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Determining the long‐term nature of the Atlantic Meridional Overturning Circulation (AMOC) presents a major step in understanding ocean temperature forcing, and is crucial both for placing the recently observed AMOC slowdown in the context of climate change and for predicting future climate. We present a time series for AMOC strength over the last 120 years which is derived solely from observations. Application of the Bernoulli inverse to hydrography yields the general geostrophic circulation in the North Atlantic without requiring additional sea surface height information, allowing AMOC evaluation in the pre‐satellite era. AMOC varies on a multidecadal timescale, leading the Atlantic Multidecadal Variability (AMV) in sea surface temperature by 2.5 years. We consider the dynamics of the implied AMOC/AMV coupling, and hypothesize that the low‐frequency variability in both parameters is driven by large‐scale density anomalies circulating in the AMOC. Plain Language Summary: The large‐scale ocean currents which influence the Earth's climate system are driven in large part by gradients in the sea surface. However, sea surface height measurements are scarce before 1993, when satellite observations began, limiting our knowledge of ocean currents over climate‐relevant time scales. Here, we use a method for determining sea surface height which does not require satellite data. We can therefore estimate the current strength in the North Atlantic over the last 120 years. We find that changes in the current strength are closely tied to changes in sea surface temperature. Key Points: Atlantic Meridional Overturning Circulation (AMOC) variability leads Atlantic Multidecadal Variability (AMV) by 2.5 yearsAMV is strongly coupled to ocean dynamicsAMOC variability associated with circulation of large‐scale density anomalies [ABSTRACT FROM AUTHOR]

This article reviews the Mahatma Gandhi National Rural Employment Guarantee Scheme (NREGA), perhaps India's foremost social security scheme, which is in the form of a right for rural households throughout India to work for up to 100 days a year in public works and to be paid the minimum wage for unskilled labourers. It is argued that self-targeting leads to a more pro-poor scheme than a cash transfer programme. However, in many states, especially poor states, work for NREGA is shown to be not a right. This is a major aspect of the corruption which gives the scheme a bad name. Also generally disappointing is the value of the assets created by the public works. But it is argued that NREGA is worth salvaging, especially if the example of the best states could be followed more widely. Attention is particularly drawn to the contribution of NREGA to the empowerment of women and scheduled castes and tribes in much of rural India. [ABSTRACT FROM AUTHOR]

This paper introduces the active labour market policies or job search policies in the UK known as the New Deal, a major part of the Labour Government's package of welfare-to-work policies. Topics covered include estimates of their overall impact on employment; their limited effectiveness with disadvantaged job-seekers, including increasing numbers of inactive, but not formally unemployed, people; and debates about these policies in relation to skill needs and areas of job decline. [ABSTRACT FROM AUTHOR]

Objectives: This article seeks to review debates about age-based rationing in health care. Methods: The article identifies four different levels (or types) of decision-making in health resource allocation--societal, strategic, programmatic, and clinical--and assesses how the issues of rationing vary in relation to each level. Results: The article concludes that rationing is least defensible at the clinical level, where it is also most covert. The role of rationing at other levels is more defensible when based on grounds of cost-effectiveness rather than equity. The article emphasizes the importance of fairness in health allocation and suggests that efficiency criteria need to be considered in that context. Discussion: The article suggests that rationing is most problematic where it is least overt. This raises further questions about how rationing can be made more explicit at different levels of decision making. [ABSTRACT FROM AUTHOR]

Investigates the spatial distribution patterns of juvenile Atlantic salmon during night and day in Great Britain. Calculations on nocturnal foraging in winter; Use of an automated activity monitoring system; Impact on growth rates.

