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To investigate the diagnosis at enrollment in the Child Health British Columbia Hip Surveillance Program for Children with Cerebral Palsy (CP) and review the etiologies of children enrolled without a CP diagnosis.Data from 959 children (543 males, 416 females; mean [SD] age at enrollment 6 years 8 months [4 years 2 months]) enrolled in the program between September 2015 and December 2019 were retrospectively reviewed. Enrollment diagnosis, Gross Motor Function Classification System level, migration percentage, and age at enrollment were included. Chart reviews were completed to confirm diagnoses for all children. Etiologies were compared to a list of conditions that are included and excluded from CP registries.Diagnosis at enrollment was CP for 612 (64%), possible CP for 120 (13%), and 'other' for 220 (23%). No diagnosis was provided for seven (1%). CP was confirmed for 700 (73%), including 106 (11.1%) enrolled as 'possible CP' or 'other'; 56 (5.8%) did not have CP due to progressive conditions. Migration percentage was similar across all groups at enrollment.One in four children were enrolled in hip surveillance without a diagnosis of CP or possible CP. Encouraging participation in hip surveillance when children meet the clinical criteria for CP but do not have a confirmed CP diagnosis can improve access to care.

Emerging evidence suggests that physical activity may be associated with improved sleep in autistic children. We aimed to determine whether physical activity associated with sufficient sleep duration in children and whether this association was modified by reported autism spectrum disorder (ASD) status. We analyzed existing data of children 6–17 years old whose caregivers completed the 2018 National Survey of Children’s Health (nonautistic N = 20,845; ASD N = 681). Logistic regression determined whether physical activity (days active in the past week) associated with sufficient sleep duration. Physical activity-by-ASD interactions were included to determine whether the association differed for autistic children. Physical activity-by-ASD-by-sex and physical activity-by-ASD-by-age-group interactions were also modeled. Physical activity was associated with increased odds of sufficient sleep duration (e.g. 0 days vs 4–6 days: odds ratio (OR) = 1.85; 95% confidence interval (CI): 1.48–2.32). We did not observe an overall statistically significant interaction between physical activity and reported ASD status; however, the positive association between physical activity and sufficient sleep duration was weaker in autistic children, especially those with more severe ASD, female autistic children, and autistic children ages 6–12 years old. In conclusion, physical activity is a promising approach to improve sufficient sleep duration but with nuanced findings in autistic children. Lay abstract Higher levels of physical activity may be associated with improved sleep in children, but this relationship is still being determined, especially in autistic children. In this study, we used existing data from the 2018 National Survey of Children’s Health. Caregivers of children 6–17 years old, including caregivers of autistic children, completed a questionnaire that included questions about physical activity (days active in the past week) and sleep duration. We then determined if children were obtaining the recommended hours of sleep for their age (i.e. sufficient sleep). We found that higher physical activity levels were associated with sufficient sleep duration, but this finding was weaker in autistic children. In particular, this association was not observed in autistic children with more severe autism spectrum disorder, female autistic children, and autistic children 6–12 years old. In conclusion, physical activity is a promising approach to help children obtain sufficient sleep duration. However, more personalized approaches to improving sleep may be needed for certain groups of autistic children.

Autistic children and adults often have sleep disturbances, which may affect their and their family's quality of life. Yet, the relationship between sleep-wake patterns and autism spectrum traits is understudied. Identifying such relationships could lead to future research elucidating common mechanistic underpinnings. Thus, we aimed to determine whether sleep-wake patterns, specifically related to sleep, physical activity, and the daily sleep-wake rhythm (i.e., circadian rhythm), are associated with autism spectrum-related traits. Accelerometer-derived sleep-wake parameters were estimated in individuals with autistic spectrum traits and their family members (N = 267). We evaluated autism spectrum traits using the Social Responsiveness Scale (SRS) to assess the presence and severity of social impairment and the Behavior Rating Inventory of Executive Function (BRIEF) to assess executive function. The linear multivariate regression analysis (using SOLAR-Eclipse) showed that in adults, increased core autism spectrum traits and executive dysfunction were associated with disruption of several sleep-wake parameters, particularly related to the daily sleep-wake rhythm, and that executive dysfunction was associated with disrupted sleep quality and level of physical activity. We highlight the interplay between daytime function and disrupted sleep-wake patterns, specifically related to the daily sleep-wake rhythm, that could guide future research into common mechanisms. LAY SUMMARY: Autistic children and adults often report sleep disturbances. To dissect the relationship between a range of autism spectrum traits and sleep-wake patterns, we assessed social interaction and executive function in participants who also wore actimetry watches on their wrists to assess their sleep-wake patterns. We found that increased impairments in social and executive function occurred with increased sleep-wake disturbances, particularly those related to the circadian rhythm, suggesting that these perturbations/disruptions in the sleep-wake cycle could be connected to autism spectrum traits.

Colorectal cancer (CRC) is a major cause of morbidity and mortality in the United States. Tumor-stromal metabolic crosstalk in the tumor microenvironment promotes CRC development and progression, but exactly how stromal cells, in particular cancer-associated fibroblasts (CAFs), affect the metabolism of tumor cells remains unknown. Here we take a data-driven approach to investigate the metabolic interactions between CRC cells and CAFs, integrating constraint-based modeling and metabolomic profiling. Using metabolomics data, we perform unsteady-state parsimonious flux balance analysis to infer flux distributions for central carbon metabolism in CRC cells treated with or without CAF-conditioned media. We find that CAFs reprogram CRC metabolism through stimulation of glycolysis, the oxidative arm of the pentose phosphate pathway (PPP), and glutaminolysis as well as inhibition of the tricarboxylic acid cycle. To identify potential therapeutic targets, we simulate enzyme knockouts and find that inhibiting the hexokinase and glucose-6-phosphate dehydrogenase reactions exploits the CAF-induced dependence of CRC cells on glycolysis and oxidative PPP. Our work gives mechanistic insights into the metabolic interactions between CRC cells and CAFs and provides a framework for testing hypotheses towards CRC-targeted therapies.

Background Surgical counting is a complex and safety-critical task that requires sustained attention by multiple members of the surgical team in order to prevent the occurrence of an unintentionally retained foreign object. Interruptions and distractions in the operating room are common and can negatively affect task performance. However, the prevalence and sources of interruptions and distractions during safety-critical tasks, such as surgical counting, have not previously been quantified. An understanding of the characteristics of these events could be used to inform targeted improvements to patient safety. Methods Observations were conducted of surgical procedures in order to quantify and describe interruptions and distractions during surgical counting activities. Analysis was separated into phases: the initial count, additions to the surgical field, removals from the surgical field, and closure counts. Results Thirty-six surgical procedures were observed. Interruptions occurred in 10.0% of initial counts, 15.4% of additions, 23.5% of removals, and 33.3% of closure counts observed. The source of 80.4% of interruptions was a surgeon, usually asking the scrub nurse for an item. Distractions were present in 46.7% of initial counts, 38.5% of additions, 41.2% of removals, and 40.9% of closure counts observed. Common sources of distraction included music, conversations, people entering and exiting the theater, and ringing phones. Conclusion Interruptions and distractions are common during surgical counts and can significantly affect patient safety by jeopardizing the accuracy of the count. A number of suggestions are provided that could reduce interruptions and distractions and their consequences.

