Specificities and commonalities of the Planctomycetes plasmidome.

Plasmids, despite their critical role in antibiotic resistance and modern biotechnology, are understood in only a few bacterial groups in terms of their natural ecological dynamics. The bacterial phylum Planctomycetes, known for its unique molecular and cellular biology, has a largely unexplored plasmidome. This study offers a thorough exploration of the diversity of natural plasmids within Planctomycetes, which could serve as a foundation for developing various genetic research tools for this phylum. Planctomycetes plasmids encode a broad range of biological functions and appear to have coevolved significantly with their host chromosomes, sharing many homologues. Recent transfer events of insertion sequences between cohabiting chromosomes and plasmids were also observed. Interestingly, 64% of plasmid genes are distantly related to either chromosomally encoded genes or have homologues in plasmids from other bacterial groups. The planctomycetal plasmidome is composed of 36% exclusive proteins. Most planctomycetal plasmids encode a replication initiation protein from the Replication Protein A family near a putative iteron-containing replication origin, as well as active type I partition systems. The identification of one conjugative and three mobilizable plasmids suggests the occurrence of horizontal gene transfer via conjugation within this phylum. This comprehensive description enhances our understanding of the plasmidome of Planctomycetes and its potential implications in antibiotic resistance and biotechnology.

An AlphaFold Structure Analysis of COQ2 as Key a Component of the Coenzyme Q Synthesis Complex.

Coenzyme Q (CoQ) is a lipidic compound that is widely distributed in nature, with crucial functions in metabolism, protection against oxidative damage and ferroptosis and other processes. CoQ biosynthesis is a conserved and complex pathway involving several proteins. COQ2 is a member of the UbiA family of transmembrane prenyltransferases that catalyzes the condensation of the head and tail precursors of CoQ, which is a key step in the process, because its product is the first intermediate that will be modified in the head by the next components of the synthesis process. Mutations in this protein have been linked to primary CoQ deficiency in humans, a rare disease predominantly affecting organs with a high energy demand. The reaction catalyzed by COQ2 and its mechanism are still unknown. Here, we aimed at clarifying the COQ2 reaction by exploring possible substrate binding sites using a strategy based on homology, comprising the identification of available ligand-bound homologs with solved structures in the Protein Data Bank (PDB) and their subsequent structural superposition in the AlphaFold predicted model for COQ2. The results highlight some residues located on the central cavity or the matrix loops that may be involved in substrate interaction, some of which are mutated in primary CoQ deficiency patients. Furthermore, we analyze the structural modifications introduced by the pathogenic mutations found in humans. These findings shed new light on the understanding of COQ2's function and, thus, CoQ's biosynthesis and the pathogenicity of primary CoQ deficiency.

Molecular Identification and Subtype Analysis of Blastocystis sp. Isolates from Wild Mussels (Mytilus edulis) in Northern France.

Blastocystis sp. is the most common single-celled eukaryote colonizing the human gastrointestinal tract worldwide. Because of the proven zoonotic potential of this protozoan, sustained research is therefore focused on identifying various reservoirs of transmission to humans, and in particular animal sources. Numerous groups of animals are considered to be such reservoirs due to their handling or consumption. However, some of them, including mollusks, remain underexplored. Therefore, a molecular epidemiological survey conducted in wild mussels was carried out in Northern France (Hauts-de-France region) to evaluate the frequency and subtypes (STs) distribution of Blastocystis sp. in these bivalve mollusks. For this purpose, 100 mussels (Mytilus edulis) were randomly collected in two sampling sites (Wimereux and Dannes) located in the vicinity of Boulogne-sur-Mer. The gills and gastrointestinal tract of each mussel were screened for the presence of Blastocystis sp. by real-time polymerase chain reaction (qPCR) assay followed by direct sequencing of positive PCR products and subtyping through phylogenetic analysis. In parallel, sequences of potential representative Blastocystis sp. isolates that were previously obtained from temporal surveys of seawater samples at marine stations offshore of Wimereux were integrated in the present analysis. By taking into account the qPCR results from all mussels, the overall prevalence of the parasite was shown to reach 62.0%. In total, more than 55% of the positive samples presented mixed infections. In the remaining mussel samples with a single sequence, various STs including ST3, ST7, ST14, ST23, ST26 and ST44 were reported with varying frequencies. Such distribution of STs coupled with the absence of a predominant ST specific to these bivalves strongly suggested that mussels might not be natural hosts of Blastocystis sp. and might rather be carriers of parasite isolates from both human and animal (bovid and birds) waste. These data from mussels together with the molecular identification of isolates from marine stations were subsequently discussed along with the local geographical context in order to clarify the circulation of this protozoan in this area. The identification of human and animal STs of Blastocystis sp. in mussels emphasized the active circulation of this protozoan in mollusks and suggested a significant environmental contamination of fecal origin. This study has provided new insights into the host/carrier range and transmission of Blastocystis sp. and emphasized its potential as an effective sentinel species for water quality and environmental contamination.

