to skin cancer. CONCLUSION: Treatment-related complications and mortality are common in frail patients after surgical excision of skin lesions clinically suspicious for skin cancer. Careful consideration should be given, and patients should be adequately counseled about treatment risks and alternative management options, including active surveillance, in particular, if the lesions are expected to remain asymptomatic.

Management of purpura fulminans skin loss at a regional burns centre: Sixteen-year experience.

INTRODUCTION: Purpura fulminans (PF) is a rare syndrome of cutaneous purpura which is the consequence of severe circulatory shock causing intravascular thrombosis, haemorrhagic necrosis, and consequent tissue loss. The aim of this study was to present our 16-year experience of managing PF in a regional burns centre. METHODS: We performed a single-centre retrospective case series of all patients admitted to the St Andrews Burns Centre at Broomfield Hospital, Chelmsford, Essex, UK, between June 2006 and July 2022 with a diagnosis of PF. Data were extracted by retrospectively searching hospital case notes. RESULTS: Thirteen individuals were identified [five children (mean age 5, range 1-14) and eight adults (mean age 39, range 24-54)]. The total body surface area of cutaneous necrosis ranged from 5% to 80%, with a mean of 27.2%. Patients were treated with an established surgical sequence of total wound debridement and immediate coverage with a cadaveric allograft, followed by staged wound autografting. The mean time from disease onset to wound autografting was 37.3 days (range 20-64 days). Eight individuals (61.6%) required major amputation of at least one limb (proximal to the ankle or wrist joint). Only one mortality (of 80% total body surface area skin loss) was observed in the identified cohort. CONCLUSIONS: The large body surface areas often involved in PF cases make management of these wounds well suited for burns centres, wherein established facilities and multidisciplinary teams exist that are familiar with managing large cutaneous burns. We provide a suggested algorithm to aid the management of PF.

A systematic review of observational management of cutaneous basal cell carcinoma.

BACKGROUND: Cutaneous basal cell carcinoma (BCC) is the commonest cancer in the United Kingdom and United States. Surgical excision is the most common treatment. This review summarises all published outcomes of observational/non-interventional management of cutaneous BCC. METHODS: This PRISMA-compliant systematic review searched MEDLINE, EMBASE and CENTRAL databases from inception-June 2021. All studies reporting outcomes of observational management for BCC were included. RESULTS: We identified 2529 titles, from which 4 full-text articles were eligible, reporting on 2298 individuals. Two studies were randomised controlled trials (RCTs) comparing histological clearance rates and adverse events following treatment with an inactive strategy (placebo cream) versus topical 5%-imiquimod (at different frequencies) for 6-12 weeks. Clearance rates ranged from 52-100% for imiquimod and 2-19% for placebo, with more adverse events associated with imiquimod. The other two studies used prospective cohort designs. One study assessed the natural history of BCCs managed expectantly in 39 individuals aged ≥80years. During the 15.8-month follow-up, 46.2% of lesions did not increase in size and 10.3% resolved. The remaining study compared treatment patterns of 1360 patients with non-melanoma skin cancer (NMSC) in individuals with or without limited life-expectancy (LLE). The LLE subgroup had a 5-year mortality rate of 43.3%, with no deaths attributed to NMSC. Only 3.3% of individuals with LLE underwent observational treatment. No study examined quality-of-life or cost-effectiveness. CONCLUSION: There has been limited investigation of observational management of BCC, despite possible advantages of this strategy. Future RCTs should compare quality-of-life outcomes and utility-adjusted survival following interventional or observational management of BCC.

QT prolongation in the STREAM Stage 1 Trial.

BACKGROUND: STREAM (Standardized Treatment Regimen of Anti-TB Drugs for Patients with MDR-TB) Stage 1 demonstrated non-inferior efficacy of a shortened regimen (the Short regimen) for rifampicin-resistant TB (RR-TB) compared to the contemporaneous WHO-recommended regimen. This regimen included moxifloxacin and clofazimine, known to cause QT prolongation, and severe prolongation was more common on the Short regimen. Here we investigate risk factors for QT prolongation with the Short regimen.METHODS: Data from patients prescribed the Short regimen (n = 282) were analysed to identify risk factors for severe QT prolongation (QT/QTcF ≥500 ms or ≥60 ms increase in QTcF from baseline).RESULTS: Of the 282 patients on the Short regimen, 94 (33.3%) developed severe QT prolongation: 31 QT/QTcF ≥500 ms; 92 experienced ≥60 ms QTcF increase from baseline. The median time to QT/QTcF ≥500 ms was 20 weeks (IQR 8-28), and the time to ≥60 ms increase from baseline was 18 weeks (IQR 8-28). Prolongation ≥500 ms was most frequent in patients from Mongolia (10/22, 45.5%) compared with 3.5-11.9% at other sites, P < 0.001. Higher baseline QTcF increased risk of prolongation to ≥500 ms (QTcF ≥400 ms: OR 5.99, 95% CI 2.04-17.62).CONCLUSION: One third of patients on the Short regimen developed severe QT prolongation. QT/QTcF ≥500 ms was more common in patients from Mongolia and in those with a higher baseline QTcF, which may have implications for implementation of treatment.