CONTEXT: Sleep is critical for optimal childhood metabolic health and neurodevelopment. However, there is limited knowledge regarding childhood sex differences in sleep, including children with neurodevelopmental disorders, and the impact of such differences on metabolic health. OBJECTIVE: To evaluate if sex differences in childhood sleep exist and if sleep associates with metabolic health outcomes equally by sex. Using autism spectrum disorder (ASD) as a case study, we also examine sleep sex differences in children with a neurodevelopmental disorder. METHODS: A narrative review explored the literature focusing on sex differences in childhood sleep. RESULTS: Sex differences in sleep were not detected among pre-adolescents. However, female adolescents were more likely to report impaired sleep than males. Childhood obesity is more common in males. Shorter sleep duration may be associated with obesity in male pre-adolescents/adolescents; although findings are mixed. ASD is male-predominant; yet, there was an indication that pre-adolescent female children with ASD had more impaired sleep. CONCLUSION: Sex differences in sleep appear to emerge in adolescence with more impaired sleep in females. This trend was also observed among pre-adolescent female children with ASD. Further research is needed on sex differences in childhood sleep and metabolic health and underlying mechanisms driving these differences.

Introduction Pharmacy education has evolved from focusing on knowledge alone to highlighting personal and professional growth. Providing a standardized process for tracking, mentoring, and guiding students in professionalism and other soft skills may help achieve compliance with the current Center for the Advancement of Pharmacy Education Educational Outcomes and Accreditation Council for Pharmacy Education Standards 2016. Commentary Becoming a pharmacist requires more than demonstrating proficiency in tasks and responsibilities associated with pharmacy practice. Exhibiting strong professional behavior and soft skills are important for the clinical practice environment. These behaviors are more difficult to measure due to the broad definition of professionalism. In the academic setting, it is important to identify students struggling in this area. Implications Promotion of professional behavior and soft skills development is a responsibility of higher education; however, it is difficult to assess. Development and implementation of an effective tracking and monitoring system for professionalism lapses will aid in identifying students struggling with professional behavior and offer mentoring opportunities for student personal growth and professional development.

Tobacco-derived pyridyloxobutyl (POB) DNA adducts are unique due to the large size and flexibility of the alkyl chain connecting the pyridyl ring to the nucleobase. Recent experimental work suggests that the O4-4-(3-pyridyl)-4-oxobut-1-yl-T (O4-POB-T) lesion can undergo both nonmutagenic (dATP) and mutagenic (dGTP) insertion by the translesion synthesis (TLS) polymerase (pol) η in human cells. Interestingly, the mutagenic rate for O4-POB-T replication is reduced compared to that for the smaller O4-methylthymine (O4-Me-T) lesion, and O4-POB-T yields a different mutagenic profile than the O2-POB-T variant (dTTP insertion). The present work uses a combination of density functional theory calculations and molecular dynamics simulations to probe the impact of the size and flexibility of O4-POB-T on pol η replication outcomes. Due to changes in the Watson-Crick binding face upon damage of canonical T, O4-POB-T does not form favorable hydrogen-bonding interactions with A. Nevertheless, dATP is positioned for insertion in the pol η active site by a water chain to the template strand, which suggests a pol η replication pathway similar to that for abasic sites. Although a favorable O4-POB-T:G mispair forms in the pol η active site and DNA duplexes, the inherent dynamical nature of O4-POB-T periodically disrupts interstrand hydrogen bonding that would otherwise facilitate dGTP insertion and stabilize damaged DNA duplexes. In addition to explaining the origin of the experimentally reported pol η outcomes associated with O4-POB-T replication, comparison to structural data for the O4-Me-T and O2-POB-T adducts highlights an emerging common pathway for the nonmutagenic replication of thymine alkylated lesions by pol η, yet underscores the broader impacts of bulky moiety size, flexibility, and position on the associated mutagenic outcomes.

Intravenous thrombolysis with alteplase bolus followed by infusion is a global standard of care for patients with acute ischaemic stroke. We aimed to determine whether tenecteplase given as a single bolus might increase reperfusion compared with this standard of care.In this multicentre, open-label, parallel-group, registry-linked, randomised, controlled trial (AcT), patients were enrolled from 22 primary and comprehensive stroke centres across Canada. Patients were eligible for inclusion if they were aged 18 years or older, with a diagnosis of ischaemic stroke causing disabling neurological deficit, presenting within 4·5 h of symptom onset, and eligible for thrombolysis per Canadian guidelines. Eligible patients were randomly assigned (1:1), using a previously validated minimal sufficient balance algorithm to balance allocation by site and a secure real-time web-based server, to either intravenous tenecteplase (0·25 mg/kg to a maximum of 25 mg) or alteplase (0·9 mg/kg to a maximum of 90mg; 0·09 mg/kg as a bolus and then a 60 min infusion of the remaining 0·81 mg/kg). The primary outcome was the proportion of patients who had a modified Rankin Scale (mRS) score of 0-1 at 90-120 days after treatment, assessed via blinded review in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment who did not withdraw consent). Non-inferiority was met if the lower 95% CI of the difference in the proportion of patients who met the primary outcome between the tenecteplase and alteplase groups was more than -5%. Safety was assessed in all patients who received any of either thrombolytic agent and who were reported as treated. The trial is registered with ClinicalTrials.gov, NCT03889249, and is closed to accrual.Between Dec 10, 2019, and Jan 25, 2022, 1600 patients were enrolled and randomly assigned to tenecteplase (n=816) or alteplase (n=784), of whom 1577 were included in the ITT population (n=806 tenecteplase; n=771 alteplase). The median age was 74 years (IQR 63-83), 755 (47·9%) of 1577 patients were female and 822 (52·1%) were male. As of data cutoff (Jan 21, 2022), 296 (36·9%) of 802 patients in the tenecteplase group and 266 (34·8%) of 765 in the alteplase group had an mRS score of 0-1 at 90-120 days (unadjusted risk difference 2·1% [95% CI - 2·6 to 6·9], meeting the prespecified non-inferiority threshold). In safety analyses, 27 (3·4%) of 800 patients in the tenecteplase group and 24 (3·2%) of 763 in the alteplase group had 24 h symptomatic intracerebral haemorrhage and 122 (15·3%) of 796 and 117 (15·4%) of 763 died within 90 days of starting treatment INTERPRETATION: Intravenous tenecteplase (0·25 mg/kg) is a reasonable alternative to alteplase for all patients presenting with acute ischaemic stroke who meet standard criteria for thrombolysis.Canadian Institutes of Health Research, Alberta Strategy for Patient Oriented Research Support Unit.

