Evaluation of fixed and adaptive concentration thresholds for particle filter systems.

Particle filtration can effectively reduce indoor concentrations of particulate matter (PM) but may incur high energy use. This study evaluates fixed and adaptive concentration thresholds to automate the operation of filtration systems. Simulated environments were derived from week-long continuous PM measurements from Dylos DC1700 (N = 104) and Alphasense OPC-N2 (N = 100) particle counters deployed in apartments in Toronto. A fixed threshold of 4.0 µg·m-3 resulted in a mean air cleaner runtime of 6.9%-21.0% depending on clean air delivery rate (CADR) and particle sensor, while providing mean concentration reductions of 67%-71% compared to operating the air cleaner constantly (runtime = 100%). In most environments, runtime could be further reduced by raising the fixed threshold while resulting in only a modest decrease in absolute and normalized mean exposure reduction. Using an adaptive threshold derived from a k-means clustering approach generally provided substantial exposure reduction while preventing high runtimes. These results were generally insensitive to cleaning power and the monitor used to measure particle concentrations. Reducing the energy usage of particle filter systems will make them a more viable and sustainable means of improving occupant health.

A construction classification system database for understanding resource use in building construction.

The building sector is a voracious consumer of primary materials. However, the study of building material use and associated impacts is challenged by the paucity of publicly available data in the field and the heterogeneity of data organization and classification between published studies. This paper makes two main contributions. First, we propose and demonstrate a building material data structure adapted from UniFormat and MasterFormat, two widely used construction classification systems in North America. Second, the dataset included provides fine grained material data for 70 buildings in North America. The dataset was developed by collecting design or construction drawings for the studied buildings and performing material takeoffs based on these drawings. The ontology is based on UniFormat and MasterFormat to facilitate interoperability with existing construction management practices, and to suggest a standardized structure for future material intensity studies. The data structure supports investigation into how form and building design are driving material use, opportunities to reduce construction material consumption and better understanding of how materials are used in buildings.

Autonomic Dysreflexia After Hip Fractures Managed by Regional Anesthesia: A Case Report.

Autonomic dysreflexia occurs after a spinal cord injury usually at the level of T6 or above, and its hallmark feature is exaggerated autonomic response to noxious stimuli resulting in uncontrolled hypertensive episodes with reflexive bradycardia that can be fatal if not controlled. We present a case highlighting regional anesthetic techniques, including peripheral nerve blocks, to ameliorate the symptoms of autonomic dysreflexia triggered by hip fractures in a 57-year-old woman with an old C5-C6 spinal cord injury before definitive hip surgery. The regional techniques described provide anesthesiologists with a simple strategy to potentially mitigate a life-threatening situation.

Ketamine in the Past, Present, and Future: Mechanisms, Metabolites, and Toxicity.

PURPOSE OF REVIEW: While ketamine's analgesia has mostly been attributed to antagonism of N-methyl-D-aspartate receptors, evidence suggests multiple other pathways are involved in its antidepressant and possibly analgesic activity. These mechanisms and ketamine's role in the nociplastic pain paradigm are discussed. Animal studies demonstrating ketamine's neurotoxicity have unclear human translatability and findings from key rodent and human studies are presented. RECENT FINDINGS: Ketamine's metabolites, and (2R,6R)-hydroxynorketamine in particular, may play a greater role in its clinical activity than previously believed. The activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and the mammalian target of rapamycin by ketamine are mechanisms that are still being elucidated. Ketamine might work best in nociplastic pain, which involves altered pain processing. While much is known about ketamine, new studies will continue to define its role in clinical medicine. Evidence supporting ketamine's neurotoxicity in humans is lacking and should not impede future ketamine clinical trials.

Whole blood thrombin generation is distinct from plasma thrombin generation in healthy volunteers and after severe injury.

