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Recapitulating inherent heterogeneity and complex microarchitectures within confined print volumes for developing implantable constructs that could maintain their structure in vivo has remained challenging. Here, we present a combinational multimaterial and embedded bioprinting approach to fabricate complex tissue constructs that can be implanted postprinting and retain their three-dimensional (3D) shape in vivo. The microfluidics-based single nozzle printhead with computer-controlled pneumatic pressure valves enables laminar flow-based voxelation of up to seven individual bioinks with rapid switching between various bioinks that can solve alignment issues generated during switching multiple nozzles. To improve the spatial organization of various bioinks, printing fidelity with the z-direction, and printing speed, self-healing and biodegradable colloidal gels as support baths are introduced to build complex geometries. Furthermore, the colloidal gels provide suitable microenvironments like native extracellular matrices (ECMs) for achieving cell growths and fast host cell invasion via interconnected microporous networks in vitro and in vivo. Multicompartment microfibers (i.e., solid, core-shell, or donut shape), composed of two different bioink fractions with various lengths or their intravolume space filled by two, four, and six bioink fractions, are successfully printed in the ECM-like support bath. We also print various acellular complex geometries such as pyramids, spirals, and perfusable branched/linear vessels. Successful fabrication of vascularized liver and skeletal muscle tissue constructs show albumin secretion and bundled muscle mimic fibers, respectively. The interconnected microporous networks of colloidal gels result in maintaining printed complex geometries while enabling rapid cell infiltration, in vivo.

Targeted temperature management (TTM) directly impacts energy expenditure via temperature modulation and shivering associated with temperature modulating devices. We hypothesized that resting energy expenditure (REE) can be accurately estimated utilizing data obtained from a surface gel pad temperature modulating device (TMD) and demographic factors. Baseline demographic data, along with concurrent temperature, sedation, and shivering data, and indirect calorimetry (IDC) were collected from patients undergoing TTM. The data from the IDC and temperature modulation device (TMD) were synchronized and averaged over 60-second intervals to provide simultaneous comparisons. Heat transfer (calories) was calculated from the TMD by an equation that assessed water temperature from the TMD to the patient, water temperature returning to the TMD, water flow rates, and device mode. A linear regression model was used to determine factors associated with REE as measured by IDC. A difference in the mean between REE and estimated REE was used to assess accuracy. There were 48 assessments conducted in 40 subjects [mean (standard deviation)] age: 58 (14) years, 60% female, body surface area (BSA): 2.0 ± 0.3 who underwent simultaneous assessments. Target temperature was 36-37°C in 75%, with a median Bedside Shivering Assessment Score of 0 (range 0-2). Factors associated with REE on multivariable linear regression included older age (

Anifrolumab is a fully humanized monoclonal antibody targeting type I interferon receptor recently approved for the treatment of moderate-to-severe systemic lupus erythematous (SLE). In addition to ameliorating systemic lupus activity, anifrolumab has emerged as a promising therapeutic option for patients with refractory cutaneous discoid lupus erythematosus (DLE), but its effect on mucosal DLE has yet to be investigated. In a prospective study of 7 patients with severe mucosal DLE treated with anifrolumab, we observed substantial improvement in mucosal disease activity within 1 month of anifrolumab initiation, suggesting that the impressive benefit of anifrolumab previously reported in cutaneous DLE extends to mucosal involvement.

