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Introduction Despite the advent of HIV cure‐related clinical trials (HCRCT) for people living with HIV (PLWH), the risks and uncertainty involved raise ethical issues. Although research has provided insights into the levers and barriers to PLWH and physicians' participation in these trials, no information exists about stakeholders' preferences for HCRCT attributes, about the different ways PLWH and physicians value future HCRCT, or about how personal characteristics affect these preferences. The results from the present study will inform researchers' decisions about the most suitable HCRCT strategies to implement, and help them ensure ethical recruitment and well‐designed informed consent. Methods Between October 2016 and March 2017, a discrete choice experiment was conducted among 195 virally controlled PLWH and 160 physicians from 24 French HIV centres. Profiles within each group, based on individual characteristics, were obtained using hierarchical clustering. Trade‐offs between five HCRCT attributes (trial duration, consultation frequency, moderate (digestive disorders, flu‐type syndrome, fatigue) and severe (allergy, infections, risk of cancer) side effects (SE), outcomes) and utilities associated with four HCRCT candidates (latency reactivation, immunotherapy, gene therapy and a combination of latency reactivation and immunotherapy), were estimated using a mixed logit model. Results Apart from severe SE – the most decisive attribute in both groups – PLWH and physicians made different trade‐offs between HCRCT attributes, the latter being more concerned about outcomes, the former about the burden of participation (consultation frequency and moderate SE). These different trades‐offs resulted in differences in preferences regarding the four candidate HCRCT. PLWH significantly preferred immunotherapy, whereas physicians preferred immunotherapy and combined therapy. Despite the heterogeneity of characteristics within the PLWH and physician profiles, results show some homogeneity in trade‐offs and utilities regarding HCRCT. Conclusions Severe SE, not outcomes, was the most decisive attribute determining future HCRCT participation. Particular attention should be paid to providing clear information, in particular on severe SE, to potential participants. Immunotherapy would appear to be the best HCRCT candidate for both PLWH and physicians. However, if the risk of cancer could be avoided, gene therapy would become the preferred strategy for the latter and the second choice for the former.

Morphine is an analgesic drug used to treat acute and chronic pain. Obesity is frequently associated with pain of various origins (e.g. arthritis, fibromyalgia, cancer), which increases the need for analgesic drugs. Obesity changes drug pharmacokinetics, and for certain drugs, specific modalities of prescription have been proposed for obese patients. However, scant data are available regarding the pharmacokinetics and pharmacodynamics of morphine in obesity. Prescription of morphine depends on pain relief but the occurrence of respiratory adverse effects correlates with obesity, and is not currently taken into account. Variations in the volume of distribution, elimination half-life and oral clearance of morphine, as well as recent advances in the respective roles of drug-metabolizing enzymes, catechol- O -methyltransferase and the μ opioid receptor in morphine pharmacokinetics and pharmacodynamics, may contribute to differences between obese and non-obese patients. In addition, drug-drug interactions may alter the disposition of morphine and its glucuronide metabolites, which may either increase the risk of adverse effects or reduce drug efficacy.

Despite the advent of HIV cure?related clinical trials (HCRCT) for people living with HIV (PLWH), the risks and uncertainty involved raise ethical issues. Although research has provided insights into the levers and barriers to PLWH and physicians' participation in these trials, no information exists about stakeholders' preferences for HCRCT attributes, about the different ways PLWH and physicians value future HCRCT, or about how personal characteristics affect these preferences. The results from the present study will inform researchers' decisions about the most suitable HCRCT strategies to implement, and help them ensure ethical recruitment and well?designed informed consent. Between October 2016 and March 2017, a discrete choice experiment was conducted among 195 virally controlled PLWH and 160 physicians from 24 French HIV centres. Profiles within each group, based on individual characteristics, were obtained using hierarchical clustering. Trade?offs between five HCRCT attributes (trial duration, consultation frequency, moderate (digestive disorders, flu?type syndrome, fatigue) and severe (allergy, infections, risk of cancer) side effects (SE), outcomes) and utilities associated with four HCRCT candidates (latency reactivation, immunotherapy, gene therapy and a combination of latency reactivation and immunotherapy), were estimated using a mixed logit model. Apart from severe SE ? the most decisive attribute in both groups ? PLWH and physicians made different trade?offs between HCRCT attributes, the latter being more concerned about outcomes, the former about the burden of participation (consultation frequency and moderate SE). These different trades?offs resulted in differences in preferences regarding the four candidate HCRCT. PLWH significantly preferred immunotherapy, whereas physicians preferred immunotherapy and combined therapy. Despite the heterogeneity of characteristics within the PLWH and physician profiles, results show some homogeneity in trade?offs and utilities regarding HCRCT. Severe SE, not outcomes, was the most decisive attribute determining future HCRCT participation. Particular attention should be paid to providing clear information, in particular on severe SE, to potential participants. Immunotherapy would appear to be the best HCRCT candidate for both PLWH and physicians. However, if the risk of cancer could be avoided, gene therapy would become the preferred strategy for the latter and the second choice for the former.

