Search

Glaciers are retreating globally and are projected to continue to lose mass in the coming decades, directly affecting downstream ecosystems through changes in glacier runoff. Estimating the future evolution of glacier runoff involves several sources of data uncertainty, which to date have not been comprehensively assessed on a regional scale. In this study, we used the Open Global Glacier Model (OGGM) to estimate the evolution of each glacier (with area > 1 km2) in the Patagonian Andes (40–56° S). As sources of uncertainty, we used different glacier inventories (n = 2), ice thickness datasets (n = 2), historical climate datasets (n = 4), general circulation models (GCMs; n = 10), emission scenarios (Shared Socioeconomic Pathways, SSPs; n = 4) and bias correction methods (BCMs; n = 3) to generate 1920 possible scenarios over the period of 1980–2099. In each scenario, glacier runoff and melt time series were characterised by 10 glacio-hydrological signatures (i.e. metrics). We used the permutation feature importance of random forest regression models to assess the relative importance of each source of uncertainty on the signatures of each catchment. Considering all scenarios, 34 % ± 13 % (mean ± 1 standard deviation) of the glacier area has already peaked in terms of glacier melt (the year 2020), and 68 % ± 21 % of the glacier area will lose more than 50 % of its volume this century. Considering the glacier melt signatures, the future sources of uncertainty (GCMs, SSPs and BCMs) were the main source in only 17 % ± 21 % of the total glacier area. In contrast, the reference climate was the main source in 69 % ± 22 % of the glacier area, highlighting the impact of calibration choices on baseline conditions, model parameters and the initial starting geometry for future projections. The results provide a basis for prioritising future efforts (e.g. the improvement of reference climate characterisation) to reduce glacio-hydrological modelling gaps in poorly instrumented regions such as the Patagonian Andes.

The Patagonian Icefields (Northern and Southern Patagonian Icefield) are the largest ice masses in the Andes Cordillera. Despite its importance, little is known about the main mechanisms that underpin the interaction between these ice masses and climate. Furthermore, the nature of large-scale climatic control over the surface mass variations of the Patagonian Icefields still remains unclear. The main aim of this study is to understand the present-day climatic control of the surface mass balance (SMB) of the Patagonian Icefields at interannual timescales, especially considering large-scale processes. We modeled the present-day (1980–2015) glacioclimatic surface conditions for the southern Andes Cordillera by statistically downscaling the output from a regional climate model (RegCMv4) from a 10 km spatial resolution to a 450 m resolution grid and then using the downscaled fields as input for a simplified SMB model. Series of spatially averaged modeled fields over the Patagonian Icefields were used to derive regression and correlation maps against fields of climate variables from the ERA-Interim reanalysis. Years of relatively high SMB are associated with the establishment of an anomalous low-pressure center near the Drake Passage, the Drake low, that induces an anomalous cyclonic circulation accompanied with enhanced westerlies impinging on the Patagonian Icefields, which in turn leads to increases in the precipitation and the accumulation over the icefields. Also, the Drake low is thermodynamically maintained by a core of cold air that tends to reduce the ablation. Years of relatively low SMB are associated with the opposite conditions. We found low dependence of the SMB on main atmospheric modes of variability (El Niño–Southern Oscillation, Southern Annular Mode), revealing a poor ability of the associated indices to reproduce the interannual variability of the SMB. Instead, this study highlights the Drake Passage as a key region that has the potential to influence the SMB variability of the Patagonian Icefields.

Glaciers and ice caps are thinning and retreating along the entire Andes ridge, and drivers of this mass loss vary between the different climate zones. The southern part of the Andes (Wet Andes) has the highest abundance of glaciers in number and size, and a proper understanding of ice dynamics is important to assess their evolution. In this contribution, we apply the ice-sheet model SICOPOLIS (SImulation COde for POLythermal Ice Sheets) to the Mocho-Choshuenco ice cap in the Chilean Lake District (40∘ S, 72∘ W; Wet Andes) to reproduce its current state and to project its evolution until the end of the 21st century under different global warming scenarios. First, we create a model spin-up using observed surface mass balance data on the south-eastern catchment, extrapolating them to the whole ice cap using an aspect-dependent parameterization. This spin-up is able to reproduce the most important present-day glacier features. Based on the spin-up, we then run the model 80 years into the future, forced by projected surface temperature anomalies from different global climate models under different radiative pathway scenarios to obtain estimates of the ice cap's state by the end of the 21st century. The mean projected ice volume losses are 56±16 % (RCP2.6), 81±6 % (RCP4.5), and 97±2 % (RCP8.5) with respect to the ice volume estimated by radio-echo sounding data from 2013. We estimate the uncertainty of our projections based on the spread of the results when forcing with different global climate models and on the uncertainty associated with the variation of the equilibrium line altitude with temperature change. Considering our results, we project a considerable deglaciation of the Chilean Lake District by the end of the 21st century.

