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Introduction: Telehealth has emerged as an important clinical setting for managing acute respiratory tract infections (ARIs), potentially reducing emergency department and urgent care overcrowding, and reducing nosocomial transmission. Many current algorithms for ARI management incorporate information on patient vital signs. However, the accuracy of vital signs collected by patients using readily available home devices and techniques has not been studied. Methods: A cross-sectional sample of patients seen for urgent conditions at a hospital emergency and urgent care center were given instructions and low-cost, readily available devices to collect their vital signs. A trained research coordinator collected a parallel set of vital signs using standard hospital equipment, serving as the gold standard. We analyzed the performance of patient-collected vital signs compared with vital signs collected by a trained research coordinator. Results: A total of 300 patients completed the study. Patient-collected vital signs were highly specific for traditional levels of abnormalities (HR >100 beats per min, RR >24 breaths per min, temperature >100.4 degrees Fahrenheit, oxygen saturation <94 percent); however, sensitivity was poor for elevated heart rate by pulse estimation (25%) and elevated respiratory rate (60%). Heart rate and oxygen saturation by pulse oximeter and oral temperature had higher sensitivity. Conclusions: Vital signs measured and provided by patients are not uniformly accurate, particularly when using manual techniques rather than automated devices. Telehealth algorithms that rely on these values could provide incorrect triage and management advice.

Background: Promoting minorities within medical specialties has been postulated to be crucial to patient care and recruitment of diverse candidates. This concept has been suspected but not formally studied in the minority of women faculty and trainees in neurosurgery. We aimed to quantitatively investigate the postulated correlation relative to female representation in neurosurgery., Methods: Data obtained from accredited neurosurgery residency programs were reviewed. Data describing the percentage of female residents and 6 demographic and 14 program-specific variables were collected. All program websites were reviewed to assess percentages of female faculty and visible commitment to diversity in applicants, evident through communicated policies, statements, or initiatives. Included programs were defined as "low" or "high" percentage of female residents or faculty relative to the grouped median value for both categories; groups were assessed for significant differences. Percentages of female faculty and residents and program-communicated diversity initiatives were investigated for significant correlation., Results: Female faculty and diversity data were available at 117 program sites; 81 programs reported female resident percentages. Analysis revealed a significant positive correlation between female faculty and female resident percentages. Programs with higher female resident percentages had higher levels of diversity in terms of race and ethnicity. No significant correlation was found between the percentage of female faculty or residents and a communicated diversity initiative., Conclusions: This study of current female representation in neurosurgery revealed a previously undocumented positive correlation between percentages of female faculty and female trainees. These data suggest a modifiable barrier to female entry into neurosurgical residency programs., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Experts estimate virtual urgent care programs could replace approximately 20% of current emergency department visits. In the absence of widespread quality guidance to programs or quality reporting from these programs, little is known about the state of virtual urgent care quality monitoring initiatives., Objective: We sought to characterize ongoing quality monitoring initiatives among virtual urgent care programs., Approach: Semi-structured interviews of virtual health and health system leaders were conducted using a pilot-tested interview guide to assess quality metrics captured related to care effectiveness and equity as well as programs' motivations for and barriers to quality measurement. We classified quality metrics according to the National Quality Forum Telehealth Measurement Framework. We developed a codebook from interview transcripts for qualitative analysis to classify motivations for and barriers to quality measurement., Key Results: We contacted 13 individuals, and ultimately interviewed eight (response rate, 61.5%), representing eight unique virtual urgent care programs at primarily academic (6/8) and urban institutions (5/8). Most programs used quality metrics related to clinical and operational effectiveness (7/8). Only one program reported measuring a metric related to equity. Limited resources were most commonly cited by participants (6/8) as a barrier to quality monitoring., Conclusions: We identified variation in quality measurement use and content by virtual urgent care programs. With the rapid growth in this approach to care delivery, more work is needed to identify optimal quality metrics. A standardized approach to quality measurement will be key to identifying variation in care and help focus quality improvement by virtual urgent care programs., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Persons living with dementia (PLWD) have high emergency department (ED) utilization. Little is known about using telemedicine with PLWD and caregivers as an alternative to ED visits for minor acute health problems. This qualitative interview-based study elicited caregivers' perspectives about the acceptability of telemedicine for acute complaints. We performed telephone interviews with 28 caregivers of PLWD from two academic EDs, one in the Northeast and another in the South. Using a combined deductive-inductive approach, we coded interview transcripts and elucidated common themes by consensus. All caregivers reported they would need to participate in the telemedicine visit to help overcome communication and digital literacy challenges. People from racial/ethnic minority groups reported lower comfort with the virtual format. In both sites, participants expressed uncertainty about illness severity that could preclude using telemedicine for acute complaints. Overall, respondents deemed acute care telemedicine acceptable, but caregivers describe specific roles as crucial intermediaries to facilitate virtual care., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Individuals with chronic ankle instability have decreased peak torque during maximum voluntary contraction in ankle evertors/invertors, and hip abductors. However, it is unclear whether individuals with chronic ankle instability and/or copers demonstrate decreased rate of torque development in ankle evertors/invertors, and hip abductors., Methods: 54 university-aged participants (18 chronic ankle instability, 18 copers, and 18 controls) performed three maximal isometric contractions for ankle evertors and invertors, and hip abductors. Rate of torque development was defined as the linear slope of the torque-time curve during the first 200 ms of each contraction and compared between the three groups using a one-way analysis of variance (α = 0.05)., Findings: The chronic ankle instability group showed 38.1% less rate of torque development than the coper (P = 0.03 and d = 0.84) and 37.1% than the control groups (P = 0.03 and d = 1.03) in the ankle evertors. For the hip abductors, there were moderate effects between the chronic ankle instability group and the copers (P = 0.06 and d = 0.70), and control groups (P = 0.06 and d = 0.75)., Interpretations: The observed between-groups differences in rate of torque development indicate that restoring rate of torque development after lateral ankle sprain may be important to reduce risk of reinjury and development of chronic ankle instability. Clinicians should consider the rate of torque development in the ankle evertors and hip abductors during rehabilitation chronic ankle instability patients., Competing Interests: Declaration of competing interest The authors declare that there have no known competing financial interests or personal relationships that could have appeared to influence the work repeated in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Carbodiimides are electrophilic functional groups that react with select nucleophiles under mild conditions. However, their potential as platforms for postpolymerization modification has been relatively underexplored. We describe the synthesis and radical polymerization of a styrenic carbodiimide which undergoes rapid nucleophilic addition with primary and secondary alkyl amines under ambient conditions, even in the presence of other protic nucleophiles. The monomer is amenable to both free and controlled radical (co)polymerization, and we further demonstrate the utility of this approach by preparing covalent adaptable networks through guanylation of the styrenic carbodiimide with difunctional amines. These materials exhibit a variation in relaxation times according to both the guanidine structure and concentration, providing a facile means for tuning dynamic behavior.

Background: We evaluated the safety, efficacy, and acceptability of a new device designed to facilitate uterine compression in women with postpartum haemorrhage (PPH)., Methods: A prospective, phase two clinical device trial with concurrent qualitative study, conducted in a UK consultant obstetric unit. The device was used in addition to standard care in women unresponsive to initial oxytocin therapy. The primary effectiveness outcome was additional blood loss of over 1000mls, whilst safety was assessed through adverse events. Interviews assessed device feasibility and acceptability, and were analysed using framework analysis., Results: We recruited 57 women with clinical PPH after vaginal birth; 67% were primiparous and 47% had undergone operative birth. All but two (96%) had atony as a cause of the haemorrhage; in addition, 30% also had bleeding from lacerations and 11% had retained tissue. After device use, only one woman had additional blood loss over 1000mls, although 3 women (7%) needed a Bakri balloon and 14% received a blood transfusion. All but one clinician felt that the device was easy to use. Clinicians stated that the device assisted management in 85% of cases. All 56 women who responded stated that if they bled in a future birth they would want the device to be used again. There were no serious adverse events related to the device. However, 3 events were judged as 'possibly' being caused by the device - 2 minor vaginal grazes and one postnatal episiotomy infection and breakdown. Lax vaginal tissue complicated the use of the device in three women. In 47 interviews, participants, birth partners, clinician users and attending midwives viewed the device positively. Clinicians found it useful as a way of stopping blood loss and as an aid to diagnose the source of bleeding., Conclusions: The PPH Butterfly may provide a rapid, acceptable and effective treatment for postpartum haemorrhage. Clinical Trial Registration prospective with ISRCTN15452399 11/09/2017 (www.isrctn.com/ISRCTN15452399)., Competing Interests: Declaration of Competing Interest ADW and PW are co-inventors of the PPH Butterfly. The patent is held by the University of Liverpool, but ADW and PW could in future receive a share of any profits generated from commercialization. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Activation of myosin light chain kinase (MLCK) by calcium ions (Ca 2+ ) and calmodulin (CaM) plays an important role in numerous cellular functions including vascular smooth muscle contraction and cellular motility. Despite extensive biochemical analysis, aspects of the mechanism of activation remain controversial, and competing theoretical models have been proposed for the binding of Ca 2+ and CaM to MLCK. The models are analytically solvable for an equilibrium steady state and give rise to distinct predictions that hold regardless of the numerical values assigned to parameters. These predictions form the basis of a recently proposed, multi-part experimental strategy for model discrimination. Here we implement this strategy by measuring CaM-MLCK binding using an in vitro FRET system. Interpretation of binding data in light of the mathematical models suggests a partially ordered mechanism for binding CaM to MLCK. Complementary data collected using orthogonal approaches that assess CaM-MLCK binding further support this conclusion., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors.)

