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PURPOSE. Genomic screening for Lynch syndrome (LS) could prevent colorectal cancer (CRC) by identifying high-risk patients and instituting intensive CRC screening. We estimated the cost-effectiveness of population-wide LS genomic screening versus family history-based screening alone in an unselected U.S. population. METHODS. We developed a decision-analytic Markov model including health states for pre-cancer, stage-specific CRC, and death, and assumed an inexpensive test cost of $200. We conducted sensitivity and threshold analyses to evaluate model uncertainty. RESULTS. Screening unselected 30-year-olds for LS variants resulted in 48 (95% credible range [CR]: 35 to 63) fewer overall CRC cases per 100,000 screened individuals, leading to 187 quality-adjusted life-years (QALYs; 95% CR: 123 to 260) gained at an incremental cost of $24.6 million (95% CR: $20.3 million to $29.1 million). The incremental cost-effectiveness ratio was $132,200, with an 8% and 71% probability of being cost-effective at $100,000 and $150,000 per QALY willingness-to-pay thresholds, respectively. CONCLUSIONS. Population LS screening may be cost-effective in younger patient populations under a $150,000 willingness-to-pay per QALY threshold and with a relatively inexpensive test cost. Further reductions in testing costs and/or the inclusion of LS testing within a broader multiplex screening panel are needed for screening to be highly cost-effective.

OBJECTIVE: To discuss and develop difference‐in‐difference estimators for categorical outcomes and apply them to estimate the effect of the Affordable Care Act's Medicaid expansion on insurance coverage. DATA SOURCES: Secondary analysis of Survey on Income and Program Participation (SIPP) data on health insurance coverage types before (January 2013) and after (December 2015) Medicaid expansion in 39 US states (19 expansion and 20 non‐expansion). STUDY DESIGN: We develop difference‐in‐difference methods for repeated measures (panel data) of categorical outcomes. We discuss scale‐dependence of DID assumptions for marginal and transition effect estimates and specify a new target estimand: the difference between outcome category transitions under treatment versus no treatment. We establish causal assumptions about transitions that are sufficient to identify this and a marginal target estimand. We contrast the marginal estimands identified by the transition approach versus an additive assumption only about marginal evolution. We apply both the marginal and transition approaches to estimate the effects of Medicaid expansion on health insurance coverage types (employer‐sponsored; other private, non‐group; public; and uninsured). DATA EXTRACTION: We analyzed 16,027 individual survey responses from people aged 18–62 years in the 2014 SIPP panel. PRINCIPAL FINDINGS: We show that the two identifying assumptions are equivalent (on the scale of the marginals) if either the baseline marginal distributions are identical or the marginals are constant in both groups. Applying our transitions approach to the SIPP data, we estimate a differential increase in transitions from uninsured to public coverage and differential decreases in transitions from uninsured to private, non‐group coverage and in remaining uninsured. CONCLUSIONS: By comparing the assumption that marginals are evolving in parallel to an assumption about transitions across outcome values, we illustrate the scale‐dependence of difference‐in‐differences. Our application shows that studying transitions can illuminate nuances obscured by changes in the marginals.

The objective of this research was to electrocodeposit turmeric particles into copper matrices, and assess the influence of turmeric on the microstructure and properties of those deposits. The inco...

Objective:Evaluate changes in antimicrobial use during COVID-19 and after implementation of a multispecialty COVID-19 clinical guidance team compared to pre–COVID-19 antimicrobial use.Design:Retrospective observational study.Setting:Tertiary-care academic medical center.Participants:Internal medicine and medical intensive care unit (MICU) provider teams and hospitalized COVID-19 patients.Methods:Difference-in-differences analyses of antibiotic days of therapy per 1,000 patient days present (DOT) for internal medicine and MICU teams treating COVID-19 patients versus teams that did not were performed for 3 periods: before COVID-19, initial COVID-19 period, and after implementation of a multispecialty COVID-19 clinical guidance team which included daily, patient-specific antimicrobial stewardship recommendations. Patient characteristics associated with antibiotic DOT were evaluated using multivariable Poisson regression.Results:In the initial COVID-19 period, compared to the pre–COVID-19 period, internal medicine and MICU teams increased weekly antimicrobial use by 145.3 DOT (95% CI, 35.1–255.5) and 204.0 DOT (95% CI, −16.9 to 424.8), respectively, compared to non–COVID-19 teams. In the intervention period, internal medicine and MICU COVID-19 teams both had significant weekly decreases of 362.3 DOT (95% CI, −443.3 to −281.2) and 226.3 DOT (95% CI, −381.2 to –71.3). Of 131 patients hospitalized with COVID-19, 86 (65.6%) received antibiotics; no specific patient factors were significantly associated with an expected change in antibiotic days.Conclusions:Antimicrobial use initially increased for COVID-19 patient care teams compared to pre–COVID-19 levels but significantly decreased after implementation of a multispecialty clinical guidance team, which may be an effective strategy to reduce unnecessary antimicrobial use.

In the present study, a model of closed-loop recycling of copper from PCBs is demonstrated, which involves the sequential application of bioleaching and electrowinning to selectively extract copper. This approach is proposed as part of the solution to resolve the challenging ever-increasing accumulation of electronic waste, e-waste, in the environment. This work is targeting copper, the most abundant metal in e-waste that represents up to 20% by weight of printed circuit boards (PCBs). In the first stage, bioleaching was tested for different pulp densities (0.25–1.00% w/v) and successfully used to extract multiple metals from PCBs using the acidophilic bacterium, Acidithiobacillus ferrooxidans. In the second stage, the method focused on the recovery of copper from the bioleachate by electrowinning. Metallic copper foils were formed, and the results demonstrated that 75.8% of copper available in PCBs had been recovered as a high quality copper foil, with 99 + % purity, as determined by energy dispersive X-ray analysis and Inductively-Coupled Plasma Optical Emission Spectrometry. This model of copper extraction, combining bioleaching and electrowinning, demonstrates a closed-loop method of recycling that illustrates the application of bioleaching in the circular economy. The copper foils have the potential to be reused, to form new, high value copper clad laminate for the production of complex printed circuit boards for the electronics manufacturing industry. Graphic Abstract

