Strategic vaccine stockpiles for regional epidemics of emerging viruses: A geospatial modeling framework.

Multinational epidemics of emerging infectious diseases are increasingly common, due to anthropogenic pressure on ecosystems and the growing connectivity of human populations. Early and efficient vaccination can contain outbreaks and prevent mass mortality, but optimal vaccine stockpiling strategies are dependent on pathogen characteristics, reservoir ecology, and epidemic dynamics. Here, we model major regional outbreaks of Nipah virus and Middle East respiratory syndrome, and use these to develop a generalized framework for estimating vaccine stockpile needs based on spillover geography, spatially-heterogeneous healthcare capacity and spatially-distributed human mobility networks. Because outbreak sizes were highly skewed, we found that most outbreaks were readily contained (median stockpile estimate for MERS-CoV: 2,089 doses; Nipah: 1,882 doses), but the maximum estimated stockpile need in a highly unlikely large outbreak scenario was 2-3 orders of magnitude higher (MERS-CoV: ∼87,000 doses; Nipah âˆ¼ 1.1 million doses). Sensitivity analysis revealed that stockpile needs were more dependent on basic epidemiological parameters (i.e., death and recovery rate) and healthcare availability than any uncertainty related to vaccine efficacy or deployment strategy. Our results highlight the value of descriptive epidemiology for real-world modeling applications, and suggest that stockpile allocation should consider ecological, epidemiological, and social dimensions of risk.

Respiratory disease contact patterns in the US are stable but heterogeneous.

Background: Contact plays a critical role in infectious disease transmission. Characterizing heterogeneity in contact patterns across individuals, time, and space is necessary to inform accurate estimates of transmission risk, particularly to explain superspreading, predict age differences in vulnerability, and inform social distancing policies. Current respiratory disease models often rely on data from the 2008 POLYMOD study conducted in Europe, which is now outdated and potentially unrepresentative of behavior in the US. We seek to understand the variation in contact patterns across spatial scales and demographic and social classifications, whether there is seasonality to contact patterns, and what social behavior looks like at baseline in the absence of an ongoing pandemic. Methods: We analyze spatiotemporal non-household contact patterns across 11 million survey responses from June 2020 - April 2021 post-stratified on age and gender to correct for sample representation. To characterize spatiotemporal heterogeneity in respiratory contact patterns at the county-week scale, we use generalized additive models. In the absence of pre-pandemic data on contact in the US, we also use a regression approach to produce baseline contact estimates to fill this gap. Findings: Although contact patterns varied over time during the pandemic, contact is relatively stable after controlling for disease. We find that the mean number of non-household contacts is spatially heterogeneous regardless of disease. There is additional heterogeneity across age, gender, race/ethnicity, and contact setting, with mean contact decreasing with age and lower in women. The contacts of white individuals and contacts at work or social events change the most under increased national incidence. Interpretation: We develop the first county-level estimates of non-pandemic contact rates for the US that can fill critical gaps in parameterizing disease models. Our results identify that spatiotemporal, demographic, and social heterogeneity in contact patterns is highly structured, informing the risk landscape of respiratory disease transmission in the US.

Revisiting resistant hypertension in kidney disease.

PURPOSE OF REVIEW: As compared to controlled or uncontrolled hypertension, resistant hypertension in patients with chronic kidney disease (CKD) poses a significantly increased healthcare burden due to greater target end-organ damage including cardiovascular disease and CKD progression. Patients with CKD have two to three times higher risk of developing resistant hypertension. True resistant hypertension needs to be distinguished from apparent treatment resistant hypertension (aTRH); however, it is usually not possible in epidemiological studies. Moreover, impact of contemporary guidelines changes in the target blood pressure (BP) goal to less than 130/80 mmHg remains to be determined. RECENT FINDINGS: Up to half of patients with CKD meet aTRH criteria using 2017 ACC/AHA target BP less than 130/80 mmHg. Excess sodium retention in extracellular and tissue compartment remains the cornerstone cause of resistance to the treatment in CKD. Maximizing and optimizing the diuretic regimen in addition to dietary sodium restriction plays a critical role in these patients. Management requires a trustworthy provider-patient relationship facilitating identification and intervention for the barriers restricting the uptake of lifestyle modifications and medications. Recently, renal denervation has been approved and many other novel agents are on the horizon for treatment of true resistant hypertension associated with CKD. SUMMARY: This review discusses the latest in the pathophysiology, definition, identification and treatment strategies of resistant hypertension in individuals with CKD. Further investigations are required to identify the prevalence, future implication and treatment outcome data for true resistant hypertension associated with CKD.

