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This paper reports the findings of a Canada based multi-institutional study designed to investigate the relationships between admissions criteria, in-program assessments, and performance on licensing exams. The study's objective is to provide valuable insights for improving educational practices across different institutions. Data were gathered from six medical schools: McMaster University, the Northern Ontario School of Medicine University, Queen's University, University of Ottawa, University of Toronto, and Western University. The dataset includes graduates who undertook the Medical Council of Canada Qualifying Examination Part 1 (MCCQE1) between 2015 and 2017. The data were categorized into five distinct sections: demographic information as well as four matrices: admissions, course performance, objective structured clinical examination (OSCE), and clerkship performance. Common and unique variables were identified through an extensive consensus-building process. Hierarchical linear regression and a manual stepwise variable selection approach were used for analysis. Analyses were performed on data set encompassing graduates of all six medical schools as well as on individual data sets from each school. For the combined data set the final model estimated 32% of the variance in performance on licensing exams, highlighting variables such as Age at Admission, Sex, Biomedical Knowledge, the first post-clerkship OSCE, and a clerkship theta score. Individual school analysis explained 41-60% of the variance in MCCQE1 outcomes, with comparable variables to the analysis from of the combined data set identified as significant independent variables. Therefore, strongly emphasising the need for variety of high-quality assessment on the educational continuum. This study underscores the importance of sharing data to enable educational insights. This study also had its challenges when it came to the access and aggregation of data. As such we advocate for the establishment of a common framework for multi-institutional educational research, facilitating studies and evaluations across diverse institutions. This study demonstrates the scientific potential of collaborative data analysis in enhancing educational outcomes. It offers a deeper understanding of the factors influencing performance on licensure exams and emphasizes the need for addressing data gaps to advance multi-institutional research for educational improvements.

ABSTRACT: Nutrition and physiological state affect hepatic metabolism. Our objective was to determine whether feeding flaxseed oil (∼50% C18:3n-3 cis), high oleic soybean oil (∼70% C18:1 cis-9), or milk fat (∼50% C16:0) alters hepatic expression of PC, PCK1, and PCK2 and the flow of carbons from propionate and pyruvate into the tricarboxylic acid (TCA) cycle in preruminating calves. Male Holstein calves (n = 40) were assigned to a diet of skim milk with either: 3% milk fat (MF; n = 8), 3% flaxseed oil (Flax; n = 8), 3% high oleic soybean oil (HOSO; n = 8), 1.5% MF + 1.5% high oleic soybean oil (MF-HOSO; n = 8), or 1.5% MF + 1.5% flaxseed oil (MF-Flax; n = 8) from d 14 to d 21 postnatal. At d 21 postnatal, a liver biopsy was taken for gene expression and metabolic flux analysis. Liver explants were incubated in [U-13C] propionate and [U-13C] pyruvate to trace carbon flux through TCA cycle intermediates or with [U-14C] lactate, [1-14C] palmitic acid, or [2-14C] propionate to quantify substrate oxidation to CO2 and acid-soluble products. Compared with other treatments, plasma C18:3n-3 cis was 10 times higher and C18:1 cis-9 was 3 times lower in both Flax (Flax and MF-Flax) treatments. PC, PCK1, and PCK2 expression and flux of [U-13C] pyruvate as well as [U-13C] propionate were not different among treatments. PC expression was negatively correlated with the enrichment of citrate M+5 and malate M+3, and PCK2 was negatively correlated with citrate M+5, suggesting that when expression of these enzymes is increased, carbon from pyruvate enters the TCA cycle via PC-mediated carboxylation, and then oxaloacetate is converted to phosphoenolpyruvate via PCK2. Acid-soluble product formation and PC expression were reduced in HOSO (MF-HOSO and HOSO) treatments compared with Flax (MF-Flax and Flax), indicating that fatty acids regulate PC expression and carbon flux, but that fatty acid flux control points are not connected to PC, PCK1, or PCK2. In conclusion, fatty acids regulate hepatic expression of PC, PCK1, and PCK2, and carbon flux, but the point of control is distinct.

Abstract Background Patients with opioid use disorder (OUD) are increasing, challenging surgeons to adjust post-operative pain management guidelines. A literature review identified limited information on how to best care for these patients. The purpose of this study was to determine surgical perioperative management of OUD, challenges, and support needed for optimal care. Methods This study utilized an anonymous voluntary survey that was distributed to members of the American College of Surgeons through the association’s electronic weekly newsletter. The survey was advertised weekly for three consecutive weeks. The survey included questions regarding surgeons’ management of perioperative pain in patients with opioid use disorder and perceived barriers in treatment. Results A total of 260 surgeons responded representing all specialties except ophthalmology. General surgery (66.5%) and plastic and reconstructive surgery (7.5%) represented the majority of responders. Ninety-five percent of surgeons reported treating a patient who used opioids in the past month and 86% encountered a patient with OUD. Nearly half (46%) reported being uncomfortable managing postoperative pain in patients with OUD. Most (67%) were not aware of any guidelines or standards pertaining to perioperative management of patients with OUD. While consultation was sought by 86% of surgeons, analyses identified lack of timely response and a lack of care coordination among specialists. Lack of knowledge and fear of harm (contributing further to addiction) were the most common themes. Conclusion Nearly half of surgeons report discomfort caring for patients with OUD with the vast majority involving a consulting service to assist with their care. Most surgeons believe that it would be helpful to have guidelines regarding the care of these patients. This provides an opportunity for increased education and training on the perioperative management of patients with OUD and further collaboration with addiction medicine, psychiatry and pain management colleagues.

