Prevalence of syphilis among adults and adolescents in five sub-Saharan African countries: findings from Population-based HIV Impact Assessment surveys.

BACKGROUND: HIV and syphilis are common sexually transmitted infections in sub-Saharan Africa. We aimed to investigate the prevalence and distribution of active syphilis while considering HIV status, demographic characteristics, and behavioural characteristics. METHODS: The Population-based HIV Impact Assessment surveys used a cross-sectional, two-stage, stratified cluster sample design to collect data in Ethiopia, Tanzania, Uganda, Zambia, and Zimbabwe from 2015 to 2018. Eligible participants were aged 15 years and older and provided demographic information, behavioural information, and blood specimens for HIV and syphilis testing. Active syphilis was defined as the presence of both treponemal and non-treponemal antibodies, measured using an antigen-based rapid test. Multivariable logistic regression models with survey weights were applied. The estimated number of participants with active syphilis in each country was calculated by multiplying the survey-weighted syphilis prevalence by the corresponding participant population size from the latest national census data. The total burden across the five countries was obtained by summing these estimates. FINDINGS: 102 831 participants enrolled in the five surveys (54 583 [57·6%] participants were female, 48 248 [42·4%] participants were male, 9036 [9·9%] participants were HIV positive). Population-based syphilis prevalence was 0·9% (95% CI 0·7-1·1) in Tanzania and Zimbabwe, 2·1% (1·9-2·4) in Uganda, and 3·0% (2·7-3·4) in Zambia. Overall, an estimated 1 027 615 (95% CI 877 243-1 158 246) participants had active syphilis across the five countries (266 383 HIV-positive and 761 232 HIV-negative individuals). Syphilis prevalence was higher among people living with HIV (range from 2·6% [95% CI 1·1-4·0] in Ethiopia to 9·6% [8·1-11·0] in Zambia) than among those without HIV (range from 0·8% [0·7-1·0] in Tanzania to 2·1% [1·8-2·4] in Zimbabwe). The odds of active syphilis were higher among people living with HIV than in those who were HIV negative (adjusted odds ratio [aOR] range from 2·5 [95% CI 1·8-3·4] in Uganda to 5·9 [3·8-9·2] in Zimbabwe), among divorced, separated, or widowed individuals (aOR range from 1·5 [1·1-2·0] in Uganda to 2·7 [1·7-4·3] in Zimbabwe), and among those reporting two or more sexual partners in the previous 12 months (aOR range from 1·1 [CI 0·8-1·5] in Uganda to 1·9 [1·1-3·3] in Zimbabwe). INTERPRETATION: This study shows the high burden of syphilis in five sub-Saharan African countries, with a correlation between HIV and active syphilis, underscoring the need for integrated sexual health services and targeted diagnosis, prevention, and treatment strategies to address this public health challenge. FUNDING: The President's Emergency Plan for AIDS Relief through the US Centers for Disease Control and Prevention.

Comparison of embryologist stress, somatization, and burnout reported by embryologists working in UK HFEA-licensed ART/IVF clinics and USA ART/IVF clinics.

