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Obsidian, originating from the Rocky Mountains and the West, was an exotic exchange commodity in Eastern North America that was often deposited in elaborate caches and burials associated with Middle Woodland era Hopewell and later complexes. In earlier times, obsidian is found only rarely. In this paper we report two obsidian flakes recovered from a now submerged paleolandscape beneath Lake Huron that are conclusively attributed to the Wagontire obsidian source in central Oregon; a distance of more than 4,000 km. These specimens, dating to ~ 9,000 BP, represent the earliest and most distant reported occurrence of obsidian in eastern North America.

OBJECTIVE:The organization of work has undergone vast transformations over the past four decades in the United States and has had profound impacts on worker health and wellbeing. The profession of commercial truck driving is one of the best examples. Particularly for long-haul truck drivers, changes in work organization have led to disproportionately poor physiological, psychological, and sleep health outcomes. METHODS:The present study examined disparities in cardiometabolic disease risk among long-haul truck drivers and the general population, and the influence of work organization and sleep in generating these outcomes. Researchers collected survey data from 260 drivers, and blood assay samples from 115 of those drivers, at a large highway truck stop in North Carolina. Comparisons were made for cardiovascular and metabolic risk against the 2011-2012 National Health and Nutrition Examination Survey (NHANES). In addition, logistic regression was used to explore predictive relationships between work organization and sleep and risk for cardiovascular and metabolic disease. RESULTS:There were statistically significant mean differences between the long-haul truck driver sample and the NHANES sample for both cardiovascular (3.71 vs. 3.10; p

Lonicera caerulea var. kamtschatica (LCK), known as blue honeysuckle or haskap berry, is rich in bioactive compounds such as polyphenols, flavonoids, and anthocyanins, which are linked to various health benefits, including anti-inflammatory and antioxidant properties. The research specifically investigates the effects of an LCK extract that has been standardized to contain a minimum of 15% anthocyanins on inflammation and oxidative stress at the cellular level. In vitro studies using A549 human lung epithelial cells and peripheral blood mononuclear cells (PBMCs) demonstrated the extract's anti-inflammatory and antioxidant properties. LCK extract significantly inhibited the nuclear translocation of NF-κB p65 and reduced the production of IL-8 in A549 cells. It also downregulated the expression of pro-inflammatory genes (RELA and PTGS2) while upregulating antioxidant genes (CAT, HMOX1, and SOD2). In PBMCs, LCK extract decreased the phosphorylation of NF-κB p65 and reduced levels of pro-inflammatory cytokines IL-1β and IL-6 following LPS stimulation. Additionally, the extract inhibited reactive oxygen species (ROS) formation and nitric oxide (NO) production, demonstrating its potential to modulate oxidative stress. Furthermore, in vitro assays indicated that LCK extract could hinder the binding of SARS-CoV-2 spike protein to the hACE2 receptor, suggesting antiviral potential. These findings suggest that LCK extract exerts significant anti-inflammatory and antioxidant effects, indicating its potential as a functional food ingredient or dietary supplement to combat inflammation and oxidative stress., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Upper respiratory tract infections (URTIs) are a prevalent health issue, causing considerable morbidity. Despite the availability of conventional treatments, there is an increasing interest in natural products due to their potential antiviral and immunomodulatory benefits. This study aims to evaluate the efficacy of an ELA blend (E- Echinacea purpurea , L- Lonicera cerulea , A- Aronia melanocarpa ) in preventing and alleviating the symptoms of URTIs. Additionally, the study examines the blend's antiviral and immunomodulatory effects both in vitro and through a clinical trial. A randomized, double-blind, placebo-controlled trial involved 61 participants prone to URTIs, with a 60-day treatment and follow-up period. A placebo group later received the ELA blend for 60 days. The ELA blend significantly reduced the incidence of URTIs during the observation period (2 vs. 8; p = 0.044) and, in particular, throat-related symptoms (8 vs. 16; p = 0.038). Analyses of PBMCs showed that baseline production of the cytokines IFN-γ ( p = 0.020), IL-1β ( p = 0.004), IL-2( p < 0.001), IL-6 ( p < 0.001), and TNF-α ( p < 0.001) increased after ELA blend treatment. Moreover, the ELA blend modulated cytokine production in response to PHA-L stimulation, decreasing IFN-γ ( p = 0.008) and IL-2 ( p = 0.012) while increasing IL-1β ( p = 0.005). Following R848 stimulation, the ELA blend enhanced the production of INF-α ( p = 0.012) and IL-2 ( p = 0.025), and decreased IL-1β ( p < 0.001), IL-6 ( p < 0.001), and TNF-α ( p = 0.049). The blend suppressed VSV replication and significantly increased cytokine levels, with IFN-γ increasing by 98 pg/mL ( p = 0.002), IL-1β rising by 233.0 pg/mL ( p = 0.004), and TNF-α showing an increase of 2905 pg/mL ( p = 0.002). These findings highlight the ELA blend's potential to alleviate URTI symptoms, modulate inflammatory and antiviral immune responses, and inhibit viral replication. Further investigations should aim to validate these findings through large-scale studies, and explore the ELA blend's long-term safety and efficacy in diverse populations. Additionally, research should investigate optimal dosing strategies and explore potential synergistic effects with conventional treatments to maximize clinical outcomes. Trial registration: retrospectively registered under NCT06020001.

