Polarized blazar X-rays imply particle acceleration in shocks.

Most of the light from blazars, active galactic nuclei with jets of magnetized plasma that point nearly along the line of sight, is produced by high-energy particles, up to around 1 TeV. Although the jets are known to be ultimately powered by a supermassive black hole, how the particles are accelerated to such high energies has been an unanswered question. The process must be related to the magnetic field, which can be probed by observations of the polarization of light from the jets. Measurements of the radio to optical polarization-the only range available until now-probe extended regions of the jet containing particles that left the acceleration site days to years earlier1-3, and hence do not directly explore the acceleration mechanism, as could X-ray measurements. Here we report the detection of X-ray polarization from the blazar Markarian 501 (Mrk 501). We measure an X-ray linear polarization degree ΠX of around 10%, which is a factor of around 2 higher than the value at optical wavelengths, with a polarization angle parallel to the radio jet. This points to a shock front as the source of particle acceleration and also implies that the plasma becomes increasingly turbulent with distance from the shock.

Understanding the conditions for the optimum nonlinear refraction of epsilon-near-zero films based on transparent conducting oxides.

Transparent Conducting Oxides (TCOs) exhibit a large and ultrafast intensity-dependent refractive index in their Epsilon-Near-Zero (ENZ) spectral region, which depends dramatically on the material properties and measurement arrangement conditions. Therefore, attempts to optimize the nonlinear response of ENZ TCOs usually involve extensive nonlinear optical measurements. In this work, we show that significant experimental work can be avoided by carrying out an analysis of the material's linear optical response. The analysis accounts for the impact of thickness-dependent material parameters on the absorption and field intensity enhancement under different measurement conditions and estimates the incidence angle required for achieving the maximum nonlinear response for a given TCO film. We perform measurements of angle-dependent and intensity-dependent nonlinear transmittance for Indium-Zirconium Oxide (IZrO) thin films with different thicknesses and demonstrate a good agreement between the experiment and theory. Our results also indicate that the film thickness and the excitation angle of incidence can be adjusted simultaneously to optimize the nonlinear optical response, allowing a flexible design of TCO-based highly nonlinear optical devices.

Maternal Epidemiology of Brachial Plexus Birth Injuries in California: 1996 to 2012.

OBJECTIVE: This study aimed to evaluate the incidence of brachial plexus birth injury (BPBI) and its associations with maternal demographic factors. Additionally, we sought to determine whether longitudinal changes in BPBI incidence differed by maternal demographics. STUDY DESIGN: We conducted a retrospective cohort study of over 8 million maternal-infant pairs using California's Office of Statewide Health Planning and Development Linked Birth Files from 1991 to 2012. Descriptive statistics were used to determine BPBI incidence and the prevalence of maternal demographic factors (race, ethnicity, age). Multivariable logistic regression was used to determine associations of year, maternal race, ethnicity, and age with BPBI. Excess population-level risk associated with these characteristics was determined by calculating population attributable fractions. RESULTS: The incidence of BPBI between 1991 and 2012 was 1.28 per 1,000 live births, with peak incidence of 1.84 per 1,000 in 1998 and low of 0.9 per 1,000 in 2008. Incidence varied by demographic group, with infants of Black (1.78 per 1,000) and Hispanic (1.34 per 1,000) mothers having higher incidences compared with White (1.25 per 1,000), Asian (0.8 per 1,000), Native American (1.29 per 1,000), other race (1.35 per 1,000), and non-Hispanic (1.15 per 1,000) mothers. After controlling for delivery method, macrosomia, shoulder dystocia, and year, infants of Black (adjusted odds ratio [AOR] = 1.88, 95% confidence interval [CI] = 1.70, 2.08), Hispanic (AOR = 1.25, 95% CI = 1.18, 1.32), and advanced-age mothers (AOR = 1.16, 95% CI = 1.09, 1.25) were at increased risk. Disparities in risk experienced by Black, Hispanic, and advanced-age mothers contributed to a 5, 10, and 2% excess risk at the population level, respectively. Longitudinal trends in incidence did not vary among demographic groups. Population-level changes in maternal demographics did not explain changes in incidence over time. CONCLUSION: Although BPBI incidence has decreased in California, demographic disparities exist. Infants of Black, Hispanic, and advanced-age mothers are at increased BPBI risk compared with White, non-Hispanic, and younger mothers. KEY POINTS: · The incidence of BPBI has decreased over time.. · Demographic disparities in BPBI incidence and risk exist.. · Infants of Black, Hispanic, and advanced age mothers are at greatest risk of BPBI..

