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Existing empirical research on voters’ responses to individual politicians’ moral transgressions pays limited attention to moral emotions, although moral emotions are an integral part of voters’ moral judgment. This study looks at U.S. voters’ discrete moral emotional responses to politician’s moral violations and examines how these discrete moral emotional responses are dependent on voters’ own moral principles and the extent to which they identify with a political party. We report on a 5 × 3 between-subjects experiment where 2026 U.S. respondents reacted to politicians’ violations of one of five moral foundations defined by Moral Foundations Theory. We randomly vary which moral foundation is violated and the partisanship of the politician. While voters’ own moral principles somewhat condition moral emotional responses, we find that voters’ moral emotional responses mostly depend on partisan identification. When voters share party identity with a politician committing a moral violation, they respond with less anger, contempt, disgust and shame than when they do not share party identity. The effect is greater among strong partisans. However, we find limited evidence that specific moral emotions are activated by violations of particular moral foundations, thereby challenging Moral Foundations Theory.

Plasma triglycerides (TGs) are an independent predictor of the risk for CAD, the leading cause of death worldwide. TGs are also positively associated with risk and severity of hyperTG-induced acute pancreatitis (HTG-AP). Current therapies are often insufficient in reducing extremely elevated TGs. We believe that apolipoprotein A-V (apoA-V, encoded by APOA5) can fill this unmet medical need. ApoA-V is a potent modulator of TG metabolism; it enhances lipoprotein lipase TG hydrolysis. We hypothesize that naturally occurring human APOA5 variants can inform ApoA-V function and identify novel ApoA-V based therapeutic axes. We used the Penn Medicine Biobank (PMBB) to identify and measure plasma TGs of carriers of APOA5 variants predicted to change ApoA-V structure-function. Then, we used hydrogen-deuterium exchange mass spectroscopy to determine the secondary structure of ApoA-V, thereby identifying putative functional domains onto which we mapped our variants of interest. Finally, we characterized the plasma lipid effects of these mutants using adeno-associated viral (AAV) vectors in apoa5 knockout (KO) mice. We identified APOA5 variants associated with changes in plasma TGs. These variants primarily fall near the central heparin binding domain or C-terminal lipid binding domain. We selected APOA5 Q275X, which removes the entire lipid binding domain, for further interrogation. Apoa5 KO mice that received APOA5 Q275X AAV had higher plasma TGs than mice treated with WT APOA5 AAV. While WT ApoA-V protein associated with VLDL and HDL particles, Q275X ApoA-V protein appeared in lipoprotein free fractions. We have identified APOA5 variants associated with plasma TG phenotypes in humans, and mapped them to an experimentally determined ApoA-V secondary structure to identify the functional domains likely impacted. We have identified APOA5 Q275X as a loss of function variant that fails to bind lipoprotein particles and is associated with elevated plasma TGs. Continued study of this and other interesting naturally occurring variants will provide insight into the function of ApoA-V in TG metabolism. These insights can help us to therapeutically enhance ApoA-V to rapidly reduce TG levels during acute HTG-AP and to help prevent recurrent HTG-AP.

We developed a simple, noninvasive mask sampling method to quantify and sequence severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from exhaled breath. We found substantial variation between individuals in SARS-CoV-2 copies exhaled over a 15-minute period, which moderately correlated with nasal swab viral load. Talking was associated with a median of 2 log10 greater exhaled viral copies. Exposure varies substantially between individuals but may be risk stratified by nasal swab viral load and whether the exposure involved conversation.

Health behaviors of physical activity and sleep are critical to the prevention of numerous chronic diseases. The health behaviors of healthcare professionals are even more critical, as healthcare providers who practice positive health behaviors are more likely to promote these healthy behaviors in their patients.To assess the health status and health behaviors of medical students, faculty, and staff in an academic health center in the US, and examine the associations between behaviors, physical and mental health outcomes and burnout.Students, faculty, residents and staff from a large university medical system completed an online survey between late-September and mid-November 2019. Associations were examined between health behaviors and health status including mental health outcomes with burnout.Participating in any leisure time physical activity and having a Pittsburgh Sleep Quality Index score 5 were associated with fewer physical health conditions and lower odds of reporting pain at any site (The current study found high rates of physical inactivity and poor sleep among medical students, faculty and staff at an academic health center. These health behaviors were associated with poor mental health and high burnout. Programs and policies are needed improve these health behaviors to reduce burnout.The online version contains supplementary material available at 10.1007/s11332-022-00902-7.

To evaluate the utility of positron-emission tomography (FDG PET) in initial staging and management of head and neck cancers. This is a retrospective study of 99 treatment naive head and neck cancer patients treated between January 2017 and December 2020 at a tertiary teaching centre. Change in initial staging and management was noted based on PET scan compared to cross-sectional imaging (CT and MRI). There were 73 (73.7%) males and 26 (26.2%) females with male-to-female ratio of 2.8:1.Overall, change in management was seen in 36/99 (36.4%) patients due to PET scan. With regards to initial staging, T, N and M stage was changed in 14/99 (14.1%), 19/99 (19.1%) and 3/99 (3%) patients, respectively. These changes were significantly higher in patients with unknown primary (63.3%, p value −0.001) and N3 (41%, p −0.045) nodal disease. PET-CT plays an important role in appropriate initial staging and subsequent treatment planning of head and neck cancers. Initial staging PETCT changes management in 36.4% cases. Accuracy of various different imaging modalities have been compared.

