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Lipid bioactivity is a result of direct action and the action of lipid mediators including oxylipins, endocannabinoids, bile acids and steroids. Understanding the factors contributing to biological variation in lipid mediators may inform future approaches to understand and treat complex metabolic diseases. This research aims to determine the contribution of genetic and environmental influences on lipid mediators involved in the regulation of inflammation and energy metabolism. This study recruited 138 monozygotic (MZ) and dizygotic (DZ) twins aged 18-65 years and measured serum oxylipins, endocannabinoids, bile acids and steroids using liquid chromatography mass-spectrometry (LC-MS). In this classic twin design, the similarities and differences between MZ and DZ twins are modelled to estimate the contribution of genetic and environmental influences to variation in lipid mediators. Heritable lipid mediators included the 12-lipoxygenase products 12-hydroxyeicosatetraenoic acid [0.70 (95% CI: 0.12,0.82)], 12-hydroxyeicosatetraenoic acid [0.73 (95% CI: 0.30,0.83)] and 14‑hydroxy-docosahexaenoic acid [0.51 (95% CI: 0.07,0.71)], along with the endocannabinoid docosahexaenoy-lethanolamide [0.52 (95% CI: 0.15,0.72)]. For others such as 13-hydroxyoctadecatrienoic acid and lithocholic acid the contribution of environment to variation was stronger. With increased understanding of lipid mediator functions in health, it is important to understand the factors contributing to their variance. This study provides a comprehensive analysis of lipid mediators and extends pre-existing knowledge of the genetic and environmental influences on the human lipidome.

Purpose: Agriculture and food production contribute to climate change. There is mounting pressure to transition to diets with less environmental impact while maintaining nutritional adequacy. MyPlanetDiet aimed to reduce diet-related greenhouse gas emissions (GHGE) in a safe, nutritionally adequate, and acceptable manner. This paper describes the trial protocol, development, and testing of personalised nutrition feedback in the MyPlanetDiet randomised controlled trial (RCT)., Methods: MyPlanetDiet was a 12-week RCT that provided standardised personalised nutrition feedback to participants based on new sustainable healthy eating guidelines (intervention) or existing healthy eating guidelines (control) using decision trees and corresponding feedback messages. To test the personalised nutrition feedback, we modelled a sample of 20 of the MyPlanetDiet participants baseline diets. Diets were modelled to adhere to control and intervention decision trees and feedback messages. Modelled nutrient intakes and environmental metrics were compared using repeated measure one-way analysis of covariance., Results: Intervention diets had significantly lower (p < 0.001) diet-related GHGE per 2500 kilocalories (kcal) (4.7 kg CO 2 -eq) relative to control (6.6 kg CO 2 -eq) and baseline (7.1 kg CO 2 -eq). Modelled control and intervention diets had higher mean daily intakes of macronutrients (carbohydrates, fibre, and protein) and micronutrients (calcium, iron, zinc, and iodine). Modelled control and intervention diets had lower percent energy from fat and saturated fat relative to baseline., Conclusions: Adherence to the MyPlanetDiet personalised nutrition feedback would be expected to lead to better nutrient intakes and reduced diet-related GHGE. The MyPlanetDiet RCT will test the effectiveness and safety of personalised feedback for a more sustainable diet., Trial Registration Number and Date of Registration: Clinical trials registration number: NCT05253547, 23 February 2022., (© 2024. The Author(s).)

Background: Mycoplasma genitalium (MG) infection is a public health concern due to antimicrobial resistance (AMR). Data are limited on repeat MG infection and AMR among US Air Force service members with HIV., Methods: US Air Force service members seeking HIV care were screened for MG infection during the surveillance period (16 May 2016-16 March 2020). Baseline and repeat MG prevalence rates were estimated. An extended Cox proportional hazards regression model evaluated characteristics associated with repeat MG infection. MG-positive rectal samples were tested for macrolide or fluoroquinolone resistance., Results: Among 299 male patients from a total of 308 patients followed during the surveillance period, baseline prevalence of MG infection was 19.7% (n = 59); among the 101 patients who screened positive for MG at any time during the surveillance period, repeat MG was 35% (n = 36). Characteristics independently associated with increased risk of repeat infection were sexually transmitted infection history vs none (adjusted hazard ratio [aHR], 2.33; 95% CI, 1.26-4.31), a sexually transmitted infection coinfection vs no positive test result in the medical records (aHR, 5.13; 95% CI, 2.78-9.49), and a new HIV diagnosis (<1 vs ≥1 year; aHR, 2.63; 95% CI, 1.45-3.73). AMR in MG-positive rectal specimens was 88% (43/49) indicating macrolide resistance, 18% (10/56) quinolone resistance, and 18% (10/56) both., Conclusions: Macrolide and fluoroquinolone resistance mutations were common. Testing for co-occurring MG infection and AMR mutations may be warranted in guiding treatment for sexually transmitted infections such as chlamydia or gonorrhea detected at HIV diagnosis., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Helicobacter pylori ( H. pylori ) eradication rates have fallen globally, likely in large part due to increasing antibiotic resistance to traditional therapy. In areas of high clarithromycin and metronidazole resistance such as ours, Maastricht VI guidelines suggest high dose amoxicillin dual therapy (HDADT) can be considered, subject to evidence for local efficacy. In this study we assess efficacy of HDADT therapy for H. pylori eradication in an Irish cohort., Aim: To assess the efficacy of HDADT therapy for H. pylori eradication in an Irish cohort as both first line, and subsequent therapy for patients diagnosed with H. pylori ., Methods: All patients testing positive for H. pylori in a tertiary centre were treated prospectively with HDADT (amoxicillin 1 g tid and esomeprazole 40 mg bid × 14 d) over a period of 8 months. Eradication was confirmed with Urea Breath Test at least 4 wk after cessation of therapy. A delta-over-baseline > 4% was considered positive. Patient demographics and treatment outcomes were recorded, analysed and controlled for basic demographics and prior H. pylori treatment., Results: One hundred and ninety-eight patients were identified with H. pylori infection, 10 patients were excluded due to penicillin allergy and 38 patients refused follow up testing. In all 139 were included in the analysis, 55% ( n = 76) were female, mean age was 46.6 years. Overall, 93 (67%) of patients were treatment-naïve and 46 (33%) had received at least one previous course of treatment. The groups were statistically similar. Self-reported compliance with HDADT was 97%, mild side-effects occurred in 7%. There were no serious adverse drug reactions. Overall the eradication rate for our cohort was 56% (78/139). Eradication rates were worse for those with previous treatment [43% (20/46) vs 62% (58/93), P = 0.0458, odds ratio = 2.15]. Age and Gender had no effect on eradication status., Conclusion: Overall eradication rates with HDADT were disappointing. Despite being a simple and possibly better tolerated regime, these results do not support its routine use in a high dual resistance country. Further investigation of other regimens to achieve the > 90% eradication target is needed., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interests., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Globally, typical dietary patterns are neither healthy nor sustainable. Recognizing the key role of dietary change in reducing noncommunicable disease risk and addressing environmental degradation, it is crucial to understand how to shift individuals toward a sustainable and healthy diet (SHD). In this literature review, we introduced the concept of a SHD and outlined the dietary behaviors necessary to transition toward SHD consumption; we reviewed the literature on factors that may influence sustainable (and unsustainable) dietary behaviors in adults; and we developed a novel scoring system to rank factors by priority for targeting in future research. Given the significant potential to promote a sustainable and healthy dietary transition on the university campus-where factors that may impact dietary behaviors can be targeted at all levels of influence (i.e., individual, interpersonal, environmental, policy)-we narrowed our focus to this setting throughout. Aided by our novel scoring system, we identified conscious habitual eating, product price, food availability/accessibility, product convenience, self-regulation skills, knowledge of animal ethics/welfare, food promotion, and eating norms as important modifiable factors that may influence university students' dietary behaviors. When scored without consideration for the university population, these factors were also ranked as highest priority, as was modified portion sizes. Our findings offer insight into factors that may warrant attention in future research aimed at promoting SHDs. In particular, the high-priority factors identified from our synthesis of the literature could help guide the development of more personalized dietary behavioral interventions within the university setting and beyond., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Climate change is driving higher coastal water levels, and models project accelerated future sea-level rise and coastal storm intensification. These dynamics paired with anthropogenic coastal alterations will drive drastic coastal change worldwide. Composite beaches with mixed sediment sizes warrant detailed study as these exhibit complex morphodynamics in response to changing hydrodynamics due to the distinct transport thresholds of different sediment types. This study uses a novel multi-method approach to investigate a composite sand-cobble beach in Atlantic Canada experiencing a shortening seasonal sand-covered period. Hydrodynamic forcing and associated beach changes were monitored over a focused eight-month period, while satellite-based visual imagery and reconstructed wave data were analyzed over longer periods. Results show that intra-annual wave energy changes drive sand dynamics, with reduced summer wave energy facilitating short-term deposition. Long-term positive trends were identified in late spring wave heights, which likely contribute to the shortening sand-covered period. Seasonal dynamics were overwhelmed by extratropical cyclone Fiona, which made landfall on September 24, 2022, generating significant wave heights up to 6.8 m in the bay, mobilizing sediment, and steepening cobble berms. A new index approach based on visual imagery facilitated the investigation of beach sand appearance/disappearance using the relative redness of sand compared to cobble. Finally, the UAV-based surveys yielded high-resolution orthomosaics and LiDAR-based elevation mapping, and highlighted pronounced longshore variability in erosion and deposition during Fiona. The beach mostly recovered to pre-storm conditions in <4 months, which indicates that proposed beach nourishment activities may only experience temporary success. The longer-term results showing a conversion of sand to cobble suggest that loss of sandy beach habitat is likely to increase, even without shoreline migration or coastal squeeze driven by sea-level rise., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Discourse on the relationship between food production, healthy eating and sustainability has become increasingly prominent and controversial in recent years. Research groups often take one perspective when reporting on sustainable diets, and several often neglect considerations for the multiple aspects that make a diet truly sustainable, such as cultural acceptability, differences in nutritional requirements amongst the population and the efficiency of long-term dietary change. Plant-based diets are associated with lower greenhouse gas emissions (GHGEs) and have been linked with better health outcomes, including lower risk of diet-related chronic disease. However, foods associated with higher GHGE, such as lean red meat, fish and dairy, have beneficial nutritional profiles and contribute significantly to micronutrient intakes. Some research has shown that diets associated with lower GHGE can be less nutritionally adequate. Several countries now include sustainability recommendations in dietary guidelines but use vague language such as "increase" or "consume regularly" when referring to plant-based foods. General population-based nutrition advice has poor adherence and does not consider differences in nutritional needs. Although modelling studies show potential to significantly reduce environmental impact with dietary changes, personalising such dietary recommendations has not been studied. Adapting recommendations to the individual through reproducible methods of personalised nutrition has been shown to lead to more favourable and longer-lasting dietary changes compared to population-based nutrition advice. When considering sustainable healthy dietary guidelines, personalised feedback may increase the acceptability, effectiveness and nutritional adequacy of the diet. A personalised approach has the potential for delivering a new structure of more sustainable healthy food-based dietary guidelines. This review evaluates the potential to develop personalised sustainable healthy food-based dietary guidelines and discusses potential implications for policy and practice., (© 2023 The Authors. Journal of Human Nutrition and Dietetics published by John Wiley & Sons Ltd on behalf of British Dietetic Association.)

