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IntroductionEstablishing robust reference intervals for clinical procedures has received much attention from international clinical laboratories, with approved guidelines. Physiological measurement laboratories have given this topic less attention; however, most of the principles are transferable.MethodsHerein, we summarise those principles and expand them to cover bilateral measurements and one-tailed reference intervals, which are common issues for those interpreting clinical visual electrophysiology tests such as electroretinograms (ERGs), visual evoked potentials (VEPs) and electrooculograms (EOGs).ResultsThe gold standard process of establishing and defining reference intervals, which are adequately reliable, entails collecting data from a minimum of 120 suitable reference individuals for each partition (e.g. sex, age) and defining limits with nonparametric methods. Parametric techniques may be used under some conditions. A brief outline of methods for defining reference limits from patient data (indirect sampling) is given. Reference intervals established elsewhere, or with older protocols, can be transferred or verified with as few as 40 and 20 suitable reference individuals, respectively. Consideration is given to small numbers of reference subjects, interpretation of serial measurements using subject-based reference values, multidimensional reference regions and age-dependent reference values. Bilateral measurements, despite their correlation, can be used to improve reference intervals although additional care is required in computing the confidence in the reference interval or the reference interval itself when bilateral measurements are only available from some of subjects.DiscussionGood quality reference limits minimise false-positive and false-negative results, thereby maximising the clinical utility and patient benefit. Quality indicators include using appropriately sized reference datasets with appropriate numerical handling for reporting; using subject-based reference limits where appropriate; and limiting tests for each patient to only those which are clinically indicated, independent and highly discriminating.

Purpose To compare the effect of variable pupil size on the flicker electroretinogram (ERG) between a stimulus having constant luminance and a stimulus having constant retinal illuminance (constant Troland) that compensates for pupil size. Methods Subjects ( n  = 18) were tested with 12 pairs of the stimuli. The stimulus pair consisted of the ISCEV standard constant luminance stimulus (3 cd·s/m 2 with a 30 cd/m 2 background) and a constant retinal illuminance stimulus (32 Td·s with a 320 Td background) selected to provide the same stimulus and background when the pupil diameter is 3.7 mm. Half the subjects were artificially dilated, and their response was measured before and during the dilation. The natural pupil group was used to assess intra- and inter-subject variability. The artificially dilated group was used to measure the flicker ERG’s dependence on pupil size. Results With natural pupils, intra-subject variability was lower with the constant Troland stimulus, while inter-subject variability was similar between stimuli. During pupil dilation, the constant Troland stimulus did not have a dependence on pupil size up to 6.3 mm and had slightly larger amplitudes with longer implicit times for fully dilated pupils. For the constant luminance stimulus, waveform amplitudes varied by 22% per mm change in pupil diameter, or by 48% over the 2.2 mm diameter range measured in dilated pupil size. There was no difference in inter-subject variability between constant Troland natural pupils and the same subjects with a constant luminance stimulus when dilated (i.e., the ISCEV standard condition). Conclusions These results suggest that a constant Troland flicker ERG test with natural pupils may be advantageous in clinical testing. Because of its insensitivity to pupil size, constant Troland stimuli should produce smaller reference ranges, which in turn should improve the sensitivity for detection of abnormalities and for monitoring changes. In addition, the test can be administered more efficiently as it does not require artificial dilation. Clinical Trial registration number This trial is registered at ClinicalTrials.gov (NCT02466607).

To evaluate the performance of the RETeval device, a handheld instrument using flicker electroretinography (ERG) and pupillography on undilated subjects with diabetes, to detect vision-threatening diabetic retinopathy (VTDR). Performance was measured using a cross-sectional, single armed, non-interventional, multi-site study with Early Treatment Diabetic Retinopathy Study 7-standard field, stereo, color fundus photography as the gold standard. The 468 subjects were randomized to a calibration phase (80%), whose ERG and pupillary waveforms were used to formulate an equation correlating with the presence of VTDR, and a validation phase (20%), used to independently validate that equation. The primary outcome was the prevalence-corrected area under the receiver operating characteristic (ROC) curve for the detection of VTDR. The area under the ROC curve was 0.86 for VTDR. With a sensitivity of 83%, the specificity was 78% and the negative predictive value was 99%. The average testing time was 2.3min. With a VTDR prevalence similar to that in the US, the RETeval device will identify about 75% of the population as not having VTDR with 99% accuracy. The device is simple to use, does not require pupil dilation, and has a short testing time.

The Defense Department's notices list restrictions at other military bases when staff members are not available to perform the procedure, according to military pilots who reviewed the notices for The Washington Post, speaking on condition of anonymity because they are not authorized to discuss the restrictions.