BackgroundTuberculosis notifications in Latin American prisons have more than doubled over the past two decades; however, treatment outcomes and their determinants among incarcerated individuals in this region are not well understood.MethodsNewly diagnosed drug-susceptible tuberculosis cases reported to Brazil’s Sistema de Informação de Agravos de Notificação (SINAN) between January 2015 and December 2017 were included. Multivariate logistic regression was used to assess socioeconomic and clinical factors associated with treatment success among incarcerated individuals.ResultsIncarcerated individuals (n=17,776) had greater treatment success than non-incarcerated individuals (n=160,728; 82.2% vs 75.1%, pConclusionTuberculosis treatment success among incarcerated individuals in Brazil is higher than non-incarcerated individuals, but both fall below WHO targets. Expanding the use of DOT and services for socially and medically vulnerable individuals may improve outcomes in carceral settings.

Simple Summary Adenoid cystic carcinoma (ACC) is a rare cancer of the head and neck. Initial treatment may involve surgery and/or radiotherapy with the aim of removing the cancer and preventing spread to other parts of the body. In patients in whom ACC has recurred or spread, systemic therapies such as chemotherapy or immunotherapy have been shown to have minimal benefit and there are currently no recommended standard systemic treatment options. More recently, the targeted therapy lenvatinib has shown promising results in treating ACC patients. We aimed to summarise the real-world experience of lenvatinib use in ACC patients in the UK and found that although some patients obtained clinical benefit, there were no significant responses on radiological imaging by centralized assessment. Abstract Adenoid cystic carcinoma (ACC) is a rare cancer of secretory glands. Recurrent or metastatic (R/M) ACC is generally considered resistant to cytotoxic chemotherapy. Recent phase II studies have reported improved objective response rates (ORR) with the use of the multi-kinase inhibitor lenvatinib. We sought to evaluate real-world experience of R/M ACC patients treated with lenvatinib monotherapy within the UK National Health Service (NHS) to determine the response rates by Response Evaluation Criteria of Solid Tumour (RECIST) and clinical outcomes. Twenty-three R/M ACC patients from eleven cancer centres were included. All treatment assessments for clinical decision making related to drug therapy were undertaken at the local oncology centre. Central radiology review was performed by an independent clinical trial radiologist and blinded to the clinical decision making. In contrast to previously reported ORR of 12–15%, complete or partial response was not observed in any patients. Eleven patients (52.4%) had stable disease and 5 patients (23.8%) had progression of disease as the best overall response. The median time on treatment was 4 months and the median survival from discontinuation was 1 month. The median PFS and OS from treatment initiation were 4.5 months and 12 months respectively. Multicentre collaborative studies such as this are required to evaluate rare cancers with no recommended standard of care therapy and variable disease courses.

