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Objectives To investigate the effect of progressive whole-body hyperthermia on maximal, and rapid voluntary torque production, and their neuromuscular determinants. Design Repeated measures, randomised. Methods Nine participants performed sets of neuromuscular assessments in HOT conditions (∼50 °C, ∼35% relative humidity) at rectal temperatures (Tre) of 37, 38.5 and 39.5 °C and in CON conditions (∼22 °C, ∼35% relative humidity) at a Tre of ∼37 °C and pre-determined comparative time-points. Electrically evoked twitch (single impulse) and octet (8 impulses at 300 Hz) responses were measured at rest. Maximum voluntary torque (MVT), surface electromyography (EMG) normalised to maximal M-wave, and voluntary activation (VA) were measured during 3−5 s isometric maximal voluntary contractions. Rate of torque development (RTD) and normalised EMG were measured during rapid voluntary isometric contractions from rest. Results All neuromuscular variables were unaffected by time in CON. In HOT, MVT, normalised EMG at MVT and VA were lower at 39.5 °C compared to 37 °C (p 0.05), despite lower normalised EMG at Tre 39.5 °C (p Conclusions Hyperthermia reduced late-phase voluntary RTD, likely due to reduced neural drive and the reduction in MVT. In contrast, early- and middle-phase voluntary RTD were unaffected by hyperthermia, likely due to the conflicting effects of reduced neural drive but faster intrinsic contractile properties.

Even as vaccination for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) expands in the United States, cases will linger among unvaccinated individuals for at least the next year, allowing the spread of the coronavirus to continue in communities across the country. Detecting these infections, particularly asymptomatic ones, is critical to stemming further transmission of the virus in the months ahead. This will require active surveillance efforts in which these undetected cases are proactively sought out rather than waiting for individuals to present to testing sites for diagnosis. However, finding these pockets of asymptomatic cases (i.e., hotspots) is akin to searching for needles in a haystack as choosing where and when to test within communities is hampered by a lack of epidemiological information to guide decision makers’ allocation of these resources. Making sequential decisions with partial information is a classic problem in decision science, the explore v. exploit dilemma. Using methods—bandit algorithms—similar to those used to search for other kinds of lost or hidden objects, from downed aircraft or underground oil deposits, we can address the explore v. exploit tradeoff facing active surveillance efforts and optimize the deployment of mobile testing resources to maximize the yield of new SARS-CoV-2 diagnoses. These bandit algorithms can be implemented easily as a guide to active case finding for SARS-CoV-2. A simple Thompson sampling algorithm and an extension of it to integrate spatial correlation in the data are now embedded in a fully functional prototype of a web app to allow policymakers to use either of these algorithms to target SARS-CoV-2 testing. In this instance, potential testing locations were identified by using mobility data from UberMedia to target high-frequency venues in Columbus, Ohio, as part of a planned feasibility study of the algorithms in the field. However, it is easily adaptable to other jurisdictions, requiring only a set of candidate test locations with point-to-point distances between all locations, whether or not mobility data are integrated into decision making in choosing places to test.

Ketamine is a dissociative anesthetic used increasingly as analgesia for different manifestations of pain, including acute, chronic, cancer and perioperative pain as well as pain in the critically ill patient population. Its distinctive pharmacologic properties may provide benefits to individuals suffering from pain, including increased pain control and reduction in opioid consumption and tolerance. Despite wide variability in proposed dosing and method of administration when used for analgesia, it is important all clinicians be familiar with the pharmacodynamics of ketamine in order to appropriately anticipate its therapeutic and adverse effects.

Objective:Investigate an outbreak of coronavirus disease 2019 (COVID-19) among operating room staff utilizing contact tracing, mass testing for severe acute respiratory coronavirus virus 2 (SARS-CoV-2), and environmental sampling.Design:Outbreak investigation.Setting:University-affiliated tertiary-care referral center.Patients:Operating room staff with positive SARS-CoV-2 molecular testing.Methods:Epidemiologic and environmental investigations were conducted including contact tracing, environmental surveys, and sampling and review of the operating room schedule for staff-to-staff, staff-to-patient, and patient-to-staff SARS-CoV-2 transmission.Results:In total, 24 healthcare personnel (HCP) tested positive for SARS-CoV-2, including nurses (29%), surgical technologists (25%), and surgical residents (16%). Moreover, 19 HCP (79%) reported having used a communal area, most commonly break rooms (75%). Overall, 20 HCP (83%) reported symptomatic disease. In total, 72 environmental samples were collected from communal areas for SARS-CoV-2 genomic testing; none was positive. Furthermore, 236 surgical cases were reviewed for transmission: 213 (90%) had negative preoperative SARS-CoV-2 testing, 21 (9%) had a positive test on or before the date of surgery, and 2 (Conclusions:Complacency in infection control practices among staff during peak community transmission of SARS-CoV-2 is believed to have driven staff-to-staff transmission. Prompt identification of the outbreak led to rapid interventions, ultimately allowing for uninterrupted surgical service.

Purpose To determine clearance of levetiracetam in patients requiring continuous renal replacement therapy (CRRT) or sustained low efficiency dialysis (SLED). Materials and methods Adult patients with acute kidney injury or end stage renal disease requiring either CRRT or SLED and levetiracetam were eligible for inclusion. Simultaneous arterial, venous, and effluent samples for analysis of levetiracetam concentrations were collected every two hours for up to 6–8 h. Levetiracetam clearance (CL) and half-life (t1/2) were calculated for each modality. Results Eight CRRT patients and 4 SLED patients completed the study: 67% male, mean age 50 ± 13 years, and 83% had AKI. Seven CRRT patients received continuous venovenous hemodiafiltration (CVVHDF) [median pre-replacement rate 700 mL/h (range 500–1000), post-replacement rate 500 mL/h (range 200–1000), effluent rate 2500 mL/h (range 1700–3650) and delivered CRRT dose 27 mL/kg/h (range 19–54)] and one patient received CVV hemofiltration (CVVH). The mm mean levetiracetam CL during CVVHDF was 31.2 ± 8.5 mL/min, and the and the mean t1/2 was 10.4 ± 2.2 h. For the patient requiring CVVH, clearance and t1/2 were 22.5 mL/min and 9.5 h, respectively. Mean levetiracetam CL during SLED performed at a blood flow rate of 250 mL/min and a dialysate flow rate of 100 mL/min was 74.0 ± 25.3 mL/min and t1/2 was 4.8 ± 2.3 h. Conclusions Levetiracetam clearance was substantial with both modalities under the operating conditions reported. There is the potential for subtherapeutic concentrations with current recommended dosing strategies that account only for kidney function and not these extracorporeal routes of elimination.

Emerging layered semiconductors present multiple advantages for optoelectronic technologies including high carrier mobilities, strong light-matter interactions, and tunable optical absorption and emission. Here, metal-semiconductor-metal avalanche photodiodes (APDs) are fabricated from Bi2O2Se crystals, which consist of electrostatically bound [Bi2O2]2+ and [Se]2− layers. The resulting APDs possess an intrinsic carrier multiplication factor up to 400 at 7 K with a responsivity gain exceeding 3,000 A/W and bandwidth of ~ 400 kHz at a visible wavelength of 515.6 nm, ultimately resulting in a gain bandwidth product exceeding 1 GHz. Due to exceptionally low dark currents, Bi2O2Se APDs also yield high detectivities up to 4.6 × 1014 Jones. A systematic analysis of the photocurrent temperature and bias dependence reveals that the carrier multiplication process in Bi2O2Se APDs is consistent with a reverse biased Schottky diode model with a barrier height of ~ 44 meV, in contrast to the charge trapping extrinsic gain mechanism that dominates most layered semiconductor phototransistors. In this manner, layered Bi2O2Se APDs provide a unique platform that can be exploited in a diverse range of high-performance photodetector applications.