Background: Bone-patellar tendon-bone (BTB) and hamstring autografts are the most common grafts used for anterior cruciate ligament (ACL) reconstruction. Patient preferences should be accounted for as a part of shared decision making., Purpose/hypothesis: The purpose of this study was to perform a discrete choice experiment that evaluated patient preferences toward ACL autografts. We hypothesized that there would be no difference in patient preferences between groups., Study Design: Cross-sectional study., Methods: Patients aged 18 to 25 years who underwent shoulder arthroscopy at a single institution between 2013 and 2019 were included in the study as a proxy for healthy controls. Patients with a history of ACL tear were excluded. A discrete choice experiment was developed from a literature search and used the following data points as they pertain to BTB or hamstring autograft: risk of developing a significant complication, return-to-play rate, risk of anterior knee pain with kneeling, and risk of additional surgery due to graft failure. Included patients completed a custom survey in which they were asked to choose between "surgery A" (hamstring) and "surgery B" (BTB)., Results: A total of 107 participants were included in the analysis. Of these participants, 39 (36.5%) chose surgery A (hamstring) and 68 (63.6%) chose surgery B (BTB). When comparing the hamstring group with the BTB group, there was no significant difference in age, sex, body mass index, race, level of education, or employment status. However, 80.5% of self-reported athletes preferred BTB ( P = .008). When controlling for age, sex, and body mass index, patients in the BTB group were more likely to rate return to sport (risk ratio [RR] = 1.49 [95% CI, 1.18-1.98]; P = .001) and the risk of requiring additional surgery due to graft failure (RR = 1.26 [95% CI, 1.02-1.58]; P = .037) as highly important. Conversely, they were less likely than patients in the hamstring group to rate pain while kneeling (RR = 0.65 [95% CI, 0.98-1.05]; P < .001) and complication risk (RR = 0.75 [95% CI, 0.59-0.94]; P = .013) as important., Conclusion: The study hypothesis was rejected, as patient values did affect ACL graft choice preference. Utilizing patient-selected values in a quantifiable way can benefit the shared decision-making process before ACL reconstruction., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: F.P.T. has received consulting fees from DePuy/Medical Device Business Services and has stock/stock options in Trice Medical. S.B.C. has received research support from Arthrex and Major League Baseball, education payments from Liberty Surgical, consulting fees from Conmed Linvatec and Zimmer, speaking fees from Zimmer, and royalties from Slack Inc. K.B.F. has received education payments from Liberty Surgical; consulting fees from DePuy/Medical Device Business Services, Innocoll, and Vericel; and speaking fees and honoraria from Vericel. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2023.)

Given the significant advance of virtual care in the past year and half, it seems timely to focus on quality frameworks and how they have evolved collaboratively across health care organizations. Massachusetts General Hospital's (MGH) Center for TeleHealth and Mass General Brigham's (MGB) Virtual Care Program are committed to hosting annual symposia on key topics related to virtual care. Subject matter experts across the country, health care organizations, and academic medical centers are invited to participate. The inaugural MGH/MGB Virtual Care Symposium, which focused on rethinking curriculum, competency, and culture in the virtual care era, was held on September 2, 2020. The second MGH/MGB Virtual Care Symposium was held on November 2, 2021, and focused on virtual care quality frameworks. Resultant topics were (1) guiding principles necessary for the future of virtual care measurement; (2) best practices deployed to measure quality of virtual care and how they compare and align with in-person frameworks; (3) evolution of quality frameworks over time; (4) how increased adoption of virtual care has impacted patient access and experience and how it has been measured; (5) the pitfalls and barriers which have been encountered by organizations in developing virtual care quality frameworks; and (6) examples of how quality frameworks have been applied in various use cases. Common elements of a quality framework for virtual care programs among symposium participants included improving the patient and provider experience, a focus on achieving health equity, monitoring success rates and uptime of the technical elements of virtual care, financial stewardship, and clinical outcomes. Virtual care represents an evolution in the access to care paradigm that helps keep health care aligned with other modern industries in digital technology and systems adoption. With advances in health care delivery models, it is vitally important that the quality measurement systems be adapted to include virtual care encounters. New methods may be necessary for asynchronous transactions, but synchronous virtual visits and consults can likely be accommodated in traditional quality frameworks with minimal adjustments. Ultimately, quality frameworks for health care will adapt to hybrid in-person and virtual care practices., (© 2022 The Authors.)

Background: Despite the high prevalence of rotator cuff (RTC) tears in older adults, there is limited literature evaluating the return to recreational sport after repair. The purpose of this study was (1) to assess the patient-reported outcomes and return to sport rates following rotator cuff repair in patients aged more than 40 years with minimum 2-year follow-up; (2) to compare baseline, preoperative and postoperative outcomes, and level of play following repair of self-reported athletes with nonathletes; and (3) to compare return to sport rates in overhead athletes compared to nonoverhead athletes., Methods: Patients undergoing arthroscopic rotator cuff repair between January 2016 and January 2019 were screened for inclusion. Inclusion criteria included (1) age more than 40 years at the time of surgery, (2) arthroscopic repair of a full thickness RTC tear, and (3) preoperative American Shoulder and Elbow Surgeons score (ASES) available. Eligible patients were contacted and invited to fill out a custom return to sport and patient-reported outcome survey., Results: Overall, 375 of the 1141 eligible patients completed the survey instrument. There were 210 self-reported athletes (mean age 59.2 ± 9.55 years) and 165 nonathletes (mean age 62.0 ± 8.27 years) ( P  = .003). Of the athletes, 193 (91.9%) returned to sport. The average age of athletes was 59.4 ± 9.33 years for those who returned to sport and 57.9 ± 12.0 years for those who did not ( P  = .631). Athletes reported higher ASES scores than nonathletes both preoperatively (49.8 ± 20.3 vs. 44.8 ± 18.9, P  = .015) and postoperatively (87.6 ± 16.7 vs. 84.9 ± 17.5, P  = .036), but there was no difference in mean ASES improvement between groups (37.7 ± 23.0 vs. 40.3 ± 24.5, P  = .307). There was no difference in postoperative Single Assessment Numeric Evaluation scores when comparing self-reported athletes to nonathletes (85.4 ± 17.5 vs. 85.0 ± 18.7, P  = .836). After controlling for age, sex, body mass index, and smoking status using a multivariate analysis, there was no difference in mean ASES improvement when comparing athletes to nonathletes., Conclusion: There is a high rate of return to sport activities (> 90%) in older adult recreational athletes following arthroscopic repair of full thickness RTC tears and rates of return to sport did not significantly differ for overhead and nonoverhead athletes. Self-reported athletes were noted to have higher baseline, preoperative, and postoperative ASES scores than nonathletes, but the mean ASES improvement following repair did not significantly differ between groups., (© 2022 The Author(s).)

NRF2 is a transcription factor that controls the cellular response to various stressors, such as reactive oxygen and nitrogen species. As such, it plays a key role in the suppression of carcinogenesis, but constitutive NRF2 expression in cancer cells leads to resistance to chemotherapeutics and promotes metastasis. As a result, inhibition of the NRF2 pathway is a target for new drugs, especially for use in conjunction with established chemotherapeutic agents like carboplatin and 5-fluorouracil. A new class of NRF2 inhibitors has been discovered with substituted nicotinonitriles, such as MSU38225. In this work, the effects on NRF2 inhibition with structural changes were explored. Through these studies, we identified a few compounds with as good or better activity than the initial hit but with greatly improved solubility. The syntheses involved a variety of metal-catalyzed reactions, including titanium multicomponent coupling reactions and various Pd and Cu coupling reactions. In addition to inhibiting NRF2 activity, these new compounds inhibited the proliferation and migration of lung cancer cells in which the NRF2 pathway is constitutively activated., Competing Interests: A patent application has been submitted on the compounds in this article., (This journal is © The Royal Society of Chemistry.)