The surface energy fluxes of glaciers determine surface melt, and their adequate parametrization is one of the keys to a successful prediction of future glacier mass balance and freshwater discharge. Chile hosts glaciers in a large range of latitudes under contrasting climatic settings: from 18∘ S in the Atacama Desert to 55∘ S on Tierra del Fuego. Using three different methods, we computed surface energy fluxes for five glaciers which represent the main glaciological zones of Chile. We found the main energy sources for surface melt change from the Central Andes, where the net shortwave radiation is driving the melt, to Patagonia, where the turbulent fluxes are an important source of energy. We inferred higher surface melt rates for Patagonian glaciers as compared to the glaciers of the Central Andes due to a higher contribution of the turbulent sensible heat flux, less negative net longwave radiation and a positive contribution of the turbulent latent heat flux. The variability in the atmospheric emissivity was high and not able to be explained exclusively by the variability in the inferred cloud cover. The influence of the stability correction and the roughness length on the magnitude of the turbulent fluxes in the different climate settings was examined. We conclude that, when working towards physical melt models, it is not sufficient to use the observed melt as a measure of model performance; the model parametrizations of individual components of the energy balance have to be validated individually against measurements.

Mobility is becoming more and more important to society and hence air transportation is expected to grow further over the next decades. Reducing anthropogenic climate impact from aviation emissions and building a climate-friendly air transportation system are required for a sustainable development of commercial aviation. A climate optimized routing, which avoids climate-sensitive regions by re-routing horizontally and vertically, is an important measure for climate impact reduction. The idea includes a number of different routing strategies (routing options) and shows a great potential for the reduction. To evaluate this, the impact of not only CO2 but also non-CO2 emissions must be considered. CO2 is a long-lived gas, while non-CO2 emissions are short-lived and are inhomogeneously distributed. This study introduces AirTraf (version 1.0) that performs global air traffic simulations, including effects of local weather conditions on the emissions. AirTraf was developed as a new submodel of the ECHAM5/MESSy Atmospheric Chemistry (EMAC) model. Air traffic information comprises Eurocontrol's Base of Aircraft Data (BADA Revision 3.9) and International Civil Aviation Organization (ICAO) engine performance data. Fuel use and emissions are calculated by the total energy model based on the BADA methodology and Deutsches Zentrum für Luft- und Raumfahrt (DLR) fuel flow method. The flight trajectory optimization is performed by a genetic algorithm (GA) with respect to a selected routing option. In the model development phase, benchmark tests were performed for the great circle and flight time routing options. The first test showed that the great circle calculations were accurate to −0.004 %, compared to those calculated by the Movable Type script. The second test showed that the optimal solution found by the algorithm sufficiently converged to the theoretical true-optimal solution. The difference in flight time between the two solutions is less than 0.01 %. The dependence of the optimal solutions on the initial set of solutions (called population) was analyzed and the influence was small (around 0.01 %). The trade-off between the accuracy of GA optimizations and computational costs is clarified and the appropriate population and generation (one iteration of GA) sizing is discussed. The results showed that a large reduction in the number of function evaluations of around 90 % can be achieved with only a small decrease in the accuracy of less than 0.1 %. Finally, AirTraf simulations are demonstrated with the great circle and the flight time routing options for a typical winter day. The 103 trans-Atlantic flight plans were used, assuming an Airbus A330-301 aircraft. The results confirmed that AirTraf simulates the air traffic properly for the two routing options. In addition, the GA successfully found the time-optimal flight trajectories for the 103 airport pairs, taking local weather conditions into account. The consistency check for the AirTraf simulations confirmed that calculated flight time, fuel consumption, NOx emission index and aircraft weights show good agreement with reference data.

We present surface mass balance simulations of the Southern Patagonia Icefield (SPI) driven by downscaled reanalysis data. The simulations were evaluated and interpreted using geodetic mass balances, measured point balances and a complete velocity field of the icefield for spring 2004. The high measured accumulation of snow of up to 15.4 m w.e. yr−1 (meters water equivalent per year) as well as the high measured ablation of up to 11 m w.e. yr−1 is reproduced by the model. The overall modeled surface mass balance was positive and increasing during 1975–2011. Subtracting the surface mass balance from geodetic balances, calving fluxes were inferred. Mass losses of the SPI due to calving were strongly increasing from 1975–2000 to 2000–2011 and higher than losses due to surface melt. Calving fluxes were inferred for the individual glacier catchments and compared to fluxes estimated from velocity data. Measurements of ice thickness and flow velocities at the glaciers' front and spatially distributed accumulation measurements can help to reduce the uncertainties of the different terms in the mass balance of the Southern Patagonia Icefield.

Background: Patient-reported outcome measures (PROMs) have gained increased importance in assessing outcomes after reconstructive surgery. This also applies to the reconstruction of vulvoperineal defects after resection of gynecological or colorectal cancers in women. The objective of this study is to analyze the current state of PROM tool use within this patient population. Methods: By systematic literature searches in Embase, Medline, and Web of Science, English-language studies published after 1980, including randomized controlled trials, cohort studies, and case series reporting on vulvoperineal defect reconstruction, which were included if they also analyzed quality of life (QoL) and/or PROMs. The PROM tools used by each study were extracted, analyzed, and compared. Results: The primary search yielded 2576 abstracts, of which 395 articles were retrieved in full text. Of these, 50 reported on vulvoperineal defect reconstruction, among which 27 studies analyzing QoL were found. Of those, 17 met the inclusion criteria for this systematic review. After full-text screening, 14 different PROM tools and 5 individual, non-standardized questionnaires were identified. Only 22% of studies used a validated PROM tool. Conclusion: Far too few studies currently use PROM tools to assess outcomes in oncological vulvoperineal defect reconstruction. Less than half of the used PROMs are validated. No PROM was designed to specifically measure QoL in this patient population. The standardized implementation of a validated PROM tool in the clinical treatment of this patient population is an essential step to improve outcomes, enable the comparison of research, and support evidence-based treatment approaches.

