Streamlining the Generation of Advanced Polymer Materials Through the Marriage of Automation and Multiblock Copolymer Synthesis in Emulsion.

Synthetic polymers are of paramount importance in modern life - an incredibly wide range of polymeric materials possessing an impressive variety of properties have been developed to date. The recent emergence of artificial intelligence and automation presents a great opportunity to significantly speed up discovery and development of the next generation of advanced polymeric materials. We have focused on the high-throughput automated synthesis of multiblock copolymers that comprise three or more distinct polymer segments of different monomer composition bonded in linear sequence. The present work has exploited automation to prepare high molar mass multiblock copolymers (typically>100,000 g mol-1) using reversible addition-fragmentation chain transfer (RAFT) polymerization in aqueous emulsion. A variety of original multiblock copolymers have been synthesised via a Chemspeed robot, exemplified by a multiblock copolymer comprising thirteen constituent blocks. Moreover, libraries of copolymers of randomized monomer compositions (acrylates, acrylamides, methacrylates, and styrenes), block orders, and block lengths were also generated, thereby demonstrating the robustness of our synthetic approach. One multiblock copolymer contained all four monomer families listed in the pool, which is unprecedented in the literature. The present work demonstrates that automation has the power to render complex and laborious syntheses of such unprecedented materials not just possible, but facile and straightforward, thus representing the way forward to the next generation of complex macromolecular architectures.

Multiblock copolymer synthesis via RAFT emulsion polymerization.

A multiblock copolymer is a polymer of a specific structure that consists of multiple covalently linked segments, each comprising a different monomer type. The control of the monomer sequence has often been described as the "holy grail" of synthetic polymer chemistry, with the ultimate goal being synthetic access to polymers of a "perfect" structure, where each monomeric building block is placed at a desired position along the polymer chain. Given that polymer properties are intimately linked to the microstructure and monomer distribution along the constituent chains, it goes without saying that there exist seemingly endless opportunities in terms of fine-tuning the properties of such materials by careful consideration of the length of each block, the number and order of blocks, and the inclusion of monomers with specific functional groups. The area of multiblock copolymer synthesis remains relatively unexplored, in particular with regard to structure-property relationships, and there are currently significant opportunities for the design and synthesis of advanced materials. The present review focuses on the synthesis of multiblock copolymers via reversible addition-fragmentation chain transfer (RAFT) polymerization implemented as aqueous emulsion polymerization. RAFT emulsion polymerization offers intriguing opportunities not only for the advanced synthesis of multiblock copolymers, but also provides access to polymeric nanoparticles of specific morphologies. Precise multiblock copolymer synthesis coupled with self-assembly offers material morphology control on length scales ranging from a few nanometers to a micrometer. It is imperative that polymer chemists interact with physicists and material scientists to maximize the impact of these materials of the future.

Technical note: Generation of a Cerenkov scatter function convolution kernel for a primary proton beam.

PURPOSE: To generate a Cerenkov scatter function (CSF) for a primary proton beam and to study the dependence of the CSF on the irradiated medium. MATERIALS AND METHODS: The MCNP 6.2 code was used to generate the CSF. The CSF was calculated for light-pigmented, medium-pigmented, and dark-pigmented stratified skin, as well as for a homogeneous optical phantom, which mimics the optical properties of human tissue. CSFs were generated by binning all of the Cerenkov photons which escape the back end (end opposite beam incidence) of a 20 × 20 × 20 cm phantom. A 4 × 4 cm, 500 × 500 bin grid was used to create a histogram of the Cerenkov photon flux on the simulated medium's back surface (surface opposite beam incidence). A triple Gaussian was then used to fit the data. RESULTS: From the triple Gaussian fit, the coefficients of the CSF for the four phantom materials was generated. The individual CSF fit coefficient errors, with respect to the Gaussian representation, were found to be between 0.92% and 4.11%. The R2 value for the fit was calculated to be 0.99. The phantom material was found to have a significant effect (63% difference between materials) on the CSF amplitude and full width at half maximum (195% difference between materials). The difference in these parameters for the three skin pigments was found to be small. CONCLUSIONS: The CSF was obtained for a proton beam using the MCNP 6.2 code for a phantom constructed of light, medium, and dark stratified human skin, as well as for an optical phantom. The CSFs were then fit with a triple-Gaussian function. The coefficients can be used to generate a radially symmetric CSF, which can then be used to deconvolve a measured Cerenkov image to obtain the dose distribution.