Study Objective: Emergency clinician-staffed telehealth programs seek to provide equitable, safe, efficient, effective, and patient-centered care. However, early studies show conflicting evidence on whether this aim is accomplished. Furthermore, how programs track the efficacy and safety of their programs remains largely unexplored. We sought to characterize ongoing quality monitoring among emergency clinician-staffed telehealth programs., Methods: We identified representatives at emergency clinician-staffed telehealth programs through professional networks and published literature. Qualitative interviews were conducted, assessing quality metrics captured as well as motivations for and barriers to quality measurement. We classified quality metric measurement using the National Quality Forum Telehealth Measurement Framework Domains and Subdomains. We developed a codebook from interview transcripts for qualitative analysis to classify motivations for and barriers to quality measurement., Results: We held 8 qualitative interviews with physician representatives at primarily academic (7/8) and urban institutions (5/8). Most widely used quality metrics were related to patient and care team experience (7/8) as well as to access to care (6/8) and effectiveness (6/8). Few programs (2/8) measured finance-related quality metrics. Motivations for quality measurement varied considerably. Common barriers to implementation included technology challenges, data availability, and the lack of quality metric standardization., Conclusion: We identified variation in the use and content of quality metrics across emergency clinician-staffed telehealth programs. Most commonly, programs used metrics related to clinical experience; financial metrics were rarely captured. Technology barriers to quality measurement were often cited across programs. Further work is needed to support the standardization and implementation of future quality measurement initiatives., (Copyright © 2022 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Membrane transport proteins are involved in the absorption, disposition, efficacy, and/or toxicity of many drugs. Numerous mechanisms (e.g., nuclear receptors, epigenetic gene regulation, microRNAs, alternative splicing, post-translational modifications, and trafficking) regulate transport protein levels, localization, and function. Various factors associated with disease, medications, and dietary constituents, for example, may alter the regulation and activity of transport proteins in the intestine, liver, kidneys, brain, lungs, placenta, and other important sites, such as tumor tissue. This white paper reviews key mechanisms and regulatory factors that alter the function of clinically relevant transport proteins involved in drug disposition. Current considerations with in vitro and in vivo models that are used to investigate transporter regulation are discussed, including strengths, limitations, and the inherent challenges in predicting the impact of changes due to regulation of one transporter on compensatory pathways and overall drug disposition. In addition, translation and scaling of in vitro observations to in vivo outcomes are considered. The importance of incorporating altered transporter regulation in modeling and simulation approaches to predict the clinical impact on drug disposition is also discussed. Regulation of transporters is highly complex and, therefore, identification of knowledge gaps will aid in directing future research to expand our understanding of clinically relevant molecular mechanisms of transporter regulation. This information is critical to the development of tools and approaches to improve therapeutic outcomes by predicting more accurately the impact of regulation-mediated changes in transporter function on drug disposition and response., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Option generation is a critical process in decision making, but previous studies have largely focused on choices between options given by a researcher. Consequently, how we self-generate options for behaviour remain poorly understood. Here, we investigated option generation in major depressive disorder and how dopamine might modulate this process, as well as the effects of modafinil (a putative cognitive enhancer) on option generation in healthy individuals. We first compared differences in self-generated options between healthy non-depressed adults [n = 44, age = 26.3 years (SD 5.9)] and patients with major depressive disorder [n = 54, age = 24.8 years (SD 7.4)]. In the second study, a subset of depressed individuals [n = 22, age = 25.6 years (SD 7.8)] underwent PET scans with 11C-raclopride to examine the relationships between dopamine D2/D3 receptor availability and individual differences in option generation. Finally, a randomized, double-blind, placebo-controlled, three-way crossover study of modafinil (100 mg and 200 mg), was conducted in an independent sample of healthy people [n = 19, age = 23.2 years (SD 4.8)] to compare option generation under different doses of this drug. The first study revealed that patients with major depressive disorder produced significantly fewer options [t(96) = 2.68, P = 0.009, Cohen's d = 0.54], albeit with greater uniqueness [t(96) = -2.54, P = 0.01, Cohen's d = 0.52], on the option generation task compared to healthy controls. In the second study, we found that 11C-raclopride binding potential in the putamen was negatively correlated with fluency (r = -0.69, P = 0.001) but positively associated with uniqueness (r = 0.59, P = 0.007). Hence, depressed individuals with higher densities of unoccupied putamen D2/D3 receptors in the putamen generated fewer but more unique options, whereas patients with lower D2/D3 receptor availability were likely to produce a larger number of similar options. Finally, healthy participants were less unique [F(2,36) = 3.32, P = 0.048, partial η2 = 0.16] and diverse [F(2,36) = 4.31, P = 0.021, partial η2 = 0.19] after taking 200 mg versus 100 mg and 0 mg of modafinil, while fluency increased linearly with dosage at a trend level [F(1,18) = 4.11, P = 0.058, partial η2 = 0.19]. Our results show, for the first time, that option generation is affected in clinical depression and that dopaminergic activity in the putamen of patients with major depressive disorder may play a key role in the self-generation of options. Modafinil was also found to influence option generation in healthy people by reducing the creativity of options produced., (© The Author(s) (2022). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: Competing interests: none.

Competing Interests: Competing interests: none.

Background: To compare the performance (as determined by lower extremity kinematics) of knee exercises in healthy middle-aged and older individuals immediately after instruction and one week later., Methods: This is a cross-sectional study in a laboratory setting. Nineteen healthy volunteers (age [y] 63.1 ± 8.6, mass [kg] 76.3 ± 14.7, height [m] 1.7 ± 0.1) participated in this study. High speed video and reflective markers were used to track motion during four exercises. The exercises were knee flexion, straight leg raise, and "V "in supine position, and hip abduction in side lying position. All participants received verbal and tactile cues during the training phase and the therapist observed and, if necessary, corrected the exercises. Upon return a week later the participants performed the same exercises without any further instructions. Knee and hip sagittal and rotational angles were extracted from the motion capture. A repeated measures t-test was used to compare the motions between two visits., Results: Participants demonstrated more knee flexion during straight leg raise and "V in" exercises at the 2nd visit compared to the 1st visit (both p <  0.05). During the "V out" exercise, they performed more external rotation (p <  0.05) while they showed more internal rotation during the "V in" exercise at the 2nd visit compared to the 1st visit., Conclusions: Exercise performance declined significantly in healthy middle-aged and older individuals one week after instruction. This decline occurred despite an instructional exercise sheet being given to every participant. Other approaches designed to help individuals retain the ability to perform rehabilitative exercises correctly need to be explored., (© 2022. The Author(s).)

Diffuse midline gliomas (DMGs) are invariably fatal pediatric brain tumours that are inherently resistant to conventional therapy. In recent years our understanding of the underlying molecular mechanisms of DMG tumorigenicity has resulted in the identification of novel targets and the development of a range of potential therapies, with multiple agents now being progressed to clinical translation to test their therapeutic efficacy. Here, we provide an overview of the current therapies aimed at epigenetic and mutational drivers, cellular pathway aberrations and tumor microenvironment mechanisms in DMGs in order to aid therapy development and facilitate a holistic approach to patient treatment.

Background: The Coronavirus disease (COVID-19) outbreak is putting the European National Health Systems under pressure. Interestingly, Emergency Department (ED) referrals for other reasons than COVID-19 seem to have declined steeply. In the present paper, we aimed to verify how the COVID-19 outbreak changed ED referral pattern., Methods: We retrospectively reviewed the clinical records of patients referred to the ED of a University Hospital in Northern Italy from 1 March to 13 April 2020. We compared the following data with those belonging to the same period in 2019: number of EDs accesses, rate of hospital admission, frequencies of the most common causes of ED referral, priority codes of access., Results: The number of ED referrals during the COVID-19 outbreak was markedly reduced when compared to the same period in 2019 (3059 vs. 5691; -46.3%). Conversely, the rate of hospital admission raised from 16.9% to 35.4% (P<0.0001), with a shift toward higher priority codes of ED admission. In 2020, we observed both a reduction of the number of patients referred for both traumatic (513, 16.8% vs. 1544, 27.1%; χ 2 =118.7, P<0.0001) and non-traumatic (4147 vs. 2546) conditions. Among the latter, suspected COVID-19 accounted for 1101 (43.2%) accesses., Conclusions: The COVID-19 pandemic completely changed the pattern of ED referral in Italy, with a marked reduction of the accesses to the hospitals. This could be related to a limited exposure to traumas and to a common fear of being infected during EDs in-stay. This may limit the misuse of EDs for non-urgent conditions but may also delay proper referrals for urgent conditions.