BackgroundMortality during and after incarceration is poorly understood in low- and middle-income countries. The need to address this knowledge gap is especially urgent in South America, which has the fastest growing prison population in the world. In Brazil, data on mortality during and after incarceration are lacking.Methods and FindingsWe linked incarceration and mortality databases for the Brazilian state of Mato Grosso do Sul to obtain a cohort of 114,751 individuals with recent incarceration. Between January 1, 2009 and December 31, 2018, we identified 3127 deaths of individuals with recent incarceration (705 in detention; 2422 following release). We analyzed age-standardized, all-cause and cause-specific mortality rates among individuals detained in different facility types and following release, compared to non-incarcerated residents. Deaths in custody were 2.2 times the number reported by the national prison administration (n = 317). Incarcerated men and boys experienced elevated mortality, compared with the non-incarcerated population, due to increased risk of death from violence, suicide, and communicable diseases, with the highest standardized incidence rate ratio (IRR) in semi-open prisons (2.4; 95% CI, 2.0-2.8), police stations (3.1; 95% CI, 2.5-3.9), and youth detention (8.1; 95% CI, 5.9-10.8). Incarcerated women had increased mortality from suicide (IRR = 6.0, 95% CI 1.2-17.7) and communicable diseases (IRR = 2.5, 95% CI 1.1-5.0). We additionally modeled mortality rates over time during and after incarceration from all causes, violence, or suicide. Following release from prison, mortality was markedly elevated for men (IRR=3.0; 95% CI, 2.8-3.1) and women (IRR=2.4; 95% CI, 2.1-2.9). The risk of violent death and suicide was highest immediately post-release and declined over time; however, all-cause mortality remained elevated eight years post-release. The limitations of this study include inability to establish causality, uncertain reliability of data during incarceration, and underestimation of mortality rates due to imperfect database linkage.ConclusionsIncarcerated individuals in Brazil experienced increased mortality from violence, suicide, and communicable diseases. Mortality was heightened following release for all leading causes of death, with particularly high risk of early violent death and elevated all-cause mortality up to eight years post-release. These disparities may have been under-recognized in Brazil due to underreporting and insufficient data.Author SummaryWhy Was This Study Done?The global prison population is growing rapidly, particularly in Latin AmericaIncarcerated and formerly incarcerated individuals may be at high risk of death from illness and external causes (i.e. homicide, suicide)Mortality during and after incarceration has been described in high-income countries but is poorly understood in low- and middle-income countries, including those in Latin AmericaIn Brazil, deaths during incarceration may be underreported, and there are no data on deaths after incarcerationWhat Did the Researchers Do and Find?We retrospectively followed over 114,000 individuals with recent incarceration in a Brazilian state and used database linkage to identify deaths between 2009 and 2018 occurring during or after incarcerationWe calculated rates of death from all causes and specific causes among incarcerated and formerly incarcerated individuals, and we compared them to those in the general populationWe found elevated mortality from violence, suicide, and communicable diseases during incarceration, which was underreported by national and state sourcesFollowing release, individuals were at increased risk of mortality from nearly all leading causes of death, with particularly high risk of violent death and suicide among men in the first two years post-releaseWhat Do These Findings Mean?While we could not establish causality between incarceration and mortality, many of our findings indicate increased mortality risk associated with exposure to the carceral environmentThe exorbitant rates of violent deaths during and after incarceration point to deep-rooted social problems that cannot be solved by incarcerationAccurate and comprehensive data on mortality during and after incarceration are needed in Brazil and other low- and middle-income countries where this issue remains poorly understoodStructural interventions are needed to reduce the mortality risk in this population, including immediate improvement of conditions and healthcare within carceral facilities, supportive programs and services for the early transition period post-release, and implementation of alternatives to incarceration

Using face mask bioaerosol sampling, we found substantial variation between individuals in SARS-CoV-2 copies exhaled over a 15-minute period, which moderately correlated with nasal swab viral load. Talking was associated with a median of 2 log10 greater exhaled viral copies. Exposure varies substantially between individuals but may be risk stratified by nasal swab viral load and whether the exposure involved conversation.

B-cell receptor (BCR) signaling pathway inhibitors (including Bruton’s tyrosine kinase [BTK] inhibitors, and phosphatidylinositol-3 kinase inhibitors [PI3Ki]) have shown clinical efficacy in non-Hodgkin lymphoma (NHL). However, responses to these agents have been limited in depth and duration. This may be due to resistance to PI3Kδ and BTK inhibitors as monotherapy [1,2,3,4,5]. The emergence of resistant clones may be addressed by combining these 2 classes of drugs. Furthermore, tolerability of these drug classes has been a concern. Combination therapy using lower doses of one or more classes of inhibitors may address some limitations.

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton’s tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and

BACKGROUND: Generalizing learned information from one motor task to another is critical for effective motor rehabilitation. A recent study demonstrated age-related declines in motor skill transfer, yet findings from other motor learning studies suggest that visuospatial impairments may explain such aging effects. AIMS: The purpose of this secondary analysis was to test whether age-related deficits in motor skill transfer were related to low visuospatial ability. METHODS: Forty-two participants (mean±SD age: 72.1±9.9 years) were tested on an upper extremity dexterity task before and after 3 days of training on an upper-extremity reaching task. Training and control data have been published previously. Prior to training, global cognitive status and specific cognitive domains (visuospatial/executive, attention, and delayed memory) were evaluated using the Montreal Cognitive Assessment. RESULTS: Backwards-stepwise regression indicated that the Visuospatial/Executive subtest was related to motor skill transfer (i.e. the amount of change in performance on the untrained motor task), such that participants with higher visuospatial scores improved more on the untrained dexterity task than those with lower scores. Global cognitive status was unrelated to motor skill transfer. DISCUSSION: Consistent with previous studies showing a positive relationship between visuospatial function and other aspects of motor learning, this secondary analysis indicates that less motor skill transfer among older adults may indeed be due to declines in the visuospatial function. CONCLUSIONS: The present study highlights the potential utility of assessing older patients’ visuospatial ability within motor rehabilitation to provide valuable insight into the extent to which they may learn and generalize motor skills through training.

Here we report on novel and potent pyridyl-cycloalkyl-carboxylic acid inhibitors of microsomal prostaglandin E synthase-1 (PTGES). PTGES produces, as part of the prostaglandin pathway, prostaglandin E2 which is a well-known driver for pain and inflammation. This fact together with the observed upregulation of PTGES during inflammation suggests that blockade of the enzyme might provide a beneficial treatment option for inflammation related conditions such as endometriosis. Compound 5a, a close analogue of the screening hit, potently inhibited PTGES in vitro, displayed excellent PK properties in vitro and in vivo and demonstrated efficacy in a CFA-induced pain model in mice and in a rat dyspareunia endometriosis model and was therefore selected for further studies.