We present 40 new 10Be exposure ages of moraines and other glacial deposits left behind by the southeastern sector of the Laurentide Ice Sheet (LIS) in southern New England and New York, summarize the regional moraine record, and interpret the dataset in the context of previously published deglaciation chronologies. The regional moraine record spans the Last Glacial Maximum (LGM), with the outermost ridge of the terminal complex dating to ∼ 26–25 ka, the innermost ridge of the terminal complex dating to ∼ 22 ka, and a series of smaller recessional limits within ∼ 50 km of the terminal complex dating to ∼ 21–20.5 ka. The chronology generally agrees with independent age constraints from radiocarbon and glacial varves. A few inconsistencies between ages from cosmogenic-nuclide measurements and those from other dating methods are explained by geological scatter, where several bedrock samples and boulders from the outer terminal moraine exhibit nuclide inheritance, while some exposure ages of large moraines are likely affected by postdepositional disturbance. The exposure age chronology places the southeastern sector of the LIS at or near its maximum extent, from ∼ 26 to 21 ka, which is broadly consistent with the LGM sea-level lowstand, local and regional temperature indicators, and local summer insolation. The net change in LIS extent, represented by this chronology, occurred more slowly (< 5 to 25 m yr−1) than the subsequent retreat through the rest of New England, consistent with a slow general rise in insolation and modeled summer temperature. We conclude that the major pulse of LIS deglaciation and accelerated recession, recorded by dated glacial deposits north of the moraines discussed here, did not begin until after atmospheric CO2 increased around 18 ka, marking the onset of Termination I.

The fungal pathogen Candida albicans transforms arachidonic acid (AA) into 3-hydroxyarachidonic acid [3(R)-HETE], and we investigated if its nonpathogenic and 3(R)-HETE-producing close relative, Dipodascopsis uninucleata, could similarly transform the endocannabinoid/endovanilloid anandamide into 3-hydroxyanandamide (3-HAEA). We found that D. uninucleata converts anandamide into 3-HAEA, and we therefore developed an enantiodivergent synthesis for this compound to study its pharmacological activity. Both enantiomers of 3-HAEA were as active as anandamide at elevating intracellular Ca2+ via TRPV1 receptors overexpressed in HEK-293 cells, while a∼70–90-fold and ∼45–60-fold lower affinity at cannabinoid CB1 and CB2 receptors was instead observed. Patch clamp recordings showed that 3(R)-HAEA activates a TRPV1-like current in TRPV1-expressing HEK-293 cells. Thus, 3(R)-HETE-producing yeasts might convert anandamide released by host cells at the site of infection into 3(R)-HAEA, and this event might contribute to the inflammatory and algogenous responses associated to fungal diseases.

Abstract An ideal tumor‐specific immunomodulatory therapy should both preferentially target the tumor, while simultaneously reduce the immunosuppressive environment within the tumor. This guiding principle led us to explore engineering Siglec‐15 (S15) targeted bispecific antibody (bsAb) to enhance therapy against triple negative breast cancer (TNBC). S15 appears to be exclusively expressed on macrophages and diverse tumor cells, including human and mouse 4T1 TNBC. TGF‐β is a growth hormone frequently associated with increased tumor invasiveness, including in TNBC. Here, to overcome the immune‐suppressive environment within TNBC tumors to enable more effective cancer therapy, we engineered a bispecific antibody (bsAb) targeting both Siglec15 and TGF‐β. In mice engrafted with orthotopic 4T1 tumors, S15/TGF‐β bsAb treatment was highly effective in suppressing tumor growth, not only compared to control monoclonal antibody (mAb) but also markedly more effective than mAbs against S15 alone, against TGF‐β alone, as well as a cocktail of both anti‐S15 and anti‐TGF‐β mAbs. We did not detect liver and lung metastasis in mice treated with S15/TGF‐β bsAb, unlike all other treatment groups at the end of the study. The enhanced anti‐tumor response observed with S15/TGF‐β bsAb correlated with a less immunosuppressive environment in the tumor. These results underscore S15‐targeted bsAb as a promising therapeutic strategy for TNBC, and possibly other S15 positive solid tumors.

Abstract NADH autofluorescence imaging is a promising approach for visualizing energy metabolism at the single-cell level. However, it is sensitive to the redox ratio and the total NAD(H) amount, which can change independently from each other, for example with aging. Here, we evaluate the potential of fluorescence lifetime imaging microscopy (FLIM) of NADH to differentiate between these modalities. We perform targeted modifications of the NAD(H) pool size and ratio in cells and mice and assess the impact on NADH FLIM. We show that NADH FLIM is sensitive to NAD(H) pool size, mimicking the effect of redox alterations. However, individual components of the fluorescence lifetime are differently impacted by redox versus pool size changes, allowing us to distinguish both modalities using only FLIM. Our results emphasize NADH FLIM’s potential for evaluating cellular metabolism and relative NAD(H) levels with high spatial resolution, providing a crucial tool for our understanding of aging and metabolism.