Abstract The article assembles efficiency and equity arguments for and against targeting the long-term unemployed in active labour market policies (ALMP), and refers to evidence from applications to date. The theory and practices of ALMP differ somewhat between low and high unemployment countries. The approach taken in Sweden in the 1960s to 1980s is used to discuss low unemployment countries, and OECD analysis in the 1990s to represent theory for the high unemployment countries. Targeting the long-term unemployed is specifically a policy for high unemployment countries, and depends particularly on effects on wage pressure. The article concludes by urging that equity arguments be considered as well as efficiency and by drawing attention to the form which targeting takes. Comments are made about Britain's New Deal in relation to the form of targeting. [ABSTRACT FROM AUTHOR]

Determines the number of accidental poisoning in children in Great Britain from 1958 to 1977. Consideration of salicylates as the most commonly fatal poison; List of drugs with toxic effects on children; Impact of drug safety packaging on mortality.

Presents research which showed the functions of the calcitonin-receptor-like receptor (CRLR). CRLR a receptor for calcitonin-gene-related peptide (CGRP) or the adrenomedullin peptide; Determination of which peptide CRLR acts as a receptor for; Importance of receptor-activity-modifying proteins (RAMPs); Roles for RAMP1 and RAMP2.

Introduces a series of articles on active labor market policies, published on the July 1, 2001 issue of the 'International Journal of Manpower.'

Eastern boundary currents are some of the most energetic features of the global ocean, contributing significantly to meridional mass, heat, and salt transports. We take a new look at the form of an oceanic slope current in equilibrium with oceanic density gradients. We depth integrate the linearized x and y momentum and continuity equations and assume an equilibrium force balance in the along-slope direction (no alongslope variation in the along-slope flow) and zero cross-slope flow at a coastal boundary. We relate the bottom stress to a bottom velocity via a simple boundary friction law (the precise details are easily modified) and then derive an expression for the slope current velocity by integrating upward including thermal wind shear. This provides an expression for the slope current as a function of depth and of cross-slope coordinate, dependent on the oceanic density field and surface and bottom stresses. This new expression for the slope current allows for more general forms of oceanic density fields than have been treated previously. Wind stress is also now considered. The emphasis here is on understanding the simplified equilibrium force balance rather than the evolution toward that balance. There is a direct relationship between the slope current strength, friction, and along-slope forcing (e.g., wind), and also between the total along-slope forcing and bottom Ekman transport, illustrating that ''slippery'' bottom boundaries in literature are a direct consequence of unrealistically assuming zero along-slope pressure gradient. We demonstrate the utility of the new expression by comparison with a high-resolution hydrodynamic numerical model. [ABSTRACT FROM AUTHOR]

Aim: To report the case of a 14-y-old boy with coeliac disease and obesity. Methods and results: A 14-y-old boy presented with episodic diarrhoea associated with eating spaghetti. His body mass index (BMI) at presentation was 37.2 kg/m 2 (>99.9th centile). Both antigliadin and anti-endomysial antibodies were positive, and coeliac disease was diagnosed by jejunal biopsy. His diarrhoea ceased and the gliadin and endomysial antibodies disappeared after starting gluten-free diet. At 17 y, his BMI increased to 42.7 kg/m 2 despite dietary support. Conclusion: Obesity in a child does not exclude the diagnosis of coeliac disease, especially if presenting with suggestive symptoms. [ABSTRACT FROM AUTHOR]