Researchers have advocated for greater insight regarding the contributions of psychological resources to sports performance. The purpose of this study was to examine the contributions of self-compassion and well-being to sports performance using a golf putting task. Male golfers (N = 87, Mage = 54.94; SDage = 15.37 years) completed the Self-Compassion Scale—Athlete Version and the Warwick Edinburgh Mental Well-Being Scale immediately prior to the golf putting task which consisted of 15 consecutive putts from 7 feet on an outdoor practice green. Performance was assessed immediately following the putting task. Simple linear regression analyses showed that self-compassion did not predict ‘perceived’ (β = −0.20, p = 0.06; ƒ2 = 0.04) or ‘actual’ (β = −0.17, p = 0.11; ƒ2 = 0.03) performance. Similarly, well-being did not predict ‘perceived’ (β = −0.16, p = 0.15; ƒ2 = 0.03) or ‘actual’ performance (β = −0.01, p = 0.91; ƒ2 = 0.00). Overall, the conclusions from this study offer converging evidence that self-compassion and well-being may not impact putting performance in adult male golfers. Greater insight into whether, and if so under what conditions, self-compassion and well-being matter to sports performance warrants additional scrutiny.

Adult house flies (Musca domestica L.) inhabiting dairy farms not only are nuisance pests but also harbor and disseminate bacteria. We examined the bacterial community composition, diversity, environmental sources, and prevalence in individual adult female house flies and cattle manure samples collected monthly from Florida, North Carolina, and Tennessee dairy farms between May and August 2021. Individual house flies carried diverse bacterial communities, encompassing all bacterial taxa (100%) identified across manure samples, and additional species likely acquired from the animals. Bacterial community assemblage in house flies and manure samples within farms varied by month. Some taxa were differentially associated with either house flies (Corynebacterium, Acinetobacter, and Staphylococcus) or manure samples (Treponema, Succinivibrio, and Clostridia). House fly bacterial communities mostly contained specialist species originating from manure, with several taxa (Escherichia, Corynebacterium, Turicibacter) being potential pathogens of livestock and humans. These findings further support the role of house flies as carriers of cattle-associated bacteria, including pathogens, and their potential for disseminating these microbes among cattle and to neighboring environments. Since their bacterial communities provide a snapshot of their surrounding environment, house flies also serve as effective sentinels in xenosurveillance strategies.

Summary: Patients with the sleep disorder narcolepsy suffer from excessive daytime sleepiness, disrupted nighttime sleep, and cataplexy—the abrupt loss of postural muscle tone during wakefulness, often triggered by strong emotion. The dopamine (DA) system is implicated in both sleep-wake states and cataplexy, but little is known about the function of DA release in the striatum and sleep disorders. Recording DA release in the ventral striatum revealed orexin-independent changes across sleep-wake states as well as striking increases in DA release in the ventral, but not dorsal, striatum prior to cataplexy onset. Tonic low-frequency stimulation of ventral tegmental efferents in the ventral striatum suppressed both cataplexy and rapid eye movement (REM) sleep, while phasic high-frequency stimulation increased cataplexy propensity and decreased the latency to REM sleep. Together, our findings demonstrate a functional role of DA release in the striatum in regulating cataplexy and REM sleep.

Abstract Gliomas are incurable brain cancers with poor prognosis, with epigenetic dysregulation being a distinctive feature. 5-hydroxymethylcytosine (5-hmC), an intermediate generated in the demethylation of 5-methylcytosine, is present at reduced levels in glioma tissue compared with normal brain, and that higher levels of 5-hmC are associated with improved patient survival. DNA demethylation is enzymatically driven by the ten–eleven translocation (TET) dioxygenases that require ascorbate as an essential cofactor. There is limited data on ascorbate in gliomas and the relationship between ascorbate and 5-hmC in gliomas has never been reported. Clinical glioma samples (11 low-grade, 26 high-grade) were analysed for ascorbate, global DNA methylation and hydroxymethylation, and methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter. Low-grade gliomas contained significantly higher levels of ascorbate than high-grade gliomas (p = 0.026). Levels of 5-hmC were significantly higher in low-grade than high-grade glioma (p = 0.0013). There was a strong association between higher ascorbate and higher 5-hmC (p = 0.004). Gliomas with unmethylated and methylated MGMT promoters had similar ascorbate levels (p = 0.96). One mechanism by which epigenetic modifications could occur is through ascorbate-mediated optimisation of TET activity in gliomas. These findings open the door to clinical intervention trials in patients with glioma to provide both mechanistic information and potential avenues for adjuvant ascorbate therapy.

IntroductionThis work explores the use of an automated facial coding software - FaceReader - as an alternative and/or complementary method to manual coding.MethodsWe used videos of parents (fathers, n = 36; mothers, n = 29) taken from the Avon Longitudinal Study of Parents and Children. The videos—obtained during real-life parent-infant interactions in the home—were coded both manually (using an existing coding scheme) and by FaceReader. We established a correspondence between the manual and automated coding categories - namely Positive, Neutral, Negative, and Surprise - before contingency tables were employed to examine the software’s detection rate and quantify the agreement between manual and automated coding. By employing binary logistic regression, we examined the predictive potential of FaceReader outputs in determining manually classified facial expressions. An interaction term was used to investigate the impact of gender on our models, seeking to estimate its influence on the predictive accuracy.ResultsWe found that the automated facial detection rate was low (25.2% for fathers, 24.6% for mothers) compared to manual coding, and discuss some potential explanations for this (e.g., poor lighting and facial occlusion). Our logistic regression analyses found that Surprise and Positive expressions had strong predictive capabilities, whilst Negative expressions performed poorly. Mothers’ faces were more important for predicting Positive and Neutral expressions, whilst fathers’ faces were more important in predicting Negative and Surprise expressions.DiscussionWe discuss the implications of our findings in the context of future automated facial coding studies, and we emphasise the need to consider gender-specific influences in automated facial coding research.