Purpose Hyperpolarized imaging experiments have conflicting requirements of high spatial, temporal, and spectral resolution. Spectral-spatial RF excitation has been shown to form an attractive magnetization-efficient method for hyperpolarized imaging, but the optimum readout strategy is not yet known. Methods In this work, we propose a novel 3D hybrid-shot spiral sequence which features two constant density regions that permit the retrospective reconstruction of either high spatial or high temporal resolution images post hoc, (adaptive spatiotemporal imaging) allowing greater flexibility in acquisition and reconstruction. Results We have implemented this sequence, both via simulation and on a preclinical scanner, to demonstrate its feasibility, in both a 1 H phantom and with hyperpolarized 13 C pyruvate in vivo. Conclusions This sequence forms an attractive method for acquiring hyperpolarized imaging datasets, providing adaptive spatiotemporal imaging to ameliorate the conflict of spatial and temporal resolution, with significant potential for clinical translation.

Transcranial ultrasound (TUS) provides a noninvasive neuromodulation method that has greater spatial precision than existing methods. The present study examined TUS, for the first time, as a potential depression intervention. Twenty-four college students with mild to moderate depression were randomly assigned to an Active TUS Condition or Placebo TUS (no power administered). Participants completed five TUS sessions within seven days. Although depression scores did not change differentially for TUS/Placebo, trait worry decreased in the Active TUS Condition and increased in the Placebo condition. Additionally, those in TUS Active Condition had an increase in global affect over the course of the study, whereas those in the Placebo Condition did not. These results have significant implications for the potential utility of TUS as an intervention for anxiety disorders or worry-related psychopathology, warranting future investigation of the impact of TUS in a larger sample.

A 14-year-old boy underwent surgery for symptomatic malunion of the clavicle. This complication, which is uncommon in adults and adolescents, occurred after a displaced midshaft clavicle fracture that had been treated conservatively. Surgery may be considered if functional impairment, pain, weakness, fatigability and neurological symptoms persist in the presence of significant clavicular deformity. Our case was unusual because the patient had a symptomatic malunion and lost range of movement of his shoulder despite a minor degree of clavicular shortening. We adopted an approach used in lower limb deformity correction but not described for the clavicle in which corrective osteotomy was planned and practised using a three-dimensional printed model of the malunited clavicle. A three-dimensional printed model of the mirror image of the opposite clavicle served as a template of normal. Three-dimensional models were printed from the computed tomography data. The patient’s symptoms resolved and he recovered full range of movement and shoulder function following the corrective osteotomy.

The contribution of somatosensation to locomotor deficits in below-knee amputees (BKAs) has not been fully explored. Unilateral disruption of plantar sensation causes able-bodied individuals to adopt locomotor characteristics that resemble those of unilateral BKAs, suggesting that restoring somatosensation may improve locomotion for amputees. In prior studies, we demonstrated that electrically stimulating the residual nerves of amputees elicited somatosensory percepts that were felt as occurring in the missing foot. Subsequently, we developed a sensory neuroprosthesis that modulated stimulation-evoked sensation in response to interactions between the prosthesis and the environment. To characterize the impact of the sensory neuroprosthesis on locomotion, we created a novel ambulatory searching task. The task involved walking on a horizontal ladder while blindfolded, which engaged plantar sensation while minimizing visual compensation. We first compared the performance of six BKAs to 14 able-bodied controls. Able-bodied individuals demonstrated higher foot placement accuracy than BKAs, indicating that the ladder test was sensitive enough to detect locomotor deficits. When three of the original six BKAs used the sensory neuroprosthesis, the tradeoff between speed and accuracy significantly improved for two of them. This study advanced our understanding of how cutaneous plantar sensation can be used to acquire action-related information during challenging locomotor tasks.

Cerebral metabolism is tightly regulated and fundamental for healthy neurological function. There is increasing evidence that alterations in this metabolism may be a precursor and early biomarker of later stage disease processes. Proton magnetic resonance spectroscopy (1H-MRS) is a powerful tool to non-invasively assess tissue metabolites and has many applications for studying the normal and diseased brain. However, the technique has limitations including low spatial and temporal resolution, difficulties in discriminating overlapping peaks, and challenges in assessing metabolic flux rather than steady-state concentrations. Hyperpolarized carbon-13 magnetic resonance imaging is an emerging clinical technique that may overcome some of these spatial and temporal limitations, providing novel insights into neurometabolism in both health and in pathological processes such as glioma, stroke and multiple sclerosis. This review will explore the growing body of pre-clinical data that demonstrates a potential role for the technique in assessing metabolism in the central nervous system. There are now a number of clinical studies being undertaken in this area and this review will present the emerging clinical data as well as the potential future applications of hyperpolarized 13C magnetic resonance imaging in the brain, in both clinical and pre-clinical studies.

Current cardiovascular magnetic resonance imaging techniques provide an exquisite assessment of the structure and function of the heart and great vessels, but their ability to assess the molecular processes that underpin changes in cardiac function in health and disease is limited by inherent insensitivity. Hyperpolarized magnetic resonance is a new technology which overcomes this limitation, generating molecular contrast agents with an improvement in magnetic resonance signal of up to five orders of magnitude. One key molecule, hyperpolarized [1-13C]pyruvate, shows particular promise for the assessment of cardiac energy metabolism and other fundamental biological processes in cardiovascular disease. This molecule has numerous potential applications of clinical relevance and has now been translated to human use in early clinical studies. This review outlines the principles of hyperpolarized magnetic resonance and key potential cardiovascular applications for this new technology. Finally, we provide an overview of the pipeline for forthcoming hyperpolarized agents and their potential applications in cardiovascular disease.

Emergency department (ED) encounters for acute agitation are common. Although nonpharmacologic interventions such as verbal de-escalation and patient engagement are first-line interventions for acute agitation, parenteral medications are often required to ensure safety and facilitate patient care. There is no consensus recommendation on pharmacologic agents for acute agitation, however emergency clinicians have historically utilized an anti-psychotic, benzodiazepine, and/or antihistamine - as monotherapy or in some combination.1,2.

Unsupervised exploratory data analysis (EDA) is often the first step in understanding complex data sets. While summary statistics are among the most efficient and convenient tools for exploring and describing sets of data, they are often overlooked in EDA. In this paper, we show multiple case studies that compare the performance, including clustering, of a series of summary statistics in EDA. The summary statistics considered here are pattern recognition entropy (PRE), the mean, standard deviation (STD), 1-norm, range, sum of squares (SSQ), and X4, which are compared with principal component analysis (PCA), multivariate curve resolution (MCR), and/or cluster analysis. PRE and the other summary statistics are direct methods for analyzing data-they are not factor-based approaches. To quantify the performance of summary statistics, we use the concept of the "critical pair," which is employed in chromatography. The data analyzed here come from different analytical methods. Hyperspectral images, including one of a biological material, are also analyzed. In general, PRE outperforms the other summary statistics, especially in image analysis, although a suite of summary statistics is useful in exploring complex data sets. While PRE results were generally comparable to those from PCA and MCR, PRE is easier to apply. For example, there is no need to determine the number of factors that describe a data set. Finally, we introduce the concept of divided spectrum-PRE (DS-PRE) as a new EDA method. DS-PRE increases the discrimination power of PRE. We also show that DS-PRE can be used to provide the inputs for the k-nearest neighbor (kNN) algorithm. We recommend PRE and DS-PRE as rapid new tools for unsupervised EDA.