A pneumococcal conjugate vaccine (PCV) specifically focused on serotypes associated with adult residual disease burden is urgently needed. We aimed to assess V116, an investigational 21-valent PCV, that contains pneumococcal polysaccharides (PnPs), which account for 74–94% of invasive pneumococcal disease in adults aged 65 years or older. We did a phase 1/2, randomised, double-blind, active comparator-controlled, multicentre, non-inferiority and superiority trial. The phase 1 study was done at two clinical sites in the USA, and the phase 2 study was done in 18 clinical sites in the USA. Eligible participants were healthy adults with or without chronic medical conditions assessed as stable, aged 18–49 years in the phase 1 trial and aged 50 years or older in the phase 2 trial. Participants were excluded if they had a history of invasive pneumococcal disease or other culture-positive pneumococcal disease within the past 3 years, known hypersensitivity to a vaccine component, known or suspected impairment of immunological function, were pregnant or were breastfeeding, or had previously received any pneumococcal vaccine. Participants had to abstain from sexual activity or use protocol approved contraception. All participants were centrally randomly assigned to a vaccine group using an interactive response technology system. Participants and investigators were masked to group assignment. In phase 1, participants were randomly assigned (1:1:1) to receive a single dose of V116-1 (2 μg per pneumococcal polysaccharide [PnP] per 0·5 mL) or V116-2 (4 μg per PnP per 1·0 mL) or the 23-valent unconjugated PnP vaccine, PPSV23 (25 μg per PnP per 0·5 mL). In phase 2, participants were randomly assigned (1:1) to receive one dose of V116 (4 μg per PnP per 1·0 mL) or PPSV23 (25 μg per PnP per 0·5 mL), stratified by age. Safety analyses included all randomly assigned participants who received study vaccine; immunogenicity analyses were per protocol. For both phases, the primary safety outcome was the proportion of participants with solicited injection-site adverse events and solicited systemic adverse events up to day 5 after vaccination and the proportion of participants with vaccine-related serious adverse events to 6 months after vaccination. In phase 2, primary immunogenicity outcomes were to test non-inferiority of V116 compared with PPSV23 as measured by serotype-specific opsonophagocytic antibody geometric mean titres (OPA-GMT) ratios for the serotypes common to the two vaccines at 30 days after vaccination (using a 0·33 margin) and to test superiority of V116 compared with PPSV23 as measured by serotype-specific OPA-GMT ratios for the serotypes unique to V116 at 30 days after vaccination (using a 1·0 margin). This trial is registered with Clinicaltrials.gov , NCT04168190. Between Dec 6 and 26, 2019, 92 volunteers were screened and 90 (98%) enrolled for phase 1 (59 [66%] women; 31 [34%] men); 30 participants were assigned to each group and received study vaccine. 30 (100%) participants in the V116-1 group, 29 (97%) in the V116-2 group, and 30 (100%) participants in the PPSV23 group were included in the per-protocol immunogenicity evaluation. From Sept 23, 2020, to Jan 12, 2021, 527 volunteers were screened, and 510 (97%) participants were enrolled in the phase 2 trial. 508 participants (>99%; 254 [100%] of 254 participants randomly assigned to the V116 group and 254 [99%] of 256 randomly assigned to PPSV23 group) received study vaccine (281 [55%] women; 227 [45%] men). 252 (99%) of 254 of participants in the V116 group and 254 (99%) of 256 participants in the PPSV23 group were included in the primary immunogenicity analyses. There were no vaccine-related serious adverse events or vaccine-related deaths in either study phase. In both phases, the most common solicited injection site adverse event was injection site pain (phase 1 22 [73%] participants in V116-1 group, 23 [77%] participants in V116-2 group, and 17 [57%] participants in the PPSV23 group; phase 2 118 [46%] of 254 participants in the V116 group and 96 [38%] of 254 in the PPSV23 group]. The most common solicited systemic adverse events in phase 1 was fatigue (eight [27%] participants in the V116-1 group, eight [27%] participants in the V116-2 group, and five [17%] participants in PPSV23 group) and myalgia (eight [27%] participants in the V116-1 group, nine (30%) participants in the V116-2 group, and four (13%) participants in the PPSV23 group]. In phase 2, the most frequently reported solicited systemic adverse event was fatigue (49 [19%] participants in V116 group, and 31 [12%] participants in PPSV23 group). In both phases, most of the solicited adverse events in all vaccine groups were mild and of short duration (≤3 days). V116 met non-inferiority criteria compared with PPSV23 for the 12 shared serotypes and met superiority criteria compared to PPSV23 for the nine unique serotypes. V116 was well tolerated with a safety profile generally similar to PPSV23; consistent with licensed pneumococcal conjugate vaccines. Functional OPA antibodies were induced to all V116 vaccine serotypes. The vaccine was non-inferior to PPSV23 for the 12 serotypes common to both vaccines and superior to PPSV23 for the nine unique serotypes in V116. Our findings support the development of V116 for prevention of pneumococcal disease in adults. Merck Sharp & Dohme, subsidiary of Merck & Co, Rahway, NJ, USA. [ABSTRACT FROM AUTHOR]

Presents information on the Web site of Scran, a recognized charity which aims to provide learners access to digital materials representing Scotland's material culture and history. Sources of its materials; Features of the site; Accessibility of the site.