Measurement of migration percentage (MP) is fundamental to successful hip surveillance for children with cerebral palsy (CP). In British Columbia, Canada, children enrolled in the province's hip surveillance program get radiographs at the province's tertiary care pediatric hospital or their local community hospital. This study aimed to review the radiology reporting of images completed as part of hip surveillance.Pelvis radiographs completed between September 2015 and December 2019 of 960 children enrolled in the province's hip surveillance program were included. MP values measured by the program coordinator and corresponding value measured by the facility's radiologist, when present, were retrieved. Agreement in MP between the program coordinator and the radiologist was measured using Bland-Altman plots and intraclass correlation coefficients. Radiology reports for images completed at community facilities that prompted a referral to a pediatric orthopaedic surgeon, when reviewed by the hip surveillance team, were further reviewed for qualitative comments.In total, 1849 radiographs were reviewed with 69.3% (1282) completed at the pediatric hospital and 30.7% (567) at 64 different hospitals or clinics. MP was reported for 20.6% (264/1282) of radiographs completed at the pediatric hospital and 3.0% (17/567) of the radiographs completed at community hospitals. Bland-Altman plot analyses found a MP mean difference of 1.2% (95% confidence interval=0.6%-1.8%) between the program coordinator and all radiologist reports with an intraclass correlation coefficient of 0.88 (95% confidence interval=0.86-0.90). There were 47 radiographs completed at community hospitals that resulted in a referral to a pediatric orthopaedic surgeon after review by the hip surveillance team. Eleven of these reports stated normal or unremarkable findings.Radiologic reporting of images completed for hip surveillance for children with CP was inadequate to allow for the detection of hip displacement. Reporting of MP was rare, particularly in community hospitals. If radiology reporting will be utilized for hip surveillance in children with CP, education of radiologists is required.

Background: We recently introduced the myocardial-ischemic-injury-index (MI3), a machine learning algorithm that predicts the likelihood of myocardial infarction in patients with suspected acute coronary syndrome. Whether this algorithm performs well in routine clinical practice or predicts subsequent events is unknown.Methods: MI3 was validated in a prespecified exploratory analysis from a multi-centre randomised trial that included consecutive patients with suspected acute coronary syndrome undergoing serial high-sensitivity cardiac troponin I measurement. Patients with ST-segment elevation myocardial infarction were excluded. MI3 incorporates age, sex, and two troponin measurements to compute a value (0-100) reflecting an individual’s likelihood of myocardial infarction during the index visit and estimates diagnostic performance metrics at the computed score. Model performance for an index diagnosis of myocardial infarction, and for subsequent myocardial infarction or cardiovascular death at one year was determined using previously defined low- and high-probability MI3 thresholds (1·6 and 49·7, respectively). Findings: In total, 20,761 patients (64±16 years, 46% women) were included of whom 3,272 (15·8%) had myocardial infarction. MI3 had an area under the receiver-operating-characteristic curve of 0·949 (95% confidence interval 0·946-0·952) identifying 12,983 (62·5%) patients as low-probability (sensitivity 99·3% [99·0-99·6%], negative predictive value 99·8% [99·8-99·9%]), and 2,961 (14·3%) as high-probability (specificity 95·0% [94·6-95·3%], positive predictive value 70·4% [68·7-72·0%]). At one year, subsequent myocardial infarction or cardiovascular death occurred more often in high-probability compared to low-probability patients (17·6% [520/2,961] versus 1·5% [197/12,983], PInterpretation: In consecutive patients undergoing serial cardiac troponin measurement for suspected acute coronary syndrome, the MI3 algorithm accurately estimates the likelihood of myocardial infarction and predicts subsequent adverse cardiovascular events.

Inhalational exposures are a known cause of interstitial lung disease (ILD), but little is understood about their prevalence across ILD subtypes and their relationship with pulmonary function and survival.Patients with fibrotic ILD were identified from the multicentre Canadian Registry for Pulmonary Fibrosis. Patients completed questionnaires regarding ILD-related occupational and environmental exposures. The relationship between exposures and the outcomes of baseline age, gender, family history, pulmonary function and survival was analysed using linear and logistic regression models, linear mixed-effect regression models and survival analysis using multivariable Cox proportional hazards along with the log-rank test.There were 3820 patients included in this study, with 2385 (62%) having ILD-related inhalational exposure. Exposed patients were younger, particularly in the idiopathic pulmonary fibrosis subgroup. Inhalational exposure was associated with male gender (adjusted OR 1.46, 95% CI 1.28-1.68, p 0.001) and family history of pulmonary fibrosis (adjusted OR 1.73, 95% CI 1.40-2.15, p 0.001). Patients with any inhalational exposure had improved transplant-free survival (hazard ratio 0.81, 95% CI 0.71-0.92, p = 0.001); this effect persisted across diagnostic subtypes. The relationship between exposures and annual change in forced vital capacity varied by ILD subtype.Patients with fibrotic ILD report high prevalence of inhalational exposures across ILD subtypes. These exposures were associated with younger age at diagnosis, male gender and family history of pulmonary fibrosis. Identification of an inhalational exposure was associated with a survival benefit. These findings suggest that inhaled exposures may impact clinical outcomes in patients with ILD, and future work should characterize the mechanisms underlying these relationships.

BACKGROUND: Low airway surface pH is associated with many airway diseases, impairs antimicrobial host defense, and worsens airway inflammation. Inhaled Optate is designed to safely raise airway surface pH and is well tolerated in humans. Raising intracellular pH partially prevents activation of SARS-CoV-2 in primary normal human airway epithelial (NHAE) cells, decreasing viral replication by several mechanisms. METHODS: We grew primary NHAE cells from healthy subjects, infected them with SARS-CoV-2 (isolate USA-WA1/2020), and used clinical Optate at concentrations used in humans in vivo to determine whether Optate would prevent viral infection and replication. Cells were pretreated with Optate or placebo prior to infection (multiplicity of infection = 1), and viral replication was determined with plaque assay and nucleocapsid (N) protein levels. Healthy human subjects also inhaled Optate as part of a Phase 2a safety trial. RESULTS: Optate almost completely prevented viral replication at each time point between 24 h and 120 h, relative to placebo, on both plaque assay and N protein expression (P < .001). Mechanistically, Optate inhibited expression of major endosomal trafficking genes and raised NHAE intracellular pH. Optate had no effect on NHAE cell viability at any time point. Inhaled Optate was well tolerated in 10 normal subjects, with no change in lung function, vital signs, or oxygenation. CONCLUSIONS: Inhaled Optate may be well suited for a clinical trial in patients with pulmonary SARS-CoV-2 infection. However, it is vitally important for patient safety that formulations designed for inhalation with regard to pH, isotonicity, and osmolality be used. An inhalational treatment that safely prevents SARS-CoV-2 viral replication could be helpful for treating patients with pulmonary SARS-CoV-2 infection.

