The consideration of post-exercise impact on SCAT3 scores in athletes immediately following a head injury.

METHODS: Symptoms were assessed immediately following completion of a rugby match (median 60 minutes). Players removed from the match for assessment due to a head hit were classified as head injured. Controls completed match without head hit. RESULTS: 209 players (67 female; 33 ± 13 years) participated with 80 experiencing a head injury. Symptom severity was significantly greater in head injured (26.2 ± 17.6) compared with controls (8.9 ± 11.5, P < 0.001). 21% of control players reporting >16 symptom severity, misclassifying them as suspected concussion. There were no significant sex differences. Factor analysis produced four symptom clusters of which Headache was most discriminatory between the head injured (median = 1.7) and controls (median = 0.0). CONCLUSION: These findings demonstrate that exercise and contact during a game affect symptom assessment, increasing the likelihood of misclassifying players with suspected concussion. Factor characterization of symptoms associated with head injury using an exercised comparison group provides more useful discrimination. These results highlight the necessity for objective measures to diagnose concussions outside of symptom self-report.

The prostaglandin pathway is activated in patients who fail medical therapy for benign prostatic hyperplasia with lower urinary tract symptoms.

BACKGROUND: Little is known about how benign prostatic hyperplasia (BPH) develops and why patients respond differently to medical therapy designed to reduce lower urinary tract symptoms (LUTS). The Medical Therapy of Prostatic Symptoms (MTOPS) trial randomized men with symptoms of BPH and followed response to medical therapy for up to 6 years. Treatment with a 5α-reductase inhibitor (5ARI) or an alpha-adrenergic receptor antagonist (α-blocker) reduced the risk of clinical progression, while men treated with combination therapy showed a 66% decrease in risk of progressive disease. However, medical therapies for BPH/LUTS are not effective in many patients. The reasons for nonresponse or loss of therapeutic response in the remaining patients over time are unknown. A better understanding of why patients fail to respond to medical therapy may have a major impact on developing new approaches for the medical treatment of BPH/LUTS. Prostaglandins (PG) act on G-protein-coupled receptors (GPCRs), where PGE2 and PGF2 elicit smooth muscle contraction. Therefore, we measured PG levels in the prostate tissue of BPH/LUTS patients to assess the possibility that this signaling pathway might explain the failure of medical therapy in BPH/LUTS patients. METHOD: Surgical BPH (S-BPH) was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy and underwent surgical intervention to relieve LUTS. Control tissue was termed Incidental BPH (I-BPH). I-BPH was TZ obtained from men undergoing radical prostatectomy for low-volume, low-grade prostatic adenocarcinoma (PCa, Gleason score ≤ 7) confined to the peripheral zone. All TZ tissue was confirmed to be cancer-free. S-BPH patients divided into four subgroups: patients on α-blockers alone, 5ARI alone, combination therapy (α-blockers plus 5ARI), or no medical therapy (none) before surgical resection. I-BPH tissue was subgrouped by prior therapy (either on α-blockers or without prior medical therapy before prostatectomy). We measured prostatic tissue levels of prostaglandins (PGF2α , PGI2 , PGE2 , PGD2 , and TxA2 ), quantitative polymerase chain reaction levels of mRNAs encoding enzymes within the PG synthesis pathway, cellular distribution of COX1 (PTGS1) and COX2 (PTGS2), and tested the ability of PGs to contract bladder smooth muscle in an in vitro assay. RESULTS: All PGs were significantly elevated in TZ tissues from S-BPH patients (n = 36) compared to I-BPH patients (n = 15), regardless of the treatment subgroups. In S-BPH versus I-BPH, mRNA for PG synthetic enzymes COX1 and COX2 were significantly elevated. In addition, mRNA for enzymes that convert the precursor PGH2 to metabolite PGs were variable: PTGIS (which generates PGI2 ) and PTGDS (PGD2 ) were significantly elevated; nonsignificant increases were observed for PTGES (PGE2 ), AKR1C3 (PGF2α ), and TBxAS1 (TxA2 ). Within the I-BPH group, men responding to α-blockers for symptoms of BPH but requiring prostatectomy for PCa did not show elevated levels of COX1, COX2, or PGs. By immunohistochemistry, COX1 was predominantly observed in the prostatic stroma while COX2 was present in scattered luminal cells of isolated prostatic glands in S-BPH. PGE2 and PGF2α induced contraction of bladder smooth muscle in an in vitro assay. Furthermore, using the smooth muscle assay, we demonstrated that α-blockers that inhibit alpha-adrenergic receptors do not appear to inhibit PG stimulation of GPCRs in bladder muscle. Only patients who required surgery to relieve BPH/LUTS symptoms showed significantly increased tissue levels of PGs and the PG synthetic enzymes. CONCLUSIONS: Treatment of BPH/LUTS by inhibition of alpha-adrenergic receptors with pharmaceutical α-blockers or inhibiting androgenesis with 5ARI may fail because of elevated paracrine signaling by prostatic PGs that can cause smooth muscle contraction. In contrast to patients who fail medical therapy for BPH/LUTS, control I-BPH patients do not show the same evidence of elevated PG pathway signaling. Elevation of the PG pathway may explain, in part, why the risk of clinical progression in the MTOPS study was only reduced by 34% with α-blocker treatment.

