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Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5’-KMT2A, two patients had a 5’-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.

Hydrocephalus is one of the earliest manifestations of mucopolysaccharidosis I-Hurler syndrome, and delayed treatment of hydrocephalus can lead to neurocognitive delay or even death. Optic nerve sheath diameter has been established as a noninvasive measurement to detect elevated intracranial pressure. This study aimed to establish correlations between optic nerve sheath diameter and opening pressure. Forty-nine MR images and opening pressures in patients with mucopolysaccharidosis I-Hurler syndrome were retrospectively reviewed from 2008 to 2020. The optic nerve sheath diameter was measured 3 mm posterior to the posterior margin of the globe (retrobulbar) and 10 mm anterior to the optic foramen (midpoint segment), and the average was taken between the 2 eyes. Opening pressure was measured with the patient in the lateral decubitus position with controlled end-tidal CO

After years of rapid growth, India has become a hotspot for emissions of aerosols and their precursors, recently surpassing China in terms of magnitude of SO2 emissions. The resulting high air pollution levels influence climate through interactions with solar radiation, clouds, and the hydrological cycle, and pose one of the greatest environmental threats to public health. Model estimates of these impacts are influenced by the substantial spread that exists between current emission inventories, in terms of both trend and magnitude. Activity and fuel data is heterogeneous and can be challenging to compile, and many emission sources are highly region specific. Hence, inventories need to be based on up-to-date national statistics and detailed sectoral information.Here we use one such inventory for Indian anthropogenic emissions, the recently developed, bottom up SNEII (Sabe National Emission Inventory for India) dataset to simulate and evaluate regional air pollution levels for 2018. SNEII includes a more detailed spatial allocation of point sources of emissions and sectoral disaggregation than many global inventories. The results are compared to estimates using the Community Emission Data System (CEDS) emissions, version 2021, also placing them in the context of the trend over the past decades. For most species, SNEII estimates higher emissions, and we explore the resulting impact of these differences on simulated aerosol abundances, as well as implications for radiative forcing and premature mortality. Finally, we quantify the sectoral contribution to air pollution with a finer breakdown than previously provided, including sectors unique for Indian/South Asian region.

We present an inter-comparison of simulated sea-salt aerosols (SSA) in CMIP6 models, including an evaluation against station observations in the Artic and Antarctic regions and satellite data. Drivers of model diversity are investigated. Historical and future trends are also explored and connected to their driving mechanisms. Additionally, the sensitivity of the polar radiative budget to SSA in CMIP6 models is quantified and put in relation to present-day uncertainties and future trends. Comparisons suggest (i) a large inter-model spread in SSA surface concentrations mostly driven by the diversity in source functions, (ii) an important overestimation of SSA surface concentrations compared to measurement stations but reasonable agreement with optical depth from satellite data, (iii) difficulties in properly capturing the annual cycle of SSA at both poles, particularly at higher latitude. A generally increasing trend in SSA concentrations is found in CMIP6 over the last decades and in future scenarios. CMIP6 models show that SSA contribute to cooling the poles significantly, implying possible uncertainties of several W/m2 in the present-day polar radiative budget.

Changes in mean and extreme precipitation are arguably the most impactful aspects of climate change. Detailed and accurate projections are therefore crucial for climate risk assessments and adaptation strategies. Generally, global mean precipitation increases with surface warming, with a global mean hydrological sensitivty of around 1 to 2 %/K, and stronger increases in rates or extreme precipitation events. Local variations are however very large, and model projections are much more uncertain than for temperature. Absorbing aerosols, notably black carbon (BC), brown carbon (BrC) and mineral dust, are an exception to the rule. Their absorption of shortwave radiation inhibits precipitation formation, through rapid adjstments that overwhelm their influence on surface temperature. The hydrological sensitivty to black carbon emissions is therefore around -4 %/K, again with large regional variations, and with a very high spread between models ( -1 to -7 %/K) In this talk, we discuss the near-term (2015-2045) dependence of precipitation change on the evolution of absorbing aerosols. We show the transient hydrological sensitivty in CMIP6, globally and regionally, and how it is affected by air quality policy (i.e. scenario choice) and model treatment of BC, BrC and dust. We confirm that, globally, while black carbon emissions have a modest impact on surface temperature, their influence on precipitation is outsized, causing a factor of 2 difference in hydrological sensitivty beween future scenarios with strict (SSP126) and weak (SSP370) air quality control measures. Further, for highly populated regions close to, or downwind from, major emission sources - notably India, China and northern Brazil - we find very high sensitivity of precipitation evolution to the levels of absorbing aerosol emissions. Several of these regions are therefore set for a "double whammy" of precipitation increase from global warming and a removal of short wave absorbing air pollution. We also discuss the rates of change of extreme precipitation events, and how they relate to absorbing aerosols in different regions. Our key message is that changes in absorbing aerosols over the coming decades is a key uncertainty in near term precipitation and extreme event evolution, and therefore a burning knowledge gap for the aerosol-climate community.

