Submillimetre Common-User Bolometer Array 2 (SCUBA-2) is an innovative 10 000 pixel bolometer camera operating at submillimetre wavelengths on the James Clerk Maxwell Telescope (JCMT). The camera has ...the capability to carry out wide-field surveys to unprecedented depths, addressing key questions relating to the origins of galaxies, stars and planets. With two imaging arrays working simultaneously in the atmospheric windows at 450 and 850 μm, the vast increase in pixel count means that SCUBA-2 maps the sky 100-150 times faster than the previous SCUBA instrument. In this paper, we present an overview of the instrument, discuss the physical characteristics of the superconducting detector arrays, outline the observing modes and data acquisition, and present the early performance figures on the telescope. We also showcase the capabilities of the instrument via some early examples of the science SCUBA-2 that have already been undertaken. In 2012 February, SCUBA-2 began a series of unique legacy surveys for the JCMT community. These surveys will take 2.5 yr and the results are already providing complementary data to the shorter wavelength, shallower, larger area surveys from Herschel. The SCUBA-2 surveys will also provide a wealth of information for further study with new facilities such as ALMA, and future telescopes such as CCAT and SPICA.
Summary From the use of antiretroviral therapy to prevent mother-to-child transmission to the possibility of HIV cure hinted at by the Mississippi baby experience, paediatric HIV infection has been ...pivotal to our understanding of HIV pathogenesis and management. Daily medication and indefinite antiretroviral therapy is recommended for children infected with HIV. Maintenance of life-long adherence is difficult and the incidence of triple-class virological failure after initiation of antiretroviral therapy increases with time. This challenge shows the urgent need to define novel strategies to provide long-term viral suppression that will allow safe interruption of antiretroviral therapy without viral rebound and any associated complications. HIV-infected babies treated within a few days of birth have a unique combination of a very small pool of integrated viruses, a very high proportion of relatively HIV resistant naive T cells, and an unparalleled capacity to regenerate an immune repertoire. These features make this group the optimum model population to investigate the potential efficacy of immune-based therapies. If successful, these investigations could change the way we manage HIV infection.
Summary Background Co-trimoxazole prophylaxis can reduce mortality from untreated HIV infection in Africa; whether benefits occur alongside combination antiretroviral therapy (ART) is unclear. We ...estimated the effect of prophylaxis after ART initiation in adults. Methods Participants in our observational analysis were from the DART randomised trial of management strategies in HIV-infected, symptomatic, previously untreated African adults starting triple-drug ART with CD4 counts lower than 200 cells per μL. Co-trimoxazole prophylaxis was not routinely used or randomly allocated, but was variably prescribed by clinicians. We estimated effects on clinical outcomes, CD4 cell count, and body-mass index (BMI) using marginal structural models to adjust for time-dependent confounding by indication. DART was registered, number ISRCTN13968779. Findings 3179 participants contributed 14 214 years of follow-up (8128 57% person-years on co-trimoxazole). Time-dependent predictors of co-trimoxazole use were current CD4 cell count, haemoglobin concentration, BMI, and previous WHO stage 3 or 4 events on ART. Present prophylaxis significantly reduced mortality (odds ratio 0·65, 95% CI 0·50–0·85; p=0·001). Mortality risk reduction on ART was substantial to 12 weeks (0·41, 0·27–0·65), sustained from 12–72 weeks (0·56, 0·37–0·86), but not evident subsequently (0·96, 0·63–1·45; heterogeneity p=0·02). Variation in mortality reduction was not accounted for by time on co-trimoxazole or current CD4 cell count. Prophylaxis reduced frequency of malaria (0·74, 0·63–0·88; p=0·0005), an effect that was maintained with time, but we observed no effect on new WHO stage 4 events (0·86, 0·69–1·07; p=0·17), CD4 cell count (difference vs non-users, −3 cells per μL −12 to 6; p=0·50), or BMI (difference vs non-users, −0·04 kg/m2 −0·20 to 0·13); p=0·68. Interpretation Our results reinforce WHO guidelines and provide strong motivation for provision of co-trimoxazole prophylaxis for at least 72 weeks for all adults starting combination ART in Africa. Funding UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.