Axon-Myelin Unit Blistering as Early Event in MS Normal Appearing White Matter.

OBJECTIVE: Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease of unknown etiology. Although the prevalent view regards a CD4+ -lymphocyte autoimmune reaction against myelin at the root of the disease, recent studies propose autoimmunity as a secondary reaction to idiopathic brain damage. To gain knowledge about this possibility we investigated the presence of axonal and myelinic morphological alterations, which could implicate imbalance of axon-myelin units as primary event in MS pathogenesis. METHODS: Using high resolution imaging histological brain specimens from patients with MS and non-neurological/non-MS controls, we explored molecular changes underpinning imbalanced interaction between axon and myelin in normal appearing white matter (NAWM), a region characterized by normal myelination and absent inflammatory activity. RESULTS: In MS brains, we detected blister-like swellings formed by myelin detachment from axons, which were substantially less frequently retrieved in non-neurological/non-MS controls. Swellings in MS NAWM presented altered glutamate receptor expression, myelin associated glycoprotein (MAG) distribution, and lipid biochemical composition of myelin sheaths. Changes in tethering protein expression, widening of nodes of Ranvier and altered distribution of sodium channels in nodal regions of otherwise normally myelinated axons were also present in MS NAWM. Finally, we demonstrate a significant increase, compared with controls, in citrullinated proteins in myelin of MS cases, pointing toward biochemical modifications that may amplify the immunogenicity of MS myelin. INTERPRETATION: Collectively, the impaired interaction of myelin and axons potentially leads to myelin disintegration. Conceptually, the ensuing release of (post-translationally modified) myelin antigens may elicit a subsequent immune attack in MS. ANN NEUROL 2021;89:711-725.

Positive predictive value of a single nucleotide polymorphism (SNP)-based NIPT for aneuploidy in twins: Experience from clinical practice.

OBJECTIVE: Twins account for approximately 1 in 30 live births in the United States. However, there are limited clinical experience studies published in noninvasive prenatal testing (NIPT) for detecting aneuploidies in twins. This study reports the performance of an SNP-based NIPT in the largest cohort with known outcomes for high-risk aneuploidy results. METHOD: This is a retrospective analysis of 18,984 results from commercial single-nucleotide polymorphism (SNP)-based NIPT tests performed in twins between October 2, 2017 and December 31, 2019. Follow-up for all 211 high-risk cases was solicited. RESULTS: Follow-up outcomes were obtained in 105 cases. Positive predictive values (PPVs) for high-risk results were 88.7% (63/71, 95% Confidence Interval [CI]: 79.0%-95.0%) for trisomy 21% and 72.7% (8/11, 95% CI: 39.0%-94.0%) for trisomy 18. The results were stratified into monozygotic (MZ) and dizygotic (DZ). The PPVs in MZ were 100% for both trisomy 21 (4/4, 95% CI: 40%-100%) and trisomy 18 (1/1, 95% CI: 2.5%-100%). No trisomy 13 cases were detected in the MZ group. The PPVs in DZ were 88.1% (59/67, 95% CI: 77.8%-94.7%), 70.0% (7/10, 95% CI: 34.8%-93.3%), and 66.7% (2/3, 95% CI: 9.4%-99.2%) for trisomy 21, trisomy 18, and trisomy 13, respectively. CONCLUSION: The performance of SNP-based NIPT in this large twin cohort was comparable to previously reported twin NIPT studies. SNP-based NIPT allows for zygosity-based PPV assessment.

