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The treatment of Parkinson’s disease has been moving into the focus of pharmaceutical development. Yet, the necessity for reliable model systems in the development phase has made research challenging and in vivo models necessary. We have established reliable, reproducible in vitro model systems to evaluate the binding and transport of dopamine-loaded PLGA nanoparticles for the treatment of Parkinson’s disease and put the results in context with comparable in vivo results. The in vitro models have provided similar results concerning the usability of the investigated nanoparticles as the previously used in vivo models and thus provide a good alternative in line with the 3R principles in pharmaceutical research.

This article presents ideas from our educational practice in chemistry teaching, focusing on understanding rather than just learning by heart. We recommend always asking students to justify statements, to use chemical formulae as a starting point and aid to reasoning, and to require as little factual knowledge as possible. Because tasks with calculations, formulae and reaction equations can be solved in a recipe-like manner, they should be supplemented with comprehension questions. If students describe processes with sketches at model level and formulate explanations in their own words, it becomes particularly clear whether they have understood the concept.

Here, combining diagnostic imaging modalities and in vivo assays, Windfelder and colleagues established tobacco hornworm larvae Manduca sexta as an alternative high-throughput platform to study the innate immunity of the gut and host-pathogen interactions. Using the platform, the authors identify mediators of gut inflammation, differentiate pathogens from gut mutualist bacteria, and demonstrate pharmacological interventions.

The endocytic degradation of plasma membrane proteins can be modulated by deubiquitylating enzymes (DUBs). Here, the authors describe two plasma membrane localized Arabidopsis DUBs that can be activated by binding to anionic lipids and influence the endocytic transport of plasma membrane proteins.

Abstract Two-dimensional (2D) heterostructures (HS) formed by transition-metal dichalcogenide (TMDC) monolayers offer a unique platform for the study of intralayer and interlayer excitons as well as moiré-pattern-induced features. Particularly, the dipolar charge-transfer exciton comprising an electron and a hole, which are confined to separate layers of 2D semiconductors and Coulomb-bound across the heterojunction interface, has drawn considerable attention in the research community. On the one hand, it bears significance for optoelectronic devices, e.g. in terms of charge carrier extraction from photovoltaic devices. On the other hand, its spatially indirect nature and correspondingly high longevity among excitons as well as its out-of-plane dipole orientation render it attractive for excitonic Bose–Einstein condensation studies, which address collective coherence effects, and for photonic integration schemes with TMDCs. Here, we demonstrate the interlayer excitons’ out-of-plane dipole orientation through angle-resolved spectroscopy of the HS photoluminescence at cryogenic temperatures, employing a tungsten-based TMDC HS. Within the measurable light cone, the directly-obtained radiation profile of this species clearly resembles that of an in-plane emitter which deviates from that of the intralayer bright excitons as well as the other excitonic HS features recently attributed to artificial superlattices formed by moiré patterns.

This study aimed to develop a tool to detect mildly lame cows by combining already existing data from sensors, AMSs, and routinely recorded animal and farm data. For this purpose, ten dairy farms were visited every 30–42 days from January 2020 to May 2021. Locomotion scores (LCS, from one for nonlame to five for severely lame) and body condition scores (BCS) were assessed at each visit, resulting in a total of 594 recorded animals. A questionnaire about farm management and husbandry was completed for the inclusion of potential risk factors. A lameness incidence risk (LCS ≥ 2) was calculated and varied widely between farms with a range from 27.07 to 65.52%. Moreover, the impact of lameness on the derived sensor parameters was inspected and showed no significant impact of lameness on total rumination time. Behavioral patterns for eating, low activity, and medium activity differed significantly in lame cows compared to nonlame cows. Finally, random forest models for lameness detection were fit by including different combinations of influencing variables. The results of these models were compared according to accuracy, sensitivity, and specificity. The best performing model achieved an accuracy of 0.75 with a sensitivity of 0.72 and specificity of 0.78. These approaches with routinely available data and sensor data can deliver promising results for early lameness detection in dairy cattle. While experimental automated lameness detection systems have achieved improved predictive results, the benefit of this presented approach is that it uses results from existing, routinely recorded, and therefore widely available data.

Compound casting is a process in which a single component is made from two metallic materials, such as aluminum and steel. Solid-liquid bimetallic compounds can be produced by suitable process control. This technology can reduce the number of joining processes, and the specific properties of the respective metal component can be used for specifically designed product properties, for example, where lightweight and high strength are needed. This paper presents an experimental methodology for producing a purely material-bonded bimetallic joint from cast aluminum and zinc-coated sheet steel in 3D sand casting using an inductive heating system. The process-related temperature characterisation in the compound zone is described using a heating test rig and temperature measurements. It shows that inductive preheating can only produce a material bond between the aluminum casting and the coated steel sheet. Shear tensile tests showed strengths between 15 MPa and 22 MPa. Laser surface pre-treatment using laser ablation cutting on the coated steel sheet was carried out to investigate the benefit of possible microform-locking. The results show a strength-reducing influence on the tensile shear tests. Micrographs showed the formation of Al4.5FeSi and Al7Fe2Si, as well as the formation of other undefined intermetallic phases. The thickness of the compound zone is 10 µm.