ECG monitoring in STREAM Stage 1: can we identify those at increased risk of QT prolongation?

BACKGROUND: STREAM (Standardised Treatment Regimen of Anti-tuberculosis Drugs for Patients with Multidrug-resistant Tuberculosis) Stage 1 was a randomised trial of a Short (9-month) regimen for rifampicin-resistant TB (RR-TB). QT or QTcF prolongation ≥500 ms occurred in 31 (11%) of 282 Short regimen participants. The frequent ECG monitoring employed might be challenging for treatment programmes. This analysis aimed to determine whether those at higher risk of severe QT prolongation could be identified early for more targeted monitoring.METHODS: Data from the first month of treatment were used to investigate whether participants were at risk of developing QT/QTcF ≥500 ms. QTcF increases from baseline at different time points were examined. Absolute QTcF measurements were categorised in 5 ms increments at each time-point. The most discriminating time points and QTcF cut-offs were combined to optimise sensitivity and specificity.RESULTS: Absolute QTcF values were more discriminating than magnitude of increase from baseline. More participants who developed QT/QTcF ≥500 ms had a QTcF of respectively ≥425 ms and ≥430 ms at 4 h and Week 3 (P < 0.05) than those who did not. By combining QTcF values ≥425 ms at 4 h and ≥430 ms at Week 3, we identified high-risk participants with 97% sensitivity and 99% negative predictive value.CONCLUSION: Reduced ECG monitoring may be possible for many Short regimen participants.

Trends in mortality from aortic dissection analyzed from the World Health Organization Mortality Database from 2000 to 2017.

BACKGROUND: We assessed trends in aortic dissection (AD) death rates in 23 countries from 2000 to 2017. METHODS: We extracted AD mortality data for countries with high usability data from the World Health Organization (WHO) Mortality Database and from the Center for Disease Control (CDC) WONDER Database for the United States of America (USA). Age Standardized Death Rates (ASDRs) per 100,000 population were computed. Trends were assessed by locally weighted scatter plot smoother (LOWESS) regression. RESULTS: Between 2000 and 2017, ASDRs from AD decreased in Australia, Belgium, Croatia, Denmark, France, Italy, New Zealand, Norway, Sweden, the United Kingdom, and the USA for both sexes. Increasing AD mortality was observed in Austria, Czech Republic, Germany, Hungary, Israel, and Japan for both sexes. The largest absolute increases in ASDR were in Japan for men (+1.59) and women (+1.11). The largest percentage decreases were in Norway for men (-0.91) and in New Zealand (-0.6) for women. In 2017, the highest mortality rates were in Japan for both sexes (3.22 and 2.09, respectively). The lowest ASDR was in Kyrgyzstan for both sexes (0.16 and 0.10, respectively). ASDRs for AD in 2017 were higher for men than women in all countries included. Spain had the greatest difference between the gender's mortality rates with a 2.71-fold higher mortality average rate in men. CONCLUSION: We identified an overall decrease in AD mortality in most included countries, while an increase was noted in other countries including Israel and Japan.

Failure or relapse predictors for the STREAM Stage 1 short regimen for RR-TB.

BACKGROUND: STREAM (Standardised Treatment Regimens of Anti-tuberculosis drugs for Multidrug-Resistant Tuberculosis) Stage 1 demonstrated non-inferior efficacy of a short regimen for rifampicin-resistant TB (RR-TB) compared to a long regimen as recommended by the WHO. The present paper analyses factors associated with a definite or probable failure or relapse (FoR) event in participants receiving the Short regimen.METHODS: This analysis is restricted to 253 participants allocated to the Short regimen and is based on the protocol-defined modified intention to treat (mITT) population. Multivariable Cox regression models were built using backwards elimination with an exit probability of P = 0.157, equivalent to the Akaike Information Criterion, to identify factors independently associated with a definite or probable FoR event.RESULTS: Four baseline factors were identified as being significantly associated with the risk of definite or probable FoR (male sex, a heavily positive baseline smear grade, HIV co-infection and the presence of costophrenic obliteration). There was evidence of association of culture positivity at Week 8 and FoR in a second model and Week 16 smear positivity, presence of diabetes and of smoking in a third model.CONCLUSION: The factors associated with FoR outcomes identified in this analysis should be considered when determining the optimal shortened treatment regimen.

Residual activity of two HIV antiretroviral regimens prescribed without virological monitoring.

