Deploying Vaccine Distribution Sites for Improved Accessibility and Equity to Support Pandemic Response.

In response to COVID-19, many countries have mandated social distancing and banned large group gatherings in order to slow down the spread of SARS-CoV-2. These social interventions along with vaccines remain the best way forward to reduce the spread of SARS CoV-2. In order to increase vaccine accessibility, states such as Virginia have deployed mobile vaccination centers to distribute vaccines across the state. When choosing where to place these sites, there are two important factors to take into account: accessibility and equity. We formulate a combinatorial problem that captures these factors and then develop efficient algorithms with theoretical guarantees on both of these aspects. Furthermore, we study the inherent hardness of the problem, and demonstrate strong impossibility results. Finally, we run computational experiments on real-world data to show the efficacy of our methods.

Quantitative biochemical rationale for differences in transmissibility of 1918 pandemic influenza A viruses.

The human adaptation of influenza A viruses is critically governed by the binding specificity of the viral surface hemagglutinin (HA) to long (chain length) alpha2-6 sialylated glycan (alpha2-6) receptors on the human upper respiratory tissues. A recent study demonstrated that whereas the 1918 H1N1 pandemic virus, A/South Carolina/1/1918 (SC18), with alpha2-6 binding preference transmitted efficiently, a single amino acid mutation on HA resulted in a mixed alpha2-3 sialylated glycan (alpha2-3)/alpha2-6 binding virus (NY18) that transmitted inefficiently. To define the biochemical basis for the observed differences in virus transmission, in this study, we have developed an approach to quantify the multivalent HA-glycan interactions. Analysis of the molecular HA-glycan contacts showed subtle changes resulting from the single amino acid variations between SC18 and NY18. The effect of these changes on glycan binding is amplified by multivalency, resulting in quantitative differences in their long alpha2-6 glycan binding affinities. Furthermore, these differences are also reflected in the markedly distinct binding pattern of SC18 and NY18 HA to the physiological glycans present in human upper respiratory tissues. Thus, the dramatic lower binding affinity of NY18 to long alpha2-6 glycans, as against a mixed alpha2-3/6 binding, correlates with its inefficient transmission. In summary, this study establishes a quantitative biochemical correlate for influenza A virus transmission.

Prioritizing allocation of COVID-19 vaccines based on social contacts increases vaccination effectiveness.

We study allocation of COVID-19 vaccines to individuals based on the structural properties of their underlying social contact network. Even optimistic estimates suggest that most countries will likely take 6 to 24 months to vaccinate their citizens. These time estimates and the emergence of new viral strains urge us to find quick and effective ways to allocate the vaccines and contain the pandemic. While current approaches use combinations of age-based and occupation-based prioritizations, our strategy marks a departure from such largely aggregate vaccine allocation strategies. We propose a novel approach motivated by recent advances in (i) science of real-world networks that point to efficacy of certain vaccination strategies and (ii) digital technologies that improve our ability to estimate some of these structural properties. Using a realistic representation of a social contact network for the Commonwealth of Virginia, combined with accurate surveillance data on spatiotemporal cases and currently accepted models of within- and between-host disease dynamics, we study how a limited number of vaccine doses can be strategically distributed to individuals to reduce the overall burden of the pandemic. We show that allocation of vaccines based on individuals' degree (number of social contacts) and total social proximity time is significantly more effective than the currently used age-based allocation strategy in terms of number of infections, hospitalizations and deaths. Our results suggest that in just two months, by March 31, 2021, compared to age-based allocation, the proposed degree-based strategy can result in reducing an additional 56-110k infections, 3.2- 5.4k hospitalizations, and 700-900 deaths just in the Commonwealth of Virginia. Extrapolating these results for the entire US, this strategy can lead to 3-6 million fewer infections, 181-306k fewer hospitalizations, and 51-62k fewer deaths compared to age-based allocation. The overall strategy is robust even: (i) if the social contacts are not estimated correctly; (ii) if the vaccine efficacy is lower than expected or only a single dose is given; (iii) if there is a delay in vaccine production and deployment; and (iv) whether or not non-pharmaceutical interventions continue as vaccines are deployed. For reasons of implementability, we have used degree, which is a simple structural measure and can be easily estimated using several methods, including the digital technology available today. These results are significant, especially for resource-poor countries, where vaccines are less available, have lower efficacy, and are more slowly distributed.