Alpine glacier-based temperature reconstructions spanning the last deglaciation provide critical constraints on local to regional climate change and have been reported from several formerly glaciated regions around the world yet remain sparse from high-northern-latitude regions. Using newly and previously 10Be-dated moraines, we report paleo-glacier equilibrium line altitudes (ELAs) for 15 time slices spanning the Last Glacial Maximum (LGM) to the Little Ice Age (LIA) for a valley in the western Alaska Range. We translate our ELA reconstructions into a proxy for summer temperature by applying a dry adiabatic lapse rate at each reconstructed ELA relative to the outermost LIA moraine. We observe ∼4 °C warming through the last deglaciation at our site that took place in two steps following initial gradual warming: ∼1.5 °C abrupt warming at 16 ka, ∼2 kyr after the onset of global CO2 rise, and ∼2 °C warming at ∼15 ka, near the start of the Bølling. Moraine deposition and modest summer cooling during Heinrich Stadial 1 and the early Younger Dryas (YD) suggest that despite these events being expressed more strongly in wintertime, the classic blueprint of North Atlantic climate variability extends to the western Arctic region.

Abstract Bivalent molecules consisting of groups connected through bridging linkers often exhibit strong target binding and unique biological effects. However, developing bivalent inhibitors with the desired activity is challenging due to the dual motif architecture of these molecules and the variability that can be introduced through differing linker structures and geometries. We report a set of alternatively linked bivalent EGFR inhibitors that simultaneously occupy the ATP substrate and allosteric pockets. Crystal structures show that initial and redesigned linkers bridging a trisubstituted imidazole ATP-site inhibitor and dibenzodiazepinone allosteric-site inhibitor proved successful in spanning these sites. The re-engineered linker yielded a compound that exhibited significantly higher potency (~60 pM) against the drug-resistant EGFR L858R/T790M and L858R/T790M/C797S, which was superadditive as compared with the parent molecules. The enhanced potency is attributed to factors stemming from the linker connection to the allosteric-site group and informs strategies to engineer linkers in bivalent agent design.

Abstract Background Information on social media may affect peoples’ contraceptive decision making. We performed an exploratory analysis of contraceptive content on Twitter (recently renamed X), a popular social media platform. Methods We selected a random subset of 1% of publicly available, English-language tweets related to reversible, prescription contraceptive methods posted between January 2014 and December 2019. We oversampled tweets for the contraceptive patch to ensure at least 200 tweets per method. To create the codebook, we identified common themes specific to tweet content topics, tweet sources, and tweets soliciting information or providing advice. All posts were coded by two team members, and differences were adjudicated by a third reviewer. Descriptive analyses were reported with accompanying qualitative findings. Results During the study period, 457,369 tweets about reversible contraceptive methods were published, with a random sample of 4,434 tweets used for final analysis. Tweets most frequently discussed contraceptive method decision-making (26.7%) and side effects (20.5%), particularly for long-acting reversible contraceptive methods and the depot medroxyprogesterone acetate shot. Tweets about logistics of use or adherence were common for short-acting reversible contraceptives. Tweets were frequently posted by contraceptive consumers (50.6%). A small proportion of tweets explicitly requested information (6.2%) or provided advice (4.2%). Conclusions Clinicians should be aware that individuals are exposed to information through Twitter that may affect contraceptive perceptions and decision making, particularly regarding long-acting reversible contraceptives. Social media is a valuable source for studying contraceptive beliefs missing in traditional health research and may be used by professionals to disseminate accurate contraceptive information.

Antibiotic resistance (AR) is a growing health concern worldwide and the Arctic represents an understudied region in terms of AR. This study aimed to quantify AR genes (ARGs) from effluent released from a wastewater treatment plant (WWTP) in Iqaluit, Nunavut, Canada, thus creating a baseline reference for future evaluations. Water, sediment, and truncate softshell clam (Mya truncata) tissue samples were compared from the wastewater, the receiving environment of Frobisher Bay, and nearby undisturbed freshwaters. The pharmaceuticals and personal care products (PPCPs) atenolol, carbamazepine, metoprolol, naproxen, sulfapyridine, and trimethoprim were found in the wastewater, but the PPCPs were undetectable in the receiving environment. However, the relative abundances of ARGs were significantly higher in wastewater than in the receiving environment or reference sites. Abundances did not significantly differ in Frobisher Bay compared to undisturbed reference sites. ARGs in clams near the WWTP had similar relative abundances as those from pristine areas. The lack of ARG detection is likely due to Frobisher Bay tides flushing inputs to levels below detection. These data suggest that the WWTP infrastructure does not influence the receiving environment based on the measured parameters; more importantly, further research must elucidate the impact and fate of AR and PPCPs in Arctic communities.

Abstract Background Eating disorders (EDs) are serious, complex disorders for which broad-based clinical training is lacking. This study aimed to evaluate the efficacy of a free, brief, web-based curriculum, PreparED, in increasing comfort and confidence with, and knowledge about EDs in healthcare trainees, and to obtain program feedback from key stakeholders (i.e., learners). Methods This programmatic evaluation study was designed as a quantitative, repeated measures (i.e., pre- and post-test intervention) investigation. A convenience sample of two groups of healthcare trainees across geographically diverse training sites completed an anonymous survey pre- and post- engagement with PreparED. The survey included items to assess prior exposure to EDs, as well as program feasibility. The main educational outcomes included (1) Confidence and Comfort with EDs and (2) Knowledge of EDs. User experience variables of interest were likeability, usability, and engagement with the training modules. Mixed effects linear regression was used to assess the association between PreparED and educational outcome variables. Results Participants (N = 67) included 41 nutrition graduate students and 26 nurse practitioner students recruited from Teacher’s College/Columbia University in New York, NY, USA, Columbia University School of Nursing in New York, NY, USA and North Dakota State University School of Nursing in Fargo, ND, USA. Confidence/Comfort scores and Knowledge scores significantly improved following engagement with PreparED (β = for effect of intervention = 1.23, p