Mosquitoes have a wide range of digestive enzymes that enable them to utilize requisite blood and sugar meals for survival and reproduction. Sugar meals, typically derived from plant sources, are critical to maintain energy in both male and female mosquitoes, whereas blood meals are taken only by females to complete oogenesis. Enzymes involved in sugar digestion have been the subject of study for decades but have been limited to a relatively narrow range of mosquito species. The southern house mosquito, Culex quinquefasciatus, is of public health importance and seldom considered in these types of studies outside of topics related to Bacillus sphaericus, a biocontrol agent that requires interaction with a specific gut-associated α-glucosidase. Here we sought to describe the nature of α-glucosidases and unexplored β-glucosidases that may aid Cx. quinquefasciatus larvae in acquiring nutrients from cellulosic sources in their aquatic habitats. Consistent with our hypothesis, we found both α- and β-glucosidase activity in larvae. Interestingly, β-glucosidase activity all but disappeared at the pupal stage and remained low in adults, while α-glucosidase activity remained in the pupal stage and then exceeded larval activity by approximately 1.5-fold. The expression patterns of the putative α- and β-glucosidase genes chosen did not consistently align with observed enzyme activities. When the α-glucosidase inhibitor acarbose was administered to adults, mortality was seen especially in males but also in females after two days of exposure and key energetic storage molecules, glycogen and lipids, were significantly lower than controls. In contrast, administering the β-glucosidase inhibitor conduritol β-epoxide to larvae did not produce mortality even at the highest soluble concentration. Here we provide insights into the importance of α- and β-glucosidases on the survival of Cx. quinquefasciatus in their three mobile life stages.

Abstract Objective: Vancomycin therapy is associated with an increased risk of acute kidney injury (AKI). Previous studies suggest that area under the curve (AUC) monitoring reduces the risk of AKI, but literature is lacking to support this in patients receiving longer durations of vancomycin therapy. Design: Retrospective cohort study. Method: Patients ≥18 years old, admitted between August 2015 and July 2017 or October 2017 and September 2019, and received at least 14 days of intravenous (IV) vancomycin therapy were included in the study. Our primary outcome was the incidence of AKI between trough monitoring and AUC monitoring groups using Kidney Disease Improving Global Outcomes criteria. Secondary outcomes included inpatient mortality, median inpatient length of stay, and median intensive care unit length of stay. Results: Overall, 582 patients were included in the study, with 318 patients included in the trough monitoring group and 264 included in the AUC monitoring group. The median duration of vancomycin therapy was 23 days (interquartile range, 16–39). Patients within the trough monitoring group had a higher incidence of AKI compared to the AUC monitoring group (45.6% vs 28.4%, p < 0.001). Furthermore, logistic regression analysis showed that AUC monitoring was associated with a 54% lower incidence of AKI (OR 0.46, 95% CI [0.31–0.69]). All-cause inpatient mortality was numerically higher in the trough monitoring group (12.9% vs 8.3%, p = 0.078). Conclusions: In patients who received at least 14 days of IV vancomycin therapy, AUC monitoring was associated with a lower incidence of AKI.

Updated by Edwin R. Burgess IV. Originally written by Phillip E. Kaufman and Emma N. I. Weeks, January 2016.

Given the widespread prevalence of sleep disorders and their impacts on health, it is critical that researchers continue to identify and evaluate novel avenues of treatment. Recently the melanin-concentrating hormone (MCH) system has attracted commercial and scientific interest as a potential target of pharmacotherapy for sleep disorders. This interest emerges from basic scientific research demonstrating a role for MCH in regulating sleep, and particularly REM sleep. In addition to this role in sleep regulation, the MCH system and the MCH receptor 1 (MCHR1) have been implicated in a wide variety of other physiological functions and behaviors, including feeding/metabolism, reward, anxiety, depression, and learning. The basic research literature on sleep and the MCH system, and the history of MCH drug development, provide cause for both skepticism and cautious optimism about the prospects of MCH-targeting drugs in sleep disorders. Extensive efforts have focused on developing MCHR1 antagonists for use in obesity, however, few of these drugs have advanced to clinical trials, and none have gained regulatory approval. Additional basic research will be needed to fully characterize the MCH system’s role in sleep regulation, for example, to fully differentiate between MCH-neuron and peptide/receptor-mediated functions. Additionally, a number of issues relating to drug design will continue to pose a practical challenge for novel pharmacotherapies targeting the MCH system.

Abstract Tick control tubes are a host‐targeted tick control method targeting immature Ixodes scapularis ticks attached to mice or found within mouse burrows and nests. Tick control tubes contain permethrin‐treated cotton inside cardboard tubes that mice use as nesting material. Ticks attached to mice or present in their burrows are exposed to the treated cotton. However, there have been variable results using these tubes for tick control. Rodent visitation and use of these tubes may influence their effectiveness. The aim of this study was to evaluate small mammal use of tick control tube cotton and to evaluate whether cotton size or odor attractants changed small mammal tube visitations and cotton removal. For the cotton size experiment, three different cotton sizes were used. In the odor attractant experiment, three different odor attractants were used (peanut butter, safflower oil, and vanillin) along with a commercially available tube as a control. A negative control group that had no cotton present in the tube was used for both experiments. Cotton loss was determined by weighing cotton in deployed tubes weekly, and mouse and nontarget species interactions were evaluated using camera‐trap data collected at each site. While the tested cotton sizes and odor attractants did not affect cotton use, mice did increasingly use cotton during cooler fall months, with the highest use of cotton in October and least use in July. These results suggest that mouse use of cotton was not related to cotton size or odor attractants but was dependent on season. This warrants future research on temporal small mammal use of tick control tubes to determine optimal deployment times for tick control.