Introduction Extravasation or partial extravasation of the positron emission tomography (PET) tracer negatively effects image quality in PET and the accuracy of the standard uptake value (SUV). A commercially available topical sensor has been validated using a number of metrics to characterise injection quality. This evaluation explores contributing factors for extravasation and refines metrics to predict extravasation based on the time-activity-curves (TAC) of the topical sensor device. Methods A multi-site, multi-national pooling of 18F FDG PET/CT data was undertaken with 863 patients from 6 sites in the USA and 2 sites in Australia. A number of dose migration metrics determined with topical application of Lara sensors were retrospectively analysed using conventional statistical analysis. Deeper insights into the complex relationship between variables was further explored using an artificial neural network. Results Extravasation was independently predicted by the time taken for the injection sensor counts to reach double the counts of the reference sensor (tc50), the normalised difference between injection and reference sensors counts at 4 min post injection (ndAvgN), or the ratio of injection sensor counts to reference sensor counts at the end of data collection (CEnd ratio). The algorithm developed using the artificial neural network produced 100% sensitivity and 100% specificity against grounded truth for detecting extravasation by weighting and scaling these 3 key metrics; CEnd ratio, ndAvgN and tc50. Conclusion Partial extravasation of a PET dose is readily detected and differentiated using TAC metrics and these metrics could provide deeper insight into the impact of partial extravasation on image quality or quantitation. Further validation of key metrics developed in this study are recommended in a larger and more diverse cohort. Implications for practice Partial extravasation undermines image quality and accuracy of quantitation, impacting efficacy of outcomes for patients. Characterisation of extravasation informs decision making to optimise protocol and procedure, enhancing patient outcomes. Awareness provides the opportunity for education and training to minimise impact. The information can be used to drive policy and regulations to support improved techniques in practice.

Inducing normothermia with surface cooling temperature modulating devices (TMDs) is cumbersome and often associated with significant shivering. We tested the safety and feasibility of a novel transnasal evaporative cooling device to induce and maintain normothermia in febrile patients following ischemic and hemorrhagic stroke. A single-center study utilizing the CoolStat® transnasal cooling device was used to achieve core temperature reduction in mechanically ventilated stroke patients with fever (T ≥ 38.3 C) refractory to acetaminophen by inducing an evaporative cooling energy exchange in the nasal turbinates thru a high flow of dehumidified air into the nasal cavity and out through the mouth. Continuous temperature measurements were obtained from tympanic and core (esophageal or bladder) temperature monitors. Safety assessments included continuous monitoring for hypertension, tachycardia, and raised intracranial pressure (when monitored). Otolaryngology (ENT) evaluations were monitored for any device-related nasal mucosal injury with a pre- and post-visual examination. Shivering was assessed every 30 min using the Bedside Shivering Assessment Scale (BSAS). Duration of device use was limited to 8 h, at which time patients were transitioned to routine care for temperature management. Ten subjects (median age: 54 years, BMI: 32.5 kg/m2, 60% men) were enrolled with normothermia achieved in 90% of subjects. One subject did not achieve normothermia and was later refractory to other TMDs. Median baseline temperature was 38.5 ± 0.1 C, with a reduction noted by 4 h (38.5 ± 0.1 vs 37.3 ± 0.8, P

This case series examines the efficacy of anifrolumab as a therapeutic option for patients with lupus erythematosus.

Fatty acid amide hydrolase (FAAH) is a membrane protein that hydrolyzes endocannabinoids, and its inhibition produces analgesic and anti-inflammatory effects. The soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids. EETs have anti-inflammatory and inflammation resolving properties, thus inhibition of sEH consequently reduces inflammation. Concurrent inhibition of both enzymes may represent a novel approach in the treatment of chronic pain. Drugs with multiple targets can provide a superior therapeutic effect and a decrease in side effects compared to ligands with single targets. Previously, microwave-assisted methodologies were employed to synthesize libraries of benzothiazole analogs from which high affinity dual inhibitors (e.g. 3, sEH IC50=9.6nM; FAAH IC50=7nM) were identified. Here, our structure-activity relationship studies revealed that the 4-phenylthiazole moiety is well tolerated by both enzymes, producing excellent inhibition potencies in the low nanomolar range (e.g. 6o, sEH IC50=2.5nM; FAAH IC50=9.8nM). Docking experiments show that the new class of dual inhibitors bind within the catalytic sites of both enzymes. Prediction of several pharmacokinetic/pharmacodynamic properties suggest that these new dual inhibitors are good candidates for further in vivo evaluation. Finally, dual inhibitor 3 was tested in the Formalin Test, a rat model of acute inflammatory pain. The data indicate that 3 produces antinociception against the inflammatory phase of the Formalin Test in vivo and is metabolically stable following intraperitoneal administration in male rats. Further, antinociception produced by 3 is comparable to that of ketoprofen, a traditional nonsteroidal anti-inflammatory drug. The results presented here will help toward the long-term goal of developing novel non-opioid therapeutics for pain management.