Critical behavior of magnetic polymers on the three-dimensional Sierpinski Gasket.

We present the (numerically) exact phase diagram of a magnetic polymer on the Sierpinsky gasket embedded in three dimensions using the renormalization group method. We report distinct phases of the magnetic polymer, including paramagnetic swollen, ferromagnetic swollen, paramagnetic collapsed, and ferromagnetic collapsed states. By evaluating critical exponents associated with phase transitions, we located the phase boundaries between different phases. If the model is extended to include a four-site interaction which disfavors configurations with a single spin of a given type, we find a rich variety of critical behaviors. Notably, we uncovered a phenomenon of reentrance, where the system transitions from a collapsed (paramagnetic) state to a swollen (paramagnetic) state followed by another collapse (paramagnetic) and ultimately reaching a ferromagnetic collapsed state. These findings shed new light on the complex behavior of (lattice) magnetic polymers.

Association of Insurance Type with Inpatient Surgical 30-day Readmissions, Emergency Department Visits/Observation Stays, and Costs.

OBJECTIVE: To assess the association of Private, Medicare, and Medicaid/Uninsured insurance type with 30-day Emergency Department visits/Observation Stays (EDOS), readmissions, and costs in a safety-net hospital (SNH) serving diverse socioeconomic status patients. SUMMARY BACKGROUND DATA: Medicare's Hospital Readmission Reduction Program (HRRP) disproportionately penalizes SNHs. METHODS: This retrospective cohort study used inpatient National Surgical Quality Improvement Program (2013-2019) data merged with cost data. Frailty, expanded Operative Stress Score, case status, and insurance type were used to predict odds of EDOS and readmissions, as well as index hospitalization costs. RESULTS: The cohort had 1,477 Private; 1,164 Medicare; and 3,488 Medicaid/Uninsured cases with a patient mean age 52.1 years [SD=14.7] and 46.8% of the cases were performed on male patients. Medicaid/Uninsured (aOR=2.69, CI=2.38-3.05, P<.001) and Medicare (aOR=1.32, CI=1.11-1.56, P=.001) had increased odds of urgent/emergent surgeries and complications versus Private patients. Despite having similar frailty distributions, Medicaid/Uninsured compared to Private patients had higher odds of EDOS (aOR=1.71, CI=1.39-2.11, P<.001), and readmissions (aOR=1.35, CI=1.11-1.65, P=.004), after adjusting for frailty, OSS, and case status, while Medicare patients had similar odds of EDOS and readmissions versus Private. Hospitalization variable cost %change was increased for Medicare (12.5%) and Medicaid/Uninsured (5.9%), but Medicaid/Uninsured was similar to Private after adjusting for urgent/emergent cases. CONCLUSIONS: Increased rates and odds of urgent/emergent cases in Medicaid/Uninsured patients drive increased odds of complications and index hospitalization costs versus Private. SNHs care for higher cost populations while receiving lower reimbursements and are further penalized by the unintended consequences of HRRP. Increasing access to care, especially for Medicaid/Uninsured patients, could reduce urgent/emergent surgeries resulting in fewer complications, EDOS/readmissions, and costs.

Cost of Failure to Achieve Textbook Outcomes: Association of Insurance Type with Outcomes and Cumulative Cost for Inpatient Surgery.