Virological residual activity (VRA) denotes the degree of HIV RNA suppression achieved by antiretroviral therapy in the presence of resistant virus. This concept is particularly important in resource-limited settings, where rapid switching after detection of virological failure may not be feasible. Using data from the NORA trial, we estimated VRA for two regimens-zidovudine-lamivudine-abacavir (ZDV-3TC-ABC) and zidovudine-lamivudine-nevirapine (ZDV-3TC-NVP)-and related this to the phenotypic drug sensitivity of the component drugs in the two regimens. Plasma samples at weeks 0, 48, and 96 were retrospectively assayed for HIV-1 RNA, and genotypic/phenotypic resistance testing was performed if HIV-1 RNA exceeded 1,000 copies/ml. Virological residual activity (VRA) was defined as the difference between log(10)(HIV RNA) at week 48 or 96 and week 0 and related to 50% inhibitory concentration (IC(50)) relative to wild-type virus for ZDV and ABC (fold change [FC]). Twenty-seven samples in the ZDV-3TC-NVP group and 56 in the ZDV-3TC-ABC group contributed to the analysis. Mean VRA was significantly higher in the ZDV-3TC-ABC group than in the ZDV-3TC-NVP at week 48 (1.62 versus 0.90) and week 96 (1.29 versus 0.78). There was a weak and nonsignificant relationship between VRA and ZDV FC, with VRA decreasing by 0.1 log(10) copies/ml per 2-fold increase in ZDV. The association with ABC FC was much stronger, with a marked reduction in VRA occurring at ABC FC values greater than approximately 2. This information should be considered in future treatment guidelines relevant to resource-poor settings.

Hyperlactataemia in HIV-infected subjects initiating antiretroviral therapy in a large randomized study (a substudy of the INITIO trial).

OBJECTIVE: The aim of the study was to evaluate the predictive value of clinical and molecular risk factors, including peripheral blood mononuclear cell (PBMC) mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA), for the development of lactic acidosis (LA) and symptomatic hyperlactataemia (SHL). METHODS: In a substudy of a large multicentre, randomized trial of three antiretroviral regimens, all containing didanosine (ddI) and stavudine (d4T), in antiretroviralnaïve, HIV-1-infected patients, patients with LA/SHL ('cases') were compared with those without LA/SHL in a univariate analysis, with significant parameters analysed in a multivariate model. In a molecular substudy, PBMC mtDNA and mtRNA from cases and matched controls at baseline and time of event were examined. RESULTS: In 911 subjects followed for a median of 192 weeks, 24 cases were identified (14 SHL and 10 LA). In univariate analysis, cases were more likely to be female (P=0.05) and to have a high body mass index (BMI) (P=0.02). In multivariate analyses, only BMI remained an independent predictor of the development of LA/SHL (P=0.03). Between cases and controls there was no significant difference in mtDNA copy number at baseline (389 vs. 411 copies/cell, respectively; P=0.60) or at time of event (329 vs. 474 copies/cell, respectively; P=0.21), in the change in mtDNA copy number from baseline to event (-65 vs. +113 copies/cell, respectively; P=0.12), in mtRNA expression at baseline or time of event, or in the change in mtRNA expression from baseline to event. CONCLUSION: The development of LA/SHL was associated with increased BMI, but PBMC mtDNA and mtRNA did not predict LA/SHL. This demonstrates the ineffectiveness of routine measurement of PBMC mtDNA in patients on ddI and d4T as a means of predicting development of LA/SHL.

Data of the maximum solid solubility limits of binary systems of elements.

This paper gives the available data for the maximum equilibrium solubility limits of each of the first 83 elements (H to Bi) of the periodic table in each of the others. This is expressed in the form of the maximum value of the equilibrium solid solubility for terminal solid solutions, expressed in atomic percentage (at%), occurring at any temperature where the room temperature phase of the pure element acting as the solvent is stable. The values thus represent the compatibility between different elements in the formation of alloys and similar combinations, and will be of use for research into fundamental solid state physics relating to elemental interactions, for the interpretation of phase structures in materials research and for the design of alloys and materials involving elemental mixing of the elements.

The effect of oxygen pickup during selective laser melting on the microstructure and mechanical properties of Ti-6Al-4V lattices.

Additive manufacturing techniques such as Selective Laser Melting (SLM) can produce complex shapes with relatively thin sections and fine detail. However, common materials for the process, such as Ti-6Al-4V, have microstructure and properties that are sensitive to the pickup of interstitial impurities, such as oxygen, which the material will be exposed to during the process. This problem would be especially severe for parts with thin sections, where surface effects can be more significant, and where poor properties may coincide with locally-elevated stress. Here we explore the effects of oxygen level in thin sections with the use of lattice materials (materials which can be considered to consist exclusively of near-surface material). Oxygen levels are artificially raised using repeated melting passes to result in more pickup, leading to significantly reduced ductility and hence reduced strength measured in compression. A ductile to brittle transition in strut failure mechanism is found with increasing number of melting passes, with significant modification in chemistry and crystallographic structure, despite the presence of a similar fine plate-like microstructure throughout.