Background Angiogenesis plays an important role in the survival of tissues, as blood vessels provide oxygen and nutrients required by the resident cells. Thus, targeting angiogenesis is a prominent strategy in many different settings, including both tissue engineering and cancer treatment. However, not all of the approaches that modulate angiogenesis lead to successful outcomes. Angiogenesis-based therapies primarily target pro-angiogenic factors such as vascular endothelial growth factor-A (VEGF) or fibroblast growth factor (FGF) in isolation, and there is a limited understanding of how these promoters combine together to stimulate angiogenesis. Targeting one pathway could be insufficient, as alternative pathways may compensate, diminishing the overall effect of the treatment strategy. Methods To gain mechanistic insight and identify novel therapeutic strategies, we have developed a detailed mathematical model to quantitatively characterize the crosstalk of FGF and VEGF intracellular signaling. The model focuses on FGF- and VEGF-induced mitogen-activated protein kinase (MAPK) signaling to promote cell proliferation and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway, which promotes cell survival and migration. We fit the model to published experimental datasets that measure phosphorylated extracellular regulated kinase (pERK) and Akt (pAkt) upon FGF or VEGF stimulation. We validate the model with separate sets of data. Results We apply the trained and validated mathematical model to characterize the dynamics of pERK and pAkt in response to the mono- and co-stimulation by FGF and VEGF. The model predicts that for certain ranges of ligand concentrations, the maximum pERK level is more responsive to changes in ligand concentration compared to the maximum pAkt level. Also, the combination of FGF and VEGF indicates a greater effect in increasing the maximum pERK compared to the summation of individual effects, which is not seen for maximum pAkt levels. In addition, our model identifies the influential species and kinetic parameters that specifically modulate the pERK and pAkt responses, which represent potential targets for angiogenesis-based therapies. Conclusions Overall, the model predicts the combination effects of FGF and VEGF stimulation on ERK and Akt quantitatively and provides a framework to mechanistically explain experimental results and guide experimental design. Thus, this model can be utilized to study the effects of pro- and anti-angiogenic therapies that particularly target ERK and/or Akt activation upon stimulation with FGF and VEGF.

Purpose The bone-conduction device attached to a percutaneous screw (BCD) is an important treatment option for individuals with severe-to-profound unilateral hearing loss (UHL). Clinicians may use subjective questionnaires and speech-in-noise measures to evaluate BCD use in this patient population; however, the translation of these metrics to real-world aided performance is unclear. The purpose of this study was twofold: first, to measure speech-in-noise performance in BCD users with severe-to-profound UHL in a simulated real-world environment, relative to individuals with normal hearing bilaterally; second, to determine if BCD users' subjective reports of aided performance relate to simulated real-world performance. Method A between-subjects design with two groups was conducted with 14 adults with severe-to-profound UHL (BCD group) and 10 age-matched participants with normal hearing bilaterally (control group). Speech-in-noise tests were administered in an eight-speaker R-Space simulating a real-world environment. To further explore speech-in-noise evaluation methods for this population, testing was also completed in a clinically common two-speaker array. The effects of various microphone settings on performance were explored for BCD users. Subjective performance was measured with the Abbreviated Profile of Hearing Aid Benefit (APHAB; Cox & Alexander, 1995) and the Speech, Spatial and Qualities of Hearing Scale (Gatehouse & Noble, 2004). Statistical analyses to explore relationships between variables included repeated-measures analysis of variance, regression analyses, independent-samples t tests, nonparametric Mann–Whitney tests, and correlations. Results In the simulated real-world environment, BCD group participants struggled with speech-in-noise understanding compared to control group participants. BCD benefit was observed for all microphone settings when speech stimuli were presented to the side with the BCD. When adaptive directional or fixed directional microphone settings were used, a relationship was noted between simulated real-world speech-in-noise performance for speech stimuli presented to the side with the BCD and subjective reports on the Background Noise subscale of the APHAB. Conclusions The Background Noise subscale of the APHAB may help estimate real-world speech-in-noise performance for BCD users with severe-to-profound UHL for signals of interest presented to the implanted side, specifically when adaptive or fixed directional microphone settings are used. This subscale may provide an efficient and accessible alternative to assessing real-world speech-in-noise performance in lieu of less clinically available measurement tools, such as an R-Space.

Natural killer (NK) cells are part of the innate immune system and are capable of killing diseased cells. As a result, NK cells are being used for adoptive cell therapies for cancer patients. The activation of NK cell stimulatory receptors leads to a cascade of intracellular phosphorylation reactions, which activates key signaling species that facilitate the secretion of cytolytic molecules required for cell killing. Strategies that maximize the activation of such intracellular species can increase the likelihood of NK cell activation upon contact with a cancer cell, and thereby improve efficacy of NK cell-based therapies. However, due to the complexity of intracellular signaling, it is difficult to deduce a priori which strategies can enhance species activation. Therefore, we constructed a mechanistic model of the CD16, 2B4 and NKG2D signaling pathways in NK cells to simulate strategies that enhance signaling. The model predictions were fit to published data and validated with a separate dataset. Model simulations demonstrate strong network activation when the CD16 pathway is stimulated. The magnitude of species activation is most sensitive to the receptor concentration and the rate at which the receptor is deactivated. Co-stimulation of CD16 and NKG2D in silico required fewer ligands to achieve half-maximal activation than other combinations, suggesting co-stimulating these pathways is most effective in activating the species. We applied the model to predict the effects of perturbing the signaling network and found two strategies that can potently enhance network activation. When the availability of ligands is low, it is more influential to engineer NK cell receptors that are resistant to proteolytic cleavage. In contrast, for high ligand concentrations, inhibiting phosphatase activity leads to more activation. The work presented here establishes a framework for understanding the complex, nonlinear aspects of NK cell signaling and provides detailed strategies for enhancing NK cell activation.

Patients with diabetes are unable to produce a sufficient amount of insulin to properly regulate their blood glucose levels. One potential method of treating diabetes is to increase the number of insulin-secreting beta cells in the pancreas to enhance insulin secretion. It is known that during pregnancy, pancreatic beta cells proliferate in response to the pregnancy hormone, prolactin (PRL). Leveraging this proliferative response to PRL may be a strategy to restore endogenous insulin production for patients with diabetes. To investigate this potential treatment, we previously developed a computational model to represent the PRL-mediated JAK–STAT signaling pathway in pancreatic beta cells. Here, we applied the model to identify the importance of particular signaling proteins in shaping the response of a population of beta cells. We simulated a population of 10 000 heterogeneous cells with varying initial protein concentrations responding to PRL stimulation. We used partial least squares regression to analyze the significance and role of each of the varied protein concentrations in producing the response of the cell. Our regression models predict that the concentrations of the cytosolic and nuclear phosphatases strongly influence the response of the cell. The model also predicts that increasing PRL receptor strengthens negative feedback mediated by the inhibitor suppressor of cytokine signaling. These findings reveal biological targets that can potentially be used to modulate the proliferation of pancreatic beta cells to enhance insulin secretion and beta cell regeneration in the context of diabetes.

Supplemental Digital Content is available in the text., Background: High-sensitivity cardiac troponin assays enable myocardial infarction to be ruled out earlier, but the safety and efficacy of this approach is uncertain. We investigated whether an early rule-out pathway is safe and effective for patients with suspected acute coronary syndrome. Methods: We performed a stepped-wedge cluster randomized controlled trial in the emergency departments of 7 acute care hospitals in Scotland. Consecutive patients presenting with suspected acute coronary syndrome between December 2014 and December 2016 were included. Sites were randomized to implement an early rule-out pathway where myocardial infarction was excluded if high-sensitivity cardiac troponin I concentrations were

Background and purpose Objective structured clinical examinations (OSCEs) are an assessment solution that can be adapted in multiple ways within the doctor of pharmacy (PharmD) curriculum to assess clinical and communication skills and to improve teaching and learning across the curriculum. Educational activity and setting The University of Florida College of Pharmacy formed an OSCE Assessment Committee, wrote blueprints for the OSCEs aligned with Entrustable Professional Activities (EPAs), and delivered OSCEs in the first and third professional years of the PharmD program. Findings Overall, students performed well on both the first year OSCE and third year OSCE (96 to 97% pass rate on first attempt). Summary OSCEs provide a number of benefits to students, faculty, and preceptors. Students are afforded the opportunity to demonstrate the knowledge and skills they have acquired during pharmacy school. Likewise, faculty are able to determine if the skills they are teaching are being retained by students. Faculty are also able to assess if students are ready for pharmacy practice rotations. OSCEs also identify areas within the curriculum which may need reinforcement or review. In order for OSCEs to provide benefit to students and to the college, thought should be given as to what skills OSCEs will assess, how they will be developed and administered, and how they will be graded and used to determine progression through the curriculum.