The isolation of human monoclonal antibodies (mAbs) that neutralize a broad spectrum of primary HIV-1 isolates and the characterization of the human neutralizing antibody B cell response to HIV-1 infection are important goals that are central to the design of an effective antibody-based vaccine. We immortalized IgG(+) memory B cells from individuals infected with diverse clades of HIV-1 and selected on the basis of plasma neutralization profiles that were cross-clade and relatively potent. Culture supernatants were screened using various recombinant forms of the envelope glycoproteins (Env) in multiple parallel assays. We isolated 58 mAbs that were mapped to different Env surfaces, most of which showed neutralizing activity. One mAb in particular (HJ16) specific for a novel epitope proximal to the CD4 binding site on gp120 selectively neutralized a multi-clade panel of Tier-2 HIV-1 pseudoviruses, and demonstrated reactivity that was comparable in breadth, but distinct in neutralization specificity, to that of the other CD4 binding site-specific neutralizing mAb b12. A second mAb (HGN194) bound a conserved epitope in the V3 crown and neutralized all Tier-1 and a proportion of Tier-2 pseudoviruses tested, irrespective of clade. A third mAb (HK20) with broad neutralizing activity, particularly as a Fab fragment, recognized a highly conserved epitope in the HR-1 region of gp41, but showed striking assay-dependent selectivity in its activity. This study reveals that by using appropriate screening methods, a large proportion of memory B cells can be isolated that produce mAbs with HIV-1 neutralizing activity. Three of these mAbs show unusual breadth of neutralization and therefore add to the current panel of HIV-1 neutralizing antibodies with potential for passive protection and template-based vaccine design.

The growth of omic data presents evolving challenges in data manipulation, analysis and integration. Addressing these challenges, Bioconductor provides an extensive community-driven biological data analysis platform. Meanwhile, tidy R programming offers a revolutionary data organization and manipulation standard. Here we present the tidyomics software ecosystem, bridging Bioconductor to the tidy R paradigm. This ecosystem aims to streamline omic analysis, ease learning and encourage cross-disciplinary collaborations. We demonstrate the effectiveness of tidyomics by analyzing 7.5 million peripheral blood mononuclear cells from the Human Cell Atlas, spanning six data frameworks and ten analysis tools.

Forty years ago, Knut Fladmark (1979) argued that the Pacific Coast offered a viable alternative to the ice-free corridor model for the initial peopling of the Americas—one of the first to support a “coastal migration theory” that remained marginal for decades. Today, the pre-Clovis occupation at the Monte Verde site is widely accepted, several other pre-Clovis sites are well documented, investigations of terminal Pleistocene subaerial and submerged Pacific Coast landscapes have increased, and multiple lines of evidence are helping decode the nature of early human dispersals into the Americas. Misconceptions remain, however, about the state of knowledge, productivity, and deglaciation chronology of Pleistocene coastlines and possible technological connections around the Pacific Rim. We review current evidence for several significant clusters of early Pacific Coast archaeological sites in North and South America that include sites as old or older than Clovis. We argue that stemmed points, foliate points, and crescents (lunates) found around the Pacific Rim may corroborate genomic studies that support an early Pacific Coast dispersal route into the Americas. Still, much remains to be learned about the Pleistocene colonization of the Americas, and multiple working hypotheses are warranted. Hace cuarenta años, Knut Fladmark (1979) argumentó que la costa del Oceano Pacífico ofrecía una alternativa viable a la ruta de Corredor sin Hielo para la población inicial de las Américas. El era una de las primeras en apoyar una “teoría de la migración costera,” lo que permaneció marginal durante décadas. Hoy en día, la ocupación pre-Clovis en el sitio de Monte Verde es ampliamente aceptada, varios otros sitios pre-Clovis están bien documentados, las investigaciones de los sitios terrestres del Pleistoceno terminal y los paisajes sumergidos de la costa del Pacífico han aumentado, y múltiples líneas de evidencia están ayudando a descifrar los patrones de dispersion humana temprana en las Américas. Sin embargo, siguen existiendo conceptos erróneos sobre el estado del conocimiento, la productividad y la cronología de la deglaciación de las líneas costeras del Pleistoceno y las posibles conexiones tecnológicas a lo largo del Pacífico. Revisamos la evidencia actual de varios agrupaciones importantes de sitios arqueológicos de la costa del Pacífico temprano en América del Norte y del Sur que incluyen yacimientos más antiguos o más antiguos que Clovis. Argumentamos que los puntos proyectiles de pedúnculo, puntos foliares y crecientes (lunados) encontrados cerca del borde del Pacífico pueden corroborar los estudios genómicos que respaldan una ruta temprana de dispersión por la costa del Pacífico a través de las Américas. Queda mucho por aprender acerca de la colonización del Pleistoceno en las Américas y se justifican múltiples hipótesis de trabajo.