Urbach-edge-assisted electro-absorption for enhanced free-space optical modulation.

In this work, we introduce an electro-absorption (EA)-based retro-modulator for effective realization of free-space optical communications via passive downlinks. Demands for deep modulation and broad directionality in such links are met by its corner-cube assembly of EA-modulators. The EA-modulators use semi-insulating InP as its band edge absorption exhibits an Urbach tail near the 980-nm wavelength of the laser light. This enables Urbach-edge-assisted EA, which allows the field-induced absorption to be optimized via temperature. The theory, from a uniting of the Einstein model and Franz-Keldysh effect, and experiments, from a prototype, show good agreement with deep (greater than 15%) modulation depths. Such functionality can meet the key demands of emerging free-space optical communication links.

Optical design of diffraction-limited x-ray telescopes.

Astronomical imaging with micro-arcsecond (µas) angular resolution could enable breakthrough scientific discoveries. Previously proposed µas x-ray imager designs have been interferometers with limited effective collecting area. Here we describe x-ray telescopes achieving diffraction-limited performance over a wide energy band with large effective area, employing a nested-shell architecture with grazing-incidence mirrors, while matching the optical path lengths between all shells. We present two compact nested-shell Wolter Type 2 grazing-incidence telescope designs for diffraction-limited x-ray imaging: a micro-arcsecond telescope design with 14 µas angular resolution and 2.9m2 of effective area at 5 keV photon energy (λ=0.25nm), and a smaller milli-arcsecond telescope design with 525 µas resolution and 645cm2 effective area at 1 keV (λ=1.24nm). We describe how to match the optical path lengths between all shells in a compact mirror assembly and investigate chromatic and off-axis aberrations. Chromatic aberration results from total external reflection off of mirror surfaces, and we greatly mitigate its effects by slightly adjusting the path lengths in each mirror shell. The mirror surface height error and alignment requirements for diffraction-limited performance are challenging but arguably achievable in the coming decades. Because the focal ratio for a diffraction-limited x-ray telescope is extremely large (f/D∼105), the only important off-axis aberration is curvature of field, so a 1 arc sec field of view is feasible with a flat detector. The detector must fly in formation with the mirror assembly, but relative positioning tolerances are on the order of 1 m over a distance of some tens to hundreds of kilometers. Although there are many challenges to achieving diffraction-limited x-ray imaging, we did not find any fundamental barriers.

Phylogeography, Population Structure, and Species Delimitation in Rockhopper Penguins (Eudyptes chrysocome and Eudyptes moseleyi).

Rockhopper penguins are delimited as 2 species, the northern rockhopper (Eudyptes moseleyi) and the southern rockhopper (Eudyptes chrysocome), with the latter comprising 2 subspecies, the western rockhopper (Eudyptes chrysocome chrysocome) and the eastern rockhopper (Eudyptes chrysocome filholi). We conducted a phylogeographic study using multilocus data from 114 individuals sampled across 12 colonies from the entire range of the northern/southern rockhopper complex to assess potential population structure, gene flow, and species limits. Bayesian and likelihood methods with nuclear and mitochondrial DNA, including model testing and heuristic approaches, support E. moseleyi and E. chrysocome as distinct species lineages with a divergence time of 0.97 Ma. However, these analyses also indicated the presence of gene flow between these species. Among southern rockhopper subspecies, we found evidence of significant gene flow and heuristic approaches to species delimitation based on the genealogical diversity index failed to delimit them as species. The best-supported population models for the southern rockhoppers were those where E. c. chrysocome and E. c. filholi were combined into a single lineage or 2 lineages with bidirectional gene flow. Additionally, we found that E. c. filholi has the highest effective population size while E. c. chrysocome showed similar effective population size to that of the endangered E. moseleyi. We suggest that the current taxonomic definitions within rockhopper penguins be upheld and that E. chrysocome populations, all found south of the subtropical front, should be treated as a single taxon with distinct management units for E. c. chrysocome and E. c. filholi.