Genomic methodologies offer unprecedented opportunities for statistically robust studies of species broadly distributed in environments conducive to high gene flow, providing valuable information for wildlife conservation and management. Here, we sequence restriction site‐associated DNA to characterize genome‐wide single nucleotide polymorphisms (SNPs) in a broadly distributed and highly migratory large pelagic fish, striped marlin (Kajikia audax). Assessment of over 4,000 SNPs resolved spatiotemporal patterns of genetic connectivity throughout the species range in the Pacific and, for the first time, Indian oceans. Individual‐based cluster analyses identified six genetically distinct populations corresponding with the western Indian, eastern Indian, western South Pacific, and eastern central Pacific oceans, as well as two populations in the North Pacific Ocean (F ST = 0.0137–0.0819). F ST outlier analyses identified a subset of SNPs (n = 59) putatively under the influence of natural selection and capable of resolving populations separated by comparatively high degrees of genetic differentiation. Temporal collections available for some regions demonstrated the stability of allele frequencies over three to five generations of striped marlin. Relative migration rates reflected lower levels of genetic connectivity between Indian Ocean populations (m R ≤ 0.37) compared with most populations in the Pacific Ocean (m R ≥ 0.57) and highlight the importance of the western South Pacific in facilitating gene flow between ocean basins. Collectively, our results provide novel insights into rangewide population structure for striped marlin and highlight substantial inconsistencies between genetically distinct populations and stocks currently recognized for fisheries management. More broadly, we demonstrate that species capable of long‐distance dispersal in environments lacking obvious physical barriers to movement can display substantial population subdivision that persists over multiple generations and that may be facilitated by both neutral and adaptive processes. Importantly, surveys of genome‐wide markers enable inference of population‐level relationships using sample sizes practical for large pelagic fishes of conservation concern.

Numerous provisions of the Affordable Care Act (ACA) were designed to make health care more affordable, yet the act’s cumulative effects on health care costs are still debated. A key question is wh...

This cross-sectional study assesses the daily percentage of floor and intensive care unit bed available at in-network hospitals for patients with COVID-19 in Tennessee.

This paper describes a two-step method to prepare novel copper-methanol nanofluids capped with a short chain molecule, (3-Aminopropyl)trimethoxysilane (APTMS). Two commercial nanopowders were dispersed at various powers using a 20 kHz ultrasonic probe into solutions of methanol and the capping agent. Ultrasonic energy input was measured by calorimetry with z-average diameters, intensity and number size distributions recorded by a dynamic light scattering technique. The stability of the dispersion was monitored visually, and quantified by recording the zeta potential. Dispersions of the bare powder were used as a control. Absorption spectroscopy was used to confirm the presence of the capping agent. The thermal conductivities of 0 to 10% wt./vol. (1.1% vol.) dispersions of the capped copper-methanol nanofluid were determined using a C-Therm analyzer. Optimum ultrasonic de-agglomeration conditions gave dispersions with a z-average particle size of

We discuss tradeoffs and errors associated with approaches to modeling health economic decisions. Through an application in pharmacogenomic (PGx) testing to guide drug selection for individuals with a genetic variant, we assessed model accuracy, optimal decisions and computation time for an identical decision scenario modeled four ways: using (1) coupled-time differential equations [DEQ]; (2) a cohort-based discrete-time state transition model [MARKOV]; (3) an individual discrete-time state transition microsimulation model [MICROSIM]; and (4) discrete event simulation [DES]. Relative to DEQ, the Net Monetary Benefit for PGx testing (vs. a reference strategy of no testing) based on MARKOV with rate-to-probability conversions using commonly used formulas resulted in different optimal decisions. MARKOV was nearly identical to DEQ when transition probabilities were embedded using a transition intensity matrix. Among stochastic models, DES model outputs converged to DEQ with substantially fewer simulated patients (1 million) vs. MICROSIM (1 billion). Overall, properly embedded Markov models provided the most favorable mix of accuracy and run-time, but introduced additional complexity for calculating cost and quality-adjusted life year outcomes due to the inclusion of “jumpover” states after proper embedding of transition probabilities. Among stochastic models, DES offered the most favorable mix of accuracy, reliability, and speed.

A novel approach to selective electroless deposition of metal on non-conductive substrates was developed. Using an electroless copper process requires the non-conductive material to be catalysed prior to electroless deposition and this is typically carried out using a Pd-Sn colloidal catalyst. In the current work, a novel magnetic Fe3O4-Ag nanoparticle (NP) catalyst was used. The composite particles were obtained by a wet chemical method. The composition, particle size and crystal structure of the particles were confirmed by transmission electron microscopy, energy dispersive X-ray spectroscopy and X-ray diffraction. The magnetic properties were characterised by vibrating sample magnetometry whilst the catalytic activity towards formaldehyde oxidation (the key reaction in electroless copper deposition) was confirmed by cyclic voltammetry. Because this new catalyst is magnetic, a magnetic field gradient can be used to manipulate the catalyst NPs. A permanent magnet was attached to the constructed steel template so that a magnetic field gradient on the FR-4 laminate substrate surface was achieved. When the magnetic field was applied, the Fe3O4-Ag catalyst NPs were attracted only to the areas of maximum magnetic field gradient on the surface, leading to selective catalysation of the substrate. Subsequent electroless copper plating only occurred at the areas where the composite magnetic NPs were deposited, meaning that selective metallisation by applying a magnetic field was achieved. The width of the selectively metallised lines was 350±20 μm.

Numerous provisions of the Affordable Care Act (ACA) were designed to make health care more affordable, yet the act's cumulative effects on health care costs are still debated. A key question is whether or not the ACA reduced the annual rate at which total national health care spending increased and brought per capita spending growth rates down. We review the direct and indirect effects of the ACA on spending across segments of the health insurance market. We highlight areas where the ACA has affected spending, but we emphasize that the ACA's long-run impact on spending will depend on sustaining the adjustments made to provider payment systems and expanding the emphasis on value across payers throughout the ACA's second decade and beyond.