Pregnancy has usually been an exclusion criterion in clinical trials with thrombolysis and endovascular therapy in acute ischemic stroke. For that reason, these therapies are not recommended causing lack of evidence and vice versa. In this case report, we describe a pregnant woman in week 33 + 3 presenting with acute ischemic stroke, which was successfully treated with systemic thrombolysis and endovascular therapy, resulting in a good clinical outcome for both mother and child. The altered fibrinolytic system and the risk factors related to pregnancy constitute a challenge for clinicians when choosing the most suitable treatment modality for treating acute ischemic stroke in pregnancy. It is still uncertain whether thrombolysis in combination with endovascular therapy or endovascular therapy alone is the most appropriate treatment option. However, there is slowly growing evidence that thrombolysis and thrombectomy in pregnancy are feasible and safe with a good clinical outcome for both the mother and the child.

One keystone to successful welfare improvement endeavors is a respected cooperation between farmer and advisor (e.g., veterinarian), which requires a thorough understanding of what motivates farmer behavior. In this respect, Q methodology offers a promising approach in investigating individual motivational patterns and to discriminate between and describe typologies of farmers. In our study we explored, based on a sample of 34 Austrian dairy farmers, how 39 potentially motivating statements regarding the improvement of dairy cow health and welfare were assessed. We were able to identify and describe four different viewpoints, explaining 47% of total study variance. All four viewpoints have in common that pride in a healthy herd is motivating to work toward improved animal health and welfare to a certain extent, but meeting legal requirements is rather not. Viewpoint 1 acknowledges welfare for economic performance, ease of work and short working hours but does not make allowance for outside interference. Participants loading on Viewpoint 2 also show a focus on economic aspects but, keep close track of the animal welfare debate recognizing its potential to improve the public image of dairy farming. Even though they cautiously criticize an exploitative application of dairy farming, they do not want to be understood as role models. With regards to animal welfare, farmers sharing Viewpoint 3 perceive themselves as superior to and show little reluctance of comparison with mainstream farming. For them, the animal as sentient being itself owns some intrinsic value and it is necessary to strike a balance between economic and other, ethical considerations. Viewpoint 4 perceives cows as equal collaborators who deserve to be treated with respect and appreciation and is willing to accept certain economic losses in order to maintain high standards regarding animal health and welfare. Using Q methodology, we have been able to draw high resolution images of different farmer typologies, enabling advisors to tailor intervention strategies specifically addressing leverage points with a high chance of farmer compliance.

While benchmarking is already used for the assessment of performance gaps in cattle herd management and welfare concerns, its application to quantifying claw health performance is relatively new. The goal here was to establish a benchmarking system for claw health in Austrian dairy cattle. We used electronically registered claw health data of cows from 512 dairy herds documented by professional hoof trimmers, culling data from the same herds, and locomotion scores taken at regular milk performance testings in 99 dairy herds during 2020. Mean, median and the 10th, 25th, 75th, and 90th percentiles of the incidences of risk of lameness, 13 common claw lesions, and the annual culling risk directly related to claw and limb disorders were used as key performance indicators. Only validated data sets were used and participating trimmers and locomotion scorers had to pass interobserver reliability tests with weighted Cohen’s kappa values ≥ 0.61 indicating substantial interobserver agreement. This claw health benchmarking system is intended to be used henceforth in the transnational cattle data network (RDV) by all participating farmers and is also available for veterinarians and consultants, with the agreement of respective farmers.

In March 2019 the HADES experiment recorded 14 billion Ag+Ag collisions at √sNN = 2.55 GeV as a part of the FAIR phase-0 physics program. In this contribution, we present and investigate our capabilities to reconstruct and analyze weakly decaying strange hadrons and hypernuclei emerging from these collisions. The focus is put on measuring the mean lifetimes of these particles.

The use of packaging and the related environmental consequences are increasingly under discussion. Despite its advantages, packaging has become the focus of public concern, mainly due to insufficient or inadequate handling of packaging waste. There is plenty of research regarding the sustainability of packaging options; however, multiple quantifiable characteristics have never been combined into a single indicator. The proposed Packaging Index (PIX) offers a tool to evaluate and compare different packaging options for the same product. To achieve these goals, the current evaluation criteria for the PIX are i) packaging quantity, ii) recyclability, and iii) environmental footprint. The resulting assessment is displayed as best to worst case scenario, with a single score for simple comparison. Using life cycle thinking, the environmental footprint of the packaging is accounted from cradle-to-grave. The suggested visualization of the PIX represents a practical comparison of diverse packaging alternatives within a defined product group. In the illustrative example, the PIX serves as an instrument to compare available bags found commonly in German online-retail. This example also shows that the PIX can analyze the packaging value chain from diverse industries and contributes to the circular economy. The usability of the PIX extends from communication (such as customer relations) to other fields like internal supply chain optimization. Lastly, we present the communication strategy of the PIX aimed at two different user groups.

