The genomic evolutionary dynamics and global circulation patterns of respiratory syncytial virus.

Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infection in young children and the second leading cause of infant death worldwide. While global circulation has been extensively studied for respiratory viruses such as seasonal influenza, and more recently also in great detail for SARS-CoV-2, a lack of global multi-annual sampling of complete RSV genomes limits our understanding of RSV molecular epidemiology. Here, we capitalise on the genomic surveillance by the INFORM-RSV study and apply phylodynamic approaches to uncover how selection and neutral epidemiological processes shape RSV diversity. Using complete viral genome sequences, we show similar patterns of site-specific diversifying selection among RSVA and RSVB and recover the imprint of non-neutral epidemic processes on their genealogies. Using a phylogeographic approach, we provide evidence for air travel governing the global patterns of RSVA and RSVB spread, which results in a considerable degree of phylogenetic mixing across countries. Our findings highlight the potential of systematic global RSV genomic surveillance for transforming our understanding of global RSV spread.

Exploring factors shaping antibiotic resistance patterns in Streptococcus pneumoniae during the 2020 COVID-19 pandemic.

Non-pharmaceutical interventions implemented to block SARS-CoV-2 transmission in early 2020 led to global reductions in the incidence of invasive pneumococcal disease (IPD). By contrast, most European countries reported an increase in antibiotic resistance among invasive Streptococcus pneumoniae isolates from 2019 to 2020, while an increasing number of studies reported stable pneumococcal carriage prevalence over the same period. To disentangle the impacts of the COVID-19 pandemic on pneumococcal epidemiology in the community setting, we propose a mathematical model formalizing simultaneous transmission of SARS-CoV-2 and antibiotic-sensitive and -resistant strains of S. pneumoniae. To test hypotheses underlying these trends five mechanisms were built into the model and examined: (1) a population-wide reduction of antibiotic prescriptions in the community, (2) lockdown effect on pneumococcal transmission, (3) a reduced risk of developing an IPD due to the absence of common respiratory viruses, (4) community azithromycin use in COVID-19 infected individuals, (5) and a longer carriage duration of antibiotic-resistant pneumococcal strains. Among 31 possible pandemic scenarios involving mechanisms individually or in combination, model simulations surprisingly identified only two scenarios that reproduced the reported trends in the general population. They included factors (1), (3), and (4). These scenarios replicated a nearly 50% reduction in annual IPD, and an increase in antibiotic resistance from 20% to 22%, all while maintaining a relatively stable pneumococcal carriage. Exploring further, higher SARS-CoV-2 R0 values and synergistic within-host virus-bacteria interaction mechanisms could have additionally contributed to the observed antibiotic resistance increase. Our work demonstrates the utility of the mathematical modeling approach in unraveling the complex effects of the COVID-19 pandemic responses on AMR dynamics.

The social contexts of behaviors and relationships: The relation of classroom and cyber victimization to number of classroom and cyber friends.

Behaviors and relationships exist within a variety of social contexts. More specifically for the current research, victimization and friendships occur in classrooms and, increasingly, in online virtual contexts. The current research examined how the number of classroom friends and number of cyber friends related to the extent of classroom victimization and extent of cyber victimization. Research has demonstrated the importance of face-to-face friendships in relation to being a victim; much less is known about the role of cyber friends in relation to being a cyber victim or how these relationships may play a role in cross-context victimization. Participants were 350 children from Grades 3 through 5 (188 girls and 162 boys). Children indicated classroom friends on a classroom roster, reported the number of their cyber friends, and indicated the extent of their cyber victimization. Peers nominated classmates for classroom victimization behaviors. A path analysis revealed that number of classroom friends was negatively associated with both extent of classroom victimization and extent of cyber victimization. Number of cyber friends was positively associated with extent of cyber victimization and was negatively related to extent of classroom victimization. Discussion of results includes the construction, use, and adaptation of social skills within and between social contexts.

GAD65Abs Are Not Associated With Beta-Cell Dysfunction in Patients With T2D in the GRADE Study.