Nine of the fourteen states that have not expanded Medicaid are in the southern census region, and two other nonexpansion states border that region. Ongoing debate over the merits of Medicaid expansion in these states has focused, in part, on whether the safety net provides sufficient access for uninsured low-income Americans. We analyzed longitudinal survey and vital status data from the twelve-state Southern Community Cohort Study (SCCS) for 15,356 nonelderly adult participants with low incomes, 86 percent of whom were enrolled at community health centers. In difference-in-differences analyses, we compared changes in self-reported health between participants in four expansion and eight nonexpansion states before (2008–13) and after (2015–17) Medicaid expansion. We found that a higher proportion of SCCS participants in expansion states reported increases in Medicaid coverage (a differential change of 7.6 percentage points), a lower proportion experienced a health status decline (−1.8 percentage points), and a higher proportion maintained their baseline health status (1.4 percentage points). The magnitude of estimated reductions in health declines would meaningfully affect a nonexpansion state’s health ranking in our sample if that state elected to expand Medicaid. Our results suggest that for low-income adults in the South, Medicaid expansions yielded health benefits—even for those with established access to safety-net care.

Despite broad spatial distributions in the Atlantic, Pacific, and Indian oceans, relatively little is known about spearfishes (family Istiophoridae, genus Tetrapturus) due to their pelagic nature and relative scarcity. The limited biological understanding of spearfishes includes uncertain taxonomic relationships complicated by conserved morphology, thus specific identification relies heavily on geographic location of capture. Previous phylogenetic studies incorporating a limited number of loci and few representatives of each species have been unable to consistently resolve the four currently recognized species comprising Tetrapturus. In the present study, we surveyed 14 nuclear microsatellite loci and the mitochondrial DNA control region across relatively large numbers of samples per species to genetically discriminate spearfish species. Molecular data resolved roundscale spearfish (n = 89) (Tetrapturus georgii Lowe, 1841) and Mediterranean spearfish (n = 12) (Tetrapturus belone Rafinesque, 1810) as genetically distinct groups. Longbill spearfish (n = 79) (Tetrapturus pfluegeri Robins and de Sylva, 1963) and shortbill spearfish (n = 29) (Tetrapturus angustirostris Tanaka, 1915) were not consistently resolved. A single individual collected in the western central Atlantic Ocean off Brazil assigned to shortbill spearfish and likely represents a vagrant. Additionally, a spearfish sampled from the Indian Ocean off eastern South Africa was morphologically identified as a longbill spearfish, and the molecular profile of this specimen was consistent with the morphological identification. Our study represents the most extensive molecular evaluation of the spearfishes to date. Results reported here underscore the substantial level of genetic similarity between longbill and shortbill spearfishes, and suggest high-resolution genomic methods may be required to unambiguously resolve these species.

Intensive care unit (ICU) delirium is highly prevalent and a potentially avoidable hospital complication. The current cost of ICU delirium is unknown.To specify the association between the daily occurrence of delirium in the ICU with costs of ICU care accounting for time-varying illness severity and death.We performed a prospective cohort study within medical and surgical ICUs in a large academic medical center.We analyzed critically ill patients (N=479) with respiratory failure and/or shock.Covariates included baseline factors (age, insurance, cognitive impairment, comorbidities, Acute Physiology and Chronic Health Evaluation II Score) and time-varying factors (sequential organ failure assessment score, mechanical ventilation, and severe sepsis). The primary analysis used a novel 3-stage regression method: first, estimation of the cumulative cost of delirium over 30 ICU days and then costs separated into those attributable to increased resource utilization among survivors and those that were avoided on the account of delirium's association with early mortality in the ICU.The patient-level 30-day cumulative cost of ICU delirium attributable to increased resource utilization was $17,838 (95% confidence interval, $11,132-$23,497). A combination of professional, dialysis, and bed costs accounted for the largest percentage of the incremental costs associated with ICU delirium. The 30-day cumulative incremental costs of ICU delirium that were avoided due to delirium-associated early mortality was $4654 (95% confidence interval, $2056-7869).Delirium is associated with substantial costs after accounting for time-varying illness severity and could be 20% higher (∼$22,500) if not for its association with early ICU mortality.

Biological invasions represent an important component of global change, with potentially huge detrimental effects on native biological biodiversity and ecosystems. Knowledge about invasion history provides information about the invasion process and the origin and genetic composition of invading populations. To clarify the source and invasive routes of a successful world-wide invader, the veined rapa whelk, Rapana venosa, genetic variability of samples from five representative native populations from coasts of Japan and China and 13 worldwide invasive populations was analyzed using 11 nuclear microsatellite loci. A dramatic decrease of genetic variation was detected in the invasive populations compared with the native populations. The results demonstrated that R. venosa was capable of establishing itself in many areas despite a dramatic genetic bottleneck, suggesting that a remarkable reduction of genetic diversity is not a limiting factor for short-term success of this invasive species. Considering the lack of mitochondrial variation previously observed in the invasive populations, the dramatic genetic bottleneck and the allele distribution detected using microsatellites suggested that the original introduced Black Sea population could have been founded by very few individuals, perhaps only a single female and a single male. The initial invasive Black Sea population was likely an accidental introduction from Japan, and then invaded the Adriatic Sea by range expansion, which served as a source for subsequent invasive populations in Europe and America by various transport vectors. In addition, microsatellite alleles in the invasive populations showed a tendency to mutate with the addition or deletion of a single repeat, which is consistent with the stepwise mutation model. Our findings provide a good example of how an aquatic invader with a drastic genetic bottleneck and very low genetic diversity rapidly expands its geographical range.

The formation of printed circuit patterns on non-conductive substrates has many applications in high value sectors such as electronics manufacturing. Current semi-additive and subtractive circuit manufacturing processes use photolithography to pattern substrates coated with a thin or relatively thick metal film. This process is often wasteful and expensive. Using an innovative approach; composite Fe3O4-Ag nanoparticles were synthesized and attracted to a magnetic field. The nanoparticles catalysed electroless copper deposition. Such a catalyst is new to electroless plating and was deposited selectively on a dielectric substrate using a gradient magnetic field. In this way, subsequent electroless copper plating occurred exclusively where the magnetic field was applied, whilst the remaining surface was free of deposited metal. The advantage of this additive method of manufacture is that less material is needed and less waste is produced.