People identified with Black/African American or Hispanic/Latinx ethnicity are more likely to exhibit a more severe multiple sclerosis disease course relative to those who identify as White. While social determinants of health account for some of this discordant severity, investigation into contributing immunobiology remains sparse. The limited immunologic data stands in stark contrast to the volume of clinical studies describing ethnicity-associated discordant presentation, and to advancement made in our understanding of MS immunopathogenesis over the past several decades. In this perspective, we posit that humoral immune responses offer a promising avenue to better understand underpinnings of discordant MS severity among Black/African American, and Hispanic/Latinx-identifying patients.

A key driving factor behind rapid Arctic climate change is black carbon, the atmospheric aerosol that most efficiently absorbs sunlight. Our knowledge about black carbon in the Arctic is scarce, mainly limited to long-term measurements of a few ground stations and snap-shots by aircraft observations. Here, we combine observations from aircraft campaigns performed over nine years, and present vertically resolved average black carbon properties. A factor of four higher black carbon mass concentration (21.6 ng m−3 average, 14.3 ng m−3 median) was found in spring, compared to summer (4.7 ng m−3 average, 3.9 ng m−3 median). In spring, much higher inter-annual and geographic variability prevailed compared to the stable situation in summer. The shape of the black carbon size distributions remained constant between seasons with an average mass mean diameter of 202 nm in spring and 210 nm in summer. Comparison between observations and concentrations simulated by a global model shows notable discrepancies, highlighting the need for further model developments and intensified measurements.

Purpose To advance the implementation of consciousness-promoting therapies in patients with acute disorders of consciousness, the availability of potential therapeutic agents in formulations suitable for administration in hospitalized patients in the presence of complex comorbid conditions is paramount. The purpose of this study is to evaluate the long-term stability of extemporaneously prepared preservative-free methylphenidate hydrochloride (HCl) 5 mg/mL intravenous solution for experimental use. Methods A methylphenidate 5 mg/mL solution was prepared under proper aseptic techniques with Methylphenidate Hydrochloride, USP, powder mixed in sterile water for solution. Methylphenidate HCl 5 mg/mL solution was sterilized by filtration technique under USP –compliant conditions. Samples were stored refrigerated (2-8°C) and analyzed at approximately days 1, 30, 60, 90, 180, and 365. At each time point, chemical and physical stability were evaluated by visual inspection, pH measurement, membrane filtration procedure, turbidometric or photometric technique, and high-performance liquid chromatography analysis. Results Over the 1-year study period, the samples retained 96.76% to 102.04% of the initial methylphenidate concentration. There was no significant change in the visual appearance, pH level, or particulate matter during the study period. The sterility of samples was maintained and endotoxin levels were undetectable throughout the 1-year stability period. Conclusion Extemporaneously prepared preservative-free methylphenidate 5 mg/mL intravenous solution was physically and chemically stable at 32, 61, 95, 186, and 365 days when stored in amber glass vials at refrigerated temperatures (2-8°C).

Changes in anthropogenic aerosol emissions have strongly contributed to global and regional trends in temperature, precipitation, and other climate characteristics, and have been one of the dominant drivers of decadal trends in Asian and African precipitation. These, and other, influences on regional climate from changes in aerosol emissions are expected to continue, and potentially strengthen, in the coming decades. However, a combination of large uncertainties in emissions pathways, radiative forcing, and the dynamical response to forcing makes anthropogenic aerosol a key factor in the spread in near-term climate projections, particularly on regional scales, and therefore an important one to constrain. For example, in terms of future emissions pathways, the uncertainty in future global aerosol and precursor gas emissions by 2050 is as large as the total increase in emissions since 1850. In terms of aerosol effective radiative forcing, which remains the largest source of uncertainty in future climate change projections, CMIP6 models span a factor of five, from -0.3 to -1.5 W m-2. Both of these sources of uncertainty are exacerbated on regional scales. The Regional Aerosol Model Intercomparison Project (RAMIP) will deliver experiments designed to quantify the role of regional aerosol emissions changes in near-term projections. This is unlike any prior MIP, where the focus has been on changes in global emissions and/or very idealized aerosol experiments. Perturbing regional emissions makes RAMIP novel from a scientific standpoint, and links the intended analyses more directly to mitigation and adaptation policy issues. From a science perspective, there is limited information on how realistic regional aerosol emissions impact local as well as remote climate conditions. Here, RAMIP will enable an evaluation of the full range of potential influences of realistic and regionally varied aerosol emission changes on near-future climate. From the policy perspective, RAMIP addresses the burning question of how local and remote decisions affecting emissions of aerosols influence climate change in any given region. Here, RAMIP will provide the information needed to make direct links between regional climate policies and regional climate change. RAMIP experiments are designed to explore sensitivities to aerosol type and location, and provide improved constraints on uncertainties driven by aerosol radiative forcing and the dynamical response to aerosol changes. The core experiments will assess the effects of differences in future global and regional (East Asia, South Asia, Africa and the Middle East) aerosol emission trajectories through 2051, while optional experiments will test the nonlinear effects of varying emission location and aerosol types along this future trajectory. All experiments are based on the Shared Socioeconomic Pathways, and are intended to be performed with sixth Climate Model Intercomparison Project (CMIP6) generation models, initialised from the CMIP6 historical experiments, to facilitate comparisons with existing projections. Requested outputs will enable analysis of the role of aerosol in near-future changes in, for example, temperature and precipitation means and extremes, storms, and air quality.