5-Methylcytosine (5mC) in DNA CpG islands is an important epigenetic biomarker for mammalian gene regulation. It is oxidized to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) by the ten-eleven translocation (TET) family enzymes, which are α-ketoglutarate (α-KG)/Fe(II)-dependent dioxygenases. In this work, we demonstrate that the epigenetic marker 5mC is modified to 5hmC, 5fC, and 5caC in vitro by another class of α-KG/Fe(II)-dependent proteins—the DNA repair enzymes in the AlkB family, which include ALKBH2, ALKBH3 in huamn and AlkB in Escherichia coli. Theoretical calculations indicate that these enzymes may bind 5mC in the syn-conformation, placing the methyl group comparable to 3-methylcytosine, the prototypic substrate of AlkB. This is the first demonstration of the AlkB proteins to oxidize a methyl group attached to carbon, instead of nitrogen, on a DNA base. These observations suggest a broader role in epigenetics for these DNA repair proteins.

T cells in the immune system are activated by binding to foreign peptides (from an external pathogen) or mutant peptide (derived from endogenous proteins) displayed on the surface of a diseased cell. This triggers a series of intracellular signaling pathways, which ultimately dictate the response of the T cell. The insights from computational models have greatly improved our understanding of the mechanisms that control T-cell activation. In this review, we focus on the use of ordinary differential equation–based mechanistic models to study T-cell activation. We highlight several examples that demonstrate the models’ utility in answering specific questions related to T-cell activation signaling, from antigen discrimination to the feedback mechanisms that initiate transcription factor activation. In addition, we describe other modeling approaches that can be combined with mechanistic models to bridge time scales and better understand how intracellular signaling events, which occur on the order of seconds to minutes, influence phenotypic responses of T-cell activation, which occur on the order of hours to days. Overall, through concrete examples, we emphasize how computational modeling can be used to enable the rational design and optimization of immunotherapies.

Human exposure to aromatic amines (AAs) can result in carcinogenic DNA adducts. To complement previous work geared toward understanding the mutagenicity of AA-derived adducts, which has almost exclusively studied (monoadducted) DNA containing a single lesion, the present work provides the first in-depth comparison of the structure of monoadducted and diadducted DNA duplexes. Specifically, molecular dynamics (MD) simulations were initially performed on DNA containing the nonmutagenic single-ringed

Our nationwide network of BME women faculty collectively argue that racial funding disparity by the National Institutes of Health (NIH) remains the most insidious barrier to success of Black faculty in our profession. We thus refocus attention on this critical barrier and suggest solutions on how it can be dismantled.

Background: Pulmonary fibrosis (PF) is associated with reduction in vital capacity (VC) and increase in expiratory flow rates, including peak expiratory flow (PEF). Full pulmonary function testing and computed tomography chest scans are limited resources in some geographic areas and a simple and sensitive screening test would be of value. We hypothesized that increase in the ratio of % predicted PEF over % predicted VC (%PEF/%VC), from spirometry alone might be sensitive to screen for pulmonary fibrosis. Methods: The %PEF/%VC from 1,000 consecutive spirometric flow volume curves was nearly normally distributed: 7.5% (approximately 1.5 standard deviations) had a ratio ≥ 1.4. We evaluated the sensitivity and specificity of this cut point for a diagnosis of PF in a retrospective chart review of 391 patients with good quality spirometry and respirologists’ confirmed diagnoses. Results: Of the 391 patients analyzed, 98 had PF, 79 were normal, 70 had a combined obstructive and restrictive processes, 57 had obstructive lung disease, 61 had extra-parenchymal restriction and 26 had non-fibrotic interstitial lung disease. A %PEF/%VC ≥ 1.4 was only 54.1% sensitive in predicting PF, however it had a specificity of 94.9%. There was a 95.1% specificity for ruling in intra-parenchymal opposed to extra-parenchymal restriction. Conclusion: A %PEF/%VC ≥ 1.4 was not sensitive enough to screen for PF but did demonstrate high specificity and thus may be helpful in identifying intraparenchymal restriction.

Evolving in sync with the computation revolution over the past 30 years, computational biology has emerged as a mature scientific field. While the field has made major contributions toward improving scientific knowledge and human health, individual computational biology practitioners at various institutions often languish in career development. As optimistic biologists passionate about the future of our field, we propose solutions for both eager and reluctant individual scientists, institutions, publishers, funding agencies, and educators to fully embrace computational biology. We believe that in order to pave the way for the next generation of discoveries, we need to improve recognition for computational biologists and better align pathways of career success with pathways of scientific progress. With 10 outlined steps, we call on all adjacent fields to move away from the traditional individual, single-discipline investigator research model and embrace multidisciplinary, data-driven, team science., Do you want to attract computational biologists to your project or to your department? Despite the major contributions of computational biology, those attempting to bridge the interdisciplinary gap often languish in career advancement, publication, and grant review. Here, sixteen computational biologists around the globe present "A field guide to cultivating computational biology," focusing on solutions.

Within the tumor microenvironment, macrophages exist in an immunosuppressive state, preventing T cells from eliminating the tumor. Due to this, research is focusing on immunotherapies that specifically target macrophages in order to reduce their immunosuppressive capabilities and promote T cell function. In this study, we develop an agent-based model consisting of the interactions between macrophages, T cells, and tumor cells to determine how the immune response changes due to three macrophage-based immunotherapeutic strategies: macrophage depletion, recruitment inhibition, and macrophage reeducation. We find that reeducation, which converts the macrophages into an immune-promoting phenotype, is the most effective strategy and that the macrophage recruitment rate and tumor proliferation rate (tumor-specific properties) have large impacts on therapy efficacy. We also employ a novel method of using a neural network to reduce the computational complexity of an intracellular signaling mechanistic model., Author summary We present a multi-scale agent-based model of macrophages and T cells within the tumor microenvironment. To increase the biological detail, we include an intracellular mechanistic model in the macrophages, employing a method of using neural networks to reduce the mechanistic model into a simple input/output model. With the mechanistic model, we are able to predict the effects of specifically inhibiting a part of the intracellular signaling pathway, as opposed to just making phenotypic predictions. Using the integrated modeling framework, we are able to predict the impacts of immunosuppressive macrophages on T cell function and predict how macrophage-based immunotherapies can reduce immunosuppression. Altogether, we present a useful framework for studying cell-cell interactions in the tumor microenvironment and the effects of immune cell-targeting therapies.