Background: The CCR5 (R5) to CXCR4 (X4) coreceptor switch in natural HIV-1 infection is associated with faster progression to AIDS, but the mechanisms remain unclear. The difficulty in elucidating the evolutionary origin of the earliest X4 viruses limits our understanding of this phenomenon., Methods: We tracked the evolution of the transmitted/founder (T/F) HIV-1 in RV217 participants identified in acute infection. The origin of the X4 viruses was elucidated by single genome amplification, deep sequencing and coreceptor assay. Mutations responsible for coreceptor switch were confirmed by mutagenesis. Viral susceptibility to neutralization was determined by neutralization assay. Virus CD4 subset preference was demonstrated by sequencing HIV-1 RNA in sorted CD4 subsets., Findings: We demonstrated that the earliest X4 viruses evolved de novo from the T/F strains. Strong X4 usage can be conferred by a single mutation. The mutations responsible for coreceptor switch can confer escape to neutralization and drive the X4 variants to replicate mainly in the central memory (CM) and naïve CD4 subsets. Likely due to the smaller viral burst size of the CM and naïve subsets, the X4 variants existed at low frequency in plasma. The origin of the X4 viruses preceded accelerated CD4 decline. All except one X4 virus identified in the current study lost the conserved V3 N301 glycan site., Interpretations: The findings demonstrate co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting which have implications for HIV-1 therapeutics and functional cure. The observations provide evidence that coreceptor switch can function as an evolutionary mechanism of immune evasion., Funding: Institute of Human Virology, National Institutes of Health, Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Thai Red Cross AIDS Research Centre, Gilead Sciences, Merck, and ViiV Healthcare., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Food fortification improves vitamin D intakes but is not yet mandated in many countries. Combining vitamin D with different dietary lipids altered vitamin D absorption in in vitro and postprandial studies. This randomised, placebo-controlled trial examined the effect of the lipid composition of a vitamin D-fortified dairy drink on change in 25-hydroxyvitamin D (25(OH)D) concentrations. Sixty-three healthy adults aged 50+ years were randomised to one of the following for 4 weeks: vitamin D-fortified olive oil dairy drink, vitamin D-fortified coconut oil dairy drink, vitamin D supplement or placebo control dairy drink. All vitamin D groups received 20 µg of vitamin D 3 daily. Serum was collected at baseline and post-intervention to measure 25(OH)D concentrations and biomarkers of metabolic health. Repeated-measures general linear model ANCOVA (RM GLM ANCOVA) compared changes over time. There was a significant time × treatment interaction effect on 25(OH)D concentrations for those classified as vitamin D-insufficient ( P < 0·001) and -sufficient at baseline ( P = 0·004). 25(OH)D concentrations increased significantly for all insufficient participants receiving vitamin D 3 in any form. However, for vitamin D-sufficient participants at baseline, 25(OH)D concentrations only increased significantly with the coconut oil dairy drink and supplement. There was no effect of vitamin D on biomarkers of metabolic health. Vitamin D fortification of lipid-containing foods may be used in lieu of supplementation when supplement adherence is low or for individuals with dysphagia. These results are important given the recent recommendation to increase vitamin D intakes to 15-20 µg for older adults in Ireland.

Introduced predators can have harmful top-down effects on their newly colonized system through competition with and direct predation on native species. Following an initial introduction of muskellunge in Lac Frontière, Québec in the 1970s at the headwaters of the Wolastoq/Saint John River, the species rapidly migrated downstream, expanding its range by ~500 km over ~20 years. Despite this expansive colonization and concern over possible threats to native species, little is known about the basic ecology of muskellunge in this system. The last downstream barrier is the hydroelectric facility, Mactaquac Generating Station (MGS), 150 km upstream of the sea. While there are no downstream fish passage facilities at MGS, adult muskellunge have been recorded downstream. In this study, muskellunge (n = 23) were surgically tagged with very-high-frequency (VHF) radio or combined acoustic radio telemetry (CART) tags and tracked over two spawning seasons. We sought to determine if there was a reproducing population downstream of MGS and tracked Tagged muskellunge over two spawning seasons. We tracked fish to locate and confirm spawning sites, and followed up with egg and/or juvenile sampling surveys. Tagged muskellunge (90%) moved upstream towards the MGS during the spawning period in each year (2016 and 2017), where they remained throughout the entire spawning period. No spawning or nursery sites were confirmed near MGS, but in 2016 three distinct spawning locations and six distinct nursery sites were confirmed 10-12 km downstream amongst a chain of flooded islands. In 2016, eggs, sac-fry and juveniles were collected and confirmed as muskellunge by genetic sequencing, providing the first empirical observation of successful spawning downstream of MGS., (© 2023 The Authors. Journal of Fish Biology published by John Wiley & Sons Ltd on behalf of Fisheries Society of the British Isles.)