Abstract: Objective:: The purpose of this study was to evaluate the efficacy and safety profile of ezetimibe/simvastatin(EZE/SIMVA) combination tablet, relative to ezetimibe (EZE) and simvastatin (SIMVA) monotherapy, in patients with primary hypercholesterolemia. Methods:: This was a randomized, multicenter, double-blind, placebo-controlled, factorial design study Aftera 6- to 8-week washout period and 4-week, single-blind, placebo run in, hypercholesterolemic patients (low-density lipoprotein cholesterol [LDL-C], 145–250 mg/dL; triglycerides [TG], ≤350 mg/dL) were randomized equally to 1 of 10 daily treatments for 12 weeks: EZE/SIMVA 10/10, 10/20, 10/40, or 10/80 mg; SIMVA 10, 20, 40, or 80 mg; EZE 10 mg; or placebo. The primary efficacy analysis was mean percent change from baseline in LDL-C to study end point Secondary end points included percent changes in other lipid variables and C-reactive protein [CRP]. Results:: There were 1528 patients randomized to treatment (792 women, 736 men); mean (SD) age ranged from 54.9 (112) years to 56.4 (10.6) years across pooled treatment groups. The treatment groups were well balanced for baseline demographics. Pooled EZE/SIMVA was associated with greater reductions in LDL-C than pooled SIMVA or EZE alone (P < 0.001). Depending on dose, EZE/SIMVA was associated with reductions in LDL-C of −44.8% to −602%, non-high-density lipoprotein cholesterol of −40.5% to −55.7%, and TG of −22.5% to −30.7%; high-density lipoprotein cholesterol increased by 5.5% to 9.8%. EZE/SIMVA was associated with greater reductions in CRP and remnant-like particle-cholesterol than SIMVA alone (P < 0.001). More patients receiving EZE/SIMVA versus SIMVA achieved LDL-C concentrations <100 mg/dL (78.6% vs 45.9%; P < 0.001). EZE/SIMVA was generally well tolerated, with a safety profile similar to SIMVA monotherapy There were no significant differences between EZE/SIMVA and SIMVA in the incidence of consecutive liver transaminase levels ≥3 times the upper limit of normal (ULN) (1 .5% for EZE/SIMVA and 1.1% for SIMVA; P = NS) or creature kinase levels ≥10 times ULN (0.0% for EZE/SIMVA and 02% for SIMVA; P = NS). Conclusion:: The EZE/SIMVA tablet was a highlyeffective and well-tolerated LDL-C-lowering therapy in this study of patients with primary hypercholesterolemia. [Copyright &y& Elsevier]

Cites the molecular identification of high and low affinity receptors for nicotinic acid. Use of niconitic acid for the treatment of dyslipidemia; Normalization of cardiovascular risk factors; Mechanism of action of nicotinic acid.