Vector-borne illnesses comprise a significant portion of human maladies, representing 17% of global infections. Transmission of vector-borne pathogens to mammals primarily occurs by hematophagous arthropods. It is speculated that blood may provide a unique environment that aids in the replication and pathogenesis of these microbes. Lipids and their derivatives are one component enriched in blood and are essential for microbial survival. For instance, the malarial parasitePlasmodium falciparumand the Lyme disease spirocheteBorrelia burgdorferi, among others, have been shown to scavenge and manipulate host lipids for structural support, metabolism, replication, immune evasion, and disease severity. In thisReview, we will explore the importance of lipid hijacking for the growth and persistence of these microbes in both mammalian hosts and arthropod vectors.

Administering objective structured clinical examinations (OSCEs) is a common approach to summative assessment of learner performance in Doctor of Pharmacy (PharmD) curricula.[1][1] The OSCE involves students rotating through multiple standardized stations designed to assess their performance of

Exposure to aristolochic acid I and II (AAI and AAII) has been implicated in aristolochic acid nephropathy and urothelial carcinoma. The toxicological effects of AAs are attributed to their ability to form aristolacatam (AL)-purine DNA adducts. Among these lesions, the AL-adenine (ALI-N

Introduction The challenging transition from learner to practicing pharmacist is frequently cited in the literature. This difficulty is due in part to a prodigious shift from utilizing class notes to assessing national guidelines. Students who create and use a pocket reference that combines their lecture material with current guidelines may become more proficient at navigating guidelines and adhering to treatment algorithms when on rotations, in residency, and as a professional. Therefore, it is important to address this identified gap of transitioning from pharmacy student to professional. Commentary Many practicing pharmacists create and use pocket references to hone their ability of extracting information and familiarize themselves with the content of each individual guideline. Students would benefit from the experience of developing their own pocket reference in regard to content development, clinical research, and guideline application. Implications Schools of pharmacy should implement a structured program for creating a personalized pocket reference that would facilitate the transition of their students to practicing professionals. Creating a customized and self-developed, tangible clinical resource will also strengthen vital skills related to clinical research, resource development, and guideline application. These skills will better prepare the student to emerge from the classroom ready to apply their knowledge.

Density functional theory (B3LYP) was used to characterize the kinetics and thermodynamics of the (nonenzymatic) deglycosylation in water for a variety of 2'-deoxycytidine (dC) and 2'-deoxyuridine (dU) nucleoside derivatives that differ in methylation and subsequent oxidation of the C5 substituent. A range of computational models are considered that combine implicit and explicit solvation of the nucleophile and nucleobase. Regardless of the model implemented, our calculations reveal that the glycosidic bond in dC is inherently more stable than that in dU. Furthermore, C5 methylation of either pyrimidine and subsequent oxidation of the methyl group yield overall small changes to the Gibbs reaction energy profiles and thereby preserve lower deglycosylation barriers for the dC compared to those for the dU nucleoside derivatives. However, hydrolytic deglycosylation becomes significantly more energetically favorable when 5-methyl-dC (5m-dC) undergoes two or three rounds of oxidation, with the Gibbs energy barrier decreasing and the reaction becoming more exergonic by up to 40 kJ/mol. In fact, two or three oxidation reactions from 5m-dC result in a deglycosylation barrier similar to that for dU, as well as those for the associated C5-methylated (2'-deoxythymidine) and oxidized (5-hydroxymethyl-dU) derivatives. These predicted trends in the inherent deglycosylation energetics in water directly correlate with the previously reported activity of thymine DNA glycosylase (TDG), which cleaves the glycosidic bond in select dC nucleosides as part of epigenetic regulation and in dU variants as part of DNA repair. Thus, our data suggests that fundamental differences in the intrinsic reactivity of the pyrimidine nucleosides help regulate the function of human enzymes that maintain cellular integrity.

Supplemental Digital Content is available in the text., Background: The introduction of more sensitive cardiac troponin assays has led to increased recognition of myocardial injury in acute illnesses other than acute coronary syndrome. The Universal Definition of Myocardial Infarction recommends high-sensitivity cardiac troponin testing and classification of patients with myocardial injury based on pathogenesis, but the clinical implications of implementing this guideline are not well understood. Methods: In a stepped-wedge cluster randomized, controlled trial, we implemented a high-sensitivity cardiac troponin assay and the recommendations of the Universal Definition in 48 282 consecutive patients with suspected acute coronary syndrome. In a prespecified secondary analysis, we compared the primary outcome of myocardial infarction or cardiovascular death and secondary outcome of noncardiovascular death at 1 year across diagnostic categories. Results: Implementation increased the diagnosis of type 1 myocardial infarction by 11% (510/4471), type 2 myocardial infarction by 22% (205/916), and acute and chronic myocardial injury by 36% (443/1233) and 43% (389/898), respectively. Compared with those without myocardial injury, the rate of the primary outcome was highest in those with type 1 myocardial infarction (cause-specific hazard ratio [HR] 5.64 [95% CI, 5.12–6.22]), but was similar across diagnostic categories, whereas noncardiovascular deaths were highest in those with acute myocardial injury (cause specific HR 2.65 [95% CI, 2.33–3.01]). Despite modest increases in antiplatelet therapy and coronary revascularization after implementation in patients with type 1 myocardial infarction, the primary outcome was unchanged (cause specific HR 1.00 [95% CI, 0.82–1.21]). Increased recognition of type 2 myocardial infarction and myocardial injury did not lead to changes in investigation, treatment or outcomes. Conclusions: Implementation of high-sensitivity cardiac troponin assays and the recommendations of the Universal Definition of Myocardial Infarction identified patients at high-risk of cardiovascular and noncardiovascular events but was not associated with consistent increases in treatment or improved outcomes. Trials of secondary prevention are urgently required to determine whether this risk is modifiable in patients without type 1 myocardial infarction. Clinical Trial Registration: https://www.clinicaltrials.gov. Unique identifier: NCT01852123.

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is a potent carcinogen found in all tobacco products that leads to a variety of DNA lesions in cells, including O6-[4-oxo-4-(3-pyridyl)butyl]guanine (POB-G) and O6-[4-hydroxy-4-(3-pyridyl)butyl]guanine (PHB-G), which differ by only a single substituent in the bulky moiety. This work uses a multiscale computational approach to shed light on the intrinsic conformational and base-pairing preferences of POB-G and PHB-G, and the corresponding properties in DNA and the polymerase η active site. Our calculations reveal that both lesions form stable pairs with C and T, with the T pairs being the least distorted relative to canonical DNA. This rationalizes the experimentally reported mutational profile for POB-G and validates our computational model. The same approach predicts that PHB-G is more mutagenic than POB-G due to a difference in the bulky moiety hydrogen-bonding pattern, which increases the stability of the PHB-G:T pair. The mutagenicity of PHB-G is likely further increased by stabilization of an intercalated DNA conformation that is associated with deletion mutations. This work thereby uncovers structural explanations for the reported mutagenicity of POB-G, provides the first clues regarding the mutagenicity of PHB-G and complements a growing body of literature highlighting that subtle chemical changes can affect the biological outcomes of DNA adducts.