STUDY QUESTION: What is the prevalence of occupational stress, somatization, and burnout reported by UK and US, embryologists and the impact of work conditions on these well-being outcomes? SUMMARY ANSWER: Surveyed UK and US embryologists reported moderate perceived stress, low somatic symptom severity, high levels of burnout, and overall stressful work conditions, but with differences that could be due to country-specific occupational and employment characteristics. WHAT IS KNOWN ALREADY?: Spanish, UK, US, and international surveys have identified high levels of occupational stress, somatization, burnout, and occupational health issues among embryologists. These issues have been attributed to embryologists' occupational challenges and work conditions. STUDY DESIGN, SIZE, DURATION: A cross-sectional web-based survey was sent to 253 embryologists working in UK ART/IVF clinics and 487 embryologists working in US ART/IVF clinics. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants self-reported their stress levels, somatization, burnout, and work conditions. Proportions across the Perceived Stress Scale (PSS), Patient Health Questionnaire (PHQ-15), Maslach Burnout Inventory-General Survey (MBI-GS), a single-item work unit grade (A-F), and customized occupational and sociodemographic questionnaires were calculated using descriptive statistics. Welch's t-test was utilized to compare PSS and PHQ-15 scores between groups. Risk ratios were calculated using log-binomial regression for all models except for levels of anxiety related to performing cryostorage tasks, for which Poisson models were used. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 50.6% (128) of the embryologists in the UK and 50.1% (244) in the US completed the survey. Both groups self-reported moderate PSS and low PHQ-15 scores, although fewer UK embryologists scored high on the MBI cynicism dimension than their US colleagues (43% UK vs 60% US embryologists, P < 0.05). The UK and US embryologists did not differ on the MBI exhaustion dimension with both scoring high for exhaustion (59% UK vs 62% US). Although 81% and 80% of UK and US embryologists, respectively, reported working overtime, more embryologists in the UK reported being adequately compensated. Increasing levels of anxiety-related to cryostorage showed a dose-dependent increased risk of burnout on at least two MBI-GS dimensions only in the UK group, and, a dose-dependent likelihood of higher PSS and PHQ-15 scores in both groups. LIMITATIONS, REASONS FOR CAUTION: Since the two groups were surveyed 9 months apart and were self-reporting, the study is limited by the differences in responsibilities, scheduling, and workload specific to the time of year. WIDER IMPLICATIONS OF THE FINDINGS: Work-related health issues and occupational challenges shared by UK and US embryologists could be addressed by organizational enhancements and technology. Lower levels of stress and burnout among UK embryologists might be due to the HFEA-provided structure/certainty. STUDY FUNDING/COMPETING INTEREST(S): This study was supported without any external funding by TMRW Life Sciences Inc., which is developing and commercializing an automated platform for embryology. M.G.C. and M.S.L. are full-time employees and stockholders/shareholders with TMRW Life Sciences, and A.M. of Novavax, Inc. was an employee of TMRW Life Sciences. G.P. is a consultant for TMRW Life Sciences. The remaining authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: NCT05326802; NCT05708963.

Sustainability in the IVF laboratory: recommendations of an expert panel.

The healthcare industry is a major contributor to greenhouse gas emissions. Assisted reproductive technology is part of the larger healthcare sector, with its own heavy carbon footprint. The social, economic and environmental costs of this collective carbon footprint are becoming clearer, as is the impact on human reproductive health. Alpha Scientists in Reproductive Medicine and the International IVF Initiative collaborated to seek and formulate practical recommendations for sustainability in IVF laboratories. An international panel of experts, enthusiasts and professionals in reproductive medicine, environmental science, architecture, biorepository and law convened to discuss the topics of importance to sustainability. Recommendations were issued on how to build a culture of sustainability in the workplace, implement green design and building, use life cycle analysis to determine the environmental impact, manage cryostorage more sustainably, and understand and manage laboratory waste with prevention as a primary goal. The panel explored whether the industry supporting IVF is sustainable. An example is provided to illustrate the application of green principles to an IVF laboratory through a certification programme. The UK legislative landscape surrounding sustainability is also discussed and a few recommendations on 'Green Conferencing' are offered.

The Internet of Things in assisted reproduction.

The Internet of Things (IoT) is a network connecting physical objects with sensors, software and internet connectivity for data exchange. Integrating the IoT with medical devices shows promise in healthcare, particularly in IVF laboratories. By leveraging telecommunications, cybersecurity, data management and intelligent systems, the IoT can enable a data-driven laboratory with automation, improved conditions, personalized treatment and efficient workflows. The integration of 5G technology ensures fast and reliable connectivity for real-time data transmission, while blockchain technology secures patient data. Fog computing reduces latency and enables real-time analytics. Microelectromechanical systems enable wearable IoT and miniaturized monitoring devices for tracking IVF processes. However, challenges such as security risks and network issues must be addressed through cybersecurity measures and networking advancements. Clinical embryologists should maintain their expertise and knowledge for safety and oversight, even with IoT in the IVF laboratory.

Cryostorage management of reproductive cells and tissues in ART: status, needs, opportunities and potential new challenges.