Aspirin and angiotensin-converting enzyme inhibitors (ACEIs) are often associated for the treatment of coronary disease and/or chronic heart failure, but conclusions of some prospective and retrospective studies show a possible negative interaction between aspirin and ACEIs. ACEIs inhibit the conversion of angiotensin I to angiotensin II and also the catabolism of bradykinin, which results in increased synthesis of vasodilatory agents [prostaglandins and nitric oxide (NO)], whereas aspirin inhibits prostaglandin synthesis. Thus, a potential interaction from the opposing effects of aspirin and ACEIs could affect the metabolism of bradykinin. We conducted an extensive Medline search, as well as a manual search, of published literature including pharmacodynamic studies and clinical trials concerning the impact of aspirin on the effect of ACEIs in hypertension, coronary disease and chronic heart failure. A review of this literature shows five studies in hypertension (all prospective and using blood pressure as the main criterion of assessment), five in coronary disease (three retrospective and two prospective trials, four of which use mortality as the criterion of assessment) and 13 in chronic heart failure (eight using haemodynamic measurements of which seven are prospective--one prospective study using pulmonary tests, four using clinical events including mortality as criterion of assessment of which two are prospective). The counteraction of ACEI efficacy by aspirin is demonstrated in one out of five studies in hypertension, one out of four of studies in coronary disease and nine out of thirteen in chronic heart failure. This counteraction is more often observed with high dosages of aspirin (greater than 250 mg/day, four out of six studies) and less often with lower dosages (less than or equal to 250 mg/day, three out of 11 studies). These studies are retrospective analyses or use haemodynamic end-points, so there is as yet no methodological argument strong enough to contraindicate the aspirin-ACEI association or to prove the clinical relevance of this interaction. In conclusion, prospective studies using mortality as a criterion of assessment are needed to offer the practitioner the answer to the question of ACEI-aspirin association.

Pancreatic ductal adenocarcinoma (PDAC) is usually incurable. Contrary to genetic mechanisms involved in PDAC pathogenesis, epigenetic alterations are ill defined. Here, we determine the contribution of epigenetically silenced genes to the development of PDAC. We analyzed enriched, highly methylated DNAs from PDACs, chronic pancreatitis (CP) and normal tissues using CpG island microarrays and identified WNK2 as a prominent candidate tumor suppressor gene being downregulated early in PDAC development. WNK2 was further investigated in tissue microarrays, methylation analysis of early pancreatic intraepithelial neoplasia (PanIN), mouse models for PDAC and pancreatitis, re-expression studies after demethylation, and cell growth assays using WNK2 overexpression. Demethylation assays confirmed the link between methylation and expression. WNK2 hypermethylation was higher in tumor than in surrounding inflamed tissues and was observed in PanIN lesions as well as in a PDAC mouse model. WNK2 mRNA and protein expressions were lower in PDAC and CP compared with normal tissues both in patients and mouse models. Overexpression of WNK2 led to reduced cell growth, and WNK2 expression in tissues correlated negatively with pERK1/2 expression, a downstream target of WNK2 responsible for cell proliferation. Downregulation of WNK2 by promoter hypermethylation occurs early in PDAC pathogenesis and may support tumor cell growth via the ERK–MAPK pathway.

We use simultaneous observations of tropospheric ozone and outgoing longwave radiation (OLR) sensitivity to tropospheric ozone from the Tropospheric Emission Spectrometer (TES) to evaluate model tropospheric ozone and its effect on OLR simulated by a suite of chemistry-climate models that participated in the Atmospheric Chemistry and Climate Model Intercomparison Project (ACCMIP). The ensemble mean of ACCMIP models show a persistent but modest tropospheric ozone low bias (5–20 ppb) in the Southern Hemisphere (SH) and modest high bias (5–10 ppb) in the Northern Hemisphere (NH) relative to TES ozone for 2005–2010. These ozone biases have a significant impact on the OLR. Using TES instantaneous radiative kernels (IRK), we show that the ACCMIP ensemble mean tropospheric ozone low bias leads up to 120mWm−2 OLR high bias locally but zonally compensating errors reduce the global OLR high bias to 39±41mWm−2 relative to TES data. We show that there is a correlation (R2 = 0.59) between the magnitude of the ACCMIP OLR bias and the deviation of the ACCMIP preindustrial to present day (1750–2010) ozone radiative forcing (RF) from the ensemble ozone RF mean. However, this correlation is driven primarily by models whose absolute OLR bias from tropospheric ozone exceeds 100mWm−2. Removing these models leads to a mean ozone radiative forcing of 394±42mWm−2. The mean is about the same and the standard deviation is about 30% lower than an ensemble ozone RF of 384±60mWm−2 derived from 14 of the 16 ACCMIP models reported in a companion ACCMIP study. These results point towards a profitable direction of combining satellite observations and chemistry-climate model simulations to reduce uncertainty in ozone radiative forcing.

Physical activity improves health, yet the molecular mechanisms remain partially understood. This study presents a high-resolution, time-resolved atlas profiling 10,127 proteins across plasma, saliva, and urine from healthy adults post-acute exercise. Exercise regulated over 3,000 proteins, revealing distinct, fluid-specific temporal dynamics. By integrating fluid-specific exercise signatures with tissue and disease atlases, we delineated the contribution of tissues and associations to various diseases. Network analysis across body fluids elucidated coordinated remodeling in the extracellular matrix and immune activation orchestrating exercise-induced networks. Many exercise-responsive plasma proteins were robust across age, sex, and exercise modalities, indicating a conserved systemic signature. Integration with genetic data established exercise-regulated proteins as modulators of metabolic traits and identified over 200 targeted by approved drugs, highlighting their impact on disease-relevant pathways. This comprehensive atlas, available as an open-access resource https://cbmr.ku.dk/research/research-groups/deshmukh-group/shiny-apps/, advances our molecular insight into exercise adaptations and enables exerkine discovery, biomarker development, and pharmacological exercise-mimetic strategies. Exercise induces robust and distinct changes across body fluid proteomes Tissue remodeling and immune activation drive exercise-induced network expansion ∼1,000 exercise-regulated plasma proteins are age, exercise mode, or sex-specific Genetic inference identifies druggable exerkines that regulate health and disease