Further exploration of the structure-activity relationship of dual soluble epoxide hydrolase/fatty acid amide hydrolase inhibitors.

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 = 9.6 nM; FAAH IC50 = 7 nM) 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 = 2.5 nM; FAAH IC50 = 9.8 nM). 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.

Safety and Feasibility of a Novel Transnasal Cooling Device to Induce Normothermia in Febrile Cerebrovascular Patients.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 < 0.001) and sustained at 8 h (38.5 ± 0.1 vs 37.1 ± 0.7, P = 0.001). Time to normothermia was 2.6 ± 1.9 h. The median BSAS was 0 (range 0-1) with only 4 episodes necessitating meperidine across 76 h of study monitoring. No treatment was discontinued due to safety concerns. ENT evaluations noted no device-related adverse findings. CONCLUSIONS: Inducing normothermia with a novel transnasal TMD appears to be safe, feasible and not associated with significant shivering. A multicenter trial testing the ability of the CoolStat to maintain normothermia for 24 h is currently underway.

Neuromuscular Electrical Stimulation and High-Protein Supplementation After Subarachnoid Hemorrhage: A Single-Center Phase 2 Randomized Clinical Trial.

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 2 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 BMI < 40 kg/m2 were randomly assigned to SOC or NMES + HPRO. NMES was delivered to bilateral quadricep muscles daily during two 30-min sessions along with HPRO (goal:1.8 g/kg/day) between post-bleed day (PBD) 0 and 14. Primary endpoint was atrophy in the quadricep muscle as measured by the percentage difference in the cross-sectional area from baseline to PBD14 on CT scan. All subjects underwent serial assessments of physical (short performance physical battery, SPPB) cognitive (Montreal Cognitive Assessment Scale, MoCA) and global functional recovery (modified Rankin Scale, mRS) at PBD 14, 42, and 90. RESULTS: Twenty-five patients (SOC = 13, NMES + HPRO = 12) enrolled between December 2017 and January 2019 with no between-group differences in baseline characteristics (58 years old, 68% women, 50% HH > 3). 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 < 0.01). Muscle atrophy was less in NMES + HPRO than the SOC group (6.5 ± 4.1% vs 12.5 ± 6.4%, P 0.01). Higher atrophy was correlated with lower daily protein intake (ρ = - 0.45, P = 0.03) and lower nitrogen balance (ρ = 0.47, P = 0.02); and worse 3 month SPPB (ρ = -  0.31, P = 0.1) and mRS (ρ = 0.4, P = 0.04). NMES + HPRO patients had a better median [25%,75] SPPB (12[10, 12] v. 9 [4, 12], P = 0.01) and mRS (1[0,2] v.2[1, 3], P = 0.04) than SOC at PBD 90. CONCLUSIONS: NMES + HPRO appears to be feasible and safe acutely after SAH and may reduce acute quadriceps muscle wasting with a lasting benefit on recovery after SAH.

N-acetylcysteine targets 5 lipoxygenase-derived, toxic lipids and can synergize with prostaglandin E2 to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice.

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.

Urinary eicosanoid metabolites in HIV-infected women with central obesity switching to raltegravir: an analysis from the women, integrase, and fat accumulation trial.