A new procedure for the fabrication of metal nanowires by template-assisted electrodeposition using porous polycarbonate templates is described. A thin sputtered film of silver (≤15nm) was deposited onto one side of the template. The silver seed layer was used to catalyse electroless copper deposition and a copper layer was grown on top (300–500nm) in less than 10min. The copper layer served to seal the pores of the template and to form an electrode of high electrical conductivity. The copper layer was easily removed with a chemical etchant to aid the release of the nanowires from the template mask after growth. To demonstrate the process, copper nanowires were prepared by controlled potential deposition and characterised by SEM and TEM. This new procedure has the ability to be applied to the preparation of a wide range of metallic nanostructures over a wide range of scales. It avoids the need for an extended vacuum deposition step and has the advantage of using low-cost metals in a combined short vacuum/wet chemical process so as to form the critical electrode layer for nanowire growth. Keywords: Electroless copper, Nanostructures, Nanowires, Template synthesis

The billfishes are a group of highly migratory fishes comprising two extant families. The family Xiphiidae is monotypic and contains only the broadbill swordfish (Xiphias gladius Linnaeus, 1758), while the nine-other species of billfishes constitute the family Istiophoridae. The outcomes of past phylogenetic investigations using partial nuclear and mitochondrial (mtDNA) sequences recommended a restructuring of Istiophoridae, by expanding the three existing genera into five: Makaira, Istiophorus, Kajikia, Istiompax, and Tetrapturus. However, several aspects of the Istiophoridae phylogeny remain unresolved, including the position of the genus Istiompax. In this investigation, we sequenced the whole mitogenomes for all istiophorid billfish species. Phylogenetic analyses supported the presence of five genera within Istiophoridae and resolved the placement of Istiompax as the sister taxon to Kajikia + Tetrapturus. Genetic identity between the striped marlin [Kajikia audax (Philippi, 1887)] and the white marlin [Kajikia albida (Poey, 1860)] was found to be higher than between Indo-Pacific and Atlantic clades of both the blue marlin (Makaira nigricans Lacepede, 1802) and sailfish [Istiophorus platypterus (Shaw, 1792)], suggesting recent isolation or ongoing genetic connectivity between K. audax and K. albida. An assessment of mtDNA gene regions identified NADH dehydrogenase subunit 4 (ND4) as best reflecting the phylogenetic reconstruction using the whole mitogenomes, while cytochrome b (Cytb) was the only gene region able to separate all species of billfishes in the present study. Our investigation increased the phylogenetic resolution of istiophorid billfishes and underscores the need for further investigations to fully resolve the complex genetic relationships within Tetrapturus and Kajikia.

Lithography is the most commonly used method for the selective metallisation of non-conductive surfaces in the manufacture of electronic devices such as printed circuit boards and antennae. However, when used in subtractive mode, lithography results in the generation of large amounts of organic solvent and metal containing waste and requires high initial capital investment. For these reasons, additive methods of selective metallisation are being widely investigated. In this work, a novel additive approach of Selective Metallisation using a Magnetic Field (SMMF) was studied. This method uses a magnetic catalyst to initiate the electroless plating process. Magnetic catalyst particles composed of magnetite-silicon dioxide-silver were synthesised by a wet-chemical procedure. Their composition was analysed by scanning electron microscopy and energy dispersive X-ray spectroscopy and the phase formation was confirmed by X-ray diffractometry. Catalytic activity towards formaldehyde oxidation and the magnetic properties of particles were confirmed by cyclic voltammetry and vibrating sample magnetometry, respectively. The results showed that the particles can be used as a catalyst for electroless copper plating and are attracted by the magnetic field. The pattern of deposition of the magnetic catalyst is defined by the magnetic field. Two different configurations of magnet and substrate were used to deposit the catalyst dispersion onto the substrate surface. In both cases, the particles were attracted by the magnetic field and deposited exclusively where the magnetic field was applied. Subsequent electroless copper plating also only occurred at these areas. Parallel lines of electroless copper were obtained. The effect of the magnetic field on magnetic catalyst deposition and subsequent electroless plating was studied and key process-specific defects were identified.

Background Pop-up satellite archival tags (PSATs) are a valuable tool for estimating mortality of pelagic fishes released from commercial and recreational fishing gears. However, the high cost of PSATs limits sample sizes, resulting in low-precision post-release mortality estimates with little management applicability. We evaluate the performance of a lower-cost PSAT designed to enable large-scale post-release mortality studies. The tag uses solar rather than battery power, does not include a depth sensor, and transmits daily summaries of light and temperature data rather than high-resolution habitat profiles, contributing to a substantially lower per-unit price. We assessed the tag’s ability to detect mortality while also estimating the post-release mortality of juvenile (119–

The selective patterning of silver nanoparticles by a patent pending process to act as a catalyst for metallization with electroless copper was explored on cotton, with a view towards application in the wearable technology sector. Whole area coverage or tracks serving as point-to-point connections were achieved by depositing the catalyst via spraying, or in more controlled manner using a microdispenser, respectively. Optimization of the catalyst deposition is described, including substrate characterization via contact angle, FTIR and surface charge measurement. The effects of the copper plating bath temperature and dwell time in the plating bath are examined. With plating times as short as 10 min, samples of good conductivity (sheet resistance, R =

The genetic basis of population structure in white marlin (Kajikia albida) is not well understood. Previous evaluation of genetic population structure in this species utilized a small number of molecular markers to survey genetic variation across opportunistically collected samples of adults, resulting in statistically significant levels of genetic differentiation for some pairwise comparisons and global levels of genetic differentiation that approached statistical significance. This study increased statistical power to improve resolution of genetic population structure in white marlin by surveying a larger number of molecular markers across sample collections of increased size, including collections from additional geographic locations and a robust collection of larvae. Increased statistical power resulted in lower levels of genetic heterogeneity compared with the previous study, and results were consistent with the presence of a single genetic stock of white marlin in the Atlantic Ocean. These results indicate that when statistical power is low, the ability to distinguish noise from a true signal of population structure is compromised. This relationship is especially important for population genetic assessments of marine fishes where genetic differentiation, if it exists, is expected to be low.