Management of Earth's surface albedo is increasingly viewed as an important climate change mitigation strategy both on (Seneviratne et al., 2018) and off (Field et al., 2018; Kravitz et al., 2018) the land. Assessing the impact of a surface albedo change involves employing a measure like radiative forcing (RF) which can be challenging to digest for decision-makers who deal in the currency of CO2-equivalent emissions. As a result, many researchers express albedo change (Δα) RFs in terms of their CO2-equivalent effects, despite the lack of a standard method for doing so, such as there is for emissions of well-mixed greenhouse gases (WMGHGs; e.g., IPCC AR5, Myhre et al. (2013)). A major challenge for converting Δα RFs into their CO2-equivalant effects in a manner consistent with current IPCC emission metric approaches stems from the lack of a universal time-dependency following the perturbation (perturbation lifetime). Here, we review existing methodologies based on the RF concept with the goal of highlighting the context(s) in which the resulting CO2-equivalent metrics may or may not have merit. To our knowledge this is the first review dedicated entirely to the topic since the first CO2-eq. metric for Δα surfaced 20 years ago. We find that, although there are some methods that sufficiently address the time-dependency issue, none address or sufficiently account for the spatial disparity between the climate response to CO2 emissions and Δα – a major critique of Δα metrics based on the RF concept (Jones et al., 2013). We conclude that considerable research efforts are needed to build consensus surrounding the RF efficacy of various surface forcing types associated with Δα (e.g., crop change, forest harvest, etc.), and the degree to which these are sensitive to the spatial pattern, extent, and magnitude of the underlying surface forcings.

Management of Earth's surface albedo is increasingly viewed as an important climate change mitigation strategy both on (Seneviratne et al., 2018) and off (Field et al., 2018; Kravitz et al., 2018) the land. Assessing the impact of a surface albedo change involves employing a measure like radiative forcing (RF) which can be challenging to digest for decision-makers who deal in the currency of CO2-equivalent emissions. As a result, many researchers express albedo change (Δα) RFs in terms of their CO2-equivalent effects, despite the lack of a standard method for doing so, such as there is for emissions of well-mixed greenhouse gases (WMGHGs; e.g., IPCC AR5, Myhre et al., 2013). A major challenge for converting Δα RFs into their CO2-equivalent effects in a manner consistent with current IPCC emission metric approaches stems from the lack of a universal time dependency following the perturbation (perturbation “lifetime”). Here, we review existing methodologies based on the RF concept with the goal of highlighting the context(s) in which the resulting CO2-equivalent metrics may or may not have merit. To our knowledge this is the first review dedicated entirely to the topic since the first CO2-eq. metric for Δα surfaced 20 years ago. We find that, although there are some methods that sufficiently address the time-dependency issue, none address or sufficiently account for the spatial disparity between the climate response to CO2 emissions and Δα – a major critique of Δα metrics based on the RF concept (Jones et al., 2013). We conclude that considerable research efforts are needed to build consensus surrounding the RF “efficacy” of various surface forcing types associated with Δα (e.g., crop change, forest harvest), and the degree to which these are sensitive to the spatial pattern, extent, and magnitude of the underlying surface forcings.