Among the wide range of procedures performed by clinical embryologists, the cryopreservation of reproductive cells and tissues represents a fundamental task in the daily routine. Indeed, cryopreservation procedures can be considered a subspecialty of medically assisted reproductive technology (ART), having the same relevance as sperm injection or embryo biopsy for preimplantation genetic testing. However, although a great deal of care has been devoted to optimizing cryopreservation protocols, the same energy has only recently been spent on developing and implementing strategies for the safe and reliable storage and transport of reproductive specimens. Herein, we have summarized the content of the available guidelines, the risks, the needs and the future perspectives regarding the management of cryopreservation biorepositories used in ART.

Point of Care CD4 Testing in National Household Surveys - Results and Quality Indicators from Eleven Population-Based HIV Impact Assessment (PHIA) Surveys.

Population-based HIV Impact Assessments (PHIAs) are national household (HH) surveys that provide HIV diagnosis and CD4 testing with an immediate return of results. Accurate CD4 results improve HIV-positive participants' clinical care and inform the effectiveness of HIV programs. Here, we present CD4 results from the PHIA surveys that were conducted in 11 countries in sub-Saharan Africa between 2015 and 2018. All of the HIV-positive participants and 2 to 5% of the HIV-negative participants were offered Pima CD4 (Abbott, IL, USA) point-of-care (POC) tests. The quality of the CD4 test was ensured by conducting instrument verification, comprehensive training, quality control, a review of testing errors and an analysis of unweighted CD4 data by HIV status, age, gender, and antiretroviral (ARV) treatment status. Overall, CD4 testing was completed for 23,085 (99.5%) of the 23,209 HIV-positive and 7,329 (2.7%) of the 270,741 negative participants in 11 surveys. The instrument error rate was 11.3% (range, 4.4% to 15.7%). The median CD4 values among HIV-positive and HIV-negative participants (aged 15+) were 468 cells/mm3 (interquartile range [IQR], 307 to 654) and 811 cells/mm3 (IQR, 647 to 1,013), respectively. Among the HIV-positive participants (aged 15+), those with detectable ARVs had higher CD4 values (508 cells/mm3) than those with undetectable ARVs (385.5 cells/mm3). Among the HIV-positive participants (aged 15+), 11.4% (2,528/22,253) had a CD4 value of less than 200 cells/mm3, and approximately half of them (1,225/2,528 = 48.5%) had detectable ARVs, whereas 51.5% (1,303/2,528) had no detectable ARVs (P < 0.0001). We successfully implemented high quality POC CD4 testing using Pima instruments. Our data come from nationally representative surveys in 11 countries and provide unique insights regarding the CD4 distribution among HIV-positive individuals as well as the baseline CD4 values among HIV-negative individuals. IMPORTANCE The manuscript describes CD4 levels among HIV-positive individuals and baseline CD4 levels among HIV-negative individuals from 11 sub-Saharan countries, thereby highlighting the importance of CD4 markers in the context of the HIV epidemic. Despite increased ARV access in each country, advanced HIV disease (CD4 < 200 cells/mm3) persists among approximately 11% of HIV-positive individuals. Therefore, it is important that our findings are shared with the scientific community to assist with similar implementations of point-of-care testing and to conduct a review of HIV programmatic gaps.

Novel Macrocyclic Antagonists of the Calcitonin Gene-Related Peptide Receptor: Design, Realization, and Structural Characterization of Protein-Ligand Complexes.

A series of macrocyclic calcitonin gene-related peptide (CGRP) receptor antagonists identified using structure-based design principles, exemplified by HTL0028016 (1) and HTL0028125 (2), is described. Structural characterization by X-ray crystallography of the interaction of two of the macrocycle antagonists with the CGRP receptor ectodomain is described, along with structure-activity relationships associated with point changes to the macrocyclic antagonists. The identification of non-peptidic/natural product-derived, macrocyclic ligands for a G protein coupled receptor (GPCR) is noteworthy.

Small understorey trees have greater capacity than canopy trees to adjust hydraulic traits following prolonged experimental drought in a tropical forest.