Background. Increasing numbers of children infected perinatally with human immunodeficiency virus (HIV) are surviving to adolescence and transitioning to adult care, yet there are scarce data on ...their clinical status at transfer. Methods. We analyzed prospective cohort data from the UK/Ireland national Collaborative HIV Pediatric Study (CHIPS). Clinical status at last pediatric clinic visit prior to transfer was described. Factors associated with higher CD4 cell count and viral load (VL) suppression<400 c/mL among patients on antiretroviral therapy (ART) at transfer were assessed using linear and logistic regression, respectively. Data were matched with the UK HIV Drug Resistance Database (UKHIVDRB) to assess cumulative resistance profiles at transfer. Results. Of 1,907 children followed in CHIPS from 1996 to November 2014, 644 (34%) transferred to adult care: 53% were female, 62% born outside the UK/Ireland, 75% black African. At last pediatric follow-up, median age was 17.4 years interquartile range 16.5,18.1, 27% had previous AIDS diagnosis, CD4 was 444 cells/mm3 280, 643, 76% were on ART, 13% off-ART, and 11% ART-naive. Among patients on ART, 74% had VL<400 c/mL. In multivariable analysis, higher CD4 at transfer was associated with younger age, higher CD4 at ART initiation and lower VL at transfer (P ≤ .001). Predictors of viral suppression include no AIDS diagnosis and later year of transfer (P ≤ .05). Of 291 patients with resistance data, 82% had resistance to ≥1 drug class, 56% to ≥2 classes and 12% had triple-class resistance. Conclusion. Three-quarters of adolescents were on stable ART at transfer, of whom 74% were virologically suppressed. The prevalence of triple-class resistance was relatively low at 12%.
Summary Background Interim results from the children with HIV early antiretroviral (CHER) trial showed that early antiretroviral therapy (ART) was life-saving for infants infected with HIV. In view ...of the few treatment options and the potential toxicity associated with lifelong ART, in the CHER trial we compared early time-limited ART with deferred ART. Methods CHER was an open-label randomised controlled trial of HIV-infected asymptomatic infants younger than 12 weeks in two South African trial sites with a percentage of CD4-positive T lymphocytes (CD4%) of 25% or higher. 377 infants were randomly allocated to one of three groups: deferred ART (ART-Def), immediate ART for 40 weeks (ART-40W), or immediate ART for 96 weeks (ART-96W), with subsequent treatment interruption. The randomisation schedule was stratified by clinical site with permuted blocks of random sizes to balance the numbers of infants allocated to each group. Criteria for ART initiation in the ART-Def group and re-initiation after interruption in the other groups were CD4% less than 25% in infancy; otherwise, the criteria were CD4% less than 20% or Centers for Disease Control and Prevention severe stage B or stage C disease. Combination therapy of lopinavir–ritonavir, zidovudine, and lamivudine was the first-line treatment regimen at ART initiation and re-initiation. The primary endpoint was time to failure of first-line ART (immunological, clinical, or virological) or death. Comparisons were done by intention-to-treat analysis, with use of time-to-event methods. This trial is registered with ClinicalTrials.gov , number NCT00102960. Findings 377 infants were enrolled, with a median age of 7·4 weeks, CD4% of 35%, and HIV RNA log 5·7 copies per mL. Median follow-up was 4·8 years; 34 infants (9%) were lost to follow-up. Median time to ART initiation in the ART-Def group was 20 weeks (IQR 16–25). Time to restarting of ART after interruption was 33 weeks (26–45) in ART-40W and 70 weeks (35–109) in ART-96W; at the end of the trial, 19% of patients in ART-40W and 32% of patients in ART-96W remained off ART. Proportions of follow-up time spent on ART were 81% in the ART-Def group, 70% in the ART-40W group, and 69% in the ART-96W group. 48 (38%) of 125 children in the ART-Def group, 32 (25%) of 126 in the ART-40W group, and 26 (21%) of 126 in the ART-96W group reached the primary endpoint. The hazard ratio, relative to ART-Def, was 0·59 (95% CI 0·38–0·93, p=0·02) for ART-40W and 0·47 (0·27–0·76, p=0·002) for ART-96W. Three children in ART-Def, three in ART-40W, and one in ART-96W switched to second-line ART. Interpretation Early time-limited ART had better clinical and immunological outcomes than deferred ART, with no evidence of excess disease progression during subsequent treatment interruption and less overall ART exposure than deferred ART. Longer time on primary ART permits longer subsequent interruption, with marginally better outcomes. Funding US National Institutes of Health.