Metabolomics can identify metabolite patterns associated with different nutrition phenotypes and determine changes in metabolism in response to nutrition interventions. Vitamin D insufficiency is associated with increased metabolic disease risk; however, the role of vitamin D in metabolic health is not fully understood. This randomised, placebo-controlled trial (RCT) examined the influence of vitamin D status and the effect of vitamin D supplementation on metabolomic profiles in older adults. Healthy adults aged 50+ were randomly assigned to consume 20 µg vitamin D3 or a placebo daily for 4 weeks. Serum samples were collected at baseline and post-intervention for 25(OH)D and metabolomics analysis via liquid chromatography tandem mass spectrometry (LC-MS/MS). Pearson's correlation examined relationships between 25(OH)D and metabolite concentrations. GLM ANCOVA compared metabolite concentrations between vitamin D-insufficient (<50 nmol/L) and -sufficient (>50 nmol/L) participants. The repeated-measures general linear model of covariance (RM GLM ANCOVA) examined changes in metabolites over time. Out of 132 metabolites, 2 short chain fatty acid concentrations were higher in the insufficient participants compared to sufficient participants, and 11 glycerophospholipid concentrations were lower in insufficient participants compared to sufficient participants at baseline. Three acylcarnitine concentrations decreased with vitamin D supplementation in vitamin D-insufficient participants. Our findings suggest that vitamin D status influences lipid metabolism in healthy older adults and supports the use of metabolomics in vitamin D research.

The role of temperature on biological activities and the correspondent exponential relationship with temperature has been known for over a century. However, lacking to date is knowledge relating to (a) the recovery of ectotherms subjected to extreme temperatures in the wild, and (b) the effects repeated extreme temperatures have on the temperatures that induce behavioural thermoregulation (aggregations). We examined these questions by testing the hypothesis that thermal thresholds which initiate aggregations in juvenile Atlantic salmon (AS) ( Salmo salar ) are not static, but are temporally dynamic across a summer and follow a hysteresis loop. To test our hypothesis, we deployed custom-made underwater camera (UWC) systems in known AS thermal refuges to observe the timing of aggregation events in a natural system and used these data to develop and test models that predict the temperatures that induce thermal aggregations. Consistent with our hypothesis our UWC observations revealed a range of aggregation onset temperatures (AOT) ranging from 24.2°C to 27.1°C, thus confirming our hypothesis that AOTs are dynamic across summer. Our models suggest it take ~ 11 days of non-thermally taxing temperatures for the AOT to rebound in the study river. Conversely, we found that as the frequency of events increased, the AOT declined, from 27.1°C to 24.2°C. Integrating both model components led to more robust model performance. Further, when these models were tested against an independent data set from the same river, the results remained robust. Our findings illustrate the complexity underlying behavioural thermoregulation in AS-a complexity that most likely extends to other salmonids. The frequency of extreme heat events is predicted to increase, and this has the capacity to decrease AOT thresholds in AS, ultimately reducing their resilience to extreme temperature events., (© The Author(s) 2023. Published by Oxford University Press and the Society for Experimental Biology.)

Introduction: Infants acquire maternal antibodies by Fc receptor transcytosis across the placenta during pregnancy. Fc receptors are expressed on immune cells and are important for activation of effector cell functions., Methods: In this study, we evaluated Fc receptor engagement and ADCC activity of plasma binding antibodies from human immunodeficiency virus-1 (HIV) -infected mothers and to identify factors that may contribute to protection from HIV vertical transmission., Results: HIV-specific binding and Fc receptor engagement of plasma antibodies varied between mothers by transmission status and infants by infection status. Non-transmitting (NT) mothers and HIV-uninfected infants had antibodies with higher neonatal Fc receptor (FcRn) and FcγR engagement, as compared to transmitting (T) mothers and HIV+ infants, respectively. A significant inverse correlation between plasma antibody FcRn and FcγR engagement was observed for T mothers, but not NT mothers. Conversely, a significant direct correlation was observed between plasma antibody FcRn and FcγR engagement for HIV- infants, but not for HIV+ infants. Consequently, we observed significantly higher plasma antibody ADCC potency and breadth in HIV- infants, as compared to HIV+ infants. However, no differences in overall ADCC potency and breadth were observed between mothers. FcRn-engagement of HIV-specific antibodies in both mothers and infants predicted a lack of vertical transmission of HIV., Discussion: This study indicates that HIV-uninfected infants acquire HIV-specific antibodies with greater Fc receptor engagement and thus, greater ADCC capacity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Barrows, Krebs, Jian, Zemil, Slike, Dussupt, Tran, Mendez-Rivera, Chang, O’Sullivan, Mann, Sanders-Buell, Shubin, Creegan, Paquin-Proulx, Ehrenberg, Laurence-Chenine, Srithanaviboonchai, Thomas, Eller, Ferrari, Robb, Rao, Tovanabutra, Polonis and Wieczorek.)

Background: Biologic medications, specifically tumour necrosis factor-α (TNF-α) inhibitors, have become increasingly prevalent in the treatment of chronic inflammatory disease (CID) in pregnancy., Objective: To determine pregnancy outcomes in women with CID exposed to biologics during pregnancy., Search Strategy: PubMed and EMBASE databases were searched through January 1998-July 2021., Selection Criteria: Peer-reviewed, English-language cohort, case-control, cross-sectional studies, and case series that contained original data., Data Collection and Analysis: Two authors independently conducted data extraction. A meta-analysis of proportions using a random-effects model was used to pool outcomes. Linear regression analysis was used to compare the mean of proportions of outcomes across exposure groups using the 'treated' group as the reference category. All studies were evaluated using an appropriate quality assessment tool. The GRADE approach was used to assess the overall certainty of evidence., Main Results: Thirty-five studies, describing 11 172 pregnancies, were eligible for inclusion. Analysis showed pooled proportions for congenital malformations as follows: treated 0.04 (95% CI 0.03-0.04; I 2  = 77) versus disease-matched 0.04 (95% CI 0.03-0.05. I 2  = 86; p = 0.238); preterm delivery treated 0.04 (95% CI 0.10-0.14; I 2  = 88) versus disease-matched 0.10 (95% CI 0.09-0.12; I 2  = 87; p = 0.250); severe neonatal infection: treated 0.05 (95% CI 0.03-0.07; I 2  = 88) versus disease-matched 0.05 (95% CI 0.02-0.07; I 2  = 94; p = 0.970); low birthweight: treated 0.10 (95% CI 0.07-0.12; I 2  = 93) versus disease-matched 0.08 (95% CI 0.07-0.09; I 2  = 0; p = 0.241); pooled miscarriage: treated 0.13 (95% CI 0.10-0.15; I 2  = 77) versus disease-matched 0.08 (95% CI 0.04-0.11; I 2  = 5; p = 0.078); pre-eclampsia; treated 0.01 (95% CI 0.01-0.02; I 2  = 0) versus disease-matched 0.01 (95% CI 0.00-0.01; I 2  = 0; p = 0.193). No statistical differences in proportions were observed. GRADE certainty of findings was low to very low., Conclusion: We demonstrated comparable pregnancy outcomes in pregnancies exposed to biologics, disease-matched controls and CID-free pregnancies using the GRADE approach., (© 2022 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

In-vitro evidence suggests that the lipid component of foods alters vitamin D absorption. This single-blinded, cross-over postprandial study examined the effect of changing the lipid component of a 20 µg vitamin D 3 fortified dairy drink on postprandial 25(OH)D concentrations. Participants consumed one dairy drink per visit: a non-lipid, a pre-formed oleic acid micelle, an olive oil and a fish oil dairy drink. There was a significant time*drink*baseline status effect on 25(OH)D concentrations ( p  = 0.039). There were no time*drink, time or drink effects on 25(OH)D in vitamin D sufficient participants (>50nmol/L). However, there was an effect of time on changes in 25(OH)D concentrations after the olive oil dairy drink ( p  = 0.034) in vitamin D insufficient participants (<50nmol/L). There were no effects after the other diary drinks. Olive oil may improve vitamin D absorption from fortified foods. Further research is needed to examine the practical implications of changing the lipid component of fortified foods.

Eliciting broadly neutralizing antibodies (bnAbs) is a cornerstone of HIV-1 vaccine strategies. Comparing HIV-1 envelope (env) sequences from the first weeks of infection to the breadth of antibody responses observed several years after infection can help define viral features critical to vaccine design. We investigated the relationship between HIV-1 env genetics and the development of neutralization breadth in 70 individuals enrolled in a prospective acute HIV-1 cohort. Half of the individuals who developed bnAbs were infected with multiple HIV-1 founder variants, whereas all individuals with limited neutralization breadth had been infected with single HIV-1 founders. Accordingly, at HIV-1 diagnosis, env diversity was significantly higher in participants who later developed bnAbs compared to those with limited breadth (p = 0.012). This association between founder multiplicity and the subsequent development of neutralization breadth was also observed in 56 placebo recipients in the RV144 vaccine efficacy trial. In addition, we found no evidence that neutralization breath was heritable when analyzing env sequences from the 126 participants. These results demonstrate that the presence of slightly different HIV-1 variants in acute infection could promote the induction of bnAbs, suggesting a novel vaccine strategy, whereby an initial immunization with a cocktail of minimally distant antigens would be able to initiate bnAb development towards breadth., Competing Interests: The authors have declared that no competing interests exist.

