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There are challenges in monitoring and managing water quality due to spatial and temporal heterogeneity in contaminant sources, transport, and transformations. We demonstrate the importance of longitudinal stream synoptic (LSS) monitoring, which can track combinations of water quality parameters along flowpaths across space and time. Specifically, we analyze longitudinal patterns of chemical mixtures of carbon, nutrients, greenhouse gasses, salts, and metals concentrations along 10 flowpaths draining 1,765 km 2 of the Chesapeake Bay region. These 10 longitudinal stream flowpaths are drained by watersheds experiencing either urban degradation, forest and wetland conservation, or stream and floodplain restoration. Along the 10 longitudinal stream flowpaths, we monitored over 300 total sampling sites along a combined stream length of 337 km. Synoptic monitoring along longitudinal flowpaths revealed: (1) increasing, decreasing, piecewise, or no trends and transitions in water quality with increasing distance downstream, which provide insights into water quality processes along flowpaths; (2) longitudinal trends and transitions in water quality along flowpaths can be quantified and compared using simple linear and non-linear statistical relationships with distance downstream and/or land use/land cover attributes, (3) attenuation and transformation of chemical cocktails along flowpaths depend on: spatial scales, pollution sources, and transitions in land use and management, hydrology, and restoration. We compared our LSS patterns with others from the global literature to synthesize a typology of longitudinal water quality trends and transitions in streams and rivers based on hydrological, biological, and geochemical processes. Applications of LSS monitoring along flowpaths from our results and the literature reveal: (1) if there are shifts in pollution sources, trends, and transitions along flowpaths, (2) which pollution sources can spread further downstream to sensitive receiving waters such as drinking water supplies and coastal zones, and (3) if transitions in land use, conservation, management, or restoration can attenuate downstream transport of pollution sources. Our typology of longitudinal water quality responses along flowpaths combines many observations across suites of chemicals that can follow predictable patterns based on watershed characteristics. Our typology of longitudinal water quality responses also provides a foundation for future studies, watershed assessments, evaluating watershed management and stream restoration, and comparing watershed responses to non-point and point pollution sources along streams and rivers. LSS monitoring, which integrates both spatial and temporal dimensions and considers multiple contaminants together (a chemical cocktail approach), can be a comprehensive strategy for tracking sources, fate, and transport of pollutants along stream flowpaths and making comparisons of water quality patterns across different watersheds and regions.

Freshwater salinization is an emerging global problem impacting safe drinking water, ecosystem health and biodiversity, infrastructure corrosion, and food production. Freshwater salinization originates from diverse anthropogenic and geologic sources including road salts, human-accelerated weathering, sewage, urban construction, fertilizer, mine drainage, resource extraction, water softeners, saltwater intrusion, and evaporative concentration of ions due to hydrologic alterations and climate change. The complex interrelationships between salt ions and chemical, biological, and geologic parameters and consequences on the natural, social, and built environment are called Freshwater Salinization Syndrome (FSS). Here, we provide a comprehensive overview of salinization issues (past, present, and future), and we investigate drivers and solutions. We analyze the expanding global magnitude and scope of FSS including its discovery in humid regions, connections to human-accelerated weathering and mobilization of ‘chemical cocktails.’ We also present data illustrating: (1) increasing trends in salt ion concentrations in some of the world’s major freshwaters, including critical drinking water supplies; (2) decreasing trends in nutrient concentrations in rivers due to regulations but increasing trends in salinization, which have been due to lack of adequate management and regulations; (3) regional trends in atmospheric deposition of salt ions and storage of salt ions in soils and groundwater, and (4) applications of specific conductance as a proxy for tracking sources and concentrations of groups of elements in freshwaters. We prioritize FSS research needs related to better understanding: (1) effects of saltwater intrusion on ecosystem processes, (2) potential health risks from groundwater contamination of home wells, (3) potential risks to clean and safe drinking water sources, (4) economic and safety impacts of infrastructure corrosion, (5) alteration of biodiversity and ecosystem functions, and (6) application of high-frequency sensors in state-of-the art monitoring and management. We evaluate management solutions using a watershed approach spanning air, land, and water to explore variations in sources, fate and transport of different salt ions (e.g. monitoring of atmospheric deposition of ions, stormwater management, groundwater remediation, and managing road runoff). We also identify tradeoffs in management approaches such as unanticipated retention and release of chemical cocktails from urban stormwater management best management practices (BMPs) and unintended consequences of alternative deicers on water quality. Overall, we show that FSS has direct and indirect effects on mobilization of diverse chemical cocktails of ions, metals, nutrients, organics, and radionuclides in freshwaters with mounting impacts. Our comprehensive review suggests what could happen if FSS were not managed into the future and evaluates strategies for reducing increasing risks to clean and safe drinking water, human health, costly infrastructure, biodiversity, and critical ecosystem services.