Future climate change predictions for tropical forests highlight increased frequency and intensity of extreme drought events. However, it remains unclear whether large and small trees have differential strategies to tolerate drought due to the different niches they occupy. The future of tropical forests is ultimately dependent on the capacity of small trees (<10 cm in diameter) to adjust their hydraulic system to tolerate drought. To address this question, we evaluated whether the drought tolerance of neotropical small trees can adjust to experimental water stress and was different from tall trees. We measured multiple drought resistance-related hydraulic traits across nine common neotropical genera at the world's longest-running tropical forest throughfall-exclusion experiment and compared their responses with surviving large canopy trees. Small understorey trees in both the control and the throughfall-exclusion treatment had lower minimum stomatal conductance and maximum hydraulic leaf-specific conductivity relative to large trees of the same genera, as well as a greater hydraulic safety margin (HSM), percentage loss of conductivity and embolism resistance, demonstrating that they occupy a distinct hydraulic niche. Surprisingly, in response to the drought treatment, small trees increased specific hydraulic conductivity by 56.3% and leaf:sapwood area ratio by 45.6%. The greater HSM of small understorey trees relative to large canopy trees likely enabled them to adjust other aspects of their hydraulic systems to increase hydraulic conductivity and take advantage of increases in light availability in the understorey resulting from the drought-induced mortality of canopy trees. Our results demonstrate that differences in hydraulic strategies between small understorey and large canopy trees drive hydraulic niche segregation. Small understorey trees can adjust their hydraulic systems in response to changes in water and light availability, indicating that natural regeneration of tropical forests following long-term drought may be possible.

From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease.

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.

Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits.

Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations. An influential but largely untested theory proposes that memory formation requires acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, feedforward inhibition from entorhinal cortex exhibits greater depression than CA3 resulting in a selective enhancement of excitatory-inhibitory balance and CA1 activation by entorhinal inputs. Entorhinal and CA3 pathways engage different feedforward interneuron subpopulations and cholinergic modulation of presynaptic function is mediated differentially by muscarinic M3 and M4 receptors, respectively. Thus, our data support a role and mechanisms for acetylcholine to prioritise novel information inputs to CA1 during memory formation.

Investigation into clinicopathological and pathological findings, prognosis, and aetiology of lorikeet paralysis syndrome in rainbow lorikeets (Trichoglossus haematodus).

OBJECTIVE: To report the temporal and spatial distribution of rainbow lorikeets presenting with lorikeet paralysis syndrome (LPS) and their clinicopathologic and pathologic findings, exposure to toxins, and response to treatment. METHODS: Records of lorikeets admitted in 2017 and 2018 to facilities in south-east Queensland (QLD) were reviewed and LPS and non-LPS cases were mapped and their distribution compared. Plasma biochemistries and complete blood counts were done on 20 representative lorikeets from south-east QLD and Grafton, New South Wales (NSW). Tissues from 28 lorikeets were examined histologically. Samples were tested for pesticides (n = 19), toxic elements (n = 23), botulism (n = 15) and alcohol (n = 5). RESULTS: LPS occurred in warmer months. Affected lorikeets were found across south-east QLD. Hotspots were identified in Brisbane and the Sunshine Coast. Lorikeets had a heterophilic leucocytosis, elevated muscle enzymes, uric acid and sodium and chloride. Specific lesions were not found. Exposure to cadmium was common in LPS and non-LPS lorikeets. Treated lorikeets had a 60-93% See Table 2 depending on severity of signs. CLINICAL SIGNIFICANCE: The primary differential diagnosis for lorikeets presenting with lower motor neuron signs during spring, summer and autumn in northern NSW and south-east Queensland should be LPS. With supportive care, prognosis is fair to good.

Safety, pharmacokinetics and exploratory pro-cognitive effects of HTL0018318, a selective M1 receptor agonist, in healthy younger adult and elderly subjects: a multiple ascending dose study.