Vitamin D intakes and status are low in many countries due to seasonal UVB exposure variation and the fact that few foods are naturally vitamin D rich. Data modelling studies show that vitamin D intakes increase with food fortification, and countries with mandatory fortification policies have higher vitamin D intakes and status compared to countries without. While many foods can be vitamin D fortified, vitamin D bioavailability differs depending on fortification methods, food structure and composition. Randomised controlled trials (RCT) report that vitamin D 2 bioavailability varies between foods, whereas vitamin D 3 is bioavailable from many foods. In vitro studies suggest that altering the lipid composition of fortified foods increases vitamin D 3 absorption. Olive oil increased vitamin D 3 absorption during in vitro digestion compared to other dietary oils. Additionally, when vitamin D 3 was incorporated into micelles formed from in vitro digestion of olive oil, more vitamin D 3 was absorbed compared to other dietary oils. However, in a human postprandial study, a preformed vitamin D 3 micelle dairy drink did not increase vitamin D 3 absorption, and a vitamin D 3 olive dairy drink increased vitamin D 3 absorption in vitamin D insufficient participants only. Action is urgently needed to improve vitamin D intakes and status worldwide. Food fortification improves vitamin D intakes; however, fortification strategies unique to each country are needed. This review will synthesise the literature describing data modelling and intervention trials that assess the safety and efficacy of vitamin D fortification strategies, and those manipulating food composition to alter vitamin D bioavailability from fortified foods. Additionally, RCT examining the impact of vitamin D fortification strategies on vitamin D intakes and status over time are reviewed.

Identifying whether viral features present in acute HIV-1 infection predetermine the development of neutralization breadth is critical to vaccine design. Incorporating such features in vaccine antigens could initiate cross-reactive antibody responses that could sufficiently protect vaccinees from HIV-1 infection despite the uniqueness of each founder virus. To understand the relationship between Env determinants and the development of neutralization breadth, we focused on 197 individuals enrolled in two cohorts in Thailand and East Africa (RV144 and RV217) and followed since their diagnosis in acute or early HIV-1 infection. We analyzed the distribution of variable loop lengths and glycans, as well as the predicted density of the glycan shield, and compared these envelope features to the neutralization breadth data obtained 3 years after infection ( n   = 121). Our study revealed limited evidence for glycan shield features that associate with the development of neutralization breadth. While the glycan shield tended to be denser in participants who subsequently developed breadth, no significant relationship was found between the size of glycan holes and the development of neutralization breadth. The parallel analysis of 3,000 independent Env sequences showed no evidence of directional evolution of glycan shield features since the beginning of the epidemic. Together, our results highlight that glycan shield features in acute and early HIV-1 infection may not play a role determinant enough to dictate the development of neutralization breadth and instead suggest that the glycan shield's reactive properties that are associated with immune evasion may have a greater impact. IMPORTANCE A major goal of HIV-1 vaccine research is to design vaccine candidates that elicit potent broadly neutralizing antibodies (bNAbs). Different viral features have been associated with the development of bNAbs, including the glycan shield on the surface of the HIV-1 Envelope (Env). Here, we analyzed data from two cohorts of individuals who were followed from early infection to several years after infection spanning multiple HIV-1 subtypes. We compared Env glycan features in HIV-1 sequences obtained in early infection to the potency and breadth of neutralizing antibodies measured 1 to 3 years after infection. We found limited evidence of glycan shield properties that associate with the development of neutralization breadth in these cohorts. These results may have important implications for antigen design in future vaccine strategies and emphasize that HIV-1 vaccines will need to rely on a complex set of properties to elicit neutralization breadth.

Genes, sex, age, diet, lifestyle, gut microbiome, and multiple other factors affect human metabolomic profiles. Understanding metabolomic variation is critical in human nutrition research as metabolites that are sensitive to change versus those that are more stable might be more informative for a particular study design. This study aims to identify stable metabolomic regions and determine the genetic and environmental contributions to stability. Using a classic twin design, 1 H nuclear magnetic resonance (NMR) urinary metabolomic profiles were measured in 128 twins at baseline, 1 month, and 2 months. Multivariate mixed models identified stable urinary metabolites with intraclass correlation coefficients ≥0.51. Longitudinal twin modeling measured the contribution of genetic and environmental influences to variation in the stable urinary NMR metabolome, comprising stable metabolites. The conservation of an individual's stable urinary NMR metabolome over time was assessed by calculating conservation indices. In this study, 20% of the urinary NMR metabolome is stable over 2 months (intraclass correlation (ICC) 0.51-0.65). Common genetic and shared environmental factors contributed to variance in the stable urinary NMR metabolome over time. Using the stable metabolome, 91% of individuals had good metabolomic conservation indices ≥0.70. To conclude, this research identifies 20% of the urinary NMR metabolome as stable, improves our knowledge of the sources of metabolomic variation over time, and demonstrates the conservation of an individual's urinary NMR metabolome.

The scale of the HIV-1 epidemic underscores the need for a vaccine. The multitude of circulating HIV-1 strains together with HIV-1's high evolvability hints that HIV-1 could adapt to a future vaccine. Here, we wanted to investigate the effect of vaccination on the evolution of the virus post-breakthrough infection. We analyzed 2,635 HIV-1 env sequences sampled up to a year post-diagnosis from 110 vaccine and placebo participants who became infected in the RV144 vaccine efficacy trial. We showed that the Env signature sites that were previously identified to distinguish vaccine and placebo participants were maintained over time. In addition, fewer sites were under diversifying selection in the vaccine group than in the placebo group. These results indicate that HIV-1 would possibly adapt to a vaccine upon its roll-out., (© The Author(s) 2021. Published by Oxford University Press.)

Background: Early applications of metabolomics in nutrition and health research identified associations between dietary patterns and metabolomic profiles. Twin studies show that diet-related phenotypes and diet-associated metabolites are influenced by genes. However, studies have not examined whether diet-metabolite associations are explained by genetic or environmental factors and whether these associations are reproducible over multiple time points., Objective: This research aims to examine the genetic and environmental factors influencing covariation in diet-metabolite associations that are reproducible over time in healthy twins., Methods: The UCD Twin Study is a semi-longitudinal classic twin study that collected repeated dietary, anthropometric, and urinary data over 2 months. Correlation analysis identified associations between diet quality measured using the Healthy Eating Index (HEI) and urinary metabolomic profiles at 3 time points. Diet-associated metabolites were examined using linear regression to identify those significantly influenced by familial factors between twins and those significantly influenced by unique factors. Cholesky decomposition modeling quantified the genetic and environmental path coefficients through associated dietary components onto the metabolites., Results: The HEI was associated with 14 urinary metabolites across 3 metabolomic profiles (r: ±0.15-0.49). For 8 diet-metabolite associations, genetic or shared environmental factors influencing HEI component scores significantly influenced variation in metabolites (β: 0.40-0.52). A significant relation was observed between dietary intakes of whole grain and acetoacetate (β: -0.50, P < 0.001) and β-hydroxybutyrate (β: -0.46, P < 0.001), as well as intakes of saturated fat and acetoacetate (β: 0.47, P < 0.001) and β-hydroxybutyrate (β: 0.52, P < 0.001). For these diet-metabolite associations a common shared environmental factor explained 66-69% of variance in the metabolites., Conclusions: This study shows that diet-metabolite associations are reproducible in 3 urinary metabolomic profiles. Components of the HEI covary with metabolites, and covariation is largely due to the shared environment., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

While large datasets of HIV-1 sequences are increasingly being generated, many studies rely on a single gene or fragment of the genome and few comparative studies across genes have been done. We performed genome-based and gene-specific Bayesian phylogenetic analyses to investigate how certain factors impact estimates of the infection dates in an acute HIV-1 infection cohort, RV217. In this cohort, HIV-1 diagnosis corresponded to the first RNA positive test and occurred a median of four days after the last negative test, allowing us to compare timing estimates using BEAST to a narrow window of infection. We analyzed HIV-1 sequences sampled one week, one month and six months after HIV-1 diagnosis in 39 individuals. We found that shared diversity and temporal signal was limited in acute infection, and insufficient to allow timing inferences in the shortest HIV-1 genes, thus dated phylogenies were primarily analyzed for env, gag, pol and near full-length genomes. There was no one best-fitting model across participants and genes, though relaxed molecular clocks (73% of best-fitting models) and the Bayesian skyline (49%) tended to be favored. For infections with single founders, the infection date was estimated to be around one week pre-diagnosis for env (IQR: 3-9 days) and gag (IQR: 5-9 days), whilst the genome placed it at a median of 10 days (IQR: 4-19). Multiply-founded infections proved problematic to date. Our ability to compare timing inferences to precise estimates of HIV-1 infection (within a week) highlights that molecular dating methods can be applied to within-host datasets from early infection. Nonetheless, our results also suggest caution when using uniform clock and population models or short genes with limited information content., Competing Interests: The authors have declared that no competing interests exist.