Chronic inflammation is a hallmark of HIV infection. Eicosanoids reflect inflammation, oxidant stress, and vascular health and vary by sex and metabolic parameters. Raltegravir (RAL) is an HIV-1 integrase inhibitor that may have limited metabolic effects. We assessed urinary F2-isoprostanes (F2-IsoPs), prostaglandin E2 (PGE-M), prostacyclin (PGI-M), and thromboxane B2 (TxB2) in HIV-infected women switching to RAL-containing antiretroviral therapy (ART). Thirty-seven women (RAL = 17; PI/NNRTI = 20) with a median age of 43 years and BMI 32 kg/m(2) completed week 24. TxB2 increased in the RAL versus PI/NNRTI arm (+0.09 versus -0.02; P = 0.06). Baseline PGI-M was lower in the RAL arm (P = 0.005); no other between-arm cross-sectional differences were observed. In the PI/NNRTI arm, 24-week visceral adipose tissue change correlated with PGI-M (rho = 0.45; P = 0.04) and TxB2 (rho = 0.44; P = 0.005) changes, with a trend seen for PGE-M (rho = 0.41; P = 0.07). In an adjusted model, age ≥ 50 years (N = 8) was associated with increased PGE-M (P = 0.04). In this randomized trial, a switch to RAL did not significantly affect urinary eicosanoids over 24 weeks. In women continuing PI/NNRTI, increased visceral adipose tissue correlated with increased PGI-M and PGE-M. Older age (≥ 50) was associated with increased PGE-M. Relationships between aging, adiposity, ART, and eicosanoids during HIV-infection require further study.

Identification of novel F2-isoprostane metabolites by specific UDP-glucuronosyltransferases.

UDP-glucuronosyltransferases (UGTs) catalyze the conjugation of glucuronic acid with endogenous and exogenous lipophilic small molecules to facilitate their inactivation and excretion from the body. This represents approximately 35 % of all phase II metabolic transformations. Fatty acids and their oxidized eicosanoid derivatives can be metabolized by UGTs. F2-isoprostanes (F2-IsoPs) are eicosanoids formed from the free radical oxidation of arachidonic acid. These molecules are potent vasoconstrictors and are widely used as biomarkers of endogenous oxidative damage. An increasing body of evidence demonstrates the efficacy of measuring the ß-oxidation metabolites of F2-IsoPs rather than the unmetabolized F2-IsoPs to quantify oxidative damage in certain settings. Yet, the metabolism of F2-IsoPs is incompletely understood. This study sought to identify and characterize novel phase II metabolites of 15-F2t-IsoP and 5-epi-5-F2t-IsoP, two abundantly produced F2-IsoPs, in human liver microsomes (HLM). Utilizing liquid chromatography-mass spectrometry, we demonstrated that glucuronide conjugates are the major metabolites of these F2-IsoPs in HLM. Further, we showed that these molecules are metabolized by specific UGT isoforms. 15-F2t-IsoP is metabolized by UGT1A3, 1A9, and 2B7, while 5-epi-5-F2t-IsoP is metabolized by UGT1A7, 1A9, and 2B7. We identified, for the first time, the formation of intact glucuronide F2-IsoPs in human urine and showed that F2-IsoP glucuronidation is reduced in people supplemented with eicosapentaenoic and docosahexaenoic acids for 12 weeks. These studies demonstrate that endogenous F2-IsoP levels can be modified by factors other than redox mechanisms.

Asymmetry-enhanced 59Co NMR thermometry in Co(iii) complexes.

Design strategies for molecular thermometers by magnetic resonance are essential for enabling new noninvasive means of temperature mapping for disease diagnoses and treatments. Herein we demonstrate a new design strategy for thermometry based on chemical control of the vibrational partition function. To do so, we performed variable-temperature 59Co NMR investigations of four air-stable Co(iii) complexes: Co(accp)3 (1), Co(bzac)3 (2), Co(tBu2-acac)3 (3), and Co(acac)3 (4) (accp = 2-acetylcyclopentanonate; bzac = benzoylacetonate; tBu2-acac = 2,2,6,6-tetramethyl-3,5-heptanedionate and acac = acetylacetonate). We discovered 59Co chemical shift temperature sensitivity (Δδ/ΔT) values of 3.50(2), 3.39(3), 1.63(3), and 2.83(1) ppm °C-1 for 1-4, respectively, at 100 mM concentration. The values observed for 1 and 2 are new records for sensitivity for low-spin Co(iii) complexes. We propose that the observed heightened sensitivities for 1 and 2 are intimately tied to the asymmetry of the accp and bzac ligands versus the acac and tBu2-acac ligands, which enables a larger number of low-energy Raman-active vibrational modes to contribute to the observed Δδ/ΔT values.

Altered Large-Scale Resting-State Functional Network Connectivity in Convergence Insufficiency Young Adults Compared With Binocularly Normal Controls.