Introduction: The human immunodeficiency virus 1 (HIV‐1) pandemic is characterized by numerous distinct sub‐epidemics (clusters) that continually fuel local transmission. The aims of this study were to identify active growing clusters, to understand which factors most influence the transmission dynamics, how these vary between different subtypes and how this information might contribute to effective public health responses. Methods: We used HIV‐1 genomic sequence data linked to demographic factors that accounted for approximately 70% of all new HIV‐1 notifications in New South Wales (NSW). We assessed differences in transmission cluster dynamics between subtype B and circulating recombinant form 01_AE (CRF01_AE). Separate phylogenetic trees were estimated using 2919 subtype B and 473 CRF01_AE sequences sampled between 2004 and 2018 in combination with global sequence data and NSW‐specific clades were classified as clusters, pairs or singletons. Significant differences in demographics between subtypes were assessed with Chi‐Square statistics. Results: We identified 104 subtype B and 11 CRF01_AE growing clusters containing a maximum of 29 and 11 sequences for subtype B and CRF01_AE respectively. We observed a > 2‐fold increase in the number of NSW‐specific CRF01_AE clades over time. Subtype B clusters were associated with individuals reporting men who have sex with men (MSM) as their transmission risk factor, being born in Australia, and being diagnosed during the early stage of infection (p < 0.01). CRF01_AE infections clusters were associated with infections among individuals diagnosed during the early stage of infection (p < 0.05) and CRF01_AE singletons were more likely to be from infections among individuals reporting heterosexual transmission (p < 0.05). We found six subtype B clusters with an above‐average growth rate (>1.5 sequences / 6‐months) and which consisted of a majority of infections among MSM. We also found four active growing CRF01_AE clusters containing only infections among MSM. Finally, we found 47 subtype B and seven CRF01_AE clusters that contained a large gap in time (>1 year) between infections and may be indicative of intermediate transmissions via undiagnosed individuals. Conclusions: The large number of active and growing clusters among MSM are the driving force of the ongoing epidemic in NSW for subtype B and CRF01_AE. [ABSTRACT FROM AUTHOR]

Research suggests that hepatitis C virus (HCV) transmission is more likely among gay and bisexual men (GBM) who engage in sexually adventurous practices, including group sex while using drugs. The current study explored drug use, sexual practices, HCV knowledge, HCV disclosure, and beliefs about HCV transmission among GBM (n = 193) reporting group sex after/while using drugs compared to those who did not. Survey findings indicate that men who participated in group sex while using drugs were more likely to have engaged in other sexually adventurous practices, ever injected drugs, have greater knowledge of HCV, and to be living with HIV. They were also more likely to perceive themselves at risk of acquiring HCV and to know that their sexual activities put them at risk. Interestingly, they had lower expectations of HCV disclosure and were less concerned about the HCV status of their partners. The lower expectations around disclosure and concern about the HCV status of their partners reflect the challenges for GBM in managing HCV transmission where there are limited effective behavioural strategies for reducing sexual transmission, This research also highlights the need to promote HCV testing and treatment to GBM who engage in group sex while using drugs. [ABSTRACT FROM AUTHOR]

Increases in hepatitis C (HCV) infections among gay and bisexual men have recently been reported in a number of countries, with sexual transmission being the primary route of infection. Given that in countries such as Australia most gay and bisexual men living with HIV are already engaged in clinical care - as are an increasing number of HIV-negative men - there is potential for reducing onward HCV transmission through proactive testing and treatment. This study explored knowledge, attitudes and practices related to HCV among 194 gay and bisexual men collected through an online survey in Australia. Overall, respondents had high levels of HCV knowledge; however, only 76% knew about the availability of new treatments for HCV. Men's knowledge of their own HCV testing history was uncertain, with one in six unaware if they had ever been tested. Among men who reported recent drug injecting, one-third had been injected by someone else, and two-thirds had injected someone else, indicating a subculture of cross-administering within sexualised drug-use networks. We argue that the robust sexual, socio-cultural and clinical infrastructure that has been developed by - and for - gay and bisexual men around HIV care and prevention creates the potential for reducing HCV in this group. [ABSTRACT FROM AUTHOR]

The rapid decline in Arctic sea ice is one of the most striking manifestations of climate change, and during recent decades, Svalbard fjords have experienced a substantial reduction in winter sea-ice extent. The reduced sea ice cover has been linked to an increased transport of warm Atlantic Water (AW) into the fjords. AW from the West Spitsbergen Current (WSC) can reach the upper shelf along western Spitsbergen and eventually flood into the fjords. Seasonal spatial hydrographic snapshots, combine with longer time series in strategic positions on the West Spitsbergen Shelf (WSS), reveal a circulation of AW in the troughs indenting the WSS, here named the Spitsbergen Trough Current (STC). From hydrographical and ocean current observations it is evident that the STC is primarily barotropic and driven by the sea surface height. A connection between the along-coast wind stress and the STC is established, and it is demonstrated how the increased occurrence of winter cyclones in Fram Strait during January–February accelerates and widens the WSC. Ultimately, this results in a strengthened STC and dominance of AW on the WSS. The STC represents a slower route of AW toward the Arctic Ocean and a large heat transport toward the West Spitsbergen fjords during winter (0.2–0.4TW toward Isfjorden). Sea ice production along West Spitsbergen has been reduced, or even nonexistent, in some fjords since 2006. Here, the authors argue that this is a consequence of the strong southerly wind periods along the WSS during winter. [ABSTRACT FROM AUTHOR]