We analyzed human immunodeficiency virus envelope diversity in 98 acute infections. The within-host genetic diversity, divergence from transmitted/founder (T/F) strain, and the observed frequency of multiple T/F infections increased with Fiebig stage. These data identify rapid viral dynamics during acute infection with implications for clinical trials conducted in this setting., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Infusion of the broadly neutralizing antibody VRC01 has been evaluated in individuals chronically infected with HIV-1. Here, we studied how VRC01 infusions affected viral rebound after cessation of antiretroviral therapy (ART) in 18 acutely treated and durably suppressed individuals. Viral rebound occurred in all individuals, yet VRC01 infusions modestly delayed rebound and participants who showed a faster decay of VRC01 in serum rebounded more rapidly. Participants with strains most sensitive to VRC01 or with VRC01 epitope motifs similar to known VRC01-susceptible strains rebounded later. Upon rebound, HIV-1 sequences were indistinguishable from those sampled at diagnosis. Across the cohort, participant-derived Env showed different sensitivity to VRC01 neutralization (including 2 resistant viruses), yet neutralization sensitivity was similar at diagnosis and after rebound, indicating the lack of selection for VRC01 resistance during treatment interruption. Our results showed that viremia rebounded despite the absence of HIV-1 adaptation to VRC01 and an average VRC01 trough of 221 μg/mL. Although VRC01 levels were insufficient to prevent a resurgent infection, knowledge that they did not mediate Env mutations in acute-like viruses is relevant for antibody-based strategies in acute infection.

Background: The benefits of cold pulsatile machine perfusion (MP) for the storage and transportation of kidneys donated after circulatory death are disputed. We conducted a UK-based multicenter, randomized controlled trial to compare outcomes of kidneys stored with MP versus static cold storage (CS)., Methods: Fifty-one pairs of kidneys donated after circulatory death were randomly allocated to receive static CS or cold pulsatile MP. The primary endpoint, delayed graft function, was analyzed by "intention-to-treat" evaluation., Results: There was no difference in the incidence of delayed graft function between CS and MP (32/51 (62.8%) and 30/51 (58.8%) P = 0.69, respectively), although the trial stopped early due to difficulty with recruitment. There was no difference in the incidence of acute rejection, or in graft or patient survival between the CS and MP groups. Median estimated glomerular filtration rate at 3 months following transplantation was significantly lower in the CS group compared with MP (CS 34 mL/min IQR 26-44 vs MP 45 mL/min IQR 36-60, P = 0.006), although there was no significant difference in estimated glomerular filtration rate between CS and MP at 12 months posttransplant., Conclusions: This study is underpowered, which limits definitive conclusions about the use of MP, as an alternative to static CS. It did not demonstrate that the use of MP reduces the incidence of delayed graft function in donation after circulatory death kidney transplantation.

Humans have the ability to permanently alter aquatic ecosystems and the introduction of species is often the most serious alteration. Non-native Smallmouth Bass ( Micropterus dolomieu ) were identified in Miramichi Lake c . 2008, which is a headwater tributary to the Southwest Miramichi River, a renowned Atlantic Salmon ( Salmo salar ) river whose salmon population is dwindling. A containment programme managed by the Department of Fisheries and Oceans, Canada (DFO) was implemented in 2009 to confine Smallmouth Bass (SMB) to the lake. We utilized environmental DNA (eDNA) as a detection tool to establish the potential escape of SMB into the Southwest Miramichi River. We sampled at 26 unique sites within Miramichi Lake, the outlet of Miramichi Lake (Lake Brook), which flows into the main stem Southwest Miramichi River, and the main stem Southwest Miramichi River between August and October 2017. We observed n  = 6 positive detections located in the lake, Lake Brook, and the main stem Southwest Miramichi downstream of the lake. No detections were observed upstream of the confluence of Lake Brook and the main stem Southwest Miramichi. The spatial pattern of positive eDNA detections downstream of the lake suggests the presence of individual fish versus lake-sourced DNA in the outlet stream discharging to the main river. Smallmouth Bass were later confirmed by visual observation during a snorkeling campaign, and angling. Our results, both eDNA and visual confirmation, definitively show Smallmouth Bass now occupy the main stem of the Southwest Miramichi., Competing Interests: None declared., (© 2020 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

HIV-1 disseminates to a broad range of tissue compartments during acute HIV-1 infection (AHI). The central nervous system (CNS) can serve as an early and persistent site of viral replication, which poses a potential challenge for HIV-1 remission strategies that target the HIV reservoir. CNS compartmentalization is a key feature of HIV-1 neuropathogenesis. Thus far, the timing of how early CNS compartmentalization develops after infection is unknown. We examined whether HIV-1 transmitted/founder (T/F) viruses differ between CNS and blood during AHI using single-genome sequencing of envelope gene and further examined subregions in pol and env using next-generation sequencing in paired plasma and cerebrospinal fluid (CSF) from 18 individuals. Different proportions of mostly minor variants were found in six of the eight multiple T/F-infected individuals, indicating enrichment of some variants in CSF that may lead to significant compartmentalization in the later stages of infection. This study provides evidence for the first time that HIV-1 compartmentalization in the CNS can occur within days of HIV-1 exposure in multiple T/F infections. Further understanding of factors that determine enrichment of T/F variants in the CNS, as well as potential long-term implications of these findings for persistence of HIV-1 reservoirs and neurological impairment in HIV, is needed.

Novel metabolomic profiling techniques combined with traditional biomarkers provide knowledge of mechanisms underlying metabolic health. Twin studies describe the impact of genes and environment on variation in traits. This study aims to identify relationships between traditional markers of metabolic health and the plasma metabolomic profile using a twin modeling approach and determine whether covariation is caused by shared genetic and environmental factors. Using a classic twin design, this study examined covariation between anthropometric, clinical chemistry, and metabolomic profiles. Cholesky decomposition modeling was used to determine the genetic and environmental path coefficients through successive anthropometric and clinical chemistry traits onto metabolomic derived metabolites. This study shows that WC, TAG, and a metabolomic signature composed of 7 metabolites are inter-related, and that covariation can be attributed to common genetic, shared and unique environmental factors as well as unique environmental factors specific to the metabolite. This quantitative modeling connecting the traditional anthropometry and clinical chemistry traits with the more recent and potentially more sensitive metabolomic profile approach may provide further insight on the pleiotropic genes or modifiable environmental factors influencing variation in metabolic health.

HIV-1 strain diversity in Bulgaria is extensive and includes contributions from nearly all major subtypes and the Circulating Recombinant Forms (CRF): 01&#95;AE, 02&#95;AG, and 05&#95;DF. Prior to this study, HIV-1 sequence information from Bulgaria has been based solely on the pro-RT gene, which represent less than 15% of the viral genome. To further characterize HIV-1 in Bulgaria, assess participant risk behaviors, and strengthen knowledge of circulating strains in the region, the study "Genetic Subtypes of HIV-1 in Bulgaria (RV240)" was conducted. This study employed the real time-PCR based Multi-region Hybridization Assay (MHA) B/non-B and HIV-1 sequencing to survey 215 of the approximately 1100 known HIV-1 infected Bulgarian adults (2008-2009) and determine if they were infected with subtype B HIV-1. The results indicated a subtype B prevalence of 40% and demonstrate the application of the MHA B/non-B in an area containing broad HIV-1 strain diversity. Within the assessed risk behaviors, the proportion of subtype B infection was greatest in men who have sex with men and lowest among those with drug use risk factors. During this study, 15 near full-length genomes and 22 envelope sequences were isolated from study participants. Phylogenetic analysis shows the presence of subtypes A1, B, C, F1, and G, CRF01&#95;AE, CRF02&#95;AG, CRF05&#95;DF, and one unique recombinant form (URF). These sequences also show the presence of two strain groups containing participants with similar risk factors. Previous studies in African and Asian cohorts have shown that co-circulation of multiple subtypes can lead to viral recombination within super-infected individuals and the emergence of new URFs. The low prevalence of URFs in the presence of high subtype diversity in this study, may be the result of successful infection prevention and control programs. Continued epidemiological monitoring and support of infection prevention programs will help maintain control of the HIV-1 epidemic in Bulgaria., Competing Interests: GHK is currently a paid employee of GlaxoSmithKline. However, his contribution to the research reported on in this paper took place prior to this commercial affiliation. This does not affect our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development, or marketed products to declare.The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Army, DoD, or US government.