Congenital Dyserythropoietic Anemia Type II With Myelofibrosis in an Adult Patient: A Report of a Rare Case With a Brief Review.

Congenital dyserythropoietic anemias (CDAs) are rare hereditary disorders, of which type II CDA is the most common. Mutations in the SEC23B gene located on chromosome 20 result in this autosomal recessive disorder. In this case report, we present a case of CDA II with unique biopsy findings being detected via genetic testing. A female aged 30 years presented with major complaints of pallor weakness and easy fatiguability since childhood. The patient gave a history of 25 units of blood transfusion, the majority of which were transfused during pregnancy, followed by regular transfusions thereafter. On examination, all her vitals were in the normal range. Pallor, frontal bossing, and malocclusion of teeth were noted. Her laboratory workup showed the following: hemoglobin (Hb): 3.7 g/dl; mean corpuscular volume: 83 fl; mean corpuscular Hb: 29 g/dl; mean corpuscular Hb concentration: 34.9 g/dl; red cell distribution width: 30.4%; reticulocyte count (RC): 6.2%; corrected RC: 1.3%; lactate dehydrogenase: 441 IU/L; direct Coombs test/indirect Coombs test: negative; serum iron: 242 microgram/dl; transferrin saturation: 96.08%; ferritin: 1,880 ng/ml; and normal high-performance liquid chromatography and eosin-5'-maleimide binding test. The peripheral blood film showed normocytic normochromic anemia with anisopoikilocytosis in the form of a few spherocytes. No immature cells were seen. After obtaining the patient's consent, we performed a hereditary hemolytic anemia gene analysis test, which showed homozygous missense variation in exon 12 of the SEC23B gene. The bone marrow examination showed hyperplasia in the erythroid series with dyserythropoiesis, and surprisingly, myelofibrosis grade I-II (WHO 2017) was also observed on biopsy. Patients with CDA type II generally present with variable degrees of anemia along with pallor, icterus, splenomegaly, gallstones, and iron overload. In our case, the diagnosis of CDA type II was made at an adult age. Also, evidence of myelofibrosis was noted in our case, making it worth reporting. The use of a hereditary hemolytic anemia gene analysis panel test came as a rescue for its exact diagnosis. This case report emphasizes the role of molecular genetic testing for early and accurate diagnosis, which, in turn, could help in appropriate treatment planning and proper genetic counseling. The prevalence of CDA type II is still vaguely known; hence, extensive workup of persistent anemias and proper follow-up would be beneficial.

Finerenone cardiovascular and kidney outcomes by age and sex: FIDELITY post hoc analysis of two phase 3, multicentre, double-blind trials.

OBJECTIVES: This study aimed to evaluate the efficacy and safety of finerenone, a selective, non-steroidal mineralocorticoid receptor antagonist, on cardiovascular and kidney outcomes by age and/or sex. DESIGN: FIDELITY post hoc analysis; median follow-up of 3 years. SETTING: FIDELITY: a prespecified analysis of the FIDELIO-DKD and FIGARO-DKD trials. PARTICIPANTS: Adults with type 2 diabetes and chronic kidney disease receiving optimised renin-angiotensin system inhibitors (N=13 026). INTERVENTIONS: Randomised 1:1; finerenone or placebo. PRIMARY AND SECONDARY OUTCOME MEASURES: Cardiovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalisation for heart failure (HHF)) and kidney (kidney failure, sustained ≥57% estimated glomerular filtration rate (eGFR) decline or renal death) composite outcomes. RESULTS: Mean age was 64.8 years; 45.2%, 40.1% and 14.7% were aged <65, 65-74 and ≥75 years, respectively; 69.8% were male. Cardiovascular benefits of finerenone versus placebo were consistent across age (HR 0.94 (95% CI 0.81 to 1.10) (<65 years), HR 0.84 (95% CI 0.73 to 0.98) (65-74 years), HR 0.80 (95% CI 0.65 to 0.99) (≥75 years); Pinteraction=0.42) and sex categories (HR 0.86 (95% CI 0.77 to 0.96) (male), HR 0.89 (95% CI 0.35 to 2.27) (premenopausal female), HR 0.87 (95% CI 0.73 to 1.05) (postmenopausal female); Pinteraction=0.99). Effects on HHF reduction were not modified by age (Pinteraction=0.70) but appeared more pronounced in males (Pinteraction=0.02). Kidney events were reduced with finerenone versus placebo in age groups <65 and 65-74 but not ≥75; no heterogeneity in treatment effect was observed (Pinteraction=0.51). In sex subgroups, finerenone consistently reduced kidney events (Pinteraction=0.85). Finerenone reduced albuminuria and eGFR decline regardless of age and sex. Hyperkalaemia increased with finerenone, but discontinuation rates were <3% across subgroups. Gynaecomastia in males was uncommon across age subgroups and identical between treatment groups. CONCLUSIONS: Finerenone improved cardiovascular and kidney composite outcomes with no significant heterogeneity between age and sex subgroups; however, the effect on HHF appeared more pronounced in males. Finerenone demonstrated a similar safety profile across age and sex subgroups. TRIAL REGISTRATION NUMBERS: NCT02540993, NCT02545049.