BACKGROUND: The cholinergic system and M1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M1 receptor partial agonist HTL0018318 is under development for the symptomatic treatment of Dementia's including Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). We investigated the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of multiple doses of HTL0018318 in healthy younger adults and elderly subjects. METHODS: This randomised, double blind, placebo-controlled study was performed, investigating oral doses of 15-35 mg/day HTL0018318 or placebo in 7 cohorts of healthy younger adult (n = 36; 3 cohorts) and elderly (n = 50; 4 cohorts) subjects. Safety, tolerability and pharmacokinetic measurements were performed. Pharmacodynamics were assessed using a battery of neurocognitive tasks and electrophysiological biomarkers of synaptic and cognitive functions. RESULTS: HTL0018318 was generally well-tolerated in multiple doses up to 35 mg/day and were associated with mild or moderate cholinergic adverse events. There were modest increases in blood pressure and pulse rate when compared to placebo-treated subjects, with tendency for the blood pressure increase to attenuate with repeated dosing. There were no clinically significant observations or changes in blood and urine laboratory measures of safety or abnormalities in the ECGs and 24-h Holter assessments. HTL0018318 plasma exposure was dose-proportional over the range 15-35 mg. Maximum plasma concentrations were achieved after 1-2 h. The apparent terminal half-life of HTL0018318 was 16.1 h (± 4.61) in younger adult subjects and 14.3 h (± 2.78) in elderly subjects at steady state. HTL0018318 over the 10 days of treatment had significant effects on tests of short-term (working) memory (n-back) and learning (Milner maze) with moderate to large effect sizes. CONCLUSION: Multiple doses of HTL0018138 showed well-characterised pharmacokinetics and were safe and generally well-tolerated in the dose range studied. Pro-cognitive effects on short-term memory and learning were demonstrated across the dose range. These data provide encouraging data in support of the development of HTL0018138 for cognitive dysfunction in AD and DLB. TRIAL REGISTRATION: Netherlands Trial Register identifier NTR5781 . Registered on 22 March 2016.

Safety, pharmacokinetics and pharmacodynamics of HTL0009936, a selective muscarinic M1 -acetylcholine receptor agonist: A randomized cross-over trial.

AIMS: HTL0009936 is a selective M1 muscarinic receptor agonist in development for cognitive dysfunction in Alzheimer's disease. Safety, tolerability and pharmacokinetics and exploratory pharmacodynamic effects of HTL0009936 administered by continuous IV infusion at steady state were investigated in elderly subjects with below average cognitive functioning (BACF). METHODS: Part A was a four-treatment open label sequential study in healthy elderly investigating 10-83 mg HTL0009936 (IV) and a 24 mg HTL0009936 single oral dose. Part B was a five-treatment randomized, double-blind, placebo and physostigmine controlled cross-over study with IV HTL0009936 in elderly subjects with BACF. Pharmacodynamic assessments were performed using neurocognitive and electrophysiological tests. RESULTS: Pharmacokinetics of HTL0009936 showed dose-proportional increases in exposure with a mean half-life of 2.4 hours. HTL0009936 was well-tolerated with transient dose-related adverse events (AEs). Small increases in mean systolic blood pressure of 7.12 mmHg (95% CI [3.99-10.24]) and in diastolic of 5.32 mmHg (95% CI [3.18-7.47]) were noted at the highest dose in part B. Overall, there was suggestive, but no definitive, positive or negative pharmacodynamic effects. Statistically significant effects were observed on P300 with HTL0009936 and adaptive tracking with physostigmine. CONCLUSIONS: HTL0009936 showed well-characterized pharmacokinetics and single doses were safe and generally well-tolerated in healthy elderly subjects. Due to physostigmine tolerability issues and subject burden, the study design was changed and some pharmacodynamic assessments (neurocognitive) were performed at suboptimal drug exposures. Therefore no clear conclusions can be made on pharmacodynamic effects of HTL0009936, although an effect on P300 is suggestive of central target engagement.

Cell viability and cytotoxicity of inkjet-printed flexible organic electrodes on parylene C.