Black carbon (BC) emissions play an important role in regional climate change in the Arctic. It is necessary to pay attention to the impact of long-range transport from regions outside the Arctic as BC emissions from local sources in the Arctic were relatively small. The task force Hemispheric Transport of Air Pollution Phase 2 (HTAP2) set up a series of simulation scenarios to investigate the response of BC in a given region to different source regions. This study investigated the responses of Arctic BC concentrations and surface temperature to 20 % anthropogenic emission reductions from six regions in 2010 within the framework of HTAP2 based on ensemble modeling results. Emission reductions from East Asia (EAS) had the most (monthly contributions: 0.2–1.5 ng m−3) significant impact on the Arctic near-surface BC concentrations, while the monthly contributions from Europe (EUR), Middle East (MDE), North America (NAM), Russia–Belarus–Ukraine (RBU), and South Asia (SAS) were 0.2–1.0, 0.001–0.01, 0.1–0.3, 0.1–0.7, and 0.0–0.2 ng m−3, respectively. The responses of the vertical profiles of the Arctic BC to the six regions were found to be different due to multiple transport pathways. Emission reductions from NAM, RBU, EUR, and EAS mainly influenced the BC concentrations in the low troposphere of the Arctic, while most of the BC in the upper troposphere of the Arctic derived from SAS. The response of the Arctic BC to emission reductions in six source regions became less significant with the increase in the latitude. The benefit of BC emission reductions in terms of slowing down surface warming in the Arctic was evaluated by using absolute regional temperature change potential (ARTP). Compared to the response of global temperature to BC emission reductions, the response of Arctic temperature was substantially more sensitive, highlighting the need for curbing global BC emissions.

Summary Background Cagrilintide, a long-acting amylin analogue, and semaglutide 2·4 mg, a glucagon-like peptide-1 analogue, are both being investigated as options for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of this drug combination. Methods In this randomised, placebo-controlled, multiple-ascending dose, phase 1b trial, individuals aged 18–55 years with a body-mass index 27·0−39·9 kg/m2 and who were otherwise healthy were recruited from a single centre in the USA. The trial included six sequential overlapping cohorts, and in each cohort eligible participants were randomly assigned (3:1) to once-weekly subcutaneous cagrilintide (0·16, 0·30, 0·60, 1·2, 2·4, or 4·5 mg) or matched placebo, in combination with once-weekly subcutaneous semaglutide 2·4 mg, without lifestyle interventions. In each cohort, the doses of cagrilintide and semaglutide were co-escalated in 4-week intervals to the desired dose over 16 weeks, participants were treated at the target dose for 4 weeks, and then followed up for 5 weeks. Participants, investigators, and the sponsor were masked to treatment assignment. The primary endpoint was number of treatment-emergent adverse events from baseline to end of follow-up. Secondary pharmacokinetic endpoints assessed from day of last dose (week 19) to end of treatment (week 20) were area under the plasma concentration-time curve from 0 to 168 h (AUC0–168 h) and maximum concentration [Cmax] of cagrilintide and semaglutide; exploratory pharmacokinetic endpoints were half-life, time to Cmax [tmax], plasma clearance, and volume of distribution of cagrilintide and semaglutide; and exploratory pharmacodynamic endpoints were changes in bodyweight, glycaemic parameters, and hormones. Safety, pharmacokinetic, and pharmacodynamic endpoints were assessed in all participants who were exposed to at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03600480, and is now complete. Findings Between July 25, 2018, and Dec 17, 2019, 285 individuals were screened and 96 were randomly assigned to cagrilintide (0·16–2·4 mg group n=12; 4·5 mg group n=11) or placebo (n=24), in combination with semaglutide 2·4 mg, of whom 95 were exposed to treatment (one patient in 0·60 mg cagrilintide group was not exposed) and included in the safety and full analysis datasets. The mean age was 40·6 years (SD 9·2), 56 (59%) of 95 participants were men and 51 (54%) were Black or African American. Of 566 adverse events reported in 92 participants (69 [97%] of 71 participants assigned to 0·16–4·5 mg cagrilintide and 23 [96%] of 24 assigned to placebo), 207 (37%) were gastrointestinal disorders. Most adverse events were mild to moderate in severity and the proportion of participants with one or more adverse event was similar across treatment groups. Exposure was proportional to cagrilintide dose and did not affect semaglutide exposure or elimination. AUC0–168 h ranged from 926 nmol × h/L to 24 271 nmol × h/L, and Cmax ranged from 6·14 nmol/L to 170 nmol/L with cagrilintide 0·16–4·5 mg. AUC0–168 h ranged from 12 757 nmol × h/L to 15 305 nmol × h/L, and Cmax ranged from 96·4 nmol/L to 120 nmol/L with semaglutide 2·4 mg. Cagrilintide 0·16−4·5 mg had a half-life of 159–195 h, with a median tmax of 24–72 h. Semaglutide 2·4 mg had a half-life of 145–165 h, with a median tmax of 12–24 h. Plasma clearance and volume of distribution for both cagrilintide and semaglutide were similar across treatment groups. At week 20, mean percentage bodyweight reductions were greater with cagrilintide 1·2 and 2·4 mg than with placebo (15·7% [SE 1·6] for cagrilintide 1·2 mg and 17·1% [1·5] for cagrilintide 2·4 mg vs 9·8% [1·2] for pooled placebo cohorts 1–5; estimated treatment difference of −6·0% [95% CI −9·9 to −2·0] for cagrilintide 1·2 mg and −7·4% [−11·2 to −3·5] for cagrilintide 2·4 mg vs pooled placebo), and with cagrilintide 4·5 mg than with matched placebo (15·4% [1·3] vs 8·0% [2·2]; estimated treatment difference −7·4% [−12·8 to −2·1]), all in combination with semaglutide 2·4 mg. Glycaemic parameters improved in all treatment groups, independently of cagrilintide dose. Changes in hormones were similar across treatment groups. Interpretation Concomitant treatment with cagrilintide and semaglutide 2·4 mg was well tolerated with an acceptable safety profile. Future larger and longer trials are needed to fully assess the efficacy and safety of this treatment combination. Funding Novo Nordisk A/S.

