Most COVID-19 vaccines require two doses, however with limited vaccine supply, policymakers are considering single-dose vaccination as an alternative strategy. Using a mathematical model combined ...with optimization algorithms, we determined optimal allocation strategies with one and two doses of vaccine under various degrees of viral transmission. Under low transmission, we show that the optimal allocation of vaccine vitally depends on the single-dose efficacy. With high single-dose efficacy, single-dose vaccination is optimal, preventing up to 22% more deaths than a strategy prioritizing two-dose vaccination for older adults. With low or moderate single-dose efficacy, mixed vaccination campaigns with complete coverage of older adults are optimal. However, with modest or high transmission, vaccinating older adults first with two doses is best, preventing up to 41% more deaths than a single-dose vaccination given across all adult populations. Our work suggests that it is imperative to determine the efficacy and durability of single-dose vaccines, as mixed or single-dose vaccination campaigns may have the potential to contain the pandemic much more quickly.
Trial results for two COVID-19 vaccines suggest at least 90% efficacy against symptomatic disease (VE
). It remains unknown whether this efficacy is mediated by lowering SARS-CoV-2 infection ...susceptibility (VE
) or development of symptoms after infection (VE
). We aim to assess and compare the population impact of vaccines with different efficacy profiles (VE
and VE
) satisfying licensure criteria. We developed a mathematical model of SARS-CoV-2 transmission, calibrated to data from King County, Washington. Rollout scenarios starting December 2020 were simulated with combinations of VE
and VE
resulting in up to 100% VE
. We assumed no reduction of infectivity upon infection conditional on presence of symptoms. Proportions of cumulative infections, hospitalizations and deaths prevented over 1 year from vaccination start are reported. Rollouts of 1 M vaccinations (5000 daily) using vaccines with 50% VE
are projected to prevent 23-46% of infections and 31-46% of deaths over 1 year. In comparison, vaccines with 90% VE
are projected to prevent 37-64% of infections and 46-64% of deaths over 1 year. In both cases, there is a greater reduction if VE
is mediated mostly by VE
. The use of a "symptom reducing" vaccine will require twice as many people vaccinated than a "susceptibility reducing" vaccine with the same 90% VE
to prevent 50% of the infections and death over 1 year. Delaying the start of the vaccination by 3 months decreases the expected population impact by more than 50%. Vaccines which prevent COVID-19 disease but not SARS-CoV-2 infection, and thereby shift symptomatic infections to asymptomatic infections, will prevent fewer infections and require larger and faster vaccination rollouts to have population impact, compared to vaccines that reduce susceptibility to infection. If uncontrolled transmission across the U.S. continues, then expected vaccination in Spring 2021 will provide only limited benefit.
Basin‐scale distributions of light absorption by chromophoric dissolved organic matter (CDOM) are positively correlated (R2 > 0.8) with apparent oxygen utilization (AOU) within the top kilometer of ...the Pacific and Indian Oceans. However, a much weaker correspondence is found for the Atlantic (R2 < 0.05). Strong correlation between CDOM and AOU indicates that CDOM is created as a byproduct of the oxidation of organic matter from sinking particles. The observed meridional‐depth sections of CDOM result from a balance between biogeochemical processes (autochthonous production and solar bleaching) and the meridional overturning circulation. Rapid mixing in the Atlantic dilutes CDOM in the interior and implies that the time scale for CDOM accumulation is greater than ∼50 years. CDOM emerges as a unique tracer for diagnosing changes in biogeochemistry and the overturning circulation, similar to dissolved oxygen, with the additional feature that it can be quantified from satellite observation.
Background
Treatment of hepatocellular carcinoma (HCC) in the setting of cirrhosis is limited by tumor size/location and underlying liver disease. Radiofrequency ablation is utilized in selected ...patients; however, local recurrence remains a concern. Microwave ablation (MWA) delivers energy to tissue in a unique fashion, reducing local recurrence. A minimally invasive operative approach allows for mobilization/protection of adjacent structures, intra-operative ultrasound, and assessment of ablation progress.