Purpose: To investigate the underlying resting-state functional connectivity (RSFC) of symptomatic convergence insufficiency (CI) compared with binocularly normal controls (BNC) using functional magnetic resonance imaging (fMRI) under The Convergence Insufficiency Neuro­mechanism Adult Population Study (NCT03593031). Methods: A total of 101 participants were eligible for this study. After removing datasets with motion artifacts, 49 CI and 47 BNC resting-state functional magnetic resonance imaging datasets were analyzed. CI was diagnosed with the following signs: (1) receded near point of convergence of 6 cm or greater, (2) decreased positive fusional vergence of less than 15∆ or failing Sheard's criteria of twice the near phoria, (3) near phoria of at least 4∆ more exophoric compared with the distance phoria, and (4) symptoms using the Convergence Insufficiency Symptom Survey (score of ≥21). RSFC was assessed using a group-level independent components analysis and dual regression. A behavioral correlation analysis using linear regression method was performed between clinical measures and RSFC using the significant difference between the CI and BNC. Results: On average, a decreased RSFC was observed within the frontoparietal network, default mode network and visual network in patients with CI, compared with the participants with BNC (P < 0.05, corrected for multiple comparisons). The default mode network RSFC strength was significantly correlated with the PFV, near point of convergence, and difference between the horizontal phoria at near compared with far (P < 0.05). Conclusions: Results support altered RSFC in patients with CI compared with participants with BNC and suggest that these differences in underlying neurophysiology may in part be in connection with the differences in optometric visual function used to diagnose CI.

Correlation between variant allele frequency and mean tumor molecules with tumor burden in patients with solid tumors.

Several studies have demonstrated the prognostic value of circulating tumor DNA (ctDNA); however, the correlation of mean tumor molecules (MTM)/ml of plasma and mean variant allele frequency (mVAF; %) with clinical parameters is yet to be understood. In this study, we analyzed ctDNA data in a pan-cancer cohort of 23 543 patients who had ctDNA testing performed using a personalized, tumor-informed assay (Signatera™, mPCR-NGS assay). For ctDNA-positive patients, the correlation between MTM/ml and mVAF was examined. Two subanalyses were performed: (a) to establish the association of ctDNA with tumor volume and (b) to assess the correlation between ctDNA dynamics and patient outcomes. On a global cohort, a positive correlation between MTM/ml and mVAF was observed. Among 18 426 patients with longitudinal ctDNA measurements, 13.3% had discordant trajectories between MTM/ml and mVAF at subsequent time points. In metastatic patients receiving immunotherapy (N = 51), changes in ctDNA levels expressed both in MTM/ml and mVAF showed a statistically significant association with progression-free survival; however, the correlation with MTM/ml was numerically stronger.

Intraputaminal Gene Delivery in Two Patients with Aromatic L-Amino Acid Decarboxylase Deficiency.

Background: Aromatic l-amino acid decarboxylase deficiency (AADCD) is a rare, early-onset, dyskinetic encephalopathy mostly reflecting a defective synthesis of brain dopamine and serotonin. Intracerebral gene delivery (GD) provided a significant improvement among AADCD patients (mean age, ≤6 years). Objective: We describe the clinical, biological, and imaging evolution of two AADCD patients ages >10 years after GD. Methods: Eladocagene exuparvovec, a recombinant adeno-associated virus containing the human complimentary DNA encoding the AADC enzyme, was administered into bilateral putamen by stereotactic surgery. Results: Eighteen months after GD, patients showed improvement in motor, cognitive and behavioral function, and in quality of life. Cerebral l-6-[18F] fluoro-3, 4-dihydroxyphenylalanine uptake was increased at 1 month, persisting at 1 year compared to baseline. Conclusion: Two patients with a severe form of AADCD had an objective motor and non-motor benefit from eladocagene exuparvovec injection even when treated after the age of 10 years, as in the seminal study.

Development of a Resting Energy Expenditure Estimation in Patients Undergoing Targeted Temperature Management with a Surface Gel Pad Temperature Modulating Device.

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 (p < 0.001), male sex (p = 0.004), higher BSA (p < 0.001), higher patient temperature (p < 0.001), and lower heat transfer (p = 0.003). Adjusted prediction coefficients from this model were then tested against REE by a Bland-Altman analysis. The difference between difference in resting energy estimation (REEdiff) and measured REE by IDC was 6.2 calories/min (REEdiff: 95% confidence interval: -14.1 calories, 26.5 calories, p = 0.5). We believe that the heat transfer data from the TMD coupled with clinical characteristics of patients can be utilized to calculate the REE for every minute of TTM. These data can be utilized to mitigate the consequences of shivering and malnutrition during TTM.