Dust bags are an effective method of horn fly and louse control. However, dust bags are only effective when hung in places where cattle are forced to use them. The best locations are areas where cattle must pass once or twice a day, or every other day, for instance between mineral boxes or water and pasture. During the field tests, forced-use dust bags provided an average of 90% horn fly control. Production was increased by an average of 34% over the normal management practice. This increase in production was equivalent to 1/3 lb/animal/day. This 5-page fact sheet was written by P. E. Kaufman and E. N. I. Weeks and originally published by the UF Department of Entomology and Nematology, November 2012. This version February 2022. http://edis.ifas.ufl.edu/ig135

BackgroundThe first pass effect has been shown to improve clinical outcomes in patients with middle cerebral artery (MCA) M1 occlusions.ObjectiveTo determine the rates of first pass effect in MCA M1 occlusions and determine if proximal or distal location of occlusion modified clinical outcomes.MethodsPatients with recanalized MCA M1 occlusions who underwent endovascular thrombectomy (EVT) were reviewed to determine the effect of first pass effect (FPE) and location of occlusion on clinical outcomes. MCA occlusions were classified as proximal if they included the first two thirds of the MCA and involved the lenticulostriate vessels, or distal if they did not.ResultsWe included 261 patients of which 27% achieved FPE. Of the cohort, there were 91 (35%) proximal MCA occlusions and 170 (65%) distal MCA occlusions. Baseline demographics and treatment time metrics were comparable across both groups. There was a trend toward good clinical outcome in patients with or without a FPE (60 vs. 46%; p = 0.06), however a higher rate of excellent clinical outcome was noted in patients with FPE (46 vs. 30%; p = 0.02). When compared by location, patients with distal MCA occlusions had a higher rate of excellent clinical outcome (40 vs. 25%; p = 0.02). Multivariable analysis showed that distal MCA occlusion was the strongest predictor of an excellent clinical outcome and first pass effect.ConclusionPatients with MCA M1 occlusions with FPE have a higher rate of excellent clinical outcomes compared to those who did not. Location of MCA occlusion appears to modify rates of first pass effect and excellent clinical outcomes.

Glioblastoma multiforme is a challenging disease with limited treatment options and poor survival. Glioblastoma tumours are characterised by hypoxia that activates the hypoxia inducible factor (HIF) pathway and controls a myriad of genes that drive cancer progression. HIF transcription factors are regulated at the post-translation level via HIF-hydroxylases. These hydroxylases require oxygen and 2-oxoglutarate as substrates, and ferrous iron and ascorbate as cofactors. In this retrospective observational study, we aimed to determine whether ascorbate played a role in the hypoxic response of glioblastoma, and whether this affected patient outcome. We measured the ascorbate content and members of the HIF-pathway of clinical glioblastoma samples, and assessed their association with clinicopathological features and patient survival. In 37 samples (37 patients), median ascorbate content was 7.6 μg ascorbate/100 mg tissue, range 0.8 – 20.4 μg ascorbate/100 mg tissue. In tumours with above median ascorbate content, HIF-pathway activity as a whole was significantly suppressed (p = 0.005), and several members of the pathway showed decreased expression (carbonic anhydrase-9 and glucose transporter-1, both p < 0.01). Patients with either lower tumour HIF-pathway activity or higher tumour ascorbate content survived significantly longer than patients with higher HIF-pathway or lower ascorbate levels (p = 0.011, p = 0.043, respectively). Median survival for the low HIF-pathway score group was 362 days compared to 203 days for the high HIF-pathway score group, and median survival for the above median ascorbate group was 390 days, compared to the below median ascorbate group with 219 days. The apparent survival advantage associated with higher tumour ascorbate was more prominent for the first 8 months following surgery. These associations are promising, suggesting an important role for ascorbate-regulated HIF-pathway activity in glioblastoma that may impact on patient survival.

As resistance to the limited number of insecticides available for medical and veterinary pests becomes more widespread, there is an urgent need for new insecticides and synergists on the market. To address this need, we conducted a study to assess the toxicity of three monoterpenoids—carvone, menthone, and fenchone—in comparison to permethrin and methomyl against adults of two common pests: the yellow fever mosquito (Aedes aegypti) and the house fly (Musca domestica). We also examined the potential for these monoterpenoids to enhance the effectiveness of permethrin and methomyl when used together. Finally, we evaluated the ability of each monoterpenoid to inhibit acetylcholinesterase, comparing them to methomyl. While all three monoterpenoids performed relatively poorly as topical insecticides (LD50 > 4000 ng/mg on M. domestica; >6000 ng/mg on Ae. aegypti), they synergized both permethrin and methomyl as well as or better than piperonyl butoxide (PBO). Carvone and menthone yielded synergistic co-toxicity factors (23 and 29, respectively), which were each higher than PBO at 24 h. Currently, the mechanism of action is unknown. During preliminary testing, symptoms of acetylcholinesterase inhibition were identified, prompting further testing. Acetylcholinesterase inhibition did not appear to explain the toxic or synergistic effects of the three monoterpenoids, with IC50 values greater than 1 mM for all, compared to the 2.5 and 1.7 µM for methomyl on Aedes aegypti and Musca domestica, respectively. This study provides valuable monoterpenoid toxicity and synergism data on two pestiferous insects and highlights the potential for these chemistries in future pest control formulations.

Culex pipiens complex is an important vector of epizootic and zoonotic pathogens, including West Nile virus. Chicago, Illinois and its suburbs have suffered high incidence of human West Nile virus infections in the past. This makes abatement programs in and around the Chicago area an essential service. The control of Cx. pipiens is often complicated by rapidly evolving resistance to pyrethroids, which are the most widely used chemical class in US mosquito abatement programs. The present study assessed Sumithrin® resistance in Cx. pipiens collected from five locations around Cook County, Illinois, neighboring the city limits of Chicago. According to CDC guidelines, samples from all five locations demonstrated some resistance to Sumithrin®. When assessed with Anvil®, a formulated product made of Sumithrin® synergized with piperonyl butoxide, susceptibility was rescued in mosquitoes from three out of the five locations, suggesting involvement of mixed-function oxidases and/or carboxylesterases in Sumithrin® resistance at these locations. Not all locations had susceptibility rescued by Anvil®, but these locations had relatively low knockdown resistance allele frequencies, suggesting that mechanisms other than knockdown resistance may be involved. Enzyme activities did not reveal any marked trends that could be related back to mortality in the bottle bioassays, which highlights the need for multiple types of assays to infer enzymatic involvement in resistance. Future directions in pyrethroid resistance management in Chicago area Cx. pipiens are discussed.

