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Seizures are made up of the coordinated activity of networks of neurons, suggesting that control of neurons in the pathologic circuits of epilepsy could allow for control of the disease. Optogenetics has been effective at stopping seizure-like activity in non-human disease models by increasing inhibitory tone or decreasing excitation, although this effect has not been shown in human brain tissue. Many of the genetic means for achieving channelrhodopsin expression in non-human models are not possible in humans, and vector-mediated methods are susceptible to species-specific tropism that may affect translational potential. Here we demonstrate adeno-associated virus-mediated, optogenetic reductions in network firing rates of human hippocampal slices recorded on high-density microelectrode arrays under several hyperactivity-provoking conditions. This platform can serve to bridge the gap between human and animal studies by exploring genetic interventions on network activity in human brain tissue., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Competing Interests: The authors declare no conflicts of interest.

Background: Mucinous ovarian carcinoma (MOC) is a rare ovarian cancer with limited evidence to support clinical care., Aims: We undertook a clinician survey to better understand current practice in treating MOC in Australia and New Zealand, and to determine any features associated with variation in care. In addition, we aimed to understand future research priorities., Methods: A RedCap survey was distributed to clinician members of the Australia New Zealand Gynaecological Oncology Group (ANZGOG). Questions included respondent demographics, three case studies and future research priorities. Clinicians were asked questions specific to their speciality., Results: Respondents (n = 47) were commonly experienced gynae-oncology specialists, most often surgical (38%) or medical (30%) oncologists. There was good consensus for surgical approaches for stage I disease; however, variation in practice was noted for advanced or recurrent MOC. Variation was also observed for medical oncologists; in early-stage disease there was no clear consensus on whether to offer chemotherapy, or which regimen to recommend. For advanced and recurrent disease a wide range of chemotherapy options was considered, with a trend away from an ovarian-type toward gastrointestinal (GI)-type regimens in advanced MOC. This practice was reflected in future research priorities, with 'Is a GI chemotherapy regimen better than an ovarian regimen?' the most highly ranked option, followed by 'Should stage 1C patients receive chemotherapy?', Conclusions: Although the number of respondents limited the analyses, it was clear that chemotherapy selection was a key point of divergence for medical oncologists. Future research is needed to establish well-evidenced guidelines for clinical care of MOC., (© 2024 The Authors. Australian and New Zealand Journal of Obstetrics and Gynaecology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Introduction: While selective dorsal rhizotomy (SDR) was originally described as a multilevel approach, single-level approaches are now popularized. Conus localization is beneficial for operative planning in single-level selective dorsal rhizotomy. Our approach to SDR involves minimal exposure for a single-level laminoplasty, preserving one attached interspinous ligament. Pre-operative conus localization is required for this tailored approach to determine the laminoplasty level and dictate rostral or caudal division of the superior spinus ligament. While rapid MRI sequences have been popularized for pediatric cranial imaging, its utility for spinal imagining is less well-described, and specific application for conus localization has not been reported., Objective: Illustrate that rapid MRI without sedation is sufficient to identify conus level for tailored single-level laminoplasty SDR., Material and Methods: Patients undergoing SDR from 2014 to 2022 at one institution were reviewed for type of pre-operative MRI (rapid vs full), conus level, procedural time for MRI, and radiology report. The typical rapid MRI has four sequences utilizing single-shot technique (scout, sagittal T2, axial T2, and axial T1) that typically take less than 1 min each of acquisition time, with non-single-shot sequences added periodically in cooperative patients. To include time for patient positioning, pre-scan shimming, procedural incidentals, and other patient-specific variations, MRI procedure length was recorded as documented in the electronic medical record., Results: N = 100 patients had documentation of an MRI for pre-operative imaging. Seventy-nine of these had a rapid MRI, and 21 required a full MRI with anesthesia for their treatment plan. Mean total procedure time for rapid MRI was 21.5 min (median 17). Mean procedure time for MRI under general anesthesia was 91.2 min (median 94). Of patients with rapid MRI imaging, 2/79 had an ambiguous conus level (1 from motion artifact, 1 from spinal hardware) vs 1/21 with a full MRI under anesthesia (due to spinal hardware)., Conclusion: Rapid spinal MRI without sedation can be used for conus localization in a pediatric population. This may be routinely used as pre-operative imaging for a single-level approach to selective dorsal rhizotomy, without sedation or intubation procedures., (© 2024. The Author(s).)

Soon after the onset of the COVID-19 pandemic, almost all Association of Zoos and Aquariums (AZA) facilities closed to the public. Resulting cost-saving and safety measures led some facilities to temporarily cease or reduce animal breeding and/or transfers. We surveyed AZA facilities and Species Survival Plan® (SSP) Coordinators for AZA's cooperative population management programs to evaluate how widespread these decisions were, if impacts varied by taxa, and how the AZA community navigated related challenges during the pandemic. We found that 60% of responding facilities did not suspend breeding and 22% did not suspend transfers. About 50% of responding zoos increased their reliance on ground transportation to move animals, while aquariums reported no change to transportation methods. SSP Coordinators reported the main reason why breeding decreased, regardless of taxa, was due to canceled or delayed transfers. The reasons transfers decreased differed by taxa, such as limited financial resources and lack of access to air transportation. The majority of respondents for both surveys stated transfers were the greatest challenge they faced. To address this, facilities utilized alternative transportation methods and worked closely with nearby zoos and aquariums for the movement of animals, while SSP Coordinators issued alternative transfer recommendations. If another pandemic or other widespread facility closure occurs, our research highlights the importance of communication, collaboration, and flexibility to fulfill breeding and transfer recommendations to maintain sustainable zoo and aquarium populations., (© 2024 Lincoln Park Zoo and Association of Zoos & Aquariums. Zoo Biology published by Wiley Periodicals LLC.)