Study Design
Retrospective review of operative MWA performed for HCC in patients with cirrhosis over a 4-year period at a single center. Complications were stratified by Clavien–Dindo classification. Incomplete ablation and local, regional, and metastatic recurrence was assessed on follow-up imaging. Survival was assessed in months.
Results
Fifty-four patients with 73 tumors underwent MWA. Median tumor size was 2.6 cm (range 0.5–8.5 cm). Cirrhosis was present in 92.6 % of patients, with a Child–Pugh score of B/C in 27.8 % and hepatitis C present in 59.3 %. A minimally invasive approach was used in 94.5 % of patients. There were no deaths within 30 days. Thirty-day morbidity was 28.9 %, with grade III complications present in 11.5 %. Delayed complications occurred in 7.8 % of patients, with a 5.6 % 90-day mortality. Incomplete ablation was identified in 5.9 % of tumors with local recurrence of 2.9 % at 9 months median follow-up. Regional and metastatic recurrence occurred in 27.5 and 11.8 % at 9 months median follow-up. Median survival was not reached at 11 months median follow-up. One- and 2-year survival was 72.3 and 58.8 %.
Conclusion
Operative, preferably minimally invasive, MWA can be performed in cirrhotic patients with HCC with acceptable morbidity and low recurrence rates. High regional and metastatic recurrence rates in these patients underscore the need for minimally invasive, low morbidity approaches to liver-directed therapy.
The ongoing Antibody Mediated Prevention (AMP) trials will uncover whether passive infusion of the broadly neutralizing antibody (bNAb) VRC01 can protect against HIV acquisition. Previous statistical ...simulations indicate these trials may be partially protective. In that case, it will be crucial to identify the mechanism of breakthrough infections. To that end, we developed a mathematical modeling framework to simulate the AMP trials and infer the breakthrough mechanisms using measurable trial outcomes. This framework combines viral dynamics with antibody pharmacokinetics and pharmacodynamics, and will be generally applicable to forthcoming bNAb prevention trials. We fit our model to human viral load data (RV217). Then, we incorporated VRC01 neutralization using serum pharmacokinetics (HVTN 104) and in vitro pharmacodynamics (LANL CATNAP database). We systematically explored trial outcomes by reducing in vivo potency and varying the distribution of sensitivity to VRC01 in circulating strains. We found trial outcomes could be used in a clinical trial regression model (CTRM) to reveal whether partially protective trials were caused by large fractions of VRC01-resistant (IC50>50 μg/mL) circulating strains or rather a global reduction in VRC01 potency against all strains. The former mechanism suggests the need to enhance neutralizing antibody breadth; the latter suggests the need to enhance VRC01 delivery and/or in vivo binding. We will apply the clinical trial regression model to data from the completed trials to help optimize future approaches for passive delivery of anti-HIV neutralizing antibodies.
Summary
Herpes simplex virus‐2 infection is characterized by frequent episodic shedding in the genital tract. Expansion in HSV‐2 viral load early during episodes is extremely rapid. However, the ...virus invariably peaks within 18 hours and is eliminated nearly as quickly. A critical feature of HSV‐2 shedding episodes is their heterogeneity. Some episodes peak at 108 HSV DNA copies, last for weeks due to frequent viral re‐expansion, and lead to painful ulcers, while others only reach 103 HSV DNA copies and are eliminated within hours and without symptoms. Within single micro‐environments of infection, tissue‐resident CD8+ T cells (TRM) appear to contain infection within a few days. Here, we review components of TRM biology relevant to immune surveillance between HSV‐2 shedding episodes and containment of infection upon detection of HSV‐2 cognate antigen. We then describe the use of mathematical models to correlate large spatial gradients in TRM density with the heterogeneity of observed shedding within a single person. We describe how models have been leveraged for clinical trial simulation, as well as future plans to model the interactions of multiple cellular subtypes within mucosa, predict the mechanism of action of therapeutic vaccines, and describe the dynamics of 3‐dimensional infection environment during the natural evolution of an HSV‐2 lesion.
