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Background: Penicillin allergy adversely impacts patient care, yet most cases do not have true allergies. Clinicians require efficient, reliable clinical tools to identify low risk patients who can be safely de-labeled. Our center implemented the FIRSTLINE electronic point-of-care decision support tool to help non-allergist practitioners risk stratify patients with penicillin allergy. We sought to explore the reliability and validity of this tool in relation to allergist assessment and actual patient outcomes. We additionally compared it with two other published stratification tools, JAMA and PENFAST, to assess ability to accurately identify low risk patients appropriate for direct oral challenge., Methods: In this single-center, retrospective, observational study, 181 pregnant females with self-reported penicillin allergy between July 2019 to June 2021 at BC Women's Hospital, Vancouver, Canada were used to assess the reliability and validity of all three tools. Physician-guided history of penicillin use and symptoms were used for scoring. Results and recommendations were compared to actual patient outcomes after clinician decision for direct oral challenge or intradermal tests. We compared the performance of JAMA, PENFAST and FIRSTLINE., Results: 181 patients were assessed. 176/181 (97.2%) patients were deemed not allergic. Each risk stratification tool labelled majority of patients as low risk with 88.4% of patients PENFAST 0-2, 60.2% of patients JAMA low risk, 86.7% of patients FIRSTLINE very low risk., Conclusion: We demonstrate that our point-of-care electronic algorithm is reliable in identifying low risk pregnant patients, as compared to an allergist assessment. To our knowledge, this is the first study to provide direct comparison between multiple decision support tools using the same population, minimizing participant bias. Providing clinical algorithms to risk stratify patients, can enable healthcare professionals to safely identify individuals who may be candidates for direct penicillin oral challenges versus needing referral to specialists. This increases the generalizability and efficiency of penicillin allergy de-labeling., (© 2024. The Author(s).)

The excellent versatility of 5-axis computer numerical control (CNC) micromilling has led to its application for prototyping NMR microcoils tailored to mass-limited samples (reducing development time and cost). However, vibrations during 5-axis milling can hinder the creation of complex 3D volume microcoils (i.e., solenoids and saddle coils). To address these limitations, a high-resolution NSCNC ELARA 4-axis milling machine was developed with the extra precision required for making complex 3D volume microcoils. Upon investigating the performance of resonators made with various copper-coated dielectrics, resonators with poly(methyl methacrylate) (PMMA) provided the best SNR/line shape. Thus, complex 1.7 mm microcoil designs were machined from Cu-coated PMMA. A milled 6.4 mm solenoid also provided 6.6× the total carbon signal for a 13 C-labeled broccoli seed compared to a commercial inverse 5 mm NMR probe (demonstrating potential for larger coil designs). However, the manufacture of coils <1.7 mm with copper-coated PMMA rods was challenging as ∼0.5 mm of remaining PMMA was needed to retain their structural integrity. To manufacture smaller microcoils, both a solenoid and saddle coil (both with 1 mm O.D., 0.1 mm thick walls) were etched from Cu-coated glass capillaries using a UV picosecond laser that was mounted onto an NSCNC 5-axis MiRA7L. Both resonators showed excellent signal and identified a wide range of metabolites in a 13 C-labeled algae extract, while the solenoid was further tested on two copepod egg sacs (∼4 μg of total sample). In summary, the flexibility to prototype complex microcoils in-house allows laboratories to tailor microcoils to specific mass-limited samples while avoiding the costs of cleanrooms.

In vivo NMR is evolving into an important tool to understand biological processes and environmental responses. Current approaches use flow systems to sustain the organisms with oxygenated water and food (e.g., algae) inside the NMR. However, such systems have the potential to leak and clog (potentially damaging costly hardware), require large volumes of media, and multiple expensive HPLC pumps. The proposed "oxygenation system", uses a simple "double slit" adapter and a single air/oxygen flow line into the NMR. The design is especially suited to larger diameter probes given that standard flow systems would require higher flow rates thus amplifying the potential and impact of leaks/clogs. Traditionally, in vivo NMR of small organisms (e.g., Daphnia ) have required 2D NMR in combination with 13 C enrichment to overcome susceptibility distortions and provide information rich metabolic profiles. Here Daphnia magna , Eisenia fetida and Artemia franciscana are used to demonstrate the potential of the oxygenation system. Survivability tests and 1 H time-resolved monitoring were first performed on D. magna , while E. fetida contained enough biomass to permit 1 H- 13 C HSQC, 13 C- 1 H HETCOR and 31 P NMR without isotopic enrichment. Finally, STOCSY of 1D 13 C NMR was used to follow the growth of A. franciscana (without 13 C enrichment) for 48 h after birth, which helps visualize trends across a series of 1D in vivo data. In summary, application of the oxygenation system toward larger diameter probes allows the collection of NMR data without enrichment, offering a promising solution to better understand processes in vivo.

Attention-deficit/hyperactivity disorder is a childhood-onset neurodevelopmental disorder that frequently persists into adulthood with 3% of adult women having a diagnosis of attention-deficit/hyperactivity disorder. Many women are diagnosed and treated during their reproductive years, which leads to management implications during pregnancy and the postpartum period. We know from clinical practice that attention-deficit/hyperactivity disorder symptoms frequently become challenging to manage during the perinatal period and require additional support and attention. There is often uncertainty among healthcare providers about the management of attention-deficit/hyperactivity disorder in the perinatal period, particularly the safety of pharmacotherapy for the developing fetus. This guideline is focused on best practices in managing attention-deficit/hyperactivity disorder in the perinatal period. We recommend (1) mitigating the risks associated with attention-deficit/hyperactivity disorder that worsen during the perinatal period via individualized treatment planning; (2) providing psychoeducation, self-management strategies or coaching, and psychotherapies; and, for those with moderate or severe attention-deficit/hyperactivity disorder, (3) considering pharmacotherapy for attention-deficit/hyperactivity disorder, which largely has reassuring safety data. Specifically, providers should work collaboratively with patients and their support networks to balance the risks of perinatal attention-deficit/hyperactivity disorder medication with the risks of inadequately treated attention-deficit/hyperactivity disorder during pregnancy. The risks and impacts of attention-deficit/hyperactivity disorder in pregnancy can be successfully managed through preconception counselling and appropriate perinatal planning, management, and support., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Extravasation is the erroneous delivery of IV medication or fluid into the extravascular space. Complications ranging from mild injury to amputation can result, depending on the physical and pharmacologic properties of the infusate. Children are at increased risk for extravasation injuries. There is a paucity of data on the treatment and outcomes of extravasation injuries, particularly in terms of the role of pharmacologic antidotes., Objectives: To describe the incidence of extravasation at a tertiary pediatric care centre (as an update to a previous study), to identify the agents most commonly involved in extravasation injuries, to describe the antidotes used for management of injuries and their related adverse drug effects, and to describe complications related to injuries., Methods: The medical records of pediatric patients who experienced an extravasation injury at the BC Children's and BC Women's Hospitals, between September 1, 2008, and September 30, 2020, were reviewed. Data regarding management (adherence with institutional protocol) and outcomes of injuries were collected., Results: The 242 charts included in the analysis noted a total of 245 extravasation injuries, for an extravasation incidence of 0.04% per patient-day. Of the 242 patients, 110 were excluded from secondary outcome analysis due to lack of data detailing the extravasation event. Of the remaining 132 patients, the majority were neonates ( n = 54, 40.9%), infants ( n = 33, 25.0%), and children ( n = 34, 25.8%), and more than a third were treated on general pediatric wards ( n = 50, 37.9%). The medications most frequently involved were total parenteral nutrition with lipids (36/132, 27.3%), vancomycin (36/132, 27.3%), and IV fluids (35/132, 26.5%). Most of the patients had mild outcomes and recovered without complications. No adverse drug events from antidotes were reported., Conclusions: The incidence of extravasation at the study institution remained low, with the medications involved being similar to those reported in the literature and the majority of patients having mild outcomes. Additional prospective studies are needed to assess the efficacy and safety of antidotes administered for extravasation injuries., Competing Interests: Competing interests: None declared., (2024 Canadian Society of Hospital Pharmacists. All content in the Canadian Journal of Hospital Pharmacy is copyrighted by the Canadian Society of Hospital Pharmacy. In submitting their manuscripts, the authors transfer, assign, and otherwise convey all copyright ownership to CSHP.)