The proposed theoretical framework explores how packaging could be assessed from gate-to-grave including the probability to become litter. A growing number of studies have confirmed the omnipresence of plastic pollution. Likewise, it has been revealed that marine litter is mainly caused by poor or insufficient waste management. In this line, the environmental impact of packaging have gained much attention due to significant increase in public awareness. Packaging is often designed for single-use and rapidly transforms into waste after a short life-time. Life Cycle Assessment (LCA) practitioners who assess packaging will need a framework to determine the probability and percentage of packaging material that becomes litter. Currently the available end-of-life scenarios to model the fate of packaging are: recycling, incineration and disposal in landfill. With the estimation of packaging litter potential and littering as an end-of-life scenario, the life cycle inventory flows of pollution can be determined. A framework like this can be adopted by LCA practitioners and decision-makers, it can enable fairer and more realistic LCA comparisons of packaging, and it can help prioritize regulatory action as well as choices within companies.

α1-antitrypsin (AAT) is a circulating serine protease inhibitor secreted from the liver and important in preventing proteolytic neutrophil elastase associated tissue damage, primarily in lungs. In humans, AAT is encoded by the SERPINA1 (hSERPINA1) gene in which a point mutation (commonly referred to as PiZ) causes aggregation of the miss-folded protein in hepatocytes resulting in subsequent liver damage. In an attempt to rescue the pathologic liver phenotype of a mouse model of human AAT deficiency (AATD), we used adenovirus to deliver Cas9 and a guide-RNA (gRNA) molecule targeting hSERPINA1. Our single dose therapeutic gene editing approach completely reverted the phenotype associated with the PiZ mutation, including circulating transaminase and human AAT (hAAT) protein levels, liver fibrosis and protein aggregation. Furthermore, liver histology was significantly improved regarding inflammation and overall morphology in hSERPINA1 gene edited PiZ mice. Genomic analysis confirmed significant disruption to the hSERPINA1 transgene resulting in a reduction of hAAT protein levels and quantitative mRNA analysis showed a reduction in fibrosis and hepatocyte proliferation as a result of editing. Our findings indicate that therapeutic gene editing in hepatocytes is possible in an AATD mouse model. Keywords: α1-antitrypsin deficiency, CRISPR/Cas9 gene editing, Liver fibrosis, Protein aggregation

Microwave radiometer observations are compared with various radiative transfer model calculations based on simultaneous radiosondes. This analysis uses observations from Payerne, Switzerland, in cloud free conditions during the Temperature Humidity and Cloud (TUC) experiment in winter 2003/04. The results show a systematic bias in the brightness temperatures measured by the Radiometrics profiler at 55-59 GHz, which has since been corrected in the control software. Observations at lower frequencies (22-30 GHz) in these cold conditions do not support recent proposed changes to the width of the 22.235 GHz water vapour line, although this is subject to the assumption of no residual bias in the radiosonde humidity. At intermediate frequencies (51-54 GHz), the absorption models produce large differences, which may be due to differences in oxygen line coupling and highlight the need for further laboratory measurements at low temperatures.

The agreement of two ground-based microwave radiometers during the Temperature, hUmidity, and Cloud (TUC) profiling campaign has been evaluated in terms of measured brightness temperature. To account effectively the instruments' specifications, we discuss and estimate an equivalent monochromatic frequency, which significantly reduces the bias introduced by ideal monochromatic modelling. The effect of this equivalent monochromatic frequency can reach 0.4 K and thus we recommend its use in further study involving TUC radiometers. This analysis showed agreement within expectations for three of the four selected pairs of channels, although results are strictly valid in a limited range. As a consequence, the derived products are expected to be of the same quality. However, the inconsistency found in the remaining pair is expected to propagate in the retrieved humidity profiles.

The retrieval of tropospheric water and temperature with the ground-based and automatically operating radiometer system ASMUWARA (All-Sky MUlti WAvelength RAdiometer) is described. This instrument operates simultaneously at microwave and IR channels. Integrated water vapour (IWV) and integrated liquid water (ILW) are retrieved with a newly developed linear algorithm to an accuracy of 0.014 kgm−2 (ILW) and 0.41 kgm−2 (IWV), thanks to the inclusion of a channel at 151 GHz. These measurements are made for the whole hemisphere and therefore provide information about the spatial distribution of water in the troposphere. With an optimal estimation algorithm, tropospheric temperature and humidity profiles are retrieved. The results are quasi bias free with a mean error of less than 2.5 K for the temperature (less than 1 K in the lowest km above ground), and less than 1 gm−3 for the humidity. Examples of all measurements are shown.

Measurements of tropospheric integrated water vapour (IWV) made with two microwave radiometers (ASMUWARA, TP/WVP-3000), GPS, and radiosondes (SRS 400) during the Temperature, hUmidity, and Cloud (TUC) profiling campaign under mid-latitude conditions in Payerne, Switzerland, in winter 2003/2004 are compared. All methods provide robust IWV retrievals in clear sky and cloudy situations. The mean difference between radiometric and radiosonde IWV is less than 0,15 kgm−2 being not significant with respect to the standard deviation and to the theoretical accuracy. The GPS IWV measurements have a persistent significant dry bias of approx. 0,5 kgm−2 with respect to radiometers and radiosondes. The different temporal and spatial resolutions of the instruments were found to have a strong influence on the standard deviation. A characteristic diurnal cycle of the GPS and radiometric IWV was observed.