Purpose: Transcranial magnetic stimulation (TMS) provides an indication of changes occurring in the corticospinal pathway. This study aimed to determine the between-day (trials 1 week apart) and within-day (trials 1 h apart) reliability of TMS and peripheral nerve stimulation.\ud \ud Methods: 22 male participants (age 23 ± 4 years; height 1.80 ± 0.07 m; body mass 75.1 ± 11.7 kg; body mass index 23.1 ± 2.5 kg.m 2) completed 2 familiarisation sessions and 3 experimental trials (trial 2 and 3 split by 1 h). The interpolated twitch technique was used to determine TMS-assessed voluntary activations (VA-TMS) superimposed on submaximal and maximal leg extension performed on a custom-built dynamometer. Reliability was assessed using equivalence tests, systematic error, 95% limits of agreement, intraclass correlation coefficient (ICC) and coefficient of variation (CV).\ud \ud Results: VA-TMS was equivalent between-day (94.1 ± 4.4% versus 93.7 ± 4.9%, P < 0.01) and within-day (93.7 ± 4.9% versus 93.7 ± 4.8%, P < 0.01). Systematic error (95% limits of agreement) for VA-TMS was 0.5% (5.1%, 4.2%) for between-day and 0.0% 2 (5.3%, 5.4%) for within-day. ICC and CV values demonstrated high reliability between-day (ICC = 0.93, CV = 2.5%) and within-day (ICC = 0.92, CV = 2.9%).\ud \ud Conclusion: Results indicate that TMS can reliably estimate the output of the motor cortex to the knee extensors, both between-day and within-day. The findings have been used to estimate sample sizes for this technique for future research.

Purpose To investigate the effects of 60 min daily, short-term (STHA) and medium-term (MTHA) isothermic heat acclimation (HA) on the physiological and perceptual responses to exercise heat stress. Methods Sixteen, ultra-endurance runners (female = 3) visited the laboratory on 13 occasions. A 45 min sub-maximal (40% Wmax) cycling heat stress test (HST) was completed in the heat (40 °C, 50% relative humidity) on the first (HSTPRE), seventh (HSTSTHA) and thirteenth (HSTMTHA) visit. Participants completed 5 consecutive days of a 60 min isothermic HA protocol (target Tre 38.5 °C) between HSTPRE and HSTSTHA and 5 more between HSTSTHA and HSTMTHA. Heart rate (HR), rectal (Tre), skin (Tsk) and mean body temperature (Tbody), perceived exertion (RPE), thermal comfort (TC) and sensation (TS) were recorded every 5 min. During HSTs, cortisol was measured pre and post and expired air was collected at 15, 30 and 45 min. Results At rest, Tre and Tbody were lower in HSTSTHA and HSTMTHA compared to HSTPRE, but resting HR was not different between trials. Mean exercising Tre, Tsk, Tbody, and HR were lower in both HSTSTHA and HSTMTHA compared to HSTPRE. There were no differences between HSTSTHA and HSTMTHA. Perceptual measurements were lowered by HA and further reduced during HSTMTHA. Conclusion A 60 min a day isothermic STHA was successful at reducing physiological and perceptual strain experienced when exercising in the heat; however, MTHA offered a more complete adaptation.

Background/Objective: Alteplase may elevate international normalized ratio (INR) results, although the exact rate of elevation occurrence is not firmly established in the literature. The purpose of this study is to determine the occurrence rate of INR elevation following alteplase administration. We also aimed to determine what factors are independently associated with the development of elevated INR following alteplase administration for ischemic stroke. Methods: We conducted a multicenter, retrospective, cohort study of patients who received alteplase for acute ischemic stroke. Patients were screened for baseline INR measurement and a repeat value within 24 hours of alteplase administration. The primary outcome was the percent of patients who experienced ≥0.4-point increase in INR. Secondary outcomes included the rate of adverse bleeding events and identification of factors independently associated with elevated INR following alteplase administration. Results and Conclusions: Two hundred and sixty-one patients were included, with 44 (16.9%) patients having an INR increase of 0.4 or more. Patients with an INR increase ≥0.4 experienced a nonstatistically significant increase in bleeding episodes (8.8% vs 18.2%; P = .10). We identified African American race (odds ratio, 3.48, 95% confidence interval, 1.5-7.6; P = .002) as an independent predictor of INR increase ≥0.04. An INR elevation is common following receipt of alteplase for ischemic stroke. Those of African American race were at increased risk of INR elevation; however, more studies are needed to determine whether these patients are at a higher bleeding risk as a result of INR elevation.

ContextPrevious case reports associated prepubertal gynecomastia with lavender-containing fragrances, but there appear to be no reports of premature thelarche.ObjectiveTo add to a case series about lavender-fragranced product use and breast growth in children and to measure endocrine-disrupting chemical activity of essential oil components.Design, Setting, and PatientsPatients experiencing premature thelarche or prepubertal gynecomastia with continuous exposure to lavender-fragranced products were evaluated in the pediatric endocrinology departments of two institutions. Mechanistic in vitro experiments using eight components of lavender and other essential oils were performed at National Institute of Environmental Health Sciences.Main Outcome MeasuresCase reports and in vitro estrogen and androgen receptor gene expression activities in human cell lines with essential oils.ResultsThree prepubertal girls and one boy with clinical evidence of estrogenic action and a history of continuous exposure to lavender-containing fragrances were studied. Breast growth dissipated in all patients with discontinuation of the fragranced products. Some of the components tested elicited estrogenic and antiandrogenic properties of varying degrees.ConclusionWe report cases of premature thelarche that resolved upon cessation of lavender-containing fragrance exposure commonly used in Hispanic communities. The precise developmental basis for such conditions could be multifactorial. In vitro demonstration of estrogenic and antiandrogenic properties of essential oil components suggests essential oils in these cases could be considered a possible source and supports a possible link with idiopathic prepubertal breast development. Whether the level of lavender oil estrogenic potency is sufficient to cause these effects is unknown.

Understanding and modelling the passage of groundwater is important for a wide range of environmental and earth science disciplines. The science of groundwater modelling is mature, and advanced modelling algorithms are routinely implemented, for example via the widely used MODFLOW software. However, for the non-specialist scientist or student, the fundamentals of such software can be difficult to comprehend, whilst the algorithms are arguably too complex to be easily applied for many applications which require integration of a groundwater model with climate, surface-water, soil or ecological data. In this context, a spreadsheet-based groundwater model (A2016), capable of solving transient groundwater behaviour in multiple spatial dimensions, was developed. Inter-comparison tests investigating nine transient groundwater scenarios were performed between MODFLOW, A2016 and the Time-dependent Groundwater Modeling using Spreadsheet Simulation (TGMSS) model. Results demonstrated that A2016 is directly comparable to MODFLOW, with identical hydraulic heads in all model experiments. TGMSS was not able to accurately simulate hydraulic heads for any of the model experiments. A groundwater–lake interaction scenario was identified for which MODFLOW will produce unrealistic results, due to the way conductance beneath lakes is determined. Applying a specified saturated thickness approximation for the region beneath the lake resulted in improved lake–groundwater interactions. A2016 is potentially useful for educational purposes and as a tool for groundwater experiments by non-specialists, as it is modular in nature and incorporates MODFLOW terminology and techniques.

Intracerebral hemorrhage (ICH) is responsible for approximately 15% of strokes annually in the United States, with nearly 1 in 3 of these patients dying without ever leaving the hospital. Because this disproportionate mortality risk has been stagnant for nearly 3 decades, a main area of research has been focused on the optimal strategies to reduce mortality and improve functional outcomes. The acute hypertensive response following ICH has been shown to facilitate ICH expansion and is a strong predictor of mortality. Rapidly reducing blood pressure was once thought to induce cerebral ischemia, though has been found to be safe in certain patient populations. Clinicians must work quickly to determine whether specific patient populations may benefit from acute lowering of systolic blood pressure (SBP) following ICH. This review provides nurses with a summary of the available literature on blood pressure control following ICH. It focuses on intravenous and oral antihypertensive medications available in the United States that may be utilized to acutely lower SBP, as well as medications outside of the antihypertensive class used during the acute setting that may reduce SBP.