Nuclear magnetic resonance (NMR) based 13 C tracing has broad applications across medical and environmental research. As many biological and environmental samples are heterogeneous, they experience considerable spectral overlap and relatively low signal. Here a 1D 1 H- 12 C/ 13 C is introduced that uses "in-phase/opposite-phase" encoding to simultaneously detect and discriminate both protons attached to 12 C and 13 C at full 1 H sensitivity in every scan. Unlike traditional approaches that focus on the 12 C/ 13 C satellite ratios in a 1 H spectrum, this approach creates separate sub-spectra for the 12 C and 13 C bound protons. These spectra can be used for both quantitative and qualitative analysis of complex samples with significant spectral overlap. Due to the presence of the 13 C dipole, faster relaxation of the 1 H- 13 C pairs results in slight underestimation compared to the 1 H- 12 C pairs. However, this is easily compensated for, by collecting an additional reference spectrum, from which the absolute percentage of 13 C can be calculated by difference. When combined with the result, 12 C and 13 C percent enrichment in both 1 H- 12 C and 1 H- 13 C fractions are obtained. As the approach uses isotope filtered 1 H NMR for detection, it retains nearly the same sensitivity as a standard 1 H spectrum. Here, a proof-of-concept is performed using simple mixtures of 12 C and 13 C glucose, followed by suspended algal cells with varying 12 C / 13 C ratios representing a complex mixture. The results consistently return 12 C/ 13 C ratios that deviate less than 1 % on average from the expected. Finally, the sequence was used to monitor and quantify 13 C% enrichment in Daphnia magna neonates which were fed a 13 C diet over 1 week. The approach helped reveal how the organisms utilized the 12 C lipids they are born with vs. the 13 C lipids they assimilate from their diet during growth. Given the experiments simplicity, versatility, and sensitivity, we anticipate it should find broad application in a wide range of tracer studies, such as fluxomics, with applications spanning various disciplines., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the effectiveness of empiric antibiotic protocols for peripartum bacteremia at a quaternary institution by describing incidence, microbial epidemiology, clinical source of infection, susceptibility patterns, and maternal and neonatal outcomes., Methods: Retrospective chart review of peripartum patients with positive blood cultures between 2010 and 2018., Results: The incidence of peripartum bacteremia was 0.3%. The most cultured organisms were Escherichia coli (51, 26.7%), Streptococcus spp. (52, 27.2%), and anaerobic spp. (35, 18.3%). Of the E. coli cases, 54.9% (28), 19.6% (10), and 19.6% (10) were resistant to ampicillin, first- and third-generation cephalosporins, respectively. Clinical sources of infection included intra-amniotic infection/endometritis (115, 67.6%), upper and/or lower urinary tract infection (23, 13.5%), and soft tissue infection (8, 4.7%). Appropriate empiric antibiotics were prescribed in 137 (83.0%) cases. There were 7 ICU admissions (4.2%), 18 pregnancy losses (9.9%), 9 neonatal deaths (5.5%), and 6 cases of neonatal bacteremia (3.7%)., Conclusion: Peripartum bacteremia remains uncommon but associated with maternal morbidity and neonatal morbidity and mortality. Current empiric antimicrobial protocols at our site remain appropriate, but continuous monitoring of antimicrobial resistance patterns is critical given the presence of pathogens resistant to first-line antibiotics., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Background and objective The current periprosthetic joint infection (PJI) diagnostic guidelines require clinicians to interpret and integrate multiple criteria into a complex scoring system. Also, PJI classifications are often inconclusive, failing to provide a clinical diagnosis. Machine learning (ML) models could be leveraged to reduce reliance on these complex systems and thereby reduce diagnostic uncertainty. This study aimed to develop an ML algorithm using synovial fluid (SF) test results to establish a PJI probability score. Methods We used a large clinical laboratory's dataset of SF samples, aspirated from patients with hip or knee arthroplasty as part of a PJI evaluation. Patient age and SF biomarkers [white blood cell count, neutrophil percentage (%PMN), red blood cell count, absorbance at 280 nm wavelength, C-reactive protein (CRP), alpha-defensin (AD), neutrophil elastase, and microbial antigen (MID) tests] were used for model development. Data preprocessing, principal component analysis, and unsupervised clustering (K-means) revealed four clusters of samples that naturally aggregated based on biomarker results. Analysis of the characteristics of each of these four clusters revealed three clusters (n=13,133) with samples having biomarker results typical of a PJI-negative classification and one cluster (n=4,032) with samples having biomarker results typical of a PJI-positive classification. A decision tree model, trained and tested independently of external diagnostic rules, was then developed to match the classification determined by the unsupervised clustering. The performance of the model was assessed versus a modified 2018 International Consensus Meeting (ICM) criteria, in both the test cohort and an independent unlabeled validation set of 5,601 samples. The SHAP (SHapley Additive exPlanations) method was used to explore feature importance. Results The ML model showed an area under the curve of 0.993, with a sensitivity of 98.8%, specificity of 97.3%, positive predictive value (PPV) of 92.9%, and negative predictive value (NPV) of 99.8% in predicting the modified 2018 ICM diagnosis among test set samples. The model maintained its diagnostic accuracy in the validation cohort, yielding 99.1% sensitivity, 97.1% specificity, 91.9% PPV, and 99.9% NPV. The model's inconclusive rate (diagnostic probability between 20-80%) in the validation cohort was only 1.3%, lower than that observed with the modified 2018 ICM PJI classification (7.4%; p<0.001). The SHAP analysis found that AD was the most important feature in the model, exhibiting dominance among >95% of "infected" and "not infected" diagnoses. Other important features were the sum of the MID test panel, %PMN, and SF-CRP. Conclusions Although defined methods and tools for diagnosis of PJI using multiple biomarker criteria are available, they are not consistently applied or widely implemented. There is a need for algorithmic interpretation of these biomarkers to enable consistent interpretation of the results to drive treatment decisions. The new model, using clinical parameters measured from a patient's SF sample, renders a preoperative probability score for PJI which performs well compared to a modified 2018 ICM definition. Taken together with other clinical signs, this model has the potential to increase the accuracy of clinical evaluations and reduce the rate of inconclusive classification, thereby enabling more appropriate and expedited downstream treatment decisions., Competing Interests: Application No.: 63/534,229 Filed: 8/23/23 Title: Methods and Techniques for Diagnosing Infection, (Copyright © 2023, Paranjape et al.)

Nuclear magnetic resonance (NMR) is a powerful technique with applications ranging from small molecule structure elucidation to metabolomics studies of living organisms. Typically, solution-state NMR requires a homogeneous liquid, and the whole sample is analyzed as a single entity. While adequate for homogeneous samples, such an approach is limited if the composition varies as would be the case in samples that are naturally heterogeneous or layered. In complex samples such as living organisms, magnetic susceptibility distortions lead to broad 1 H line shapes, and thus, the additional spectral dispersion afforded by 2D heteronuclear experiments is often required for metabolite discrimination. Here, a novel, slice-selective 2D, 1 H- 13 C heteronuclear single quantum coherence (HSQC) sequence was developed that exclusively employs shaped pulses such that only spins in the desired volume are perturbed. In turn, this permits multiple volumes in the tube to be studied during a single relaxation delay, increasing sensitivity and throughput. The approach is first demonstrated on standards and then used to isolate specific sample/sensor elements from a microcoil array and finally study slices within a living earthworm, allowing metabolite changes to be discerned with feeding. Overall, slice-selective NMR is demonstrated to have significant potential for the study of layered and other inhomogeneous samples of varying complexity. In particular, its ability to select subelements is an important step toward developing microcoil receive-only arrays to study environmental toxicity in tiny eggs, cells, and neonates, whereas localization in larger living species could help better correlate toxin-induced biochemical responses to the physical localities or organs involved.