A convenient synthetic route based on a sodium-mediated aromatic cross-coupling reaction is described for the multi-gram preparation of the ω-bromo-1-(4-cyanobiphenyl-4'−yl) alkanes (CBnBr, n = ...2-10). These materials are not only key intermediates in the synthesis of oligomers and polymers but also exhibit fascinating liquid crystal behaviour in their own right. Nematic behaviour is observed for n⩾5, and the nematic-isotropic transition temperature, T
NI
, increases in essentially a linear manner on n. The properties of the ω-bromo-1-(4-cyanobiphenyl-4'−yloxy) alkanes (CBOnBr, n = 2-9) are also reported, and nematic behaviour is seen for n⩾3. The values of T
NI
show a weak odd-even effect on n in which the odd members show the higher values. The sense of this alternation is opposite to that seen for the 4-alkyloxy-4'-cyanobiphenyls, and this is attributed to the steric bulk of the bromine atom. The absence of smectic behaviour for both the CBnBr and CBOnBr series is attributed largely to electrostatic interactions that would arise from the concentration of the bromine atoms at the layer interfaces in an interdigitated smectic phase. A comparison of a range of cyanobiphenyl-based materials containing a chain with a terminal polar or polarisable group suggests that their phase behaviour is governed largely by their average molecular shapes.
Little information is available about the timing of mother-to-child transmission of hepatitis C virus (HCV), and no interventions to decrease transmission rates have been identified. We examined the ...effect of risk factors, including mode of delivery, on the vertical transmission rate.
Data from HCV-infected women and their infants from three hospitals in Ireland and from a British Paediatric Surveillance Unit study of infants born to HCV-infected mothers were used to estimate the vertical transmission rate and risk factors for transmission. We used a probabilistic model using methods that simultaneously estimated the time to HCV-antibody loss in uninfected infants and the diagnostic accuracy of PCR tests for HCV RNA.
441 mother-child pairs from the UK (227) and Ireland (214) were included. 50% of uninfected children became HCV-antibody negative by 8 months and 95% by 13 months. The estimated specificity of PCR for HCV RNA was 97% (95% Cl 96·99) and was unrelated to age; sensitivity was only 22% (7–46) in the first month but rose sharply to 97% (85–100) thereafter. The vertical transmission rate was 6·7% (4·1–10·2) overall, and 3·8 times higher in HIV coinfected (n=22) than in HIV-negative women after adjustment for other factors (p=0·06). No effect of breastfeeding on transmission was observed, although only 59 women breastfed. However, delivery by elective caesarean section before membrane rupture was associated with a lower transmission risk than vaginal or emergency caesarean-section delivery (odds ratio 0 0–0·87, p=0·04, after adjustment for other factors).
The low sensitivity of HCV RNA soon after birth and the finding of a lower transmission rate after delivery by elective caesarean section suggest that HCV transmission occurs predominantly around the time of delivery. If the findings on elective caesarean section are confirmed in other studies, the case for antenatal HCV testing should be reconsidered.
The syntheses and characterisation of the 4‐{4‐({n‐4‐(4‐cyanophenyl)phenyl‐n‐yl}oxy)phenyl‐methylidene}aminophenyl‐4‐alkoxybenzoates (CBnOIBeOm) are reported with n=8 and 10 and m=1–10. The two ...series display fascinating liquid crystal polymorphism. All twenty reported homologues display an enantiotropic nematic (N) phase at high temperature. When the length of the spacer (n) is greater than that of the terminal chain (m), the twist‐bend nematic (NTB) phase is observed at temperatures below the N phase. As the length of the terminal chain is increased and extends beyond the length of the spacer up to three smectic phases are observed on cooling the N phase. One of these smectic phases has been assigned as the rare twist‐bend smectic C subphase, the SmCTB‐α phase. In all the smectic phases, a monolayer packing arrangement is seen, and this is attributed to the anti‐parallel associations of the like mesogenic units.