A zymogen-like activated factor X variant (FXa) is being developed for treating acute bleeding conditions. Activated factor V is an essential cofactor to FXa for activating prothrombin to thrombin. Thrombi/emboli formation was observed microscopically in FXa toxicity studies in animals. The objective of this research was to evaluate candidate biomarkers for FXa-induced thrombi/emboli formation to inform safety monitoring and dose-escalation decisions in FXa clinical trials. Effects of intravenous FXa administration on platelets, fibrinogen, activated partial thromboplastin time (aPTT), prothrombin time (PT), D-dimer, tissue factor pathway inhibitor, thrombin : antithrombin complex, antithrombin, and factor V, and protein C (PC) activities were evaluated in mice, rats, and monkeys. Mice had endogenous factor V activity 10× that of monkeys and were overly sensitive to FXa-induced thrombi/emboli formation. In monkeys, decreases in fibrinogen and prolongation in aPTT and PT emerged as potential biomarkers for impending FXa-induced thrombi/emboli formation, based on association of changes with microscopically observable thrombi/emboli (0-97 thrombi/emboli per monkey). PC decreases, measured by a clot-based assay, were also observed. A similar reduction in PC activity, when measured by clot-based assay, was observed in a phase 1 clinical trial. However, an in-vitro experiment with human plasma spiked with increasing concentrations of FXa indicated dose-dependent FXa-induced interference with clot-based assays and no depletion of PC or S by FXa in non-clot-based assays. Nonclinical biomarker studies identified fibrinogen, aPTT and PT as potential biomarkers for monitoring the clinical safety of FXa. Results of clot-based assays with FXa treatment should be interpreted with caution.

We use comprehensive patient-level discharge data to study the effect of Medicaid on the use of hospital services. Our analysis relies on cross-state variation in the Affordable Care Act’s Medicaid expansion, along with within-state variation across ZIP Codes in exposure to the expansion. We find that the Medicaid expansion increased Medicaid visits and decreased uninsured visits. The net effect is positive for all visits, suggesting that those who gain coverage through Medicaid consume more hospital services than they would if they remained uninsured. The increase in emergency department visits is largely accounted for by “deferrable” medical conditions. Those who gained coverage under the Medicaid expansion appear to be those who had relatively high need for hospital services, suggesting that the expansion was well targeted. Lastly, we find significant heterogeneity across Medicaid-expansion states in the effects of the expansion, with some states experiencing a large increase in total utilization and other states experiencing little change. Increases in hospital utilization were larger in Medicaid-expansion states that had more residents gaining coverage and lower pre-expansion levels of hospital uncompensated care costs.

We discuss a decision-theoretic approach to building a panel-based, preemptive genotyping program. The method is based on findings that a large percentage of patients are prescribed medications that are known to have pharmacogenetic associations, and over time, a substantial proportion are prescribed additional such medication. Preemptive genotyping facilitates genotype-guided therapy at the time medications are prescribed; panel-based testing allows providers to reuse previously collected genetic data when a new indication arises. Because it is cost-prohibitive to conduct panel-based genotyping on all patients, we describe a three-step approach to identify patients with the highest anticipated benefit. First, we construct prediction models to estimate the risk of being prescribed one of the target medications using readily available clinical data. Second, we use literature-based estimates of adverse event rates, variant allele frequencies, secular death rates, and costs to construct a discrete event simulation that estimates the expected benefit of having an individual’s genetic data in the electronic health record after an indication has occurred. Finally, we combine medication prescription risk with expected benefit of genotyping once a medication is indicated to calculate the expected benefit of preemptive genotyping. For each patient-clinic visit, we calculate this expected benefit across a range of medications and select patients with the highest expected benefit overall. We build a proof of concept implementation using a cohort of patients from a single academic medical center observed from July 2010 through December 2012. We then apply the results of our modeling strategy to show the extent to which we can improve clinical and economic outcomes in a cohort observed from January 2013 through December 2015.

Policy Points: Increasingly, Americans are relying on coverage through a family member to maintain continuous insurance when their own employer-sponsored insurance (ESI) ends. Meanwhile, employers have responded by limiting access to and imposing surcharges on dependent coverage elections. Between 2005 and 2013, adults who transitioned off ESI became likely to enroll in a non-group plan and were twice as likely to become uninsured. Special Enrollment Period enrollment figures under the Affordable Care Act (ACA) suggest these dynamics have not meaningfully changed since 2014. Moving forward, more Americans will rely on alternative sources for affordable health insurance outside the ESI system. New ACA outreach efforts are needed to identify and enroll the large and increasing number of individuals who face the end of ESI benefits throughout the year. Context Employer-sponsored insurance (ESI) is the predominant form of health insurance coverage in the United States, yet little is known about transitions into and out of ESI or whether turnover has increased over time. Methods We fit multistate dynamic transition models for adults aged 18-61 using Survey of Income and Program Participation data from 2005-2007 to 2010-2013 and preliminary Medical Expenditure Panel Survey from the period 2012-2014. Findings Over a 2-year period beginning in 2010, 34.6% of adults with ESI experienced a change, up from 31.7% in 2005-2007. Transitions occurred most frequently among young adults, Hispanic adults, low-income adults, those in fair or poor health, and service industry workers. But even the groups with the lowest turnover—older adults, married adults, and those with a college degree—had 2-year rates of change of up to 30%. The probability that an ESI policyholder regained an employer-based policy after a job change declined by 15% between 2005 and 2013. Meanwhile, the probability that an ESI policyholder enrolled as a dependent on another family member's plan or became uninsured increased twofold. We found little evidence of changes in these dynamics during the first year (2014) of the Affordable Care Act's (ACA) major coverage reforms. Conclusions Increasingly, Americans are relying on dependent ESI coverage through a family member to maintain continuous insurance when their own employer-based benefits end. Those who transitioned off ESI were also less likely to enroll in a non-group plan and were twice as likely to become uninsured. The first year of the ACA did not see material changes in the likelihood that an ESI-insured adult became uninsured or switched to an alternative public or private plan. New ACA outreach efforts are needed to identify and enroll the large and increasing number of individuals who face the end of ESI benefits throughout the year.