Gestational maternal immune activation (MIA) in mice induces persistent brain microglial activation and a range of neuropathologies in the adult offspring. Although long-term phenotypes are well documented, how MIA in utero leads to persistent brain inflammation is not well understood. Here, we found that offspring of mothers treated with polyriboinosinic–polyribocytidylic acid [poly(I:C)] to induce MIA at gestational day 13 exhibit blood–brain barrier (BBB) dysfunction throughout life. Live MRI in utero revealed fetal BBB hyperpermeability 2 d after MIA. Decreased pericyte–endothelium coupling in cerebral blood vessels and increased microglial activation were found in fetal and 1- and 6-mo-old offspring brains. The long-lasting disruptions result from abnormal prenatal BBB formation, driven by increased proliferation of cyclooxygenase-2 (COX2; Ptgs2)-expressing microglia in fetal brain parenchyma and perivascular spaces. Targeted deletion of the Ptgs2 gene in fetal myeloid cells or treatment with the inhibitor celecoxib 24 h after immune activation prevented microglial proliferation and disruption of BBB formation and function, showing that prenatal COX2 activation is a causal pathway of MIA effects. Thus, gestational MIA disrupts fetal BBB formation, inducing persistent BBB dysfunction, which promotes microglial overactivation and behavioral alterations across the offspring life span. Taken together, the data suggest that gestational MIA disruption of BBB formation could be an etiological contributor to neuropsychiatric disorders.

Recent years have seen unprecedented fire activity at Arctic latitudes, leading to severe consequences including unhealthy air quality in high latitude towns and cities. While wildfire occurrence and severity result from a complex interplay between natural and anthropogenic factors, weather is a key factor.Weather conditions that promote high wildfire risk are characterized by the combination of high temperatures, little precipitation and low humidity, and often high winds. All of these can be affected by human-induced climate change and evidence is emerging that wildfire risk is already increasing in many regions. Such changes not only manifest as shifts in the means and extremes of the weather variables but can also be changes in the shape of their distributions. The importance of the full, regional Probability Density Functions (PDFs) of individual and aggregated variables, which contain information on expected weather not apparent from the distribution mean or tails, but through changes to their overall shape, for understanding climate risk has been broadly discussed in the literature. Furthermore, while simulations with regional climate models to derive such information are costly and time consuming, the advent of large ensembles of coupled climate model simulations has recently opened new opportunities.Here we present a detailed characterization of the distribution and variability of weather variables conducive to wildfire risk across five high-latitude boreal regions in North America, Scandinavia and Russia. Building on methodology developed in Samset et al. (2019), we quantify the PDFs of daily data for a broad set of individual variables, as well as for the aggregate change expressed using the Canadian Fire Weather Index. Using ensembles of coupled simulations from two climate models (CanESM5 and MPI-ESM1-2) and two CMIP6 scenarios (the Shared Socioeconomic Pathways SSP1-2.6 and SSP5-8.5), we consistently quantify the changes of regionally and seasonally resolved PDFs under different levels of global warming. Our results provide a comprehensive picture of the potential future changes in drivers of fire weather and wildfire risk in the pan-Arctic region and demonstrate the difference between regions. We also show how statistical descriptions combined with emulation of Earth System Model (ESM) information can offer an alternative pathway to resource demanding model runs, for rapidly translating science to user-oriented information.