Effect of a pre-milking teat foam and a liner disinfectant on the presence of mesophilic and (proteolytic) psychrotrophic bacteria prior to milking.

Contamination of raw milk by psychrotrophs can lead to the production of heat-resistant proteases and subsequent spoilage of UHT milk. Therefore, this research communication evaluated the effect of a pre-milking teat disinfectant (active components: L-(+)-lactic acid and salicylic acid) and a liner disinfectant (active components: peracetic acid and hydrogen peroxide) on the number of mesophilic and (proteolytic) psychrotrophic bacteria prior to milking. The teat orifices of 10 cows were sampled using a swabbing procedure before and after treatment with a pre-milking teat disinfectant on six subsequent days. On the teat orifices, there was a small but statistically significant decrease in the psychrotrophic bacterial counts between pre and post dipping. No differences were observed for the mesophilic bacterial counts and proteolytic active counts. Liners were also sampled using swabs pre and post disinfection. No statistically significant decrease in the bacterial counts was observed post liner disinfection, although there was a numerical decrease. Sixty-two percent of the proteolytic psychrotrophs were pseudomonads: 16.5% of which were P. fragi, 14.3% P. lundensis, 10.0% P. fluorescens and 2.9% P. putida. Trinitrobenzenesulfonic acid (TNBS) analysis revealed a wide variety in proteolytic activity (from 0 to 55 µmol glycine/ml milk) and the presence of high producers. It can be concluded that there was only a minor effect of teat and liner disinfection on the psychrotrophic bacterial counts indicating that the measures presented did not result in a reduction of the targeted bacteria on teat orifices and liners.

Possibilities for Groundwater Flow Sensing with Fiber Bragg Grating Sensors.

An understanding of groundwater flow near drinking water extraction wells is crucial when it comes to avoiding well clogging and pollution. A promising new approach to groundwater flow monitoring is the deployment of a network of optical fibers with fiber Bragg grating (FBG) sensors. In preparation for a field experiment, a laboratory scale aquifer was constructed to investigate the feasibility of FBG sensors for this application. Multiparameter FBG sensors were able to detect changes in temperature, pressure, and fiber shape with sensitivities influenced by the packaging. The first results showed that, in a simulated environment with a flow velocity of 2.9 m/d, FBG strain effects were more pronounced than initially expected. FBG sensors of a pressure-induced strain implemented in a spatial array could form a multiplexed sensor for the groundwater flow direction and magnitude. Within the scope of this research, key technical specifications of FBG interrogators for groundwater flow sensing were also identified.

Dynamic Consolidation Measurements in a Well Field Using Fiber Bragg Grating Sensors.

Currently available groundwater flow prediction tools and methods are limited by insufficient spatial resolution of subsurface data and the unknown local heterogeneity. In this field study, fiber Bragg grating (FBG) sensors were installed in an extraction well field to investigate its potential to measure groundwater flow velocity. Reference in-situ pore pressure and temperature measurements were used to identify possible sources of FBG responses. FBG strain sensors were able to detect soil consolidation caused by groundwater extraction from 250 m distance. The results show that FBG responses were influenced by interface friction between soil and FBG packaging. FBG packaging slipped in soil and the effect was more pronounced during higher groundwater flow around a nearby well. These FBG fibers could be applied for indirect flow monitoring that does not require any tracer and provide real-time and long-term data during regular operation of extraction wells.

Label-Free Prostate Cancer Detection by Characterization of Extracellular Vesicles Using Raman Spectroscopy.