Myoclonic status epilepticus (MSE) is a sign of severe neurologic injury in cardiac arrest patients. To our knowledge, MSE has not been described as a result of prolonged hyperpyrexia. A 56-year-old man with coronavirus disease 2019 presented with acute respiratory distress syndrome, septic/hypovolemic shock, and presumed community-acquired pneumonia. Five days after presentation, he developed a sustained fever of 42.1°C that did not respond to acetaminophen or ice water gastric lavage. After several hours, he was placed on surface cooling. Three hours after fever resolution, new multifocal myoclonus was noted in the patient’s arms and trunk. Electroencephalography showed midline spikes consistent with MSE, which resolved with 40 mg/kg of levetiracetam. This case demonstrates that severe hyperthermia can cause cortical injury significant enough to trigger MSE and should be treated emergently using the most aggressive measures available. Providers should have a low threshold for electroencephalography in intubated patients with a recent history of hyperpyrexia.

Abstract Background Dementia is a common disease with around 55 million cases worldwide. Therefore, dietary changes and lifestyle interventions are important approaches to delay the progress of a decline in cognitive function. The study aims to explore the association of various sources of free sugars (FS) and intrinsic sugars with dementia risk in the prospective population-based UK Biobank cohort. Methods Sugar consumption was assessed in 186,622 UK Biobank participants with at least one web-based dietary questionnaire (Oxford WebQ). Over a mean follow-up of 10.6 (standard deviation 1.1) years, 1498 incident dementia cases occurred. The hazard ratios (HR) for incident dementia were assessed with Cox proportional hazard regression models including sugar intake from different sources as penalized cubic splines to allow for non-linear predictor effects. Results The intake of FS and intrinsic sugar was significantly associated with dementia risk in a J-shaped fashion with the HR-nadir observed at 9% and 8% total energy (%E), respectively. FS in beverages were significantly associated with dementia risk in an ascending approximately linear way, whereas no significant association was found for FS in solids. Assessing beverage subtypes, FS in soda/fruit drinks, milk-based drinks and to a lesser extent in juice were significantly and positively related to dementia risk, whereas no association was found for FS in tea/coffee. The association between sugar subtype consumption and dementia risk remained consistent in most sensitivity analyses but changed from a J-shape to a more linear shape when the analysis was restricted to participants with at least two Oxford WebQs. Conclusions A linear-shaped association between sugar subtype intake and dementia risk is most consistently found for FS in beverages and more specifically for FS in soda/fruit drinks, as well as in milk-based drinks. Graphical Abstract

IntroductionA greater sense of purpose in life is associated with several health benefits relevant for active aging, but the mechanisms remain unclear. We evaluated if purpose in life was associated with indices of brain health.MethodsWe examined data from the Midlife in the United States (MIDUS) Neuroscience Project. Diffusion weighted magnetic resonance imaging data (n=138; mean age 65.2 years, age range 48-95; 80 females; 37 black, indigenous, and people of color) were used to estimate microstructural indices of brain health such as axonal density, and axonal orientation. The seven-item purpose in life scale was used. Permutation analysis of linear models was used to examine associations between purpose in life scores and the diffusion metrics in white matter and in the bilateral hippocampus, adjusting for age, sex, education, and race.Results and discussionGreater sense of purpose in life was associated with brain microstructural features consistent with better brain health. Positive associations were found in both white matter and the right hippocampus, where multiple convergent associations were detected. The hippocampus is a brain structure involved in learning and memory that is vulnerable to stress but retains the capacity to grow and adapt through old age. Our findings suggest pathways through which an enhanced sense of purpose in life may contribute to better brain health and promote healthy aging. Since purpose in life is known to decline with age, interventions and policy changes that facilitate a greater sense of purpose may extend and improve the brain health of individuals and thus improve public health.

Abstract Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in infants, the immunocompromised, and the elderly. RSV infects the airway epithelium via the apical membrane and almost exclusively sheds progeny virions back into the airway mucus (AM), making RSV difficult to target by systemically administered therapies. An inhalable “muco‐trapping” variant of motavizumab (Mota‐MT), a potent neutralizing mAb against RSV F is engineered. Mota‐MT traps RSV in AM via polyvalent Fc‐mucin bonds, reducing the fraction of fast‐moving RSV particles in both fresh pediatric and adult AM by ≈20–30‐fold in a Fc‐glycan dependent manner, and facilitates clearance from the airways of mice within minutes. Intranasal dosing of Mota‐MT eliminated viral load in cotton rats within 2 days. Daily nebulized delivery of Mota‐MT to RSV‐infected neonatal lambs, beginning 3 days after infection when viral load is at its maximum, led to a 10 000‐fold and 100 000‐fold reduction in viral load in bronchoalveolar lavage and lung tissues relative to placebo control, respectively. Mota‐MT‐treated lambs exhibited reduced bronchiolitis, neutrophil infiltration, and airway remodeling than lambs receiving placebo or intramuscular palivizumab. The findings underscore inhaled delivery of muco‐trapping mAbs as a promising strategy for the treatment of RSV and other acute respiratory infections.