BACKGROUND: Surgical outcome/cost analyses typically focus on single outcomes and do not include encounters beyond the index hospitalization. STUDY DESIGN: This cohort study used NSQIP (2013-2019) data with electronic health record and cost data risk-adjusted for frailty, preoperative acute serious conditions (PASC), case status, and operative stress assessing cumulative costs of failure to achieve textbook outcomes defined as absence of 30-day Clavien-Dindo level III and IV complications, emergency department visits/observation stays (EDOS), and readmissions across insurance types (private, Medicare, Medicaid, uninsured). Return costs were defined as costs of all 30-day emergency department visits/observation stays and readmissions. RESULTS: Cases were performed on patients (private 1,506; Medicare 1,218; Medicaid 1,420; uninsured 2,178) with a mean age 52.3 years (SD 14.7) and 47.5% male. Medicaid and uninsured patients had higher odds of presenting with preoperative acute serious conditions (adjusted odds ratios 1.89 and 1.81, respectively) and undergoing urgent/emergent surgeries (adjusted odds ratios 2.23 and 3.02, respectively) vs private. Medicaid and uninsured patients had lower odds of textbook outcomes (adjusted odds ratios 0.53 and 0.78, respectively) and higher odds of emergency department visits/observation stays and readmissions vs private. Not achieving textbook outcomes was associated with a greater than 95.1% increase in cumulative costs. Medicaid patients had a relative increase of 23.1% in cumulative costs vs private, which was 18.2% after adjusting for urgent/emergent cases. Return costs were 37.5% and 65.8% higher for Medicaid and uninsured patients, respectively, vs private. CONCUSIONS: Higher costs for Medicaid patients were partially driven by increased presentation acuity (increased rates/odds of preoperative acute serious conditions and urgent/emergent surgeries) and higher rates of multiple emergency department visits/observation stays and readmission occurrences. Decreasing surgical costs/improving outcomes should focus on reducing urgent/emergent surgeries and improving postoperative care coordination, especially for Medicaid and uninsured populations.

Association of Cumulative Colorectal Surgery Hospital Costs, Readmissions, and Emergency Department/Observation Stays with Insurance Type.

BACKGROUND/PURPOSE: Medicare's Hospital Readmission Reduction Program disproportionately penalizes safety-net hospitals (SNH) caring for vulnerable populations. This study assessed the association of insurance type with 30-day emergency department visits/observation stays (EDOS), readmissions, and cumulative costs in colorectal surgery patients. METHODS: Retrospective inpatient cohort study using the National Surgical Quality Improvement Program (2013-2019) with cost data in a SNH. The odds of EDOS and readmissions and cumulative variable (index hospitalization and all 30-day EDOS and readmissions) costs were modeled adjusting for frailty, case status, presence of a stoma, and open versus laparoscopic surgery. RESULTS: The cohort had 245 private, 195 Medicare, and 590 Medicaid/uninsured cases, with a mean age 55.0 years (SD = 13.3) and 52.9% of the cases were performed on male patients. Most cases were open surgeries (58.7%). Complication rates were 41.8%, EDOS 12.0%, and readmissions 20.1%. Medicaid/uninsured had increased odds of urgent/emergent surgeries (aOR = 2.15, CI = 1.56-2.98, p < 0.001) and complications (aOR = 1.43, CI = 1.02-2.03, p = 0.042) versus private patients. Medicaid/uninsured versus private patients had higher EDOS (16.6% versus 4.1%) and readmissions (22.9% versus 14.3%) rates and higher odds of EDOS (aOR = 4.81, CI = 2.57-10.06, p < 0.001), and readmissions (aOR = 1.62, CI = 1.07-2.50, p = 0.025), while Medicare patients had similar odds versus private. Cumulative variable cost %change was increased for Medicare and Medicaid/uninsured, but Medicaid/uninsured was similar to private after adjusting for urgent/emergent cases. CONCLUSIONS: Increased urgent/emergent cases in Medicaid/uninsured populations drive increased complications odds and higher costs compared to private patients, suggesting lack of access to outpatient care. SNH care for higher cost populations, receive lower reimbursements, and are penalized by value-based programs. Increasing healthcare access for Medicaid/uninsured patients could reduce urgent/emergent surgeries, resulting in fewer complications, EDOS/readmissions, and costs.

Association of Insurance Type With Inpatient Surgery 30-Day Complications and Costs.