Alongside global climate change, many freshwater ecosystems are experiencing substantial shifts in the concentrations and compositions of salt ions coming from both land and sea. We synthesize a risk framework for anticipating how climate change and increasing salt pollution coming from both land and saltwater intrusion will trigger chain reactions extending from headwaters to tidal waters. Salt ions trigger ‘chain reactions,’ where chemical products from one biogeochemical reaction influence subsequent reactions and ecosystem responses. Different chain reactions impact drinking water quality, ecosystems, infrastructure, and energy and food production. Risk factors for chain reactions include shifts in salinity sources due to global climate change and amplification of salinity pulses due to the interaction of precipitation variability and human activities. Depending on climate and other factors, salt retention can range from 2 to 90% across watersheds globally. Salt retained in ecosystems interacts with many global biogeochemical cycles along flowpaths and contributes to ‘fast’ and ‘slow’ chain reactions associated with temporary acidification and long-term alkalinization of freshwaters, impacts on nutrient cycling, CO 2 , CH 4 , N 2 O, and greenhouse gases, corrosion, fouling, and scaling of infrastructure, deoxygenation, and contaminant mobilization along the freshwater-marine continuum. Salt also impacts the carbon cycle and the quantity and quality of organic matter transported from headwaters to coasts. We identify the double impact of salt pollution from land and saltwater intrusion on a wide range of ecosystem services. Our salinization risk framework is based on analyses of: (1) increasing temporal trends in salinization of tributaries and tidal freshwaters of the Chesapeake Bay and freshening of the Chesapeake Bay mainstem over 40 years due to changes in streamflow, sea level rise, and watershed salt pollution; (2) increasing long-term trends in concentrations and loads of major ions in rivers along the Eastern U.S. and increased riverine exports of major ions to coastal waters sometimes over 100-fold greater than forest reference conditions; (3) varying salt ion concentration-discharge relationships at U.S. Geological Survey (USGS) sites across the U.S.; (4) empirical relationships between specific conductance and Na + , Cl − , SO 4 2− , Ca 2+ , Mg 2+ , K + , and N at USGS sites across the U.S.; (5) changes in relationships between concentrations of dissolved organic carbon (DOC) and different salt ions at USGS sites across the U.S.; and (6) original salinization experiments demonstrating changes in organic matter composition, mobilization of nutrients and metals, acidification and alkalinization, changes in oxidation–reduction potentials, and deoxygenation in non-tidal and tidal waters. The interaction of human activities and climate change is altering sources, transport, storage, and reactivity of salt ions and chain reactions along the entire freshwater-marine continuum. Our salinization risk framework helps anticipate, prevent, and manage the growing double impact of salt ions from both land and sea on drinking water, human health, ecosystems, aquatic life, infrastructure, agriculture, and energy production.

HIV/AIDS is a leading cause of disease burden in sub-Saharan Africa. Existing evidence has demonstrated that there is substantial local variation in the prevalence of HIV; however, subnational variation has not been investigated at a high spatial resolution across the continent. Here we explore within-country variation at a 5 × 5-km resolution in sub-Saharan Africa by estimating the prevalence of HIV among adults (aged 15–49 years) and the corresponding number of people living with HIV from 2000 to 2017. Our analysis reveals substantial within-country variation in the prevalence of HIV throughout sub-Saharan Africa and local differences in both the direction and rate of change in HIV prevalence between 2000 and 2017, highlighting the degree to which important local differences are masked when examining trends at the country level. These fine-scale estimates of HIV prevalence across space and time provide an important tool for precisely targeting the interventions that are necessary to bringing HIV infections under control in sub-Saharan Africa. Fine-scale estimates of the prevalence of HIV in adults across sub-Saharan Africa reveal substantial within-country variation and local differences in both the direction and rate of change in the prevalence of HIV between 2000 and 2017.