BACKGROUND: Plasma thrombin generation has been used to characterize trauma-induced coagulopathy, but description of whole blood thrombin generation is lacking. This study aimed to evaluate plasma and whole blood thrombin generation in healthy volunteers and trauma patients. We hypothesized that (1) plasma and whole blood thrombin generation are distinct, (2) whole blood thrombin generation is more pronounced in trauma patients than in healthy volunteers, and (3) thrombin generation correlates with clinical coagulation assays. METHODS: Blood was collected from healthy volunteers and trauma patients at a single, level-1 trauma center. Whole blood thrombin generation was assessed with a prototype point-of-care whole blood thrombin generation device, and plasma thrombin generation was measured with a calibrated automated thrombogram analogue. Plasma and whole blood thrombin generation were compared and correlated with international normalized ratio and thrombelastography. RESULTS: Overall, 10 healthy volunteers (average age 30, 50% men) were included and 58 trauma patients (average age 34, 76% men, 55% blunt mechanism, and with a median new injury severity score of 17) were included. Plasma and whole blood thrombin generation differed with more robust thrombin generation in plasma. Trauma patients had a significantly increased whole blood thrombin generation compared with healthy volunteers]. Plasma thrombin generation correlated with international normalized ratio, whereas whole blood thrombin generation did not correlate with thrombelastography. CONCLUSION: Plasma and whole blood thrombin generation are distinct, highlighting the need to perform standardized assays to better understand their correlation and to assess how whole blood thrombin generation confers differential outcomes in trauma.

Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer.

IMPORTANCE: Novel sensitive methods for detection and monitoring of residual disease can improve postoperative risk stratification with implications for patient selection for adjuvant chemotherapy (ACT), ACT duration, intensity of radiologic surveillance, and, ultimately, outcome for patients with colorectal cancer (CRC). OBJECTIVE: To investigate the association of circulating tumor DNA (ctDNA) with recurrence using longitudinal data from ultradeep sequencing of plasma cell-free DNA in patients with CRC before and after surgery, during and after ACT, and during surveillance. DESIGN, SETTING, AND PARTICIPANTS: In this prospective, multicenter cohort study, ctDNA was quantified in the preoperative and postoperative settings of stages I to III CRC by personalized multiplex, polymerase chain reaction-based, next-generation sequencing. The study enrolled 130 patients at the surgical departments of Aarhus University Hospital, Randers Hospital, and Herning Hospital in Denmark from May 1, 2014, to January 31, 2017. Plasma samples (n = 829) were collected before surgery, postoperatively at day 30, and every third month for up to 3 years. MAIN OUTCOMES AND MEASURES: Outcomes were ctDNA measurement, clinical recurrence, and recurrence-free survival. RESULTS: A total of 130 patients with stages I to III CRC (mean [SD] age, 67.9 [10.1] years; 74 [56.9%] male) were enrolled in the study; 5 patients discontinued participation, leaving 125 patients for analysis. Preoperatively, ctDNA was detectable in 108 of 122 patients (88.5%). After definitive treatment, longitudinal ctDNA analysis identified 14 of 16 relapses (87.5%). At postoperative day 30, ctDNA-positive patients were 7 times more likely to relapse than ctDNA-negative patients (hazard ratio [HR], 7.2; 95% CI, 2.7-19.0; P < .001). Similarly, shortly after ACT ctDNA-positive patients were 17 times (HR, 17.5; 95% CI, 5.4-56.5; P < .001) more likely to relapse. All 7 patients who were ctDNA positive after ACT experienced relapse. Monitoring during and after ACT indicated that 3 of the 10 ctDNA-positive patients (30.0%) were cleared by ACT. During surveillance after definitive therapy, ctDNA-positive patients were more than 40 times more likely to experience disease recurrence than ctDNA-negative patients (HR, 43.5; 95% CI, 9.8-193.5 P < .001). In all multivariate analyses, ctDNA status was independently associated with relapse after adjusting for known clinicopathologic risk factors. Serial ctDNA analyses revealed disease recurrence up to 16.5 months ahead of standard-of-care radiologic imaging (mean, 8.7 months; range, 0.8-16.5 months). Actionable mutations were identified in 81.8% of the ctDNA-positive relapse samples. CONCLUSIONS AND RELEVANCE: Circulating tumor DNA analysis can potentially change the postoperative management of CRC by enabling risk stratification, ACT monitoring, and early relapse detection.

Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma.