INTRODUCTION: Safety-net hospitals (SNHs) have higher postoperative complications and costs versus low-burden hospitals. Do low socioeconomic status/vulnerable patients receive care at lower-quality hospitals or are there factors beyond providers' control? We studied the association of private, Medicare, and vulnerable insurance type with complications/costs in a high-burden SNH. METHODS: Retrospective inpatient cohort study using National Surgical Quality Improvement Program (NSQIP) data (2013-2019) with cost data risk-adjusted by frailty, preoperative serious acute conditions (PASC), case status, and expanded operative stress score (OSS) to evaluate 30-day unplanned reoperations, any complication, Clavien-Dindo IV (CDIV) complications, and hospitalization variable costs. RESULTS: Cases (Private 1517; Medicare 1224; Vulnerable 3648) with patient mean age 52.3 y [standard deviation = 14.7] and 47.3% male. Adjusting for frailty and OSS, vulnerable patients had higher odds of PASC (aOR = 1.71, CI = 1.39-2.10, P < 0.001) versus private. Adjusting for frailty, PASC and OSS, Medicare (aOR = 1.27, CI = 1.06-1.53, P = 0.009), and vulnerable (aOR = 2.44, CI = 2.13-2.79, P < 0.001) patients were more likely to undergo urgent/emergent surgeries. Vulnerable patients had increased odds of reoperation and any complications versus private. Variable cost percentage change was similar between private and vulnerable after adjusting for case status. Urgent/emergent case status increased percentage change costs by 32.31%. We simulated "switching" numbers of private (3648) versus vulnerable (1517) cases resulting in an estimated variable cost of $49.275 million, a 25.2% decrease from the original $65.859 million. CONCLUSIONS: Increased presentation acuity (PASC and urgent/emergent surgeries) in vulnerable patients drive increased odds of complications and costs versus private, suggesting factors beyond providers' control. The greatest impact on outcomes may be from decreasing the incidence of urgent/emergent surgeries by improving access to care.

Retrospective cohort study comparing surgical inpatient charges, total costs, and variable costs as hospital cost savings measures.

We analyzed differences (charges, total, and variable costs) in estimating cost savings of quality improvement projects using reduction of serious/life-threatening complications (Clavien-Dindo Level IV) and insurance type (Private, Medicare, and Medicaid/Uninsured) to evaluate the cost measures. Multiple measures are used to analyze hospital costs and compare cost outcomes across health systems with differing patient compositions. We used National Surgical Quality Improvement Program inpatient (2013-2019) with charge and cost data in a hospital serving diverse socioeconomic status patients. Simulation was used to estimate variable costs and total costs at 3 proportions of fixed costs (FC). Cases (Private 1517; Medicare 1224; Medicaid/Uninsured 3648) with patient mean age 52.3 years (Standard Deviation = 14.7) and 47.3% male. Medicare (adjusted odds ratio = 1.55, 95% confidence interval = 1.16-2.09, P = .003) and Medicaid/Uninsured (adjusted odds ratio = 1.41, 95% confidence interval = 1.10-1.82, P = .008) had higher odds of complications versus Private. Medicaid/Uninsured had higher relative charges versus Private, while Medicaid/Uninsured and Medicare had higher relative variable and total costs versus Private. Targeting a 15% reduction in serious complications for robust patients undergoing moderate-stress procedures estimated variable cost savings of $286,392. Total cost saving estimates progressively increased with increasing proportions of FC; $443,943 (35% FC), $577,495 (50% FC), and $1184,403 (75% FC). In conclusion, charges did not identify increased costs for Medicare versus Private patients. Complications were associated with > 200% change in costs. Surgical hospitalizations for Medicare and Medicaid/Uninsured patients cost more than Private patients. Variable costs should be used to avoid overestimating potential cost savings of quality improvement interventions, as total costs include fixed costs that are difficult to change in the short term.

Association of Insurance Type With Colorectal Surgery Outcomes and Costs at a Safety-Net Hospital: A Retrospective Observational Study.