Previous studies have highlighted the beneficial properties of plants rich in polyphenols, such as Lonicera caerulea var. Kamtschatica Sevast. (LCK), Aronia melanocarpa (AM), and Echinacea purpurea (EP). These plants have demonstrated antioxidant, immunomodulatory, and potential antiviral effects. Thus, the objective of this study was to investigate the impact of the ELA blend, a polyphenol-rich blend containing EP, LCK, and AM, on the cellular mechanisms involved in viral infection. To assess the effects of the ELA blend, various experiments were conducted using A549 cells and a mucociliary tissue 3D model called EpiAirway™. Inflammation and oxidative stress induced by LPS were evaluated through measurements of SOD activity, ELISA, and qPCR analysis. Additionally, antiviral assays were performed in a cell-present environment to examine the blend's effectiveness against HCoV-OC43. The results showed that the ELA blend-treated group exhibited reduced expression of IL1B , CXCL8 , ICAM1 , MCP1 , and RELA in both A549 cells and EpiAirway™. Moreover, the blend enhanced the expression of CAT , HMOX1 , SOD1 , and SOD2 in A549 cells. The antiviral activity of the ELA blend was also investigated, i.e. its influence on viral replication cycle, to determine the potential as an antiviral preparation. At the highest non-cytotoxic concentration, the ELA blend demonstrated a 87.5 % reduction in viral titer when administered simultaneously with HCoV-OC43. It emphasize potential ability of the preparation to block viral entry to the host cells. At the same time, ELA blend did not express virucidal activity, i.e. inactivation of free viral particles, against HCoV-OC43. In conclusion, ELA blend displayed antiviral activity and exhibited immunomodulatory and antioxidant effects. Based on these findings, it can be concluded that ELA blend has potential for the prevention and treatment of viral infections., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Krzysztof Lemke reports financial support was provided by National Center for Research and Development. Paulina Kowalczyk has patent #P.444627; P.446422 pending to Licensee. Katarzyna Zima has patent #P.444627; P.446422 pending to Licensee. Krzysztof Lemke has patent #P.444627; P.446422 pending to Licensee. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Type 2 diabetes, characterized by insulin resistance and impaired glucose homeostasis, is commonly managed through lifestyle interventions and medications such as metformin. Although metformin is generally well-tolerated, it may cause gastrointestinal adverse effects and, in rare cases, precipitate lactic acidosis, necessitating cautious use in individuals with renal dysfunction. Additionally, concerns regarding its impact on hepatic function have led to its discontinuation in cirrhotic patients. This study explores the potential synergistic benefits of a polyphenol-rich blend containing black currant, chokeberry, and black elderberry extracts alongside metformin in managing type 2 diabetes. In vitro results highlighted distinct effects of AMPK pathway modulation, showcasing reductions in cholesterol and triglyceride levels alongside a notable enhancement in glucose uptake. The blend, when combined with metformin, significantly reduced insulin levels and fasting glucose concentrations in an in vivo model. Furthermore, hepatic analyses unveiled a modulation in cellular pathways, suggesting a potential influence on lipid metabolism, attenuation of inflammatory pathways, a decrease in cellular stress response, and antioxidant defense mechanisms, collectively implying a potential reduction in liver fat accumulation. The findings suggest a potential complementary role of polyphenols in enhancing the efficacy of metformin, possibly allowing for reduced metformin dosage and mitigating its side effects. Further clinical studies are warranted to validate these findings and establish the safety and efficacy of this nutraceutical approach in managing type 2 diabetes., Competing Interests: K.Z., B.K., L.B., K.L., and P.K. are employees of AronPharma Ltd. K.Z., B.K., K.L., and P.K. have a patent pending for AP029 blend no. P.444522., (Copyright © 2024 Katarzyna Zima et al.)