The impact of spatial connectivity on NPIs effectiveness.

BACKGROUND: France implemented a combination of non-pharmaceutical interventions (NPIs) to manage the COVID-19 pandemic between September 2020 and June 2021. These included a lockdown in the fall 2020 - the second since the start of the pandemic - to counteract the second wave, followed by a long period of nighttime curfew, and by a third lockdown in the spring 2021 against the Alpha wave. Interventions have so far been evaluated in isolation, neglecting the spatial connectivity between regions through mobility that may impact NPI effectiveness. METHODS: Focusing on September 2020-June 2021, we developed a regionally-based epidemic metapopulation model informed by observed mobility fluxes from daily mobile phone data and fitted the model to regional hospital admissions. The model integrated data on vaccination and variants spread. Scenarios were designed to assess the impact of the Alpha variant, characterized by increased transmissibility and risk of hospitalization, of the vaccination campaign and alternative policy decisions. RESULTS: The spatial model better captured the heterogeneity observed in the regional dynamics, compared to models neglecting inter-regional mobility. The third lockdown was similarly effective to the second lockdown after discounting for immunity, Alpha, and seasonality (51% vs 52% median regional reduction in the reproductive number R0, respectively). The 6pm nighttime curfew with bars and restaurants closed, implemented in January 2021, substantially reduced COVID-19 transmission. It initially led to 49% median regional reduction of R0, decreasing to 43% reduction by March 2021. In absence of vaccination, implemented interventions would have been insufficient against the Alpha wave. Counterfactual scenarios proposing a sequence of lockdowns in a stop-and-go fashion would have reduced hospitalizations and restriction days for low enough thresholds triggering and lifting restrictions. CONCLUSIONS: Spatial connectivity induced by mobility impacted the effectiveness of interventions especially in regions with higher mobility rates. Early evening curfew with gastronomy sector closed allowed authorities to delay the third wave. Stop-and-go lockdowns could have substantially lowered both healthcare and societal burdens if implemented early enough, compared to the observed application of lockdown-curfew-lockdown, but likely at the expense of several labor sectors. These findings contribute to characterize the effectiveness of implemented strategies and improve pandemic preparedness.

Role of Diuretics in Cardiovascular Events and Mortality in Systolic Blood Pressure Intervention Trial: A Post Hoc Analysis.

BACKGROUND: In a post hoc analysis, we examined whether postrandomization diuretics use can explain and/or mediate the beneficial effects of intensive systolic BP lowering on cardiovascular disease and all-cause mortality in the Systolic Blood Pressure Intervention Trial (SPRINT). METHODS: SPRINT was a randomized, controlled trial of 9361 participants comparing the effects of intensive (systolic BP target <120 mm Hg) versus standard (systolic BP target <140 mm Hg) BP control on a primary composite cardiovascular end point in participants aged 50 years or older with systolic BP of 130-180 mm Hg. In time-varying multivariable Cox analyses, we assessed hazard ratios (HRs) of cardiovascular end points and all-cause mortality in participants on thiazide type, loop and/or potassium (K) sparing, or no diuretics. We also conducted mediation analysis to formally assess the role of diuretics in the effects of intensive systolic BP lowering. RESULTS: At baseline, diuretics were prescribed in 46% and 48% of participants in standard and intensive systolic BP-lowering groups, respectively, and in 46% and 74% in the corresponding groups during the trial. The lower risk of cardiovascular end points in the intensive group (HR, 0.75; 95% confidence interval [CI], 0.64 to 0.89) persisted after adjustment for postrandomization time-varying diuretics use (HR, 0.74; 95% CI, 0.62 to 0.89). Across the entire study population, time-varying diuretics use was not associated with cardiovascular end points (compared with no diuretics, HR for thiazide type, 0.89; 95% CI, 0.73 to 1.10, and loop/K sparing, 1.29; 95% CI, 0.97 to 1.73). However, thiazide-type diuretics were associated with lower risk of cardiovascular end points in the intensive (HR, 0.62; 95% CI, 0.46 to 0.85) but not in the standard (HR, 1.07; 95% CI, 0.82 to 1.39) group. In mediation analysis, HRs for total effect, direct effect (not mediated through diuretics use), and indirect effect (mediated through diuretics) of the intervention on cardiovascular end points were 0.66 (95% CI, 0.54 to 0.79), 0.67 (95% CI, 0.54 to 0.81), and 0.98 (95% CI, 0.88 to 1.10), respectively. The results were largely similar for all-cause mortality. CONCLUSIONS: The favorable effects of intensive systolic BP lowering on cardiovascular end points and all-cause mortality in SPRINT were independent of and not mediated by time-varying diuretics use. However, thiazide-type diuretics use associated with benefit if intensive systolic BP lowering was targeted.