Visceral Obesity Promotes Lung Cancer Progression-Toward Resolution of the Obesity Paradox in Lung Cancer.

INTRODUCTION: Although obesity is associated with adverse cancer outcomes in general, most retrospective clinical studies suggest a beneficial effect of obesity in NSCLC. METHODS: Hypothesizing that this "obesity paradox" arises partly from the limitations of using body mass index (BMI) to measure obesity, we quantified adiposity using preoperative computed tomography images. This allowed the specific determination of central obesity as abdominal visceral fat area normalized to total fat area (visceral fat index [VFI]). In addition, owing to the previously reported salutary effect of metformin on high-BMI patients with lung cancer, metformin users were excluded. We then explored associations between visceral obesity and outcomes after surgical resection of stage I and II NSCLC. We also explored potential immunologic underpinnings of such association using complimentary analyses of tumor gene expression data from NSCLC tumors and the tumor transcriptome and immune microenvironment in an immunocompetent model of lung cancer with diet-induced obesity. RESULTS: We found that in 513 patients with stage I and II NSCLC undergoing lobectomy, a high VFI is associated with decreased recurrence-free and overall survival. VFI was also inversely related to an inflammatory transcriptomic signature in NSCLC tumors, consistent with observations made in immunocompetent murine models wherein diet-induced obesity promoted cancer progression while exacerbating elements of immune suppression in the tumor niche. CONCLUSIONS: In all, this study uses multiple lines of evidence to reveal the adverse effects of visceral obesity in patients with NSCLC, which align with those found in animal models. Thus, the obesity paradox may, at least in part, be secondary to the use of BMI as a measure of obesity and the confounding effects of metformin use.

Glycans as receptors for influenza pathogenesis.

Influenza A viruses, members of the Orthomyxoviridae family, are responsible for annual seasonal influenza epidemics and occasional global pandemics. The binding of viral coat glycoprotein hemagglutinin (HA) to sialylated glycan receptors on host epithelial cells is the critical initial step in the infection and transmission of these viruses. Scientists believe that a switch in the binding specificity of HA from Neu5Acα2-3Gal linked (α2-3) to Neu5Acα2-6Gal linked (α2-6) glycans is essential for the crossover of the viruses from avian to human hosts. However, studies have shown that the classification of glycan binding preference of HA based on sialic acid linkage alone is insufficient to establish a correlation between receptor specificity of HA and the efficient transmission of influenza A viruses. A recent study reported extensive diversity in the structure and composition of α2-6 glycans (which goes beyond the sialic acid linkage) in human upper respiratory epithelia and identified different glycan structural topologies. Biochemical examination of the multivalent HA binding to these diverse sialylated glycan structures also demonstrated that high affinity binding of HA to α2-6 glycans with a characteristic umbrella-like structural topology is critical for efficient human adaptation and human-human transmission of influenza A viruses. This review summarizes studies which suggest a new paradigm for understanding the role of the structure of sialylated glycan receptors in influenza virus pathogenesis.

Modelling disease outbreaks in realistic urban social networks.

Most mathematical models for the spread of disease use differential equations based on uniform mixing assumptions or ad hoc models for the contact process. Here we explore the use of dynamic bipartite graphs to model the physical contact patterns that result from movements of individuals between specific locations. The graphs are generated by large-scale individual-based urban traffic simulations built on actual census, land-use and population-mobility data. We find that the contact network among people is a strongly connected small-world-like graph with a well-defined scale for the degree distribution. However, the locations graph is scale-free, which allows highly efficient outbreak detection by placing sensors in the hubs of the locations network. Within this large-scale simulation framework, we then analyse the relative merits of several proposed mitigation strategies for smallpox spread. Our results suggest that outbreaks can be contained by a strategy of targeted vaccination combined with early detection without resorting to mass vaccination of a population.

An intelligent real-time scheduler for out-patient clinics: A multi-agent system model.