PURPOSE: Novel sensitive methods for early detection of relapse and for monitoring therapeutic efficacy may have a huge impact on risk stratification, treatment, and ultimately outcome for patients with bladder cancer. We addressed the prognostic and predictive impact of ultra-deep sequencing of cell-free DNA in patients before and after cystectomy and during chemotherapy. PATIENTS AND METHODS: We included 68 patients with localized advanced bladder cancer. Patient-specific somatic mutations, identified by whole-exome sequencing, were used to assess circulating tumor DNA (ctDNA) by ultra-deep sequencing (median, 105,000×) of plasma DNA. Plasma samples (n = 656) were procured at diagnosis, during chemotherapy, before cystectomy, and during surveillance. Expression profiling was performed for tumor subtype and immune signature analyses. RESULTS: Presence of ctDNA was highly prognostic at diagnosis before chemotherapy (hazard ratio, 29.1; P = .001). After cystectomy, ctDNA analysis correctly identified all patients with metastatic relapse during disease monitoring (100% sensitivity, 98% specificity). A median lead time over radiographic imaging of 96 days was observed. In addition, for high-risk patients (ctDNA positive before or during treatment), the dynamics of ctDNA during chemotherapy was associated with disease recurrence (P = .023), whereas pathologic downstaging was not. Analysis of tumor-centric biomarkers showed that mutational processes (signature 5) were associated with pathologic downstaging (P = .024); however, no significant correlation for tumor subtypes, DNA damage response mutations, and other biomarkers was observed. Our results suggest that ctDNA analysis is better associated with treatment efficacy compared with other available methods. CONCLUSION: ctDNA assessment for early risk stratification, therapy monitoring, and early relapse detection in bladder cancer is feasible and provides a basis for clinical studies that evaluate early therapeutic interventions.

Personalized Detection of Circulating Tumor DNA Antedates Breast Cancer Metastatic Recurrence.

PURPOSE: Up to 30% of patients with breast cancer relapse after primary treatment. There are no sensitive and reliable tests to monitor these patients and detect distant metastases before overt recurrence. Here, we demonstrate the use of personalized circulating tumor DNA (ctDNA) profiling for detection of recurrence in breast cancer. EXPERIMENTAL DESIGN: Forty-nine primary patients with breast cancer were recruited following surgery and adjuvant therapy. Plasma samples (n = 208) were collected every 6 months for up to 4 years. Personalized assays targeting 16 variants selected from primary tumor whole-exome data were tested in serial plasma for the presence of ctDNA by ultradeep sequencing (average >100,000X). RESULTS: Plasma ctDNA was detected ahead of clinical or radiologic relapse in 16 of the 18 relapsed patients (sensitivity of 89%); metastatic relapse was predicted with a lead time of up to 2 years (median, 8.9 months; range, 0.5-24.0 months). None of the 31 nonrelapsing patients were ctDNA-positive at any time point across 156 plasma samples (specificity of 100%). Of the two relapsed patients who were not detected in the study, the first had only a local recurrence, whereas the second patient had bone recurrence and had completed chemotherapy just 13 days prior to blood sampling. CONCLUSIONS: This study demonstrates that patient-specific ctDNA analysis can be a sensitive and specific approach for disease surveillance for patients with breast cancer. More importantly, earlier detection of up to 2 years provides a possible window for therapeutic intervention.

The chemistry and pharmacology of synthetic cannabinoid SDB-006 and its regioisomeric fluorinated and methoxylated analogs.

Synthetic cannabinoids are the largest and most structurally diverse class of new psychoactive substances, with manufacturers often using isomerism to evade detection and circumvent legal restriction. The regioisomeric methoxy- and fluorine-substituted analogs of SDB-006 (N-benzyl-1-pentyl-1H-indole-3-carboxamide) were synthesized and could not be differentiated by gas chromatography-mass spectrometry (GC-MS), but were distinguishable by liquid chromatography-quadrupole time-of-flight-MS (LC-QTOF-MS). In a fluorescence-based plate reader membrane potential assay, SDB-006 acted as a potent agonist at human cannabinoid receptors (CB1 EC50 = 19 nM). All methoxy- and fluorine-substituted analogs showed reduced potency compared to SDB-006, although the 2-fluorinated analog (EC50 = 166 nM) was comparable to known synthetic cannabinoid RCS-4 (EC50 = 146 nM). Using biotelemetry in rats, SDB-006 and RCS-4 evoked comparable reduction in body temperature (~0.7°C at a dose of 10 mg/kg), suggesting lower potency than the recent synthetic cannabinoid AB-CHMINACA (>2°C, 3 mg/kg).

Fentanyl and a Novel Synthetic Opioid U-47700 Masquerading as Street "Norco" in Central California: A Case Report.