In environmental research, it is critical to understand how toxins impact invertebrate eggs and egg banks, which, due to their tiny size, are very challenging to study by conventional nuclear magnetic resonance (NMR) spectroscopy. Microcoil technology has been extensively utilized to enhance the mass-sensitivity of NMR. In a previous study, 5-axis computer numerical control (CNC) micromilling (shown to be a viable alternative to traditional microcoil production methods) was used to create a prototype copper slotted-tube resonator (STR). Despite the excellent limit of detection (LOD) of the resonator, the quality of the line shape was very poor due to the magnetic susceptibility of the copper resonator itself. This is best solved using magnetic susceptibility-matched materials. In this study, approaches are investigated that improve the susceptibility while retaining the versatility of coil milling. One method involves machining STRs from various copper/aluminum alloys, while the other involves machining ones from an aluminum 2011 alloy and electroplating them with copper. In all cases, combining copper and aluminum to produce resonators resulted in improved line shape and SNR compared to pure copper resonators due to their reduced magnetic susceptibility. However, the copper-plated aluminum resonators showed optimal performance from the devices tested. The enhanced LOD of these STRs allowed for the first 1 H- 13 C heteronuclear multiple quantum coherence (HMQC) of a single intact 13 C-labeled Daphnia magna egg (∼4 μg total biomass). This is a key step toward future screening programs that aim to elucidate the toxic processes in aquatic eggs.

Background: To describe baseline antimicrobial stewardship (AMS) metrics and apply AMS interventions in an inpatient obstetrical population., Methods: From October 2018 to October 2019, our tertiary-care obstetrical center reviewed components of our AMS program, which included: (1) antimicrobial consumption data, (2) point prevalence surveys (PPS), and (3) prospective audit and feedback. We reviewed institutional data for antimicrobial consumption from the pharmacy database. Detailed point prevalence surveys were conducted for all antimicrobial prescriptions on two predefined dates each month. Daily audits and feedback assessed the appropriateness of all non-protocolized antimicrobials., Results: Our average antimicrobial length of therapy (LOT) was 12 days per 100 patient-days, where erythromycin (2.33), amoxicillin (2.28), and ampicillin (1.81) were the greatest contributors. Point prevalence surveys revealed that 28.8% of obstetrical inpatients were on antimicrobials, of which 11.2% were inappropriate. Protocolized antimicrobials were 62% less likely ( p = 0.027) to be inappropriate. From 565 audited prescriptions, 110 (19.5%) resulted in feedback, where 90% of recommendations were accepted and implemented. The most common reasons for interventions include incorrect dosage, recommending a diagnostic test before continuing antimicrobials, and changing antimicrobials based on specific culture and sensitivity., Conclusions: Antimicrobial use in obstetrics is unique compared to general inpatients. We provide a baseline set of metrics for AMS at our obstetrical center intending to lay the groundwork for AMS programming in our discipline. Antimicrobial protocolization, as well as audit and feedback, are feasible interventions to improve antimicrobial prescribing patterns., Competing Interests: The authors have nothing to disclose., (© Association of Medical Microbiology and Infectious Disease Canada (AMMI Canada), 2023.)

Prostate cancer is well known to be dependent on the androgen receptor (AR) for growth and survival. Thus, AR is the main pharmacological target to treat this disease. However, after an initially positive response to AR-targeting therapies, prostate cancer will eventually evolve to castration-resistant prostate cancer, which is often lethal. Tumour growth was initially thought to become androgen-independent following treatments; however, results from molecular studies have shown that most resistance mechanisms involve the reactivation of AR. Consequently, tumour cells become resistant to castration - the blockade of testicular androgens - and not independent of AR per se. However, confusion still remains on how to properly define preclinical models of prostate cancer, including cell lines. Most cell lines were isolated from patients for cell culture after evolution of the tumour to castration-resistant prostate cancer, but not all of these cell lines are described as castration resistant. Moreover, castration refers to the blockade of testosterone production by the testes; thus, even the concept of "castration" in vitro is questionable. To ensure maximal transfer of knowledge from scientific research to the clinic, understanding the limitations and advantages of preclinical models, as well as how these models recapitulate cancer cell androgen dependency and can be used to study castration resistance mechanisms, is essential., (© 2023. Springer Nature Limited.)

Objectives: Untreated opioid use disorder (OUD) in pregnancy may lead to adverse outcomes for the individual and fetus. Injectable opioid agonist therapy (iOAT) is the highest intensity treatment for severe refractory OUD currently available; however, research on perinatal administration is limited. We present the first known case series of 13 pregnant or postpartum participants who received intravenous hydromorphone while admitted to the Families in Recovery (FIR) unit, an in-patient perinatal stabilization unit in Canada., Methods: Patients who received iOAT at FIR between 2019 and 2022 were invited to participate. Prospectively enrolled participants completed a self-report sociodemographics and exposures survey. Medical/social backgrounds of participants at admission, iOAT and other opioid agonist therapy administration, and health/social outcomes of mother and infant at discharge were collected on all participants via retrospective maternal and infant medical chart review., Results: Participants initiated iOAT while pregnant (n = 5) or postpartum (n = 8) and received iOAT for 23 days on average. At discharge, 8 participants underwent planned transition to community with infant in their care and a discharge plan including outpatient prescriptions, housing arrangements, follow-up appointments, and supportive programming. All infants received oral morphine after delivery and were discharged in good health., Conclusions: This is the first known case series of iOAT administration in the peripartum. The cases illustrate iOAT as an option that can achieve OUD stabilization in perinatal individuals to support patient engagement and retention in care., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Addiction Medicine.)

With sensitivity being the Achilles' heel of nuclear magnetic resonance (NMR), the superior mass sensitivity offered by micro-coils can be an excellent choice for tiny, mass limited samples such as eggs and small organisms. Recently, complementary metal oxide semiconductor (CMOS)-based micro-coil transceivers have been reported and demonstrate excellent mass sensitivity. However, the ability of broadband CMOS micro-coils to study heteronuclei has yet to be investigated, and here their potential is explored within the lens of environmental research. Eleven nuclei including 7 Li, 19 F, 31 P and, 205 Tl were studied and detection limits in the low to mid picomole range were found for an extended experiment. Further, two environmentally relevant samples (a sprouting broccoli seed and a D. magna egg) were successfully studied using the CMOS micro-coil system. 13 C NMR was used to help resolve broad signals in the 1 H spectrum of the 13 C enriched broccoli seed, and steady state free precession was used to improve the signal-to-noise ratio by a factor of six. 19 F NMR was used to track fluorinated contaminants in a single D. magna egg, showing potential for studying egg-pollutant interactions. Overall, CMOS micro-coil NMR demonstrates significant promise in environmental research, especially when the future potential to scale to multiple coil arrays (greatly improving throughput) is considered.

Objectives: Two cross-sectional (Studies 1, N = 283 and 2, N = 275) and one prospective (Study 3, N = 238) studies investigated the role of passion (for academia) and emotions in the process of resilience in the education domain and in life in general., Method: Participants were examined when facing a stressful situation related to their passion for academia (end-of-term exam period and a timed education task)., Results: All three studies showed that harmonious passion, through its positive relationship with positive emotions, was positively associated with high positive outcomes in the education domain (satisfaction with one's studies, subjective and objective performance in one's studies) and in life in general via the subjective evaluation of one's life and general health indicators (subjective vitality and fewer negative physical symptoms). On the other hand, obsessive passion was related to mixed effects on resilience. Specifically, obsessive passion related to low levels of functioning (Studies 1 and 3) and also hindered the positive outcomes (Studies 1-3) through its positive relationships with positive and negative emotions, respectively., Conclusions: In sum, under stress, harmonious passion facilitates high resilience across life domains, whereas obsessive passion yields low resilience across the life or no resilience at all., (© 2022 Wiley Periodicals LLC.)