Scheduling of resources and patients are crucial in outpatient clinics, particularly when the patient demand is high and patient arrivals are random. Generally, outpatient clinic systems are push systems where scheduling is based on average demand prediction and is considered for long term (monthly or bimonthly). Often, planning and actual scenario vary due to uncertainty and variability in demand and this mismatch results in prolonged waiting times and under-utilization of resources. In this article, we model an outpatient clinics as a multi-agent system and propose an intelligent real-time scheduler that schedules patients and resources based on the actual status of departments. Two algorithms are implemented: one for resource scheduling that is based on predictive demand and the other is patient scheduling which performs path optimization depending on the actual status of departments. In order to match resources with stochastic demand, a coordination mechanism is developed that reschedules the resources in the outpatient clinics in real time through auction-bidding procedures. First, a simulation study of intelligent real-time scheduler is carried out followed by implementation of the same in an outpatient clinic of Aravind Eye Hospital, Madurai, India. This hospital has huge patient demand and the patient arrivals are random. The results show that the intelligent real-time scheduler improved the performance measures like waiting time, cycle time, and utilization significantly compared to scheduling of resources and patients in isolation. By scheduling resources and patients, based on system status and demand, the outpatient clinic system becomes a pull system. This scheduler transforms outpatient clinics from open loop system to closed-loop system.

Integral patient scheduling in outpatient clinics under demand uncertainty to minimize patient waiting times.

This study addressed the problem of scheduling walk-in patients in real time. Outpatient clinics encounter uncertainty in patient demand. In addition, the disparate departments are locally (department-centric) organized, leading to prolonged waiting times for patients. The proposed integral patient scheduling model incorporates the status and information of all departments in the outpatient clinic along with all possible pathways to direct patients, on their arrival, to the optimal path. The developed hybrid ant agent algorithm identifies the optimal path to reduce the patient waiting time and cycle time (time from registration to exit). An outpatient clinic in Aravind Eye Hospital, Madurai, has a huge volume of walk-in patients and was selected for this study. The simulation study was performed for diverse scenarios followed by implementation study. The results indicate that integral patient scheduling reduced waiting time significantly. The path optimization in real time makes scheduling effective and efficient as it captures the changes in the outpatient clinic instantly.

Nucleus management with irrigating vectis.

The main objective in modern cataract surgery is to achieve a better unaided visual acuity with rapid post-surgical recovery and minimal surgery-related complications. Early visual rehabilitation and better unaided vision can be achieved only by reducing the incision size. In manual small incision cataract surgery (MSICS), incision is between 5.5 to 7 mm. Once the nucleus is prolapsed into the anterior chamber, it can be extracted through the tunnel. Nucleus extraction with an irrigating vectis is a very simple technique, which combines mechanical and hydrostatic forces to express out the nucleus. This technique is time-tested with good results and more than 95% of nuclei in MSICS are extracted in this way offering all the merits of phacoemulsification with the added benefits of having wider applicability, better safety, shorter learning curve and lower cost.

Chip-based polyketide biosynthesis and functionalization.

We demonstrate construction and novel compound synthesis from a synthetic metabolic pathway consisting of a type III polyketide synthase (PKS) known as 1,3,6,8-tetrahydroxynaphthalene synthase (THNS) from Streptomyces coelicolor and soybean peroxidase (SBP) in a microfluidic platform. THNS immobilized to Ni-NTA agarose beads is prepacked into a microfluidic channel, while SBP is covalently attached to the walls of a second microfluidic channel precoated with a reactive poly(maleic anhydride) derivative. The result is a tandem, two-step biochip that enables the synthesis of novel polyketide derivatives. The first microchannel, consisting of THNS, results in the conversion of malonyl-CoA to flaviolin in yields up to 40% with a residence time of 6 min. This conversion is similar to that obtained in several-milliliter batch reactions after 2 h. Linking this microchannel to the SBP microchannel results in biflaviolin synthesis. During the course of this work, we discovered that the substrate specificity of THNS could be manipulated by simply changing the reaction pH. As a result, the starter acyl-CoA specificity can be broadened to yield a series of truncated pyrone products. When combined with variations in the ratio of acyl-CoA and malonyl-CoA (extender substrate) feed rates, high yields of the pyrone products could be achieved, which is further structurally diversified from self- and cross-coupling in the SBP microchannel. The ability to rapidly evaluate the effects of reaction conditions and synthetic multienzyme pathways on a microfludic platform provides a new paradigm for performing metabolic pathway engineering, namely, the reconstruction of pathways for use in new compound discovery.

Novel silicon-carbon fullerene-like nanostructures: an Ab initio study on the stability of Si54C6 and Si60C6 clusters.