RAFT Emulsion Polymerization: MacroRAFT Agent Self-Assembly Investigated Using a Solvachromatic Dye.

Polymerization-induced self-assembly (PISA) and amphiphilic-macroRAFT-mediated emulsion polymerization are commonly used approaches for synthesis of well-defined polymers and sophisticated particle morphologies. One aspect of these systems that remains relatively unexplored is the conformational state of macroRAFT agents in aqueous solution. To redress this deficiency, we have used fluorescence spectrometry experiments to conduct detailed investigations of the coil conformation across a wide range of pH values for a series of poly(acrylic acid) (PAA) and poly(methacrylic acid) (PMAA) macroRAFT agents with different Z-groups (-S-(CH2)2-COOH, -S-(CH2)3-CH3, and -S-(CH2)11-CH3), as well as amphiphilic macroRAFT agents (PMAA-b-poly(methyl methacrylate)(PMMA) and PAA-b-polystyrene(PS)). The critical aggregate concentrations (CAC) or critical micelle concentrations (CMC) for all systems ranged from 7.48 × 10-7 to 2.57 × 10-3 mol L-1. Overall, an extensive library of CAC/CMC values has been compiled for PAA- and PMAA-based macroRAFT agents at different pH conditions, providing important information related to the mechanistic understanding and optimization of macroRAFT-assisted emulsion polymerization.

Disability and the Family in South Wales Coalfield Society, c.1920-1939.

This article utilises the south Wales coalfield in the interwar period as a case study to illustrate the applicability of two sociological theories - family systems theory and the social ecology of the family - to impairment in the past. It demonstrates that a theoretically-informed approach can help to situate impairment in its particular contexts, most especially the family and the community, and give a better sense of the lived experience of disability. It also demonstrates the complexity of the experience of disability as the family and economic circumstances of each impaired individual varied and led to different forms of care-giving or the utilisation of different sources of support. The article also sheds further light on the ubiquity of disability as many families included a number of individuals with different impairments and this too had consequences for experiences and coping strategies.

From Value Assessment to Value Cocreation: Informing Clinical Decision-Making with Medical Claims Data.

Big data and advances in analytical processes represent an opportunity for the healthcare industry to make better evidence-based decisions on the value generated by various tests, procedures, and interventions. Value-based reimbursement is the process of identifying and compensating healthcare providers based on whether their services improve quality of care without increasing cost of care or maintain quality of care while decreasing costs. In this article, we motivate and illustrate the potential opportunities for payers and providers to collaborate and evaluate the clinical and economic efficacy of different healthcare services. We conduct a case study of a firm that offers advanced biomarker and disease state management services for cardiovascular and cardiometabolic conditions. A value-based analysis that comprised a retrospective case/control cohort design was conducted, and claims data for over 7000 subjects who received these services were compared to a matched control cohort. Study subjects were commercial and Medicare Advantage enrollees with evidence of CHD, diabetes, or a related condition. Analysis of medical claims data showed a lower proportion of patients who received biomarker testing and disease state management services experienced a MI (p < 0.01) or diabetic complications (p < 0.001). No significant increase in cost of care was found between the two cohorts. Our results illustrate the opportunity healthcare payers such as Medicare and commercial insurance companies have in terms of identifying value-creating healthcare interventions. However, payers and providers also need to pursue system integration efforts to further automate the identification and dissemination of clinically and economically efficacious treatment plans to ensure at-risk patients receive the treatments and interventions that will benefit them the most.

The Incident Command System: a literature review.

Given the foundational and the fundamental role that the Incident Command System (ICS) is intended to play in on-scene response efforts across the United States, it is important to determine what is known about the system and how this is known. Accordingly, this study addresses the following research question: 'How has research explored the ICS?'. To probe this question, a methodological review of the scant, but widening, pool of research literature directly related to the ICS was conducted. This paper reports on the findings of the analysis related to the focus, theoretical frameworks, population and sampling, methods, results, and conclusions of the existing research literature. While undertaken using different methodological approaches, the ICS research suggests that the system may be limited in its usefulness. In addition, the paper discusses the implications of the research for the state of knowledge of the system and for the direction of future research.

Insulin family polymorphisms in pregnancies complicated by small for gestational age infants.