Canine dystocia is a relatively common veterinary presentation. First opinion emergency care clinical data from 50 Vets Now clinics across the UK were used to explore dystocia management and outcomes in bitches. Caesarean section (CS) was performed on 341/701 (48.6 per cent (95 per cent CI 44.9 to 52.4)) of dystocia cases. The bulldog (OR 7.60, 95 per cent CI 1.51 to 38.26, P=0.014), Border terrier (OR 4.89, 95 per cent CI 0.92 to 25.97, P=0.063) and golden retriever (OR 4.07, 95 per cent CI 0.97 to 17.07, P=0.055) had the highest odds of CS among dystocic bitches compared with crossbreds. Brachycephalic dystocic bitches had 1.54 (95 per cent CI 1.05 to 2.28, P=0.028) times the odds of CS compared with non-brachycephalics. Oxytocin was administered to 380/701 (54.2 per cent) and calcium gluconate was administered to 82/701 (11.7 per cent) of dystocic bitches. 12 of 701 dystocia cases (1.7 per cent) died during emergency care. These results can help veterinary surgeons to provide better evidence on the risks to owners who may be contemplating breeding from their bitches. In addition, the results on the management and clinical trajectory of dystocia can facilitate clinical benchmarking and encourage clinical audit within primary care veterinary practice., Competing Interests: Competing interests: None declared., (© British Veterinary Association 2019. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Lineage-based vaccine design is an attractive approach for eliciting broadly neutralizing antibodies (bNAbs) against HIV-1. However, most bNAb lineages studied to date have features indicative of unusual recombination and/or development. From an individual in the prospective RV217 cohort, we identified three lineages of bNAbs targeting the membrane-proximal external region (MPER) of the HIV-1 envelope. Antibodies RV217-VRC42.01, -VRC43.01, and -VRC46.01 used distinct modes of recognition and neutralized 96%, 62%, and 30%, respectively, of a 208-strain virus panel. All three lineages had modest levels of somatic hypermutation and normal antibody-loop lengths and were initiated by the founder virus MPER. The broadest lineage, VRC42, was similar to the known bNAb 4E10. A multimeric immunogen based on the founder MPER activated B cells bearing the unmutated common ancestor of VRC42, with modest maturation of early VRC42 intermediates imparting neutralization breadth. These features suggest that VRC42 may be a promising template for lineage-based vaccine design., (Published by Elsevier Inc.)

The analysis of HIV-1 sequences has helped understand the viral molecular epidemiology, monitor the development of antiretroviral drug resistance, and design candidate vaccines. The introduction of single genome amplification (SGA) has been a major advancement in the field, allowing for the characterization of multiple sequences per patient while preserving linkage among polymorphisms in the same viral genome copy. Sequencing of SGA amplicons is performed by capillary Sanger sequencing, which presents low throughput, requires a high amount of template, and is highly sensitive to template/primer mismatching. In order to meet the increasing demand for HIV-1 SGA amplicon sequencing, we have developed a platform based on benchtop next-generation sequencing (NGS) (IonTorrent) accompanied by a bioinformatics pipeline capable of running on computer resources commonly available at research laboratories. During assay validation, the NGS-based sequencing of 10 HIV-1 env SGA amplicons was fully concordant with Sanger sequencing. The field test was conducted on plasma samples from 10 US Navy and Marine service members with recent HIV-1 infection (sampling interval: 2005-2010; plasma viral load: 5,884-194,984 copies/ml). The NGS analysis of 101 SGA amplicons (median: 10 amplicons/individual) showed within-individual viral sequence profiles expected in individuals at this disease stage, including individuals with highly homogeneous quasispecies, individuals with two highly homogeneous viral lineages, and individuals with heterogeneous viral populations. In a scalability assessment using the Ion Chef automated system, 41/43 tested env SGA amplicons (95%) multiplexed on a single Ion 318 chip showed consistent gene-wide coverage >50×. With lower sample requirements and higher throughput, this approach is suitable to support the increasing demand for high-quality and cost-effective HIV-1 sequences in fields such as molecular epidemiology, and development of preventive and therapeutic strategies.

Background: Across sub-Saharan Africa, men who have sex with men (MSM) and transgender women (TGW) have disproportionately poor HIV treatment outcomes. Stigma and criminalization create barriers to health-care engagement and adherence to antiretroviral therapy (ART), potentially promoting the development of HIV drug resistance (HIVDR). We evaluated transmitted, pre-treatment and acquired HIVDR among MSM and TGW in Lagos and Abuja, Nigeria., Methods: Adults with HIV RNA ≥1,000 copies/ml in the TRUST/RV368 cohort, including incident cases diagnosed via 3-monthly screening, underwent HIVDR testing using the Sanger sequencing method. Major mutations conferring resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were identified from the 2017 IAS-USA list. World Health Organization surveillance drug resistance mutations (SDRMs) were identified in ART-naive participants., Results: From March 2013 to June 2017, 415 participants with median age 24 (interquartile range [IQR] 21-27) years, CD4 + T-cell count 370 (IQR 272-502) cells/mm 3 , and HIV RNA 4.73 (IQR 4.26-5.15) log 10 copies/ml underwent HIVDR testing. SDRMs were observed in 36 of 373 ART-naive participants (9.7%, 95% confidence interval [95% CI 6.8, 13.1%]), including 8 of 39 incident cases (20.5%, [95% CI] 9.3, 36.5%). Among 42 ART-experienced participants, NNRTI resistance was detected in 18 (42.9%, 95% CI 27.7, 59.0%) and NRTI resistance in 10 (23.8%, 95% CI 12.0, 39.4%). No PI resistance was detected., Conclusions: The high prevalence of transmitted and acquired drug resistance among Nigerian MSM and TGW living with HIV suggests the need for programmatic solutions to improve uninterrupted access to ART and timely switch to second-line regimens in cases of viral failure.