Introduction: The COVID-19 pandemic has exacerbated many social conditions associated with violence. The objective of this systematic review was to examine trends in hospital reported violent trauma associated with the pandemic., Methods: Databases were searched in using terms "trauma" or "violence" and "COVID-19," yielding 4,473 records (2,194 de-duplicated). Exclusion criteria included non-hospital based studies and studies not reporting on violent trauma. 44 studies were included in the final review., Results: Most studies reported no change in violent trauma incidence. Studies predominately assessed trends with violent trauma as a proportion of all trauma. All studies demonstrating an increase in violent trauma were located in the United States., Conclusions: A disproportionate rise in violence has been reported within the US. However, most studies examined violent trauma as a proportion of all trauma; results may reflect relative changes from lockdowns. Future studies should examine rates of violent trauma to provide additional context., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The integration of soft, stimuli-responsive materials in robotic systems is a promising approach to introduce dexterous and delicate manipulation of objects. Electrical control of mechanical response offers many benefits in robotic systems including the availability of this energy input, the associated response time, magnitude of actuation, and opportunity for self-regulation. Here, a materials chemistry is detailed to prepare liquid crystal elastomers (LCEs) with a 14:1 modulus contrast and increase in dielectric constant to enhance electromechanical deformation. The inherent modulus contrast of these LCEs (when coated with compliant electrodes) directly convert an electric field to a directional expansion of 20%. The electromechanical response of LCE actuators is observed upon application of voltage ranging from 0.5 to 6 kV. The deformation of these materials is rapid, reaching strain rates of 18% s -1 . Upon removal of the electric field, little hysteresis is observed. Patterning the spatial orientation of the nematic director of the LCEs results in a 2D-3D shape transformation to a cone 8 mm in height. Individual and sequential addressing of an array of LCE actuators is demonstrated as a haptic surface., (© 2021 Wiley-VCH GmbH.)

A pro-thrombotic milieu and a higher risk of thrombotic events were observed in patients with CoronaVirus disease-19 (COVID-19). Accordingly, recent data suggested a beneficial role of low molecular weight heparin (LMWH), but the optimal dosage of this treatment is unknown. We evaluated the association between prophylactic vs. intermediate-to-fully anticoagulant doses of enoxaparin and in-hospital adverse events in patients with COVID-19. We retrospectively included 436 consecutive patients admitted in three Italian hospitals. Outcome according to the use of prophylactic (4000 IU) vs. higher (> 4000 IU) daily dosage of enoxaparin was evaluated. The primary end-point was in-hospital death. Secondary outcome measures were in-hospital cardiovascular death, venous thromboembolism, new-onset acute respiratory distress syndrome (ARDS) and mechanical ventilation. A total of 287 patients (65.8%) were treated with the prophylactic enoxaparin regimen and 149 (34.2%) with a higher dosing regimen. The use of prophylactic enoxaparin dose was associated with a similar incidence of all-cause mortality (25.4% vs. 26.9% with the higher dose; OR at multivariable analysis, including the propensity score: 0.847, 95% CI 0.400-0.1.792; p = 0.664). In the prophylactic dose group, a significantly lower incidence of cardiovascular death (OR 0.165), venous thromboembolism (OR 0.067), new-onset ARDS (OR 0.454) and mechanical intubation (OR 0.150) was observed. In patients hospitalized for COVID-19, the use of a prophylactic dosage of enoxaparin appears to be associated with similar in-hospital overall mortality compared to higher doses. These findings require confirmation in a randomized, controlled study., (© 2021. The Author(s).)

Introduction: The clinical course of Coronavirus Disease 2019 (COVID-19) is highly heterogenous, ranging from asymptomatic to fatal forms. The identification of clinical and laboratory predictors of poor prognosis may assist clinicians in monitoring strategies and therapeutic decisions., Materials and Methods: In this study, we retrospectively assessed the prognostic value of a simple tool, the complete blood count, on a cohort of 664 patients ( F 260; 39%, median age 70 (56-81) years) hospitalized for COVID-19 in Northern Italy. We collected demographic data along with complete blood cell count; moreover, the outcome of the hospital in-stay was recorded., Results: At data cut-off, 221/664 patients (33.3%) had died and 453/664 (66.7%) had been discharged. Red cell distribution width (RDW) ( χ 2 10.4; p < 0.001), neutrophil-to-lymphocyte (NL) ratio ( χ 2 7.6; p = 0.006), and platelet count ( χ 2 5.39; p = 0.02), along with age ( χ 2 87.6; p < 0.001) and gender ( χ 2 17.3; p < 0.001), accurately predicted in-hospital mortality. Hemoglobin levels were not associated with mortality. We also identified the best cut-off for mortality prediction: a NL ratio > 4.68 was characterized by an odds ratio for in-hospital mortality (OR) = 3.40 (2.40-4.82), while the OR for a RDW > 13.7% was 4.09 (2.87-5.83); a platelet count > 166,000/ μ L was, conversely, protective (OR: 0.45 (0.32-0.63))., Conclusion: Our findings arise the opportunity of stratifying COVID-19 severity according to simple lab parameters, which may drive clinical decisions about monitoring and treatment., Competing Interests: The authors have no conflict of interest to declare., (Copyright © 2021 Mattia Bellan et al.)

Objective: The coronavirus disease 2019 pandemic has presented emergency departments (EDs) with many challenges to address the acute care needs of patients. Many EDs have leveraged telehealth to innovatively respond to these challenges. This review describes the landscape of telehealth initiatives in emergency care that have been described during the coronavirus disease 2019 pandemic., Methods: We conducted a comprehensive, systematic review of the literature using PubMed, supplemented by a review of the gray literature (ie, non-peer reviewed), with input from subject matter experts to identify telehealth initiatives in emergency care during coronavirus disease 2019. We categorized types of telehealth use based on purpose and user characteristics., Results: We included 27 papers from our review of the medical literature and another 8 sources from gray literature review. The vast majority of studies (32/35) were descriptive in nature, with the additional inclusion of 2 cohort studies and one randomized clinical trial. There were 5 categories of ED telehealth use during the pandemic: (1) pre-ED evaluation and screening, (2) within ED (including as a means of limiting staff and patient exposure and facilitating consultation with specialists), (3) post-ED discharge monitoring and treatment, (4) educating trainees and health care workers, and (5) coordinating resources and patient care., Conclusion: Telehealth has been used in a variety of manners during the coronavirus disease 2019 pandemic, enabling innovation in emergency care delivery. The findings from this study can be used by institutions to consider how telehealth may address challenges in emergency care during the coronavirus disease 2019 pandemic and beyond. Because few studies included cost data and given the variability in institutional resources, how organizations implement telehealth programs will likely vary. Future work should further explore barriers and facilitators of innovation, and the impact on care delivery and patient outcomes., Competing Interests: TAJ and KSZ conceived the study. EH aided with study design and methods. KSZ, EH, LUP, JS, LHS and AM provided guidance on review methods and scope. TAJ and KSZ conducted the review. All authors reviewed findings, contributed to manuscript development and revisions. TAJ takes responsibility for the manuscript as a whole.The authors declare no conflicts of interest., (© 2021 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG., Competing Interests: Declaration of interests K.G. and A.V.G. are co-inventors on patents describing CBL0137. The remaining authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Two experiments were conducted to evaluate the effects of Fe injection timing after birth on suckling and subsequent nursery and growing-finishing pig performance. The injectable Fe source used in both experiments was GleptoForte (Ceva Animal Health, LLC., Lenexa, KS). GleptoForte contains gleptoferron which is a Fe macromolecule complex. In Exp. 1, a total of 324 newborn pigs (DNA 241 × 600, initially 1.6 ± 0.04 kg body weight [BW]) within 27 litters were used. Two days after birth, all piglets were weighed, and six barrows and six gilts per litter were allotted to 1 of 6 treatments consisting of no Fe injection or 200 mg of injectable Fe provided in a single injection on d 2, 4, 6, 8, or 10 of age. Pigs were weaned (~21 d of age) and allotted to nursery pens with all pigs in each pen having received the same Fe treatment. In Exp. 2, a total of 1,892 newborn pigs (PIC 359 × C40; initially 1.5 ± 0.02 kg BW) within 172 litters were used. One day after birth, piglets were weighed, and 11 pigs within each litter were allotted to 1 of 6 treatments consisting of no Fe injection or 200 mg of injectable Fe provided on d 1, 3, 5, or 7 of age, or 200 mg on d 1 plus 200 mg on d 12 of age. Pigs were weaned (19 d of age) and placed in a commercial wean-to-finish facility in a total of 15 pens with equal representation of treatments in each pen. In both experiments, not providing an Fe injection after birth decreased (P < 0.05) preweaning average daily gain (ADG), weaning weight, and hemoglobin and hematocrit values compared with all other treatments. In Exp. 1, increasing the age that piglets received an Fe injection until 4 or 6 d after birth provided marginal evidence for an improvement (quadratic; P = 0.070) in preweaning ADG. For the nursery period, increasing the age that piglets received an Fe injection improved (quadratic; P = 0.013) d 80 BW, but there was no evidence of a difference (P > 0.10) in d 173 BW at the end of the grow-finish period. In Exp. 2, increasing the age that piglets received a 200 mg Fe injection showed no evidence of difference (P > 0.10) for subsequent nursery and growing-finishing ADG. In both experiments, hemoglobin and hematocrit values were decreased (linear; P < 0.05) at weaning with increasing age when pigs received an Fe injection. These experiments suggest that providing a 200 mg Fe injection within 7 d after farrowing is sufficient for optimizing preweaning and subsequent growth performance., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Modern feed quality sorghum grain has been bred to reduce anti-nutrients, most conspicuously condensed tannins, but its inclusion in the diets of monogastric animals can still result in variable performance that is only partially understood. Sorghum grain contains several negative intrinsic factors, including non-tannin phenolics and polyphenols, phytate, and kafirin protein, which may be responsible for these muted feed performances. To better understand the non-tannin phenolic and polyphenolic metabolites that may have negative effects on nutritional parameters, the chemical composition of sorghum grain polyphenol extracts from three commercial varieties (MR-Buster, Cracka, and Liberty) was determined through the use of an under-studied, alternative analytical approach involving Fourier-transform infrared (FT-IR) spectroscopy and direct ionization mass spectrometry. Supervised analyses and interrogation of the data contributing to variation resulted in the identification of a variety of metabolites, including established polyphenols, lignin-like anti-nutrients, and complex sugars, as well as high levels of fatty acids which could contribute to nutritional variation and underperformance in monogastrics. FT-IR and mass spectrometry could both discriminate among the different sorghum varieties indicating that FT-IR, rather than more sophisticated chromatographic and mass spectrometric methods, could be incorporated into quality control applications., Competing Interests: AC is employed by DSM Nutritional Products. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hodges, Walker, Cowieson, Falconer and Cameron.)