BackgroundThe relationship between atherosclerosis and endotypes of myocardial ischaemia with no obstructive coronary artery disease (INOCA) is unclear. We investigated potential associations between cumulative atherosclerotic plaque burden quantified using the Gensini score, novel invasive indices of coronary microvascular function (microvascular resistance reserve (MRR); resistive reserve ratio (RRR)) and related INOCA endotypes.MethodsCoronary angiography and invasive coronary function tests were simultaneously acquired in the CorMicA cohort. A comprehensive physiological assessment was performed using both a thermodilution-based diagnostic guidewire and intracoronary acetylcholine provocation testing. Angiograms were examined for luminal stenosis in each segment of the SYNTAX coronary model. Cumulative plaque burden was quantified using the Gensini score, which incorporated both the number of diseased coronary segments and stenosis severity. Results were compared with indices of microvascular function and INOCA endotypes. Angiographic analyses were performed blind to coronary physiology findings.ResultsIn 151 participants (median age 61 years; 73.5% female) without flow-limiting coronary artery disease, medical history included 41.7% smoking, 63.6% hypertension and 19.2% diabetes mellitus. The left anterior descending artery underwent diagnostic guidewire testing in 85.4%, and 55.0% of participants had abnormal coronary flow reserve (CFR) and/or Index of Microcirculatory Resistance (IMR). The median Gensini score was 6.0 (IQR 2.5–11.0). CFR (p=0.012), MRR (p=0.026) and RRR (p=0.026), but not IMR (p=0.445), were univariably associated with raised Gensini scores. These significant effects persisted in multivariable models controlling for potential confounders. Considering INOCA endotypes, Gensini scores differed among participants with microvascular angina (MVA) (7.0 (2.5–11.0)), vasospastic angina (VSA) (4.5 (2.0–10.0)), mixed MVA/VSA (9.0 (5.0–11.5)) and non-cardiac symptoms (3.5 (1.5–8.0)); Kruskal-Wallis p=0.030.ConclusionsReduced CFR, MRR and RRR, and MVA were associated with increased coronary atherosclerotic plaque burden, as evidenced by higher Gensini scores. These novel findings provide a mechanistic link between INOCA and cardiovascular events, reinforcing the importance of antiatherosclerosis therapy in patients with MVA.

Diffuse disease has been identified as one of the main reasons leading to low post-PCI fractional flow reserve (FFR) and residual angina after PCI. Coronary pressure pullbacks allow for the evaluation of hemodynamic coronary artery disease (CAD) patterns. The pullback pressure gradient (PPG) is a novel metric that quantifies the distribution and magnitude of pressure losses along the coronary artery in a focal-to-diffuse continuum. The primary objective is to determine the predictive capacity of the PPG for post-PCI FFR. This prospective, large-scale, controlled, investigator-initiated, multicenter study is enrolling patients with at least 1 lesion in a major epicardial vessel with a distal FFR ≤ 0.80 intended to be treated by PCI. The study will include 982 subjects. A standardized physiological assessment will be performed pre-PCI, including the online calculation of PPG from FFR pullbacks performed manually. PPG quantifies the CAD pattern by combining several parameters from the FFR pullback curve. Post-PCI physiology will be recorded using a standardized protocol with FFR pullbacks. We hypothesize that PPG will predict optimal PCI results (post-PCI FFR ≥ 0.88) with an area under the ROC curve (AUC) ≥ 0.80. Secondary objectives include patient-reported and clinical outcomes in patients with focal vs. diffuse CAD defined by the PPG. Clinical follow-up will be collected for up to 36 months, and an independent clinical event committee will adjudicate events. Recruitment is ongoing and is expected to be completed in the second half of 2023. This international, large-scale, prospective study with pre-specified powered hypotheses will determine the ability of the preprocedural PPG index to predict optimal revascularization assessed by post-PCI FFR. In addition, it will evaluate the impact of PPG on treatment decisions and the predictive performance of PPG for angina relief and clinical outcomes. [Display omitted]

Maternal iron deficiency occurs in 40–50% of all pregnancies and is associated with an increased risk of respiratory disease and asthma in children. We used murine models to examine the effects of lower iron status during pregnancy on lung function, inflammation and structure, as well as its contribution to increased severity of asthma in the offspring. A low iron diet during pregnancy impairs lung function, increases airway inflammation, and alters lung structure in the absence and presence of experimental asthma. A low iron diet during pregnancy further increases these major disease features in offspring with experimental asthma. Importantly, a low iron diet increases neutrophilic inflammation, which is indicative of more severe disease, in asthma. Together, our data demonstrate that lower dietary iron and systemic deficiency during pregnancy can lead to physiological, immunological and anatomical changes in the lungs and airways of offspring that predispose to greater susceptibility to respiratory disease. These findings suggest that correcting iron deficiency in pregnancy using iron supplements may play an important role in preventing or reducing the severity of respiratory disease in offspring. They also highlight the utility of experimental models for understanding how iron status in pregnancy affects disease outcomes in offspring and provide a means for testing the efficacy of different iron supplements for preventing disease.