INTRODUCTION: Aneurysmal subarachnoid hemorrhage(SAH) survivors live with long term residual physical and cognitive disability. We studied whether neuromuscular electrical stimulation(NMES) and high protein supplementation(HPRO) in the first two weeks after SAH could preserve neuromotor and cognitive function as compared to standard of care(SOC) for nutrition and mobilization. METHODS: SAH subjects with a Hunt Hess(HH) grade>1, modified Fisher score>1 and BMI3). Median duration of interventions was 12 days(range 9 – 14) with completion of 98% of NMES sessions and 83% of goal HPRO, and no reported serious adverse events. There was no difference in caloric intake between groups, but HPRO+NMES group received more protein(1.5+/−0.5 g/kg/d v 0.9+/−0.4 g/kg/d, P

Background: Primary resistance to immunotherapy can be observed in approximately 40&ndash, 65% of the stage IV melanoma patients treated with immune checkpoint inhibitors. A minority of the patients receive a second-line therapy, and the clinical benefit is small. Patients and methods: Stage IV melanoma patients treated with first-line PD-1-based immunotherapy between January 2015 and December 2018 were investigated. Primary resistance was defined as progressive disease (PD) at the time of the first tumor assessment after starting immunotherapy. Patients with complete response, partial response, and stable disease were classified as having disease control (DC). Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan&ndash, Meier estimator. Univariate and multivariate logistic regression analyses were performed to determine prognostic factors associated with OS. Results: Three hundred and nineteen patients were included, and 40% had primary resistance to immunotherapy. The median follow-up time was 22 months. Patients with primary resistance had 1-, 2-, and 3-year OS rates of 41%, 15%, and 10%, respectively, compared to 91%, 81%, and 65% for the patients who achieved DC. The following independently significant prognostic factors for OS were identified: protein S100B level and primary tumor localization. There was a statistically significant difference for OS (p &lt, 0.0001) but not for PFS (p = 0.230) when analyzing risk groups formed with a combination of these two variables (low-, intermediate-, and high-risk subgroups). Conclusions: Melanoma patients with primary resistance to immunotherapy have a dismal prognosis. Response at the first tumor assessment after starting immunotherapy is a stronger prognostic factor for the further course of the disease than pretreatment risk factors.

Introduction: Extravasation or partial extravasation of the radiopharmaceutical dose quality in positron emission tomography (PET) can undermine standard uptake value (SUV) and image quality. A topical sensor (Lara) has been validated using a number of metrics to characterise injection quality following manual injection. An assessment of the performance of these metrics for autoinjector administration has been undertaken. Methods: A single site, single PET/CT scanner was used to characterise injections using a KARL100 autoinjector with standardised apparatus, flush volume and infusion rate using Rad-inject pump (1 min infusion followed by 2 syringe flushes) for 18F-FDG, 68Ga-PSMA and 68Ga-DOTATATE. 296 patients with topical application of Lara sensors were retrospectively analysed using conventional statistical analysis and an artificial neural network. Results: Partial extravasation was noted in 1.1% of studies with 9.1% (inclusive of partial extravasation) identified to have an injection anomaly (eg. venous retention). Extravasation was independently predicted by the time elapsed as the counts recorded by the injection sensor fall from the maximum value to within 200% of the reference sensor counts (tc50) greater than 1200 seconds, the difference in counts for injection and reference sensors, normalized by dose, from 4 minutes post injection (ndAvgN) greater than 25, and the ratio of the average counts per second recorded by the injection sensor at the end of a monitoring period to those of the reference sensor (CEnd ratio) greater than 2. Conclusion: Extravasation and partial extravasation of PET doses are readily detected and differentiated using TAC metrics. The metrics can provide the insights that could inform image quality or SUV accuracy issues. Further validation of key metrics are recommended in a larger and more diverse cohort.