We assessed breakpoint changes of 13,101 Enterobacterales and Pseudomonas aeruginosa isolates from the past decade. All β-lactams and fluoroquinolones demonstrated decreased susceptibilities following breakpoint changes. Enterobacter cloacae experienced the largest average decrease in susceptibility amongst the Enterobacterales at 5.3% and P. aeruginosa experienced an average decrease in susceptibility of 9.3%.

Abstract Objective: The objective of this study was to determine antibiotic appropriateness based on Loeb minimum criteria (LMC) in patients with and without altered mental status (AMS). Design: Retrospective, quasi-experimental study assessing pooled data from 3 periods pertaining to the implementation of a UTI management guideline. Setting: Academic medical center in Lexington, Kentucky. Patients: Adult patients aged ≥18 years with a collected urinalysis receiving antimicrobial therapy for a UTI indication. Methods: Appropriateness of UTI management was assessed in patients prior to an institutional UTI guideline, after guideline introduction and education, and after implementation of a prospective audit-and-feedback stewardship intervention from September to November 2017–2019. Patient data were pooled and compared between patients noted to have AMS versus those with classic UTI symptoms. Loeb minimum criteria were used to determine whether UTI diagnosis and treatment was warranted. Results: In total, 600 patients were included in the study. AMS was one of the most common indications for testing across the 3 periods (19%–30.5%). Among those with AMS, 25 patients (16.7%) met LMC, significantly less than the 151 points (33.6%) without AMS (P < .001). Conclusions: Patients with AMS are prescribed antibiotic therapy without symptoms indicative of UTI at a higher rate than those without AMS, according to LMC. Further antimicrobial stewardship efforts should focus on prescriber education and development of clearly defined criteria for patients with and without AMS.

Abstract Objective: The coronavirus disease 2019 (COVID-19) pandemic has required healthcare systems and hospitals to rapidly modify standard practice, including antimicrobial stewardship services. Our study examines the impact of COVID-19 on the antimicrobial stewardship pharmacist. Design: A survey was distributed nationally to all healthcare improvement company members. Participants: Pharmacist participants were mostly leaders of antimicrobial stewardship programs distributed evenly across the United States and representing urban, suburban, and rural health-system practice sites. Results: Participants reported relative increases in time spent completing tasks related to medication access and preauthorization (300%; P = .018) and administrative meeting time (34%; P = .067) during the COVID-19 pandemic compared to before the pandemic. Time spent rounding, making interventions, performing pharmacokinetic services, and medication reconciliation decreased. Conclusion: A shift away from clinical activities may negatively affect the utilization of antimicrobials.

Abstract Background The primary aim was to estimate the incidence of primary and secondary childhood glaucoma in Scotland over a 2-year period. The secondary aim was to gauge the confidence and experience of ophthalmologists in Scotland in managing these patients. Methods A 7 question electronic survey was distributed to all consultant members of the Scottish Paediatric Club and Scottish Glaucoma Club. Respondents were asked to report the number of cases and types of childhood glaucoma they had managed in the last 2 years. Respondents were also asked about experience and confidence in a range of glaucoma procedures, number of patients requiring referral to specialist centres and interest in the development of a centre of excellence in Scotland. Results The survey returned a 56% response rate, reporting 85 new cases of paediatric glaucoma in Scotland over the preceding 2 years. 11 (12.9%) had primary glaucoma and 74 (87.1%) had secondary glaucoma. The most common subtype of secondary glaucoma was uveitic glaucoma (n = 29). None of the respondents declared confidence or experience in trabeculotomy or goniotomy procedures. Eleven children required referral to a specialist unit outside Scotland. 85.7% of respondents felt Scotland would benefit from a specialist unit for paediatric glaucoma. Conclusions This survey reflects an appetite for a specialist service for paediatric glaucoma in Scotland. However, further consideration is needed to determine if there is sufficient patient load to maintain such a service.

Gliomas are a heterogeneous group of cancers that predominantly arise from glial cells in the brain, but may also arise from neural stem cells, encompassing low-grade glioma and high-grade glioblastoma. Whereas better diagnosis and new treatments have improved patient survival for many cancers, glioblastomas remain challenging with a highly unfavorable prognosis. This review discusses a super-family of enzymes, the 2-oxoglutarate dependent dioxygenase enzymes (2-OGDD) that control numerous processes including epigenetic modifications and oxygen sensing, and considers their many roles in the pathology of gliomas. We specifically describe in more detail the DNA and histone demethylases, and the hypoxia-inducible factor hydroxylases in the context of glioma, and discuss the substrate and cofactor requirements of the 2-OGDD enzymes. Better understanding of how these enzymes contribute to gliomas could lead to the development of new treatment strategies.

Citrus bioflavonoids are polyphenolic plant-derived pigments found in high levels in oranges, lemons, grapefruits and other citrus fruits. The three most abundant types of citrus bioflavonoids are hesperidin, naringenin and eriocitrin. Citrus bioflavonoids have long been known to possess powerful free radical-scavenging properties and cardioprotective effects. The study involved the analysis of 10 commercially available citrus bioflavonoid supplements from three different countries: Australia, the United States and Canada. The supplements were tested for their citrus bioflavonoid content which varied from 0.8 to 33.3% w/w. The daily bioflavonoid dose varied from 19 mg to 560 mg. Hesperidin was the major citrus bioflavonoid in nine out of ten supplements. One supplement was found to contain less than 10% of the quantity of rutin claimed to have been added. The DPP-4 inhibitory potential, compared through an estimation of rutin equivalence, ranged from 1.9 mg to 400 mg per day. This data highlights the variability between the supplements in their potential to inhibit DPP-4 for subsequent health benefits.