Objectives/hypothesis Injection laryngoplasty has become valuable in treating laryngologic disorders including vocal cord atrophy, paralysis, and paresis. Although materials such as carboxymethylcellulose and calcium hydroxylapatite are Food and Drug Administration (FDA) approved, they are not without limitations. Juvederm (hyaluronic acid) is an alternative treatment that is not FDA approved. Although studies have examined Juvederm's longevity in cutaneous injections, there are limited data examining durability of Juvederm used in laryngoplasty. We aimed to determine the longevity and effectiveness of Juvederm used in injection laryngoplasty. Study design Retrospective cohort study. Methods Subjects who underwent injection laryngoplasty using Juvederm were reviewed. Longevity was defined as the time between injection and the date that a patient first noted subjective deterioration of their voice. All subjects were subsequently followed using videostroboscopy to evaluate for Juvederm resorption. Longevity was analyzed using a Kaplan-Meier survival model, and effectiveness of laryngoplasty was determined using the Voice-Related Quality of Life index scores and analyzed using a Wilcoxon signed ranks test. Results Fifty-nine subjects met inclusion criteria and underwent Juvederm injection laryngoplasty. Kaplan-Meier survival analysis revealed a mean longevity of 10.6 months (95% confidence interval: 9.1-12.0 months). Wilcoxon signed ranks analysis of the pre- and postinjection Voice Related Quality of Life (VRQOL) scores revealed improvement, with a mean preinjection VRQOL of 49.2 (standard deviation [SD] = 25.8) and mean postinjection VRQOL of 68.2 (SD = 27.5) (P Conclusions Injection laryngoplasty using Juvederm is an effective treatment for vocal cord atrophy, paralysis, and paresis. Knowledge of the patient-defined duration of benefit following laryngoplasty using Juvederm plays an important role in counseling patients as well as in the planning of future interventions. Level of evidence 4 Laryngoscope, 129:2744-2747, 2019.

This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) 13C magnetic resonance imaging’s (MRI’s) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized 13C MRI in 2011, preclinical studies involving [1-13C]pyruvate as well a number of other 13C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1-13C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP 13C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind.

The Cleveland Neural Engineering Workshop (NEW) was established as a biennial meeting in 2011, with subsequent meetings taking place in 2013, 2015, and most recently, June 2017. This fourth biennial NEW was hosted by the Cleveland Advanced Platform for Technology National Veterans Affairs Center, the Functional Electrical Stimulation National Veterans Affairs Center, the Biomedical Engineering Department at Case Western Reserve University in Cleveland, Ohio, and Northwell Health’s Feinstein Institute for Medical Research of New York. The workshop connects leaders and stakeholders in the neural engineering community who are devoted to developing and deploying technological solutions to those with neurological disorders. The meeting in 2017 continued strategic conversations initiated at the third Cleveland NEW conference in 2015. The goal of the 2017 workshop was to was to determine specific actions by which the neural engineering community might advance the goals outlined in 2015, assess progress towards that plan, adjust as necessary, and establish continued strategic direction. This meeting report summarizes the outcomes.

Type 2 diabetes (T2D) impairs Hypoxia-Inducible Factor (HIF)1α activation, a master transcription factor that drives cellular adaptation to hypoxia. Reduced activation of HIF1α contributes to the impaired post-ischaemic remodelling observed following myocardial infarction in T2D. Molidustat is a HIF stabiliser currently undergoing clinical trials for the treatment of renal anaemia associated with chronic kidney disease, however, it may provide a route to pharmacologically activate HIF1α in the T2D heart. In human cardiomyocytes, molidustat stabilised HIF1α and downstream HIF target genes, promoting anaerobic glucose metabolism. In hypoxia, insulin resistance blunted HIF1α activation and downstream signalling, but this was reversed by molidustat. In T2D rats, oral treatment with molidustat rescued the cardiac metabolic dysfunction caused by T2D, promoting glucose metabolism and mitochondrial function, whilst suppressing fatty acid oxidation and lipid accumulation. This resulted in beneficial effects on post-ischemic cardiac function, with the impaired contractile recovery in T2D heart reversed by molidustat treatment. In conclusion, pharmacological HIF1α stabilisation can overcome the blunted hypoxic response induced by insulin resistance. In vivo this corrected the abnormal metabolic phenotype and impaired post-ischaemic recovery of the diabetic heart. Therefore, molidustat may be an effective compound to further explore the clinical translatability of HIF1α activation in the diabetic heart.

Supplemental Digital Content is available in the text., Objectives: Advance directives can help guide care in the ICU. As a healthcare quality improvement initiative, we sought to increase the percentage of patients with a healthcare power of attorney and/or practitioner orders for life-sustaining treatment in our ICU and to increase medical resident experience with advance directives through routine screening and documentation of advance directives in the ICU. Design: Prospective analysis. Setting: Urban U.S. community teaching hospital. Patients: All patients admitted to the ICU from September 2018 to February 2019. Interventions: Internal medicine residents in the ICU received a lecture about advance directives and instructions to screen their patients for advance directives. For willing and decisional patients, residents facilitated the creation of a healthcare power of attorney and/or practitioner orders for life-sustaining treatment. Residents were anonymously surveyed at the beginning and end of the ICU rotation about their experience and level of comfort with healthcare power of attorney and practitioner orders for life-sustaining treatment completion. Measurements and Main Results: Three-hundred seventy-five patients were admitted to the ICU during the study period. Healthcare power of attorney documents were generated by 34% of all ICU patients without a prior healthcare power of attorney, increased from a baseline rate of 10% (p < 0.001). The number of practitioner orders for life-sustaining treatment documents for patients with code status of “no cardiopulmonary resuscitation” did not increase significantly. The percentage of residents who facilitated completion of a healthcare power of attorney document increased significantly from 56% to 100% (p < 0.001), whereas their practitioner orders for life-sustaining treatment experience did not change significantly by the end of their ICU rotation. On a Likert scale of 0–10, mean resident comfort increased significantly both with healthcare power of attorney documentation, rising from 6.14 to 8.84 (p = 0.005) and with practitioner orders for life-sustaining treatment form completion, increasing from 6.00 to 7.84 (p = 0.008). Conclusions: Training ICU medical residents to routinely screen for and facilitate completion of advance directives significantly increased the percentage of ICU patients with a healthcare power of attorney and significantly improved medical resident comfort with healthcare power of attorney and practitioner orders for life-sustaining treatment form completion.

Although when used as a lung cancer screening tool low-dose computed tomography (LDCT) has demonstrated a significant reduction in lung cancer related mortality, it is not without pitfalls. The associated high false positive rate, inability to distinguish between benign and malignant nodules, cumulative radiation exposure, and resulting patient anxiety have all demonstrated the need for adjunctive testing in lung cancer screening. Current research focuses on developing liquid biomarkers to complement imaging as non-invasive lung cancer diagnostics. Biomarkers can be useful for both the early detection and diagnosis of disease, thereby decreasing the number of unnecessary radiologic tests performed. Biomarkers can stratify cancer risk to further enrich the screening population and augment existing risk prediction. Finally, biomarkers can be used to distinguish benign from malignant nodules in lung cancer screening. While many biomarkers require further validation studies, several, including autoantibodies and blood protein profiling, are available for clinical use. This paper describes the need for biomarkers as a lung cancer screening tool, both in terms of diagnosis and risk assessment. Additionally, this paper will discuss the goals of biomarker use, describe properties of a good biomarker, and review several of the most promising biomarkers currently being studied including autoantibodies, complement fragments, microRNA, blood proteins, circulating tumor DNA, and DNA methylation. Finally, we will describe future directions in the field of biomarker development.