Here, we present cosmogenic-10Be and cosmogenic-3He data from Ferrar dolerite pyroxenes in surficial rock samples and a bedrock core from the McMurdo Dry Valleys, Antarctica, with the goal of refining the laboratory methods for extracting beryllium from pyroxene, further estimating the 10Be production rate in pyroxene and demonstrating the applicability of 10Be–3He in mafic rock. The ability to routinely measure cosmogenic 10Be in pyroxene will open new opportunities for quantifying exposure durations and Earth surface processes in mafic rocks. We describe scalable laboratory methods for isolating beryllium from pyroxene, which include a simple hydrofluoric acid leaching procedure for removing meteoric 10Be and the addition of a pH 8 precipitation step to reduce the cation load prior to ion exchange chromatography. 10Be measurements in pyroxene from the surface samples have apparent 3He exposure ages of 1–6 Myr. We estimate a spallation production rate for 10Be in pyroxene, referenced to 3He, of 3.6 ± 0.2 atoms g−1 yr−1. 10Be and 3He measurements in the bedrock core yield initial estimates for parameters associated with 10Be and 3He production by negative-muon capture (f10∗=0.00183 and f3∗fCfD=0.00337). Next, we demonstrate that the 10Be–3He pair in pyroxene can be used to simultaneously resolve erosion rates and exposure ages, finding that the measured cosmogenic-nuclide concentrations in our surface samples are best explained by 2–8 Myr of exposure at erosion rates of 0–35 cm Myr−1. Finally, given the low 10Be in our laboratory blanks (average of 5.7 × 103 atoms), the reported measurement precision, and our estimated production rate, it should be possible to measure 2 g samples with 10Be concentrations of 6 × 104 and 1.5 × 104 atoms g−1 with 5 % and 15 % uncertainty, respectively. With this level of precision, Last Glacial Maximum to Late Holocene surfaces can now be dated with 10Be in pyroxene. Application of 10Be in pyroxene, alone or in combination with 3He, will expand possibilities for investigating glacial histories and landscape change in mafic rock.

Introduction Pregnancy is a known independent risk factor for a severe course of COVID-19. The relationship of SARS-CoV-2 infection and gestational diabetes mellitus (GDM) on neonatal outcomes is unclear. Our aim was to determine if SARS-CoV-2 infection represents an independent risk factor for adverse perinatal outcomes in pregnancy with GDM.Research design and methods We compared data from two German registries including pregnant women with GDM, established during the SARS-CoV-2 pandemic (COVID-19-Related Obstetric and Neonatal Outcome Study (CRONOS), a multicenter prospective observational study) and already existing before the pandemic (German registry of pregnant women with GDM; GestDiab). In total, 409 participants with GDM and SARS-CoV-2 infection and 4598 participants with GDM, registered 2018–2019, were eligible for analyses. The primary fetal and neonatal outcomes were defined as: (1) combined: admission to neonatal intensive care unit, stillbirth, and/or neonatal death, and (2) preterm birth before 37+0 weeks of gestation. Large and small for gestational age, maternal insulin therapy, birth weight >4500 g and cesarean delivery were considered as secondary outcomes.Results Women with SARS-CoV-2 infection were younger (32 vs 33 years) and had a higher median body mass index (28 vs 27 kg/m²). In CRONOS, more neonates developed the primary outcome (adjusted OR (aOR) 1.48, 95% CI 1.11 to 1.97) and were born preterm (aOR 1.50, 95% CI 1.07 to 2.10). Fasting glucose was higher in women in CRONOS versus GestDiab (5.4 vs 5.3 mmol/L) considering each 0.1 mmol/L increase was independently associated with a 5% higher risk of preterm birth among women in CRONOS only (aOR 1.05, 95% CI 1.01 to 1.09).Conclusions GDM with SARS-CoV-2 infection in pregnancy is associated with an increased risk of adverse fetal and neonatal outcomes as compared with GDM without SARS-CoV-2 infection.

Abstract Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi‐allelic pathogenic variants in BLM, encoding a nuclear‐binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult‐onset mitochondrial disease resulting from bi‐allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory‐motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom‐like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult‐onset mitochondrial disease and more severe variants causing a Bloom‐like syndrome with mitochondrial dysfunction in childhood.

We demonstrate that a gradual interface between gold and silver supports the propagation of a novel kind of surface electromagnetic wave, which is different from the more well-known surface plasmon polaritons. The existence of such surface waves leads to a paradoxical situation in which a continuous metal barrier which does not have any pinholes may exhibit considerably increased light transmission if the barrier is made of two different metals. A spectroscopic study of this effect is reported.

Greater cortisol reactivity to stress is often assumed to lead to heightened negative affective reactivity to stress. Conversely, a growing body of evidence demonstrates mood-protective effects of cortisol elevations in the context of acute stress. We administered a laboratory-based stressor, the Trier Social Stress Test (TSST), and measured cortisol and emotional reactivity in 68 adults (48 women) between the ages of 25 and 65. In accordance with our pre-registered hypothesis (https://osf.io/t8r3w) and prior research, negative affective reactivity was inversely related to cortisol reactivity assessed immediately after the stressor. We found that greater cortisol response to acute stress is associated with smaller increases in negative affect, consistent with mood-protective effects of cortisol elevations in response to acute stress.