Mammalian cells release extracellular vesicles (EVs) into their microenvironment that travel the entire body along the stream of bodily fluids. EVs contain a wide range of biomolecules. The transported cargo varies depending on the EV origin. Knowledge of the origin and chemical composition of EVs can potentially be used as a biomarker to detect, stage, and monitor diseases. In this paper, we demonstrate the potential of EVs as a prostate cancer biomarker. A Raman optical tweezer was employed to obtain Raman signatures from four types of EV samples, which were red blood cell- and platelet-derived EVs of healthy donors and the prostate cancer cell lines- (PC3 and LNCaP) derived EVs. EVs' Raman spectra could be clearly separated/classified into distinct groups using principal component analysis (PCA) which permits the discrimination of the investigated EV subtypes. These findings may provide new methodology to detect and monitor early stage cancer.

Colonization and diversification of the white-browed shortwing (Aves: Muscicapidae: Brachypteryx montana) in the Philippines.

Molecular phylogenetic approaches have greatly improved our knowledge of the pattern and process of biological diversification across the globe; however, many regions remain poorly documented, even for well-studied vertebrate taxa. The Philippine archipelago, one of the least-studied 'biodiversity hotspots', is an ideal natural laboratory for investigating the factors driving diversification in an insular and geologically dynamic setting. We investigated the history and geography of diversification of the Philippine populations of a widespread montane bird, the White-browed Shortwing (Brachypteryx montana). Leveraging dense archipelago-wide sampling, we generated a multi-locus genetic dataset (one nuclear and two mtDNA markers), which we analyzed using phylogenetic, population genetic, and coalescent-based methods. Our results demonstrate that Philippine shortwings (1) likely colonized the Philippines from the Sunda Shelf to Mindanao in the late Miocene or Pliocene, (2) diversified across inter-island barriers into three divergent lineages during the Pliocene and early Pleistocene, (3) have not diversified within the largest island, Luzon, contrary to patterns observed in other montane taxa, and (4) colonized Palawan from the oceanic Philippines rather than from Borneo, challenging the assumption of Palawan functioning exclusively as a biogeographic extension of the Sunda Shelf. Additionally, our finding that divergent (c. 4.0 mya) lineages are coexisting in secondary sympatry on Mindanao without apparent gene flow suggests that the speciation process is likely complete for these shortwing lineages. Overall, these investigations provide insight into how topography and island boundaries influence diversification within remote oceanic archipelagos and echo the results of many other studies in demonstrating that taxonomic diversity continues to be underestimated in the Philippines.

A Standardized Approach for Category II Fetal Heart Rate with Significant Decelerations: Maternal and Neonatal Outcomes.

OBJECTIVE: To determine if a standardized intervention process for Category II fetal heart rates (FHRs) with significant decels (SigDecels) would improve neonatal outcome and to determine the impact on mode of delivery rates. STUDY DESIGN: Patients with Category II FHRs from six hospitals were prospectively managed using a standardized approach based on the presence of recurrent SigDecels. Maternal and neonatal outcomes were compared between pre- (6 months) and post-(11 months) implementation. Neonatal outcomes were: 5-minute APGAR scores of <7, <5, <3, and severe unexpected newborn complications (UNC). Maternal outcomes included primary cesarean and operative vaginal birth rates of eligible deliveries. RESULTS: Post implementation there were 8,515 eligible deliveries, 3,799 (44.6%) were screened, and 361 (9.5%) met criteria for recurrent SigDecels. Compliance with the algorithm was 97.8%. The algorithm recommended delivery in 68.0% of cases. Relative to pre-implementation, 5-minute APGAR score of <7 were reduced by 24.6% (p < 0.05) and severe UNC by -26.6%, p = < .05. The rate of primary cesarean decreased (19.8 vs 18.3%, p < 0.05), while there were nonsignificant increases in vaginal (74.6 vs 75.8%, p = 0.13) and operative vaginal births (5.7 vs 5.9%, p = 0.6). CONCLUSION: Standardized management of recurrent SigDecels reduced the rate of 5-minute APGAR scores of < 7 and severe UNC.