Silicon fullerene like nanostructures with six carbon atoms on the surface of Si60 cages by substitution, as well as inside the cage at various symmetry orientations have been studied within the generalized gradient approximation to density functional theory. Full geometry optimizations have been performed without any symmetry constraints using the Gaussian 03 suite of programs and the LANL2DZ basis set. Thus, for the silicon atom, the Hay-Wadt pseudopotential with the associated basis set are used for the core electrons and the valence electrons, respectively. For the carbon atom, the Dunning/Huzinaga double zeta basis set is employed. Electronic and geometric properties of the nanostructures are presented and discussed in detail. It was found that optimized silicon-carbon fullerene like nanostructures have increased stability compared to bare Si60 cage and the stability depends on the orientation of carbon atoms, as well as on the nature of bonding between silicon and carbon atoms and also on the carbon-carbon bonding.

A Sustainable Model For Delivering High-Quality, Efficient Cataract Surgery In Southern India.

Cataracts are a leading cause of reversible blindness in India, where millions of people can be effectively treated for this condition with surgery. The Aravind Eye Care System in southern India developed an efficient system for delivering high-quality and low-cost cataract surgery. We provide a detailed accounting of costs of cataract surgery at the system and a cost-utility analysis. Total costs per operation were US$120, or $195 per quality-adjusted life-year gained. Using these data and population-based estimates of cataract prevalence, we calculate that eliminating cataract-related blindness and low vision in India would cost $2.6 billion and would yield a net societal benefit of $13.5 billion. Factors contributing to the highly cost-effective care at the Aravind Eye Care System include the domestic manufacturing of supplies, the use of a specialized workforce and standardized protocols, and the presence of few regulatory hurdles. Lessons learned from the system can help improve the delivery of cataract surgery and other ambulatory care surgeries in India and abroad.

Towards numerical temporal-frequency system modelling of associations between electrocardiogram and ballistocardiogram.

Ballistocardiogram (BCG) is a vital sign of ballistic forces generated by each heartbeat. With the advancements in related sensor and computing technologies in recent years, BCG has become far more accessible and thus regained its interest in both research and industry fields. Here we would like to promote the system modelling approach to BCG computing that allows to explore the underlying association between BCG and other physiological signals such as electrocardiogram (ECG). This is in contrast to most of the existing works in the related signal processing domain, which focus on detecting heart rate only. The system modelling approach may eventually improve the clinical significance of the BCG by extracting deeply embedded information. Towards this goal, here we present our preliminary study where we design a Wavelet-based temporal-frequency system model for associating BCG and ECG. To validate the model, we also collect simultaneous BCG and ECG recordings from 4 healthy subjects. We use the system model to build a BCG to ECG predicting algorithm. We demonstrate that this temporal-frequency model and algorithm is far superior, in terms of accuracy, to the naïve method of linear modelling.

Visual experience during phacoemulsification under topical versus retrobulbar anesthesia: results of a prospective, randomized, controlled trial.

PURPOSE: To compare the subjective visual experience of cataract patients during phacoemulsification and intraocular lens implantation under topical anesthesia (TA) vs retrobulbar anesthesia (RA). DESIGN: Prospective, randomized, controlled trial. METHODS: Three hundred six cataract patients eligible for phacoemulsification and intraocular lens implantation were randomized to receive either TA or RA during surgery by one of three surgeons. The surgeons were familiar with both anesthetic techniques and operated on the patients using the technique to which the patients were randomized. A masked interviewer conducted in-person interviews with the patients using a standardized questionnaire about their intraoperative visual experience and their reaction to their visual experience between 30 minutes and 4 hours after the surgery. RESULTS: Two patients (one in each group) had intraoperative posterior capsule rupture and were excluded from analysis. There was no statistically significant difference between TA (n = 154) and RA (n = 150) groups, except that more males compared with females had TA (P = .03). More patients who had TA reported perception of light (P < .001) and colors (P < .001) and a change (either increase or decrease) in light brightness during the course of the surgery (P < .001). There was no statistically significant difference in the proportions of patients who saw movements, flashes, instruments, or the surgeon or medical staff during the operation and who found their visual sensations frightening in the two groups. However, 10.4% in the TA group and 9.3% in the RA group found their visual experience frightening. CONCLUSIONS: More patients undergoing cataract surgery under TA compared with RA reported perception of light, colors, and a change in light brightness. A significant proportion of patients in both groups found the visual experience frightening.

The Effect of Random Edge Removal on Network Degree Sequence.