Being born small for gestational age (SGA) increases the risk for adverse perinatal outcomes and later life vascular and metabolic disorders. The insulin family plays a vital role in intrauterine growth. We investigated the association of functional SNPs in insulin (INS), insulin receptor (INSR) and insulin receptor substrate 2 (IRS2) with small for gestational age (SGA) pregnancies, uterine and umbilical artery Doppler and plasma insulin level. We conducted a nested case-control study of 1401 nulliparous Caucasian women, their partners and babies (216 SGA and 1185 uncomplicated). SGA was defined as a birthweight less than the 10th customized birthweight percentile adjusted for maternal height, weight, parity, ethnicity, gestational age at delivery and infant sex. Uterine and umbilical artery Doppler was performed at 20 ± 1 week gestation. The SNPs in the parent infant trios were genotyped using Sequenom MassARRAY. Plasma insulin was measured by double antibody RIA in 188 healthy non-pregnant adults to assess correlations between SNP genotypes and circulating insulin. Paternal [odds ratio (OR) (95% CI) = 2.2 (1.3-3.9), P = 0.005] and infant [OR (95% CI) = 3.3 (1.7-6.2), P = 0.0001] INSR rs2059806 AA genotype was associated with SGA. Infant INSR rs2059806 A allele was associated with abnormal umbilical artery Doppler [OR (95% CI) = 1.3(1.0-1.7), P = 0.04]. INSR rs2059806 AA homozygous individuals had lower plasma insulin compared with heterozygotes (P = 0.03) and GG homozygotes (P = 0.03). The INSR rs2059806 SNP previously associated with adult vascular and metabolic diseases is also associated with SGA pregnancies. This polymorphism may associate with the risk of vascular and metabolic disorders across the life course.

Evaluating health care delivery reform initiatives in the face of "cost disease".

The authors analyzed historical claims data from 2007 to 2011 from the Vermont All-Payer Claims database for all individuals covered by commercial insurance and Medicaid to determine per capita inpatient expenditures, cost per discharge, and cost per inpatient day. The authors further evaluated the proportion of all health care expenditure allocated to mental health, maternity care, surgical services, and medical services. Although utilization of inpatient services declined during the study period, cost per discharge and cost per inpatient day increased in a compensatory manner. Although the utilization of inpatient services by the Medicaid population decreased by 8%, cost per discharge increased by 84%. Among the commercially insured, discharges per 1000 members were essentially unchanged during the study period and inpatient cost per discharge increased by a relatively modest 32%. The relative utilization of mental health, maternity care, surgical services, and medical services was unchanged during the study period. The significant increase in the cost of inpatient services increased the proportion of total expenditure on surgical services from 21% in 2007 to 33% in 2011. The authors conclude that although health care providers are increasingly being assessed on their ability to control health care costs while achieving better outcomes, there are many cost drivers that are outside of their control. Efforts to assess initiatives, such as patient-centered medical homes, should be focused on utilization trends and outcomes rather than cost or, at a minimum, reflect cost drivers that physicians and other providers cannot influence.

'This is the country of premature old men' Ageing and Aged Miners in the South Wales Coalfield, c.1880-1947.

This article considers the effects of work in the south Wales coal industry either side of the turn of the twentieth century and, specifically, the ways in which work aged workers prematurely. It examines the consequences of working practices for miners' bodies, the expedients utilized by miners to try and cope with the effects of premature ageing, and the consequences for their living standards, experiences and status. It situates these phenomena in the contexts of industrial relations and welfare provision. In so doing, the article engages with historiographies of the life-cycle, the aged, and pensions provision in modern Britain.

Polymorphisms in the fibrinolytic pathway genes and the risk of recurrent spontaneous abortion.

Impaired fibrinolytic activity is implicated in the pathogenesis of recurrent spontaneous abortion (RSA). This case-control study assessed the prevalence of polymorphisms in fibrinolytic system genes in RSA. Cases comprised 202 Sinhalese women who had experienced at least two first-trimester spontaneous abortions and had no living children; controls were 202 women with no history of spontaneous abortion and two or more living children. The groups were matched for age and ethnicity. DNA was genotyped using the Sequenom MassARRAY system. The PLAUR rs4251923 A (OR 95% CI 2.3 [1.3 to 4.0]), SERBP2 rs6098 A (OR 95% CI 1.4 [1.1 to 1.9]) and SERBP2 rs6103 C alleles (OR 95% CI 1.4 [1.1 to 1.9]) were increased in the RSA group compared with controls. The prevalence of PLAUR rs4251923/ SERBP2 rs6098/ SERBP2 rs6103 GG/AA/CC (OR 95% CI 2.4 [1.2 to 4.9], GA/GA/GC(OR 95% CI 3.9 [1.3 to 11.2]), GA/AA/CC (OR 95% CI 2.9 [1.0 to 8.6] and GA/GG/GG (OR 95% CI 21.3 [1.1 to 410.3]) genotypes were also increased in cases. Polymorphisms in the fibrinolytic system genes are associated with RSA in Sinhalese women. These likely impair implantation.