Background: The Novara-COVID score was developed to help the emergency physician to decide which Coronavirus disease (COVID) patient required hospitalization at Emergency Department (ED) presentation and to which intensity of care. We aimed at evaluating its prognostic role., Methods: We retrospectively collected data of COVID patients admitted to our ED between March 16 and April 22, 2020. The Novara-COVID score was systematically applied to all COVID patients since its introduction in clinical practice and adopted to decide patients' destination. The ability of the Novara-COVID score to predict in-hospital clinical stability and in-hospital mortality were evaluated through multivariable logistic regression and cox regression hazard models, respectively., Results: Among the 480 COVID patients admitted to the ED, 338 were hospitalized: the Novara-COVID score was 0-1 in 49.7%, 2 in 24.6%, 3 in 15.4% and 4-5 in 10.3% of patients. Novara-COVID score values of 3 and 4-5 were associated with lower clinical stability with adjusted odds ratios of 0.28 (0.13-0.59) and 0.03 (0.01-0.12), respectively. When in-hospital mortality was evaluated, a significant difference emerged between scores of 0-1 and 2 vs. 3 and 4-5. In particular, the death adjusted hazard ratio for Novara-COVID scores of 3 and 4-5 were 2.6 (1.4-4.8) and 8.4 (4.7-15.2), respectively., Conclusions: The Novara-COVID score reliably predicts in-hospital clinical instability and mortality of COVID patients at ED presentation. This tool allows the emergency physician to detect patients at higher risk of clinical deterioration, suggesting a more aggressive therapeutic management from the beginning.

Importance: Although plenty of data exist regarding clinical manifestations, course, case fatality rate, and risk factors associated with mortality in severe coronavirus disease 2019 (COVID-19), long-term respiratory and functional sequelae in survivors of COVID-19 are unknown., Objective: To evaluate the prevalence of lung function anomalies, exercise function impairment, and psychological sequelae among patients hospitalized for COVID-19, 4 months after discharge., Design, Setting, and Participants: This prospective cohort study at an academic hospital in Northern Italy was conducted among a consecutive series of patients aged 18 years and older (or their caregivers) who had received a confirmed diagnosis of severe acute respiratory coronavirus 2 (SARS-CoV-2) infection severe enough to require hospital admission from March 1 to June 29, 2020. SARS-CoV-2 infection was confirmed via reverse transcription-polymerase chain reaction testing, bronchial swab, serological testing, or suggestive computed tomography results., Exposure: Severe COVID-19 requiring hospitalization., Main Outcomes and Measures: The primary outcome of the study was to describe the proportion of patients with a diffusing lung capacity for carbon monoxide (Dlco) less than 80% of expected value. Secondary outcomes included proportion of patients with severe lung function impairment (defined as Dlco <60% expected value); proportion of patients with posttraumatic stress symptoms (measured using the Impact of Event Scale-Revised total score); proportion of patients with functional impairment (assessed using the Short Physical Performance Battery [SPPB] score and 2-minute walking test); and identification of factors associated with Dlco reduction and psychological or functional sequelae., Results: Among 767 patients hospitalized for severe COVID-19, 494 (64.4%) refused to participate, and 35 (4.6%) died during follow-up. A total of 238 patients (31.0%) (median [interquartile range] age, 61 [50-71] years; 142 [59.7%] men; median [interquartile range] comorbidities, 2 [1-3]) consented to participate to the study. Of these, 219 patients were able to complete both pulmonary function tests and Dlco measurement. Dlco was reduced to less than 80% of the estimated value in 113 patients (51.6%) and less than 60% in 34 patients (15.5%). The SPPB score was suggested limited mobility (score <11) in 53 patients (22.3%). Patients with SPPB scores within reference range underwent a 2-minute walk test, which was outside reference ranges of expected performance for age and sex in 75 patients (40.5%); thus, a total of 128 patients (53.8%) had functional impairment. Posttraumatic stress symptoms were reported in a total of 41 patients (17.2%)., Conclusions and Relevance: These findings suggest that at 4 months after discharge, respiratory, physical, and psychological sequelae were common among patients who had been hospitalized for COVID-19.

Clinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO 2 /FiO 2 ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to nearly every continent, registering over 1,250,000 deaths worldwide. The effects of SARS-CoV-2 on host targets remains largely limited, hampering our understanding of Coronavirus Disease 2019 (COVID-19) pathogenesis and the development of therapeutic strategies. The present study used a comprehensive untargeted metabolomic and lipidomic approach to capture the host response to SARS-CoV-2 infection. We found that several circulating lipids acted as potential biomarkers, such as phosphatidylcholine 14:0&#95;22:6 (area under the curve (AUC) = 0.96), phosphatidylcholine 16:1&#95;22:6 (AUC = 0.97), and phosphatidylethanolamine 18:1&#95;20:4 (AUC = 0.94). Furthermore, triglycerides and free fatty acids, especially arachidonic acid (AUC = 0.99) and oleic acid (AUC = 0.98), were well correlated to the severity of the disease. An untargeted analysis of non-critical COVID-19 patients identified a strong alteration of lipids and a perturbation of phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, aminoacyl-tRNA degradation, arachidonic acid metabolism, and the tricarboxylic acid (TCA) cycle. The severity of the disease was characterized by the activation of gluconeogenesis and the metabolism of porphyrins, which play a crucial role in the progress of the infection. In addition, our study provided further evidence for considering phospholipase A2 (PLA2) activity as a potential key factor in the pathogenesis of COVID-19 and a possible therapeutic target. To date, the present study provides the largest untargeted metabolomics and lipidomics analysis of plasma from COVID-19 patients and control groups, identifying new mechanisms associated with the host response to COVID-19, potential plasma biomarkers, and therapeutic targets.