Many networks arise in a random and distributed fashion, and yet result in having a specific type of degree structure: e.g., the WWW, many social networks, biological networks, etc., exhibit power-law, stretched exponential, or similar degree structures. Much work has examined how a graph's degree-structure influences other graph properties such as connectivity, diameter, etc. Probabilistic edge removal models link failures, information spreading, and processes that consider (random) subgraphs. They also model spreading influence of information as in the independent cascade model [20]. We examine what happens to a graph's degree structure under edge failures where the edges are removed independently with identical probabilities. We start by analyzing the effect of edge failure on the degree sequence for power-law and exponential networks, and improve upon results of Martin, Carr & Faulon and Cooper & Lu; then, using intuition from the power-law case, we derive asymptotic results for almost any degree sequence of interest. Our major result shows a classification of degree sequences which leads to simple rules that give much of the new expected degree sequence after random edge-removal; we also provide associated concentration bounds.

Determinants of glycan receptor specificity of H2N2 influenza A virus hemagglutinin.

The H2N2 subtype of influenza A virus was responsible for the Asian pandemic of 1957-58. However, unlike other subtypes that have caused pandemics such as H1N1 and H3N2, which continue to circulate among humans, H2N2 stopped circulating in the human population in 1968. Strains of H2 subtype still continue to circulate in birds and occasionally pigs and could be reintroduced into the human population through antigenic drift or shift. Such an event is a potential global health concern because of the waning population immunity to H2 hemagglutinin (HA). The first step in such a cross-species transmission and human adaptation of influenza A virus is the ability for its surface glycoprotein HA to bind to glycan receptors expressed in the human upper respiratory epithelia. Recent structural and biochemical studies have focused on understanding the glycan receptor binding specificity of the 1957-58 pandemic H2N2 HA. However, there has been considerable HA sequence divergence in the recent avian-adapted H2 strains from the pandemic H2N2 strain. Using a combination of structural modeling, quantitative glycan binding and human respiratory tissue binding methods, we systematically identify mutations in the HA from a recent avian-adapted H2N2 strain (A/Chicken/PA/2004) that make its quantitative glycan receptor binding affinity (defined using an apparent binding constant) comparable to that of a prototypic pandemic H2N2 (A/Albany/6/58) HA.

Glycan topology determines human adaptation of avian H5N1 virus hemagglutinin.

A switch in specificity of avian influenza A viruses' hemagglutinin (HA) from avian-like (alpha2-3 sialylated glycans) to human-like (alpha2-6 sialylated glycans) receptors is believed to be associated with their adaptation to infect humans. We show that a characteristic structural topology--and not the alpha2-6 linkage itself--enables specific binding of HA to alpha2-6 sialylated glycans and that recognition of this topology may be critical for adaptation of HA to bind glycans in the upper respiratory tract of humans. An integrated biochemical, analytical and data mining approach demonstrates that HAs from the human-adapted H1N1 and H3N2 viruses, but not H5N1 (bird flu) viruses, specifically bind to long alpha2-6 sialylated glycans with this topology. This could explain why H5N1 viruses have not yet gained a foothold in the human population. Our findings will enable the development of additional strategies for effective surveillance and potential therapeutic interventions for H5N1 and possibly other influenza A viruses.

The catalytic machinery of chondroitinase ABC I utilizes a calcium coordination strategy to optimally process dermatan sulfate.

The chondroitinases are bacterial lyases that specifically cleave chondroitin sulfate and/or dermatan sulfate glycosaminoglycans. One of these enzymes, chondroitinase ABC I from Proteus vulgaris, has the broadest substrate specificity and has been widely used to depolymerize these glycosaminoglycans. Biochemical and structural studies to investigate the active site of chondroitinase ABC I have provided important insights into the catalytic amino acids. In this study, we demonstrate that calcium, a divalent ion, preferentially increases the activity of chondroitinase ABC I toward dermatan versus chondroitin substrates in a concentration-dependent manner. Through biochemical and biophysical investigations, we have established that chondroitinase ABC I binds calcium. Experiments using terbium, a fluorescent calcium analogue, confirm the specificity of this interaction. On the basis of theoretical structural models of the enzyme-substrate complexes, specific amino acids that could potentially play a role in calcium coordination were identified. These amino acids were investigated through site-directed mutagenesis studies and kinetic assays to identify possible mechanisms for calcium-mediated processing of the dermatan substrate in the active site of the enzyme.