Introduction: Thailand plays a substantial role in global HIV-1 transmission of CRF01&#95;AE. Worldwide, men who have sex with men (MSM) are at elevated risk for HIV-1 infection. Hence, understanding HIV-1 diversity in a primarily Thai MSM cohort with acute infection, and its connections to the broader HIV-1 transmission network in Asia is crucial for research and development of HIV-1 vaccines, treatment and cure., Methods: Subtypes and diversity of infecting viruses from individuals sampled from 2009 to 2015 within the RV254/SEARCH 010 cohort were assessed by multiregion hybridization assay (MHAbce), multiregion subtype-specific PCR assay (MSSPbce) and full-length single-genome sequencing (SGS). Phylogenetic analysis was performed by maximum likelihood. Pairwise genetic distances of envelope gp160 sequences obtained from the cohort and from Asia (Los Alamos National Laboratory HIV Database) were calculated to identify potential transmission networks., Results: MHAbce/MSSPbce results identified 81.6% CRF01&#95;AE infecting strains in RV254. CRF01&#95;AE/B recombinants and subtype B were found at 7.3% and 2.8% respectively. Western subtype B strains outnumbered Thai B' strains. Phylogenetic analysis revealed one C, one CRF01&#95;AE/CRF02&#95;AG recombinant and one CRF01&#95;AE/B/C recombinant. Asian network analysis identified one hundred and twenty-three clusters, including five clusters of RV254 participants. None of the RV254 sequences clustered with non-RV254 sequences. The largest international cluster involved 15 CRF01&#95;AE strains from China and Vietnam. The remaining clusters were mostly intracountry connections, of which 31.7% included Thai nodes and 43.1% included Chinese nodes., Conclusion: While the majority of strains in Thailand are CRF01&#95;AE and subtype B, emergence of unique recombinant forms (URFs) are found in a moderate fraction of new HIV-1 infections. Approaches to vaccine design and immunotherapeutics will need to monitor and consider the expanding proportion of recombinants and the increasing genetic diversity in the region. Identified HIV-1 transmission networks indicate ongoing spread of HIV-1 among MSM. As HIV-1 epidemics continue to expand in other Asian countries, transmission network analyses can inform strategies for prevention, intervention, treatment and cure., (© 2018 Henry M. Jackson Foundation for the Advancement of Military Medicine Inc. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background: B cells produce alloantibodies and activate alloreactive T cells, negatively affecting kidney transplant survival. By contrast, regulatory B cells are associated with transplant tolerance. Immunotherapies are needed that inhibit B-cell effector function, including antibody secretion, while sparing regulators and minimising infection risk. B lymphocyte stimulator (BLyS) is a cytokine that promotes B-cell activation and has not previously been targeted in kidney transplant recipients. We aimed to determine the safety and activity of an anti-BLyS antibody, belimumab, in addition to standard-of-care immunosuppression in adult kidney transplant recipients. We used an experimental medicine study design with multiple secondary and exploratory endpoints to gain further insight into the effect of belimumab on the generation of de-novo IgG and on the regulatory B-cell compartment., Methods: We undertook a double-blind, randomised, placebo-controlled phase 2 trial of belimumab, in addition to standard-of-care immunosuppression (basiliximab, mycophenolate mofetil, tacrolimus, and prednisolone) at two centres, Addenbrooke's Hospital, Cambridge, UK, and Guy's and St Thomas' Hospital, London, UK. Participants were eligible if they were aged 18-75 years and receiving a kidney transplant and were planned to receive standard-of-care immunosuppression. Participants were randomly assigned (1:1) to receive either intravenous belimumab 10 mg per kg bodyweight or placebo, given at day 0, 14, and 28, and then every 4 weeks for a total of seven infusions. The co-primary endpoints were safety and change in the concentration of naive B cells from baseline to week 24, both of which were analysed in all patients who received a transplant and at least one dose of drug or placebo (the modified intention-to-treat [mITT] population). This trial has been completed and is registered with ClinicalTrials.gov, NCT01536379, and EudraCT, 2011-006215-56., Findings: Between Sept 13, 2013, and Feb 8, 2015, of 303 patients assessed for eligibility, 28 kidney transplant recipients were randomly assigned to receive belimumab (n=14) or placebo (n=14). 25 patients (12 [86%] patients assigned to the belimumab group and 13 [93%] patients assigned to the placebo group) received a transplant and were included in the mITT population. We observed similar proportions of adverse events in the belimumab and placebo groups, including serious infections (one [8%] of 12 in the belimumab group and five [38%] of 13 in the placebo group during the 6-month on-treatment phase; and none in the belimumab group and two [15%] in the placebo group during the 6-month follow-up). In the on-treatment phase, one patient in the placebo group died because of fatal myocardial infarction and acute cardiac failure. The co-primary endpoint of a reduction in naive B cells from baseline to week 24 was not met. Treatment with belimumab did not significantly reduce the number of naive B cells from baseline to week 24 (adjusted mean difference between the belimumab and placebo treatment groups -34·4 cells per μL, 95% CI -109·5 to 40·7)., Interpretation: Belimumab might be a useful adjunct to standard-of-care immunosuppression in renal transplantation, with no major increased risk of infection and potential beneficial effects on humoral alloimmunity., Funding: GlaxoSmithKline., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: To determine whether performance in any of the Health Professions Admissions Test (HPAT) sections, most specifically the interpersonal understanding section, correlates with self-reported empathy levels in medical students., Setting: The study was conducted in University College Cork, Ireland., Participants: 290 students participated in the study. Matching HPAT scores were available for 263 students. All male and female undergraduate students were invited to participate. Postgraduate and international students were excluded., Primary and Secondary Outcome Measures: Primary measures: HPAT-Ireland and Jefferson Scale of Physician Empathy (JSE) scores were compared including subsection analysis. Secondary measures: comparisons were made between groups such as gender and year of programme., Results: A total of 290 students participated. Males scored significantly higher than females for total HPAT-Ireland (U=7329, z=-2.04, p<0.05), HPAT-Ireland section 1 (U=5382, z=-5.21, p<0.001) and section 3 scores (U=6833, z=-2.85, p<0.01). In contrast, females scored significantly higher than males on HPAT-Ireland section 2 (U=5844, z=-4.46, p<0.001). Females demonstrated significantly higher total JSE scores relative to males (mean score ± SEM: 113.33±1.05 vs 109.21±0.95; U=8450, z=-2.83, p<0.01). No significant association was observed between JSE scores and any of the HPAT-Ireland measures (all p>0.05). There was no effect of programme year on JSE scores (all p>0.05)., Conclusion: The introduction of the HPAT-Ireland test was partly designed to identify students with strong interpersonal skills. A significant finding of this study is that JSE values did not correlate with HPAT-Ireland scores. This study suggests no clear link between scores on a selection test, the HPAT-Ireland, which is designed to assess several skill domains including interpersonal skills, and scores on a psychometric measure of empathy, at any point during medical education., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

In order to inform the rational design of HIV-1 preventive and cure interventions it is critical to understand the events occurring during acute HIV-1 infection (AHI). Using viral deep sequencing on six participants from the early capture acute infection RV217 cohort, we have studied HIV-1 evolution in plasma collected twice weekly during the first weeks following the advent of viremia. The analysis of infections established by multiple transmitted/founder (T/F) viruses revealed novel viral profiles that included: a) the low-level persistence of minor T/F variants, b) the rapid replacement of the major T/F by a minor T/F, and c) an initial expansion of the minor T/F followed by a quick collapse of the same minor T/F to low frequency. In most participants, cytotoxic T-lymphocyte (CTL) escape was first detected at the end of peak viremia downslope, proceeded at higher rates than previously measured in HIV-1 infection, and usually occurred through the exploration of multiple mutational pathways within an epitope. The rapid emergence of CTL escape variants suggests a strong and early CTL response. Minor T/F viral strains can contribute to rapid and varied profiles of HIV-1 quasispecies evolution during AHI. Overall, our results demonstrate that early, deep, and frequent sampling is needed to investigate viral/host interaction during AHI, which could help identify prerequisites for prevention and cure of HIV-1 infection.

While abundant sequence information is available from human immunodeficiency virus type 1 (HIV-1) subtypes A, B, C and CRF01&#95;AE for HIV-1 vaccine design, sequences from West Africa are less represented. We sought to augment our understanding of HIV-1 variants circulating in 6 Nigerian cities as a step to subsequent HIV-1 vaccine development.The G/CRF02&#95;AG multi-region hybridization assay (MHA) was developed to differentiate subtype G, CRF02&#95;AG and their recombinants from other subtypes based on 7 HIV-1 segments. Plasma from 224 HIV-1 infected volunteers enrolled in a cohort examining HIV-1 prevalence, risk factor, and subtype from Makurdi (30), Abuja (18), Enugu (11), Kaduna (12), Tafa (95), and Ojo/Lagos (58) was analyzed using MHA. HIV-1 genomes from 42 samples were sequenced to validate the MHA and fully explore the recombinant structure of G and CRF02&#95;AG variants.The sensitivity and specificity of MHA varied between 73-100% and 90-100%, respectively. The subtype distribution as identified by MHA among 224 samples revealed 38% CRF02&#95;AG, 28% G, and 26% G/CRF02&#95;AG recombinants while 8% remained nontypeable strains. In envelope (env) gp120, 38.84% of the samples reacted to a G probe while 31.25% reacted to a CRF02 (subtype A) probe. Full genome characterization of 42 sequences revealed the complexity of Nigerian HIV-1 variants.CRF02&#95;AG, subtype G, and their recombinants were the major circulating HIV-1 variants in 6 Nigerian cities. High proportions of samples reacted to a G probe in env gp120 confirms that subtype G infections are abundant and should be considered in strategies for global HIV-1 vaccine development.