Introduction:  There is a concern in the field of arthroplasty that synovial fluid transport delays may reduce the accuracy of synovial fluid culture. However, synovial fluid samples collected in the office, and sometimes in a hospital setting, often require transport to a third-party central or specialty laboratory, causing delays in the initiation of culture incubation. This study investigated the impact of transportation delays on synovial fluid culture results., Methods:  A retrospective review of prospectively collected data at one clinical laboratory, from 2016 to 2022, was conducted. A total of 125,270 synovial fluid samples from knee arthroplasties, from 2,858 different US institutions, were transported to a single clinical laboratory for diagnostic testing including synovial fluid culture (blood culture bottles). Synovial fluid to be cultured was transported in red top tubes without additives. Samples were grouped into six-time cohorts based on the number of days between aspiration and culture initiation (1-day-delay to 6-day-delay). Metrics such as culture positivity, false-positive culture rate, culture sensitivity, and proportional growth of top genera of organisms were assessed across the cohorts., Results:  Of the 125,270 samples in this study, 71.2% were received the day after aspiration (1-day-delay), with an exponential decrease in samples received on each subsequent day. Culture-positive rates for synovial fluid samples received after 1, 2, 3, 4, 5, and 6 days of transport time were 12.2%, 13.3%, 13.5%, 13.1%, 11.6%, and 11.0%, respectively. The maximum absolute difference in culture-positive rate compared to the 1-day-delay cohort was an increase of 1.3% in the 3-day-delay cohort, which was not considered a clinically meaningful difference. The estimated false-positive culture rate remained relatively consistent across time cohorts, with values of 0.3%, 0.4%, 0.3%, 0.2%, 0.5%, and 0.5% for 1, 2, 3, 4, 5, and 6 days of transport time, respectively. None of the cohorts showed a statistically significant difference after adjustment for multiplicity compared to the 1-day-delay cohort. Culture sensitivity was estimated at 68.2%, 67.2%, 70.5%, 70.7%, 65.9%, and 70.7% for 1, 2, 3, 4, 5, and 6 days of transport time, respectively. None of the cohorts showed a statistically significant difference after adjustment for multiplicity compared to the 1-day-delay cohort. Organism proportions were consistent across time cohorts, with Staphylococcus being the most commonly identified organism. No statistically significant differences were found in the proportional contribution of major genera across the cohorts., Conclusions:  Synovial fluid culture exhibited surprisingly consistent results despite variable transport time to the destination laboratory, with differences that have minimal clinical importance. While the authors of this study advocate for short transport times as a best practice to expedite diagnosis, it appears that concerns regarding the rapid degradation of culture results due to synovial fluid transportation is unwarranted., Competing Interests: Several authors have patents (issued and pending) in the field of diagnostics. None of these patents relate to the subject of this study.. Alex McLaren is a Board member of the Musculoskeletal Infection Society., (Copyright © 2023, Deirmengian et al.)

Background: Inaccurate penicillin allergy labels lead to inappropriate antibiotic prescriptions and harmful patient consequences. System-wide efforts are needed to remove incorrect penicillin allergy labels, but more health services research is required on how to best deliver these services., Methods: Data was extracted from five hospitals in Vancouver, British Columbia, Canada from October 2018-May 2022. The primary outcomes of this study were to outline de-labelling protocol designs, identify the roles of various healthcare professionals in de-labelling protocols and identify rates of de-labelling penicillin allergies and associated adverse events at various institutions. Our secondary outcome was to describe de-labelling rates for special populations, including pediatric, obstetric and immunocompromised subpopulations. To achieve these outcomes, participating institutions provided their de-labelling protocol designs and data on program participants. Protocols were then compared to find common themes and differences. Furthermore, adverse events were reviewed and percentages of patients de-labelled at each institution and in total were calculated., Results: Protocols demonstrated a high level of variability, including different methods of participant identification, risk-stratification and roles of providers. All protocols used oral and direct oral challenges, heavily involved pharmacists and had physician oversight. Despite the differences, of the 711 patients enrolled in all programs, 697 (98.0%) were de-labelled. There were 9 adverse events (1.3%) with oral challenges with mainly minor symptoms., Conclusions: Our data demonstrates that de-labelling programs effectively and safely remove penicillin allergy labels, including pediatric, obstetric and immunocompromised patients. Consistent with current literature, most patients with a penicillin allergy label are not allergic. De-labelling programs could benefit from increasing clinician engagement by increasing accessibility of resources to providers, including guidance for de-labelling of special populations., (© 2023. The Author(s).)

Toxicity testing is currently undergoing a paradigm shift from examining apical end points such as death, to monitoring sub-lethal toxicity in vivo. In vivo nuclear magnetic resonance (NMR) spectroscopy is a key platform in this endeavor. A proof-of-principle study is presented which directly interfaces NMR with digital microfluidics (DMF). DMF is a "lab on a chip" method allowing for the movement, mixing, splitting, and dispensing of μL-sized droplets. The goal is for DMF to supply oxygenated water to keep the organisms alive while NMR detects metabolomic changes. Here, both vertical and horizontal NMR coil configurations are compared. While a horizontal configuration is ideal for DMF, NMR performance was found to be sub-par and instead, a vertical-optimized single-sided stripline showed most promise. In this configuration, three organisms were monitored in vivo using 1 H- 13 C 2D NMR. Without support from DMF droplet exchange, the organisms quickly showed signs of anoxic stress; however, with droplet exchange, this was completely suppressed. The results demonstrate that DMF can be used to maintain living organisms and holds potential for automated exposures in future. However, due to numerous limitations of vertically orientated DMF, along with space limitations in standard bore NMR spectrometers, we recommend future development be performed using a horizontal (MRI style) magnet which would eliminate practically all the drawbacks identified here.

Background: Injectable opioid agonist therapy (iOAT) is the highest-intensity treatment currently available in Canada for individuals with severe opioid use disorder. However, there is limited data on iOAT administration in the perinatal period, with no research, practice guidelines, or known reports of breastfeeding on iOAT. This article presents the first known case of an individual breastfeeding on iOAT., Case Summary: We present a case of a pregnant 32-year-old woman from Canada with severe opioid use disorder, who stabilized with iOAT and chose to breastfeed her infant. She presented to hospital at 38 + 6 gestation in labor, unstable in her substance use disorder despite multiple interventions and was initiated on iOAT (intravenous hydromorphone) shortly after delivery. Before initiation of breastfeeding the infant was admitted to the neonatal intensive care unit for monitoring. On day 9 of life the infant received breastmilk for the first time, and was discharged from neonatal intensive care unit on day 12 of life with no clinical evidence of sedation or respiratory depression. The infant maintained mixed feeding and at 58 days of life was discharged in the mother and father's care, a healthy infant with stable vitals., Discussion: This case suggests positive infant and maternal health and social outcomes for breastfeeding on iOAT. Further research on perinatal iOAT use and the pharmacokinetics of high-dose hydromorphone in breastmilk is required to inform clinical practice guidelines to safely support individuals and their infants who are impacted by substance use., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Addiction Medicine.)

Objective: To evaluate the change in consumption of specific antibiotics in a neonatal intensive care unit after the implementation of an antimicrobial stewardship program (ASP)., Design: Retrospective cohort study between January 1, 2010, and December 31,2019., Setting: The neonatal intensive care unit at British Columbia Women's Hospital (Vancouver Canada), a tertiary-care center., Patients: Admitted neonates prescribed antibiotics., Methods: We implemented an ASP with an early implementation phase starting in January 2014 (period 2) and a later phase starting in January 2017 (period 3). Patient demographics were collected, including birth weight, gestational age, history of necrotizing enterocolitis (NEC), and surgical operations from existing databases. Interrupted time-series analysis was used, and comparison of antibiotic days of therapy (DOT) averages were conducted across the preimplementation period (period 1), period 2, and period 3 regarding total patients and subgroups., Results: We identified 4,512 infants. There was a significant decrease in DOT from 472 (95% confidence interval [CI], 431-517) in period 1 to 405 (95% CI, 367-446) in period 2 to 313 (95% CI, 280-350) in period 3. We detected a significant decrease in the use of ampicillin, aminoglycosides, cloxacillin, and linezolid but not in vancomycin or cefotaxime. Subgroup analyses of infants <1,500 g and those without NEC or surgery showed decreases in the use of cloxacillin, aminoglycosides, and linezolid., Conclusions: The implementation of an ASP was associated with a significant decrease in the overall DOT and use of certain antibiotics. This study presents important targets for ongoing ASP work.