A solid polymer electrolyte with a polyvinyl alcohol (PVA) matrix and a mixture of ethylene glycol (EG) and phosphoric acid as proton conductor has been developed. These complexes have been studied by X-ray diffraction (XRD), infrared Fourier transform spectrometry (FTIR) and electrochemical impedance spectrometry (EIS). The optimum ionic conductivity value of the ternary PVA-EG(45 wt%)-H3PO4(5 wt%) complex film has been achieved to be 5.2 10−3 S cm−1 at RH = 100% with adequate mechanical properties (especially flexibility) and with a low activation energy of 9 kJ mol−1. Due to its good electrical and mechanical properties, this material has been successfully used as solid state proton electrolyte in Zn/MnO2 cell delivering a capacity of 220 Ah kg−1 and an energy density of up to 286 Wh kg−1.

This study examines effects of negative campaigning by political parties on citizens’ electoral preferences in the 2015 General Election in England. We do so by using a large Internet panel study and an operationalisation of (perceived) negative campaigning that avoids social desirability. Our study acknowledges England’s multiparty system by distinguishing between the campaign tones of all parties. Potential problems of endogeneity are addressed by leveraging the panel structure of the data and by extensive controls. We find that electoral preferences are weakened for parties engaging in negative campaigning and that this backlash effect gets stronger over the course of the campaign. We also find support for a second-preferences boost hypothesis: preferences for one’s second-most preferred party are strengthened if its campaign is more positive than that of one’s most-preferred party.

Hydrogen-deuterium exchange mass spectrometry (HDX MS) has become an important technique for the analysis of protein structure and dynamics. Data analysis remains a bottleneck in the workflow. Sophisticated computer analysis is required to scan through the voluminous MS output in order to find, identify, and validate many partially deuterated peptides, elicit the HDX information, and extend the results to higher structural resolution. We previously made available two software suites, ExMS for identification and analysis of peptide isotopic envelopes in the HDX MS raw data and HDsite for residue-level resolution. Further experience has led to advances in the usability and performance of both programs. Also, newly added modules deal with ETD/ECD analysis, multimodal mass spectra analysis, and presentation options. These advances have been integrated into a stand-alone software solution named ExMS2. The package has been successfully tested by many workers in fine scale epitope mapping, in protein folding studies, and in dissecting structure and structure change of large protein complexes. A description and tutorial for this major upgrade are given here.

We compare measures of the tone of parties’ campaigns in the 2015 General Election in England, based on, respectively, coverage of parties’ campaigns in six national newspapers, citizens’ perceptio...

Ziel der Operation ist die Wiederherstellung einer beschwerdearmen Schulterfunktion durch Implantation eines modularen, proximalen Humerusersatzes in der Revisionsendoprothetik bei ausgepragtem segmentalem humeralem Knochenverlust. Segmentale humerale Knochendefekte in der Revisionsendoprothetik des Schultergelenks nach Tumorresektion, Trauma, pathologischen Frakturen, postinfektios oder fehlgeschlagener Osteosynthese. Lokale floride Infektionen, ausgedehnte diaphysare Knochendefekte mit ausgedunnter Kortikalis und weitem diaphysarem Markraum, die eine diaphysare Prothesenverankerung nicht erlauben. Relative Kontraindikationen: Sehr kurze Lebenserwartung (

Background Age-related declines in function can limit older adults' independence with activities of daily living (ADLs). While task-specific training maybe a viable approach to improve function, limited clinical resources prevent extensive training on wide ranges of skills and contexts. Thus, training on one task for the benefit of another (i.e., transfer) is important in geriatric physical rehabilitation. The purpose of this study was to test whether motor transfer would occur between two functionally different upper extremity tasks that simulate ADLs in a sample of older adults following task-specific training. Methods Ninety community dwelling adults ages 43 to 94 years old performed two trials of a functional dexterity and functional reaching task at baseline, and were then assigned to one of two groups. The training group completed 3 days of task-specific training (150 trials) on the functional reaching task, whereas the no-training group received no training on either task. Both groups were re-tested on both tasks at the end of Day 3. Results No significant interactions were observed between group (training vs. no-training) and time (baseline vs. re-test) on the functional dexterity task (i.e. transfer task), indicating no difference in the average amount of change from baseline to re-test between the groups. However, post hoc bivariate linear regression revealed an effect of age on motor transfer within the training group. For those who trained on the functional reaching task, the amount of transfer to the dexterity task was inversely related to age. There was no significant relationship between age and motor transfer for the no-training group. Discussion and conclusions Results of our a priori group analysis suggest that functional reaching training did not, on average, transfer to the dexterity task. However, post hoc regression analysis showed that motor transfer was both experience- and age-dependent, such that motor transfer may decline with advanced age. Future research will consider how functional and cognitive aging influences transfer of motor skills across different activities of daily living.