In this paper, a graph-based nonlocal total variation method (NLTV) is proposed for unsupervised classification of hyperspectral images (HSI). The variational problem is solved by the primal-dual hybrid gradient (PDHG) algorithm. By squaring the labeling function and using a stable simplex clustering routine, an unsupervised clustering method with random initialization can be implemented. The effectiveness of this proposed algorithm is illustrated on both synthetic and real-world HSI, and numerical results show that the proposed algorithm outperforms other standard unsupervised clustering methods such as spherical K-means, nonnegative matrix factorization (NMF), and the graph-based Merriman-Bence-Osher (MBO) scheme.

PET and SUV depend on reliable pharmacokinetic modeling, part of which is predictable dose delivery. Partial extravasation of the intravenous dose administered undermines the predictability of dose delivery and, potentially, the accuracy of the SUV calculation. Use of the Lara device with topical sensors is a simple, noninvasive way to determine partial dose extravasation. As part of routine monitoring of 18F-FDG PET administrations, an interesting case was identified that mimicked extravasation but represented dose leakage during infusion via an automatic injector. The Lara device provided a useful tool for more timely critical evaluation and problem solving, extending advantages to the patient and practice.

Calculation of the standard uptake value (SUV) and image quality in positron emission tomography (PET) hinges on accurate dose delivery. Extravasation or partial extravasation of the radiopharmaceutical dose can undermine SUV and image quality, and contribute to unnecessary imaging (time and CT dose). Topical sensor characterisation of injections has been reported, with extravasation rates ranging from 9% to 23% for 18F-FDG after manual injection.A single site, single PET/CT scanner was used to characterise injections using an autoinjector with standardised apparatus, flush volume and infusion rate using 18F-FDG, 68Ga-PSMA and 68Ga-DOTATATE; more reflective of Australian PET facilities. 296 patients with topical application of LARA sensors were retrospectively analysed.Only 1.1% of studies showed evidence of partial dose extravasation. In total, 9.1% were identified to have an injection anomaly (including venous retention). No statistically significant differences were noted across the radiopharmaceuticals for demographic data. Although not demonstrating a statistically significant correlation, there was more extravasated doses associated with female patients (P = .334), right side (P = .372), and hand injections (P = .539). Extravasation was independent of dose administered (P = .495), the radiopharmaceutical (P = .887), who injected the dose (P = .343), height (P = .438), weight (P = .607) or age (P = .716). Extravasation was associated with higher glucose levels (P.001), higher t-half (P = .019) and higher aUCR10, tc50, aUCR1 and c1 (all P.001).Topical monitoring and characterisation of PET dose administration is possible and practical with the LARA device. Extravasation and partial extravasation of PET doses are not only readily detected but they are also preventable. The LARA device can provide the insights into variables that could eliminate extravasation as a cause of image quality or SUV accuracy issues.

PET and SUV depend on reliable pharmacokinetic modeling, part of which is predictable dose delivery. Partial extravasation of the intravenous dose administered undermines the predictability of dose delivery and, potentially, the accuracy of the SUV calculation. Use of the Lara device with topical sensors is a simple, noninvasive way to determine partial dose extravasation. As part of routine monitoring of