Background Mitochondrial disorders are known to cause diverse neurological phenotypes which cause a diagnostic challenge to most neurologists. Pathogenic polymerase gamma (POLG) variants have been described as a cause of chronic progressive external ophthalmoplegia, which manifests with ptosis, horizontal and vertical eye movement restriction and myopathy. Autosomal dominant progressive external ophthalmoplegia is rarely associated with Parkinsonism responsive to levodopa.Methods We report a case of a 58-year-old man who presented with an eye movement disorder then Parkinsonism who made his way through the myasthenia then the movement disorder clinic.Results A diagnostic right tibialis anterior biopsy revealed classical hallmarks of mitochondrial disease, and genetic testing identified compound heterozygous pathogenic gene variants in the POLG gene. The patient was diagnosed with autosomal recessive POLG disease.Conclusions It is important to maintain a high index of suspicion of pathogenic POLG variants in patients presenting with atypical Parkinsonism and ophthalmoplegia. Patients with POLG-related disease will usually have ptosis, and downgaze is typically preserved until late in the disease. Accurate diagnosis is essential for appropriate prognosis and genetic counselling.

The preservation of cosmogenic nuclides that accumulated during periods of prior exposure but were not subsequently removed by erosion or radioactive decay complicates interpretation of exposure, erosion, and burial ages used for a variety of geomorphological applications. In glacial settings, cold-based, non-erosive glacier ice may fail to remove inventories of inherited nuclides in glacially transported material. As a result, individual exposure ages can vary widely across a single landform (e.g., moraine) and exceed the expected or true depositional age. The surface processes that contribute to inheritance remain poorly understood, thus limiting interpretations of cosmogenic nuclide datasets in glacial environments. Here, we present a compilation of new and previously published exposure ages of multiple lithologies in local Last Glacial Maximum (LGM) and older Pleistocene glacial sediments in the McMurdo Sound region of Antarctica. Unlike most Antarctic exposure chronologies, we are able to compare exposure ages of local LGM sediments directly against an independent radiocarbon chronology of fossil algae from the same sedimentary unit that brackets the age of the local LGM between 12.3 and 19.6 ka. Cosmogenic exposure ages vary by lithology, suggesting that bedrock source and surface processes prior to, during, and after glacial entrainment explain scatter. 10Be exposure ages of quartz in granite, sourced from the base of the stratigraphic section in the Transantarctic Mountains, are scattered but young, suggesting that clasts entrained by sub-glacial plucking can generate reasonable apparent exposure ages. 3He exposure ages of pyroxene in Ferrar Dolerite, which crops out above outlet glaciers in the Transantarctic Mountains, are older, which suggests that clasts initially exposed on cliff faces and glacially entrained by rock fall carry inherited nuclides. 3He exposure ages of olivine in basalt from local volcanic bedrock in the McMurdo Sound region contain many excessively old ages but also have a bimodal distribution with peak probabilities that slightly pre-date and post-date the local LGM; this suggests that glacial clasts from local bedrock record local landscape exposure. With the magnitude and geological processes contributing to age scatter in mind, we examine exposure ages of older glacial sediments deposited by the most extensive ice sheet to inundate McMurdo Sound during the Pleistocene. These results underscore how surface processes operating in the Transantarctic Mountains are expressed in the cosmogenic nuclide inventories held in Antarctic glacial sediments.

Microcystins are toxic chemicals generated by certain freshwater cyanobacteria. These chemicals can accumulate to dangerous levels during harmful algal blooms. When exposed to microcystins, humans are at risk of hepatic injury, including liver failure. Here, we describe a method to detect microcystins in human plasma by using immunocapture followed by a protein phosphatase inhibition assay. At least 279 microcystins have been identified, and most of these compounds share a common amino acid, the Adda side chain. We targeted this Adda side chain using a commercial antibody and extracted microcystins from human samples for screening and analysis. To quantitate the extracted microcystins, we fortified plasma with microcystin-LR, one of the most well-studied, commonly detected, and toxic microcystin congeners. The quantitation range for the detection of microcystin in human plasma using this method is 0.030–0.50 ng/mL microcystin-LR equivalents. This method detects unconjugated and conjugated forms (cysteine and glutathione) of microcystins. Quality control sample accuracies varied between 98.9% and 114%, with a precision of 7.18–15.8%. Finally, we evaluated plasma samples from a community health surveillance project of Florida residents living or working near harmful algae blooms.

Objective Regular cardiac surveillance is advocated for patients with primary mitochondrial DNA disease. However, there is limited information to guide clinical practice in mitochondrial conditions caused by nuclear DNA defects. We sought to determine the frequency and spectrum of cardiac abnormalities identified in adult mitochondrial disease originated from the nuclear genome.Methods Adult patients with a genetically confirmed mitochondrial disease were identified and followed up at the national clinical service for mitochondrial disease in Newcastle upon Tyne, UK (January 2009 to December 2018). Case notes, molecular genetics reports, laboratory data and cardiac investigations, including serial electrocardiograms and echocardiograms, were reviewed.Results In this cohort-based observational study, we included 146 adult patients (92 women) (mean age 53.6±18.7 years, 95% CI 50.6 to 56.7) with a mean follow-up duration of 7.9±5.1 years (95% CI 7.0 to 8.8). Eleven different nuclear genotypes were identified: TWNK, POLG, RRM2B, OPA1, GFER, YARS2, TYMP, ETFDH, SDHA, TRIT1 and AGK. Cardiac abnormalities were detected in 14 patients (9.6%). Seven of these patients (4.8%) had early-onset cardiac manifestations: hypertrophic cardiomyopathy required cardiac transplantation (AGK; n=2/2), left ventricular (LV) hypertrophy and bifascicular heart block (GFER; n=2/3) and mild LV dysfunction (GFER; n=1/3, YARS2; n=1/2, TWNK; n=1/41). The remaining seven patients had acquired heart disease most likely related to conventional cardiovascular risk factors and presented later in life (14.6±12.8 vs 55.1±8.9 years, p