Emerging evidence associates translation factors and regulators to tumorigenesis. However, our understanding of translational changes in cancer resistance is still limited. Here, we generated an enzalutamide-resistant prostate cancer (PCa) model, which recapitulated key features of clinical enzalutamide-resistant PCa. Using this model and poly(ribo)some profiling, we investigated global translation changes that occur during acquisition of PCa resistance. We found that enzalutamide-resistant cells exhibit an overall decrease in mRNA translation with a specific deregulation in the abundance of proteins involved in mitochondrial processes and in translational regulation. However, several mRNAs escape this translational downregulation and are nonetheless bound to heavy polysomes in enzalutamide-resistant cells suggesting active translation. Moreover, expressing these corresponding genes in enzalutamide-sensitive cells promotes resistance to enzalutamide treatment. We also found increased association of long non-coding RNAs (lncRNAs) with heavy polysomes in enzalutamide-resistant cells, suggesting that some lncRNAs are actively translated during enzalutamide resistance. Consistent with these findings, expressing the predicted coding sequences of known lncRNAs JPX, CRNDE and LINC00467 in enzalutamide-sensitive cells drove resistance to enzalutamide. Taken together, this suggests that aberrant translation of specific mRNAs and lncRNAs is a strong indicator of PCa enzalutamide resistance, which points towards novel therapeutic avenues that may target enzalutamide-resistant PCa., (© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Cancer.)

Microcoils provide a cost-effective approach to improve detection limits for mass-limited samples. Single-sided planar microcoils are advantageous in comparison to volume coils, in that the sample can simply be placed on top. However, the considerable drawback is that the RF field that is produced by the coil decreases with distance from the coil surface, which potentially limits more complex multi-pulse NMR pulse sequences. Unfortunately, 1 H NMR alone is not very informative for intact biological samples due to line broadening caused by magnetic susceptibility distortions, and 1 H- 13 C 2D NMR correlations are required to provide the additional spectral dispersion for metabolic assignments in vivo or in situ. To our knowledge, double-tuned single-sided microcoils have not been applied for the 2D 1 H- 13 C analysis of intact 13 C enriched biological samples. Questions include the following: Can 1 H- 13 C 2D NMR be performed on single-sided planar microcoils? If so, do they still hold sensitivity advantages over conventional 5 mm NMR technology for mass limited samples? Here, 2D 1 H- 13 C HSQC, HMQC, and HETCOR variants were compared and then applied to 13 C enriched broccoli seeds and Daphnia magna (water fleas). Compared to 5 mm NMR probes, the microcoils showed a sixfold improvement in mass sensitivity (albeit only for a small localized region) and allowed for the identification of metabolites in a single intact D. magna for the first time. Single-sided planar microcoils show practical benefit for 1 H- 13 C NMR of intact biological samples, if localized information within ~0.7 mm of the 1 mm I.D. planar microcoil surface is of specific interest., (© 2021 John Wiley & Sons, Ltd.)

The present study fills a void in research on passion by examining for the first time the role of passion in physiological responses. The aim of the study was to investigate the role of passion, and the mediating role of cognitive appraisals, in the psychological and physiological responses to a stressful situation related to one's passion. Students (43 women, 12 men, M age = 27.21 years), who were passionate for their studies, completed the Passion Scale for their studies and the Cognitive Appraisal Scale (assessing perceptions of challenge/threat). Then, they engaged in an education task under stressful conditions, and a subsequent unrelated leisure task under no-stress. Physiological reactivity was measured throughout the entire session and their perceptions of situational vitality and positive and negative emotions were assessed directly after the education task. Results showed that harmonious passion (HP) positively predicted challenge appraisals that, in turn, were positively related to positive emotions, vitality, and positive cardiovascular adaptation while engaging in the stressful education task, but less so with the leisure task (unrelated to one's passion for academia). On the other hand, obsessive passion (OP) positively predicted threat appraisals. In turn, threat appraisals were positively related to negative emotions, negatively associated with vitality, and not related to cardiovascular reactivity. The present findings suggest that HP creates the onset of an adaptive psychological and physiological response whereas the response is less adaptive with OP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Vallerand, Paquette and Richard.)

Prostate cancer (PCa) cells rely on the androgen receptor (AR) signaling axis to reprogram metabolism to sustain aberrant proliferation. Whether additional transcription factors participate to this reprogramming remains mostly unknown. To identify such factors, DNA motif analyses were performed in the promoter and regulatory regions of genes sensitive to androgens in PCa cells. These analyses identified two transcription factors, KLF5 and NFYA, as possibly associated with PCa cell metabolism. In clinical datasets, KLF5 and NFYA expression levels were associated with disease aggressiveness, being significantly decreased and increased, respectively, during PCa progression. Their expression was next investigated by qPCR and Western blot in human PCa cell models, revealing a positive regulation of KLF5 by androgens and a correlation between NFYA and AR protein expression status. siRNA-mediated knockdown of KLF5 increased human PCa cell proliferation rate in AR-positive cell models, suggesting a tumor suppressor function. Live-cell metabolic assays showed that knockdown of KLF5 promoted mitochondrial respiration, a key metabolic pathway associated with PCa progression. The opposite was observed for knockdown of NFYA regarding proliferation and respiration. RNA-seq analyses following the knockdown of either KLF5 and NFYA confirmed that both factors regulated distinct metabolic gene signatures, as well as other gene signatures, explaining their differential impact on PCa cell proliferation and metabolism. Overall, our findings identify KLF5 and NFYA as novel regulators of PCa cell metabolism.

Introduction: Early empiric treatment with broad-spectrum antimicrobials is common in neonatal intensive care units (NICU) due to the non-specific clinical presentation of infection. However, excessive and inappropriate antimicrobial use can lead to the emergence of drug-resistant organisms and adverse neonatal outcomes. This study aims to develop and implement a nationwide NICU-specific antimicrobial stewardship programme (ASP) to promote judicious antimicrobial use and control the emergence of multidrug-resistant organisms (MDROs) in Canada., Methods and Analysis: Our study population will include all very low-birth-weight neonates admitted to participating tertiary NICU in Canada. Based on the existing limited literature, we will develop consensus on NICU antimicrobial stewardship interventions to enhance best practices. Using an expanded Canadian Neonatal Network (CNN) platform, we will collect data on antimicrobial use and the susceptibility of organisms identified in clinical samples from blood and cerebrospinal fluid over a period of 2 years. These data will be used to provide all NICU stakeholders with benchmarked centre-adjusted antimicrobial use and MDRO prevalence reports. An ASP plan will be developed at both individual unit and national levels in the subsequent years. Knowledge translation strategies will be implemented through the well-established Evidence-based Practice for Improving Quality methodology., Ethics and Dissemination: Ethics for the study has been granted by the University of British Columbia Children's & Women's Research Ethics Board (H19-02490) and supported by CNN Executive Committee. The study results will be disseminated through national organisations and open access peer-reviewed publications., Trial Registration Number: NCT04388293., Competing Interests: Competing interests: JT is supported by the Investigator Grant Award Program through the British Columbia Children’s Hospital Research Institute. Dr Prakesh S Shah reported holding an Applied Research Chair in Reproductive and Child Health Services and Policy Research awarded by the Canadian Institutes of Health Research (grant APR-126340)., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The superior mass sensitivity of microcoil technology in nuclear magnetic resonance (NMR) spectroscopy provides potential for the analysis of extremely small-mass-limited samples such as eggs, cells, and tiny organisms. For optimal performance and efficiency, the size of the microcoil should be tailored to the size of the mass-limited sample of interest, which can be costly as mass-limited samples come in many shapes and sizes. Therefore, rapid and economic microcoil production methods are needed. One method with great potential is 5-axis computer numerical control (CNC) micromilling, commonly used in the jewelry industry. Most CNC milling machines are designed to process larger objects and commonly have a precision of >25 μm (making the machining of common spiral microcoils, for example, impossible). Here, a 5-axis MiRA6 CNC milling machine, specifically designed for the jewelry industry, with a 0.3 μm precision was used to produce working planar microcoils, microstrips, and novel microsensor designs, with some tested on the NMR in less than 24 h after the start of the design process. Sample wells could be built into the microsensor and could be machined at the same time as the sensors themselves, in some cases leaving a sheet of Teflon as thin as 10 μm between the sample and the sensor. This provides the freedom to produce a wide array of designs and demonstrates 5-axis CNC micromilling as a versatile tool for the rapid prototyping of NMR microsensors. This approach allowed the experimental optimization of a prototype microstrip for the analysis of two intact adult Daphnia magna organisms. In addition, a 3D volume slotted-tube resonator was produced that allowed for 2D 1 H- 13 C NMR of D. magna neonates and exhibited 1 H sensitivity ( n LOD ω 600 = 1.49 nmol s 1/2 ) close to that of double strip lines, which themselves offer the best compromise between concentration and mass sensitivity published to date.