The best-characterized Toll-like receptor 4 (TLR4) ligands are lipopolysaccharide (LPS) and its chemically modified and detoxified variant, monophosphoryl lipid A (MPL). Although both molecules are active for human TLR4, they demonstrate a potency preference for mouse TLR4 based on data from transfected cell lines and primary cells of both species. After a high throughput screening process of small molecule libraries, we have discovered a new class of TLR4 agonist with a species preference profile differing from MPL. Products of the 4-component Ugi synthesis reaction were demonstrated to potently trigger human TLR4-transfected HEK cells but not mouse TLR4, although inclusion of the human MD2 with mTLR4 was able to partially recover activity. Co-expression of CD14 was not required for optimal activity of Ugi compounds on transfected cells, as it is for LPS. The species preference profile for the panel of Ugi compounds was found to be strongly active for human and cynomolgus monkey primary cells, with reduced but still substantial activity for most Ugi compounds on guinea pig cells. Mouse, rat, rabbit, ferret, and cotton rat cells displayed little or no activity when exposed to Ugi compounds. However, engineering the human versions of TLR4 and MD2 to be expressed in mTLR4/MD2 deficient mice allowed for robust activity by Ugi compounds both in vitro and in vivo. These findings extend the range of compounds available for development as agonists of TLR4 and identify novel molecules which reverse the TLR4 triggering preference of MPL for mouse TLR4 over human TLR4. Such compounds may be amenable to formulation as more potent human-specific TLR4L-based adjuvants than typical MPL-based adjuvants. [ABSTRACT FROM AUTHOR]

Background Clostridium difficile , a major cause of nosocomial and antibiotic-associated diarrhea, carries a significant disease and cost burden. This study aimed to select an optimal formulation and schedule for a candidate toxoid vaccine against C. difficile toxins A and B. Methods Randomized, placebo-controlled, two-stage, Phase 2 study in a total of 661 adults aged 40–75 years. Stage I: low (50 μg antigen) or high (100 μg antigen) dose with or without aluminum hydroxide (AlOH) adjuvant, or placebo, administered on Days 0–7–30. Stage II: Days 0–7–30, 0–7–180, and 0–30–180, using the formulation selected in Stage I through a decision tree defined a priori and based principally on a bootstrap ranking approach. Administration was intramuscular. Blood samples were obtained on Days 0, 7, 14, 30, 60 (Stage I and II), 180, and 210 (Stage II); IgG to toxins A and B was measured by ELISA and in vitro functional activity was measured by toxin neutralizing assay (TNA). Safety data were collected using diary cards. Results In Stage I the composite immune response against toxins A and B (percentage of participants who seroconverted for both toxins) was highest in the high dose + adjuvant group (97% and 92% for Toxins A and B, respectively) and was chosen for Stage II. In Stage II the immune response profile for this formulation through Day 180 given on Days 0–7–30 ranked above the other two administration schedules. There were no safety issues. Conclusions The high dose + adjuvant (100 μg antigen + AlOH) formulation administered at 0–7–30 days elicited the best immune response profile, including functional antibody responses, through Day 180 and was selected for use in subsequent clinical trials. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus ( EBV) is associated with several malignancies, including post-transplant lymphoproliferative disorder ( PTLD). Conventional treatments for PTLD are often successful, but risk organ rejection and cause significant side effects. EBV-specific cytotoxic T lymphocytes ( CTLs) generated in vitro from peripheral blood lymphocytes provide an alternative treatment modality with few side effects, but autologous CTLs are difficult to use in clinical practice. Here we report the establishment and operation of a bank of EBV-specific CTLs derived from 25 blood donors with human leucocyte antigen ( HLA) types found at high frequency in European populations. Since licensure, there have been enquiries about 37 patients, who shared a median of three class I and two class II HLA types with these donors. Cells have been infused into ten patients with lymphoproliferative disease, eight of whom achieved complete remission. Neither patient with refractory disease was matched for HLA class II. Both cases of EBV-associated non-haematopoietic sarcoma receiving cells failed to achieve complete remission. Thirteen patients died before any cells could be issued, emphasizing that the bank should be contacted before patients become pre-terminal. Thus, this third party donor-derived EBV-specific CTL cell bank can supply most patients with appropriately matched cells and most recipients have good outcomes. [ABSTRACT FROM AUTHOR]