Thermodynamic atmospheric profiles have been retrieved from ground-based microwave radiometers during the Temperature, hUmidity, and Cloud (TUC) profiling campaign. A variety of inversion methods is presented, in terms of requirements, advantages, and limitations. Results confirm the theoretical expectation that retrievals' accuracy and resolution degrade steadily with height up to 3 km, then more rapidly. At higher levels the retrievals' accuracy does not improve on that of a Numerical Weather Prediction model, which provides a background for the variational technique. Most retrieval methods produce a bias in the temperature profile above 1 km, which may be due to a bias in the absorption model used and/or observations at 51-54 GHz. Elevation scanning is shown to improve the accuracy and resolution of the retrievals in the boundary layer, but is limited by technical shortcomings.

Abstract Background In the Lepidoptera it was historically believed that adult butterflies rely primarily on larval-derived nutrients for reproduction and somatic maintenance. However, recent studies highlight the complex interactions between storage reserves and adult income, and that the latter may contribute significantly to reproduction. Effects of adult diet were commonly assessed by determining the number and/or size of the eggs produced, whilst its consequences for egg composition and offspring viability were largely neglected (as is generally true for insects). We here specifically focus on these latter issues by using the fruit-feeding tropical butterfly Bicyclus anynana, which is highly dependent on adult-derived carbohydrates for reproduction. Results Adult diet of female B. anynana had pronounced effects on fecundity, egg composition and egg hatching success, with butterflies feeding on the complex nutrition of banana fruit performing best. Adding vitamins and minerals to a sucrose-based diet increased fecundity, but not offspring viability. All other groups (plain sucrose solution, sucrose solution enriched with lipids or yeast) had a substantially lower fecundity and egg hatching success compared to the banana group. Differences were particularly pronounced later in life, presumably indicating the depletion of essential nutrients in sucrose-fed females. Effects of adult diet on egg composition were not straightforward, indicating complex interactions among specific compounds. There was some evidence that total egg energy and water content were related to hatching success, while egg protein, lipid, glycogen and free carbohydrate content did not seem to limit successful development. Conclusion The patterns shown here exemplify the complexity of reproductive resource allocation in B. anynana, and the need to consider egg composition and offspring viability when trying to estimate the effects of adult nutrition on fitness in this butterfly and other insects.

Background: Limited clinical data exists regarding use of direct oral anticoagulants (DOACs) in extreme obesity, specifically those ≥140 kg or having a body mass index (BMI) ≥ 50 kg/m 2 . Objective: Evaluate the safety and efficacy of DOACs in extreme obesity. Patients/Methods: A retrospective chart review was performed at a single center of patients aged 18-89 years and weight ≥140 kg or BMI ≥50 kg/m 2 receiving warfarin or DOAC therapy. Patients were followed for 1 year from prescribing/study inclusion. The primary outcome was the difference in rates of any bleed (composite of major, nonmajor clinically relevant, or minor bleeding events as defined by International Society of Thrombosis and Haemostasis (ISTH) criteria) between groups. Secondary outcomes included individual components of the composite primary outcome and effectiveness in preventing thrombotic events within 12 months. Post-hoc multivariate analysis evaluated potential predictors of bleeding events within overall patient population. Results: Two-hundred eighty-five patients were included, 80 and 205 in the DOAC and warfarin groups, respectively. Rates of any documented bleeding event were comparable in DOAC and warfarin groups (17.5% vs 17.1%, P > .05). No significant difference in rates of minor ( P = .067), nonmajor clinically relevant ( P = .825), and major ( P = 1) bleeding events were observed. Two thrombotic events occurred in the warfarin group compared to none in the DOAC group. Increasing weight was associated with bleeding events in multivariate analysis. Conclusions: This data did not demonstrate a difference in safety or efficacy outcomes between DOACs and warfarin when utilized in patients with extreme obesity., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Air pollution might accelerate cognitive ageing; it is unclear whether large-scale interventions, such as China's Clean Air Act (CCAA), can mitigate cognitive deterioration. We aimed to evaluate the effect of CCAA on changes in cognitive function in older adults., Methods: In this population-based, quasi-experimental study, we did a difference-in-differences analysis of the data collected during the 2014 and 2018 waves of the Chinese Longitudinal Healthy Longevity Survey (CLHLS). The study design used a counterfactual analysis feature by dividing CLHLS participants into two groups. The intervention group included participants who lived in areas where the provincial government set a target of reducing particulate matter (PM) by at least 5% annually from 2014 onward, whereas the control group consisted of individuals who lived in areas without a PM reduction target. Global cognitive function was measured using the Mini-Mental State Examination (MMSE). We used fixed-effects models to examine the between-group differences in MMSE score changes before and after CCAA implementation. We associated longitudinal changes in MMSE scores with changes in concentrations of PM with a diameter of less than 2·5 μm (PM 2·5 ) concentration and other regulated pollutants. We used alternative models and sensitivity analyses to evaluate the robustness of the results from the main models., Findings: 2812 individuals participated in the 2014 and 2018 surveys (mean age 81·0 years [SD 9·3] in 2014; 1408 [50·1%] female and 1404 [49·9%] male). 2251 (80·0%) were included in the intervention group and 561 (20·0%) in the control group. After controlling for potential confounders, the intervention group had a significantly smaller decline in MMSE scores from 2014 to 2018 compared with the control group: the mean between-group difference was 2·45 points (95% CI 1·32-3·57). Interquartile increases in PM 2·5 were associated with a significant MMSE score decline of 0·83 points (95% CI 0·24-1·42); similarly, increases in SO 2 were also associated with a significant MMSE score decline of 0·80 points (0·32-1·29)., Interpretation: Implementing stringent clean air policies might mitigate the risk of air pollutant-associated cognitive ageing in older people., Funding: National Natural Sciences Foundation of China, National Key R&D Program of China, China Postdoctoral Science Foundation funded project, the Duke/Duke-National University of Singapore Collaboration Pilot Project, the National Institute on Aging and Peking University-Baidu Fund, Energy Foundation, and the Fundamental Research Funds for the Central Universities., Competing Interests: Declaration of interests We declare no competing interests.