The ability of brown seaweed extracts, Ascophyllum nodosum, Laminaria hyperborea, Pelvetia canaliculata, Fucus vesiculosus and Fucus serratus to protect against tert-butyl hydroperoxide (tert-BOOH) induced stress in Caco-2 cells was investigated. Oxidative stress was determined by measuring alteration in the enzymatic activity of catalase (CAT) and superoxide dismutases (SOD) and cellular levels of glutathione (GSH). L. hyperborea, P. canaliculata and F. serratus significantly protected against tert-BOOH induced SOD reduction but did not protect against the reduction in CAT activity or the increased cellular levels of GSH. The ability of F. serratus and F. vesiculosus to protect against H(2)O(2) and tert-BOOH induced DNA damage was also assessed. The DNA protective effects of the two seaweed extracts was compared to those of three metal chelators; deferoxamine mesylate (DFO), 1,10-phenanthroline (o-phen) and 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (BAPTA-AM). F. serratus and F. vesiculosus significantly protected (P<0.05) against H(2)O(2) (50 μM) induced DNA damage but not tert-BOOH induced damage., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Methods for pathogen inactivation are currently available in some European countries for treatment of plasma and platelet (PLT) components; no approved method for treatment of red cells (RBCs) or whole blood is ready for implementation. In a previous study, thiazole orange (TO), a dye commonly used to count reticulated RBCs and PLTs, exhibited potent photoactivity against human immunodeficiency virus-1 and several model viruses in RBC suspensions. The aim of this study is to further evaluate the ability of TO to inactivate pathogens by measuring its activity against the protozoa Leishmania donovani infantum and Trypanosoma cruzi., Study Design and Methods: RBC suspensions were deliberately contaminated with L. donovani infantum promastigotes or T. cruzi trypomastigotes and either maintained as an untreated control, incubated with 80 mumol per L TO in the dark, or treated with TO and light. Control and treated samples were inoculated into medium and subsequently microscopically examined for growth., Results: No growth was observed in samples treated with TO in the presence or absence of light, while matched control samples lacking TO and diluted up to 5 log consistently demonstrated Leishmania or T. cruzi growth (n = 3)., Conclusion: TO inactivated Leishmania or T. cruzi to the limit of detection in RBC suspensions without intentional illumination.

Several groups report stability results for freeze-dried whole plasma intended for use as a transfusion product [Hellstern P, Sachse H, Schwinn H, Oberfrank K. Manufacture and in vitro characterization of a solvent/detergent-treated human plasma. Vox Sang 1992;63:178-185; Trobisch H. Results of a quality-control study of lyophilized pooled plasmas which have been virally inactivated using a solvent detergent method (modified Horowitz procedure). Beitr Infusionsther 1991;28:92-109; Hugler P, Trobish H, Neuman H, Moller, Sirtl C, Derdak M, Laubenthal H. Quality control of three different conventional fresh-frozen plasma preparations and one new virus-inactivated lyophilized pooled plasma preparation. Klin Wochenschr 1991;69:157-161; Krutvacho T, Chuansumrit A, Isarangkura P, Pintadit P, Hathirat P, Chiewsilp P. Response of hemophilia with bleeding to fresh dry plasma. Southeast Asian J Trop Med Public Health 1993;24:169-173; Chuansumrit A, Krasaesub S, Angchaisuksiri P, Hathirat P, Isarangkura P. Survival analysis of patients with haemophilia at the International Haemophilia Training Centre, Bangkok, Thailand. Haemophilia 2004;10:542-549]. Plasma coagulation properties are substantially impaired in these freeze-dried plasmas, while pH levels are close to alkaline. In this work, plasma supplemented with 60mM sucrose, trehalose, mannitol, sorbitol or glycine was freeze-dried. The samples were subjected to forced degradation at 40 degrees C for 10 days in order to quickly evaluate the effectiveness of the different stabilizers. Initial PT, APTT and TT values were 14.4+/-0. 5s, 31.4+/-1.5s and 18.3+/-0.6s, respectively. At the end of the degradation period, PT, APTT and TT were substantially prolonged, and were 19.1+/-0. 5s, 43.1+/-0.6s and 26.1+/-1.0s, respectively. In the presence of glycine, at the end of the degradation period, PT, APTT and TT values remained close to the initial values and were 15.5+/-0. 4s, 35.7+/-0.9s and 19.4+/-0.2s, respectively. Percent activities of the coagulation factors V, VII, VIII, IX, X and the coagulation inhibitors protein C, protein S and antithrombin III were recorded. Factors V and VIII were most prone to degradation. Factor V and VIII activities, in control plasma, were approx. 44+/-3.5% and 58+/-2.3%, at the end of storage. In contrast, much higher factor V and VIII activities were maintained in the lyophilized glycine-supplemented plasma: approx. 60+/-3.5% and 74+/-7.0%, correspondingly. The most stable protein was protein C, which showed no signs of degradation under the testing conditions of this study. All tested stabilizers provided protection. Glycine, however, outperformed all tested polyols, providing superior preservation of plasma clotting properties. Thermograms of 60mM glycine in water and 60mM glycine in plasma show that, in the presence of plasma, glycine does not crystallize. The process of freeze-drying caused a complete loss of plasma pCO(2) (gas) and a substantial increase in plasma pH. Citric acid was found to be a suitable pH adjuster for lyophilized/rehydrated plasma.

Endotoxin was administered to mice on their 13th day of pregnancy at doses which caused the resorption of approximately 50% of the implanted foetuses. The iron chelator desferrioxamine was found to significantly inhibit the percentage of resorptions induced by endotoxin in a dose-dependent manner. The highest dose of desferrioxamine (5 mg) given intravenously 30 min prior to, immediately after, and 4 and 24 h after endotoxin inoculation, reduced the percentage of resorptions from 56.9 to 17.9%. Administration of the novel selenium-containing compound ebselen, which is both an antioxidant and an inhibitor of leukotriene synthesis, was also found to significantly protect against endotoxin-induced foetal resorptions, reducing the percentage of resorbed foetuses from 52.9 to 26.0% when given at a dose of 50 mg/kg (s.c.) at the time of endotoxin inoculation and 24 and 48 h following. Both these compounds also significantly reduced the increase in spleen weights observed when the mice were given endotoxin. These results provide evidence that the iron-catalysed production of hydroxyl radicals from other oxygen-derived species and the formation of leukotrienes play an important role in the mechanism by which endotoxin causes foetal resorptions in the mouse.

Information on employment was obtained from 157 adults with spina bifida aged 18-26 years. Ninety were given an additional interview, 43% had been employed at some time, but only 19% currently. They mainly did routine, non-manual work for average working hours, but below average pay. They enjoyed their jobs, principally for the social contact, and were well accepted by employees and work-mates. Unfortunately, job retention was poor. The 81% who were unemployed largely hoped to find a job, but suitable ones were not available. They considered that they should have more help to find jobs. Their days were mainly spent at home or at day centres. They had no doubts that being unemployed had many disadvantages, of which the principal one was lack of social contact, but financial hardship was also mentioned.

Purified lipopolysaccharide (LPS) obtained from isolates of Campylobacter fetus ss. fetus and Campylobacter jejuni impaired fetal development when administered to mice on day 13 of pregnancy. Strikingly more fetal resorption was produced by C. jejuni LPS than by similar amounts of C. fetus ss. fetus LPS. Three of the four Campylobacter strains examined produced LPS that had no effect on maternal health, but LPS from one C. jejuni strain killed all of the mice to which it was administered.

Intravenous injection of eight human strains of Campylobacter fetus ss fetus and Campylobacter jejuni into mice at various stages of pregnancy demonstrated significant strain differences in ability to affect implantation of the fertilised ovum and to cause resorption of the mouse fetus. Implantation was significantly impaired when C. fetus ss fetus was injected intravenously on day 2 of pregnancy, but no effect was observed in mice receiving C. jejuni. On day 6 of pregnancy, before the development of placental circulation, both C. fetus ss fetus and C. jejuni impaired fetal growth; one strain of C. jejuni had a greater effect than others of the same species. In animals inoculated on day 13 of pregnancy, after the development of placental circulation, six of the eight campylobacter strains caused resorption of the mouse embryos. A similar effect on the embryos was observed after injection of heat-killed organisms, and endotoxin-like substances may have been responsible. It is also suggested that factors other than endotoxin-like substances have a deleterious effect on embryonic growth.

Pregnant guinea pigs were used to compare the virulence of four human isolates of Campylobacter fetus ss. fetus and four of C. jejuni on the basis of their ability to cause abortion and bacteraemia. Of the four strains of C. fetus ss. fetus two produced abortion readily after intramuscular injection. The four C. jejuni isolates were, however, of comparatively low virulence and no differences between them were demonstrated. Some of the isolates differed in their ability to survive in vitro in human and guinea-pig serum. It is suggested that campylobacters vary in their virulence for man and that this may influence the outcome of infections. Guinea pigs may prove useful in studying the pathogenesis of systemic campylobacter infections.