A small-molecule natural product,euodenine A (1),was identified as an agonist of the human TLR4 receptor. EuodenineA was isolated from the leaves of Euodia asteridula(Rutaceae) found in Papua New Guinea and has an unusual U-shapedstructure. It was synthesized along with a series of analogues thatexhibit potent and selective agonism of the TLR4 receptor. SAR developmentaround the cyclobutane ring resulted in a 10-fold increase in potency.The natural product demonstrated an extracellular site of action,which requires the extracellular domain of TLR4 to stimulate a NF-κBreporter response. 1is a human-selective agonist thatis CD14-independent, and it requires both TLR4 and MD-2 for full efficacy.Testing for immunomodulation in PBMC cells shows the induction ofthe cytokines IL-8, IL-10, TNF-α, and IL-12p40 as well as suppressionof IL-5 from activated PBMCs, indicating that compounds like 1could modulate the Th2 immune response without causing lungdamage. [ABSTRACT FROM AUTHOR]

Identifies the acetate anion as an agonist of human G protein-coupled receptor 43 (GPR43) during routine ligand bank screening in yeast. Functions of GPR41 and GPR43; Activation of the receptors by propionate and other short chain carboxylic acids; Expression of GPR41 primarily in adipose tissue; Localization of GPR43 in immune cells.

Reports a case study of patients in Australia with soft tissue infections due to gram-negative insect bacilli Photorhabdus species. Information on the patients; Background on the pathogen; Conclusions.

Reports the cloning of a complementary DNA encoding a subtype of the gamma-aminobutyric acid B (GABAB) receptor (GABABR2), which was identified by mining expressed-sequence-tag databases. The indication that, in vivo, functional brain GABAB receptors may be heterodimers composed of GABABR1 and GABABR2; GABA being the main inhibitory neurotransmitter in the mammalian central nervous system.