'A Plentiful Crop of Cripples Made by All This Progress': Disability, Artificial Limbs and Working-Class Mutualism in the South Wales Coalfield, 1890-19481.

Historians of orthopaedics, artificial limbs and disability have devoted a great deal of attention to children and soldiers but have neglected to give sufficient space in their studies to industrial workers, the other patient group that has been identified as crucial to the development of these areas. Furthermore, this attention has led to an imbalanced focus on charitable and philanthropic activities as the main means of assistance and the neglect of a significant part of the voluntary sphere, the labour movement. This article, focusing on industrial south Wales, examines the efforts of working-class organisations to provide artificial limbs and a range of other surgical appliances to workers and their family members in the late nineteenth and early twentieth centuries. It finds that a distinctive, labourist conception of disability existed which envisaged disabled workers as an important priority and one to which significant time, effort and resources were devoted.

The changing role of ancillary health care service providers: an evaluation of Health Diagnostic Laboratory, Inc.

In an effort to reduce cost and improve quality, health care payers have enacted a number of incentives to motivate providers to focus their efforts on achieving better clinical outcomes and reducing the prevalence and progression of disease. In response to these incentives, providers are entering into new arrangements such as accountable care organizations and patient-centered medical homes to redesign delivery processes and achieve quality and cost objectives. This article reports the results of a study designed to evaluate the impact on cost and quality of care resulting from services provided by Health Diagnostic Laboratory, Inc., a clinical laboratory with a comprehensive care model. The results show that patients who utilized these laboratory services experienced lower total cost of care (23% reduction, P<0.01) and improved lipid profiles during the follow-up period. Total cost reductions were related to cost reductions found in both inpatient and ambulatory care. These findings suggest that accountable care organizations, patient-centered medical homes, and other groups entering shared savings initiatives should consider the potential role ancillary service providers with comprehensive care models can play in the delivery of integrated care.

The association of maternal ACE A11860G with small for gestational age babies is modulated by the environment and by fetal sex: a multicentre prospective case-control study.

UNLABELLED: We aimed to determine whether the ACE A11860G genotype is associated with small for gestational age babies (SGA) and to determine whether the association is affected by environmental factors and fetal sex. Overall, 3234 healthy nulliparous women with singleton pregnancies, their partners and babies were prospectively recruited in Adelaide, Australia and Auckland, New Zealand. Data analyses were confined to 2121 Caucasian parent-infant trios, among which 216 were pregnancies with SGA infants and 1185 were uncomplicated pregnancies. Women with the ACE A11860G GG genotype in the combined and Adelaide cohorts had increased risk for SGA [odds ratios (OR) 1.5, 95% confidence interval (CI) 1.1-2.1 and OR 2.0, 95% CI 1.3-3.3, respectively) and delivered lighter babies (P = 0.02; P = 0.007, respectively) compared with those with AA/AG genotypes. The maternal ACE A11860G GG genotype was associated with higher maternal plasma ACE concentration at 15 weeks' gestation than AA/AG genotypes (P < 0.001). When the Adelaide cohort was stratified by maternal socio-economic index (SEI) and pre-pregnancy green leafy vegetable intake, the ACE A11860G GG genotype was only associated with an increased risk for SGA (OR 4.9, 95% CI 1.8-13.4 and OR 3.3, 95% CI 1.6-7.0, respectively) and a reduction in customized birthweight centile (P = 0.006 and P = 0.03) if superimposed on maternal SEI <34 or pre-pregnancy green leafy vegetable intake <1 serve/day. Furthermore, the associations of maternal ACE A11860G with customized birthweight centile observed among Adelaide women with SEI <34 or pre-pregnancy green leafy vegetable intake <1 serve/day were female specific. The current study identified a novel association of maternal ACE A11860G with SGA. More interestingly, this association was modified by environmental factors and fetal sex, suggesting ACE A11860G-environment-fetal sex interactions. Trial Registry Name: Screening nulliparous women to identify the combinations of clinical risk factors and/or biomarkers required to predict pre-eclampsia, SGA babies and spontaneous preterm birth. URL: http://www.anzctr.org.au. REGISTRATION NUMBER: ACTRN12607000551493.

