The rockefeller university

Background: One-third of people living with dementia (PLWD) have highly fragmented care (i.e., care spread across many ambulatory providers without a dominant provider). It is unclear whether PLWD with fragmented care and their caregivers perceive gaps in communication among the providers involved and whether any such gaps are perceived as benign inconveniences or as clinically meaningful, leading to adverse events. We sought to determine the frequency of perceived gaps in communication (coordination) among providers and the frequency of self-reported adverse events attributed to poor coordination. Methods: We conducted a cross-sectional study in the context of a Medicare accountable care organization (ACO) in New York in 2022-2023. We included PLWD who were attributed to the ACO, had fragmented care in the past year by claims (reversed Bice-Boxerman Index >= 0.86), and were in a pragmatic clinical trial on care management. We used an existing survey instrument to determine perceptions of care coordination and perceptions of four adverse events (repeat tests, drug-drug interactions, emergency department visits, and hospital admissions). ACO care managers collected data by telephone, using clinical judgment to determine whether each survey respondent was the patient or a caregiver. We used descriptive statistics to summarize results. Results: Of 167 eligible PLWD, surveys were completed for 97 (58.1%). Of those, 88 (90.7%) reported having >1 ambulatory visit and >1 ambulatory provider and were thus at risk for gaps in care coordination and included in the analysis. Of those, 23 respondents were patients (26.1%) and 64 were caregivers (72.7%), with one respondent's role missing. Overall, 57% of respondents reported a problem (or "gap") in the coordination of care and, separately, 18% reported an adverse event that they attributed to poor care coordination. Conclusion: Gaps in coordination of care for PLWD are reported to be very common and often perceived as hazardous.

The complex carbohydrate structures decorating human proteins and lipids, also called glycans, are abundantly present at cell surfaces and in the secretome. Glycosylation is vital for biological processes including cell-cell recognition, immune responses, and signaling pathways. Therefore, the structural and functional characterization of the human glycome is gaining more and more interest in basic biochemistry research and in the context of developing new therapies, diagnostic tools, and biotechnology applications. For glycomics to reach its full potential in these fields, it is critical to appreciate the specific factors defining the function of the human glycome. Here, we review the glycosyltransferases (the writers) that form the glycome and the glycan-binding proteins (the readers) with an essential role in decoding glycan functions. While abundantly present throughout different cells and tissues, the function of specific glycosylation features is highly dependent on their context. In this review, we highlight the relevance of studying the glycome in the context of specific carrier proteins, cell types, and subcellular locations. With this, we hope to contribute to a richer understanding of the glycome and a more systematic approach to identifying the roles of glycosylation in human physiology.

Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained1,2. Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR-Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE. A study of two childhood cases of herpes simplex encephalitis shows that TMEFF1 interacts with the HSV-1 cell-surface receptor NECTIN-1, preventing HSV-1 from fusing with the cell membrane and entering cortical neurons.

Background. Development of a screening assay for the clinical use of broadly neutralizing antibodies (bnAbs) is a priority for HIV therapy and cure initiatives. Methods. We assessed the PhenoSense Monoclonal Antibody Assay (Labcorp-Monogram Biosciences), which is Clinical Laboratory Improvement Amendments (CLIA) validated and has been used prospectively and retrospectively in multiple recent bnAb clinical trials. Results. When performed on plasma and longitudinal peripheral blood mononuclear cell samples (before and during antiretroviral therapy, respectively), as sourced from a recent clinical trial, the PhenoSense assay produced robust reproducibility, concordance across sample types, and expected ranges in the susceptibility measures of bnAbs in clinical development. When applied retrospectively to baseline samples from 3 recent studies, the PhenoSense assay correlated with published laboratory-based study evaluations, but baseline bnAb susceptibility was not consistently predictive of durable virus suppression. Assessment of assay feasibility in 4 recent clinical studies provides estimates of assay success rate and processing time. Conclusions. The PhenoSense Monoclonal Antibody Assay provides reproducible bnAb susceptibility measurements across relevant sample types yet is not consistently predictive of virus suppression. Logistical and operational assay requirements can affect timely clinical trial conduct. These results inform bnAb studies in development.

Patients with severe West Nile virus and SARS-CoV-2 infections deserve accurate diagnosis of underlying diseases, determining possible anti-interferon autoantibody production, since they must receive antiviral and immunological therapies to enhance antiviral response.The current study aimed to investigate determinants of severity in a previously healthy patient who experienced 2 life-threatening infections, from West Nile Virus (WNV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). During coronavirus disease 2019 (COVID-19) hospitalization he was diagnosed with a thymoma, retrospectively identified as already present at the time of WNV infection. Heterozygosity for p.Pro554Ser in the TLR3 gene, which increases susceptibility to severe COVID-19, and homozygosity for CCR5 c.554_585del, associated with severe WNV infection, were found. Neutralizing anti-interferon (IFN)-alpha and anti-IFN-omega autoantibodies were detected, likely induced by the underlying thymoma and increasing susceptibility to both severe COVID-19 pneumonia and West Nile encephalitis.

A search for direct production of low-mass dimuon resonances is performed using root s = 13TeV proton-proton collision data collected by the CMS experiment during the 2017-2018 operation of the CERN LHC with an integrated luminosity of 96.6 fb(-1). The search exploits a dedicated high-rate trigger stream that records events with two muons with transverse momenta as low as 3 GeV but does not include the full event information. The search is performed by looking for narrow peaks in the dimuon mass spectrum in the ranges of 1.1-2.6 GeV and 4.2-7.9 GeV. No significant excess of events above the expectation from the standard model background is observed. Model-independent limits on production rates of dimuon resonances within the experimental fiducial acceptance are set. Competitive or world's best limits are set at 90% confidence level for a minimal dark photon model and for a scenario with two Higgs doublets and an extra complex scalar singlet (2HDM+S). Values of the squared kinetic mixing coefficient epsilon(2) in the dark photon model above 10(-6) are excluded over most of the mass range of the search. In the 2HDM+S, values of the mixing angle sin(theta(H)) above 0.08 are excluded over most of the mass range of the search with a fixed ratio of the Higgs doublets vacuum expectation tan beta = 0.5.

A new measurement of inclusive-jet cross sections in the Breit frame in neutral current deep inelastic scattering using the ZEUS detector at the HERA collider is presented. The data were taken in the years 2004-2007 at a centre-of-mass energy of 318 GeV and correspond to an integrated luminosity of 347 pb(-1). The jets were reconstructed using the k(t)-algorithm in the Breit reference frame. They have been measured as a function of the squared momentum transfer, Q(2), and the transverse momentum of the jets in the Breit frame, p(perpendicular to,Breit). The measured jet cross sections are compared to previous measurements and to perturbative QCD predictions. The measurement has been used in a next-to-next-to-leading-order QCD analysis to perform a simultaneous determination of parton distribution functions of the proton and the strong coupling, resulting in a value of alpha(s) (M-Z(2)) = 0.1142 +/- 0.0017 (experimental/fit)(-0.0007)(+0.0006) (model/parameterisation)(-0.0004)(+0.0006) (scale), whose accuracy is improved compared to similarmeasurements. In addition, the running of the strong coupling is demonstrated using data obtained at different scales.