Mitigation of non-CO2 emissions plays a key role in meeting the Paris Agreement ambitions and sustainable development goals. Implementation of respective policies addressing these targets mainly occur at sectoral and regional levels, and designing efficient mitigation strategies therefore relies on detailed knowledge about the mix of emissions from individual sources and their subsequent climate impact. Here we present a comprehensive dataset of near- and long-term global temperature responses to emissions of CO2 and individual short-lived climate forcers (SLCFs) from 7 sectors and 13 regions – for both present-day emissions and their continued evolution as projected under the Shared Socioeconomic Pathways (SSPs). We demonstrate the key role of CO2 in driving both near- and long-term warming and highlight the importance of mitigating methane emissions from agriculture, waste management, and energy production as the primary strategy to further limit near-term warming. Due to high current emissions of cooling SLCFs, policies targeting end-of-pipe energy sector emissions may result in net added warming unless accompanied by simultaneous methane and/or CO2 reductions. We find that SLCFs are projected to play a continued role in many regions, particularly those including low- to medium-income countries, under most of the SSPs considered here. East Asia, North America, and Europe will remain the largest contributors to total net warming until 2100, regardless of scenario, while South Asia and Africa south of the Sahara overtake Europe by the end of the century in SSP3-7.0 and SSP5-8.5. Our dataset is made available in an accessible format, aimed also at decision makers, to support further assessment of the implications of policy implementation at the sectoral and regional scales.

The uptake of water by atmospheric aerosols has a pronounced effect on particle light scattering properties, which in turn are strongly dependent on the ambient relative humidity (RH). Earth system models need to account for the aerosol water uptake and its influence on light scattering in order to properly capture the overall radiative effects of aerosols. Here we present a comprehensive model–measurement evaluation of the particle light scattering enhancement factor f(RH), defined as the particle light scattering coefficient at elevated RH (here set to 85 %) divided by its dry value. The comparison uses simulations from 10 Earth system models and a global dataset of surface-based in situ measurements. In general, we find a large diversity in the magnitude of predicted f(RH) amongst the different models, which can not be explained by the site types. Based on our evaluation of sea salt scattering enhancement and simulated organic mass fraction, there is a strong indication that differences in the model parameterizations of hygroscopicity and model chemistry are driving at least some of the observed diversity in simulated f(RH). Additionally, a key point is that defining dry conditions is difficult from an observational point of view and, depending on the aerosol, may influence the measured f(RH). The definition of dry also impacts our model evaluation, because several models exhibit significant water uptake between RH = 0 % and 40 %. The multisite average ratio between model outputs and measurements is 1.64 when RH = 0 % is assumed as the model dry RH and 1.16 when RH = 40 % is the model dry RH value. The overestimation by the models is believed to originate from the hygroscopicity parameterizations at the lower RH range which may not implement all phenomena taking place (i.e., not fully dried particles and hysteresis effects). This will be particularly relevant when a location is dominated by a deliquescent aerosol such as sea salt. Our results emphasize the need to consider the measurement conditions in such comparisons and recognize that measurements referred to as dry may not be dry in model terms. Recommendations for future model–measurement evaluation and model improvements are provided.

Objective Previous studies have shown additive weight loss when intensive behavioral therapy (IBT) was combined with weight-loss medication. The present multisite study provides the first evaluation, in primary care, of the effect of the Centers for Medicare and Medicaid Services-based IBT benefit, delivered alone (with placebo) or in combination with liraglutide 3.0 mg. Methods The Satiety and Clinical Adiposity-Liraglutide Evidence in individuals with and without diabetes (SCALE) IBT was a 56-week, randomized, double-blind, placebo-controlled, multicenter trial in individuals with obesity who received liraglutide 3.0 mg (n = 142) or placebo (n = 140) as an adjunct to IBT. Results At week 56, mean weight loss with liraglutide 3.0 mg plus IBT was 7.5% and 4.0% with placebo combined with IBT (estimated treatment difference [95% CI]-3.4% [-5.3% to -1.6%], P = 0.0003). Significantly more individuals on liraglutide 3.0 mg than placebo achieved ≥ 5% weight loss (61.5% vs. 38.8%; odds ratio [OR] 2.5% [1.5% to 4.1%], P = 0.0003), > 10% weight loss (30.5% vs. 19.8%; OR 1.8% [1.0% to 3.1%], P = 0.0469), and > 15% weight loss (18.1% vs. 8.9%; OR 2.3% [1.1% to 4.7%], P = 0.0311). Liraglutide 3.0 mg in combination with IBT was well tolerated, with no new safety signals identified. Conclusions In a primary care setting, Centers for Medicare and Medicaid Services-based IBT produced clinically meaningful weight loss at 56 weeks, enhanced by the addition of liraglutide 3.0 mg.