Phytases are important commercial enzymes that catalyze the dephosphorylation of myo-inositol hexakisphosphate (phytate) to its lower inositol phosphate (IP) esters, IP6 to IP1. Digestion of phytate by Citrobacter braakii 6-phytase deviates significantly from monophasic Michaelis-Menten kinetics. Analysis of phytate digestion using isothermal titration calorimetry (ITC) using the single injection method produced a thermogram with two peaks consistent with two periods of high enzyme activity. Continuous-flow electrospray ionization time-of-flight mass spectroscopy (ESI-ToF-MS) provided real-time analysis of phytase catalysis. It was able to show that the first two cleavage steps were rapid and concurrent but the third cleavage step from IP4 to IP3 was slow. The third (IP4 to IP3), fourth (IP3 to IP2) and fifth (IP2 to IP1) cleavages were effectively sequential due to the preferred association of the more phosphorylated species with the phytase catalytic site. This created a bottleneck during the cleavage of IP4 to IP3 until the point at which IP4 was exhausted and was followed by the rapid cleavage of IP3 to IP2, which was observed as the second peak in the ITC thermogram. This work illustrates the importance of an orthogonal approach when studying non-specific or complex enzyme catalyzed reactions., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A total of 336 newborn pigs (DNA 241 × 600, initially 1.75 ± 0.05 kg bodyweight [BW]) from 28 litters were used in a 63-d study evaluating the effects of increasing injectable Fe dose on suckling and subsequent nursery pig performance and blood Fe status. GleptoForte (Ceva Animal Health, LLC, Lenexa, KS) contains gleptoferron which is an Fe macromolecule complex that is commercially used as an injectable Fe source for suckling piglets. On the day of processing (day 3 after birth), all piglets were weighed and 6 barrows and 6 gilts per litter were allotted within sex to 1 of 6 treatments in a completely randomized design. Treatments consisted of a negative control receiving no Fe injection and increasing injectable Fe to achieve either 50, 100, 150, 200 mg, or 200 mg plus a 100 mg injection on day 11 after birth. Pigs were weaned (~21 d of age) and allotted to nursery pens based on BW and corresponding treatment in a completely randomized design. During lactation, increasing injectable Fe up to 100 mg improved (quadratic; P < 0.05) average daily gain (ADG) and day 21 BW with no further improvement thereafter. There was no evidence of differences (P > 0.10) observed between the 200 mg and 200 mg + 100 mg treatments for growth. For the nursery period, increasing Fe dosage increased (linear; P < 0.05) ADG, average daily feed intake, and day 42 BW. There was no evidence of differences (P > 0.10) between the 200 mg and 200 mg + 100 mg treatments for nursery growth. For blood criteria, significant treatment × day interactions (P = 0.001) were observed for hemoglobin (Hb) and hematocrit (Hct). The interactions occurred because pigs that had <150 mg of injectable Fe had decreased values to day 21 and then increased to day 63 while pigs with 150 or 200 mg of injectable Fe had increased values to day 21 then stayed relatively constant to day 63. In summary, piglet performance during lactation was maximized at 100 mg while nursery growth performance and blood Fe status were maximized with a 200 mg Fe injection at processing. Providing an additional 100 mg of Fe on day 11 of age increased Hb, and Hct values at weaning and 14 d into the nursery but did not provide a growth performance benefit in lactation or nursery. These results indicate that providing 200 mg of injectable Fe provided from GleptoForte is sufficient to optimize lactation and subsequent nursery growth performance and blood Fe status., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Two experiments were conducted to determine the effects of increasing amounts of soybean meal (SBM) in swine diets and estimate the energy value of SBM., Methods: A total of 2233 pigs (PIC 337 × 1050, Hendersonville, TN) and 3796 pigs (PIC 359 × C40), initially 11.0 kg and 17.6 kg body weight (BW), were used in Exp. 1 and 2, respectively. In Exp. 1, pigs were placed in 92 pens each containing 20 to 27 pigs. In Exp. 2, pigs were placed in 84 pens each containing 37 to 43 pigs. Treatments were assigned in a randomized complete block design with BW as the blocking factor. Dietary treatments consisted of 21%, 27%, 33%, or 39% SBM in Exp. 1 and 17.5%, 22%, 26.5%, 31%, 35.5%, or 40% SBM in Exp. 2, obtained by changing the inclusion rate of feed-grade amino acids and corn grain. For Exp. 1, representative samples of corn grain, SBM, and distillers dried grains with solubles were analyzed for total AA content prior to diet formulation. For Exp. 2, diets were formulated using NRC (2012) nutrient loadings. Treatment diets were fed for 21 and 22 d (Exp. 1 and 2) and there were 23 replicates in Exp. 1 and 14 replicates in Exp. 2. Pigs were weighed and feed disappearance measured weekly to calculate average daily gain (ADG), average daily feed intake (ADFI), gain-to-feed ratio (G:F), and caloric efficiency (CE). Data were analyzed with block as a random effect and treatment as a fixed effect, and contrasts were constructed to test the linear and quadratic effects of increasing SBM., Results: In Exp. 1, there was a tendency (linear, P  = 0.092) for a decrease in ADFI as SBM increased. There was a tendency ( P  = 0.090) for a quadratic response for ADG, with a decrease in ADG observed with 39% SBM inclusion. Pigs fed diets with increasing SBM had a tendency (quadratic, P  = 0.069) for an increase in G:F up to 33% SBM and an improvement (linear, P  = 0.001; quadratic, P  = 0.063) in CE with increasing SBM. Using CE to estimate the energy of SBM relative to corn, a value of 105.4% of corn energy or 2816 kcal/kg NE was determined using all data points. When removing the CE value of the 39% SBM treatment due to the quadratic tendency, SBM was estimated to have 121.1% of corn energy or 3236 kcal/kg NE. In Exp. 2, there was a decrease (linear, P  = 0.001) in ADFI. Pigs fed increasing SBM had a tendency (linear, P  = 0.065) for reduced ADG but an improvement (linear, P  = 0.001) in G:F and CE as SBM increased. The energy value of SBM was estimated as 124.7% of corn energy or 3332 kcal/kg NE., Conclusions: The results suggest that feeding increasing levels of SBM improves G:F and CE. The energy value of SBM was estimated to be between 105% and 125% of corn, which is much greater than the NRC (2012) would indicate., Competing Interests: Competing interestsThe authors declare that they have no competing interests, (© The Author(s) 2020.)

A total of 140 weanling pigs (241 × 600, DNA, Columbus, NE; initially 5.5 ± 0.79 kg body weight) were used in a 32-d study evaluating the effects of increasing dietary Fe from either iron sulfate (FeSO4) or iron carbonate (FeCO3) on nursery pig growth performance and blood Fe status. The pigs used for this trial did not receive an Fe injection after birth in order to increase the sensitivity to added dietary Fe after weaning. Pigs were weaned at approximately 21 d and allotted to pens based on the initial weight in a completely randomized block design with five pigs in each pen and four pens per treatment. Experimental treatments were arranged as a 2 × 3 + 1 factorial with main effects of dietary Fe source (FeSO4 vs. FeCO3) and level (10, 30, or 50 mg/kg of added Fe) plus a negative control with no additional dietary Fe. The basal diet contained 40 mg/kg total dietary Fe based on ingredient contributions and was formulated with an Fe-free trace mineral premix. Experimental diets were formulated below the pigs recommended Fe requirement based on NRC (2012) estimates. Experimental diets were fed in pellet form in a single phase for the duration of the trial. From day 0 to 32, there was no evidence for source × level interactions for growth performance, hemoglobin (Hb), or hematocrit (Hct) values. There was no evidence for a difference (P > 0.10) in dietary Fe source. Providing increasing Fe levels in the diet from either FeSO4 or FeCO3 improved (P < 0.05) average daily gain, average daily feed intake, gain-to-feed ratio, and increased (P < 0.05) Hb and Hct values. A day effect (P = 0.001) was observed for both Hb and Hct with values increasing throughout the study. Increasing dietary Fe levels in the diet from either FeSO4 or FeCO3 increased (linear; P < 0.05) Hb and Hct values on days 14, 21, and 32. In summary, these data suggest that the micronized form of FeCO3 is a source of Fe that can be added to nursery diets to yield similar responses to those observed from FeSO4 supplementation. Similar to previous research, increasing dietary Fe improved the growth performance and increased Hb and Hct values when pigs have low Fe status at weaning., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To test whether providing psychological self-help materials would significantly lower the incidence of post-traumatic stress disorder (PTSD) at 6-12 weeks postnatally., Design: Open-label randomised controlled trial, with blinded outcome assessment., Setting: Community midwifery services in two National Health Service (NHS) trusts in the North West., Sample: A cohort of 2419 women receiving normal NHS postnatal care., Methods: Midwives screened women for traumatic birth experience; 678 women who screened positively (28.1%) were randomly allocated to self-help with usual care (n = 336) or to usual care alone (n = 342). The self-help materials were a leaflet and online film designed to prevent the development of PTSD after trauma exposure through explaining how to manage early psychological responses., Main Outcome Measure: The primary outcome was a composite of diagnostic and subdiagnostic PTSD at 6-12 weeks postnatally using the gold-standard Clinician-Administered PTSD Scale (CAPS-5) interview., Results: Of the 678 women correctly randomised plus the nine women randomised in error, 478 (70.5%) were followed up. Diagnostic or subdiagnostic PTSD rates at follow-up did not differ between groups who received self-help (26.7%, 65/243) or usual care alone (26.2%, 64/244) (intention-to-treat analysis: RR 1.02, 95% CI 0.68-1.53). Findings remained consistent in the per-protocol analysis (RR 1.04, 95% CI 0.85-1.27). Women viewed the materials very positively. There were no adverse effects. Health economic micro-costing indicated implementation would be very low cost., Conclusions: Many women experience a traumatic birth and risk developing PTSD, but self-help strategies without professional support are insufficient and should not be routinely introduced., Tweetable Abstract: Self-help information alone does not reduce the number of women developing PTSD after a traumatic childbirth., (© 2020 Royal College of Obstetricians and Gynaecologists.)