Assessing coronary physiology after stent implantation facilitates the optimisation of percutaneous coronary intervention (PCI). Coronary artery disease (CAD) patterns can be characterised by the pullback pressure gradient (PPG) index. The impact of focal vs. diffuse disease on physiology-guided incremental optimisation strategy (PIOS) is unknown. This is a sub-study of the TARGET-FFR randomized clinical trial (NCT03259815). The study protocol directed that optimisation be attempted for patients in the PIOS arm when post-PCI FFR was <0.90. Overall, 114 patients (n = 61 PIOS and 53 controls) with both pre-PCI fractional flow reserve (FFR) pullbacks and post-PCI FFR were included. A PPG ≥ 0.74 defined focal CAD. The PPG correlated significantly with post-PCI FFR (r = 0.43; 95% CI 0.26 to 0.57; p-value < 0.001) and normalised delta FFR (r = 0.49; 95% CI 0.34 to 0.62; p-value < 0.001). PIOS was more frequently applied to vessels with diffuse CAD (6% focal vs. 42% diffuse; p-value = 0.006). In patients randomized to PIOS, those with focal disease achieved higher post-PCI FFR than patients with diffuse CAD (0.93 ± 0.05 vs. 0.83 ± 0.07, p < 0.001). There was a significant interaction between CAD patterns and the randomisation arm for post-PCI FFR (p-value for interaction = 0.004). Physiology-guided stent optimisation was applied more frequently to vessels with diffuse disease; however, patients with focal CAD at baseline achieved higher post-PCI FFR.

Objectives The Eastern Mediterranean Region faces several health challenges at a difficult time with wars, unrest, and economic change. Methods We used the Global Burden of Disease 2015 study to present the burden of diseases, injuries, and risk factors in the Eastern Mediterranean Region from 1990 to 2015. Results Ischemic heart disease was the leading cause of death in the region in 2015, followed by cerebrovascular disease. Changes in total deaths ranged from a reduction of 25% for diarrheal diseases to an increase of about 42% for diabetes and tracheal, bronchus, and lung cancer. Collective violence and legal intervention increased by 850% during the time period. Diet was the leading risk factor for disability-adjusted life years (DALYs) for men compared to maternal malnutrition for females. Childhood undernutrition was the leading risk factor for DALYs in 1990 and 2005, but the second in 2015 after high blood pressure. Conclusions Our study shows that the region is facing several health challenges and calls for global efforts to stabilise the region and to address the current and future burden of disease.

All of life encodes information with DNA. While tools for sequencing, synthesis, and editing of genomic code have transformed biological research, intelligently composing new biological systems would also require a deep understanding of the immense complexity encoded by genomes. We introduce Evo 2, a biological foundation model trained on 9.3 trillion DNA base pairs from a highly curated genomic atlas spanning all domains of life. We train Evo 2 with 7B and 40B parameters to have an unprecedented 1 million token context window with single-nucleotide resolution. Evo 2 learns from DNA sequence alone to accurately predict the functional impacts of genetic variation--from noncoding pathogenic mutations to clinically significant BRCA1 variants--without task-specific finetuning. Applying mechanistic interpretability analyses, we reveal that Evo 2 autonomously learns a breadth of biological features, including exon-intron boundaries, transcription factor binding sites, protein structural elements, and prophage genomic regions. Beyond its predictive capabilities, Evo 2 generates mitochondrial, prokaryotic, and eukaryotic sequences at genome scale with greater naturalness and coherence than previous methods. Guiding Evo 2 via inference-time search enables controllable generation of epigenomic structure, for which we demonstrate the first inference-time scaling results in biology. We make Evo 2 fully open, including model parameters, training code, inference code, and the OpenGenome2 dataset, to accelerate the exploration and design of biological complexity.Competing Interest StatementM.G.D. acknowledges outside interest in Stylus Medicine. M.P. is an employee of Liquid AI. C.R. acknowledges outside interest in Factory and Google Ventures. D.P.B. acknowledges outside interest as a Google Advisor. H.G. acknowledges outside interest as a co-founder of Exai Bio, Vevo Therapeutics, and Therna Therapeutics, serves on the board of directors at Exai Bio, and is a scientific advisory board member for Verge Genomics and Deep Forest Biosciences. P.D.H. acknowledges outside interest as a co-founder of Terrain Biosciences, Stylus Medicine, and Spotlight Therapeutics, serves on the board of directors at Stylus Medicine, is a board observer at EvolutionaryScale and Terrain Biosciences, a scientific advisory board member at Arbor Biosciences and Veda Bio, and an advisor to NFDG, Varda Space, and Vial Health. B.L.H. acknowledges outside interest in Prox Biosciences as a scientific co-founder. All other authors declare no competing interests.