Background Context: High quality evidence is difficult to generate, leaving substantial knowledge gaps in the treatment of spinal conditions. Appropriate use criteria (AUC) are a means of determining appropriate recommendations when high quality evidence is lacking., Purpose: Define appropriate use criteria (AUC) of cervical fusion for treatment of degenerative conditions of the cervical spine., Study Design/setting: Appropriate use criteria for cervical fusion were developed using the RAND/UCLA appropriateness methodology. Following development of clinical guidelines and scenario writing, a one-day workshop was held with a multidisciplinary group of 14 raters, all considered thought leaders in their respective fields, to determine final ratings for cervical fusion appropriateness for various clinical situations., Outcome Measures: Final rating for cervical fusion recommendation as either "Appropriate," "Uncertain" or "Rarely Appropriate" based on the median final rating among the raters., Methods: Inclusion criteria for scenarios included patients aged 18 to 80 with degenerative conditions of the cervical spine. Key modifiers were defined and combined to develop a matrix of clinical scenarios. The median score among the raters was used to determine the final rating for each scenario. The final rating was compared between modifier levels. Spearman's rank correlation between each modifier and the final rating was determined. A multivariable ordinal regression model was fit to determine the adjusted odds of an "Appropriate" final rating while adjusting for radiographic diagnosis, number of levels and symptom type. Three decision trees were developed using decision tree classification models and variable importance for each tree was computed., Results: Of the 263 scenarios, 47 (17.9 %) were rated as rarely appropriate, 66 (25%) as uncertain and 150 (57%) were rated as appropriate. Symptom type was the modifier most strongly correlated with the final rating (adjusted ρ2 = 0.58, p<.01). A multivariable ordinal regression adjusting for symptom type, diagnosis, and number of levels and showed high discriminative ability (C statistic = 0.90) and the adjusted odds ratio (aOR) of receiving a final rating of "Appropriate" was highest for myelopathy (aOR, 7.1) and radiculopathy (aOR, 4.8). Three decision tree models showed that symptom type and radiographic diagnosis had the highest variable importance., Conclusions: Appropriate use criteria for cervical fusion in the setting of cervical degenerative disorders were developed. Symptom type was most strongly correlated with final rating. Myelopathy or radiculopathy were most strongly associated with an "Appropriate" rating, while axial pain without stenosis was most associated with "Rarely Appropriate.", (Copyright © 2021 Elsevier Inc. All rights reserved.)

MRI allows non-invasive assessment of intervertebral disc degeneration with the added clinical benefit of using non-ionizing radiation. What has remained unclear is the relationship between assessed disc degeneration and lumbar spine kinematics. Kinematic outcomes of 54 multi-segment (L1-Sacrum) lumbar spine specimens were calculated to discover if such an underlying relationship exists with degeneration assessed using the Pfirrmann grading system. Further analyses were also conducted to determine if kinematic outcomes were affected by motion segment level, gender or applied compressive preload. Range of motion, hysteresis, high flexibility zone size and rotational stiffness in flexion-extension, lateral bending and axial rotation were the kinematic outcomes. Caudal intervertebral discs in our study sample were more degenerative than cranial discs. L5-S1 discs had the largest flexion-extension range of motion (p < 0.005) and L1-L2 discs the lowest flexion high flexibility zone size (p < 0.013). No other strict cranial-caudal differences in kinematic outcomes were found. Low flexibility zone rotational stiffness increased with disc degeneration grade in extension, lateral bending and axial rotation (p < 0.001). Trends towards higher hysteresis and lower range of motion with increased degeneration were observed in flexion-extension and lateral bending. Applied compressive preload increased flexion-extension hysteresis and augmented the effect of degeneration on hysteresis (p < 0.0005). Female specimens had about one degree larger range of motion in all rotational modes, and higher flexion extension hysteresis (p = 0.016). These results suggest that gender differences exist in lumbar spine kinematics. Additionally high disc loads, applied compressive preload or applied moment, are needed to kinematically distinguish discs with different levels of degeneration. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1389-1398, 2016., (© 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