Context: Autoantibodies directed against the 65-kilodalton isoform of glutamic acid decarboxylase (GAD65Abs) are markers of autoimmune type 1 diabetes (T1D) but are also present in patients with Latent Autoimmune Diabetes of Adults and autoimmune neuromuscular diseases, and also in healthy individuals. Phenotypic differences between these conditions are reflected in epitope-specific GAD65Abs and anti-idiotypic antibodies (anti-Id) against GAD65Abs. We previously reported that 7.8% of T2D patients in the GRADE study have GAD65Abs but found that GAD65Ab positivity was not correlated with beta-cell function, glycated hemoglobin (HbA1c), or fasting glucose levels. Context: In this study, we aimed to better characterize islet autoantibodies in this T2D cohort. This is an ancillary study to NCT01794143. Methods: We stringently defined GAD65Ab positivity with a competition assay, analyzed GAD65Ab-specific epitopes, and measured GAD65Ab-specific anti-Id in serum. Results: Competition assays confirmed that 5.9% of the patients were GAD65Ab positive, but beta-cell function was not associated with GAD65Ab positivity, GAD65Ab epitope specificity or GAD65Ab-specific anti-Id. GAD65-related autoantibody responses in GRADE T2D patients resemble profiles in healthy individuals (low GAD65Ab titers, presence of a single autoantibody, lack of a distinct epitope pattern, and presence of anti-Id to diabetes-associated GAD65Ab). In this T2D cohort, GAD65Ab positivity is likely unrelated to the pathogenesis of beta-cell dysfunction. Conclusion: Evidence for islet autoimmunity in the pathophysiology of T2D beta-cell dysfunction is growing, but T1D-associated autoantibodies may not accurately reflect the nature of their autoimmune process.

Shared Decision-Making and Patient Communication in Nephrology Practice.

Shared decision-making (SDM) is the standard of care for patient or surrogates and their clinicians to arrive at a medical decision. Evidence suggests that SDM increases patients' understanding of their illness and satisfaction with their decision-making process. Dialysis patients often report the perception that they were passive participants in the decision to start dialysis, suggesting further opportunities for enhancing the application of SDM in decision-making with patients with kidney disease. The hallmark feature of SDM is sensitive, culturally- and equity-informed communication and effective partnership between patient or surrogate and clinician. In the process, the patient's personal expertise in the realm of their values and priorities is elicited, and the clinician's medical expertise is shared. The integration of this shared expertise then leads to an informed treatment decision. Frameworks such as the Serious Illness Conversation Guide and REMAP are guides for the SDM process, and communication tools and mnemonics can help facilitate SDM conversations. This paper will address SDM in nephrology practice, reviewing underlying supportive evidence, context, and timing for employing SDM in the trajectory of chronic kidney disease and acute kidney injury, special considerations in vulnerable populations to promote health equity, and communication tools and frameworks to facilitate the SDM process. By learning and applying these frameworks and tools, nephrology providers will be able to employ SDM in the management of kidney disease.

Estimating Glycemia From HbA1c and CGM: Analysis of Accuracy and Sources of Discrepancy.

OBJECTIVE: To examine the accuracy of different periods of continuous glucose monitoring (CGM), hemoglobin A1c (HbA1c), and their combination for estimating mean glycemia over 90 days (AG90). RESEARCH DESIGN AND METHODS: We retrospectively studied 985 CGM periods of 90 days with <10% missing data from 315 adults (86% of whom had type 1 diabetes) with paired HbA1c measurements. The impact of mean red blood cell age as a proxy for nonglycemic effects on HbA1c was estimated using published theoretical models and in comparison with empirical data. Given the lack of a gold standard measurement for AG90, we applied correction methods to generate a reference (eAG90) that we used to assess accuracy for HbA1c and CGM. RESULTS: Using 14 days of CGM at the end of the 90-day period resulted in a mean absolute error (95th percentile) of 14 (34) mg/dL when compared with eAG90. Nonglycemic effects on HbA1c led to a mean absolute error for average glucose calculated from HbA1c of 12 (29) mg/dL. Combining 14 days of CGM with HbA1c reduced the error to 10 (26) mg/dL. Mismatches between CGM and HbA1c >40 mg/dL occurred more than 5% of the time. CONCLUSIONS: The accuracy of estimates of eAG90 from limited periods of CGM can be improved by averaging with an HbA1c-based estimate or extending the monitoring period beyond ∼26 days. Large mismatches between eAG90 estimated from CGM and HbA1c are not unusual and may persist due to stable nonglycemic factors.

Antigen-specific age-related memory CD8 T cells induce and track Alzheimer's-like neurodegeneration.