Three cobalt(II) complexes based on 4′-chloro-2,2′:6′,2″-terpyridine (4′-Cltpy) have been synthesized and structurally characterized by X-ray crystallography. The reaction with a 1:1 metal-to-ligand ratio in a mixed CH2Cl2–MeOH solvent afforded the mononuclear complex Co(4′-Cltpy)Cl2 (1) that mimicks the previously reported Cu(4′-Cltpy)Cl2, while altering the metal-to-ligand ratio to 2:1 under the same reaction conditions resulted in the formation of a different complex with a component of [Co(4′-Cltpy)Cl2][Co2(4′-Cltpy)2Cl4] (2), based on single crystal X-ray structural analysis. The presence of both a mononuclear molecule Co(4′-Cltpy)Cl2 and dinuclear Cl-bridging Co2(4′-Cltpy)2Cl4 in 2 was revealed. The replacement of CoCl2 with Co(SCN)2 under the same reaction conditions as for 1 gave a similar mononuclear Co(4′-Cltpy)(SCN)2 (3). The cobalt(II) complexes along with the known copper analogue 4 were investigated for their in vitro cytotoxic activity towards two human cancer cell lines, the human breast cancer (MCF-7) and leukemia (K562) cells, and distinct cytotoxicity was observed.

State health departments commonly use quality improvement coaching as an implementation strategy for improving low human papillomavirus (HPV) vaccination coverage, but such coaching can be resource intensive. To explore opportunities for improving efficiency, we compared in-person and webinar delivery of coaching sessions on implementation outcomes, including reach, acceptability, and delivery cost. In 2015, we randomly assigned 148 high-volume primary care clinics in Illinois, Michigan, and Washington State to receive either in-person or webinar coaching. Coaching sessions lasted about 1 hr and used our Immunization Report Card to facilitate assessment and feedback. Clinics served over 213,000 patients ages 11-17. We used provider surveys and delivery cost assessment to collect implementation data. This report is focused exclusively on the implementation aspects of the intervention. More providers attended in-person than webinar coaching sessions (mean 9 vs. 5 providers per clinic, respectively, p = .004). More providers shared the Immunization Report Card at clinic staff meetings in the in-person than webinar arm (49% vs. 20%; p = .029). In both arms, providers' belief that their clinics' HPV vaccination coverage was too low increased, as did their self-efficacy to help their clinics improve (p < .05). Providers rated coaching sessions in the two arms equally highly on acceptability. Delivery cost per clinic was $733 for in-person coaching versus $461 for webinar coaching. In-person and webinar coaching were well received and yielded improvements in provider beliefs and self-efficacy regarding HPV vaccine quality improvement. In summary, in-person coaching cost more than webinar coaching per clinic reached, but reached more providers. Further implementation research is needed to understand how and for whom webinar coaching may be appropriate.

Objectives N‐acetylcysteine (NAC) is a clinically approved thiol‐containing redox modulatory compound currently in trials for many neurological and psychiatric disorders. Although generically labeled as an “antioxidant,” poor understanding of its site(s) of action is a barrier to its use in neurological practice. Here, we examined the efficacy and mechanism of action of NAC in rodent models of hemorrhagic stroke. Methods Hemin was used to model ferroptosis and hemorrhagic stroke in cultured neurons. Striatal infusion of collagenase was used to model intracerebral hemorrhage (ICH) in mice and rats. Chemical biology, targeted lipidomics, arachidonate 5‐lipoxygenase (ALOX5) knockout mice, and viral‐gene transfer were used to gain insight into the pharmacological targets and mechanism of action of NAC. Results NAC prevented hemin‐induced ferroptosis by neutralizing toxic lipids generated by arachidonate‐dependent ALOX5 activity. NAC efficacy required increases in glutathione and is correlated with suppression of reactive lipids by glutathione‐dependent enzymes such as glutathione S‐transferase. Accordingly, its protective effects were mimicked by chemical or molecular lipid peroxidation inhibitors. NAC delivered postinjury reduced neuronal death and improved functional recovery at least 7 days following ICH in mice and can synergize with clinically approved prostaglandin E2 (PGE2). Interpretation NAC is a promising, protective therapy for ICH, which acted to inhibit toxic arachidonic acid products of nuclear ALOX5 that synergized with exogenously delivered protective PGE2 in vitro and in vivo. The findings provide novel insight into a target for NAC, beyond the generic characterization as an antioxidant, resulting in neuroprotection and offer a feasible combinatorial strategy to optimize efficacy and safety in dosing of NAC for treatment of neurological disorders involving ferroptosis such as ICH. Ann Neurol 2018;84:854–872