The population structure and behaviour of univoltine butterfly species have been studied intensively. However, much less is known about bivoltine species. In particular, in-depth studies of the differences in population structure, behaviour, and ecology between these two generations are largely lacking. Therefore, we here present a mark-release-recapture study of two successive generations of the fritillary butterfly Boloria selene performed in eastern Brandenburg (Germany). We revealed intersexual and intergenerational differences regarding behaviour, dispersal, population characteristics, and protandry. The observed population densities were higher in the second generation. The flight activity of females decreased in the second generation, but remained unchanged in males. This was further supported by the rate of wing decay. The first generation displayed a linear correlation between wing decay and passed time in both sexes, whereas the linear correlation was lost in second-generation females. The proportion of resting individuals in both sexes increased in the second generation, as well as the number of nectaring females. The choice of plant genera used for nectaring seems to be more specialised in the first and more opportunistic in the second generation. The average flight distances were generally higher for females than for males and overall higher in the first generation. Predictions of long-distance movements based on the inverse power function were also generally higher in females than in males but lower in the first generation. Additionally, we found protandry only in the first but not in the second generation, which might correlate with the different developmental pathways of the two generations. These remarkable differences between both generations might reflect an adaptation to the different ecological demands during the flight season and the different tasks they have, i.e. , growth in the spring season; dispersal and colonisation of new habitats during the summer season., Competing Interests: The authors declare there are no competing interests., (©2024 Sing et al.)

Although the enormous potential of droplet-based microfluidics has been successfully demonstrated in the past two decades for medical, pharmaceutical, and academic applications, its inherent potential has not been fully exploited until now. Nevertheless, the cultivation of biological cells and 3D cell structures like spheroids and organoids, located in serially arranged droplets in micro-channels, has a range of benefits compared to established cultivation techniques based on, e.g., microplates and microchips. To exploit the enormous potential of the droplet-based cell cultivation technique, a number of basic functions have to be fulfilled. In this paper, we describe microfluidic modules to realize the following basic functions with high precision: (i) droplet generation, (ii) mixing of cell suspensions and cell culture media in the droplets, (iii) droplet content detection, and (iv) active fluid injection into serially arranged droplets. The robustness of the functionality of the Two-Fluid Probe is further investigated regarding its droplet generation using different flow rates. Advantages and disadvantages in comparison to chip-based solutions are discussed. New chip-based modules like the gradient, the piezo valve-based conditioning, the analysis, and the microscopy module are characterized in detail and their high-precision functionalities are demonstrated. These microfluidic modules are micro-machined, and as the surfaces of their micro-channels are plasma-treated, we are able to perform cell cultivation experiments using any kind of cell culture media, but without needing to use surfactants. This is even more considerable when droplets are used to investigate cell cultures like stem cells or cancer cells as cell suspensions, as 3D cell structures, or as tissue fragments over days or even weeks for versatile applications.