Seasonal snow cover plays a major role in the climate system of the Northern Hemisphere via its effect on land surface albedo and fluxes. In climate models the parameterization of interactions between snow and atmosphere remains a source of uncertainty and biases in the representation of local and global climate. Here, we evaluate the ability of an ensemble of regional climate models (RCMs) coupled with different land surface models to simulate snow–atmosphere interactions over Europe in winter and spring. We use a previously defined index, the snow-albedo sensitivity index (SASI), to quantify the radiative forcing associated with snow cover anomalies. By comparing RCM-derived SASI values with SASI calculated from reanalyses and satellite retrievals, we show that an accurate simulation of snow cover is essential for correctly reproducing the observed forcing over middle and high latitudes in Europe. The choice of parameterizations, and primarily the choice of the land surface model, strongly influences the representation of SASI as it affects the ability of climate models to simulate snow cover accurately. The degree of agreement between the datasets differs between the accumulation and ablation periods, with the latter one presenting the greatest challenge for the RCMs. Given the dominant role of land surface processes in the simulation of snow cover during the ablation period, the results suggest that, during this time period, the choice of the land surface model is more critical for the representation of SASI than the atmospheric model.

The rate of global surface warming is crucial for tracking progress towards global climate targets, but is strongly influenced by interannual-to-decadal variability, which precludes rapid detection of the temperature response to emission mitigation. Here we use a physics based Green’s function approach to filter out modulations to global mean surface temperature from sea-surface temperature (SST) patterns, and show that it results in an earlier emergence of a response to strong emissions mitigation. For observed temperatures, we find a filtered 2011–2020 surface warming rate of 0.24 °C per decade, consistent with long-term trends. Unfiltered observations show 0.35 °C per decade, partly due to the El Nino of 2015–2016. Pattern filtered warming rates can become a strong tool for the climate community to inform policy makers and stakeholder communities about the ongoing and expected climate responses to emission reductions, provided an effort is made to improve and validate standardized Green’s functions.

The Major Histocompatibility Complex (MHC) makes the largest genetic contribution to multiple sclerosis (MS) susceptibility, with 32 independent effects across the region explaining 20% of the heritability in European populations. Variation is high across populations with allele frequency differences and population-specific risk alleles identified. We sought to identify MHC-specific MS susceptibility variants and assess the effect of ancestral risk modification within 2652 Latinx and Hispanic individuals as well as 2435 Black and African American individuals. We have identified several novel susceptibility alleles which are rare in European populations including HLA-B*53:01, and we have utilized the differing linkage disequilibrium patterns inherent to these populations to identify an independent role for HLA-DRB1*15:01 and HLA-DQB1*06:02 on MS risk. We found a decrease in Native American ancestry in MS cases vs controls across the MHC, peaking near the previously identified MICB locus with a decrease of ~5.5% in Hispanics and ~0.4% in African Americans. We have identified several susceptibility variants, including within the MICB gene region, which show global ancestry risk modification and indicate ancestral differences which may be due in part to correlated environmental factors. We have also identified several susceptibility variants for which MS risk is modified by local ancestry and indicate true ancestral genetic differences; including HLA-DQB1*06:02 for which MS risk for European allele carriers is almost two times the risk for African allele carriers. These results validate the importance of investigating MS susceptibility at an ancestral level and offer insight into the epidemiology of MS phenotypic diversity.

Multiple Sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by autoimmune and neurodegenerative pathologies for which there is no cure and no defined etiology. Although several, modestly effective, disease modifying drugs are available to treat MS, there are presently no treatments that offer neuroprotection and prevent clinical progression. Therapies are needed that control immune homeostasis, prevent disease progression, and stimulate regeneration in the CNS. Components of the renin-angiotensin-system (RAS) have recently been identified as chemical mediators in the CNS and in neurological disease. Here we show the beneficial effect of therapeutic treatment with the Mas receptor agonist and metabolite of the protective arm of RAS, angiotensin 1-7 (A(1-7)), in the experimental autoimmune encephalomyelitis (EAE) animal model of MS. Therapeutic treatment with A(1-7) caused a dose-dependent reduction both in clinical disease severity and progression, and was dependent on Mas receptor activation. Further analysis of the most optimal dose of A(1-7) treatment revealed that the reductions in clinical disease course were associated with decreased immune infiltration and demyelination, axonal loss and oxidative stress in the spinal cord. In addition A(1-7) treatment was also associated with increases in circulating alternatively activated monocytes/macrophages.