A Comparison of the Nulliparous-Term-Singleton-Vertex and Society of Maternal-Fetal Medicine Cesarean Birth Metrics Based on Hospital Size.

OBJECTIVE: The purpose of this study was to compare the nulliparous-term-singleton-vertex (NTSV) and the Society of Maternal-Fetal Medicine (SMFM) cesarean birth metrics as tools for quality improvement efforts based on hospital size. MATERIALS AND METHODS: Cesarean birth rates from 275 hospitals from six states were used to evaluate the NTSV metric and 81 hospitals from four states for the SMFM metric. Data were assessed based on delivery volume, their use as an effective tool for ongoing quality improvement programs, and their ability to serve as performance-based payline indicators. RESULTS: The average NTSV and SMFM cesarean birth rates were 25.6 and 13.0%, respectively. The number of deliveries included in the NTSV metric was stable across all hospital sizes (33.1-36.2%). With the SMFM metric, there was a progressive decline in the number of deliveries included, 90.0 versus 69.6%, in relatively small to large facilities. Variability was less and precision increased with the SMFM metric, which reduced the number of hospitals that could be incorrectly categorized when using performance-based predefined cesarean birth rate paylines. CONCLUSION: The SMFM metric appears to be better suited as a tool for rapid process improvement programs aimed at reducing cesarean birth rates in low-risk patients.

Relationship between mutant Cu/Zn superoxide dismutase 1 maturation and inclusion formation in cell models.

A common property of Cu/Zn superoxide dismutase 1 (SOD1), harboring mutations associated with amyotrophic lateral sclerosis, is a high propensity to misfold and form abnormal aggregates. The aggregation of mutant SOD1 has been demonstrated in vitro, with purified proteins, in mouse models, in human tissues, and in cultured cell models. In vitro translation studies have determined that SOD1 with amyotrophic lateral sclerosis mutations is slower to mature, and thus perhaps vulnerable to off-pathway folding that could generate aggregates. The aggregation of mutant SOD1 in living cells can be monitored by tagging the protein with fluorescent fluorophores. In this study, we have taken advantage of the Dendra2 fluorophore technology in which excitation can be used to switch the output color from green to red, thereby clearly creating a time stamp that distinguishes pre-existing and newly made proteins. In cells that transiently over-express the Ala 4 to Val variant of SOD1-Dendra2, we observed that newly made mutant SOD1 was rapidly captured by pathologic intracellular inclusions. In cell models of mutant SOD1 aggregation over-expressing untagged A4V-SOD1, we observed that immature forms of the protein, lacking a Cu co-factor and a normal intramolecular disulfide, persist for extended periods. Our findings fit with a model in which immature forms of mutant A4V-SOD1, including newly made protein, are prone to misfolding and aggregation.

Evaluation of the impact of tumor HPV status on outcome in patients with locally advanced unresectable head and neck squamous cell carcinoma (HNSCC) receiving cisplatin, 5-fluorouracil with or without docetaxel: a subset analysis of EORTC 24971 study.