Relicts of subducted oceanic lithosphere provide key information for the tectonic reconstructions of convergent margins. In the Central Alps, such relicts occur as isolated mafic-ultramafic lenses within the migmatites of the southern Adula nappe and Cima-Lunga unit. Analysis of the major-, minor-, and accessory minerals of these ophiolitic relicts, combined with zircon and rutile U-Pb ages and zircon oxygen isotopes, allows the reconstruction of different stages of their complex evolution. The mafic-ultramafic suite in Valle di Moleno consists of chlorite-harzburgites associated with metarodingites and retrogressed eclogites. Relic omphacite and kyanite in retrogressed eclogites provide evidence for subduction-related metamorphism. Increasing X Prp in the garnet mantle towards the rim documents heating during high-pressure metamorphism up to 800-850 °C. Polyphase inclusions and chemical zoning in garnet suggest fluid-assisted melting during high-pressure metamorphism dated at 31.0 ± 0.9 Ma. In Val Cama, chlorite-harzburgites, metarodingites and calcsilicate-metasediments occur. Detrital zircon ages in the metasediment suggest a Mesozoic deposition. The metarodingite-metaperidotite-metasediment association and the low δ 18 O signatures of zircon (δ 18 O 3.0-3.7‰), inherited from seafloor metasomatism of the protoliths, show that the rocks are derived from former altered oceanic crust. Amphibolite facies metamorphism related to the Central Alps Barrovian evolution in Val Cama occurred at 28.8 ± 1.5 Ma. The combined data from Moleno and Cama indicate a rapid transition (~ 2 Ma) from subduction to collisional metamorphism with corresponding exhumation rates of 3-6 cm/year. Fast exhumation tectonics may have been favored by slab break-off or slab extraction. U-Pb dating of rutile from both localities yields ages of ~ 20 Ma, suggesting that these rocks remained at amphibolite-facies conditions for about 10 Ma and underwent a second fast exhumation of 3 cm/year associated with vertical movements along the Insubric line., Supplementary Information: The online version contains supplementary material available at 10.1186/s00015-024-00462-7., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2024.)

Coenzyme Q (or ubiquinone) is a redox-active lipid that serves as universal electron carrier in the mitochondrial respiratory chain and antioxidant in the plasma membrane limiting lipid peroxidation and ferroptosis. Mechanisms allowing cellular coenzyme Q distribution after synthesis within mitochondria are not understood. Here we identify the cytosolic lipid transfer protein STARD7 as a critical factor of intracellular coenzyme Q transport and suppressor of ferroptosis. Dual localization of STARD7 to the intermembrane space of mitochondria and the cytosol upon cleavage by the rhomboid protease PARL ensures the synthesis of coenzyme Q in mitochondria and its transport to the plasma membrane. While mitochondrial STARD7 preserves coenzyme Q synthesis, oxidative phosphorylation function and cristae morphogenesis, cytosolic STARD7 is required for the transport of coenzyme Q to the plasma membrane and protects against ferroptosis. A coenzyme Q variant competes with phosphatidylcholine for binding to purified STARD7 in vitro. Overexpression of cytosolic STARD7 increases ferroptotic resistance of the cells, but limits coenzyme Q abundance in mitochondria and respiratory cell growth. Our findings thus demonstrate the need to coordinate coenzyme Q synthesis and cellular distribution by PARL-mediated STARD7 processing and identify PARL and STARD7 as promising targets to interfere with ferroptosis., (© 2023. The Author(s).)