Prophylactic use of probiotics decreases the incidence of necrotizing enterocolitis (NEC) in premature infants. However, there are ongoing concerns related to the routine use of probiotics including inconsistent literature regarding optimal dose and strain, lack of regulatory standards in production and reports regarding potential side effects. There is limited data regarding the incidence of probiotic bacteremia and its impact on relevant clinical outcomes in the premature population. We report the first case of Bifidobacterium longum bacteremia in our center since the routine introduction of probiotics. The neonate had NEC with perforation on day of life 7, which likely led to translocation of the probiotic strain to the blood stream. The neonate did not have any hemodynamic instability and the repeat blood culture was negative after starting antibiotic therapy. We also conducted a literature review and found 13 other cases of probiotic bacteremia in premature or very low birth weight neonates. Although the incidence of probiotic bacteremia is low, it can impact several clinical outcomes including prolonged exposure to antibiotics, removal of central lines and additional laboratory testing such as lumbar puncture. There has been no mortality attributable to probiotic bacteremia and there is no data regarding long term neurodevelopmental outcomes., Competing Interests: Declaration of competing interest The authors do not have any conflict of interest to report., (Copyright © 2020 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Coagulase-negative staphylococci (CoNS) frequently causes late-onset sepsis in preterm infants. Vancomycin is the first-line therapy, but the emergence of reduced vancomycin-susceptibility strains has resulted in linezolid use, of which long-term safety in preterm infants is unknown., Objective: Evaluate the association between linezolid exposure and neurodevelopmental impairment (NDI) or death at 18-21 months of corrected age, in preterm infants with CoNS sepsis., Methods: Multicentric retrospective cohort study comparing long-term outcomes of preterm infants exposed to linezolid versus other antistaphylococcal antimicrobials. We included infants ≤28 weeks' gestational age (GA), with CoNS sepsis, admitted between January 2011 and June 2015 in 3 level-3 Canadian NICUs. Primary outcome was a composite of death or significant NDI (sNDI) at 18-21 months of corrected age. Secondary outcomes included NDI and individual components of the primary outcome. We assessed the relationship between linezolid exposure and outcomes using a multivariable logistic regression., Results: Of 274 infants included, 67 (24.4%) were exposed to linezolid. Median GA was 26 weeks and clinical characteristics were similar between groups. There was no difference in composite outcome of death or sNDI among the infants of both groups, but significantly more death by 18-21 months in the linezolid group (29.9% vs. 17.6%; P = 0.01)., Conclusions: Linezolid exposure was not associated with composite outcome of death or sNDI at 18-21 months. The association between linezolid and death may be due to indication bias. Further studies are warranted.

Background: Our objective was to evaluate the appropriateness of antibiotic prescriptions in the neonatal intensive care unit using standardized criteria and determine the effects of an antimicrobial stewardship program (ASP) on patterns of antibiotic usage., Methods: A retrospective audit of antibiotic use from July 2010 to June 2013 was conducted, focusing on prescriptions of vancomycin, cefotaxime, meropenem and linezolid for >3 calendar-days. We evaluated the appropriateness of each course of antibiotic treatment based on the Centers for Disease Control and Prevention 12-Step Guidelines to Prevent Antimicrobial Resistance (steps 4, 6 and 9). An ASP was introduced in August 2014, and the same audit criteria were applied to review antimicrobial use in the subsequent 12 months., Results: In the pre-ASP era, 26.3%, 12.1%, 11.4% and 0% of meropenem, cefotaxime, vancomycin and linezolid courses, respectively, were inappropriate. The most common instance of inappropriate utilization included failure to use narrow-spectrum antimicrobials when appropriate. After the introduction of ASP program, 22.2%, 7.5%, 5.4% and 0% of meropenem, cefotaxime, vancomycin and linezolid courses, respectively, were inappropriate. The numbers of inappropriate antibiotic-days/1000 days of therapy with meropenem, cefotaxime and vancomycin changed from 1.89 to 1.96 [rate ratio (RR), 1.04 (0.70-1.52)], 3.56 to 1.73 [RR, 0.49 (0.33-0.71)] and 2.70 to 1.01 [RR, 0.37 (0.22-0.60)], respectively. In subgroup analysis, very low birth weight infants (birth weight, <1500 g) showed no improvement in the rates of inappropriate antibiotic prescriptions., Conclusions: In this study, we found that ASP initiatives can be applied in neonatal populations to reduce inappropriate antimicrobial prescriptions, though a different approach may be needed among very low birth weight infants.

The transient receptor potential (TRP) family is a large family of widely expressed ion channels that regulate the intracellular concentration of ions and metals and respond to various chemical and physical stimuli. TRP subfamily M member 7 (TRPM7) is unusual in that it contains both an ion channel and a kinase domain. TRPM7 is a divalent cation channel with preference for Ca 2+ and Mg 2+ It is required for the survival of DT40 cells, a B cell line; however, deletion of TRPM7 in T cells does not impair their development. We found that expression of TRPM7 was required for B cell development in mice. Mice that lacked TRPM7 in B cells failed to generate peripheral B cells because of a developmental block at the pro-B cell stage. The loss of TRPM7 kinase activity alone did not affect the proportion of peripheral mature B cells or the development of B cells in the bone marrow. However, supplementation with a high concentration of extracellular Mg 2+ partially rescued the development of TRPM7-deficient B cells in vitro. Thus, our findings identify a critical role for TRPM7 ion channel activity in B cell development., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Levetiracetam is a broad-spectrum antiepileptic drug (AED) with a unique mechanism of action. Older AEDs can cause serious short- and long-term adverse drug reactions and complications, rendering them undesirable to use in pediatric patients. Characteristics that make levetiracetam a near-ideal AED include its broad spectrum of activity, good tolerability profile, and minimal drug-drug interactions. Clinical pharmacokinetic monitoring (CPM) is often recommended in pediatric patients for certain AEDs due to large interindividual pharmacokinetic differences and unpredictable drug disposition. Our objective was to determine whether monitoring levetiracetam concentrations is warranted for pediatric patients with epilepsy, using a previously published 9-step decision-making algorithm. A literature search of the MEDLINE (1946-August 2016), EMBASE (1974-August 2016), CENTRAL, and Google Scholar databases was performed to identify relevant English-language articles and answer the questions posed in the algorithm for levetiracetam CPM in pediatric epilepsies. Additional articles were identified from a manual bibliographic review of the relevant literature. We found that levetiracetam CPM met some criteria of the algorithm: levetiracetam is an appropriate adjunctive or monotherapy for pediatric patients with either focal or generalized seizures; it is readily measurable in plasma, with an appropriate degree of sensitivity, accuracy, and precision; it exhibits interindividual variation in pharmacokinetics; often, its pharmacologic effect cannot be easily measured; and the duration of therapy is expected to be long-term. However, important criteria not met include the following: there is no clear evidence for a concentration-response relationship for efficacy or toxicity; the proposed therapeutic range of 12-46 μg/mL is not well-defined and is generally considered as wide. Thus, clinical decision making is unlikely to be affected as a result of routine levetiracetam CPM. In general, routine CPM of levetiracetam cannot be recommended for pediatric patients with epilepsy. However, CPM may be beneficial in select cases, such as patients in whom noncompliance is suspected, those who have severe overdoses, those switching between product brands, or patients for whom an 'individual therapeutic concentration' is documented. Nonetheless, in the majority of pediatric patients with epilepsy, measurement of levetiracetam concentrations is not expected to yield a therapeutic benefit. Thus, clinical assessment and judgment, without measuring drug concentrations, remain the monitoring strategy of choice for levetiracetam therapy.