Objective. To create a task force on recruitment, admission, and retention, and assess pharmacy students' opinions and perceived value of the initiatives implemented. Methods. A task force on recruitment, admission, and retention was created at the University of Florida College of Pharmacy to build relationships between the college and incoming students and improve the admissions process. Admission and retention initiatives were implemented over a three-year period. All applicants who received an offer of admission, whether they accepted or declined, were invited to complete an online survey designed to solicit feedback on the admissions and retention initiatives. Results. The response rate to the survey was 80.3% in 2016 and 85.7% in 2017. The majority of students who responded reported that the admission and retention initiatives were helpful with regard to building connections with the college of pharmacy. In the three years after the task force implemented the admissions and retention initiatives, the admission yield (total number of students who accepted admission divided by the number offered admission) increased from 72.5% in 2015 to 79.5% in 2016 and 81.9% in 2017. Conclusion. Development of a task force specifically aimed to build relationships with students accepted to the college through strategic initiatives was instrumental in increasing admission yield and reducing the number of applicants who initially accepted an offer of admission and then chose not to attend the college.

Objectives Rural primary care practitioners (PCPs) have a pivotal role to play in frontline pediatric mental health care, given limited options for referral and consultation. Yet they report a lack of adequate training and confidence to provide this care. The aim of this study was to test the effectiveness of the Practitioner Training in Child and Adolescent Psychiatry (PTCAP) program, which was designed to enhance PCPs’ pediatric mental health care confidence. The program includes brief therapeutic skills and practice guidelines PCPs can use to address both subthreshold concerns and diagnosable conditions, themselves. Methods The study design was a pilot, cluster-randomized, multicenter trial. Practices were randomly assigned to intervention ( n practices = 7; n PCPs = 42) or to wait-list control ( n practices = 6; n PCPs = 34). The intervention involved 8 hr of training in practice guidelines and brief therapeutic skills for depression, anxiety, attention deficit hyperactivity disorder, and behavioral disorders with case discussion and video examples, while the control practiced as usual. A linear random-effects model controlling for clustering and baseline was carried out on the individual-level data to examine between-group differences in the primary (i.e., confidence) and secondary (i.e., attitude and knowledge) outcomes at 1-week follow-up. Results Findings were a statistically significant difference in the primary outcomes. Compared to the control group, the intervention group indicated significantly greater confidence in managing diagnosable conditions ( d = 1.81) and general concerns ( d = 1.73), as well as in making necessary referrals ( d = 1.27) and obtaining consults ( d = 0.74). While the intervention did not significantly impact secondary outcomes (attitudes and knowledge), regression analysis indicated that the intervention may have increased confidence, in part, by ameliorating the adverse impact of negative mental health care attitudes. Conclusion PTCAP enhances PCPs’ child/youth mental health care confidence in managing both general and diagnosable concerns. However, an 8-hr session focused on applying brief therapeutic skills was insufficient to significantly change attitudes and knowledge. Formal testing of PTCAP may be warranted, perhaps using more intensive training and including outcome assessments capable of determining whether increased PCP confidence translates to more effective management and better patient outcomes.

Background The objective of this study was to use nationally-representative data on Americans greater than 50 years of age to determine the association between grip strength and inflammation as independent predictors of incident disability, chronic multimorbidity and dementia. Methods Middle age and older adults (n = 12,618) from the 2006–2008 waves of the Health and Retirement Study with 8-years of follow-up were included. Longitudinal modeling was performed to examine the association between baseline grip strength (normalized to body mass: NGS) and high sensitivity C-reactive protein (hs-CRP) (≥3.0 mg/L) with incident physical disabilities (i.e., ≥2 limitations to activities of daily living), chronic multimorbidity (≥2 of chronic conditions), and dementia. Results The odds of incident disability were 1.25 (95% CI: 1.20–1.30) and 1.31 (95% CI: 1.26–1.36) for men and women respectively, for each 0.05-unit lower NGS. The odds of incident chronic multimorbidity were 1.14 (95% CI: 1.08–1.20) and 1.14 (95% CI: 1.07–1.21) for men and women respectively for each 0.05-unit lower NGS. The odds of incident dementia were 1.10 for men (95% CI: 1.02–1.20) for each 0.05-unit lower NGS, but there was no significant association for women. Elevated hs-CRP was only associated with chronic multimorbidity among men (OR = 1.29; 95% CI: 1.00–1.73) and women (OR = 1.60; 95% CI: 1.26–2.02). Conclusions Our findings indicate a robust inverse association between NGS and disability and chronic, multimorbidity in older men and women, and dementia in men. Elevated hs-CRP was only associated with chronic multimorbidity in men and women. Healthcare providers should implement measures of grip strength in routine health assessments and discuss the potential dangers of weakness as well as interventions to improve strength with their patients.

Diverting loop ileostomies are frequently created to divert the fecal stream in an effort to protect downstream anastomoses. These are later reversed to restore intestinal continuity. The goal of this study is to evaluate risk factors for postoperative complications following diverting loop ileostomy takedown. Patients who underwent diverting loop ileostomy takedown between January 1, 2010 and April 28, 2015 were identified in the Michigan Surgical Quality Collaborative registry. Candidate covariates were identified and a hierarchical logistic regression model was used to identify risk factors for postoperative complications. 1,737 patients met the inclusion criteria. Rates of postoperative complications were generally low. Mean length of stay (LOS) was 5.6 (± 4.5) days. Outcomes of interest were the following: overall morbidity, serious morbidity, extended LOS, SSI, UTI, pneumonia, readmission, reoperation, and mortality. Risk factors for these outcomes included the following: ASA class, bleeding disorder, prolonged operative time, race, tobacco use, gender, steroid use, peripheral vascular disease, weight loss, and functional status. Diverting loop ileostomy takedown has a complication rate of approximately 20%. Higher ASA class, longer operative times, history of bleeding disorder, and functional status were identified as risk factors for most complications.

OBJECTIVE To assess the variation in hospitals' approaches to intraoperative fluid management and their association with postoperative recovery. BACKGROUND Despite increasing interest in goal-directed, restricted-volume fluid administration for major surgery, there remains little consensus on optimal strategies, due to the lack of institution-level studies of resuscitation practices. METHODS Among 64 hospitals in a state-wide surgical collaborative, we profiled fluid administration practices during 8404 intestinal resections, 22,854 hysterectomies, and 1471 abdominopelvic endovascular procedures. We computed intraoperative fluid balance, accounting for patient morphometry, crystalloid, colloid, blood products, urine, blood loss, duration, and approach. We stratified hospitals by average fluid balance quartile, and compared patterns across disciplines and associations with risk-adjusted postoperative length of stay (pLOS). RESULTS There was wide variation in fluid balance between hospitals (P < 0.001, all procedures), but significant within-hospital correlation across operations (Pearson rho: intestinal-hysterectomy = 0.50, intestinal-endovascular = 0.36, hysterectomy-endovascular = 0.54, all P < 0.05). Highest fluid balance hospitals had significantly longer adjusted pLOS than lowest balance hospitals for intestinal resection (6.5 vs 5.7 d, P < 0.001) and hysterectomy (1.9 vs 1.7 d, P < 0.001), but not endovascular (2.1 vs 2.3 d, P = 0.69). Risk-adjusted complication rates were not associated with fluid balance rankings. CONCLUSIONS Hospitals' approaches to intraoperative fluid administration vary widely, and their practice patterns are pervasive across disparate procedures. High fluid balance hospitals have 12% to 14% longer risk-adjusted pLOS for visceral abdominal surgery, independent of patient complexity and complications. These findings are consistent with evidence that isovolemic resuscitation in enhanced recovery protocols accelerates recovery of bowel function.