BACKGROUND rhIGF-I has been used effectively to promote growth in growth hormone insensitivity syndrome (GHIS) in doses ranging from 40 μg/kg twice daily to 150–200 μg/kg once daily. It appears that the dose of 80 μg/kg twice daily s.c. may induce an equivalent response to higher doses with less side-effects. OBJECTIVE To study the efficacy and safety of rhIGF-I, 80 μg/kg twice daily s.c., in children with GHIS and to analyse the relationship of growth response to severity of phenotype. PATIENTS AND DESIGN: Eleven prepubertal children (3 females, 8 males) with GHIS; basal GH > 2.5 μg/l, IGF-I < 50 μg/l, IGFBP-3 < - 2SD; were treated with IGF-I 80 μg/kg twice daily in a multi-centre study. The baseline characteristics of these patients were as follows (mean ± SD): age, 7.5 ± 2.5 years (range, 2.5–11.7 years), bone age (Tanner–Whitehouse - 2 RUS), 5.2 ± 2.4 years (range, 2.3–9.1 years), mean height SDS, - 5.6 ± 1.6 (range, - 3.1 to - 8.1), height velocity (HV), 3.1 ± 1.1 cm/year (range, 1.9–4.9 cm/year). Height, HV, weight, skinfold thickness, puberty stage and bone age were measured at baseline and 6 monthly for 2 years. RESULTS During the first 12 months of IGF-I therapy, the mean ± SD HV was 7.7 ± 1.6 cm/year (range, 6.1–11.2 cm/year), the mean ± SD increase in HV was 4.7 ± 2.1 cm/year (range, 1.7–8.8 cm/year) and the mean ± SD progression of bone age was 1.9 ± 1.0 years (range, 0.8–3.8 years). Pre-treatment height SDS at the start of IGF-I therapy correlated positively with pretreatment serum IGFBP-3 SDS levels (r = 0.85; P < 0.01). There was a significant inverse correlation between gain in height SDS and pre-treatment height SDS (r = - 0.76; P < 0.01). During the 2nd 12 months of therapy, mean HV was 7.0 ± 3.4 cm/year (range 3.8–12.4) change in height SDS from 12 to 24 months was not significantly correlated with pre-treatment height SDS. Subscapular skinfold SDS decreased significantly (P < 0.05) during the study period, whereas there was no significant change in body mass index and triceps skinfold thickness SDS. Adverse events reported in the patient group included headache (2 patients), hypoglycaemia (2 patients), papilloedema (transient, 1 patient), lipohypertrophy (5 patients) and tonsillectomy/adenoidectomy (2 patients). CONCLUSION This study reveals that IGF-I treatment at a dose of 80 μg/kg twice daily is effective in patients with growth hormone insensitivity syndrome. During the first 12 months of therapy, there was a significant inverse relationship between growth response to IGF-I therapy and the severity of the phenotype of growth hormone insensitivity syndrome, as measured by height SDS, at the start of therapy. Patients with a more severe clinical phenotype of growth hormone insensitivity syndrome, who also had most severe IGFBP-3 deficiency, responded better than those who were more mildly affected. An analogous situation has been shown to be the case in GH-deficient patients treated with hGH. [ABSTRACT FROM AUTHOR]

Changes over time in HIV-1 subtype diversity within a population reflect changes in factors influencing the development of local epidemics. Here we report on the genetic diversity of 2364 reverse transcriptase sequences from people living with HIV-1 in New South Wales (NSW) notified between 2004 and 2018. These data represent >70% of all new HIV-1 notifications in the state over this period. Phylogenetic analysis was performed to identify subtype-specific transmission clusters. Subtype B and non-B infections differed across all demographics analysed (p < 0.001). We found a strong positive association for infections among females, individuals not born in Australia or reporting heterosexual transmission being of non-B origin. Further, we found an overall increase in non-B infections among men who have sex with men from 50 to 79% in the last 10 years. However, we also found differences between non-B subtypes; heterosexual transmission was positively associated with subtype C only. In addition, the majority of subtype B infections were associated with clusters, while the majority of non-B infections were singletons. However, we found seven non-B clusters (≥5 sequences) indicative of local ongoing transmission. In conclusion, we present how the HIV-1 epidemic has changed over time in NSW, becoming more heterogeneous with distinct subtype-specific demographic associations. [ABSTRACT FROM AUTHOR]

The subpolar North Atlantic is an important region for climate, where intense ocean-atmosphere exchanges take place. The desire to understand the variability of volume, heat and freshwater fluxes and their relationship with water mass transformations, led to the establishment of a purposefully designed international observing system. The Overturning in the Subpolar North Atlantic Program (OSNAP) was deployed in July 2014 and consists of multiple transatlantic mooring arrays supplemented by hydrographic and glider observations. Here, we present the first three years of results from the eastern boundary of the array which comprises of four moorings within the Rockall Trough. These moorings capture the warmest and saltiest branch of Atlantic Water on the OSNAP section which is transporting heat and salt to the Nordic Seas. Transports at the boundaries of the Rockall Trough are estimated from direct current measurements, whilst fluxes in the interior are calculated from end-point density moorings referenced to altimetry. The resulting transports are the first continuous, direct measurements for the warm water path through the Rockall Trough. Finally, we place our results in context by comparison with multi-decadal length hydrographic time-series and discuss the implications for both the regional and large-scale circulation in the subpolar North Atlantic. [ABSTRACT FROM AUTHOR]