White Marlin Kajikia albida are targeted by recreational fisheries in tropical and subtropical waters of the Atlantic Ocean. Off the U.S. East Coast, the vast majority of White Marlin are released after capture. Federal regulations prohibit anglers from removing a White Marlin from the water unless the fish is to be retained; however, numerous photographs of anglers holding White Marlin out of the water are posted on the Internet each summer, demonstrating that there is considerable noncompliance with this management measure. To better understand the effect of air exposure on postrelease survival of White Marlin, we attached pop-up satellite archival tags (PSATs; programmed to release after 30 d) to individuals that were caught on natural baits rigged with circle hooks and that were removed from the water for a period of 1 min (n = 6 fish), 3 min (n = 5 fish), or 5 min (n = 7 fish). We compared our results with those from a previous study in which PSATs were used to follow the fates of 59 White Ma...

The combination of oceanographic barriers and habitat heterogeneity are known to reduce connectivity and leave specific genetic signatures in the demographic history of marine species. However, barriers to gene flow in the marine environment are almost never impermeable which inevitably allows secondary contact to occur. In this study, eight sampling sites (five along the South African coastline, one each in Angola, Senegal and Portugal) were chosen to examine the population genetic structure and phylogeographic history of the cosmopolitan bluefish (Pomatomus saltatrix), distributed across a large South-east Atlantic upwelling zone. Molecular analyses were applied to mtDNA cytochrome b, intron AM2B1 and 15 microsatellite loci. We detected uncharacteristically high genetic differentiation (FST 0.15–0.20; P

Strategic alignment and integration is currently in vogue throughout the health care industry, but its diffusion and pace have not been documented in recent years. The full range of downstream implications from greater alignment between hospitals and physicians has also not been completely explored.We track the organizational landscape among all office-based US physician practices from 2009 to 2015 and document the degree of vertical integration over time. Then, we examine the implications of vertical integration on practices' acceptance of publicly insured patients.We use descriptive trends and linear regression models with practice level fixed effects to capture the relationships between within-office changes in integration behavior and changes in public payer acceptance.Independent (nonintegrated) physician practices are still the most common organizational type, but their share is declining as the share of practices integrated with a health system increases 3-fold between 2009 and 2015. Although80% of practices that are part of a health system accept Medicaid,60% of independent practices will see these patients. Vertically integrating with a health system makes it more likely a practice will start seeing Medicaid patients.Integration-and possibly consolidation-appears to be occurring and may be increasing over time in the United States. However, it also seems to increase the number of physician practices participating in the Medicaid program. This beneficial side effect has not been previously documented and should be kept in mind as policymakers weigh the pros and cons of a more integrated health care system.

Macrophages play a crucial role in the pathogenesis of osteoarthritis (OA). In this study, the feasibility of a formyl peptide receptor 1 (Fpr1)-targeting peptide probe cFLFLF-PEG-(64) Cu via positron emission tomography (PET) imaging was investigated for detection of macrophage activity during development of OA. Monoiodoacetate (MIA) was intraarticularly injected into the knee joint of Sprague-Dawley rats to induce OA. Five days later, cFLFLF-PEG-(64) Cu (∼7,400 kBq/rat) was injected into the tail vein and microPET/CT imaging was performed to assess the OA inflammation by detecting infiltration of macrophages by Fpr1 expression. In addition, a murine macrophage cell line RAW264.7 and two fluorescent probes cFLFLF-PEG-cyanine 7 (cFLFLF-PEG-Cy7) and cFLFLF-PEG-cyanine 5 (cFLFLF-PEG-Cy5) were used to define the binding specificity of the peptide to macrophages. It was found with the MIA model that the maximal standard uptake values (SUVmax ) for right (MIA treated) and left (control) knees were 17.96 ± 5.45 and 3.00 ± 1.40, respectively. Histological evaluation of cryomicrotome sections showed that Fpr1 expression, cFLFLF-PEG-Cy5 binding, and tartrate-resistant acid phosphatase activity were elevated in the injured synovial membranes. The in vitro experiments demonstrated that both fluorescent peptide probes could bind specifically to RAW264.7 cells, which was blocked by cFLFLF but not by the scramble peptide. The findings highlighted the use of cFLFLF-PEG-(64) Cu/PET as an effective method potentially applied for detection and treatment evaluation of OA. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1529-1538, 2016.

Among existing water treatment methods for organic-containing wastewaters, advanced oxidation process, particularly electrocatalytic oxidation, is a technique allowing to reach high degradation and mineralization efficiencies. Electrodes tested for use in electrocatalytic oxidation processes contain either expensive or platinum/group metals such as Pt-, Ru-, Ir-, Pd-, or boron-doped diamond and Sb and Pb compounds which are toxic for the environment. Thereby, there is a need for environmentally friendly and less expensive electrodes. The objectives of this research were to optimize annealing temperature of Ti/Ta2O5–SnO2 electrodes, establish the working media for organic compound oxidation processes as well as check degradation, mineralization and current efficiencies for methylene blue dye oxidation. Decolorisation efficiency of 95 % was achieved in 2 h at pH = 6.5. Neutral media showed also higher efficiency towards COD decrease which was equal to 85 % after 2 h of electrolysis. The lowest energy consumption of 7.7 kWh m−3 required for 100 % decolorisation was observed for the electrodes annealed at 550 °C at pH = 2. The highest current efficiency of 10.1 % attributed to 80 % of COD reduction was obtained for the electrode annealed at 550 °C at pH = 6.5. The optimization data allow further extrapolating of electrocatalytic oxidation process on Ti/Ta2O5–SnO2 electrodes to pilot scale.