Background Glass slide preparations from a variety of specimens (blood, masses, effusions) are commonly made as part of the diagnostic work-up, however the effects of various drying methods in veterinary practice and diagnostic laboratory settings is not clear. Objective Compare the effects of four drying methods on results of microscopic examination of canine blood smears and direct smears of pleural or peritoneal effusion fluid. Methods Twelve canine blood samples (6 from healthy dogs, 6 from sick dogs) and 6 canine peritoneal or pleural effusion samples. Four smears were prepared from each of the 18 samples and dried using the following methods: air-dry, hair dryer with or without heat, and heat block at 58 °C. Observers, blinded to the drying method, independently reviewed the slides microscopically, using a scoring system to evaluate cell morphology and (for blood smears) echinocyte numbers; scoring results were analyzed statistically. Results For blood smears, several comparisons showed more adverse effects on morphology using the heat block method than for one or more other drying methods. For effusion fluid smears, RBCs dried with the heat block or air-dry methods had more poorly preserved morphology than RBCs dried by the hair dryer method without heat. Conclusions and clinical relevance The results (1) indicate that different drying methods had a significant effect, (2) support using a hair dryer without heat for both blood smears and effusion fluid smears, and (3) discourage using a 58 °C heat block.

Purpose One of the main pathophysiological mechanisms of chronic obstructive pulmonary disease is inflammation, which has been associated with lymphadenopathy. Intrapulmonary lymph nodes can be identified on CT as perifissural nodules (PFN). We investigated the association between the number and size of PFNs and measures of COPD severity. Materials and Methods CT images were obtained from COPDGene. 50 subjects were randomly selected per GOLD stage (0 to 4), GOLD-unclassified, and never-smoker groups and allocated to either “Healthy,” “Mild,” or “Moderate/severe” groups. 26/350 (7.4%) subjects had missing images and were excluded. Supported by computer-aided detection, a trained researcher prelocated non-calcified opacities larger than 3 mm in diameter. Included lung opacities were classified independently by two radiologists as either “PFN,” “not a PFN,” “calcified,” or “not a nodule”; disagreements were arbitrated by a third radiologist. Ordinal logistic regression was performed as the main statistical test. Results A total of 592 opacities were included in the observer study. A total of 163/592 classifications (27.5%) required arbitration. A total of 17/592 opacities (2.9%) were excluded from the analysis because they were not considered nodular, were calcified, or all three radiologists disagreed. A total of 366/575 accepted nodules (63.7%) were considered PFNs. A maximum of 10 PFNs were found in one image; 154/324 (47.5%) contained no PFNs. The number of PFNs per subject did not differ between COPD severity groups (p = 0.50). PFN short-axis diameter could significantly distinguish between the Mild and Moderate/severe groups, but not between the Healthy and Mild groups (p = 0.021). Conclusions There is no relationship between PFN count and COPD severity. There may be a weak trend of larger intrapulmonary lymph nodes among patients with more advanced stages of COPD.

Abstract Mitochondrial disease associated with the pathogenic m.3243A>G variant is a common, clinically heterogeneous, neurogenetic disorder. Using multiple linear regression and linear mixed modelling, we evaluated which commonly assayed tissue (blood N = 231, urine N = 235, skeletal muscle N = 77) represents the m.3243A>G mutation load and mitochondrial DNA (mtDNA) copy number most strongly associated with disease burden and progression. m.3243A>G levels are correlated in blood, muscle and urine (R2 = 0.61–0.73). Blood heteroplasmy declines by ~2.3%/year; we have extended previously published methodology to adjust for age. In urine, males have higher mtDNA copy number and ~20% higher m.3243A>G mutation load; we present formulas to adjust for this. Blood is the most highly correlated mutation measure for disease burden and progression in m.3243A>G‐harbouring individuals; increasing age and heteroplasmy contribute (R2 = 0.27, P G heteroplasmy is the most convenient and reliable measure for routine clinical assessment, additional factors such as mtDNA copy number may also influence disease severity.

Background Organ cross-talk describes interactions between a primary affected organ and a secondarily injured remote organ, particularly in lung-brain interactions. A common theory is the systemic distribution of inflammatory mediators that are released by the affected organ and transferred through the bloodstream. The present study characterises the baseline immunogenic effects of a novel experimental model of random allogeneic blood transfusion in pigs designed to analyse the role of the bloodstream in organ cross-talk. Methods After approval of the State and Institutional Animal Care Committee, 20 anesthetized pig were randomized in a donor and an acceptor (each n = 8): the acceptor animals each received high-volume whole blood transfusion from the donor (35–40 ml kg−1). Four animals received balanced electrolyte solution instead of blood transfusion (control group; n = 4). Afterwards the animals underwent extended cardiorespiratory monitoring for eight hours. Post mortem assessment included pulmonary, cerebral and systemic mediators of early inflammatory response (IL-6, TNF-alpha, iNOS), wet to dry ratio, and lung histology. Results No adverse events or incompatibilities occurred during the blood transfusion procedures. Systemic cytokine levels and pulmonary function were unaffected. Lung histopathology scoring did not display relevant intergroup differences. Neither within the lung nor within the brain an up-regulation of inflammatory mediators was detected. High volume random allogeneic blood transfusion in pigs neither impaired pulmonary integrity nor induced systemic, lung, or brain inflammatory response. Conclusion This approach can represent a novel experimental model to characterize the blood-bound transmission in remote organ injury.