Cerebral (Aß) plaque and (pTau) tangle deposition are hallmarks of Alzheimer's disease (AD), yet are insufficient to confer complete AD-like neurodegeneration experimentally. Factors acting upstream of Aß/pTau in AD remain unknown, but their identification could enable earlier diagnosis and more effective treatments. T cell abnormalities are emerging AD hallmarks, and CD8 T cells were recently found to mediate neurodegeneration downstream of tangle deposition in hereditary neurodegeneration models. The precise impact of T cells downstream of Aß/fibrillar pTau, however, appears to vary depending on the animal model used. Our prior work suggested that antigen-specific memory CD8 T (" hi T") cells act upstream of Aß/pTau after brain injury. Here we examine whether hi T cells influence sporadic AD-like pathophysiology upstream of Aß/pTau. Examining neuropathology, gene expression, and behavior in our hi T mouse model we show that CD8 T cells induce plaque and tangle-like deposition, modulate AD-related genes, and ultimately result in progressive neurodegeneration with both gross and fine features of sporadic human AD. T cells required Perforin to initiate this pathophysiology, and IFNγ for most gene expression changes and progression to more widespread neurodegenerative disease. Analogous antigen-specific memory CD8 T cells were significantly elevated in the brains of human AD patients, and their loss from blood corresponded to sporadic AD and related cognitive decline better than plasma pTau-217, a promising AD biomarker candidate. Our work is the first to identify an age-related factor acting upstream of Aß/pTau to initiate AD-like pathophysiology, the mechanisms promoting its pathogenicity, and its relevance to human sporadic AD. Significance Statement: This study changes our view of Alzheimer's Disease (AD) initiation and progression. Mutations promoting cerebral beta-amyloid (Aß) deposition guarantee rare genetic forms of AD. Thus, the prevailing hypothesis has been that Aß is central to initiation and progression of all AD, despite contrary animal and patient evidence. We show that age-related T cells generate neurodegeneration with compelling features of AD in mice, with distinct T cell functions required for pathological initiation and neurodegenerative progression. Knowledge from these mice was applied to successfully predict previously unknown features of human AD and generate novel tools for its clinical management.

Longitudinal Effects of Glucose-Lowering Medications on ß-Cell Responses and Insulin Sensitivity in Type 2 Diabetes: The GRADE Randomized Clinical Trial.

OBJECTIVE: To compare the long-term effects of glucose-lowering medications (insulin glargine U-100, glimepiride, liraglutide, and sitagliptin) when added to metformin on insulin sensitivity and ß-cell function. RESEARCH DESIGN AND METHODS: In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) cohort with type 2 diabetes (n = 4,801), HOMA2 was used to estimate insulin sensitivity (HOMA2-%S) and fasting ß-cell function (HOMA2-%B) at baseline and 1, 3, and 5 years on treatment. Oral glucose tolerance test ß-cell responses (C-peptide index [CPI] and total C-peptide response [incremental C-peptide/incremental glucose over 120 min]) were evaluated at the same time points. These responses adjusted for HOMA2-%S in regression analysis provided estimates of ß-cell function. RESULTS: HOMA2-%S increased from baseline to year 1 with glargine and remained stable thereafter, while it did not change from baseline in the other treatment groups. HOMA2-%B and C-peptide responses were increased to variable degrees at year 1 in all groups but then declined progressively over time. At year 5, CPI was similar between liraglutide and sitagliptin, and higher for both than for glargine and glimepiride [0.80, 0.87, 0.74, and 0.64 (nmol/L)/(mg/dL) * 100, respectively; P < 0.001], while the total C-peptide response was greatest with liraglutide, followed in descending order by sitagliptin, glargine, and glimepiride [1.54, 1.25, 1.02, and 0.87 (nmol/L)/(mg/dL) * 100, respectively, P < 0.001]. After adjustment for HOMA2-%S to obtain an estimate of ß-cell function, the nature of the change in ß-cell responses reflected those in ß-cell function. CONCLUSIONS: The differential long-term effects on insulin sensitivity and ß-cell function of four different glucose-lowering medications when added to metformin highlight the importance of the loss of ß-cell function in the progression of type 2 diabetes.

Use of Rapid Antigen Triple Test Nasal Swabs (COVID-VIRO ALL-IN TRIPLEX: Severe Acute Respiratory Syndrome Coronavirus 2, Respiratory Syncytial Virus, and Influenza) in Children With Respiratory Symptoms: A Real-life Prospective Study.

Background: In autumn 2022, the epidemics due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respiratory syncytial virus (RSV), and influenza overlapped, and these diseases can present with the same symptomatology. The use of a triple antigen test (SARS-CoV-2 + influenza A/B + RSV) seems crucial for accurate viral diagnosis in the context of implementing long-acting monoclonal antibody vaccination against RSV in the upcoming RSV season. Methods: We assessed the usefulness of the triple test in real life in this prospective study performed from October 2022 to May 2023 and involving 116 pediatricians (2 emergency department pediatricians and 114 ambulatory pediatricians). Children <15 years old with flu-like illness (with fever), bronchiolitis (dyspnea ± wheezing), otitis, and croup were enrolled and sampled with a nasal triple test. Results: For 8329 children with flu-like illness (65.3%), bronchiolitis (17.9%), otitis (8.8%), and croup (6.3%), the use of the triple test led to a viral diagnosis in 47.9% of cases. The highest RSV positivity occurred in children with bronchiolitis (32.9%). The highest influenza A and B positivity (24.6% and 19.6%) occurred in children with flu-like illness. A succession of 3 epidemics (RSV and influenza A and B) occurred over time with several overlap periods. Conclusions: The triple test allowed for a viral diagnosis in half of our cases. The upcoming introduction of RSV prevention will emphasize the need for active surveillance with viral results both in ambulatory settings and hospitals. Clinical Trials Registration. NCT0441231.