Introduction Emergence delirium (ED) is characterized by agitation, confusion, and violent physical and verbal behavior associated with awakening from general anesthesia. Combat exposure among U.S. military veterans has been identified as a risk factor for ED. Preoperative baseline anxiety was shown to be a predictor of ED, and combat veterans are known to be at high risk for anxiety as well as depression and PTSD. Dexmedetomidine is an alpha-2 receptor agonist proven to mitigate ED in several patient populations. Perioperative use of dexmedetomidine demonstrated promising benefits in pediatric ED but has not been evaluated in combat veterans. Materials and Methods This study was a multi-site, prospective, randomized controlled investigation of 369 patients with a history of military combat exposure who were scheduled for elective surgery with a general anesthetic as the primary means of anesthesia. The trial was funded by the Tri-Service Nursing Research Program Grant HU0001-14-TS05 (N14-PO3) and approved by the Institutional Review Boards at the Naval Medical Center San Diego, Womack Army Medical Center, Walter Reed National Military Medical Center, and the Uniformed Services University of the Health Sciences, Bethesda, MD. All subjects were administered the State-Trait Anxiety Inventory (STAI) to evaluate baseline anxiety. Those enrolled subjects with a low anxiety level (STAI Results The central tendencies of demographics and clinical characteristics are reported. PAED among those randomized to dexmedetomidine (median 7, interquartile interval (IQI) 5.2-9.2) tended to be less (P Conclusions Dexmedetomidine was effective at reducing PAED among combat veterans who were experiencing symptoms of pre-operative anxiety (i.e., STAI-State ≥39). Although psychological morbidity is not unique to the military population, combat veterans carry some of the highest rates of anxiety, PTSD and depression compared to the general population. Dexmedetomidine can be safety employed by anesthesia providers to reduce symptoms of ED in the perioperative period. The double-blind randomized, controlled study design strengthens our analyses; however, this study did not control for the type of surgical procedure or the duration of anesthetic. Furthermore, we only enrolled patients with combat exposure experiencing symptoms of anxiety and did not investigate the role of dexmedetomidine in combat veterans with less anxiety. Further study of the relationship between psychological comorbidities, ED, and dexmedetomidine is warranted.

Rationale: In diabetic patients, heart failure with predominant left ventricular (LV) diastolic dysfunction is a common complication for which there is no effective treatment. Oxidation of the NOS (nitric oxide synthase) cofactor tetrahydrobiopterin (BH4) and dysfunctional NOS activity have been implicated in the pathogenesis of the diabetic vascular and cardiomyopathic phenotype. Objective: Using mice models and human myocardial samples, we evaluated whether and by which mechanism increasing myocardial BH4 availability prevented or reversed LV dysfunction induced by diabetes. Methods and Results: In contrast to the vascular endothelium, BH4 levels, superoxide production, and NOS activity (by liquid chromatography) did not differ in the LV myocardium of diabetic mice or in atrial tissue from diabetic patients. Nevertheless, the impairment in both cardiomyocyte relaxation and [Ca 2+ ]i (intracellular calcium) decay and in vivo LV function (echocardiography and tissue Doppler) that developed in wild-type mice 12 weeks post–diabetes induction (streptozotocin, 42–45 mg/kg) was prevented in mGCH1-Tg (mice with elevated myocardial BH4 content secondary to trangenic overexpression of GTP-cyclohydrolase 1) and reversed in wild-type mice receiving oral BH4 supplementation from the 12th to the 18th week after diabetes induction. The protective effect of BH4 was abolished by CRISPR/Cas9-mediated knockout of nNOS (the neuronal NOS isoform) in mGCH1-Tg. In HEK (human embryonic kidney) cells, S-nitrosoglutathione led to a PKG (protein kinase G)-dependent increase in plasmalemmal density of the insulin-independent glucose transporter GLUT-1 (glucose transporter-1). In cardiomyocytes, mGCH1 overexpression induced a NO/sGC (soluble guanylate cyclase)/PKG–dependent increase in glucose uptake via GLUT-1, which was instrumental in preserving mitochondrial creatine kinase activity, oxygen consumption rate, LV energetics (by 31 phosphorous magnetic resonance spectroscopy), and myocardial function. Conclusions: We uncovered a novel mechanism whereby myocardial BH4 prevents and reverses LV diastolic and systolic dysfunction associated with diabetes via an nNOS-mediated increase in insulin-independent myocardial glucose uptake and utilization. These findings highlight the potential of GCH1/BH4–based therapeutics in human diabetic cardiomyopathy. Graphic Abstract: A graphic abstract is available for this article.

The diabetic heart has a decreased ability to metabolize glucose. The anti‐ischemic drug meldonium may provide a route to counteract this by reducing l‐carnitine levels, resulting in improved cardiac glucose utilization. Therefore, the aim of this study was to use the novel technique of hyperpolarized magnetic resonance to investigate the in vivo effects of treatment with meldonium on cardiac metabolism and function in control and diabetic rats. Thirty‐six male Wistar rats were injected either with vehicle, or with streptozotocin (55 mg/kg) to induce a model of type 1 diabetes. Daily treatment with either saline or meldonium (100 mg/kg/day) was undertaken for three weeks. in vivo cardiac function and metabolism were assessed with CINE MRI and hyperpolarized magnetic resonance respectively. Isolated perfused hearts were challenged with low‐flow ischemia/reperfusion to assess the impact of meldonium on post‐ischemic recovery. Meldonium had no significant effect on blood glucose concentrations or on baseline cardiac function. However, hyperpolarized magnetic resonance revealed that meldonium treatment elevated pyruvate dehydrogenase flux by 3.1‐fold and 1.2‐fold in diabetic and control animals, respectively, suggesting an increase in cardiac glucose oxidation. Hyperpolarized magnetic resonance further demonstrated that meldonium reduced the normalized acetylcarnitine signal by 2.1‐fold in both diabetic and control animals. The increase in pyruvate dehydrogenase flux in vivo was accompanied by an improvement in post‐ischemic function ex vivo, as meldonium elevated the rate pressure product by 1.3‐fold and 1.5‐fold in the control and diabetic animals, respectively. In conclusion, meldonium improves in vivo pyruvate dehydrogenase flux in the diabetic heart, contributing to improved cardiac recovery after ischemia., Glucose metabolism is decreased in the diabetic heart. Meldonium may provide a route to counteract this by reducing L‐carnitine levels and decreasing the uptake of fatty acids into the mitochondria, resulting in improved cardiac glucose utilization. Hyperpolarized magnetic resonance has revealed that meldonium treatment elevated pyruvate dehydrogenase flux in the diabetic heart, indicating an increase in cardiac glucose oxidation. In‐vivo glucose oxidation elevation was accompanied by an improvement in ex‐vivo post‐ischemic function, where meldonium elevated rate pressure following global ischemia.

Objectives To investigate the effects of pre- and per-cooling interventions on subsequent 15-min time-trial (TT) cycling performance in the heat. Design Randomized cross-over design. Methods Nine male athletes completed four experimental trials in the heat (40 °C, 50% rh): no-cooling (CON); warm-up per-cooling (PER: neck-cooling collar applied during the preload); pre-cooling (PRE: 30 min of cold water (22 °C) immersion [CWI]); and pre- and per-cooling combined (PRE + PER). In each trial, participants completed a 45-min preload exercise (50% VO2peak), followed by a 15-min TT. Physiological (rectal [Tre], skin [Tsk], and neck [Tneck] temperature, and heart rate [HR]) and perceptual data (ratings of perceived exertion [RPE], thermal comfort [TC] and thermal sensation [TS]) were measured throughout. Results Tre and Tsk were lower in PRE and PRE + PER at the start of the preload (p Conclusions Pre-cooling induced thermoregulatory benefits for ~45 min and perceptual benefits for the same duration when supplemented with per-cooling. Neck per-cooling offered no such benefits when used in isolation. Neither pre- nor per-cooling, in isolation or combination, improved subsequent 15-min cycling time-trial performance in well-trained participants in the heat (40 °C).