FUS is a nucleic acid binding protein that, when mutated, cause a subset of familial amyotrophic lateral sclerosis (ALS). Expression of FUS in yeast recapitulates several pathological features of the disease-causing mutant proteins, including nuclear to cytoplasmic translocation, formation of cytoplasmic inclusions, and cytotoxicity. Genetic screens using the yeast model of FUS have identified yeast genes and their corresponding human homologs suppressing FUS induced toxicity in yeast, neurons and animal models. To expand the search for human suppressor genes of FUS induced toxicity, we carried out a genome-scale genetic screen using a newly constructed library containing 13570 human genes cloned in an inducible yeast-expression vector. Through multiple rounds of verification, we found 37 human genes that, when overexpressed, suppress FUS induced toxicity in yeast. Human genes with DNA or RNA binding functions are overrepresented among the identified suppressor genes, supporting that perturbations of RNA metabolism is a key underlying mechanism of FUS toxicity., (Copyright © 2020 Hayden et al.)

Objective: Telemedicine has the potential to improve the delivery of emergency medical care: however, the extent of its adoption in United States (US) emergency departments is not known. Our objective was to characterise the prevalence of telemedicine use among all US emergency departments, describe clinical applications for which it is most commonly used, and identify emergency department characteristics associated with its use., Methods: As part of the National Emergency Department Inventory-USA survey, we queried all 5375 US emergency departments open in 2016. Multivariable logistic regression analyses identified characteristics associated with emergency department receipt of telemedicine services., Results: Overall, 4507 emergency departments (84%) responded to our survey, with 4031 responding to both telemedicine questions (75%). Although 1694 emergency departments (42%) reported no telemedicine in 2016, most did: 1923 (48%) emergency departments received telemedicine services, 149 (4%) emergency departments received telemedicine services and were in hospitals that provided telemedicine, and 265 emergency departments (7%) did not receive telemedicine but were in hospitals that provided telemedicine services. Among emergency departments receiving telemedicine, the most common applications were stroke/neurology (76%), psychiatry (38%), and paediatrics (15%). In multivariable analysis, telemedicine-receiving emergency departments had higher annual total visit volume for adults and lower annual total visit volume by children; were less likely to be academic or freestanding; and varied by region. In multivariable analysis, emergency departments in telemedicine-providing hospitals had higher annual total visit volume for adults and children, were more likely to be academic and were less likely to be freestanding., Conclusion: In 2016, telemedicine was used in most US emergency departments (58%), especially for stroke/neurology and psychiatry. Future research is needed to understand the value of telemedicine for different clinical applications, and the barriers to its implementation.

Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, lack of speech, and ataxia. The gene responsible for AS was identified as Ube3a and it encodes for E6AP, an E3 ubiquitin ligase. Currently, there is very little known about E6AP's mechanism of action in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. Elucidating the mechanistic action of E6AP would enhance our understanding of AS and drive current research into new avenues that could lead to novel therapeutic approaches that target E6AP's various functions. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat phenotypically mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS. Autism Res 2020, 13: 397-409. © 2020 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, difficulty speaking, and ataxia. The gene responsible for AS was identified as UBE3A, yet very little is known about its function in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS., (© 2020 International Society for Autism Research, Wiley Periodicals, Inc.)

Vitamin D is a pleiotropic molecule with a well-characterised immunomodulatory activity in vitro; however, its potential clinical application in autoimmune conditions has yet to be clarified. Several authors have investigated the use of vitamin D as a disease-modifying anti-rheumatic drug (DMARD) in rheumatoid arthritis (RA), obtaining divergent conclusions. This systematic review summarises and critically analyses the findings of papers assessing the impact of vitamin D supplementation on pain relief, disease activity, functional status and flare rate. We conclude that the correction of hypovitaminosis D may have a beneficial effect on pain perception; moreover, the achievement of an adequate plasma vitamin D concentration obtained with high-dose regimens might evoke immunomodulatory activities of vitamin D and favourably impact on disease control. Nevertheless, the current evidence is still not strong enough to support the use of cholecalciferol as a DMARD in RA, and further studies are required to clarify this issue.

A total of 710 pigs (Line 400 × 200, DNA, Columbus, net energy (NE)) were used in two experiments (Exp. 1: initially, 6.3 ± 0.05 kg; Exp. 2: initially, 6.8 ± 0.05 kg) to evaluate the effects of two medium-chain fatty acid (MCFA) based products on nursery pig growth performance. Following their arrival at the nursery facility, pigs were randomized to pens (five pigs per pen) and allowed a 4-d acclimation period. Thereafter, pens of pigs were blocked by initial weight and randomized to dietary treatment. In Exp. 1, the dietary treatments were a dose titration of: 0%, 0.5%, 1.0%, or 2.0% MCFA-based additive, as well as a diet including 1.0% MCFA from a 1:1:1 blend of C6:0, C8:0, and C10:0. In Exp.2, dietary treatments consisted of a basal diet containing no MCFA (control), the control diet with a 1.0% inclusion of four different blends of MCFA, lactic acid, and monolaurin or a diet with 1.0% added MCFA (a 1:1:1 blend of C6:0, C8:0, and C10:0). The four blends consisted of 50% C6:0, 20% lactic acid, and increasing levels of monolaurin (0%, 10%, 20%, and 30%) at the expense of C12:0 (30%, 20%, 10%, and 0%). Treatment diets were formulated and manufactured in two dietary phases. Data were analyzed as a randomized complete block design with pen as the experimental unit. In Exp. 1, overall (days 0-34), increasing CaptiSURE increased (linear, P ≤ 0.014) average daily gain (ADG) and average daily feed intake (ADFI). Feed efficiency improved (quadratic, P = 0.002) with increasing CaptiSURE up to 1.0% of the diet with no benefit thereafter. There was no evidence for differences between pigs fed 1.0% CaptiSURE and pigs fed the 1.0% MCFA blend of C6:0, C8:0, and C10:0. In Exp. 2, overall (days 0-35), pigs fed the 1.0% 1:1:1 MCFA blend had increased ( P < 0.034) ADFI and ADG resulting in 0.9 kg greater final weight ( P = 0.014) compared with the control group. There was no evidence that the mean performance of pigs fed the four blends of MCFA, lactic acid, and monolaurin were different from the pigs fed the control diet. In summary, the addition of a 1.0% 1:1:1 blend of C6:0, C8:0, and C10:0 in nursery pig diets improved ADG, ADFI, and gain to feed ratio (G:F) compared with pigs fed the control diet. In addition, providing nursery pigs with the MCFA product CaptiSURE, up to 2% of the diet, resulted in linear improvements in ADG and ADFI. Altering the C12:0 to monolaurin ratio and adding lactic acid did not improve growth performance compared with pigs fed the control diet., (Published by Oxford University Press on behalf of the American Society of Animal Science 2020.)

Programming the local orientation of liquid crystal elastomers (LCEs) is a differentiated approach to prepare monolithic material compositions with localized deformation. Our prior efforts prepared LCEs with surface-enforced spatial variations in orientation to localize deformation when the LCEs were subjected to directional load. However, because these surface alignment methods included regions of planar orientation, the deformation of these programmed LCEs is inherently directional. The absence of macroscopic orientation in polydomain LCEs results in uniform, nonlinear deformation in all axes (omnidirectional soft elasticity). Here, we exploit the distinct mechanical response of polydomain LCEs prepared with isotropic or nematic genesis. By localizing the polydomain genesis via masked photopolymerizations conducted at different temperatures, we detail the preparation of main-chain, polydomain LCEs that are homogeneous in composition but exhibit spatially localized programmability in their mechanical response that is uniform in all directions.