A Short-Term Longitudinal Examination of the Relation of Forms of Antipathy Relationships to Children's Loneliness, Peer Optimism, and Peer Sociability Behaviors.

Researchers have focused on children's friendship relationships more than antipathy (disliking) relationships. The present one-year longitudinal research examined the relation of different forms of antipathy nominations (Mutual, Unilateral Given, Unilateral Received) to children's social competence (self-reports of loneliness and peer optimism, classroom peer nominations for sociability behaviors) for 121 third and fourth graders (fourth and fifth graders in Year 2). From path analyses, the pattern between forms of antipathy relationships to the measures of social competence was identical for concurrent findings at Time 1 and between forms of antipathy relationships and the measures of social competence one year later. Higher numbers of Mutual Antipathies and higher numbers of Unilateral Received Antipathies were related to greater loneliness and fewer peer nominations for sociability behaviors. In addition, higher numbers of Unilateral Received Antipathies were related to less peer optimism. Interestingly, numbers of Unilateral Given Antipathies were not significantly related to any of the social competence measures at Time 1 or one year later. These findings suggest that dislike relationships, whether mutual or unilateral received, may have important negative associations for children's concurrent and later social competence.

Progressive Massive Fibrosis Identified at Federally Funded Black Lung Clinics in the US.

This study of US Black Lung Clinics (established to treat coal miners) reports the prevalence of progressive massive fibrosis identified through June 2023.

Primary care diabetes assessment when HbA1c and other measures of glycemia disagree.

AIMS: Although diabetes management decisions in primary care are typically based largely on HbA1c, mismatches between HbA1c and other measures of glycemia that are increasingly more available present challenges to optimal management. This study aimed to assess a systematic approach to identify the frequency of mismatches of potential clinical significance amongst various measures of glycemia in a primary care setting. METHODS: Following screening to exclude conditions known to affect HbA1c interpretation, HbA1c, and fructosamine were obtained and repeated after ∼90 days on 53 adults with prediabetes or type 2 diabetes. A subset of 13 participants with repeat labs wore continuous glucose monitoring (CGM) for 10 days. RESULTS: As expected, HbA1c and fructosamine only modestly correlated (initial R2 = 0.768/repeat R2 = 0.655). The HbA1c/fructosamine mismatch frequency of ± 0.5% (using the following regression HbA1c = 0.015 *fructosamine + 2.994 calculated from the initial sample) was 27.0%. Of the 13 participants with CGM data, HbA1c and CGM-based Glucose Management Indicator correlated at R2 = 0.786 with a mismatch frequency of ± 0.5% at 46.2% compared to a HbA1c/fructosamine mismatch frequency of ± 0.5% at 30.8%. CONCLUSIONS: HbA1c is frequently mismatched with fructosamine and CGM data. As each of the measures has strengths and weaknesses, the utilization of multiple different measures of glycemia may be informative for diabetes assessment in the clinical setting.

Association of Baseline Factors With Glycemic Outcomes in GRADE: A Comparative Effectiveness Randomized Clinical Trial.

OBJECTIVE: To describe the individual and joint associations of baseline factors with glycemia, and also with differential effectiveness of medications added to metformin. RESEARCH DESIGN AND METHODS: Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) participants (with type 2 diabetes diagnosed for <10 years, on metformin, and with HbA1c 6.8-8.5%; N = 5,047) were randomly assigned to a basal insulin (glargine), sulfonylurea (glimepiride), glucagon-like peptide 1 agonist (liraglutide), or dipeptidyl peptidase 4 inhibitor (sitagliptin). The glycemic outcome was HbA1c ≥7.0%, subsequently confirmed. Univariate and multivariate regression and classification and regression tree (CART) analyses were used to assess the association of baseline factors with the glycemic outcome at years 1 and 4. RESULTS: In univariate analyses at baseline, younger age (<58 years), Hispanic ethnicity, higher HbA1c, fasting glucose, and triglyceride levels, lower insulin secretion, and relatively greater insulin resistance were associated with the glycemic outcome at years 1 and/or 4. No factors were associated with differential effectiveness of the medications by year 4. In multivariate analyses, treatment group, younger age, and higher baseline HbA1c and fasting glucose were jointly associated with the glycemic outcome by year 4. The superiority of glargine and liraglutide at year 4 persisted after multiple baseline factors were controlled for. CART analyses indicated that failure to maintain HbA1c <7% by year 4 was more likely for younger participants and those with baseline HbA1c ≥7.4%. CONCLUSIONS: Several baseline factors were associated with the glycemic outcome but not with differential effectiveness of the four medications. Failure to maintain HbA1c <7% was largely driven by younger age and higher HbA1c at baseline. Factors that predict earlier glycemic deterioration could help in targeting patients for more aggressive management.