A piperacillin/tazobactam (PT) restriction was initiated at our institution on 15 July 2012 requiring clinical pharmacy or infectious diseases approval for durations exceeding 72 h. A retrospective review was undertaken to determine whether this restriction decreased PT usage and/or rates of acute renal failure (ARF) (defined as a 50% increase or 0.5 mg dl(-1) increase in serum creatinine from baseline). Patients prescribed at least 1 day of PT with a creatinine clearance of ≥ 39 ml min(-1) at the time of initiation in the 3 months prior to the restriction were compared with patients in the 5 months after restriction implementation. Overall, 115 unique patients were included in the pre-implementation group and compared with 117 unique patients in the post-implementation group. The pre-implementation group received a mean of 5.22 days of PT, compared with 4.71 days in the post-implementation group (P = 0.224). Ten per cent (12/115) of patients in the pre-implementation group developed ARF compared with 9.17% (11/120) of patients in the post-implementation group (P = 0.0309). Ninety-five patients in the pre-implementation group and 91 in the post-implementation group received combination therapy with vancomycin. ARF occurred in 11.6% (11/95) of those in the pre-implementation group and 12.1% (11/91) in the post-implementation (P>0.05). Overall, 11.8% (22/186) of patients who received therapy with PT and vancomycin developed ARF, compared with 1.7% (1/56) who received PT monotherapy (P < 0.0001). This restriction resulted in a numeric reduction in the number of PT days in the post-implementation group and a significant reduction in the rate of ARF.

Glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells is triggered by metabolism of the sugar to increase ATP/ADP ratio that blocks the KATP channel leading to membrane depolarization and insulin exocytosis. Other metabolic pathways believed to augment insulin secretion have yet to be fully elucidated. To study metabolic changes during GSIS, liquid chromatography with mass spectrometry was used to determine levels of 87 metabolites temporally following a change in glucose from 3 to 10 mM glucose and in response to increasing concentrations of glucose in the INS-1 832/13 β-cell line. U-[(13)C]Glucose was used to probe flux in specific metabolic pathways. Results include a rapid increase in ATP/ADP, anaplerotic tricarboxylic acid cycle flux, and increases in the malonyl CoA pathway, support prevailing theories of GSIS. Novel findings include that aspartate used for anaplerosis does not derive from the glucose fuel added to stimulate insulin secretion, glucose flux into glycerol-3-phosphate, and esterification of long chain CoAs resulting in rapid consumption of long chain CoAs and de novo generation of phosphatidic acid and diacylglycerol. Further, novel metabolites with potential roles in GSIS such as 5-aminoimidazole-4-carboxamide ribotide (ZMP), GDP-mannose, and farnesyl pyrophosphate were found to be rapidly altered following glucose exposure.

A comprehensive two-dimensional gas chromatography (GC×GC) time-of-flight mass spectrometry method was developed for determination of fatty acids (irrespective of origin, i.e., both free fatty acids and fatty acids bound in sources such as triglycerides) in cultured mammalian cells. The method was applied to INS-1 cells, an insulin-secreting cell line commonly used as a model in diabetes studies. In the method, lipids were extracted and transformed to fatty acid methyl esters for analysis. GC×GC analysis revealed the presence of 30 identifiable fatty acids in the extract. This result doubles the number of fatty acids previously identified in these cells. The method yielded linear calibrations and an average relative standard deviation of 8.4% for replicate injections of samples and 12.4% for replicate analysis of different samples. The method was used to demonstrate changes in fatty acid content as a function of glucose concentration on the cells. These results demonstrate the utility of this method for analysis of fatty acids in mammalian cell cultures., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A simple, fast, and reproducible sample preparation procedure was developed for relative quantification of metabolites in adherent mammalian cells using the clonal β-cell line INS-1 as a model sample. The method was developed by evaluating the effect of different sample preparation procedures on high performance liquid chromatography- mass spectrometry quantification of 27 metabolites involved in glycolysis and the tricarboxylic acid cycle on a directed basis as well as for all detectable chromatographic features on an undirected basis. We demonstrate that a rapid water rinse step prior to quenching of metabolism reduces components that suppress electrospray ionization thereby increasing signal for 26 of 27 targeted metabolites and increasing total number of detected features from 237 to 452 with no detectable change of metabolite content. A novel quenching technique is employed which involves addition of liquid nitrogen directly to the culture dish and allows for samples to be stored at -80 °C for at least 7 d before extraction. Separation of quenching and extraction steps provides the benefit of increased experimental convenience and sample stability while maintaining metabolite content similar to techniques that employ simultaneous quenching and extraction with cold organic solvent. The extraction solvent 9:1 methanol: chloroform was found to provide superior performance over acetonitrile, ethanol, and methanol with respect to metabolite recovery and extract stability. Maximal recovery was achieved using a single rapid (∼1 min) extraction step. The utility of this rapid preparation method (∼5 min) was demonstrated through precise metabolite measurements (11% average relative standard deviation without internal standards) associated with step changes in glucose concentration that evoke insulin secretion in the clonal β-cell line INS-1.