Objective: Using mixed methods, we explored properties of long-haul truckers' social networks potentially influencing STI/BBI acquisition and transmission. Methods: We recruited inner-city drug and sex network members (N = 88) for interviews. Blood and urine samples and vaginal swabs were collected to test for STIs/BBIs. Data were collected on participants' role in the network (trucker, sex worker, or intermediary), sexual and substance-use behaviors, and dyadic relationships with drug and/or sex contacts. We analyzed network data using UCINET. Results: Data revealed 2 major network clusters (58 male truckers, 6 male intermediaries, and 24 female sex workers; 27.3% STI/BBI positive). Overall, 18.8% of network members had more than one type of risky relationship with the same person (multiplexity), 11.4% of dyads were between 2 STI/ BBI positive people (assortative mixing), 36.4% were between one STI/BBI positive person and one negative person (disassortative mixing), 44.3% of people were connected to more than one person who was STI/BBI positive (concurrency), and 62.5% of nodes were just one path removed from an STI/BBI positive individual (bridging). Conclusion: Despite only 27.3% of the network being STI/BBI positive, our results revealed network characteristics (and potential intervention points) that amplify risk of disease spread within trucker-centered networks.

Background: An individual's risk for future opioid overdoses is usually assessed using a 12-month "lookback" period. Given the potential urgency of acting rapidly, we compared the performance of alternative predictive models with risk information from the past 3, 6, 9, and 12 months., Methods: We included 1,014,033 Maryland residents aged 18-80 with at least 1 opioid prescription and no recorded death in 2015. We used 2015 Maryland prescription drug monitoring data to identify risk factors for nonfatal opioid overdoses from hospital discharge records and investigated fatal opioid overdose from medical examiner data in 2016. Prescription drug monitoring program-derived predictors included demographics, payment sources for opioid prescriptions, count of unique opioid prescribers and pharmacies, and quantity and types of opioids and benzodiazepines filled. We estimated a series of logistic regression models that included 3, 6, 9, and 12 months of prescription drug monitoring program data and compared model performance, using bootstrapped C-statistics and associated 95% confidence intervals., Results: For hospital-treated nonfatal overdose, the C-statistic increased from 0.73 for a model including only the fourth quarter to 0.77 for a model with 4 quarters of data. For fatal overdose, the area under the curve increased from 0.80 to 0.83 over the same models. The strongest predictors of overdose were prescription fills for buprenorphine and Medicaid and Medicare as sources of payment., Conclusions: Models predicting opioid overdose using 1 quarter of data were nearly as accurate as models using all 4 quarters. Models with a single quarter may be more timely and easier to identify persons at risk of an opioid overdose.

Importance: Responding to the opioid crisis requires tools to identify individuals at risk of overdose. Given the expansion of illicit opioid deaths, it is essential to consider risk factors across multiple service systems., Objective: To develop a predictive risk model to identify opioid overdose using linked clinical and criminal justice data., Design, Setting, and Participants: A cross-sectional sample was created using 2015 data from 4 Maryland databases: all-payer hospital discharges, the prescription drug monitoring program (PDMP), public-sector specialty behavioral treatment, and criminal justice records for property or drug-associated offenses. Maryland adults aged 18 to 80 years with records in any of 4 databases were included, excluding individuals who died in 2015 or had a non-Maryland zip code. Logistic regression models were estimated separately for risk of fatal and nonfatal opioid overdose in 2016. Model performance was assessed using bootstrapping. Data analysis took place from February 2018 to November 2019., Exposures: Controlled substance prescription fills and hospital, specialty behavioral health, or criminal justice encounters., Main Outcomes and Measures: Fatal opioid overdose defined by the state medical examiner and 1 or more nonfatal overdoses treated in Maryland hospitals during 2016., Results: There were 2 294 707 total individuals in the sample, of whom 42.3% were male (n = 970 019) and 53.0% were younger than 50 years (647 083 [28.2%] aged 18-34 years and 568 160 [24.8%] aged 35-49 years). In 2016, 1204 individuals (0.05%) in the sample experienced fatal opioid overdose and 8430 (0.37%) experienced nonfatal opioid overdose. In adjusted analysis, the factors mostly strongly associated with fatal overdose were male sex (odds ratio [OR], 2.40 [95% CI, 2.08-2.76]), diagnosis of opioid use disorder in a hospital (OR, 2.93 [95% CI, 2.17-3.80]), release from prison in 2015 (OR, 4.23 [95% CI, 2.10-7.11]), and receiving opioid addiction treatment with medication (OR, 2.81 [95% CI, 2.20-3.86]). Similar associations were found for nonfatal overdose. The area under the curve for fatal overdose was 0.82 for a model with hospital variables, 0.86 for a model with both PDMP and hospital variables, and 0.89 for a model that further added behavioral health and criminal justice variables. For nonfatal overdose, the area under the curve using all variables was 0.85., Conclusions and Relevance: In this analysis, fatal and nonfatal opioid overdose could be accurately predicted with linked administrative databases. Hospital encounter data had higher predictive utility than PDMP data. Model performance was meaningfully improved by adding PDMP records. Predictive models using linked databases can be used to target large-scale public health programs.