This study reports on the fabrication of biocompatible organic devices by means of inkjet printing with a novel combination of materials. The devices were fabricated on Parylene C (PaC), a biocompatible and flexible polymer substrate. The contact tracks were inkjet-printed using a silver nanoparticle ink, while the active sites were inkjet-printed using a poly (3,4ethylenedioxythiophene)/polystyrene sulfonate (PEDOT:PSS) solution. To insulate the final device, a polyimide ink was used to print a thick film, leaving small open windows upon the active sites. Electrical characterization of the final device revealed conductivities in the order of 103 and 102 S.cm-1 for Ag and PEDOT based inks, respectively. Cell adhesion assays performed with PC-12 cells after 96 h of culture, and B16F10 cells after 24 h of culture, demonstrated that the cells adhered on top of the inks and cell differentiation occurred, which indicates Polyimide and PEDOT:PSS inks are non-toxic to these cells. The results indicate that PaC, along with its surface-treated variants, is a potentially useful material for fabricating cell-based microdevices.

First-in-man study to investigate safety, pharmacokinetics and exploratory pharmacodynamics of HTL0018318, a novel M1 -receptor partial agonist for the treatment of dementias.

AIMS: HTL0018318 is a selective M1 receptor partial agonist currently under development for the symptomatic treatment of cognitive and behavioural symptoms in Alzheimer's disease and other dementias. We investigated safety, tolerability, pharmacokinetics and exploratory pharmacodynamics (PD) of HTL0018318 following single ascending doses. METHODS: This randomized, double-blind, placebo-controlled study in 40 healthy younger adult and 57 healthy elderly subjects, investigated oral doses of 1-35 mg HTL0018318. Pharmacodynamic assessments were performed using a battery of neurocognitive tasks and electrophysiological measurements. Cerebrospinal fluid concentrations of HTL0018318 and food effects on pharmacokinetics of HTL0018318 were investigated in an open label and partial cross-over design in 14 healthy subjects. RESULTS: Pharmacokinetics of HTL0018318 were well-characterized showing dose proportional increases in exposure from 1-35 mg. Single doses of HTL0018318 were associated with mild dose-related adverse events of low incidence in both younger adult and elderly subjects. The most frequently reported cholinergic AEs included hyperhidrosis and increases in blood pressure up to 10.3 mmHg in younger adults (95% CI [4.2-16.3], 35-mg dose) and up to 11.9 mmHg in elderly subjects (95% CI [4.9-18.9], 15-mg dose). There were no statistically significant effects on cognitive function but the study was not powered to detect small to moderate effect sizes of clinical relevance. CONCLUSION: HTL0018318 showed well-characterized pharmacokinetics and following single doses were generally well tolerated in the dose range studied. These provide encouraging data in support of the development for HTL0018318 for Alzheimer's disease and other dementias.

Small molecule AZD4635 inhibitor of A2AR signaling rescues immune cell function including CD103+ dendritic cells enhancing anti-tumor immunity.

Accumulation of extracellular adenosine within the microenvironment is a strategy exploited by tumors to escape detection by the immune system. Adenosine signaling through the adenosine 2A receptor (A2AR) on immune cells elicits a range of immunosuppressive effects which promote tumor growth and limit the efficacy of immune checkpoint inhibitors. Preclinical data with A2AR inhibitors have demonstrated tumor regressions in mouse models by rescuing T cell function; however, the mechanism and role on other immune cells has not been fully elucidated. METHODS: We report here the development of a small molecule A2AR inhibitor including characterization of binding and inhibition of A2AR function with varying amounts of a stable version of adenosine. Functional activity was tested in both mouse and human T cells and dendritic cells (DCs) in in vitro assays to understand the intrinsic role on each cell type. The role of adenosine and A2AR inhibition was tested in DC differentiation assays as well as co-culture assays to access the cross-priming function of DCs. Syngeneic models were used to assess tumor growth alone and in combination with alphaprogrammed death-ligand 1 (αPD-L1). Immunophenotyping by flow cytometry was performed to examine global immune cell changes upon A2AR inhibition. RESULTS: We provide the first report of AZD4635, a novel small molecule A2AR antagonist which inhibits downstream signaling and increases T cell function as well as a novel mechanism of enhancing antigen presentation by CD103+ DCs. The role of antigen presentation by DCs, particularly CD103+ DCs, is critical to drive antitumor immunity providing rational to combine a priming agent AZD4635 with check point blockade. We find adenosine impairs the maturation and antigen presentation function of CD103+ DCs. We show in multiple syngeneic mouse tumor models that treatment of AZD4635 alone and in combination with αPD-L1 led to decreased tumor volume correlating with enhanced CD103+ function and T cell response. We extend these studies into human DCs to show that adenosine promotes a tolerogenic phenotype that can be reversed with AZD4635 restoring antigen-specific T cell activation. Our results support the novel role of adenosine signaling as an intrinsic negative regulator of CD103+ DCs maturation and priming. We show that potent inhibition of A2AR with AZD4635 reduces tumor burden and enhances antitumor immunity. This unique mechanism of action in CD103+ DCs may contribute to clinical responses as AZD4635 is being evaluated in clinical trials with IMFINZI (durvalumab, αPD-L1) in patients with solid malignancies. CONCLUSION: We provide evidence implicating suppression of adaptive and innate immunity by adenosine as a mechanism for immune evasion by tumors. Inhibition of adenosine signaling through selective small molecule inhibition of A2AR using AZD4635 restores T cell function via an internal mechanism as well as tumor antigen cross-presentation by CD103+ DCs resulting in antitumor immunity.