Object: There is limited data on the pullout strength of spinal fixation devices in the thoracic spine among individuals with different bone quality. An in vitro biomechanical study on the thoracic spine was performed to compare the pullout strength and the mechanism of failure of 4 posterior fixation thoracic constructs in relation to bone mineral density (BMD)., Methods: A total of 80 vertebrae from 11 fresh-frozen thoracic spines (T2-12) were used. Based on the results from peripheral quantitative CT, specimens were divided into 2 groups (normal and osteopenic) according to their BMD. They were then randomly assigned to 1 of 4 different instrumentation systems (sublaminar wires, pedicle screws, lamina claw hooks, or pedicle screws with wires). The construct was completed with 2 titanium rods and 2 transverse connectors, creating a stable frame. The pullout force to failure perpendicular to the rods as well as the pattern of fixation failure was recorded., Results: Mean pullout force in the osteopenic Group A (36 vertebrae) was 473.2 ± 179.2 N and in the normal BMD Group B (44 vertebrae) was 1414.5 ± 554.8 N. In Group A, no significant difference in pullout strength was encountered among the different implants (p = 0.96). In Group B, the hook system failed because of dislocation with significantly less force than the other 3 constructs (931.9 ± 345.1 N vs an average of 1538.6 ± 532.7 N; p = 0.02). In the osteopenic group, larger screws demonstrated greater resistance to pullout (p = 0.011). The most common failure mechanism in both groups was through pedicle base fracture., Conclusions: Bone quality is an important factor that influences stability of posterior thoracic implants. Fixation strength in the osteopenic group was one-fourth of the value measured in vertebrae with good bone quality, irrespective of the instrumentation used. However, in normal bone quality vertebrae, the lamina hook claw system dislocated with significantly less force when compared with other spinal implants. Further studies are needed to investigate the impact of different transpedicular screw designs on the pullout strength in normal and osteopenic thoracic spines.

Background Context: Total disc replacement (TDR) has been recommended to reduce pain of presumed discogenic origin while preserving spinal motion. The floating core of Charité TDR is professed to allow the replication of the kinematics of a healthy disc under physiologic loads. While segmental motion after Charité TDR has been measured, little is known about the effects of a physiologic compressive preload on vertebral motion and the motion of prosthesis components after TDR., Purpose: (1) Does Charité TDR allow restoration of normal load-displacement behavior of a lumbar motion segment under physiologic loads? (2) How do the prosthesis components move relative to each other under physiologic loads when implanted in a lumbar motion segment?, Study Design: A biomechanical study using human lumbar spines (L1-sacrum)., Methods: Five lumbar spines (age: 52+/-9.3) were used. Specimens were tested under flexion (8 Nm) and extension (6 Nm) moments with compressive follower preloads of 0 N and 400 N in the following sequence: (i) intact, (ii) Charité TDR at L5-S1, (iii) simulated healed fusion at L5-S1 with Charité TDR at L4-L5. Segmental motion was measured optoelectronically. Motions between prosthesis end plates and core were visually assessed using sequential digital video-fluoroscopy over the full range of motion. Here we report on kinematics of 10 Charité TDRs: 5 at L5-S1 and 5 at L4-L5., Results: Charité TDR increased the flexion-extension range of motion of lumbar segments (p<.05). At 400 N preload, the range of motion increased from intact values of 6.8+/-4.4 to 10.0+/-2.4 degrees at L5-S1 and from 7.0+/-2.6 to 10.8+/-2.9 degrees at L4-L5. Charité TDR increased segmental lordosis by 8.1+/-6.9 degrees at L5-S1 (p<.05) and 5.4+/-3.5 degrees at L4-L5 (p<.05). Four patterns of prosthesis component motion were noted: (1) angular motion only between the upper end plate and core, with little or no visual evidence of core translation (9 of 10 TDRs at 0 N preload and 5 of 10 TDRs at 400 N preload); (2) lift-off of upper prosthesis end plate from core or of core from lower end plate (observed in extension in 9 of 10 TDRs under 0 N preload only); (3) core entrapment, resulting in a locked core over a portion of the range of motion (observed in extension in 8 of 10 TDRs under 400 N preload); (4) angular motion between both the upper and lower end plates and core, with visual evidence of core translation (1 of 10 TDRs at 0 N preload, 5 of 10 TDRs at 400 N preload). The pattern of load-displacement curves was substantially changed under a physiologic preload in 8 of 10 TDRs; instead of a relatively gradual change in angle with changing moment application as seen for an intact segment, the TDR displayed regions of both relatively small and relatively large angular changes with gradual moment application., Conclusions: Charité TDR restored near normal quantity of flexion-extension range of motion under a constant physiologic preload; however, the quality of segmental motion differed from the intact case over the flexion-extension range. Whereas some TDRs showed visual evidence of core translation, the predominant angular motion within the prosthesis occurred between the upper end plate and the polyethylene core. Likely factors affecting the function of the Charité TDR include implant placement and orientation, intraoperative change in lordosis, and magnitude of physiologic compressive preload. Further work is needed to assess the effects of the prosthesis motion patterns identified in the study on the load sharing at the implanted level and polyethylene core wear.