Ethnopharmacological Relevance: Nigella sativa L. seed extracts and oils have been embraced by traditional medicine of cultures inhabiting Middle East and North Africa for centuries. Among other uses, it has been applied against dermatitis and eczema often worsened by staphylococcal colonization of the skin., Aim of the Study: The study was conducted to evaluate applicability of N. sativa seed extract in antibacterial skin formulations by examination of its activity against methicillin-resistant Staphylococcus aureus as well as cytotoxicity against human dermal fibroblasts., Materials and Methods: Two variants of N. sativa seed extract containing 9.91 and 2.10 % of thymoquinone were prepared by supercritical carbon dioxide extraction. The extracts and standards of their major volatile ingredients; thymoquinone, thymol, p-cymene alongside with the reference antiseptics; chlorquinaldol and a combination of amylmetacresol with 2,4-dichlorobenzyl alcohol were subjected to evaluation of antibacterial efficacy against a collection of Staphylococcus aureus strains. The preparation based on Vaseline containing 1% of N. sativa extract was applied on Mueller-Hinton agar plates and its ability to inhibit S. aureus growth was examined. The MTT assay was employed to study cytotoxic effects of the thymoquinone-rich N. sativa seed extract against HDFa fibroblasts., Results: N. sativa seed extract and thymoquinone have shown potent bacteriostatic and bactericidal effect against Staphylococcus aureus, including methicillin-resistant strains (MRSA) isolated in Poland. Results suggest that N. sativa seed extract activity against S. aureus should mainly be attributed to thymoquinone, which was effective in concentrations of 4-16 μg/ml. Regarding the activity against S. aureus, thymoquinone was more efficient than a combination of amylmetacresol with 2,4-dichlorobenzyl alcohol and comparable to chlorquinaldol. The Vaseline-based preparation containing N. sativa extract caused growth inhibition comparable to an equally concentrated DMSO solution of the extract. The IC50 of N. sativa extract against HDFa fibroblast was determined at 0.2 mg/ml, which was 2-fold higher than the average MIC and MBC of the extract against S. aureus., Conclusions: The observed effectiveness of N. sativa seed extracts against bacteria was found to be dominantly dependent on concentration of thymoquinone. Its efficiency against S. aureus isolates as well as results of cytotoxicity examination against human dermal fibroblasts indicate on its applicability as an antibacterial agent for topical use and motivates further research in this area., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Payers and providers still primarily use ordinary least squares (OLS) to estimate expected economic and clinical outcomes for risk adjustment purposes. Penalized linear regression represents a practical and incremental step forward that provides transparency and interpretability within the familiar regression framework. This study conducted an in-depth comparison of prediction performance of standard and penalized linear regression in predicting future health care costs in older adults., Methods and Findings: This retrospective cohort study included 81,106 Medicare Advantage patients with 5 years of continuous medical and pharmacy insurance from 2009 to 2013. Total health care costs in 2013 were predicted with comorbidity indicators from 2009 to 2012. Using 2012 predictors only, OLS performed poorly (e.g., R2 = 16.3%) compared to penalized linear regression models (R2 ranging from 16.8 to 16.9%); using 2009-2012 predictors, the gap in prediction performance increased (R2:15.0% versus 18.0-18.2%). OLS with a reduced set of predictors selected by lasso showed improved performance (R2 = 16.6% with 2012 predictors, 17.4% with 2009-2012 predictors) relative to OLS without variable selection but still lagged behind the prediction performance of penalized regression. Lasso regression consistently generated prediction ratios closer to 1 across different levels of predicted risk compared to other models., Conclusions: This study demonstrated the advantages of using transparent and easy-to-interpret penalized linear regression for predicting future health care costs in older adults relative to standard linear regression. Penalized regression showed better performance than OLS in predicting health care costs. Applying penalized regression to longitudinal data increased prediction accuracy. Lasso regression in particular showed superior prediction ratios across low and high levels of predicted risk. Health care insurers, providers and policy makers may benefit from adopting penalized regression such as lasso regression for cost prediction to improve risk adjustment and population health management and thus better address the underlying needs and risk of the populations they serve., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: This study applied algorithms for grouping diagnosis codes and prescription drugs from the ACG case-mix/risk adjustment methodology, developed at Johns Hopkins Bloomberg School of Public Health. The Johns Hopkins University receives royalties for non-academic use of the software based on the ACG methodology. Dr. Kan, Dr. Chang, Dr. Kharrazi, Dr. Bodycombe, Dr. Lemke and Dr. Weiner receive a portion of their salary support from this revenue. This does not alter our adherence to all PLOS ONE policies on sharing data and materials.