The risks and opportunities of the globalization of health care delivery.

The pace and scale of globalization in health care services delivery have accelerated over the past decade. There have been numerous collaborations in health care service delivery between the private sector in North America and Europe with public and private entities in various emerging markets. These partnerships can be extremely fruitful, but also carry significant challenges. Johns Hopkins Medicine International (JHI) has been active for more than a decade in supporting international partners in building capacity and improving delivery systems. In addressing the challenges of globalization we have learned a number of lessons and have come up with several innovations to better help providers in emerging markets respond to the health care needs unique to their regions.

The interaction between the maternal BMI and angiogenic gene polymorphisms associates with the risk of spontaneous preterm birth.

Obesity is associated with an increased level of inflammation. Interactions between inflammatory and angiogenic pathways are implicated in the major pregnancy disorders. The aim of this study was to investigate whether functional polymorphisms in angiogenesis-regulating genes (VEGFA rs699947, VEGFA rs3025039, KDR rs2071559 and ANGPT1 rs2507800) interact with the maternal BMI to modify the risk of a spontaneous preterm birth (sPTB). We conducted a nested case-control study of 1190 nulliparous Caucasian women (107 sPTBs and 1083 controls). Spontaneous PTB was defined as spontaneous preterm labour or a preterm premature rupture of membranes resulting in a preterm birth at <37 weeks of gestation. DNA was extracted from the peripheral blood and genotyped using the Sequenom MassARRAY system. Among overweight or obese women (BMI ≥25), the VEGFA rs699947 AA genotype was associated with a higher risk of sPTBs [odds ratio (OR) = 2.4, 95% confidence interval (CI): 1.4-4.6, P = 0.001] and a significant interaction between the BMI and the polymorphism was detected (OR = 4.2, 95% CI: 1.7-10.9, P = 0.003). Among women with a BMI <25, ANGPT1 rs2507800 AA genotype was associated with a higher risk of sPTB (OR = 2.3, 95% CI: 1.2-4.4, P= 0.02) and a significant interaction between BMI and the polymorphism was detected (OR = 3.3, 95% CI: 1.1-9.3, P = 0.02). All results remained significant after adjusting for potential confounding factors. The maternal BMI interacts with angiogenesis-regulating gene polymorphisms to modify the risk of sPTBs.

Single-nucleotide polymorphisms in the KDR gene in pregnancies complicated by gestational hypertensive disorders and small-for-gestational-age infants.

INTRODUCTION: Pregnancies complicated by preeclampsia and small-for-gestational-age (SGA) infants share placental vascular abnormalities and both disorders confer increased risk of later life coronary artery disease. Kinase insert domain receptor (KDR) is the main receptor for vascular endothelial growth factor A, a potent angiogenic factor which regulates the development of the placental vasculature. Two polymorphisms in KDR (-604T/C and Val297Ile) are known to be associated with coronary artery disease. We investigated the association of these polymorphisms with preeclampsia, gestational hypertension, and SGA infants. METHOD: Nulliparous pregnant women, their partners, and infants were recruited to a prospective cohort study (n = 1169). Doppler ultrasound of the uterine and umbilical arteries was performed at 20 weeks of gestation. Preeclampsia, gestational hypertension, and SGA were defined according to international guidelines. DNA extracted from peripheral venous or cord blood was genotyped using the Sequenom MassARRAY system. Multivariable logistic regression was used to compare the odds for the pregnancy complications between the genotype groups adjusting for potential confounders. RESULTS: Among 937 Caucasian pregnancies, 427 (45.6%) were uncomplicated, 75 (8.0%) developed preeclampsia, 102 (10.9%) developed gestational hypertension, and 72 (7.7%) had SGA infants in the absence of maternal hypertensive disease. Paternal and neonatal KDR-604T/C was associated with preeclampsia (adjusted odds ratio [aOR] 1.6, 95% confidence interval [CI] 1.0-3.0 and aOR 2.2, 95% CI 1.0-4.4), SGA (aOR 1.9, 95% CI 1.1-3.3 and aOR 2.2, 95% CI 1.2-3.9), and SGA with abnormal Doppler (aOR 2.7, 95% CI 1.2-5.9 and aOR 3.2, 95% CI 1.2-5.9). CONCLUSION: Paternal and neonatal carriage of the KDR-604T/C polymorphism is associated with the risk of preeclampsia and SGA infants.