Comparative approaches in social network ecology.

Social systems vary enormously across the animal kingdom, with important implications for ecological and evolutionary processes such as infectious disease dynamics, anti-predator defence, and the evolution of cooperation. Comparing social network structures between species offers a promising route to help disentangle the ecological and evolutionary processes that shape this diversity. Comparative analyses of networks like these are challenging and have been used relatively little in ecology, but are becoming increasingly feasible as the number of empirical datasets expands. Here, we provide an overview of multispecies comparative social network studies in ecology and evolution. We identify a range of advancements that these studies have made and key challenges that they face, and we use these to guide methodological and empirical suggestions for future research. Overall, we hope to motivate wider publication and analysis of open social network datasets in animal ecology.

Heart Failure With Preserved Ejection Fraction With CKD: A Narrative Review of a Multispecialty Disorder.

Heart failure with preserved ejection fraction (HFpEF) is a heterogenous syndrome with varying phenotypic expression. The phenotype chronic kidney disease (CKD) associated HFpEF is increasing in prevalence globally and is associated with increased morbidity and mortality compared to other HFpEF variants. These 2 conditions share common risk factors, including obesity, diabetes, and metabolic syndrome, as well as similar pathophysiology, including systemic inflammation, oxidative stress, elevated neurohormones, mineralocorticoid-receptor activation, and venous congestion. Given the coexistence of CKD and HFpEF, the diagnosis of HFpEF can be difficult. Moreover, treatment options for HFpEF have remained limited despite the success seen in its counterpart, heart failure with reduced ejection fraction. HFpEF encompasses complex multisystem pathophysiological perturbations beyond neurohormones, it is unlikely that a single agent can have significant benefit in this population. Recent data on sodium-glucose cotransporter 2 (SGLT2) inhibitors in HFpEF and CKD, and on glucagon-like peptide-1 (GLP-1) agonists and mineralocorticoid-receptor antagonists in metabolic syndrome, which target multiple pathways simultaneously, have led to promising therapeutics for HFpEF and CKD. In this perspective, our goal is to increase awareness of HFpEF as a multisystem disorder that shares the same disease processes seen in CKD and to emphasize that its management in individuals with CKD warrants a collective and multidisciplinary approach.

Contrast-Associated Acute Kidney Injury: Definitions, Epidemiology, Pathophysiology, and Implications.

Acute kidney injury (AKI) is a common occurrence after contrast media administration. Hemodynamic changes, direct tubular injury, and reactive oxygen species are the proposed mechanisms involved in AKI. However, in most scenarios, it is not possible to establish causality despite extensive clinical evaluation, therefore, contrast-associated AKI (CA-AKI) has become a widely accepted term to define AKI postcontrast. CA-AKI is associated with worse clinical outcomes including cardiovascular events and mortality; however, discussions are ongoing whether CA-AKI is a marker of an increased risk of adverse outcomes or a mediator of such outcomes.

Perplexity of Preoperative Multimodal Investigations in a Case of Parotid MALToma.

Mucosa-associated lymphoid tissue(MALT) lymphoma is a distinct subtype of lymphoma, presenting as a diffuse gland involvement or a discrete mass. Pre-operative diagnosis is a challenge as Fine Needle Aspiration Cytology is often inconclusive and presently no radiological investigation is confirmatory, therefore final diagnosis is made after surgical resection and immunohistopathology. We report a case of MALT lymphoma, which clinically presented as a unilateral large diffuse swelling of the parotid gland with a diagnostic dilemma eventually underwent total parotidectomy to be finally diagnosed as MALT lymphoma of parotid gland and received field radiotherapy with complete cure and no recurrence in a 2-year follow-up.