Background Peripheral nerve stimulation with implanted nerve cuff electrodes can restore standing, stepping and other functions to individuals with spinal cord injury (SCI). We performed the first study to evaluate the clinical electrodiagnostic changes due to electrode implantation acutely, chronic presence on the nerve peri- and post-operatively, and long-term delivery of electrical stimulation. Methods A man with bilateral lower extremity paralysis secondary to cervical SCI sustained 5 years prior to enrollment received an implanted standing neuroprosthesis including composite flat interface nerve electrodes (C-FINEs) electrodes implanted around the proximal femoral nerves near the inguinal ligaments. Electromyography quantified neurophysiology preoperatively, intraoperatively, and through 1 year postoperatively. Stimulation charge thresholds, evoked knee extension moments, and weight distribution during standing quantified neuroprosthesis function over the same interval. Results Femoral compound motor unit action potentials increased 31% in amplitude and 34% in area while evoked knee extension moments increased significantly (p Conclusions This is the first human trial reporting acute and chronic neurophysiologic changes due to application of and stimulation through nerve cuff electrodes. Electrodiagnostics indicated preserved nerve health with strengthened responses following stimulated exercise. Temporary electrodiagnostic changes suggest minor nerve irritation only intra- and peri-operatively, not continuing chronically nor impacting function. These outcomes follow implantation of a neuroprosthesis enabling standing and demonstrate the ability to safely implant electrodes on the proximal femoral nerve close to the inguinal ligament. We demonstrate the electrodiagnostic findings that can be expected from implanting nerve cuff electrodes and their time-course for resolution, potentially applicable to prostheses modulating other peripheral nerves and functions. Trial registration ClinicalTrials.govNCT01923662, retrospectively registered August 15, 2013.

The heart has a massive adenosine triphosphate (ATP) requirement, produced from the oxidation of metabolic substrates such as fat and glucose. Magnetic resonance spectroscopy offers a unique opportunity to probe this biochemistry: (31)Phosphorus spectroscopy can demonstrate the production of ATP and quantify levels of the transport molecule phosphocreatine while 13Carbon spectroscopy can demonstrate the metabolic fates of glucose in real time. These techniques allow the metabolic deficits in heart failure to be interrogated and can be a potential future clinical tool.

Background and Aims Intestinal biopsy sampling during IBD trials represents a valuable adjunct strategy for understanding drug responses at the tissue level. Given the length and distinctive embryonic origins of the proximal and distal colon, we investigated whether inherent regional differences of immune cell composition could introduce confounders when sampling different disease stages, or pre/post drug administration. Here, we capitalise on novel mass cytometry technology to perform deep immunophenotyping of distinct healthy colonic segments, using the limited numbers of biopsies that can be harvested from patients. Methods Biopsies [2.8 mm] were collected from the caecum, transverse colon, descending colon, and rectum of normal volunteers. Intestinal leukocytes were isolated, stained with a panel of 37 antibodies, and mass cytometry data acquired. Results Site-specific patterns of leukocyte localisation were observed. The proximal colon featured increased CD8+ T cells [particularly resident memory], monocytes, and CD19+ B cells. Conversely, the distal colon and rectum tissues exhibited enrichment for CD4+ T cells and antibody-secreting cells. The transverse colon displayed increased abundance of both γδ T cells and NK cells. Subsets of leukocyte lineages also displayed gradients of expression along the colon length. Conclusions Our results show an inherent regional immune cell variation within colonic segments, indicating that regional mucosal signatures must be considered when assessing disease stages or the prospective effects of trial drugs on leukocyte subsets. Precise protocols for intestinal sampling must be implemented to allow for the proper interpretation of potential differences observed within leukocyte lineages present in the colonic lamina propria.

Background and Purpose: While an association between hyperchloremia and worse outcomes, such as acute kidney injury and increased mortality, has been demonstrated in hemorrhagic stroke, it is unclear whether the same relationship exists after acute ischemic stroke. This study aims to determine the relationship between moderate hyperchloremia (serum chloride ≥115 mmol/L) and acute kidney injury in patients with ischemic stroke. Methods: This is a multicenter, retrospective, propensity-matched cohort study of adults admitted for acute ischemic stroke. The primary objective was to determine the relationship between moderate hyperchloremia and acute kidney injury, as defined by the Acute Kidney Injury Network criteria. Secondary objectives included mortality and hospital length of stay. Results: A total of 407 patients were included in the unmatched cohort (332 nonhyperchloremia and 75 hyperchloremia) and 114 patients (57 in each group) were matched based upon propensity scores. In the matched cohort, hyperchloremia was associated with an increased risk of acute kidney injury (relative risk 1.91 [95% confidence interval 1.01-3.59]) and a longer hospital length of stay (16 vs 12 days; P = .03). Mortality was higher in the hyperchloremia group (19.3% vs 10.5%, P = .19), but this did not reach statistical significance. Conclusions: In this study, hyperchloremia after ischemic stroke was associated with increased rates of acute kidney injury and longer hospital length of stay. Further research is needed to determine which interventions may increase chloride levels in patients with acute ischemic stroke and the association between hyperchloremia and clinical outcomes.

Doxorubicin is a commonly used chemotherapeutic agent for the treatment of a range of cancers, but despite its success in improving cancer survival rates, doxorubicin is cardiotoxic and can lead to congestive heart failure. Therapeutic options for this patient group are limited to standard heart failure medications with the only drug specific for doxorubicin cardiotoxicity to reach FDA approval being dexrazoxane, an iron-chelating agent targeting oxidative stress. However, dexrazoxane has failed to live up to its expectations from preclinical studies while also bringing up concerns about its safety. Despite decades of research, the molecular mechanisms of doxorubicin cardiotoxicity are still poorly understood and oxidative stress is no longer considered to be the sole evil. Mitochondrial impairment, increased apoptosis, dysregulated autophagy and increased fibrosis have also been shown to be crucial players in doxorubicin cardiotoxicity. These cellular processes are all linked by one highly conserved intracellular kinase: adenosine monophosphate–activated protein kinase (AMPK). AMPK regulates mitochondrial biogenesis via PGC1α signalling, increases oxidative mitochondrial metabolism, decreases apoptosis through inhibition of mTOR signalling, increases autophagy through ULK1 and decreases fibrosis through inhibition of TGFβ signalling. AMPK therefore sits at the control point of many mechanisms shown to be involved in doxorubicin cardiotoxicity and cardiac AMPK signalling itself has been shown to be impaired by doxorubicin. In this review, we introduce different agents known to activate AMPK (metformin, statins, resveratrol, thiazolidinediones, AICAR, specific AMPK activators) as well as exercise and dietary restriction, and we discuss the existing evidence for their potential role in cardioprotection from doxorubicin cardiotoxicity.