Study Design: Human vertebral morphologic data were compiled from anatomic skeletal collections from three museums., Objectives: To quantify the morphometric characteristics of the pedicles of the immature thoracolumbar spine., Summary of Background Data: Little is known of pedicle morphology of the immature spine as related to pedicle screw fixation., Methods: A total of 75 anatomic skeletal specimens were acquired from C1 to L5 in the age range of 3 to 19 years. The data were collected and analyzed using a computerized video analysis system. Each vertebral pedicle was measured in the axial and sagittal planes. The measurements included the minimum pedicle width, the pedicle angle, the distance to anterior cortex, and anteroposterior and interpedicular spinal canal diameters., Results: Wide variation in pedicle morphology between specimens at each vertebral level was found in the young population. In general, compared with the average adult data, a younger spine demonstrated a near uniform reduction in the linear pedicle dimensions at each vertebral level. Pedicles from the lower lumbar vertebrae attained dimensions acceptable for standard screw sizes at an earlier age than in the thoracic vertebrae., Conclusions: The data in this study indicates that pedicle screws may be used in the adolescent spine. However, care should taken to accurately ascertain pedicle size before surgery so that improper use of screws can be avoided. Growth of the pedicles in relation to the spinal canal indicates that the increase in pedicle size is lateral to the spinal canal.

Study Design: Change in lumbar lordosis was measured in patients that had undergone posterolateral lumbar fusions using transpedicular instrumentation. The biomechanical effects of postoperative lumbar malalignment were measured in cadaveric specimens., Objectives: To determine the extent of postoperative lumbar sagittal malalignment caused by an intraoperative kneeling position with 90 degrees of hip and knee flexion, and to assess its effect on the mechanical loading of the instrumented and adjacent segments., Summary of Background Data: The importance of maintaining the baseline lumbar lordosis after surgery has been stressed in the literature. However, there are few objective data to evaluate whether postoperative hypolordosis in the instrumented segments can increase the likelihood of junctional breakdown., Methods: Segmental lordosis was measured on preoperative standing, intraoperative prone, and postoperative standing radiographs. In human cadaveric spines, a lordosis loss of up to 8 degrees was created across L4-S1 using calibrated transpedicular devices. Specimens were tested in extension and under axial loading in the upright posture., Results: In patients who underwent L4-S1 fusions, the lordosis within the fusion decreased by 10 degrees intraoperatively and after surgery. Postoperative lordosis in the proximal (L2-L3 and L3-L4) segments increased by 2 degrees each, as compared with the preoperative measures. Hypolordosis in the instrumented segments increased the load across the posterior transpedicular devices, the posterior shear force, and the lamina strain at the adjacent level., Conclusions: Hypolordosis in the instrumented segments caused increased loading of the posterior column of the adjacent segments. These biomechanical effects may explain the degenerative changes at the junctional level that have been observed as long-term consequences of lumbar fusion.

A retrospective case-control study was undertaken to determine the best technique to measure neural canal encroachment at each lumbar level following burst fracture and its relationship to the presence of neurologic deficit. Only patients with postinjury CT scans demonstrating a disrupted posterior body with a retropulsed bone fragment were included. Patients were divided into groups based on the level of bony injury (T12-L5) and neurologic status. Neurologic injury was classified as follows: normal (N), root (R), or cauda equina/conus/paraplegic/paraparetic (C/P). The mean transverse spinal area (TSA, cm2), spinal canal percentage patency (PP), and midsagittal diameter (MSD) were determined for each neurologic group and lumbar level. A "calculated" TSA, based on midsagittal and anterior-posterior diameters, was also derived for each patient. The data were compared level by level and correlated with the patient's neurologic status. At L1, the critical TSA was 1.0 cm2. All patients with TSAs less than this were paraplegic. At both T12 and L1, TSAs in the range of 1.0-1.25 cm2 were observed in both normal and neurologically impaired patients. A critically significant TSA was not established for levels T12, L2, L3, L4, or L5; however, the data indicated that a smaller TSA can be tolerated at successively caudal levels without neurologic deficit. No meaningful correlation between root injury and TSA was observed. The data also indicated that measurement of TSA is a more accurate method for evaluating neural canal encroachment than PP or MSD. The "calculated" TSA is a simple, objective method for obtaining this information without the aid of a computer. This study suggests that absolute TSA should be utilized in future studies evaluating decompressive treatment of thoracolumbar pathology.

Thirty-nine sites of Pseudomonas aeruginosa bone and joint infection in thirty-five intravenous drug abusers were treated over a four-year period. Early diagnosis was based on a history of drug abuse and demonstration of the site of infection by a technetium bone scan. Most patients responded to long-term therapy with intravenous aminoglycoside and carbenicillin. Extensive early surgical procedures were rarely indicated except in patients with infection of a large synovial joint.

An average follow-up of 40 years was obtained for 12 patients with spondylolisthesis treated at Hines Veterans Administration Hospital between 1944 and 1951. In each case, the slip had been Grade 1 and at the L5-S1 level. Five had been treated conservatively and seven surgically with a Hibbs fusion from L4 to S1. Of the conservatively managed patients, all functioned well during their working years, although one did have chronic, nondisabling, low-back pain. This same patient demonstrated radiographic evidence of progression to a Grade 2 spondylolisthesis. Among those undergoing surgery, the poor results were confined to those patients whose fusion attempts failed. Management for low-grade spondylolisthesis should be conservative where possible. When the low-back pain is disabling and surgery becomes necessary, failure to obtain a fusion portends a poor clinical result.

A dorsal closing wedge proximal V metatarsal osteotomy is described for treatment of painful plantar callosities due to prominence of any of the five metatarsal heads. Forty-one osteotomies were performed over a 3-year period. In all patients so treated relief of symptoms was achieved, plantar callosities were resolved, and no significant complications occurred.