Charting the spatial dynamics of early SARS-CoV-2 transmission in Washington state.

The spread of SARS-CoV-2 has been geographically uneven. To understand the drivers of this spatial variation in SARS-CoV-2 transmission, in particular the role of stochasticity, we used the early stages of the SARS-CoV-2 invasion in Washington state as a case study. We analysed spatially-resolved COVID-19 epidemiological data using two distinct statistical analyses. The first analysis involved using hierarchical clustering on the matrix of correlations between county-level case report time series to identify geographical patterns in the spread of SARS-CoV-2 across the state. In the second analysis, we used a stochastic transmission model to perform likelihood-based inference on hospitalised cases from five counties in the Puget Sound region. Our clustering analysis identifies five distinct clusters and clear spatial patterning. Four of the clusters correspond to different geographical regions, with the final cluster spanning the state. Our inferential analysis suggests that a high degree of connectivity across the region is necessary for the model to explain the rapid inter-county spread observed early in the pandemic. In addition, our approach allows us to quantify the impact of stochastic events in determining the subsequent epidemic. We find that atypically rapid transmission during January and February 2020 is necessary to explain the observed epidemic trajectories in King and Snohomish counties, demonstrating a persisting impact of stochastic events. Our results highlight the limited utility of epidemiological measures calculated over broad spatial scales. Furthermore, our results make clear the challenges with predicting epidemic spread within spatially extensive metropolitan areas, and indicate the need for high-resolution mobility and epidemiological data.

Estimating county-level flu vaccination in the United States.

In the United States, influenza vaccines are an important part of public health efforts to blunt the effects of seasonal influenza epidemics. This in turn emphasizes the importance of understanding the spatial distribution of influenza vaccination coverage. Despite this, high quality data at a fine spatial scale and spanning a multitude of recent flu seasons are not readily available. To address this gap, we develop county-level counts of vaccination across five recent, consecutive flu seasons and fit a series of regression models to these data that account for bias. We find that the spatial distribution of our bias-corrected vaccination coverage estimates is generally consistent from season to season, with the highest coverage in the Northeast and Midwest but is spatially heterogeneous within states. We also observe a negative relationship between a county's vaccination coverage and social vulnerability. Our findings stress the importance of quantifying flu vaccination coverage at a fine spatial scale, as relying on state or region-level estimates misses key heterogeneities.

Disentangling the rhythms of human activity in the built environment for airborne transmission risk: An analysis of large-scale mobility data.

Background: Since the outset of the COVID-19 pandemic, substantial public attention has focused on the role of seasonality in impacting transmission. Misconceptions have relied on seasonal mediation of respiratory diseases driven solely by environmental variables. However, seasonality is expected to be driven by host social behavior, particularly in highly susceptible populations. A key gap in understanding the role of social behavior in respiratory disease seasonality is our incomplete understanding of the seasonality of indoor human activity. Methods: We leverage a novel data stream on human mobility to characterize activity in indoor versus outdoor environments in the United States. We use an observational mobile app-based location dataset encompassing over 5 million locations nationally. We classify locations as primarily indoor (e.g. stores, offices) or outdoor (e.g. playgrounds, farmers markets), disentangling location-specific visits into indoor and outdoor, to arrive at a fine-scale measure of indoor to outdoor human activity across time and space. Results: We find the proportion of indoor to outdoor activity during a baseline year is seasonal, peaking in winter months. The measure displays a latitudinal gradient with stronger seasonality at northern latitudes and an additional summer peak in southern latitudes. We statistically fit this baseline indoor-outdoor activity measure to inform the incorporation of this complex empirical pattern into infectious disease dynamic models. However, we find that the disruption of the COVID-19 pandemic caused these patterns to shift significantly from baseline and the empirical patterns are necessary to predict spatiotemporal heterogeneity in disease dynamics. Conclusions: Our work empirically characterizes, for the first time, the seasonality of human social behavior at a large scale with a high spatiotemporal resolutio and provides a parsimonious parameterization of seasonal behavior that can be included in infectious disease dynamics models. We provide critical evidence and methods necessary to inform the public health of seasonal and pandemic respiratory pathogens and improve our understanding of the relationship between the physical environment and infection risk in the context of global change. Funding: Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R01GM123007.