Rationale: The recent development of hyperpolarized 13 C magnetic resonance spectroscopy has made it possible to measure cellular metabolism in vivo, in real time. Objective: By comparing participants with and without type 2 diabetes mellitus (T2DM), we report the first case-control study to use this technique to record changes in cardiac metabolism in the healthy and diseased human heart. Methods and Results: Thirteen people with T2DM (glycated hemoglobin, 6.9±1.0%) and 12 age-matched healthy controls underwent assessment of cardiac systolic and diastolic function, myocardial energetics ( 31 P-magnetic resonance spectroscopy), and lipid content ( 1 H-magnetic resonance spectroscopy) in the fasted state. In a subset (5 T2DM, 5 control), hyperpolarized [1- 13 C]pyruvate magnetic resonance spectra were also acquired and in 5 of these participants (3 T2DM, 2 controls), this was successfully repeated 45 minutes after a 75 g oral glucose challenge. Downstream metabolism of [1- 13 C]pyruvate via PDH (pyruvate dehydrogenase, [ 13 C]bicarbonate), lactate dehydrogenase ([1- 13 C]lactate), and alanine transaminase ([1- 13 C]alanine) was assessed. Metabolic flux through cardiac PDH was significantly reduced in the people with T2DM (Fasted: 0.0084±0.0067 [Control] versus 0.0016±0.0014 [T2DM], Fed: 0.0184±0.0109 versus 0.0053±0.0041; P =0.013). In addition, a significant increase in metabolic flux through PDH was observed after the oral glucose challenge ( P Conclusions: This work represents the first demonstration of the ability of hyperpolarized 13 C magnetic resonance spectroscopy to noninvasively assess physiological and pathological changes in cardiac metabolism in the human heart. In doing so, we highlight the potential of the technique to detect and quantify metabolic alterations in the setting of cardiovascular disease.

Transcranial focused ultrasound (tFUS) is an emerging method for non-invasive neuromodulation akin to transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). tFUS offers several advantages over electromagnetic methods including high spatial resolution and the ability to reach deep brain targets. Here we describe two experiments assessing whether tFUS could modulate mood in healthy human volunteers by targeting the right inferior frontal gyrus (rIFG), an area implicated in mood and emotional regulation. In a randomized, placebo-controlled, double-blind study, participants received 30 s of 500 kHz tFUS or a placebo control. Visual Analog Mood Scales (VAMS) assessed mood four times within an hour (baseline and three times after tFUS). Participants who received tFUS reported an overall increase in Global Affect (GA), an aggregate score from the VAMS scale, indicating a positive shift in mood. Experiment 2 examined resting-state functional (FC) connectivity using functional magnetic resonance imaging (fMRI) following 2 min of 500 kHz tFUS at the rIFG. As in Experiment 1, tFUS enhanced self-reported mood states and also decreased FC in resting state networks related to emotion and mood regulation. These results suggest that tFUS can be used to modulate mood and emotional regulation networks in the prefrontal cortex.

New evidence and increased use of intracranial devices have increased the frequency of intraventricular (IVT) medication administration in the neurologic intensive care unit. Significant benefits and risks are associated with administration of medications directly into the central nervous system. This review summarizes important literature, along with key information for clinicians regarding the administration, dosing, monitoring, and adverse effects related to IVT medication usage. Multiple medications have supporting literature for their use in critically ill patients including amphotericin B, aminoglycosides, colistimethate, daptomycin, quinupristin/dalfopristin, vancomycin, alteplase, and nicardipine. Sterile preparation and delivery, along with different types of devices that support medication administration, are also reviewed. One randomized, placebo-controlled trial of alteplase demonstrated decreased mortality but no change in good functional outcome. Other reports of IVT medication use are mainly limited to case reports and retrospective case series. There is a need for increased research on the topic; however, several practical barriers decrease the likelihood of a large, placebo-controlled, prospective study for most indications. Providers should consider implementing protocols to maximize safety of IVT medication delivery to ensure optimal patient outcomes.

With exceptional charge carrier mobilities and a direct bandgap at most thicknesses, indium selenide (InSe) is an emerging layered semiconductor that has generated significant interest for electronic and optoelectronic applications. However, exfoliated InSe nanosheets are susceptible to rapid degradation in ambient conditions, thus limiting their technological potential. In addition to morphological changes upon ambient exposure, the mobilities and current modulation on/off ratios of InSe transistors, as well as the responsivities of InSe photodetectors, decrease by over 3 orders of magnitude within 12 h of ambient exposure. In an effort to mitigate these deleterious effects, here we present an encapsulation scheme based on seeded atomic layer deposition that provides pinhole-free growth of alumina without compromising the intrinsic electronic properties of the underlying InSe. In particular, this encapsulation provides reproducible InSe field-effect transistor characteristics and InSe photodetector responsivities in excess of 107 A/W following ambient exposure for time periods on the order of months. Because atomic layer deposition is a highly scalable and manufacturable process, this work will accelerate ongoing efforts to integrate InSe nanosheets into electronic and optoelectronic technologies.

Scrotal reconstruction may be required in any setting where the patient sustains loss of a large area of scrotal or penile skin, as in repair of scrotal lymphedema and the adult acquired buried penis. Massive scrotal lymphedema and adult acquired buried penis are two conditions closely linked to obesity and are largely refractory to non-operative management. The demand for surgical repair of these conditions is increasing. The aim of this article is to provide an overview of the preoperative considerations, surgical techniques, and postoperative outcomes in the repair of scrotal lymphedema and adult buried penis. Scrotal lymphedema and adult buried penis are associated with significant medical comorbidities and can cause sexual and urinary dysfunction. Surgical repair requires a multidisciplinary approach. Skin grafts are often required. There is no consensus regarding optimal postoperative management of these surgical wounds. Consideration should be given to extended duration chemical prophylaxis of thromboembolic events. Though complications are common, patient quality of life is significantly improved following repair. The demand for surgical repairs of scrotal lymphedema and adult buried penis are increasing. Though patients have significant comorbidities and surgical repair may be complex, patient outcomes are good and quality of life can be greatly improved.

Background We have previously conducted computer-based tournaments to compare the yield of alternative approaches to deploying mobile HIV testing services in settings where the prevalence of undetected infection may be characterized by ‘hotspots’. We report here on three refinements to our prior assessments and their implications for decision-making. Specifically, (1) enlarging the number of geographic zones; (2) including spatial correlation in the prevalence of undetected infection; and (3) evaluating a prospective search algorithm that accounts for such correlation. Methods Building on our prior work, we used a simulation model to create a hypothetical city consisting of up to 100 contiguous geographic zones. Each zone was randomly assigned a prevalence of undetected HIV infection. We employed a user-defined weighting scheme to correlate infection levels between adjacent zones. Over 180 days, search algorithms selected a zone in which to conduct a fixed number of HIV tests. Algorithms were permitted to observe the results of their own prior testing activities and to use that information in choosing where to test in subsequent rounds. The algorithms were (1) Thompson sampling (TS), an adaptive Bayesian search strategy; (2) Besag York Mollié (BYM), a Bayesian hierarchical model; and (3) Clairvoyance, a benchmarking strategy with access to perfect information. Results Over 250 tournament runs, BYM detected 65.3% (compared to 55.1% for TS) of the cases identified by Clairvoyance. BYM outperformed TS in all sensitivity analyses, except when there was a small number of zones (i.e., 16 zones in a 4 × 4 grid), wherein there was no significant difference in the yield of the two strategies. Though settings of no, low, medium, and high spatial correlation in the data were examined, differences in these levels did not have a significant effect on the relative performance of BYM versus TS. Conclusions BYM narrowly outperformed TS in our simulation, suggesting that small improvements in yield can be achieved by accounting for spatial correlation. However, the comparative simplicity with which TS can be implemented makes a field evaluation critical to understanding the practical value of either of these algorithms as an alternative to existing approaches for deploying HIV testing resources. Electronic supplementary material The online version of this article (10.1186/s12916-018-1129-0) contains supplementary material, which is available to authorized users.