Recent Developments in Therapeutic Peptides for the Glucagon-like Peptide 1 and 2 Receptors.

Glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2) are proglucagon derived peptides that are released from gut endocrine cells in response to nutrient intake. These molecules are rapidly inactivated by the action of dipeptidyl peptidase IV (DPP-4) which limits their use as therapeutic agents. The recent emergence of three-dimensional structures of GPCRs such as GLP-1R and glucagon receptor has helped to drive the rational design of innovative peptide molecules that hold promise as novel peptide therapeutics. One emerging area is the discovery of multifunctional molecules that act at two or more pharmacological systems to enhance therapeutic efficacy. In addition, drug discovery efforts are also focusing on strategies to improve patient convenience through alternative routes of peptide delivery. These novel strategies highlight the broad utility of peptide-based therapeutics in human disease settings where unmet needs still exist.

Identification of a novel allosteric GLP-1R antagonist HTL26119 using structure- based drug design.

A series of novel allosteric antagonists of the GLP-1 receptor (GLP-1R), exemplified by HTL26119, are described. SBDD approaches were employed to identify HTL26119, exploiting structural understanding of the allosteric binding site of the closely related Glucagon receptor (GCGR) (Jazayeri et al., 2016) and the homology relationships between GCGR and GLP-1R. The region around residue C3476.36b of the GLP-1R receptor represents a key difference from GCGR and was targeted for selectivity for GLP-1R.

Comparison of 36 assisted reproduction laboratories monitoring environmental conditions and instrument parameters using the same quality-control application.

RESEARCH QUESTION: Assisted reproduction laboratories record instrument performance periodically. No standardized guidelines have been produced for this activity despite mandatory auditing systems in several countries. This study of 36 laboratories in 12 different countries was conducted to assess differences and similarities between quality assurance programmes using an adaptable cloud-based quality-control app for instrument monitoring. DESIGN: A total of 36 deidentified IVF laboratories that subscribed to the same quality-assurance application were studied. Data were evaluated based on instrument types allocated to 10 domains: incubators, gas tanks, warming surfaces, refrigerators and freezers, cryo-storage, environment, water purification, peripheral equipment, checklists and miscellaneous. RESULTS: The incubator domain constituted the greatest proportion of parameters (35%), followed by surface warming instruments at 15%. Most incubator O2 readings were monitored between 4.5 and 5.5%, and between 5.5 and 6.5% for CO2. The altitude of the laboratory was poorly correlated with the CO2 setting. Incubator display and measured values of gases and temperature by built-in sensors vary considerably compared with third-party sensors. A quality-control diligence score or mean average data points was calculated for each laboratory. This score is independent of number of instruments or laboratory size. Higher scores were associated with laboratories in countries with government regulations and mandatory auditing systems. CONCLUSIONS: Major differences exist in instrument monitoring practices among laboratories. Although incubator monitoring is the largest domain, many other sensitive instruments are diligently monitored by most laboratories. International standardization and guidelines are needed.