A signature feature of HIV infection is poor control of herpes virus infections, which reactivate from latency and cause opportunistic infections. While the general mechanism underlying this ...observation is deficient CD4+T-cell function, it is unknown whether increased severity of herpes virus infections is due primarily to poor immune control in latent or lytic sites of infection, or whether CD4+ immunodeficiency leads to more critical downstream deficits in humoral or cell-mediated immunologic responses. Here we compare genital shedding patterns of herpes simplex virus-2 (HSV-2) in 98 HIV infected and 98 HIV uninfected men matched on length of infection, HSV-1 serostatus and nationality. We demonstrate that high copy HSV-2 shedding is more frequent in HIV positive men, particularly in participants with CD4+ T-cell count <200/μL. Genital shedding is more frequent due to higher rate of shedding episodes, as well as a higher proportion of prolonged shedding episodes. Peak episode viral load was not found to differ between HIV infected and uninfected participants regardless of CD4+ T-cell count. We simulate a mathematical model which recapitulates these findings and identifies that rate of HSV-2 release from neural tissue increases, duration of mucosal cytolytic immune protection decreases, and cell-free viral lifespan increases in HIV infected participants. These results suggest that increased HSV-2 shedding in HIV infected persons may be caused by impaired immune function in both latent and lytic tissue compartments, with deficits in clearance of HSV-2 infected cells and extracellular virus.
In many forested ecosystems, the architecture and functional ecology of certain tree species define forest structure and their species-specific traits control ecosystem dynamics. Such foundation tree ...species are declining throughout the world due to introductions and outbreaks of pests and pathogens, selective removal of individual taxa, and over-harvesting. Through a series of case studies, we show that the loss of foundation tree species changes the local environment on which a variety of other species depend; how this disrupts fundamental ecosystem processes, including rates of decomposition, nutrient fluxes, carbon sequestration, and energy flow; and dramatically alters the dynamics of associated aquatic ecosystems. Forests in which dynamics are controlled by one or a few foundation species appear to be dominated by a small number of strong interactions and may be highly susceptible to alternating between stable states following even small perturbations. The ongoing decline of many foundation species provides a set of important, albeit unfortunate, opportunities to develop the research tools, models, and metrics needed to identify foundation species, anticipate the cascade of immediate, short- and long-term changes in ecosystem structure and function that will follow from their loss, and provide options for remedial conservation and management.
OBJECTIVE:This study hypothesized that tumor size, number of tumors, surgical approach, and tumor histology significantly affected microwave ablation (MWA) success and recurrence-free survival.
...BACKGROUND:Although many hepatobiliary centers have adopted MWA, the factors that influence local control are not well described.
METHODS:Consecutive patients with hepatic malignancy treated by MWA were included from 4 high-volume institutions (2003–2011) and grouped by histologyhepatocellular carcinoma (HCC), colorectal liver metastases, neuroendocrine liver metastases, and other cancers. Independent significance of outcome variables was established with logistic regression and Cox proportional hazards models.
RESULTS:Four hundred fifty patients were treated with 473 procedures (139 HCC, 198 colorectal liver metastases, 61 neuroendocrine liver metastases, and 75 other) for a total of 875 tumors. Median follow-up was 18 months. Concurrent hepatectomy was performed in 178 patients (38%), and when performed was associated with greater morbidity. Complete ablation was confirmed for 839 of 865 tumors (97.0%) on follow-up cross-sectional imaging (10 were unevaluable). A surgical approach (open, laparoscopic, or percutaneous) had no significant impact on complication rates, recurrence, or survival. The local recurrence rate was 6.0% overall and was highest for HCC (10.1%, P = 0.045) and percutaneously treated lesions (14.1%, P = 0.014). In adjusted models, tumor size 3 cm or more predicted poorer recurrence-free survival (hazard ratio1.60, 95% CI1.02–2.50, P = 0.039).
CONCLUSIONS:In this large data set, patients with 3 cm or more tumors showed a propensity for early recurrence, regardless of histology. Higher rates of local recurrence were noted in HCC patients, which may reflect underlying liver disease. There were no significant differences in morbidity or survival based on the surgical approach; however, local recurrence rates were highest for percutaneously ablated tumors.
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