Summary: After fertilization, microtubule (MT) sperm asters undergo long-range migration to accurately position pronuclei. Due to the large sizes of zygotes, the forces driving aster migration are considered to be from pulling on the astral MTs by dynein, with no significant contribution from pushing forces. Here, we re-investigate the forces responsible for sperm aster centration in sea urchin zygotes. Our quantifications of aster geometry and MT density preclude a pulling mechanism. Manipulation of aster radial lengths and growth rates, combined with quantitative tracking of aster migration dynamics, indicates that aster migration is equal to the length of rear aster radii, supporting a pushing model for centration. We find that dynein inhibition causes an increase in aster migration rates. Finally, ablation of rear astral MTs halts migration, whereas front and side ablations do not. Collectively, our data indicate that a pushing mechanism can drive the migration of asters in a large cell type.

Functional paragangliomas are rare neuroendocrine tumours that secrete catecholamines and are infrequently found in the mediastinum. We report a case of a young male with symptoms of catecholamine excess and a personal and family history of the paraganglioma predisposing succinate dehydrogenase subunit B mutation. The lesion had anatomical intrapericardial juxtaposition to important cardiac anatomy and posed the significant challenge of dissection at surgery. The lesion was successfully resected via sternotomy on cardiopulmonary bypass and confirmed histopathologically as paraganglioma. Intrapericardial paraganglioma is rare and treatment is difficult and time critical considering the proximity of cardiac anatomy as well as malignant potential.

Tumour-associated macrophages (TAMs) are ubiquitously present in tumours and commonly associated with poor prognosis. In immune cells, ascorbate affects epigenetic regulation, differentiation and phenotype via its co-factor activity for the 2-oxoglutarate dependent dioxygenase enzymes. Here, we determined the effect of ascorbate on TAM development in response to tumour microenvironmental cues. Naïve murine bone marrow monocytes were cultured with Lewis Lung Carcinoma conditioned media (LLCM) or macrophage colony-stimulating factor (MCSF) to encourage the development into tumour-associated macrophages. Cells were stimulated with hypoxia (1% O2), with or without ascorbate (500 µM) supplementation. Cells and media were harvested for gene, cell surface marker and protein analyses. LLCM supported bone marrow monocyte growth with >90% of cells staining CD11b+F4/80+, indicative of monocytes/macrophages. LLCM-grown cells showed increased expression of M2-like and TAM genes compared to MCSF-grown cells, which further increased with hypoxia. In LLCM-grown cells, ascorbate supplementation was associated with increased F4/80 cell surface expression, and altered gene expression and protein secretion. Our study shows that ascorbate modifies monocyte phenotype when grown under tumour microenvironmental conditions, but this was not clearly associated with either a pro- or anti-tumour phenotype, and reflects a complex and nuanced response of macrophages to ascorbate. Overall, ascorbate supplementation clearly has molecular consequences for TAMs, but functional and clinical consequences remain unknown.

Diabetes mellitus is one of the most common chronic diseases in the United States and peripheral neuropathy (PN) affects at least 50% of diabetic patients. Medications available for patients ameliorate symptoms (pain), but do not protect against cellular damage and come with severe side effects, leading to discontinued use. Our research group uses differentiated SH-SY5Y cells treated with advanced glycation end products (AGE) as a model to mimic diabetic conditions and to study the mechanisms of oxidative stress mediated cell damage and antioxidant protection. N-acetylcysteine (NAC), a common antioxidant supplement, was previously shown by our group to fully protect against AGE-induced damage. We have also shown that 3H-1,2-dithiole-3-thione (D3T), a cruciferous vegetable constituent and potent inducer of nuclear factor (erythroid-derived 2)- like 2 (Nrf2), can significantly increase cellular GSH concentrations and protect against oxidant species–induced cell death. Paradoxically, D3T conferred no protection against AGE-induced cell death or neurite degeneration. In the present study we establish a mechanism for this paradox by showing that D3T in combination with AGE increased oxidant species generation and depleted GSH via inhibition of glutathione reductase (GR) activity and increased expression of the NADPH generating enzyme glucose-6-phosphate dehydrogenase (G6PD). Blocking NADPH generation with the G6PD inhibitor dehydroepiandrosterone was found to protect against AGE-induced oxidant species generation, loss of viability, and neurite degeneration. It further reversed the D3T potentiation effect under AGE-treated conditions. Collectively, these results suggest that strategies aimed at combating oxidative stress that rely on upregulation of the endogenous antioxidant defense system via Nrf2 may backfire and promote further damage in diabetic PN. Keywords: Peripheral neuropathy, Diabetes, D3T, NAC, Redox balance, Oxidative stress

Pseudomonas aeruginosa is a common pathogen implicated in nosocomial infections with increasing resistance to a limited arsenal of antibiotics. Monte Carlo simulation provides antimicrobial stewardship teams with an additional tool to guide empiric therapy. We modeled empiric therapies with antipseudomonal β-lactam antibiotic regimens to determine which were most likely to achieve probability of target attainment (PTA) of ≥90%. Microbiological data for P. aeruginosa was reviewed for 2012. Antibiotics modeled for intermittent and prolonged infusion were aztreonam, cefepime, meropenem, and piperacillin/tazobactam. Using minimum inhibitory concentrations (MICs) from institution-specific isolates, and pharmacokinetic and pharmacodynamic parameters from previously published studies, a 10,000-subject Monte Carlo simulation was performed for each regimen to determine PTA. MICs from 272 isolates were included in this analysis. No intermittent infusion regimens achieved PTA ≥90%. Prolonged infusions of cefepime 2000 mg Q8 h, meropenem 1000 mg Q8 h, and meropenem 2000 mg Q8 h demonstrated PTA of 93%, 92%, and 100%, respectively. Prolonged infusions of piperacillin/tazobactam 4.5 g Q6 h and aztreonam 2 g Q8 h failed to achieved PTA ≥90% but demonstrated PTA of 81% and 73%, respectively. Standard doses of β-lactam antibiotics as intermittent infusion did not achieve 90% PTA against P. aeruginosa isolated at our institution; however, some prolonged infusions were able to achieve these targets.