A field study was conducted for three consecutive seasons in the hot climate of central California to assess the performance of ‘Merlot’ grapevine (Vitis vinifera) grafted onto ‘Freedom’ [Fresno 1613-59 × Dog Ridge 5 (27% V. vinifera hybrid)] during training system conversion to facilitate mechanization. The traditional head-trained and cane-pruned (CP) system was either retained or converted either to a bilateral cordon-trained, spur-pruned California sprawl training system (HP), or to a bilateral cordon-trained, mechanically box-pruned single high-wire sprawling system (SHMP). After the conversion, SHMP sustained greater yield with more clusters per vine and smaller berries without affecting the canopy microclimate. This was due to a higher number of nodes retained after dormant pruning. The SHMP canopies, compared with CP and HP; filled allotted canopy space earlier based on photosynthetically active radiation (PAR) transmitted through the canopies, populating the space allotted per vine, favoring higher production efficiency. There were no adverse effects of training systems on berry composition or flavonoid concentration, during or after conversion to mechanical management. However, experimental year effect was obvious on anthocyanin composition of ‘Merlot’ berries, increasing trihydroxylated (i.e., delphinidin-based) anthocyanins in the latter years of the experiment. Our results also provided evidence that earlier canopy growth coupled with sufficient reproductive compensating responses allowed for increased yields while reaching commercial maturity without a decline in anthocyanin content with the SHMP. Converting CP to SHMP reduced labor operations costs by 90%. Furthermore, the SHMP had greater gross revenue and resulted in greater net income per acre even when the conversion year was taken into account. Therefore, SHMP is recommended for growers within the hot climate of the central San Joaquin Valley as a means to maintain productivity of vineyards while not sacrificing berry composition at the farm gate.

We document the ability of the new-generation Oslo chemistry-transport model, Oslo CTM3, to accurately simulate present-day aerosol distributions. The model is then used with the new Community Emission Data System (CEDS) historical emission inventory to provide updated time series of anthropogenic aerosol concentrations and consequent direct radiative forcing (RFari) from 1750 to 2014. Overall, Oslo CTM3 performs well compared with measurements of surface concentrations and remotely sensed aerosol optical depth. Concentrations are underestimated in Asia, but the higher emissions in CEDS than previous inventories result in improvements compared to observations. The treatment of black carbon (BC) scavenging in Oslo CTM3 gives better agreement with observed vertical BC profiles relative to the predecessor Oslo CTM2. However, Arctic wintertime BC concentrations remain underestimated, and a range of sensitivity tests indicate that better physical understanding of processes associated with atmospheric BC processing is required to simultaneously reproduce both the observed features. Uncertainties in model input data, resolution, and scavenging affect the distribution of all aerosols species, especially at high latitudes and altitudes. However, we find no evidence of consistently better model performance across all observables and regions in the sensitivity tests than in the baseline configuration. Using CEDS, we estimate a net RFari in 2014 relative to 1750 of −0.17 W m−2, significantly weaker than the IPCC AR5 2011–1750 estimate. Differences are attributable to several factors, including stronger absorption by organic aerosol, updated parameterization of BC absorption, and reduced sulfate cooling. The trend towards a weaker RFari over recent years is more pronounced than in the IPCC AR5, illustrating the importance of capturing recent regional emission changes.

Alemtuzumab is a highly effective treatment for relapsing-remitting multiple sclerosis. It selectively targets the CD52 antigen to induce profound lymphocyte depletion, followed by recovery of T and B cells with regulatory phenotypes. We previously showed that regulatory T cell function is restored with cellular repletion, but little is known about the functional capacity of regulatory B-cells and peripheral blood monocytes during the repletion phase. In this study (ClinicalTrials.gov ID# NCT03647722) we simultaneously analyzed the change in composition and function of both regulatory lymphocyte populations and distinct monocyte subsets in cross-sectional cohorts of MS patients prior to or 6, 12, 18, 24 or 36 months after their first course of alemtuzumab treatment. We found that the absolute number and percentage of cells with a regulatory B cell phenotype were significantly higher after treatment and were positivity correlated with regulatory T cells. In addition, B cells from treated patients secreted higher levels of IL-10 and BDNF, and inhibited the proliferation of autologous CD4+CD25-T cell targets. Though there was little change in monocytes populations overall, following the second annual course of treatment, CD14+monocytes had a significantly increased anti-inflammatory bias in cytokine secretion patterns. These results confirmed that the immune system in alemtuzumab-treated patients is altered in favor of a regulatory milieu that involves expansion and increased functionality of multiple regulatory populations including B cells, T cells and monocytes. Here, we showed for the first time that functionally competent regulatory B cells re-appear with similar kinetics to that of regulatory T-cells, whereas the change in anti-inflammatory bias of monocytes does not occur until after the second treatment course. These findings justify future studies of all regulatory cell types following alemtuzumab treatment to reveal further insights into mechanisms of drug action, and to identify key immunological predictors of durable clinical efficacy in alemtuzumab-treated patients.

A new method for classifying bacteria is presented and applied to a large set of biochemical data for the