Estimating heterogeneous treatment effects has become increasingly important in many fields and life and death decisions are now based on these estimates: for example, selecting a personalized course of medical treatment. Recently, a variety of procedures relying on different assumptions have been suggested for estimating heterogeneous treatment effects. Unfortunately, there are no compelling approaches that allow identification of the procedure that has assumptions that hew closest to the process generating the data set under study and researchers often select one arbitrarily. This approach risks making inferences that rely on incorrect assumptions and gives the experimenter too much scope for $p$-hacking. A single estimator will also tend to overlook patterns other estimators could have picked up. We believe that the conclusion of many published papers might change had a different estimator been chosen and we suggest that practitioners should evaluate many estimators and assess their similarity when investigating heterogeneous treatment effects. We demonstrate this by applying 28 different estimation procedures to an emulated observational data set; this analysis shows that different estimation procedures may give starkly different estimates. We also provide an extensible \texttt{R} package which makes it straightforward for practitioners to follow our recommendations.

In organic electronics, local crystalline order is of critical importance for the charge transport. Grain boundaries between molecularly ordered domains are generally known to hamper or completely suppress charge transfer and detailed knowledge of the local electronic nature is critical for future minimization of such malicious defects. However, grain boundaries are typically hidden within the bulk film and consequently escape observation or investigation. Here, a minimal model system in form of monolayer-thin films with sub-nm roughness of a prototypical n-type organic semiconductor is presented. Since these films consist of large crystalline areas, the detailed energy landscape at single grain boundaries can be studied using Kelvin probe force microscopy. By controlling the charge-carrier density in the films electrostatically, the impact of the grain boundaries on charge transport in organic devices is modeled. First, two distinct types of grain boundaries are identified, namely energetic barriers and valleys, which can coexist within the same thin film. Their absolute height is found to be especially pronounced at charge-carrier densities below 10

The aim was to investigate side-to-side and sex differences of anterior and inferior capsule thickness (ACT, ICT) between the throwing and non-throwing shoulder (TS, NTS) in youth elite handball players. 125 youth female and male elite handball players (14.1±0.7yo) were assessed for ACT and ICT by ultrasound . ACT measurement was performed from anterior (3 o'clock) in upright position and for ICT from inferior (6 o'clock) in supine position. Measurements of ICT in the TS of all athletes (1.4±0.2 mm) differed significantly but marginally to those in the NTS (1.3±0.2 mm) (p = 0.001). Female (1.2±0.2 mm vs. 1.3±0.2 mm; p = 0.007) but not male youth players (1.4±0.2 mm vs. 1.4±0.2 mm, p = n.s.) demonstrated slight differences in ICT in the TS compared with the NTS. Although significant, the thickness in the TS compared to the NTS was within the measurement accuracy of the ultrasonic assessment. No difference in ACT was observed in the TS (1.4±0.3 mm) compared to the NTS (1.4±0.3 mm) for both sexes (n.s.).In conclusion, the anterior and inferior capsule thickness in youth elite handball athletes is not or only marginally different between throwing and non-throwing shoulders.

BackgroundGlobally, prisons are high-incidence settings for tuberculosis. Yet the role of prisons as reservoirs of M. tuberculosis, propagating epidemics through spillover from prisons to surrounding communities, has been difficult to measure directly.Methods and FindingsTo quantify the role of prisons in driving wider community M. tuberculosis transmission, we conducted prospective genomic surveillance in Central West Brazil from 2014 to 2019. We whole genome sequenced 1,152 M. tuberculosis isolates collected during active and passive surveillance inside and outside prisons and linked genomes to detailed incarceration histories. We applied multiple phylogenetic and genomic clustering approaches and inferred timed transmission trees. We found that M. tuberculosis sequences from incarcerated and non-incarcerated people were closely related in a maximum likelihood phylogeny. The majority (70.8%; 46/65) of genomic clusters including people with no incarceration history also included individuals with a recent history of incarceration. Among cases in individuals with no incarceration history, 50.6% (162/320) were in clusters that included individuals with recent incarceration history, suggesting that transmission chains often span prisons and communities. We identified a minimum of 18 highly probable spillover events, M. tuberculosis transmission from people with a recent incarceration history to people with no prior history of incarceration, occurring in the state’s four largest cities and across sampling years. We additionally found that frequent transfers of people between the state’s prisons creates a highly connected prison network that likely disseminates M. tuberculosis across the state.ConclusionsWe developed a framework for measuring spillover from high-incidence environments to surrounding communities by integrating genomic and spatial information to reconstruct tuberculosis transmission chains. Our findings indicate that, in this setting, prisons serve not only as disease reservoirs, but also disseminate M. tuberculosis across highly connected prison networks, both amplifying and propagating M. tuberculosis risk in surrounding communities.

Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations: P.1 from Brazil, B.1.351 from South Africa and B.1.1.7 from the UK (12, 10 and 9 changes in the spike respectively). All have mutations in the ACE2 binding site with P.1 and B.1.351 having a virtually identical triplet: E484K, K417N/T and N501Y, which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine induced antibody responses than B.1.351 suggesting that changes outside the RBD impact neutralisation. Monoclonal antibody 222 neutralises all three variants despite interacting with two of the ACE2 binding site mutations, we explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies., Structural and functional analysis of the P.1 variant of SARS-CoV-2 from Brazil reveals less resistance to antibodies generated from natural infection or vaccination compared to another similar variant, B.1.351. A monoclonal antibody mAb 222 is able to neutralize all three variants (P.1, B.1.351 and B.1.1.7), with its light chain able to restore neutralization potency to broad group of antibodies.

SARS-CoV-2 has undergone progressive change with variants conferring advantage rapidly becoming dominant lineages e.g. B.1.617. With apparent increased transmissibility variant B.1.617.2 has contributed to the current wave of infection ravaging the Indian subcontinent and has been designated a variant of concern in the UK. Here we study the ability of monoclonal antibodies, convalescent and vaccine sera to neutralize B.1.617.1 and B.1.617.2 and complement this with structural analyses of Fab/RBD complexes and map the antigenic space of current variants. Neutralization of both viruses is reduced when compared with ancestral Wuhan related strains but there is no evidence of widespread antibody escape as seen with B.1.351. However, B.1.351 and P.1 sera showed markedly more reduction in neutralization of B.1.617.2 suggesting that individuals previously infected by these variants may be more susceptible to reinfection by B.1.617.2. This observation provides important new insight for immunisation policy with future variant vaccines in non-immune populations., The B.1.617 lineage of SARS-CoV-2, especially the delta strain that is B.1.617.2 has contributed to the wave of infection in the Indian subcontinent. Structural and serological analyses show no evidence of antibody escape but individuals previously infected with either the B.1.351 (beta) and P.1 (gamma) variants are likely more susceptible to reinfection by the delta strain. Vaccines based on B.1.1.7 (alpha) are likely to provide the broadest protection against current variants.

3115 Background: Tumours rely on lactate transporters (MCT1-4) to maintain glycolytic flux and avoid intracellular acidification. In haematological tumours the MCT1 transporter acts as a lactate and pyruvate exporter. AZD3965 is a potent and specific inhibitor of MCT1 causing intracellular lactate accumulation. In vivo efficacy was observed in xenografts of DLBCL and BL, expressing high levels of MCT1 and no or low levels of MCT4. In the AZD3965 phase I (NCT01791595) dose-escalation an oral recommended phase 2 dose (RP2D) of 10mg twice-daily (bd) was determined. Pharmacokinetic (PK) showed exposure estimated to produce a minimum MCT1 occupancy of 90% (based on modelling). DLTs were primarily on-target dose-dependent, reversible, asymptomatic alterations in retinal function seen on ERG. Methods: This expansion cohort enrolled patients with relapsed/refractory DLBCL and BL. Expression of MCT1/MCT4 was assessed by immunohistochemistry. Pharmacokinetic (PK) sampling was performed and pharmacodynamic assessments included [18F]FDG-PET/CT imaging and plasma/urine metabolomics. Results: 11 DLBCL patients were treated with AZD3965 10mg bd. PK showed exposure to be broadly in line with the escalation cohort. No significant ERG changes were observed. One patient experienced a dose-limiting SUSAR of Troponin I increase. MCT1 is expressed in erythrocytes, however no serious events of anaemia were seen, with one non-clinically significant episode of grade 3 anaemia reported. Urine analysis showed increased excretion of lactate and ketone bodies post AZD3965 treatment consistent with renal target engagement. No alteration was detected in plasma. Ongoing stable disease at cycle 5 was observed in one patient and an additional patient had a confirmed complete response (CR) lasting 15 months, with no significant toxicity. In the patient showing CR a reduction in tumour FDG uptake was observed on day 3 of cycle 1. The other four patients who consented to research imaging did not have a clinical response and no changes were observed on FDG-PET. Conclusions: AZD3965 can be safely administered at 10mg bd. In one DLBCL patient monotherapy activity was observed with changes in FDG-PET providing evidence indicative of proof of mechanism. These changes in FDG uptake as early as on day 3 in the responding patient warrant further investigation of FDG-PET as a predictive biomarker. Further biomarker analysis and preclinical studies are ongoing to understand the biology and explore effective combinations with other agents targeting tumour cell metabolism Clinical trial information: NCT01791595.

SUMMARYWNTs play key roles in development and disease, by binding both Frizzled (FZD) seven-pass transmembrane receptors and numerous co-receptors that include the ROR and RYK receptor tyrosine kinases (RTKs). We describe crystal structures and WNT-binding characteristics of extracellular regions from the Drosophila ROR and RYK orthologs Nrk (neurospecific receptor tyrosine kinase) and Derailed-2 (Drl-2). RORs bind WNTs though a FZD-related cysteine-rich domain (CRD), and RYKs through a WNT-inhibitory factor (WIF) domain. Our structures suggest that neither the Nrk CRD nor the Drl-2 WIF domain can accommodate the acyl chain typically attached to WNTs. The Nrk CRD contains a deeply buried bound fatty acid, unlikely to be exchangeable with a WNT acyl chain. The Drl-2 WIF domain lacks the lipid-binding site seen in WIF-1. We also show that DWnt-5, which regulates Drosophila ROR and RYK orthologs, lacks an acyl chain. Together with analysis of WNT/receptor interaction sites, these structures provide new insight into how WNTs recruit their RTK co-receptors into signaling complexes.