Topical Sensor for the Assessment of Injection Quality for 18F-FDG, 68Ga-PSMA and 68Ga-DOTATATE Positron Emission Tomography.

INTRODUCTION: 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. METHOD: 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. RESULTS: 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). CONCLUSION: 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.

Detection of 18F-FDG Dose Leakage Using a Topical Device.

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.

Topical Sensor for the Assessment of PET Dose Administration: Metric Performance with an Autoinjector.

Extravasation or partial extravasation of the radiopharmaceutical dose in PET can undermine SUV and image quality. A topical sensor has been validated using several metrics to characterize injection quality after manual injection. The performance of these metrics for autoinjector administration has been assessed. Methods: A single PET/CT scanner at a single site was used to characterize injections using an autoinjector with standardized apparatus, flush volume, and infusion rate (1-min infusion followed by 2 syringe flushes) for 18F-FDG, 68Ga-prostate-specific membrane antigen, and 68Ga-DOTATATE. In total, 296 patients with topical application of sensors were retrospectively analyzed using conventional statistical analysis and an artificial neural network. Results: Partial extravasation was noted in 1.3% of studies, with 9.1% (inclusive of partial extravasation) identified to have an injection anomaly (e.g., venous retention). Extravasation was independently predicted by the time that elapsed as the counts recorded by the injection sensor fell from the maximum value to within 200% of the reference sensor counts greater than 1,200 s; as the difference in counts for injection and reference sensors, normalized by dose, from 4 min after injection greater than 25; and as 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 greater than 2. Conclusion: Extravasation and partial extravasation of PET doses are readily detected and differentiated using time-activity curve metrics. The metrics can provide the insight that could inform image quality or SUV accuracy issues. Further validation of key metrics is recommended in a larger and more diverse cohort.

At-Risk Butterfly Captive Propagation Programs to Enhance Life History Knowledge and Effective Ex Situ Conservation Techniques.

Improving knowledge of ex situ best practices for at-risk butterflies is important for generating successful conservation and recovery program outcomes. Research on such captive populations can also yield valuable data to address key information gaps about the behavior, life history, and ecology of the target taxa. We describe a protocol for captive propagation of the federally endangered Cyclargus thomasi bethunebakeri that can be used as a model for other at-risk butterfly ex situ programs, especially those in the family Lycaenidae. We further provide a simple and straightforward protocol for recording various life history metrics that can be useful for informing ex situ methodologies as well as adapted for laboratory studies of other lepidoptera.

Primary Resistance to PD-1-Based Immunotherapy-A Study in 319 Patients with Stage IV Melanoma.

BACKGROUND: Primary resistance to immunotherapy can be observed in approximately 40-65% 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-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 < 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.

Oxidant stress in HIV-infected women from the Women's Interagency HIV Study.

BACKGROUND: Oxidant stress contributes to the pathogenesis of multiple conditions and can be assessed by measuring plasma F(2)-isoprostane concentrations. We hypothesized that oxidant stress is associated with plasma homocysteine concentration and risk factors for atherosclerosis in HIV-infected women. METHODS: We measured plasma F(2)-isoprostane concentrations in a cross-sectional study of 249 HIV-infected women attending the Bronx (NY, USA) site of the Women's Interagency HIV Study and assessed associations with plasma homocysteine concentration and other metabolic parameters by linear regression. RESULTS: In multivariate analysis, hepatitis C virus (HCV) viraemia, waist circumference, homocysteine concentration and serum aspartate aminotransferase level were positively associated with log F(2)-isoprostane concentration (all P<0.005). There was a trend for an inverse association between log F(2)-isoprostane and CD4(+) T-cell percentage (P=0.06). Among women with HCV infection, the FIB-4 index, an indirect marker of liver fibrosis derived from routine laboratory tests, was positively associated with log F(2)-isoprostane concentration. CONCLUSIONS: In this cross-sectional study of HIV-infected women, plasma F(2)-isoprostane concentration was positively associated with homocysteine concentration, as well as HCV infection, abdominal obesity and aspartate aminotransferase level.

Coaching primary care clinics for HPV vaccination quality improvement: Comparing in-person and webinar implementation.

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.