Twist‐bend liquid crystalline phases have been of particular scientific interest over the past decade due to their fascinating chiral symmetry breaking properties despite being formed by achiral molecules. Herein we present a series of non‐symmetric liquid crystalline dimers which display a plethora of liquid crystal polymorphism including the twist‐bend nematic (NTB) and the rare heliconical twist‐bend smectic C (SmCTB) phases.
Summary Co-trimoxazole is an inexpensive, broad-spectrum antimicrobial drug that is widely used in developing countries. Before antiretroviral therapy (ART) scale-up, co-trimoxazole prophylaxis ...reduced morbidity and mortality in adults and children with HIV by preventing bacterial infections, diarrhoea, malaria, and Pneumocystis jirovecii pneumonia, despite high levels of microbial resistance. Co-trimoxazole prophylaxis reduces early mortality by 58% (95% CI 39–71) in adults starting ART. Co-trimoxazole provides ongoing protection against malaria and non-malaria infections after immune reconstitution in ART-treated individuals in sub-Saharan Africa, leading to a change in WHO guidelines, which now recommend long-term co-trimoxazole prophylaxis for adults and children in settings with a high prevalence of malaria or severe bacterial infections. Co-trimoxazole prophylaxis is recommended for HIV-exposed infants from age 4–6 weeks; however, the risks and benefits of co-trimoxazole during infancy are unclear. Co-trimoxazole prophylaxis reduces anaemia and improves growth in children with HIV, possibly by reducing inflammation, either through direct immunomodulatory activity or through effects on the intestinal microbiota leading to reduced microbial translocation. Ongoing trials are now assessing the ability of adjunctive co-trimoxazole to reduce mortality in children after severe anaemia or severe acute malnutrition. In this Review, we discuss the mechanisms of action, benefits and risks, and clinical trials of co-trimoxazole in developing countries.
Background. Recent evidence suggests that decreases in morbidity and mortality in cohorts of adults infected with human immunodeficiency virus (HIV) are showing signs of reversal. We describe changes ...over time in these characteristics and in the response to treatment among children in the United Kingdom and Ireland with perinatally acquired HIV infection, many of whom are now adolescents. Methods. We analyzed prospective cohort data reported to the National Study of HIV in Pregnancy and Childhood (NSHPC) and the Collaborative HIV Paediatric Study. Results. By mid 2006, 1441 HIV-infected children were reported to NSHPC; 40% were ⩾10 years old at their most recent follow-up visit, and 34% were receiving care outside London. The proportion of children born abroad increased from 24% during 1994–1996 to 64% during 2003–2006. The percentage of total child time during which children received highly active antiretroviral therapy (HAART) increased from 36% during 1997–1999 to 61% during 2000–2002 and 63% during 2003–2006. Of children who were naive to antiretroviral therapy at the start of HAART, the percentage with an HIV-1 RNA load of <400 copies/mL after 12 months increased from 52% during 1997–1999 to 79% during 2003–2006. In multivariate analysis, only calendar time predicted virological response, whereas both younger age and lower CD4 cell percentage at HAART initiation predicted increases of >10% in the CD4 cell percentage. A total of 31% of children aged 5–14 years and 38% aged ⩾15 years at their most recent follow-up visit had been exposed to drugs from each of the 3 main HAART classes. The rate of AIDS and mortality combined decreased from 13.3 cases per 100 person-years before 1997 to 3.1 and 2.5 cases per 100 person-years, respectively, during 2000–2002 and 2003–2006; rates of hospital admission also declined during this interval. Of 18 children known to have died since 2003, 9 died within 1 month after presentation. Conclusions. Morbidity and mortality rates among HIV-infected children continue to decrease over time. Because these children are increasingly dispersed outside London, specialist care is now provided in national clinical networks. Transition pathways to adolescent and adult services and long-term observation to monitor the effects of prolonged exposure to both HIV and HAART are required.
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