After 20 years of successful targeting of pro-inflammatory cytokines for the treatment of IBD, an alternative therapeutic strategy has emerged, based on several decades of advances in understanding the pathogenesis of IBD. The targeting of molecules involved in leukocyte traffic has recently become a safe and effective alternative. With 2 currently approved drugs (ie, natalizumab, vedolizumab) and several others in phase 3 trials (eg, etrolizumab, ozanimod, anti-MAdCAM-1), the blockade of trafficking molecules has firmly emerged as a new therapeutic era for IBD. We discuss the targets that have been explored in clinical trials: chemokines and its receptors (eg, IP10, CCR9), integrins (eg, natalizumab, AJM300, vedolizumab, and etrolizumab), and its endothelial ligands (MAdCAM-1, ICAM-1). We also discuss a distinct strategy that interferes with lymphocyte recirculation by blocking lymphocyte egress from lymph nodes (small molecule sphingosine-phosphate receptor [S1PR] agonists: fingolimod, ozanimod, etrasimod, amiselimod). Strategies on the horizon include additional small molecules, allosteric inhibitors that specifically bind to the active integrin form and nanovectors that allow for the use of RNA interference in the quest to modulate pro-inflammatory leukocyte trafficking in IBD.

1,3-dimethylamylamine (DMAA) is an alkylamine with stimulating properties that has been used predominantly as an additive in dietary supplements. DMAA is mostly consumed by professional athletes, and several doping cases reported since 2008 led to its prohibition by the World Anti-Doping Agency (WADA) in 2010. Adverse effects have indicated DMAA toxicity, and there is few data regarding its safety, so it was banned by regulatory agencies from Brazil and the United States. Ambient ionization methods such as Direct Analysis in Real Time Tandem Mass Spectrometry (DART-MS/MS) are an alternative for dietary supplements analysis, because they enable the analysis of samples at atmospheric pressure in a very short time and with only minimal sample preparation. Therefore, the aim of this work was to develop a methodology by DART-MS/MS to detect the presence of DMAA, ephedrine, synephrine, caffeine, sibutramine, and methylphenidate in 108 dietary supplements seized by the Brazilian Federal Police (BFP). The results show that DART-MS/MS screening was successfully employed to simultaneously detect the six substances in casework samples with rapid and reliable results and with minimum sample preparation. DMAA was present in 20% of the seized dietary supplements, being more prevalent along with sibutramine and caffeine. Out of the 108 samples, almost 50% were positive for sibutramine and 10% for methylphenidate. It appears that even after prohibition, dietary supplements and weight-loss products containing DMAA are still being commercialized.

We present device standards for low-power non-invasive electrical brain stimulation devices classified as limited output transcranial electrical stimulation (tES). Emerging applications of limited output tES to modulate brain function span techniques to stimulate brain or nerve structures, including transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial pulsed current stimulation (tPCS), have engendered discussion on how access to technology should be regulated. In regards to legal regulations and manufacturing standards for comparable technologies, a comprehensive framework already exists, including quality systems (QS), risk management, and (inter)national electrotechnical standards (IEC). In Part 1, relevant statutes are described for medical and wellness application. While agencies overseeing medical devices have broad jurisdiction, enforcement typically focuses on those devices with medical claims or posing significant risk. Consumer protections regarding responsible marketing and manufacture apply regardless. In Part 2 of this paper, we classify the electrical output performance of devices cleared by the United States Food and Drug Administration (FDA) including over-the-counter (OTC) and prescription electrostimulation devices, devices available for therapeutic or cosmetic purposes, and devices indicated for stimulation of the body or head. Examples include iontophoresis devices, powered muscle stimulators (PMS), cranial electrotherapy stimulation (CES), and transcutaneous electrical nerve stimulation (TENS) devices. Spanning over 13 FDA product codes, more than 1200 electrical stimulators have been cleared for marketing since 1977. The output characteristics of conventional tDCS, tACS, and tPCS techniques are well below those of most FDA cleared devices, including devices that are available OTC and those intended for stimulation on the head. This engineering analysis demonstrates that with regard to output performance and standing regulation, the availability of tDCS, tACS, or tPCS to the public would not introduce risk, provided such devices are responsibly manufactured and legally marketed. In Part 3, we develop voluntary manufacturer guidance for limited output tES that is aligned with current regulatory standards. Based on established medical engineering and scientific principles, we outline a robust and transparent technical framework for ensuring limited output tES devices are designed to minimize risks, while also supporting access and innovation. Alongside applicable medical and government activities, this voluntary industry standard (LOTES-2017) further serves an important role in supporting informed decisions by the public.

ObjectiveThe COVID-19 pandemic has precipitated widespread shortages of filtering facepiece respirators (FFRs) and the creation and sharing of proposed substitutes (novel designs, repurposed materials) with limited testing against regulatory standards. We aimed to categorically test the efficacy and fit of potential N95 respirator substitutes using protocols that can be replicated in university laboratories.SettingAcademic medical centre with occupational health-supervised fit testing along with laboratory studies.ParticipantsSeven adult volunteers who passed quantitative fit testing for small-sized (n=2) and regular-sized (n=5) commercial N95 respirators.MethodsFive open-source potential N95 respirator substitutes were evaluated and compared with commercial National Institute for Occupational Safety and Health (NIOSH)-approved N95 respirators as controls. Fit testing using the 7-minute standardised Occupational Safety and Health Administration fit test was performed. In addition, protocols that can be performed in university laboratories for materials testing (filtration efficiency, air resistance and fluid resistance) were developed to evaluate alternate filtration materials.ResultsAmong five open-source, improvised substitutes evaluated in this study, only one (which included a commercial elastomeric mask and commercial HEPA filter) passed a standard quantitative fit test. The four alternative materials evaluated for filtration efficiency (67%–89%) failed to meet the 95% threshold at a face velocity (7.6 cm/s) equivalent to that of a NIOSH particle filtration test for the control N95 FFR. In addition, for all but one material, the small surface area of two 3D-printed substitutes resulted in air resistance that was above the maximum in the NIOSH standard.ConclusionsTesting protocols such as those described here are essential to evaluate proposed improvised respiratory protection substitutes, and our testing platform could be replicated by teams with similar cross-disciplinary research capacity. Healthcare professionals should be cautious of claims associated with improvised respirators when suggested as FFR substitutes.

Background Electrical stimulation of the peripheral nerves has been shown to be effective in restoring sensory and motor functions in the lower and upper extremities. This neural stimulation can be applied via non-penetrating spiral nerve cuff electrodes, though minimal information has been published regarding their long-term performance for multiple years after implantation. Methods Since 2005, 14 human volunteers with cervical or thoracic spinal cord injuries, or upper limb amputation, were chronically implanted with a total of 50 spiral nerve cuff electrodes on 10 different nerves (mean time post-implant 6.7 ± 3.1 years). The primary outcome measures utilized in this study were muscle recruitment curves, charge thresholds, and percent overlap of recruited motor unit populations. Results In the eight recipients still actively involved in research studies, 44/45 of the spiral contacts were still functional. In four participants regularly studied over the course of 1 month to 10.4 years, the charge thresholds of the majority of individual contacts remained stable over time. The four participants with spiral cuffs on their femoral nerves were all able to generate sufficient moment to keep the knees locked during standing after 2–4.5 years. The dorsiflexion moment produced by all four fibular nerve cuffs in the active participants exceeded the value required to prevent foot drop, but no tibial nerve cuffs were able to meet the plantarflexion moment that occurs during push-off at a normal walking speed. The selectivity of two multi-contact spiral cuffs was examined and both were still highly selective for different motor unit populations for up to 6.3 years after implantation. Conclusions The spiral nerve cuffs examined remain functional in motor and sensory neuroprostheses for 2–11 years after implantation. They exhibit stable charge thresholds, clinically relevant recruitment properties, and functional muscle selectivity. Non-penetrating spiral nerve cuff electrodes appear to be a suitable option for long-term clinical use on human peripheral nerves in implanted neuroprostheses.