Background Little is known about the geographic distribution of the overall primary care workforce that includes both physician and nonphysician clinicians--particularly in areas with restrictive nurse practitioner scope-of-practice laws and where there are relatively large numbers of uninsured. Objective We investigated whether geographic accessibility to primary care clinicians (PCCs) differed across urban and rural areas and across states with more or less restrictive scope-of-practice laws. Research design An observational study. Subjects 2013 Area Health Resource File (AHRF) and US Census Bureau county travel data. Measures The measures included percentage of the population in low-accessibility, medium-accessibility, and high-accessibility areas; number of geographically accessible primary care physicians (PCMDs), nurse practitioners (PCNPs), and physician assistants (PCPAs) per 100,000 population; and number of uninsured per PCC. Results We found divergent patterns in the geographic accessibility of PCCs. PCMDs constituted the largest share of the workforce across all settings, but were relatively more concentrated within urban areas. Accessibility to nonphysicians was highest in rural areas: there were more accessible PCNPs per 100,000 population in rural areas of restricted scope-of-practice states (21.4) than in urban areas of full practice states (13.9). Despite having more accessible nonphysician clinicians, rural areas had the largest number of uninsured per PCC in 2012. While less restrictive scope-of-practice states had up to 40% more PCNPs in some areas, we found little evidence of differences in the share of the overall population in low-accessibility areas across scope-of-practice categorizations. Conclusions Removing restrictive scope-of-practice laws may expand the overall capacity of the primary care workforce, but only modestly in the short run. Additional efforts are needed that recognize the locational tendencies of physicians and nonphysicains.

Bluefin Tuna Thunnus thynnus are highly sought after in commercial and recreational fisheries along the East Coast of North America. To appropriately assess and manage Atlantic Bluefin Tuna (ABT), it is necessary to understand their habitat use during multiple ontogenetic stages. We tagged 17 juvenile ABT in the northwest Atlantic Ocean with pop-up satellite archival tags (PSATs) to determine environmental factors that may affect habitat use. The PSATs were deployed off the coast of Massachusetts in August and September 2012. A generalized linear mixed model was applied to determine factors affecting the mean depth occupied by fish, and beta regression was used to understand factors affecting the proportion of time spent below the thermocline. Thermocline depth significantly affected the mean depth occupied by juvenile ABT and the proportion of time they spent below the thermocline. Time period (dawn, day, dusk, and night) also significantly affected the mean depth occupied by juvenile ABT. Additi...

Key Points Question How does the breadth of health care networks and the degree to which they overlap vary within and across specialties and insurance markets? Findings In this cross-sectional study of 1192 health care networks, large-group employer networks were broader than small-group employer, marketplace, Medicare Advantage, and Medicaid managed care networks. In many states, narrower networks had as much, if not more, overlap across different insurers’ networks than the broadest networks; areas with less concentrated insurance, physician, and hospital markets had narrower and more exclusive networks. Meaning These findings suggest that the structure of plan networks may be a factor in determining care affordability and continuity in the United States, particularly given how frequently individuals change insurance plans., This cross-sectional study quantifies network breadth and exclusivity (ie, overlap) among primary care physician, cardiology, and general acute care hospital networks for employer-based, individually purchased, Medicare Advantage, and Medicaid managed care plans., Importance Little is known about the breadth of health care networks or the degree to which different insurers’ networks overlap. Objective To quantify network breadth and exclusivity (ie, overlap) among primary care physician (PCP), cardiology, and general acute care hospital networks for employer-based (large group and small group), individually purchased (marketplace), Medicare Advantage (MA), and Medicaid managed care (MMC) plans. Design, Setting, and Participants This cross-sectional study included 1192 networks from Vericred. The analytic unit was the network–zip code–clinician type–market, which captured attributes of networks from the perspective of a hypothetical patient seeking access to in-network clinicians or hospitals within a 60-minute drive. Exposures Enrollment in a private insurance plan. Main Outcomes and Measures Percentage of in-network physicians and/or hospitals within a 60-minute drive from a hypothetical patient in a given zip code (breadth). Number of physicians and/or hospitals within each network that overlapped with other insurers’ networks, expressed as a percentage of the total possible number of shared connections (exclusivity). Descriptive statistics (mean, quantiles) were produced overall and by network breadth category, as follows: extra-small (60%). Networks were analyzed by insurance type, state, and insurance, physician, and/or hospital market concentration level, as measured by the Hirschman-Herfindahl index. Results Across all US zip code–network observations, 415 549 of 511 143 large-group PCP networks (81%) were large or extra-large compared with 138 485 of 202 702 MA (68%), 191 918 of 318 082 small-group (60%), 60 425 of 149 841 marketplace (40%), and 21 781 of 66 370 MMC (40%) networks. Large-group employer networks had broader coverage than all other network plans (mean [SD] PCP breadth: large-group employer-based plans, 57.3% [20.1]; small-group employer-based plans, 45.7% [21.4]; marketplace, 36,4% [21.2]; MMC, 32.3% [19.3]; MA, 47.4% [18.3]). MMC networks were the least exclusive (a mean [SD] overlap of 61.3% [10.5] for PCPs, 66.5% [9.8] for cardiology, and 60.2% [12.3] for hospitals). Networks were narrowest (mean [SD] breadth 42.4% [16.9]) and most exclusive (mean [SD] overlap 47.7% [23.0]) in California and broadest (79.9% [16.6]) and least exclusive (71.1% [14.6]) in Nebraska. Rising levels of insurer and market concentration were associated with broader and less exclusive networks. Markets with concentrated primary care and insurance markets had the broadest (median [interquartile range {IQR}], 75.0% [60.0%-83.1%]) and least exclusive (median [IQR], 63.7% [52.4%-73.7%]) primary care networks among large-group commercial plans, while markets with least concentration had the narrowest (median [IQR], 54.6% [46.8%-67.6%]) and most exclusive (median [IQR], 49.4% [41.9%-56.9%]) networks. Conclusions and Relevance In this study, narrower health care networks had a relatively large degree of overlap with other networks in the same geographic area, while broader networks were associated with physician, hospital, and insurance market concentration. These results suggest that many patients could switch to a lower-cost, narrow network plan without losing in-network access to their PCP, although future research is needed to assess the implications for care quality and clinical integration across in-network health care professionals and facilities in narrow network plans.