Association of insurance type with colorectal surgical complications, textbook outcomes (TO), and cost in a safety-net hospital (SNH). Background: SNHs have higher surgical complications and costs compared to low-burden hospitals. How does presentation acuity and insurance type influence colorectal surgical outcomes? Methods: Retrospective cohort study using single-site National Surgical Quality Improvement Program (2013-2019) with cost data and risk-adjusted by frailty, preoperative serious acute conditions (PASC), case status and open versus laparoscopic to evaluate 30-day reoperations, any complication, Clavien-Dindo IV (CDIV) complications, TO, and hospitalization variable costs. Results: Cases (Private 252; Medicare 207; Medicaid/Uninsured 619) with patient mean age 55.2 years (SD = 13.4) and 53.1% male. Adjusting for frailty, open abdomen, and urgent/emergent cases, Medicaid/Uninsured patients had higher odds of presenting with PASC (adjusted odds ratio [aOR] = 2.02, 95% confidence interval [CI] = 1.22-3.52, P = 0.009) versus Private. Medicaid/Uninsured (aOR = 1.80, 95% CI = 1.28-2.55, P < 0.001) patients were more likely to undergo urgent/emergent surgeries compared to Private. Medicare patients had increased odds of any and CDIV complications while Medicaid/Uninsured had increased odds of any complication, emergency department or observations stays, and readmissions versus Private. Medicare (aOR = 0.51, 95% CI = 0.33-0.88, P = 0.003) and Medicaid/Uninsured (aOR = 0.43, 95% CI = 0.30-0.60, P < 0.001) patients had lower odds of achieving TO versus Private. Variable cost %change increased in Medicaid/Uninsured patients to 13.94% (P = 0.005) versus Private but was similar after adjusting for case status. Urgent/emergent cases (43.23%, P < 0.001) and any complication (78.34%, P < 0.001) increased %change hospitalization costs. Conclusions: Decreasing the incidence of urgent/emergent colorectal surgeries, possibly by improving access to care, could have a greater impact on improving clinical outcomes and decreasing costs, especially in Medicaid/Uninsured insurance type patients.

Analysis of Health Care Billing via Quantile Variable Selection Models.

Fraudulent billing of health care insurance programs such as Medicare is in the billions of dollars. The extent of such overpayments remains an issue despite the emerging use of analytical methods for fraud detection. This motivates policy makers to also be interested in the provider billing characteristics and understand the common factors that drive conservative and/or aggressive behavior. Statistical approaches to tackling this problem are confronted by the asymmetric and/or leptokurtic distributions of billing data. This paper is a first attempt at using a quantile regression framework and a variable selection approach for medical billing analysis. The proposed method addresses the varying impacts of (potentially different) variables at the different quantiles of the billing aggressiveness distribution. We use the mammography procedure to showcase our analysis and offer recommendations on fraud detection.

Critical behavior of magnetic polymers in two and three dimensions.

We explore the critical behavior of two- and three-dimensional lattice models of polymers in dilute solution where the monomers carry a magnetic moment which interacts ferromagnetically with near-neighbor monomers. Specifically, the model explored consists of a self-avoiding walk on a square or cubic lattice with Ising spins on the visited sites. In three dimensions we confirm and extend previous numerical work, showing clearly the first-order character of both the magnetic transition and the polymer collapse, which happen together. We present results in two dimensions, where the transition is seen to be continuous. Finite-size scaling is used to extract estimates for the critical exponents and the transition temperature in the absence of an external magnetic field.

Efimov-DNA phase diagram: Three stranded DNA on a cubic lattice.

We define a generalized model for three-stranded DNA consisting of two chains of one type and a third chain of a different type. The DNA strands are modeled by random walks on the three-dimensional cubic lattice with different interactions between two chains of the same type and two chains of different types. This model may be thought of as a classical analog of the quantum three-body problem. In the quantum situation, it is known that three identical quantum particles will form a triplet with an infinite tower of bound states at the point where any pair of particles would have zero binding energy. The phase diagram is mapped out, and the different phase transitions are examined using finite-size scaling. We look particularly at the scaling of the DNA model at the equivalent Efimov point for chains up to 10 000 steps in length. We find clear evidence of several bound states in the finite-size scaling. We compare these states with the expected Efimov behavior.

A Bayes Decision Rule to Assist Policymakers during a Pandemic.