Oxidant stress has been implicated in a wide variety of disease processes. One method to quantify oxidative injury is to measure lipid peroxidation. Quantification of a group of prostaglandin F(2)-like compounds derived from the nonezymatic oxidation of arachidonic acid, termed the F(2)-isoprostanes (F(2)-IsoPs), provides an accurate assessment of oxidative stress both in vitro and in vivo. In fact, in a recent National Institutes of Health-sponsored independent study, F(2)-IsoPs were shown to be the most reliable index of in vivo oxidant stress when compared against other well-known biomarkers. This article summarizes current methodology used to quantify these molecules. Our laboratory's method to measure F(2)-IsoPs in biological fluids and tissues using gas chromatography-mass spectrometry is detailed herein. In addition, other mass spectrometric approaches, as well as immunological methods to measure these compounds, are discussed. Finally, the utility of these molecules as in vivo biomarkers of oxidative stress is summarized.

e are currently seniors at Norman Thomas High School in Manhattan, New York. We have been using the ellevue school-based health center (SBHC) since we started high school here. The SBHC has been able to rovide us with many services. As we are both varsity athletes, we get our annual physicals at the health center nd our clearance for sports. Additionally, we, along with many of our teammates, have been helped when we ustained injuries while playing. Some of our teammates with more serious orthopedic injuries have required ore extensive orthopedic treatment at Bellevue, in the Partners for Youth program, as part of their close elationship with the SBHC. All consultation and treatment through this special program is free of charge to all tudent athletes in New York City, and coordinated through our health center. As part of the annual care we receive, we get screenings, blood work, and vaccines. We also have obtained ealth and nutrition education, as well as education in the prevention of pregnancy and sexually transmitted iseases. Both of us have seen the social workers at the SBHC for counseling. We have recommended the service nd have taken some of our friends for help when they needed it. Our program has 2 social workers who are upportive and offer help, and they have many diverse resources. Several groups dealing with various issues are un weekly by the social workers and are open to everyone. They work closely with the nurse practitioners. One of the best things regarding our school-based health program is that reproductive health services are vailable to all those students needing it. Most importantly, all these services are confidential and easy to obtain. he staff provides screenings and treatment for sexually transmitted infections in a private and sensitive manner o that everyone is comfortable seeking out this service. For many teenagers, it is difficult to find the time to travel to the doctor, and therefore, many of our friends do ot receive regular health care; many have no health insurance. Our SBHC is convenient, and the nurse ractitioners are always available to help us, no matter what. We do not have to rely on a parent to take us, and e do not have to deal with waiting several weeks for an appointment. The relationship between the staff and the students is closer and more comfortable than kids generally have with heir doctors. The nurse practitioners have come to know us well over the past several years and are a part of our igh school life. We have come to know them, too, as opposed to seeing different providers every time we go o the doctor. The staff is always welcoming, supportive, understanding, and open to helping with any problem. e are also lucky that Bellevue is so close so we can access all the services in the hospital as well. We both articipated in the New York University School of Medicine BODY project, which stands for Banishing Obesity nd Diabetes in Youth. The team works from the SBHC, and the health center staff told us about the program nd recommended us for it. As seniors graduating in 2012, we will miss the easy relationship we have with the health center, but as a result f taking care of our personal health for the past 4 years, we will always keep our health a priority. Experiencing he helping relationship with the nurse practitioners over the past few years has motivated us to pursue careers here we can do the same for others in the future.