Impairment of pneumococcal antigen specific isotype-switched IgG memory B-cell immunity in HIV infected Malawian adults

Pneumococcal disease is associated with a particularly high morbidity and mortality amongst adults in HIV endemic countries. Our previous findings implicating a B-cell defect in HIV-infected children from the same population led us to comprehensively characterize B-cell subsets in minimally symptomatic HIV-infected Malawian adults and investigate the isotype-switched IgG memory B-cell immune response to the pneumococcus. We show that similar to vertically acquired HIV-infected Malawian children, horizontally acquired HIV infection in these adults is associated with IgM memory B-cell (CD19+ CD27+ IgM+ IgD+) depletion, B-cell activation and impairment of specific IgG B-cell memory to a range of pneumococcal proteins. Our data suggest that HIV infection affects both T-cell independent and T-cell dependent B-cell maturation, potentially leading to impairment of humoral responses to extracellular pathogens such as the pneumococcus, and thus leaving this population susceptible to invasive disease.Oluwadamilola H. Iwajomo, Adam Finn, Abiodun D. Ogunniyi, Neil A. Williams, Robert S. Heyderma

Observations on Sensitisation or "ide" Eruptions Following Varicose Ulceration, Varicose Eczema and Infectious Eczematoid Dermatitis

Abstract Not Provided

Core-Clickable PEG-Branch-Azide Bivalent-Bottle-Brush Polymers by ROMP: Grafting-Through and Clicking-To

The combination of highly efficient polymerizations with modular "click" coupling reactions has enabled the synthesis of a wide variety of novel nanoscopic tructures. Here we demonstrate the facile synthesis of a new class of clickable, branched nanostructures, polyethylene glycol (PEG)-branch-azide bivalent-brush polymers, facilitated by "graft-through" ring-opening metathesis polymerization of a branched norbornene-PEG-chloride macromonomer followed by halide-azide exchange. The resulting bivalent-brush polymers possess azide groups at the core near a polynorbornene backbone with PEG chains extended into solution; the structure resembles a unimolecular micelle. We demonstrate copper-catalyzed azide-alkre cycloaddition (CuAAC) "click-to" coupling of a photocleavable doxorubicin (DOX)-alkyne derivative to the azide core. The CuAAC coupling was quantitative across a wide range of nanoscopic sizes (similar to 6-similar to 50 nrn); UV photolysis of the resulting DOX-loaded materials yielded free DOX that was therapeutically effective against human cancer cells

Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up.

PurposeIn the initial PALOMA-2 (NCT01740427) analysis with median follow-up of 23 months, palbociclib plus letrozole significantly prolonged progression-free survival (PFS) in women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) [hazard ratio (HR) 0.58; P < 0.001]. Herein, we report results overall and by subgroups with extended follow-up.MethodsIn this double-blind, phase 3 study, post-menopausal women with ER+/HER2- ABC who had not received prior systemic therapy for their advanced disease were randomized 2:1 to palbociclib-letrozole or placebo-letrozole. Endpoints include investigator-assessed PFS (primary), safety, and patient-reported outcomes (PROs).ResultsAfter a median follow-up of approximately 38 months, median PFS was 27.6 months for palbociclib-letrozole (n = 444) and 14.5 months for placebo-letrozole (n = 222) (HR 0.563; 1-sided P < 0.0001). All subgroups benefited from palbociclib treatment. The improvement of PFS with palbociclib-letrozole was maintained in the next 2 subsequent lines of therapy and delayed the use of chemotherapy (40.4 vs. 29.9 months for palbociclib-letrozole vs. placebo-letrozole). Safety data were consistent with the known profile. Patients' quality of life was maintained.ConclusionsWith approximately 15 months of additional follow-up, palbociclib plus letrozole continued to demonstrate improved PFS compared with placebo plus letrozole in the overall population and across all patient subgroups, while the safety profile remained favorable and quality of life was maintained. These data confirm that palbociclib-letrozole should be considered the standard of care for first-line therapy in patients with ER+/HER2- ABC, including those with low disease burden or long disease-free interval. Sponsored by Pfizer; ClinicalTrials.gov: NCT01740427

Aperture synthesis for gravitational-wave data analysis: Deterministic Sources

Gravitational wave detectors now under construction are sensitive to the phase of the incident gravitational waves. Correspondingly, the signals from the different detectors can be combined, in the analysis, to simulate a single detector of greater amplitude and directional sensitivity: in short, aperture synthesis. Here we consider the problem of aperture synthesis in the special case of a search for a source whose waveform is known in detail: \textit{e.g.,} compact binary inspiral. We derive the likelihood function for joint output of several detectors as a function of the parameters that describe the signal and find the optimal matched filter for the detection of the known signal. Our results allow for the presence of noise that is correlated between the several detectors. While their derivation is specialized to the case of Gaussian noise we show that the results obtained are, in fact, appropriate in a well-defined, information-theoretic sense even when the noise is non-Gaussian in character. The analysis described here stands in distinction to ``coincidence analyses'', wherein the data from each of several detectors is studied in isolation to produce a list of candidate events, which are then compared to search for coincidences that might indicate common origin in a gravitational wave signal. We compare these two analyses --- optimal filtering and coincidence --- in a series of numerical examples, showing that the optimal filtering analysis always yields a greater detection efficiency for given false alarm rate, even when the detector noise is strongly non-Gaussian.Comment: 39 pages, 4 figures, submitted to Phys. Rev.