Monkeys demonstrate gastrointestinal barrier dysfunction (leaky gut) as evidenced by higher biomarkers of microbial translocation (MT) and inflammation with ageing despite equivalent health status, and lifelong diet and environmental conditions. We evaluated colonic structural, microbiomic and functional changes in old female vervet monkeys ( Chlorocebus aethiops sabeus ) and how age-related leaky gut alters responses to Western diet. We additionally assessed serum bovine immunoglobulin therapy to lower MT burden. MT was increased in old monkeys despite comparable histological appearance of the ascending colon. Microbiome profiles from 16S sequencing did not show large differences by age grouping, but there was evidence for higher mucosal bacterial loads using qPCR. Innate immune responses were increased in old monkeys consistent with higher MT burdens. Western diet challenge led to elevations in glycemic and hepatic biochemistry values only in old monkeys, and immunoglobulin therapy was not effective in reducing MT markers or improving metabolic health. We interpret these findings to suggest that ageing may lead to lower control over colonization at the mucosal surface, and reduced clearance of pathogens resulting in MT and inflammation. Leaky gut in ageing, which is not readily rescued by innate immune support with immunoglobulin, primes the liver for negative consequences of high fat, high sugar diets.

Background Hypertension affects nearly half of adults in the U.S., with African American and Black (AA/B) adults experiencing some of the highest rates domestically and globally. Despite improvements in blood pressure control in the general population, rates of control among AA/B adults have stagnated, contributing to significant health disparities in the prevalence of hypertension and its long-term health impacts. Systemic barriers, including poverty and historically earned distrust in healthcare, hinder patient and clinician adherence to best practices for hypertension management. Community-based interventions, particularly those involving faith-based organizations, show promise in improving blood pressure control among AA/B adults. Methods The CIRCL-Chicago Implementation Research Center will test the effectiveness of a community-adapted hypertension control program, a “bundled” intervention developed by and tested in the Kaiser Permanente system, in South Side Chicago community health centers. A key partner for this trial, the Total Resource Community Development Organization, isa faith-based community outreach hub networked with faith-based organizations throughout Chicago’s South Side community. The study employs a type 3 hybrid effectiveness-implementation approach with a parallel cluster-randomized trial. Sixteen clinics will be randomized to implement a community-adapted Kaiser bundle with or without practice facilitation. We will recruit adults who live, work, or practice their faith in Chicago’s South Side community to populate a community-based hypertension registry (target n = 5,760 participants). The primary implementation outcome is the reach of the intervention, measured by the proportion of eligible patients in the registry who receive the adapted Kaiser bundle. Secondary outcomes include blood pressure control rates, assessed at 12 months post-enrollment. The study will use community-engaged adaptation, practice facilitation, and education and training strategies to support implementation. Discussion The CIRCL-Chicago study aims to address cardiovascular health disparities by integrating clinical and community-based approaches to hypertension management. By leveraging trusted community settings and engaging local partners, the study seeks to enhance the reach and effectiveness of evidence-based hypertension interventions. The findings could inform scalable models for hypertension control in diverse urban communities, potentially reducing health disparities for AA/B adults. Trial registration Clinicaltrials.gov NCT04755153 on 24 August 2023, https://www.centerwatch.com/clinical-trials/listings/NCT04755153/community-intervention-to-reduce-cardiovascular-disease-in-chicago

Transmission of HIV-1 via intercellular connections has been estimated as 100–1000 times more efficient than a cell-free process, perhaps in part explaining persistent viral spread in the presence of neutralizing antibodies 1 , 2 . Such effective intercellular transfer of HIV-1 could occur through virological synapses 3 , 4 , 5 or target-cell filopodia connected to infected cells 6 . Here we report that membrane nanotubes, formed when T cells make contact and subsequently part, provide a new route for HIV-1 transmission. Membrane nanotubes are known to connect various cell types, including neuronal and immune cells 7 , 8 , 9 , 10 , 11 , 12 , 13 , and allow calcium-mediated signals to spread between connected myeloid cells 9 . However, T-cell nanotubes are distinct from open-ended membranous tethers between other cell types 7 , 12 , as a dynamic junction persists within T-cell nanotubes or at their contact with cell bodies. We also report that an extracellular matrix scaffold allows T-cell nanotubes to adopt variably shaped contours. HIV-1 transfers to uninfected T cells through nanotubes in a receptor-dependent manner. These data lead us to propose that HIV-1 can spread using nanotubular connections formed by short-term intercellular unions in which T cells specialize.