Objective To describe new technologies (biomarkers and tests) used to assess and monitor the severity and progression of multiple organ dysfunction syndrome in children as discussed as part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development MODS Workshop (March 26-27, 2015). Data sources Literature review, research data, and expert opinion. Study selection Not applicable. Data extraction Moderated by an experienced expert from the field, investigators developing and assessing new technologies to improve the care and understanding of critical illness presented their research and the relevant literature. Data synthesis Summary of presentations and discussion supported and supplemented by relevant literature. Conclusions There are many innovative tools and techniques with the potential application for the assessment and monitoring of severity of multiple organ dysfunction syndrome. If the reliability and added value of these candidate technologies can be established, they hold promise to enhance the understanding, monitoring, and perhaps, treatment of multiple organ dysfunction syndrome in children.

Due to the variability of protein expression, cells of the same population can exhibit different responses to stimuli. It is important to understand this heterogeneity at the individual level, as population averages mask these underlying differences. Using computational modeling, we can interrogate a system much more precisely than by using experiments alone, in order to learn how the expression of each protein affects a biological system. Here, we examine a mechanistic model of CAR T cell signaling, which connects receptor-antigen binding to MAPK activation, to determine intracellular modulations that can increase cellular response. CAR T cell cancer therapy involves removing a patient’s T cells, modifying them to express engineered receptors that can bind to tumor-associated antigens to promote cell killing, and then injecting the cells back into the patient. This population of cells, like all cell populations, would have heterogeneous protein expression, which could affect the efficacy of treatment. Thus, it is important to examine the effects of cell-to-cell heterogeneity. We first generated a dataset of simulated cell responses via Monte Carlo simulations of the mechanistic model, where the initial protein concentrations were randomly sampled. We analyzed the dataset using partial least-squares modeling to determine the relationships between protein expression and ERK phosphorylation, the output of the mechanistic model. Using this data-driven analysis, we found that only the expressions of proteins relating directly to the receptor and the MAPK cascade, the beginning and end of the network, respectively, are relevant to the cells’ response. We also found, surprisingly, that increasing the amount of receptor present can actually inhibit the cell’s ability to respond due to increasing the strength of negative feedback from phosphatases. Overall, we have combined data-driven and mechanistic modeling to generate detailed insight into CAR T cell signaling.

Background Major disparities between women and men in the diagnosis, management, and outcomes of acute coronary syndrome are well recognized. Objectives The aim of this study was to evaluate the impact of implementing a high-sensitivity cardiac troponin I assay with sex-specific diagnostic thresholds for myocardial infarction in women and men with suspected acute coronary syndrome. Methods Consecutive patients with suspected acute coronary syndrome were enrolled in a stepped-wedge, cluster-randomized controlled trial across 10 hospitals. Myocardial injury was defined as high-sensitivity cardiac troponin I concentration >99th centile of 16 ng/l in women and 34 ng/l in men. The primary outcome was recurrent myocardial infarction or cardiovascular death at 1 year. Results A total of 48,282 patients (47% women) were included. Use of the high-sensitivity cardiac troponin I assay with sex-specific thresholds increased myocardial injury in women by 42% and in men by 6%. Following implementation, women with myocardial injury remained less likely than men to undergo coronary revascularization (15% vs. 34%) and to receive dual antiplatelet (26% vs. 43%), statin (16% vs. 26%), or other preventive therapies (p, Central Illustration

Ochratoxin A (OTA) is a ubiquitous food toxin associated with chronic nephropathy in humans and renal carcinogenicity in rodents. The mutational spectra of cells exposed to OTA reveal that one-base deletions comprise the largest percentage (73%) of the total mutations that occur upon OTA exposure. To contribute toward understanding the prevalence of OTA-induced one-base deletion mutations, the present work uses molecular dynamics (MD) simulations to analyze the conformational preferences of one-base deletion duplexes containing OT-G, the major OTA adduct (addition product) at the C8-site of guanine. Specifically, the influence of OT-G in four possible ionization states and three sequence contexts (G1, G2 and G3 in the NarI (5′–G1G2CG3CC–3′), a prokaryotic mutational hotspot sequence) on the structure of the adducted DNA is investigated. Our data reveal that the damaged helices are stable in two (B-type (B) and stacked (S)) conformations that are structurally similar to those adopted by common N-linked C8-...

Whether the nom de guerre is Mathematical Oncology, Computational or Systems Biology, Theoretical Biology, Evolutionary Oncology, Bioinformatics, or simply Basic Science, there is no denying that mathematics continues to play an increasingly prominent role in cancer research. Mathematical Oncology—defined here simply as the use of mathematics in cancer research—complements and overlaps with a number of other fields that rely on mathematics as a core methodology. As a result, Mathematical Oncology has a broad scope, ranging from theoretical studies to clinical trials designed with mathematical models. This Roadmap differentiates Mathematical Oncology from related fields and demonstrates specific areas of focus within this unique field of research. The dominant theme of this Roadmap is the personalization of medicine through mathematics, modelling, and simulation. This is achieved through the use of patient-specific clinical data to: develop individualized screening strategies to detect cancer earlier; make predictions of response to therapy; design adaptive, patient-specific treatment plans to overcome therapy resistance; and establish domain-specific standards to share model predictions and to make models and simulations reproducible. The cover art for this Roadmap was chosen as an apt metaphor for the beautiful, strange, and evolving relationship between mathematics and cancer., Graphical Abstract ‘Two Beasts’ (2017) Artist: Ben Day Todd. Acrylic, gouache on canvas ’Two Beasts’ is an exploration of form and colour. By adding and subtracting paint, pushing and pulling colour, new information is found and previously unknown dialogues are recorded.

Despite remarkable stability, the phosphodiester bond of nucleic acids is hydrolytically cleaved in critical biological processes. Although this reaction is commonly accepted to take place via a two-metal-assisted mechanism, recent experimental evidence suggests that several enzymes use a single-metal ion, but the precise catalytic mechanism is unknown. In the present work, we employ a multiscale computational approach to decipher the phosphodiester cleavage mechanism for this unique pathway by focusing on the human APE1 repair enzyme, which catalyzes the incision of phosphodiester bonds adjacent to DNA lesions. To resolve ambiguity in the literature regarding the role of the single-metal (Mg(II)) center, several catalytic mechanisms were carefully examined. Our predicted preferred hydrolysis pathway proceeds in two steps via a pentacovalent phosphorane intermediate in the absence of substrate ligation to Mg(II), with a rate-limiting barrier (19.3 kcal/mol) in close agreement with experiment (18.3 kcal/mol). In this mechanism, D210 promotes catalysis by activating water for nucleophilic attack at the 5'-phosphate group with respect to the damaged site. Subsequently, a Mg(II)-bound water triggers leaving group departure by neutralizing the 3'-hydroxyl of the neighboring nucleotide. Consistent with experimental kinetic and mutational data, several other active site residues (N212, Y171, and H309) play multiple roles throughout the reaction to facilitate this challenging chemistry. In addition to revealing previously unknown mechanistic features of the APE1 catalyzed reaction, our work sets the stage for exploring the phosphodiester bond cleavage catalyzed by other single-metal-dependent enzymes, as well as different pharmaceutical and biotechnological applications.