In 2013 and 2014, more than 700 deaths were attributed to fentanyl and fentanyl analogues in the United States. Of recent concern is the cluster of unintentional fentanyl overdoses because of tablets thought to be "Norco" purchased on the street in Northern California. U-47700 (trans-3,4-dichloro-N-[2-(dimethyl-amino)cyclohexyl]-N-methylbenz-amide) is a nonfentanyl-based synthetic opioid with 7.5 times the binding affinity of morphine to µ-opioid. We report a case of fentanyl and U-47700 intoxication from what was thought to be illicitly purchased Norco. A 41-year-old woman presented to the emergency department (ED) for altered mental status shortly after ingesting 3 beige Norco pills bearing a Watson imprint. She had pinpoint pupils and respiratory depression, which reversed after 0.4 mg naloxone administration intravenously. She had complete recovery and was discharged from the ED after a 4-hour observation period. Serum testing with liquid chromatography-quadrupole time-of-flight mass spectrometry (LC 1260 QTOF/MS 6550; Agilent, Santa Clara, CA) confirmed the presence of the medications the patient reported receiving, and additionally fentanyl (15.2 ng/mL) and U-47700 (7.6 ng/mL). In this case report, street Norco purchased in Central California resulted in altered mental status requiring naloxone reversal because of fentanyl and the novel synthetic opioid U-47700. Because these compounds are not detected by routine urine drug testing and physical examination findings are similar to those of a traditional opioid toxidrome, emergency providers should use the patient's history and other circumstantial details to aid in diagnosis. In cases with suspicion of opioid or opioid analogue cause, we recommend that emergency providers contact their local poison control center, medical toxicologist, or public health department to aid in the investigation.

The Whiteboard Revolution: Illuminating Science Communication in the Digital Age.

Journal-based science communication is not accessible or comprehensible to a general public curious about science and eager for the next wave of scientific innovation. We propose an alternative medium for scientists to communicate their work to the general public in an engaging and digestible way through the use of whiteboard videos. We describe the process of producing science whiteboard videos and the benefits and challenges therein.

Artemether-Lumefantrine Exposure in HIV-Infected Nigerian Subjects on Nevirapine-Containing Antiretroviral Therapy.

Coadministration of nevirapine-based antiretroviral therapy (ART) and artemether-lumefantrine is reported to result in variable changes in lumefantrine exposure. We conducted an intensive pharmacokinetic study with 11 HIV-infected adults who were receiving artemether-lumefantrine plus nevirapine-based ART, and we compared the results with those for 16 HIV-negative adult historical controls. Exposure to artemether and lumefantrine was significantly lower and dihydroartemisinin exposure was unchanged in subjects receiving nevirapine-based ART, compared with controls. Nevirapine exposure was unchanged before and after artemether-lumefantrine administration.

Determination of artemether and dihydroartemisinin in human plasma with a new hydrogen peroxide stabilization method.

BACKGROUND: Numerous methods have been reported for the determination of artemether (ARM) and its metabolite dihydroartemisinin (DHA) in plasma. However, stability issues in patient plasma have not received enough attention. RESULTS: An LC-MS/MS method for simultaneous determination of ARM and DHA in human plasma (K3EDTA) turned out to be problematic: ARM and DHA were degraded partially or completely in some patient plasma samples as indicated by the stable isotope-labeled internal standards. We postulated iron II (Fe(2+)) in hemoglobin or its derived products from malaria patients causes degradation of the drugs, and found that hydrogen peroxide (H2O2) protected the drugs from degradation. Acidifying plasma increased recovery of ARM significantly. Using only 50 µl of plasma sample, the method has a LLOQ at 0.5 ng/ml for both ARM and DHA. CONCLUSION: H2O2 is a stabilizing agent for artemisinin derivatives. The modified method is reliable and sensitive.

Shaken, not stirred: collapsing a peptoid monolayer to produce free-floating, stable nanosheets.

Two-dimensional nanomaterials play a critical role in biology (e.g., lipid bilayers) and electronics (e.g., graphene) but are difficult to directly synthesize with a high level of precision. Peptoid nanosheet bilayers are a versatile synthetic platform for constructing multifunctional, precisely ordered two-dimensional nanostructures. Here we show that nanosheet formation occurs through an unusual monolayer intermediate at the air-water interface. Lateral compression of a self-assembled peptoid monolayer beyond a critical collapse pressure results in the irreversible production of nanosheets. An unusual thermodynamic cycle is employed on a preparative scale, where mechanical energy is used to buckle an intermediate monolayer into a more stable nanosheet. Detailed physical studies of the monolayer-compression mechanism revealed a simple preparative technique to produce nanosheets in 95% overall yield by cyclical monolayer compressions in a rotating closed vial. Compression of monolayers into stable, free-floating products may be a general and preparative approach to access 2D nanomaterials.