A new decision rule based on net benefit per capita is proposed and exemplified with the aim of assisting policymakers in deciding whether to lockdown or reopen an economy-fully or partially-amidst a pandemic. Bayesian econometric models using Markov chain Monte Carlo algorithms are used to quantify this rule, which is illustrated via several sensitivity analyses. While we use COVID-19 data from the United States to demonstrate the ideas, our approach is invariant to the choice of pandemic and/or country. The actions suggested by our decision rule are consistent with the closing and reopening of the economies made by policymakers in Florida, Texas, and New York; these states were selected to exemplify the methodology since they capture the broad spectrum of COVID-19 outcomes in the U.S.

Association of Socioeconomic Area Deprivation Index with Hospital Readmissions After Colon and Rectal Surgery.

BACKGROUND: Risk adjustment for reimbursement and quality measures omits social risk factors despite adversely affecting health outcomes. Social risk factors are not usually available in electronic health records (EHR) or administrative data. Socioeconomic status can be assessed by using US Census data. Distressed Communities Index (DCI) is based upon zip codes, and the Area Deprivation Index (ADI) provides more granular estimates at the block group level. We examined the association of neighborhood disadvantage using the ADI, DCI, and patient-level insurance status on 30-day readmission risk after colorectal surgery. METHODS: Our 677 patient cohort was derived from the 2013-2017 National Surgical Quality Improvement Program at a safety net hospital augmented with EHR data to determine insurance status and 30-day readmissions. Patients' home addresses were linked to the ADI and DCI. RESULTS: Our cohort consisted of 53.9% males and 63.8% Hispanics with a 22.9% 30-day readmission rate from the date of discharge; > 50% lived in highly deprived neighborhoods. Controlling for medical comorbidities and complications, ADI was associated with increased risk of 30 days from the date of discharge readmissions among patients living in medium (OR = 2.15, p = .02) or high (OR = 1.88, p = .03) deprived areas compared to less-deprived neighborhoods, but not insurance status or DCI. CONCLUSIONS: The ADI identified patients living in deprived communities with increased readmission risk. Our results show that block-group level ADI can potentially be used in risk adjustment, to identify high-risk patients and to design better care pathways that improve health outcomes.

Stockpiling Ventilators for Influenza Pandemics.

In preparing for influenza pandemics, public health agencies stockpile critical medical resources. Determining appropriate quantities and locations for such resources can be challenging, given the considerable uncertainty in the timing and severity of future pandemics. We introduce a method for optimizing stockpiles of mechanical ventilators, which are critical for treating hospitalized influenza patients in respiratory failure. As a case study, we consider the US state of Texas during mild, moderate, and severe pandemics. Optimal allocations prioritize local over central storage, even though the latter can be deployed adaptively, on the basis of real-time needs. This prioritization stems from high geographic correlations and the slightly lower treatment success assumed for centrally stockpiled ventilators. We developed our model and analysis in collaboration with academic researchers and a state public health agency and incorporated it into a Web-based decision-support tool for pandemic preparedness and response.

Assessing key cost drivers associated with caring for chronic kidney disease patients.

BACKGROUND: To examine key factors influencing chronic kidney disease (CKD) patients' total expenditure and offer recommendations on how to reduce total cost of CKD care without compromising quality. METHODS: Using the 2002-2011 Medical Expenditure Panel Survey (MEPS) data, our cross-sectional study analyzed 197 patient records-79 patients with one record and 59 with two entries per patient (138 unique patients). We used three patient groups, based on international statistical classification of diseases version 9 code for condition (ICD9CODX) classification, to focus inference from the analysis: (a) non-dialysis dependent CKD, (b) dialysis and (c) transplant. Covariate information included region, demographic, co-morbid conditions and types of services. We used descriptive methods and multivariate generalized linear models to understand the impact of cost drivers. We compared actual and predicted CKD cost of care data using a hold-out sample of nine, randomly selected patients to validate the models. RESULTS: Total costs were significantly affected by treatment type, with dialysis being significantly higher than non-dialysis and transplant groups. Costs were highest in the West region of the U.S. Average costs for patients with public insurance were significantly higher than patients with private insurance (p < .0743), and likewise, for patients with co-morbid conditions over those without co-morbid conditions (p < .001). CONCLUSIONS: Managing CKD patients both before and after the onset of dialysis treatment and managing co-morbid conditions in individuals with CKD are potential sources of substantial cost savings in the care of CKD patients. Comparing total costs pre and post the United States Affordable Care Act could provide invaluable insights into managing the cost-quality tradeoff in CKD care.