Hierarchical search strategy for the detection of gravitational waves from coalescing binaries: Extension to post-Newtonian wave forms

The detection of gravitational waves from coalescing compact binaries would be a computationally intensive process if a single bank of template wave forms (i.e., a one step search) is used. In an earlier paper we had presented a detection strategy, called a two step search}, that utilizes a hierarchy of template banks. It was shown that in the simple case of a family of Newtonian signals, an on-line two step search was about 8 times faster than an on-line one step search (for initial LIGO). In this paper we extend the two step search to the more realistic case of zero spin 1.5 post-Newtonian wave forms. We also present formulas for detection and false alarm probabilities which take statistical correlations into account. We find that for the case of a 1.5 post-Newtonian family of templates and signals, an on-line two step search requires about 1/21 the computing power that would be required for the corresponding on-line one step search. This reduction is achieved when signals having strength S = 10.34 are required to be detected with a probability of 0.95, at an average of one false event per year, and the noise power spectral density used is that of advanced LIGO. For initial LIGO, the reduction achieved in computing power is about 1/27 for S = 9.98 and the same probabilities for detection and false alarm as above.Comment: 30 page RevTeX file and 17 figures (postscript). Submitted to PRD Feb 21, 199

LGBT+ Histories and Historians

In February 2019, the Royal Historical Society established a working group to explore the teaching of LGBT+ and queer histories, and to coIn February 2019, the RHS established a working group to explore the teaching of LGBT+ and queer histories, and to consider the experiences of LGBT+ historians. Between July and September 2019 we ran an open survey which attracted 852 responses. This is the resulting report. While indicating that much more needs to be done, the report noted that “LGBT+ and queer histories are an integral part of human history. To reflect the methodological advances and rich research findings across a wide spectrum of fields, chronologies and geographical regions more fully, LGBT+ histories and perspectives in all their diversity need to be represented in teaching and university-based research, as well as in museums, galleries, archives and libraries.

A Demonstration of LISA Laser Communication

Over the past few years questions have been raised concerning the use of laser communications links between sciencecraft to transmit phase information crucial to the reduction of laser frequency noise in the LISA science measurement. The concern is that applying medium frequency phase modulations to the laser carrier could compromise the phase stability of the LISA fringe signal. We have modified the table-top interferometer presented in a previous article by applying phase modulations to the laser beams in order to evaluate the effects of such modulations on the LISA science fringe signal. We have demonstrated that the phase resolution of the science signal is not degraded by the presence of medium frequency phase modulations.Comment: minor corrections found in the CQG versio

Predicted distribution of High Nature Value farmland in the Republic of Ireland

peer-reviewedHigh Nature Value (HNV) farmland is typically characterised by low-intensity farming associated with high biodiversity and species of conservation concern. Mapping the occurrence and distribution of such farmland are useful for appropriate targeting of conservation measures and supporting associated rural communities. We mapped the likely distribution of HNV farmland in the Republic of Ireland using a linear regression model incorporating established European indicators, adapted for Ireland and weightings based on expert opinion. The indicators used were semi-natural habitat cover, stocking density, hedgerow density, river and stream density and soil diversity, with highest weightings placed on the first two indicators (40% and 30%, respectively). The map provides information on the likely occurrence and distribution of HNV farmland in each electoral division as a reference point for future monitoring of the distribution of HNV farmland in the Republic of Ireland in order to assist with planning and policy development for the rural environment.This study was conducted by Teagasc and IT Sligo as part of the IDEAL-HNV project [Ref. 11/S/108], funded by the Department of Agriculture, Food and the Marine (DAFM) under the National Development Plan 2007–2013

Application of asymptotic expansions of maximum likelihood estimators errors to gravitational waves from binary mergers: the single interferometer case

In this paper we describe a new methodology to calculate analytically the error for a maximum likelihood estimate (MLE) for physical parameters from Gravitational wave signals. All the existing litterature focuses on the usage of the Cramer Rao Lower bounds (CRLB) as a mean to approximate the errors for large signal to noise ratios. We show here how the variance and the bias of a MLE estimate can be expressed instead in inverse powers of the signal to noise ratios where the first order in the variance expansion is the CRLB. As an application we compute the second order of the variance and bias for MLE of physical parameters from the inspiral phase of binary mergers and for noises of gravitational wave interferometers . We also compare the improved error estimate with existing numerical estimates. The value of the second order of the variance expansions allows to get error predictions closer to what is observed in numerical simulations. It also predicts correctly the necessary SNR to approximate the error with the CRLB and provides new insight on the relationship between waveform properties SNR and estimation errors. For example the timing match filtering becomes optimal only if the SNR is larger than the kurtosis of the gravitational wave spectrum