In the past decade, tuberculosis incidence has declined in much of the world, but has risen in central and South America. It is not yet clear what is driving this reversal of progress in tuberculosis control. Since 2000, the incarcerated population in central and South America has grown by 206%, the greatest increase in the world. Over the same period, notified tuberculosis cases among the incarcerated population (hereinafter termed persons deprived of their liberty [PDL], following the Inter-American Commission on Human Rights) have risen by 269%. In both central and South America, the rise of disease among PDL more than offsets tuberculosis control gains in the general population. Tuberculosis is increasingly concentrated among PDL; currently, 11% of all notified tuberculosis cases in central and South America occur among PDL who comprise less than 1% of the population. The extraordinarily high risk of acquiring tuberculosis within prisons creates a health and human rights crisis for PDL that also undermines wider tuberculosis control efforts. Controlling tuberculosis in this region will require countries to take urgent measures to prioritise the health of PDL.

Background Motor learning has been investigated using various paradigms, including serial reaction time tasks (SRTT) that examine upper extremity reaching and pointing while seated. Few studies have used a stepping SRTT, which could offer additional insights into motor learning involving postural demands. For a task to measure motor learning, naive participants must demonstrate a) improved performance with task practice, and b) a dose-response relationship to learning the task. Research question Is a stepping SRTT feasible and efficacious for measuring motor learning? Methods In this prospective study, 20 participants stood on an instrumented mat and were presented with stimuli on a computer screen. They stepped to the corresponding positions on the mat as quickly as possible. Presented stimuli included random sequences and a blinded imbedded repeating sequence. Three days after completing the randomly assigned practice dose [high dose group (n = 10) performed 4320 steps; low dose group (n = 10) performed 144 steps], a retention test of 72 steps was performed. Feasibility was measured as the proportion of participants who completed the assigned practice dose without adverse events. Efficacy was measured as within-group performance improvement on the random sequences and on the repeating sequence (paired t-tests), as well as a dose-response relationship to learning both types of sequences (independent t-tests). Results All participants (mean age 26.8 years) completed all practice sessions without adverse events, indicating feasibility. High dose practice resulted in performance improvement while low dose did not; a dose-response relationship was found, with high dose practice resulting in greater learning of the task than low dose practice, indicating efficacy. Significance This stepping SRTT is a feasible and efficacious way to measure motor learning, which could provide critical insights into anticipatory stepping, postural control, and fall risk. Future research is needed to determine feasibility, efficacy, and optimal practice dosages for older and impaired populations.

Lack of blood flow to the brain, i.e., ischemic stroke, results in loss of nerve cells and therefore loss of function in the effected brain regions. There is no effective treatment to improve lost function except restoring blood flow within the first several hours. Rehabilitation strategies are widely used with limited success. The purpose of this study was to examine the effect of electrical stimulation on the impaired upper extremity to improve functional recovery after stroke. We developed a rodent model using an electrode cuff implant onto a single peripheral nerve (median nerve) of the paretic forelimb and applied daily electrical stimulation. The skilled forelimb reaching test was used to evaluate functional outcome after stroke and electrical stimulation. Anterograde axonal tracing from layer V pyramidal neurons with biotinylated dextran amine was done to evaluate the formation of new neuronal connections from the contralesional cortex to the deafferented spinal cord. Rats receiving electrical stimulation on the median nerve showed significant improvement in the skilled forelimb reaching test in comparison with stroke only and stroke with sham stimulation. Rats that received electrical stimulation also exhibited significant improvement in the latency to initiate adhesive removal from the impaired forelimb, indicating better sensory recovery. Furthermore, axonal tracing analysis showed a significant higher midline fiber crossing index in the cervical spinal cord of rats receiving electrical stimulation. Our results indicate that direct peripheral nerve stimulation leads to improved sensorimotor recovery in the stroke-impaired forelimb, and may be a useful approach to improve post-stroke deficits in human patients.

SummaryTerminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations: P.1 from Brazil, B.1.351 from South Africa and B.1.1.7 from the UK (12, 10 and 9 changes in the spike respectively). All have mutations in the ACE2 binding site with P.1 and B.1.351 having a virtually identical triplet: E484K, K417N/T and N501Y, which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine induced antibody responses than B.1.351 suggesting that changes outside the RBD impact neutralisation. Monoclonal antibody 222 neutralises all three variants despite interacting with two of the ACE2 binding site mutations, we explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.