Simulating school closure policies for cost effective pandemic decision making.

BACKGROUND: Around the globe, school closures were used sporadically to mitigate the 2009 H1N1 influenza pandemic. However, such closures can detrimentally impact economic and social life. METHODS: Here, we couple a decision analytic approach with a mathematical model of influenza transmission to estimate the impact of school closures in terms of epidemiological and cost effectiveness. Our method assumes that the transmissibility and the severity of the disease are uncertain, and evaluates several closure and reopening strategies that cover a range of thresholds in school-aged prevalence (SAP) and closure durations. RESULTS: Assuming a willingness to pay per quality adjusted life-year (QALY) threshold equal to the US per capita GDP ($46,000), we found that the cost effectiveness of these strategies is highly dependent on the severity and on a willingness to pay per QALY. For severe pandemics, the preferred strategy couples the earliest closure trigger (0.5% SAP) with the longest duration closure (24 weeks) considered. For milder pandemics, the preferred strategies also involve the earliest closure trigger, but are shorter duration (12 weeks for low transmission rates and variable length for high transmission rates). CONCLUSIONS: These findings highlight the importance of obtaining early estimates of pandemic severity and provide guidance to public health decision-makers for effectively tailoring school closures strategies in response to a newly emergent influenza pandemic.

Algorithmic guided screening of drug combinations of arbitrary size for activity against cancer cells.

The standard treatment for most advanced cancers is multidrug therapy. Unfortunately, combinations in the clinic often do not perform as predicted. Therefore, to complement identifying rational drug combinations based on biological assumptions, we hypothesized that a functional screen of drug combinations, without limits on combination sizes, will aid the identification of effective drug cocktails. Given the myriad possible cocktails and inspired by examples of search algorithms in diverse fields outside of medicine, we developed a novel, efficient search strategy called Medicinal Algorithmic Combinatorial Screen (MACS). Such algorithms work by enriching for the fitness of cocktails, as defined by specific attributes through successive generations. Because assessment of synergy was not feasible, we developed a novel alternative fitness function based on the level of inhibition and the number of drugs. Using a WST-1 assay on the A549 cell line, through MACS, we screened 72 combinations of arbitrary size formed from a 19-drug pool across four generations. Fenretinide, suberoylanilide hydroxamic acid, and bortezomib (FSB) was the fittest. FSB performed up to 4.18 SD above the mean of a random set of cocktails or "too well" to have been found by chance, supporting the utility of the MACS strategy. Validation studies showed FSB was inhibitory in all 7 other NSCLC cell lines tested. It was also synergistic in A549, the one cell line in which this was evaluated. These results suggest that when guided by MACS, screening larger drug combinations may be feasible as a first step in combination drug discovery in a relatively small number of experiments.

A multivariate Poisson-lognormal regression model for prediction of crash counts by severity, using Bayesian methods.

Numerous efforts have been devoted to investigating crash occurrence as related to roadway design features, environmental factors and traffic conditions. However, most of the research has relied on univariate count models; that is, traffic crash counts at different levels of severity are estimated separately, which may neglect shared information in unobserved error terms, reduce efficiency in parameter estimates, and lead to potential biases in sample databases. This paper offers a multivariate Poisson-lognormal (MVPLN) specification that simultaneously models crash counts by injury severity. The MVPLN specification allows for a more general correlation structure as well as overdispersion. This approach addresses several questions that are difficult to answer when estimating crash counts separately. Thanks to recent advances in crash modeling and Bayesian statistics, parameter estimation is done within the Bayesian paradigm, using a Gibbs Sampler and the Metropolis-Hastings (M-H) algorithms for crashes on Washington State rural two-lane highways. Estimation results from the MVPLN approach show statistically significant correlations between crash counts at different levels of injury severity. The non-zero diagonal elements suggest overdispersion in crash counts at all levels of severity. The results lend themselves to several recommendations for highway safety treatments and design policies. For example, wide lanes and shoulders are key for reducing crash frequencies, as are longer vertical curves.