Liquid crystal elastomers (LCEs) are anisotropic polymeric materials. When subjected to an applied stress, liquid crystalline (LC) mesogens within the elastomeric polymer network (re)orient to the loading direction. The (re)orientation during deformation results in nonlinear stress-strain dependence (referred to as soft elasticity). Here, we uniquely explore mechanotropic phase transitions in elastomers with appreciable mesogenic content and compare these responses to LCEs in the polydomain orientation. The isotropic (amorphous) elastomers undergo significant directional orientation upon loading, evident in strong birefringence and x-ray diffraction. Functionally, the mechanotropic displacement of the elastomers to load is also nonlinear. However, unlike the analogous polydomain LCE compositions examined here, the isotropic elastomers rapidly recover after deformation. The mechanotropic orientation of the mesogens in these materials increase the toughness of these thiol-ene photopolymers by nearly 1300 % relative to a chemically similar elastomer prepared from wholly isotropic precursors., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: To describe and report outcomes after lateral translation of the manus for limb-sparing management of distal radial osteosarcoma in dogs., Study Design: Retrospective case series., Study Population: Eighteen client-owned dogs., Methods: The distal aspect of the affected radius and associated neoplastic tissues were excised. The distal aspect of the ulna was preserved except for its medial cortex, which was removed en bloc with the radial segment. The manus was translated laterally to place the radial carpal bone in contact with the distal aspect of the ulna. A limb-sparing or locking compression plate was placed on the remaining proximal radius and the 3rd metacarpal bone. A 3.5-mm SOP (string of pearls) plate was placed on the lateral aspect of the proximal ulna and the 4th metacarpal bone. Dogs were administered chemotherapy. Data were collected to assess surgical and oncologic outcomes. Limb function was subjectively assessed., Results: The percentage of radius removed ranged from 43% to 94% (median 54%). Complications developed in 12 limbs, with infection in 10, biomechanical complications in 6, and local recurrence in 4. Limb function was subjectively assessed as acceptable. Median disease-free interval was 219 days, and median survival time was 370 days., Conclusion: Outcomes after lateral translation of the manus compared favorably to other limb-sparing techniques for dogs with distal radial osteosarcoma, particularly in dogs requiring excision of a large segment of the radius., Clinical Significance: The lateral manus translation provides an alternative limb-sparing technique that does not require an allograft, endoprosthesis, or autograft., (© 2018 The American College of Veterinary Surgeons.)

Objective: The aim of this study is to identify scheduling inefficiencies and to develop a personalized schedule based on diagnosis, service time (face-to-face time between the patient and the provider), and patient wait time using a Gantt diagram in a chronic pain clinic., Design: This is an observational prospective cohort quality improvement (QI) study., Setting: This study was carried out at a single outpatient multidisciplinary pain management clinic in a university teaching hospital., Subjects: New and established chronic pain patients at the University of Pittsburgh Medical Center (UPMC) Montefiore Chronic Pain Clinic were recruited for this study., Methods: Time tracking data for each phase of clinic visit and pain-related diagnoses were collected from 81 patients on 5 clinic days in March 2016 for patient flow analysis., Results: A Gantt diagram was created using Microsoft Excel ® software. Areas of overbooking and underbooking were identified. Median service times (minutes) differed dramatically based on the diagnosis and were highest for facial pain (23 [IQR, 15-31]) and chronic abdominal and/or pelvic pain (21.5 [IQR, 16-27]) and lowest for myalgia. Abdominal and/or pelvic pain and facial pain median service times consistently exceeded the 15-minute allocation for return visits., Conclusion: Schedule efficiency analysis using the Gantt diagram identified trends of overbooking and underbooking and inefficiencies in examination room utilization. A 15-minute appointment for all return patients is unrealistic due to variation of service times for some diagnoses. Scheduling appointments based on the diagnosis is an innovative approach that may reduce scheduling inefficiencies and improve patient satisfaction and the overall quality of care. To the best of our knowledge, this type of scheduling diagram has not been used in a chronic pain clinic., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

A total of 300 nursery pigs (initially 5.9 ± 0.05 kg BW) were used in a 42-d growth trial to evaluate the effects of feeding a therapeutic level of chlortetracycline (CTC) with or without direct fed microbials (DFM) on growth performance and antimicrobial resistance (AMR) of fecal Escherichia coli. CTC is a broad-spectrum in-feed antibiotic commonly used in the swine industry. Weaned pigs (~21 d of age) were allotted to pens based on initial BW and fed a common starter diet for 4 d. Pens were then blocked by BW and allotted to dietary treatments in a completely randomized block design. Dietary treatments were arranged in a 2 × 3 factorial consisting of combinations of CTC (none vs. 400 mg/kg from days 0 to 42) and DFM (0 vs. 0.05% DFM 1 vs. 0.05% DFM 2). Fecal samples were collected from three randomly selected pigs from each pen on days 0, 21, and 42 for E. coli isolation and AMR determination. Overall, pigs fed diets containing CTC had improved (P < 0.001) ADG, ADFI, and BW compared to those not fed CTC with no evidence for any effect of either DFM 1 or DFM 2. Regardless of CTC, inclusion of DFM 2 in diets improved (P < 0.05) ADFI from days 0 to 14 and on day 14 BW compared to diets that did not include DFM 2. The addition of CTC with or without DFMs to nursery pig diets increased (P < 0.05) the probability of AMR to tetracycline and ceftiofur of fecal E. coli isolates, but this resistance generally decreased (P < 0.05) over time. A decrease (P < 0.05) in AMR to ampicillin and tetracycline (TET) throughout the trial was observed, while resistance to ceftriaxone decreased (P < 0.020) from days 0 to 21 and increased from days 21 to 42 amongst dietary treatments regardless of CTC or DFM inclusion in the diet. A CTC × DFM × day interaction (P < 0.015) was observed for streptomycin, whereby from days 21 to 42 AMR increased in diets containing either CTC or DFM 1 alone, but the combination decreased resistance. There was no evidence for any effect of DFMs on AMR of fecal E. coli isolates to any other antibiotics evaluated. In conclusion, therapeutic levels of added CTC with or without DFM inclusion improved nursery pig performance, but increased AMR of fecal E. coli isolates to TET and ceftiofur. A moderate improvement in intake and day 14 BW was observed when DFM 2 was included in the diet with or without CTC, but, except for streptomycin, there was no evidence that added dietary DFMs affected resistance of fecal E. coli to antibiotics.

We demonstrate that nucleic acid (NA) mononucleotide triphosphates (dNTPs and rNTPs), at sufficiently high concentration and low temperature in aqueous solution, can exhibit a phase transition in which chromonic columnar liquid crystal ordering spontaneously appears. Remarkably, this polymer-free state exhibits, in a self-assembly of NA monomers, the key structural elements of biological nucleic acids, including: long-ranged duplex stacking of base pairs, complementarity-dependent partitioning of molecules, and Watson-Crick selectivity, such that, among all solutions of adenosine, cytosine, guanine, and thymine NTPs and their binary mixtures, duplex columnar ordering is most stable in the A-T and C-G combinations., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Three studies evaluated the effects of added dietary salt on growth performance of pigs weighing 7 to 10, 11 to 30, and 27 to 65 kg. In experiment 1, 325 pigs were used with 5 pigs per pen and 13 pens per treatment. Pigs were fed a diet (0.39% Na and 0.78% Cl) for 7 d after weaning, then randomly assigned to diets with either 0, 0.20, 0.40, 0.60, or 0.80% added salt for 14 d. All diets were corn-soybean meal-based with 10% dried whey. Calculated Na concentrations were 0.11, 0.19, 0.27, 0.35, and 0.43% and calculated Cl concentrations were 0.23, 0.35, 0.47, 0.59, and 0.70%, respectively. Increasing salt increased (linear, P < 0.05) average daily gain (ADG) and gain to feed ratio ( G:F ). For ADG, the linear, quadratic polynomial ( QP ), and broken-line linear ( BLL ) models were competing with the breakpoint for the BLL at 0.59% salt. For G:F, the BLL reported a breakpoint at 0.33% while the QP indicated maximum G:F at 0.67% added salt. In experiment 2, 300 pigs were used in a 34-d trial with 5 pigs per pen and 12 pens per treatment. Pigs were weaned at 21 d of age and fed a phase 1 diet (0.50% Na and 0.67% Cl) for 11 d and then a phase 2 diet (0.35% Na and 0.59% Cl) for 14 d. Then pens of pigs were randomly assigned to corn-soybean meal-based diets containing 0.20, 0.35, 0.50, 0.65, or 0.80% added salt. Calculated dietary Na concentration were 0.10, 0.16, 0.22, 0.28, and 0.34% and calculated Cl concentrations were 0.23, 0.32, 0.41, 0.50, and 0.59%, respectively. Overall, ADG and G:F increased (quadratic, P < 0.07) with increasing added salt. For ADG, the QP and BLL had similar fit with the breakpoint for BLL at 0.51% added salt. For G:F, the BLL model predicted a break point at 0.35% added salt. In experiment 3, 1,188 pigs were used in a 44-d study with 27 pigs per pen and 11 pens per treatment. Pens of pigs were randomly assigned to corn-soybean meal-based diets containing 0.10, 0.33, 0.55, or 0.75% added salt. Calculated dietary Na concentrations were 0.10, 0.19, 0.28, and 0.36% and calculated Cl concentrations were 0.23, 0.36, 0.49, and 0.61%, respectively. Overall, there was no evidence to indicate that added salt above 0.10% of the diet affected growth. In conclusion, the BLL models suggested to maximize ADG for 7 to 10 and 11 to 30 kg pigs was 0.59% (0.34% Na and 0.58% Cl) and 0.51% added salt (0.22% Na and 0.42% Cl), respectively. There was no evidence that growth of 27 to 65 kg pigs was improved beyond 0.10% added salt (0.11% Na and 0.26% Cl)., (Published by Oxford University Press on behalf of the American Society of Animal Science 2018.)