The zygote is defined as a diploid cell resulting from the fusion of two haploid gametes. Union of haploid male and female pronuclei in many animals occurs through rearrangements of the microtubule cytoskeleton into a radial array of microtubules known as the sperm aster. The sperm aster nucleates from paternally-derived centrioles attached to the male pronucleus after fertilization. Nematode, echinoderm, and amphibian eggs have proven as invaluable models to investigate the biophysical principles for how the sperm aster unites male and female pronuclei with precise spatial and temporal regulation. In this review, we compare these model organisms, discussing the dynamics of sperm aster formation and the different force generating mechanism for sperm aster and pronuclear migration. Finally, we provide new mechanistic insights for how sperm aster growth may influence sperm aster positioning.

The U.S. National Oceanic and Atmospheric Administration (NOAA) Coral Reef Watch (CRW) program has developed a daily global 5-km product suite based on satellite observations to monitor thermal stress on coral reefs. These products fulfill requests from coral reef managers and researchers for higher resolution products by taking advantage of new satellites, sensors and algorithms. Improvements of the 5-km products over CRW’s heritage global 50-km products are derived from: (1) the higher resolution and greater data density of NOAA’s next-generation operational daily global 5-km geo-polar blended sea surface temperature (SST) analysis; and (2) implementation of a new SST climatology derived from the Pathfinder SST climate data record. The new products increase near-shore coverage and now allow direct monitoring of 95% of coral reefs and significantly reduce data gaps caused by cloud cover. The 5-km product suite includes SST Anomaly, Coral Bleaching HotSpots, Degree Heating Weeks and Bleaching Alert Area, matching existing CRW products. When compared with the 50-km products and in situ bleaching observations for 2013–2014, the 5-km products identified known thermal stress events and matched bleaching observations. These near reef-scale products significantly advance the ability of coral reef researchers and managers to monitor coral thermal stress in near-real-time.

Polymyxins B and E (colistin) exert a bactericidal effect on the gram-negative bacterial cell wall, causing permeability changes in the cytoplasmic membrane, leading to cell death. Their use was substantially decreased in clinical practice from the 1970s to 2000s due to their significant nephrotoxicity and neurotoxicity compared to the newly introduced antibiotics. The increasing prevalence of multidrug-resistant gram-negative bacteria infections in this century has led to an upsurge in the use of these “older” drugs. Respiratory paralysis caused by neuromuscular blockage associated with the use of polymyxin B and E was reported mostly in literature published in the 1960s to 1970s with a few reports after 2000. In addition, such a reaction might be enhanced by the presence of other classes of drugs. We report a case of polymyxin B and E–induced apnea in a patient receiving “muscle relaxants.”

The experiment presented in this paper was conducted at the Holme Moss site, which is located in the southern Pennines region in Northwestern England during November–December 2006. The strong southwesterly wind during the experimental period, which enhanced the transport of urban pollutants from the conurbations of Greater Manchester and Liverpool, in addition to the seasonally increased nearby residential heating activities, made this site a receptor for pollutants from a range of sources. A factor analysis is applied to the mass spectra of organic matter (OM) measured by the Aerodyne Aerosol Mass Spectrometer (AMS) to attribute the pollutant sources. Besides the oxygenated organic aerosol (OOA), this site was found to contain a considerable fraction of primary organic aerosols (POA, mass fraction 50–70% within total mass of OM). The POA sources are attributed to be traffic emission and solid fuel burning, which are identified as hydrocarbon-like organic aerosol (HOA) and solid fuel organic aerosol (SFOA) respectively. There were strongly combined emissions of black carbon (BC) particles from both sources. The refractory BC component (rBC) was characterized by a single particle soot photometer. This site began to be influenced during the late morning by fresh traffic emissions, whereas solid fuel burning became dominant from late afternoon until night. A covariance analysis of rBC and POA was used to derive source specific emission factors of 1.61 μgHOA/μgrBC and 1.96 μgHOA/μgrBC. The absorbing properties of aerosols were characterized at multiple wavelengths (λ), and a stronger spectral dependence of absorption was observed when this site was significantly influenced by solid fuel burning. The rBC was estimated to contribute 3–16% of submicron aerosol mass. The single scattering albedo at λ = 700 nm (SSA700 nm) was significantly anti-correlated with the rBC mass fraction, but also associated with the BC mixing state. The BC incorporation/removal process therefore may play a role in modulating the radiative properties of aerosols at the site under the influence of fresh sources. Given that traffic and residential combustion of solid fuels are significant contributors of carbonaceous aerosols over Europe, these results provide important source-specific information on modeling the anthropogenic carbonaceous aerosols.