BACKGROUND: EORTC 24971 was a phase III trial demonstrating superiority of induction regimen TPF (docetaxel, cisplatin, 5-fluorouracil) over PF (cisplatin/5-fluorouracil), in terms of progression-free (PFS) and overall survival (OS) in locoregionally advanced unresectable head and neck squamous cell carcinomas. We conducted a retrospective analysis of prospectively collected data aiming to evaluate whether only HPV(-) patients (pts) benefit from adding docetaxel to PF, in which case deintensifying induction treatment in HPV(+) pts could be considered. PATIENTS AND METHODS: Pretherapy tumor biopsies (blocks or slides) were assessed for high-risk HPV by p16 immunohistochemistry, PCR and quantitative PCR. HPV-DNA+ and/or p16+ tumors were subjected to in situ hybridization (ISH) and HPV E6 oncogene expression qRT-PCR analysis. Primary and secondary objectives were to evaluate the value of HPV/p16 status as predictive factor of treatment benefit in terms of PFS and OS. The predictive effect was analyzed based on the model used in the primary analysis of the study with the addition of a treatment by marker interaction term and tested at two-sided 5% significance level. RESULTS: Of 358, 119 pts had available tumor samples and 58 of them had oropharyngeal cancer. Median follow-up was 8.7 years. Sixteen of 119 (14%) evaluable samples were p16+ and 20 of 79 (25%) evaluable tumors were HPV-DNA+. 13 of 40 pts (33%) assessed with HPV-DNA ISH and 12 of 28 pts (43%) assessed for HPV E6 mRNA were positive. The preplanned analysis showed no statistical evidence of predictive value of HPV/p16 status for PFS (P = 0.287) or OS (P = 0.118). CONCLUSIONS: The incidence of HPV positivity was low in the subset of EORTC 24971 pts analyzed. In this analysis only powered to detect a large treatment by marker interaction, there was no statistical evidence that treatment effect found overall was different in magnitude in HPV(+) or HPV(-) pts. These results do not justify selection of TPF versus PF according to HPV status.

Early standardized treatment of critical blood pressure elevations is associated with a reduction in eclampsia and severe maternal morbidity.

BACKGROUND: Hypertensive disorders of pregnancy result in significant maternal morbidity and mortality. State and national guidelines have been proposed to increase treatment of patients with hypertensive emergencies or critically elevated blood pressures. There are limited data available to assess the impact of these recommendations on maternal morbidity. OBJECTIVE: The purpose of this prospective quality improvement project was to determine if maternal morbidity would be improved using a standardized approach for treatment of critically elevated blood pressures. STUDY DESIGN: In all, 23 hospitals participated in this project. Treatment recommendations included the use of an intravenous blood pressure medication and magnesium sulfate when there was a sustained blood pressure of ≥160 mm Hg systolic and/or ≥110 mm Hg diastolic. Compliance with the metric recommendations was monitored based on the number of patients treated with an intravenous blood pressure medication, use of magnesium sulfate, and if they received a timely postpartum follow-up appointment. The metric was scored as all or none; missing any of the 3 metric components was considered noncompliant. From January through June 2015 baseline data were collected and hospitals were made aware that ongoing monitoring of compliance would begin in July 2015 through June 2016. The primary outcomes were composite metric compliance, the incidence of eclampsia per 1000 births, and severe maternal morbidity. RESULTS: During the 18 months of this study there were 69,449 births. Within this population, 2034 met criteria for a critically elevated blood pressure, preeclampsia, or superimposed preeclampsia with severe features. Of this group, 1520 had a sustained critical blood elevation. Initial compliance with treatment recommendations was low (50.5%) and increased to >90% after April 2016 (P < .001). Compliance with utilization of intravenous blood pressure medication increased by 33.2%, from a baseline of 57.1-90.3% (P < .01) during the last 6 months of monitoring. Compliance with utilization of magnesium sulfate increased by 10.8%, from a baseline of 85.4-96.2% (P < .01). The incidence of eclampsia declined by 42.6% (1.15 ± 0.15/1000 to 0.62 ± 0.09/1000 births). Severe maternal morbidity decreased by 16.7% from 2.4 ± 0.10% to 2.0 ± 0.15% (P < .01). CONCLUSION: We noted 3 important findings: (1) compliance with state and national treatment guidelines is low without monitoring; (2) high levels of compliance can be achieved in a relatively short period of time; and (3) early intervention with intravenous blood pressure medication and magnesium sulfate for verified sustained critical maternal blood pressures resulted in a significant reduction in the rate of eclampsia and severe maternal morbidity. The reduction in the rate of eclampsia could only partially be attributed to the increase in the use of magnesium sulfate, suggesting an additive or synergistic effect of the combined treatment of an antihypertensive medication and magnesium sulfate on the rate of eclampsia and severe maternal morbidity.