Background: The progression of cystic fibrosis (CF) in patients with the rare mutation P67L was examined to determine if it induced a milder form of CF compared to the common severe ΔF508 mutation., Methods: Parameters of lung function, level of bacterial infection, nutritional status and hospitalization were used to represent CF progression. Age at diagnosis and pancreatic status were used to assess CF presentation. Analysis of data from the CF Canada Registry collected over a 15-year period included 266 ΔF508/ΔF508 homozygote patients from CF clinics in Atlantic Canada and 26 compound heterozygote patients with the rare P67L mutation from clinics across Canada., Results: Late age at diagnosis, high incidence of pancreatic sufficiency, maintained Body Mass Index (BMI) with age, delayed life-threatening bacterial infection, and fewer days in hospital were observed for P67L heterozygote patients included in this study. Although the decline of lung function did not differ from ΔF508 homozygotes, the fact that a greater proportion of P67L heterozygotes live to an older age suggests that lung function is not the primary factor determining CF progression for P67L heterozygote patients., Conclusion: The P67L mutation is associated with a mild disease, even when combined with the severe ΔF508 mutation., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Purpose: To review the evidence for efficacy and safety of lacosamide in adult patients with refractory epilepsy and refractory status epilepticus (RSE)., Methods: A systematic literature search of MEDLINE, PubMed, EMBASE, IPA, Google and Google Scholar (through October 2014) was performed., Results: Fourteen studies assessing lacosamide in 3509 refractory epilepsy patients were included. In 3 RCTs, more patients had at least 50% reduction in seizure frequency with lacosamide compared to placebo with 38.3-41.1%, 38.1-41.2%, and 18.3-25.8%, in the 400 mg/day, 600 mg/day, and placebo groups, respectively. In non-comparative trials, 18-69% of patients achieved at least 50% reduction in seizure frequency, and 1.7-26.2% achieved seizure freedom. Non-responders were documented in two trials, with 26.2-34% having no response. Thirteen studies assessing lacosamide in 390 RSE patients were included. When assessing lacosamide's ability to terminate RSE, one comparative cohort study found no improvement in SE duration or seizure control with addition of lacosamide. Another study documented no difference compared to use of phenytoin. Eleven descriptive studies using lacosamide as add-on RSE therapy revealed seizure termination rates of 0-100% (median 64.7%). In all patients receiving lacosamide, dizziness (21.8%), vision disturbances (10.4%), drowsiness (7.4%), headache (7.0%), nausea (6.5%), and coordination problems (5.8%) were the most common adverse effects., Conclusion: Based on evidence to date, adjunctive lacosamide is a treatment option to reduce seizure frequency in patients with refractory epilepsy and terminate seizures in patients with RSE. The safety information summary can be used to advise patients of potential adverse effects., (Copyright © 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Extravasation, the inadvertent leakage of intravenous (IV) medication from the vein into the surrounding tissue, is a iatrogenic cause of patient injury. Extravasation has been reported to occur in 0.1% to 6.5% of hospital inpatients. The incidence may be higher among children because they have multiple risk factors, including small and fragile veins, decreased peripheral circulation, capillary leakage, and flexible subcutaneous tissue., Objectives: To describe the incidence of extravasation at a pediatric tertiary care hospital, to identify the agents causing extravasation, and to describe the use of antidotes to manage identified cases. A secondary objective was to describe adverse drug effects associated with the antidotes administered., Methods: The medical records of pediatric patients with documented extravasation of an IV medication between January 1, 2006, and August 31, 2008, were analyzed retrospectively. The appropriateness of antidote use was determined in terms of adherence to the institution's protocol for treatment of extravasation., Results: A total of 42 patients had documented extravasation, for an overall incidence of 0.04% per patient-day. Of the 40 cases in which location was documented, 12 (30%) occurred on the general pediatric wards, 10 (25%) on the surgical ward, 9 (22%) in the neonatal intensive care unit, 5 (12%) in the pediatric intensive care unit, 3 (8%) in day care, and 1 (2%) in the emergency department. The most common medications involved were fluids for IV administration (18 [43%]), potassium chloride (11 [26%]), antibiotics (8 [19%]), total parenteral nutrition (8 [19%]), calcium chloride (2 [5%]), and epinephrine (2 [5%]). Multiple drugs were involved in some cases of extravasation. The decision to administer an antidote and the choice of antidote (if required) were appropriate in 50% of the cases. No adverse drug effects were reported with use of antidotes., Conclusions: The incidence of extravasation was low. The medications most commonly involved were similar to those reported in the literature. Antidotes were well tolerated but were appropriately used in only half of the events. Prospective trials are needed to determine the clinical severity of injury and to assess the effectiveness and safety of antidotes.

Beryllium (Be) is still not well understood from a toxicological point of view, and studies that involve the determination of different Be compounds species in tissues need to be conducted. In this paper we describe the development and validation of reliable methods for the detection of ultra-trace levels of Be in various biological matrices. Blood and tissues (liver, lung, spleen, and kidney) were used in this study. The samples were digested with a mixture of nitric and perchloric acids for Be and BeAl and an addition of sulfuric acid was made for BeO. The solutions were analyzed by inductively coupled plasma mass spectrometry with (6)Li as internal standard. The detection limits are in the order of 0.02 ng/g for tissue and 0.03 ng/mL for blood, and were compared to existing reference methods. To our knowledge, this is the first study that assesses dissolution of the different Be compounds in biological matrices, while also undergoing a rigorous optimization and complete validation. This method has proven that it is reliable, among the most sensitive available in the literature, and that it can be used in trace toxicological studies for Be.

This study aimed to determine the toxicity and toxicokinetic of three Be chemical species A total of 120 mice (four groups of 30) were nose-only exposed. The first group was used as a control while the three others were exposed to 250 microg m(-3) of fine particles of three different Be species (Be metal, Be-F; Be oxide, BeO-F; Be aluminium, BeAl-F). Exposure lasted over three consecutive weeks, five days per week and 6 h per day. Blood and several tissues were collected one week after exposure. Urines were collected before the beginning of exposure, at the end of every week of exposure and one week after exposure. Results showed that urine concentrations were different from one Be species to another and that excretion continued after the end of exposure. Except for BeO-F, where Be urine concentrations were stable during the three weeks of exposure, concentrations of Be-F and BeAl-F reached a peak after the first week. According to particle size, BeO-F obtained the highest theoretical pulmonary deposition rate, which partially led to the highest Be lung concentration. This group also presented the lowest urine concentration but that did not lead to more severe lung inflammation. Moreover, even if BeAl-F obtained the lowest percentage theoretical pulmonary deposition, it showed the highest Be urinary concentration, the lowest Be lung concentration and the lowest lung toxicity. In this specific case, a high Be concentration in urine did not reflect a high exposure or a severe toxic effect., (Copyright (c) 2010 John Wiley & Sons, Ltd.)

Recent advances in power spectral analysis of electroencephalography (EEG) signals and brain-computer interface (BCI) technology may significantly contribute to the development of psychoneurotherapies. The goal of this study was to measure the effect of a psychoneurotherapy on brain source generators of abnormal EEG activity in individuals with major depressive disorder (MDD). Thirty participants with unipolar MDD were recruited in the community. The proposed psychoneurotherapy was developed based on the relationship between the localization of abnormal EEG activity and depressive symptomatology. Brain electromagnetic abnormalities in MDD were identified with low resolution brain electromagnetic tomography (LORETA) and a normative EEG database. Localization of brain changes after treatment was assessed through the standardized version of LORETA (sLORETA). Before treatment, excessive high-beta (18-30 Hz) activity was noted in several brain regions located in the fronto-temporal regions. After treatment, only participants who successfully normalized EEG activity in cortico-limbic/paralimbic regions could be considered in clinical remission. In these regions, significant correlations were found between the percentage of change of depressive symptoms and the percentage of reduction in high-beta activity. These results suggest that the normalization of high-beta activity in cortico-limbic/paralimbic regions can be associated with a significant reduction of depressive symptoms.