Background: Newborn screening (NBS) is a national initiative for early identification of serious illnesses, the clinical consequences of which can be reduced by disease-specific early interventions. The Rhode Island Department of Health (RIDOH) has been screening for sickle cell disease (SCD) since 1990. In this work the authors sought to determine the success of NBS and explore aspects of the program that could be improved., Methods: A convenience sample of PCPs with privileges at Women and Infants Hospital of Rhode Island was surveyed by a Survey Monkey® questionnaire to determine exactly how NBS results were handled in each PCP's office and to gather information on how to improve the process as it currently stands., Results: The process appeared to work efficiently. Recommendations were made to improve the service, examples of which are provided with this paper., Discussion: Although NBS has a national focus, the responsibility of ensuring that babies are screened successfully and that follow-up is complete, rests with individual states. This study revealed that the screening process in Rhode Island for SCD is successful but provided suggestions for improvements. The investigators have followed up with the suggestions.

Pancreatic cancer exhibits a worst prognosis owed to an aggressive tumor progression i.a. driven by chemoresistance or tumor-stroma-interactions. The identification of candidate genes, which promote this progression, can lead to new therapeutic targets and might improve patient's outcome. The identification of these candidates in a plethora of genes requires suitable screening protocols. The aim of the present study was to establish a universally usable device which ensures versatile cultivation, screening and handling protocols of cancer cells with the 3D spheroid model, an approved model to study tumor biology. By surface modification and alternative handling of a commercial 384-well plate, a modified device enabling (i) 3D cultivation either by liquid overlay or by a modified hanging drop method for (ii) screening of substances as well as for tumor-stroma-interactions (iii) either with manual or automated handling was established. The here presented preliminary results of cell line dependent dose-response-relations and a stromal-induced spheroid-formation of the pancreatic cancer cells demonstrate the proof-of-principle of the versatile functionality of this device. By adapting the protocols to automation, a higher reproducibility and the ability for high-throughput analyses were ensured.

Although the great potential of droplet based microfluidic technologies for routine applications in industry and academia has been successfully demonstrated over the past years, its inherent potential is not fully exploited till now. Especially regarding to the droplet generation reproducibility and stability, two pivotally important parameters for successful applications, there is still a need for improvement. This is even more considerable when droplets are created to investigate tissue fragments or cell cultures (e.g. suspended cells or 3D cell cultures) over days or even weeks. In this study we present microfluidic chips composed of a plasma coated polymer, which allow surfactants-free, highly reproducible and stable droplet generation from fluids like cell culture media. We demonstrate how different microfluidic designs and different flow rates (and flow rate ratios) affect the reproducibility of the droplet generation process and display the applicability for a wide variety of bio(techno)logically relevant media.