Reduction of Mycobacterium avium ssp. paratuberculosis in colostrum: Development and validation of 2 methods, one based on curdling and one based on centrifugation.

The aim of this study was to develop and validate 2 protocols (for use on-farm and at a central location) for the reduction of Mycobacterium avium ssp. paratuberculosis (MAP) in colostrum while preserving beneficial immunoglobulins (IgG). The on-farm protocol was based on curdling of the colostrum, where the IgG remain in the whey and the MAP bacteria are trapped in the curd. First, the colostrum was diluted with water (2 volumes colostrum to 1 volume water) and 2% rennet was added. After incubation (1 h at 32°C), the curd was cut and incubated again, after which whey and curd were separated using a cheesecloth. The curd was removed and milk powder was added to the whey. Approximately 1 log reduction in MAP counts was achieved. A reduction in total proteins and IgG was observed due to initial dilution of the colostrum. After curd formation, more than 95% of the immunoglobulins remained in the whey fraction. The semi-industrial protocol was based on centrifugation, which causes MAP to precipitate, while the IgG remain in the supernatant. This protocol was first developed in the laboratory. The colostrum was diluted with skimmed colostrum (2 volumes colostrum to 1 volume skimmed colostrum), then skimmed and centrifuged (at 15,600 × g for 30 min at room temperature). We observed on average 1.5 log reduction in the MAP counts and a limited reduction in proteins and IgG in the supernatant. To obtain a semi-industrial protocol, dairy pilot appliances were evaluated and the following changes were applied to the protocol: after 2:1 dilution as above, the colostrum was skimmed and subsequently clarified, after which the cream was heat treated and added to the supernatant. To investigate the effect of the colostrum treatment on the nutritional value and palatability of the colostrum and the IgG transfer, an animal experiment was conducted with 24 calves. Six received the dam's colostrum, 6 were given untreated purchased colostrum (control), and 2 groups of 6 calves received colostrum treated according to both of the above-mentioned methods. No significant differences were found between the test groups and the dam's colostrum group in terms of animal health, IgG uptake in the blood serum, milk, or forage uptake. Two protocols to reduce MAP in colostrum (for use on-farm or at a central location) were developed. Both methods preserve the vital IgG.

Intracellular Delivery of Poorly Soluble Polyphenols: Elucidating the Interplay of Self-Assembling Nanocarriers and Human Chondrocytes.

Increased molecular understanding of multifactorial diseases paves the way for novel therapeutic approaches requiring sophisticated carriers for intracellular delivery of actives. We designed and characterized self-assembling lipid-core nanocapsules for coencapsulation of two poorly soluble natural polyphenols curcumin and resveratrol. The polyphenols were identified as high-potential therapeutic candidates intervening in the intracellular inflammation cascade of chondrocytes during the progress of osteoarthritis. To elucidate the interplay between chondrocytes and nanocapsules and their therapeutic effect, we pursued a complementary analytical approach combining label-free visualization with biological assays. Primary human chondrocytes did not show any adverse effects upon nanocapsule application and coherent anti-Stokes Raman scattering images visualized their intracellular uptake. Further, by systematically blocking different uptake mechanisms, an energy independent uptake into the cells could be identified. Additionally, we tested the therapeutic effect of the polyphenol-loaded carriers on inflamed chondrocytes. Treatment with nanocapsules resulted in a major reduction of nitric oxide levels, a well-known apoptosis trigger during the course of osteoarthritis. For a more profound examination of this protective effect on joint cells, we pursued studies with atomic force microscopy investigations. Significant changes in the cell cytoskeleton as well as prominent dents in the cell membrane upon induced apoptosis were revealed. Interestingly, these effects could not be detected for chondrocytes which were pretreated with the nanocapsules. Overall, besides presenting a sophisticated carrier system for joint application, these results highlight the necessity of establishing combinatorial analytical approaches to elucidate cellular uptake, the interplay of codelivered drugs and their therapeutic effect on the subcellular level.