The race to produce vaccines against SARS-CoV-2 began when the first sequence was published, and this forms the basis for vaccines currently deployed globally. Independent lineages of SARS-CoV-2 have recently been reported: UK–B.1.1.7, South Africa–B.1.351 and Brazil–P.1. These variants have multiple changes in the immunodominant spike protein which facilitates viral cell entry via the Angiotensin converting enzyme-2 (ACE2) receptor. Mutations in the receptor recognition site on the spike are of great concern for their potential for immune escape. Here we describe a structure-function analysis of B.1.351 using a large cohort of convalescent and vaccinee serum samples. The receptor binding domain mutations provide tighter ACE2 binding and widespread escape from monoclonal antibody neutralization largely driven by E484K although K417N and N501Y act together against some important antibody classes. In a number of cases it would appear that convalescent and some vaccine serum offers limited protection against this variant., Structure-function analysis of the SARS-CoV-2 variant B.1.351 using serum samples from convalescent and vaccinated individuals reveals how mutations in the viral spike protein result in tighter binding to the receptor ACE2 and allow escape from monoclonal antibody neutralization.

SARS-CoV-2 has caused over 2M deaths in little over a year. Vaccines are being deployed at scale, aiming to generate responses against the virus spike. The scale of the pandemic and error-prone virus replication is leading to the appearance of mutant viruses and potentially escape from antibody responses. Variant B.1.1.7, now dominant in the UK, with increased transmission, harbours 9 amino-acid changes in the spike, including N501Y in the ACE2 interacting-surface. We examine the ability of B.1.1.7 to evade antibody responses elicited by natural SARS-CoV-2 infection or vaccination. We map the impact of N501Y by structure/function analysis of a large panel of well-characterised monoclonal antibodies. B.1.1.7 is harder to neutralize than parental virus, compromising neutralization by some members of a major class of public antibodies through light chain contacts with residue 501. However, widespread escape from monoclonal antibodies or antibody responses generated by natural infection or vaccination was not observed., The SARS-CoV-2 B.1.1.7 variant is not neutralized as easily as the original form of the virus. Some public antibodies cannot neutralize B.1.1.7, due to altered light chain contacts with residue 501. However, B.1.1.7 does not show widespread escape from monoclonal antibodies, natural antibody responses, or vaccines.

(1) Background: The purpose of this exploratory study was to describe variation in age of onset of functional limitations of Native Hawaiian and Pacific Islanders (NHPI) compared to other racial and ethnic groups. (2) Methods: Adults age 45 years and older who responded to the Functioning and Disability module within the 2014 National Health Interview Survey (NHIS) were included (n = 628 NHPI, 7122 non-Hispanic Whites, 1418 Blacks, 470 Asians, and 1216 Hispanic adults). The NHIS Functioning and Disability module included 13 items, which we organized into three domains of functional limitations using factor analysis: Mobility, Gross Motor Skills, and Fine Motor Skills. Responses were summed within each domain. (3) Results: After adjusting for age and sex, we found that racial/ethnic minority groups, with the exception of Asians, experience more functional limitations than Whites. Results further indicate that NHPI adults experienced an earlier surge in all three domains of functional limitations compared to other racial/ethnic groups. (4) Conclusions: These findings are novel and provide additional evidence to the existence of disparities in functional health outcomes across racial/ethnic groups. Future studies are needed to develop targeted and culturally tailored interventions for those most in need.

We report the first discovery of a transiting circumbinary planet detected from a single sector of TESS data. During Sector 21, the planet TIC 172900988b transited the primary star and then 5 days later it transited the secondary star. The binary is itself eclipsing, with a period of P = 19.7 days and an eccentricity of e = 0.45. Archival data from ASAS-SN, Evryscope, KELT, and SuperWASP reveal a prominent apsidal motion of the binary orbit, caused by the dynamical interactions between the binary and the planet. A comprehensive photodynamical analysis of the TESS, archival and follow-up data yields stellar masses and radii of M1 = 1.2384 +/- 0.0007 MSun and R1 = 1.3827 +/- 0.0016 RSun for the primary and M2 = 1.2019 +/- 0.0007 MSun and R2 = 1.3124 +/- 0.0012 RSun for the secondary. The radius of the planet is R3 = 11.25 +/- 0.44 REarth (1.004 +/- 0.039 RJup). The planet's mass and orbital properties are not uniquely determined - there are six solutions with nearly equal likelihood. Specifically, we find that the planet's mass is in the range of 824 < M3 < 981 MEarth (2.65 < M3 < 3.09 MJup), its orbital period could be 188.8, 190.4, 194.0, 199.0, 200.4, or 204.1 days, and the eccentricity is between 0.02 and 0.09. At a V = 10.141 mag, the system is accessible for high-resolution spectroscopic observations, e.g. Rossiter-McLaughlin effect and transit spectroscopy., 57 pages, 30 figures, 25 tables; Accepted AJ

Horizontally curved concrete bridges are widely used in urban viaducts and overpasses all over the world. A box cross-section is often used in curved concrete girders because of its high re...