Aim: To measure brain activity in near-death experiencers during a meditative state., Methods: In two separate experiments, brain activity was measured with functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) during a Meditation condition and a Control condition. In the Meditation condition, participants were asked to mentally visualize and emotionally connect with the "being of light" allegedly encountered during their "near-death experience". In the Control condition, participants were instructed to mentally visualize the light emitted by a lamp., Results: In the fMRI experiment, significant loci of activation were found during the Meditation condition (compared to the Control condition) in the right brainstem, right lateral orbitofrontal cortex, right medial prefrontal cortex, right superior parietal lobule, left superior occipital gyrus, left anterior temporal pole, left inferior temporal gyrus, left anterior insula, left parahippocampal gyrus and left substantia nigra. In the EEG experiment, electrode sites showed greater theta power in the Meditation condition relative to the Control condition at FP1, F7, F3, T5, P3, O1, FP2, F4, F8, P4, Fz, Cz and Pz. In addition, higher alpha power was detected at FP1, F7, T3 and FP2, whereas higher gamma power was found at FP2, F7, T4 and T5., Conclusions: The results indicate that the meditative state was associated with marked hemodynamic and neuroelectric changes in brain regions known to be involved either in positive emotions, visual mental imagery, attention or spiritual experiences.

Functional neuroimaging studies have shown that romantic love and maternal love are mediated by regions specific to each, as well as overlapping regions in the brain's reward system. Nothing is known yet regarding the neural underpinnings of unconditional love. The main goal of this functional magnetic resonance imaging study was to identify the brain regions supporting this form of love. Participants were scanned during a control condition and an experimental condition. In the control condition, participants were instructed to simply look at a series of pictures depicting individuals with intellectual disabilities. In the experimental condition, participants were instructed to feel unconditional love towards the individuals depicted in a series of similar pictures. Significant loci of activation were found, in the experimental condition compared with the control condition, in the middle insula, superior parietal lobule, right periaqueductal gray, right globus pallidus (medial), right caudate nucleus (dorsal head), left ventral tegmental area and left rostro-dorsal anterior cingulate cortex. These results suggest that unconditional love is mediated by a distinct neural network relative to that mediating other emotions. This network contains cerebral structures known to be involved in romantic love or maternal love. Some of these structures represent key components of the brain's reward system.

Mystical experiences relate to a fundamental dimension of human existence. These experiences, which are characterized by a sense of union with God, are commonly reported across all cultures. To date, no electroencephalography (EEG) study has been conducted to identify the neuroelectrical correlates of such experiences. The main objective of this study was to measure EEG spectral power and coherence in 14 Carmelite nuns during a mystical experience. EEG activity was recorded from 19 scalp locations during a resting state, a control condition and a mystical condition. In the mystical condition compared to control condition, electrode sites showed greater theta power at F3, C3, P3, Fz, Cz and Pz, and greater gamma1 power was detected at T4 and P4. Higher delta/beta ratio, theta/alpha ratio and theta/beta ratio were found for several electrode sites. In addition, FP1-C3 pair of electrodes displayed greater coherence for theta band while F4-P4, F4-T6, F8-T6 and C4-P4 pairs of electrodes showed greater coherence for alpha band. These results indicate that mystical experiences are mediated by marked changes in EEG power and coherence. These changes implicate several cortical areas of the brain in both hemispheres.

Background: Little is known about the specific contribution of serotonin (5-HT) to the neurobiology of emotion and mood in healthy people. In an exploratory study, we sought to investigate the effect of rapid and sustained changes of emotional state on the trapping of 11C-labelled alpha-methyl-L-tryptophan (11C-alphaMtrp) used as a proxy of 5-HT synthesis, using positron emission tomography (PET)., Method: In a within-subject repeated-measure design, participants recalled autobiographical memories to self-induce sadness, happiness and a neutral emotional state during scanning to measure brain trapping of 11C-alphaMtrp. Three separate scan acquisitions, counterbalanced for order across subjects, took place at the McConnell Brain Imaging Center, Montréal., Results: Whole brain analysis revealed positive and negative correlations between experienced levels of emotions and 11C-alphaMtrp trapping in the right anterior cingulate cortex., Conclusion: These findings point to a mechanism whereby state-related changes in a proxy of 5-HT synthesis underscore aspects of the self-regulation of normal mood.

The main goal of this functional magnetic resonance imaging (fMRI) study was to identify the neural correlates of a mystical experience. The brain activity of Carmelite nuns was measured while they were subjectively in a state of union with God. This state was associated with significant loci of activation in the right medial orbitofrontal cortex, right middle temporal cortex, right inferior and superior parietal lobules, right caudate, left medial prefrontal cortex, left anterior cingulate cortex, left inferior parietal lobule, left insula, left caudate, and left brainstem. Other loci of activation were seen in the extra-striate visual cortex. These results suggest that mystical experiences are mediated by several brain regions and systems.

An inability to self-regulate negative emotions appears to play a pivotal role in the genesis of major depressive disorder. This inability may be related to a dysfunction of the neural circuitry underlying emotional self-regulation. This functional magnetic resonance imaging study was conducted to test this hypothesis. Depressed individuals and controls were scanned while they attempted to voluntarily down-regulate sad feelings. The degree of difficulty experienced during down-regulation of sadness was higher in depressed individuals. Furthermore, there was greater activation in the right dorsal anterior cingulate cortex, right anterior temporal pole, right amygdala, and right insula in depressed individuals. These results suggest that emotional dysregulation in major depressive disorder is related to a disturbance in the neural circuitry of emotional self-regulation.

Low serotonin neurotransmission is thought to increase vulnerability to suicidal behavior. To test this hypothesis, we measured brain regional serotonin synthesis, as indexed by PET and alpha-[(11)C]methyl-L-tryptophan trapping, in 10 patients who had made a high-lethality suicide attempt and 16 healthy controls. Compared to healthy controls, suicide attempters had reduced normalized alpha-[(11)C]methyl-L-tryptophan trapping in orbital and ventromedial prefrontal cortex. alpha-[(11)C]Methyl-L-tryptophan trapping in these regions correlated negatively with suicide intent. Low serotonin synthesis in the prefrontal cortex might lower the threshold for suicidal behavior.

The question of whether distinct or similar neural substrates underlie primary emotions has not been resolved yet. To address this issue, we used fMRI to scan professional actors during self-induced states of sadness and happiness. Results demonstrated that, relative to an emotionally Neutral state, both the Sad and the Happy states were associated with significant loci of activation, bilaterally, in the orbitofrontal cortex, and in the left medial prefrontal cortex, left ventrolateral prefrontal cortex, left anterior temporal pole, and right pons. These loci of activation were localized distinctly within these regions, that is, in different sub-regions. These results suggest that sadness and happiness may be associated with similar brain regions but distinct sub-regions and neural circuits.

Background: The ability to voluntarily self-regulate negative emotion is essential to a healthy psyche. Indeed, a chronic incapacity to suppress negative emotion might be a key factor in the genesis of depression and anxiety. Regarding the neural underpinnings of emotional self-regulation, a recent functional neuroimaging study carried out by our group has revealed that the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex are involved in voluntary suppression of sexual arousal. As few things are known, still, with respect to the neural substrate underlying volitional self-regulation of basic emotions, here we used functional magnetic resonance imaging to identify the neural circuitry associated with the voluntary suppression of sadness., Methods: Twenty healthy female subjects were scanned during a Sad condition and a Suppression condition. In the Sad condition, subjects were instructed to react normally to sad film excerpts whereas, in the Suppression condition, they were asked to voluntarily suppress any emotional reaction in response to comparable stimuli., Results: Transient sadness was associated with significant loci of activation in the anterior temporal pole and the midbrain, bilaterally, as well as in the left amygdala, left insula, and right ventrolateral prefrontal cortex (VLPFC) (Brodmann area [BA] 47). Correlational analyses carried out between self-report ratings of sadness and regional blood oxygen level dependent (BOLD) signal changes revealed the existence of positive correlations in the right VLPFC (BA 47), bilaterally, as well as in the left insula and the affective division of the left anterior cingulate gyrus (BA 24/32). In the Suppression condition, significant loci of activation were noted in the right DLPFC (BA 9) and the right orbitofrontal cortex (OFC) (BA 11), and positive correlations were found between the self-report ratings of sadness and BOLD signal changes in the right OFC (BA 11) and right DLPFC (BA 9)., Conclusions: These results confirm the key role played by the DLPFC in emotional self-regulation. They also indicate that the right DLPFC and right OFC are components of a neural circuit implicated in voluntary suppression of sadness.