Nanoparticles of iron oxide (crystalline and amorphous), silicon oxide and magnesium oxide were investigated for their propensity to nucleate ice over the temperature range 180–250 K, using the AIDA chamber in Karlsruhe, Germany. All samples were observed to initiate ice formation via the deposition mode at threshold ice super-saturations (RHithresh) ranging from 105% to 140% for temperatures below 220 K. Approximately 10% of amorphous Fe2O3 particles (modal diameter = 30 nm) generated in situ from a photochemical aerosol reactor, led to ice nucleation at RHithresh = 140% at an initial chamber temperature of 182 K. Quantitative analysis using a singular hypothesis treatment provided a fitted function [ns(190 K)=10(3.33×sice)+8.16] for the variation in ice-active surface site density (ns:m−2) with ice saturation (sice) for Fe2O3 nanoparticles. This was implemented in an aerosol-cloud model to determine a predicted deposition (mass accommodation) coefficient for water vapour on ice of 0.1 at temperatures appropriate for the upper atmosphere. Classical nucleation theory was used to determine representative contact angles (θ) for the different particle compositions. For the in situ generated Fe2O3 particles, a slight inverse temperature dependence was observed with θ = 10.5° at 182 K, decreasing to 9.0° at 200 K (compared with 10.2° and 11.4° respectively for the SiO2 and MgO particle samples at the higher temperature). These observations indicate that such refractory nanoparticles are relatively efficient materials for the nucleation of ice under the conditions studied in the chamber which correspond to cirrus cloud formation in the upper troposphere. The results also show that Fe2O3 particles do not act as ice nuclei under conditions pertinent for tropospheric mixed phase clouds, which necessarily form above ~233 K. At the lower temperatures (

We present results of experiments at the aerosol interactions and dynamics in the atmosphere (AIDA) chamber facility looking at the freezing of water by three different types of mineral particles at temperatures between −12°C and −33°C. The three different dusts are Asia Dust-1 (AD1), Sahara Dust-2 (SD2) and Arizona test Dust (ATD). The dust samples used had particle concentrations of sizes that were log-normally distributed with mode diameters between 0.3 and 0.5 μm and standard deviations, σg, of 1.6–1.9. The results from the freezing experiments are consistent with the singular hypothesis of ice nucleation. The dusts showed different nucleation abilities, with ATD showing a rather sharp increase in ice-active surface site density at temperatures less than −24°C. AD1 was the next most efficient freezing nuclei and showed a more gradual increase in activity than the ATD sample. SD2 was the least active freezing nuclei. We used data taken with particle counting probes to derive the ice-active surface site density forming on the dust as a function of temperature for each of the three samples and polynomial curves are fitted to this data. The curve fits are then used independently within a bin microphysical model to simulate the ice formation rates from the experiments in order to test the validity of parameterising the data with smooth curves. Good agreement is found between the measurements and the model for AD1 and SD2; however, the curve for ATD does not yield results that agree well with the observations. The reason for this is that more experiments between −20 and −24°C are needed to quantify the rather sharp increase in ice-active surface site density on ATD in this temperature regime. The curves presented can be used as parameterisations in atmospheric cloud models where cooling rates of approximately 1°C min−1 or more are present to predict the concentration of ice crystals forming by the condensation-freezing mode of ice nucleation. Finally a polynomial is fitted to all three samples together in order to have a parameterisation describing the average ice-active surface site density vs. temperature for an equal mixture of the three dust samples.

Agouti-related-peptide (AgRP) neurons—interoceptive neurons in the arcuate nucleus of the hypothalamus (ARC)—are both necessary and sufficient for driving feeding behavior. To better understand the functional roles of AgRP neurons, we performed optetrode electrophysiological recordings from AgRP neurons in awake, behaving AgRP-IRES-Cre mice. In free-feeding mice, we observed a fivefold increase in AgRP neuron firing with mounting caloric deficit in afternoon vs morning recordings. In food-restricted mice, as food became available, AgRP neuron firing dropped, yet remained elevated as compared to firing in sated mice. The rapid drop in spiking activity of AgRP neurons at meal onset may reflect a termination of the drive to find food, while residual, persistent spiking may reflect a sustained drive to consume food. Moreover, nearby neurons inhibited by AgRP neuron photostimulation, likely including satiety-promoting pro-opiomelanocortin (POMC) neurons, demonstrated opposite changes in spiking. Finally, firing of ARC neurons was also rapidly modulated within seconds of individual licks for liquid food. These findings suggest novel roles for antagonistic AgRP and POMC neurons in the regulation of feeding behaviors across multiple timescales.

Chromosome 7 deletions are highly prevalent in myelodysplastic syndrome (MDS) and likely contribute to aberrant growth through haploinsufficiency. We generated mice with a heterozygous germ line deletion of a 2-Mb interval of chromosome band 5A3 syntenic to a commonly deleted segment of human 7q22 and show that mutant hematopoietic cells exhibit cardinal features of MDS. Specifically, the long-term hematopoietic stem cell (HSC) compartment is expanded in 5A3+/del mice, and the distribution of myeloid progenitors is altered. 5A3+/del HSCs are defective for lymphoid repopulating potential and show a myeloid lineage output bias. These cell autonomous abnormalities are exacerbated by physiologic aging and upon serial transplantation. The 5A3 deletion partially rescues defective repopulation in Gata2 mutant mice. 5A3+/del hematopoietic cells exhibit decreased expression of oxidative phosphorylation genes, increased levels of reactive oxygen species, and perturbed oxygen consumption. These studies provide the first functional data linking 7q22 deletions to MDS pathogenesis.

Imatinib (Gleevec/STI-571/CGP57148B, Novartis) is a small-molecule, tyrosine kinase inhibitor developed to target BCR-ABL, c-Kit, and PDGF-R. Through inhibition of these oncogenic kinases, imatinib is effective in the treatment of BCR-ABLpositive leukemia, gastrointestinal stromal tumor, and hypereosinophilic syndrome, respectively. However, clinical success of imatinib is hampered by acquired resistance that may occur through several mechanisms including kinase domain mutation, target amplification, and activation of alternate signaling pathways. Strategies to overcome resistance have included targeting BCR-ABL stability and downstream signaling pathways important for tumor growth. Additional work has shown that new BCR-ABL kinase inhibitors with increased potency or alternate conformation-binding properties can target imatinib resistance. This review focuses on the mechanisms of imatinib resistance and the strategies currently being developed to overcome clinical resistance.