Key Points Question Is it cost-effective to implement population-wide genomic screening for hereditary breast and ovarian cancer (HBOC)? Findings This decision analytical model study found that genomic screening for HBOC among unselected women may be cost-effective depending on the age distribution of the women screened. Cascade testing of first-degree relatives added a modest improvement in clinical and economic value. Meaning Population-level genomic screening for HBOC targeting women aged 20 to 35 years could be considered in settings in which the outcomes of screening can be evaluated, particularly to avoid a reduction in mammography screening among patients with negative test results., Importance Genomic screening for hereditary breast and ovarian cancer (HBOC) in unselected women offers an opportunity to prevent cancer morbidity and mortality, but the potential clinical impact and cost-effectiveness of such screening have not been well studied. Objective To estimate the lifetime incremental incidence of HBOC and the quality-adjusted life-years (QALYs), costs, and cost-effectiveness of HBOC genomic screening in an unselected population vs family history–based testing. Design, Setting, and Participants In this study conducted from October 27, 2017, to May 3, 2020, a decision analytic Markov model was developed that included health states for precancer, for risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), for earlier- and later-stage HBOC, after cancer, and for death. A complimentary cascade testing module was also developed to estimate outcomes in first-degree relatives. Age-specific RRM and RRSO uptake probabilities were estimated from the Geisinger MyCode Community Health Initiative and published sources. Parameters including RRM and RRSO effectiveness, variant-specific cancer risk, costs, and utilities were derived from published sources. Sensitivity and scenario analyses were conducted to evaluate model assumptions and uncertainty. Main Outcomes and Measures Lifetime cancer incidence, QALYs, life-years, and direct medical costs for genomic screening in an unselected population vs family history–based testing only were calculated. The incremental cost-effectiveness ratio (ICER) was calculated as the difference in cost between strategies divided by the difference in QALYs between strategies. Earlier-stage and later-stage cancer cases prevented and total cancer cases prevented were also calculated. Results The model found that population screening of 30-year-old women was associated with 75 (95% credible range [CR], 60-90) fewer overall cancer cases and 288 QALYs (95% CR, 212-373 QALYs) gained per 100 000 women screened, at an incremental cost of $25 million (95% CR, $21 millon to $30 million) vs family history–based testing; the ICER was $87 700 (78% probability of being cost-effective at a threshold of $100 000 per QALY). In contrast, population screening of 45-year-old women was associated with 24 (95% CR, 18-29) fewer cancer cases and 97 QALYs (95% CR, 66-130 QALYs) gained per 100 000 women screened, at an incremental cost of $26 million (95% CR, $22 million to $30 million); the ICER was $268 200 (0% probability of being cost-effective at a threshold of $100 000 per QALY). A scenario analysis without cascade testing increased the ICER to $92 600 for 30-year-old women and $354 500 for 45-year-old women. A scenario analysis assuming a 5% absolute decrease in mammography screening in women without a variant was associated with the potential for net harm (−90 QALYs per 100 000 women screened; 95% CR, −180 to 10 QALYs). Conclusions and Relevance The results of this study suggest that population HBOC screening may be cost-effective among younger women but not among older women. Cascade testing of first-degree relatives added a modest improvement in clinical and economic value. The potential for harm conferred by inappropriate reduction in mammography among noncarriers should be quantified., This decision analysis estimates the lifetime incremental incidence of hereditary breast and ovarian cancer and the quality-adjusted life-years, costs, and cost-effectiveness of hereditary breast and ovarian cancer genomic screening in an unselected population vs family history–based testing.

The western stock of Atlantic bluefin tuna receives recruits principally from spawning habitats in the Gulf of Mexico although the recent discovery of bluefin tuna larvae in the western North Atlantic Slope Sea calls into question whether there is another key source of recruits to the western stock. We tested whether age-0 juveniles occurring in the US Mid-Atlantic Bight during the late summer might originate from Slope Sea spawning by estimating the hatch date distribution based on otolith microstructural analysis given larval production occurs approximately two months later in the Slope Sea (late June to early August) than in the Gulf of Mexico (early April to mid-June). Following a review of the literature on ageing methodology for Thunnini species, we attempted trials on both sectioned and whole un-sectioned otoliths, and adopted the latter based on higher precision levels. Estimated ages ranged from 122 to 175 (days post hatch) for fish ranging 23.2–36.3 cm fork length. Hatch dates ranged 20 March to 12 May 2010, exhibiting a unimodal distribution. Hatch dates mainly occurred in early-April 2010, which corresponded to the spawning and larval production period for the Gulf of Mexico. Estimated growth rate (size-at-age) was 1.1 mm d−1. Thus, we failed to observe evidence for recruitment from the newfound Slope Sea spawning region, albeit our sample represents only a single year and region. More conclusive inferences on recruitment from the Slope Sea spawning will depend on a greater sample of age-0 juveniles sampled across years or molecular approaches that can identify recruits in older juveniles and adults.

While commercial and recreational fisheries are often considered to compete with one another, in the Atlantic bluefin tuna fishery along the U.S. east coast individual fishermen are permitted to fish either commercially or recreationally on a trip-by-trip basis. How these individuals choose to fish can affect whether the fishery adheres to domestic bluefin tuna regulations and could impact the United States' ability to comply with international management measures. We applied a contingent sequential stated choice survey to bluefin tuna fishermen to identify key factors governing disposition decisions, evaluate the impact of inertia (habit formation), and forecast future harvest patterns. Those who primarily fished recreationally demonstrated more opportunistic harvest tendencies than their commercial counterparts, who were more stable in their preference to harvest fish for sale. Simulations based on model results indicated that fish disposition (harvest commercially, harvest recreationally, or release) varied widely based on regulatory, individual, and fishery characteristics. Such results can help managers to forecast harvest patterns and adopt regulatory tools to ensure that harvest remains within prescribed limits.