Asteroids with diameters less than about 5 km have complex histories because they are small enough for radiative torques (that is, YORP, short for the Yarkovsky-O'Keefe-Radzievskii-Paddack effect) 1 to be a notable factor in their evolution 2 . (152830) Dinkinesh is a small asteroid orbiting the Sun near the inner edge of the main asteroid belt with a heliocentric semimajor axis of 2.19 AU; its S-type spectrum 3,4 is typical of bodies in this part of the main belt 5 . Here we report observations by the Lucy spacecraft 6,7 as it passed within 431 km of Dinkinesh. Lucy revealed Dinkinesh, which has an effective diameter of only 720 m, to be unexpectedly complex. Of particular note is the presence of a prominent longitudinal trough overlain by a substantial equatorial ridge and the discovery of the first confirmed contact binary satellite, now named (152830) Dinkinesh I Selam. Selam consists of two near-equal-sized lobes with diameters of 210 m and 230 m. It orbits Dinkinesh at a distance of 3.1 km with an orbital period of about 52.7 h and is tidally locked. The dynamical state, angular momentum and geomorphologic observations of the system lead us to infer that the ridge and trough of Dinkinesh are probably the result of mass failure resulting from spin-up by YORP followed by the partial reaccretion of the shed material. Selam probably accreted from material shed by this event., (© 2024. The Author(s).)

Abstract: The goal of medical education is to produce a physician workforce capable of delivering high-quality equitable care to diverse patient populations and communities. To achieve this aim amidst explosive growth in medical knowledge and increasingly complex medical care, a system of personalized and continuous learning, assessment, and feedback for trainees and practicing physicians is urgently needed. In this perspective, the authors build on prior work to advance a conceptual framework for such a system: precision education (PE).PE is a system that uses data and technology to transform lifelong learning by improving personalization, efficiency, and agency at the individual, program, and organization levels. PE "cycles" start with data inputs proactively gathered from new and existing sources, including assessments, educational activities, electronic medical records, patient care outcomes, and clinical practice patterns. Through technology-enabled analytics , insights are generated to drive precision interventions . At the individual level, such interventions include personalized just-in-time educational programming. Coaching is essential to provide feedback and increase learner participation and personalization. Outcomes are measured using assessment and evaluation of interventions at the individual, program, and organizational levels, with ongoing adjustment for repeated cycles of improvement. PE is rooted in patient, health system, and population data; promotes value-based care and health equity; and generates an adaptive learning culture.The authors suggest fundamental principles for PE, including promoting equity in structures and processes, learner agency, and integration with workflow (harmonization). Finally, the authors explore the immediate need to develop consensus-driven standards: rules of engagement between people, products, and entities that interact in these systems to ensure interoperability, data sharing, replicability, and scale of PE innovations., (Copyright © 2024 the Association of American Medical Colleges.)

Abstract: Almost one quarter of physicians and physicians-in-training in the United States are international medical graduates (IMGs), meaning they have graduated from a medical school not accredited in the United States. Some IMGs are U.S. citizens and others are foreign nationals. IMGs, many of whom have years of training and experience gained in their countries of origin, have long contributed to the U.S. health care system, especially by providing care to populations that have been historically underserved. Additionally, many IMGs contribute to the diversity of the health care workforce, which can enhance the health of the population. The diversity of the United States is increasing, and racial and ethnic concordance between a physician and a patient has been linked to improved health outcomes.IMGs must meet national- and state-level licensing and credentialing standards like any other U.S. physician. This assures the ongoing quality of the care provided by the medical workforce and protects the public. However, at the state level, variation in standards and standards that may be more challenging to meet than those for U.S. medical school graduates may hamper IMGs' contributions. IMGs who are not U.S. citizens also face visa and immigration barriers.In this article, the authors present insights gleaned from Minnesota's model IMG integration program as well as changes made in 2 states in response to the COVID-19 pandemic. Improving and streamlining processes for IMGs to be licensed and credentialed as well as the policies governing visas and immigration, where appropriate, can ensure that IMGs will be willing and able to continue to practice when and where they are needed. This, in turn, could increase the contribution of IMGs to addressing health care inequities, improving health care access through service in federally designated Health Professional Shortage Areas, and reducing the impact of potential physician shortages., (Copyright © 2023 the Association of American Medical Colleges.)

Background and Aims: Involving patients in research, not only as trial subjects, is not a newly established practice. Over the last two decades, patient roles have gradually expanded to become active research contributors, creating a more patient-centered research landscape. Our survey has explored the scope of patient involvement within the Gynecologic Cancer InterGroup (GCIG), an International Gynecologic Cancer Research Consortium, and identified challenges in developing a systematic, meaningful and sustainable level of patient involvement., Methods: In late 2019, the GCIG Harmonisation Operations Committee conducted an online survey across 26 national and/or international research cooperative groups, aiming to identify current patient involvement practices implemented by each group. Twelve questions were asked. The results have been generated to support a systematic strategic planning process to increase patient involvement into clinical research projects., Results: More than half of the 26 participating groups have either already involved (15, [58%]) or are planning (6, [23%]) to involve patients in their research activities. Gaining patient support in raising public awareness around clinical trials appears to be one of the most desired benefits (21, [81%]). Ten respondents managed to integrate patient involvement into their standard practice. When involving patients in research the groups mostly consider that patients bring added value to the study (19, [73%]), although only eight groups (40%) have a well-organized process in doing so., Conclusion: Even though patient involvement is considered a significant added value to clinical research, its application within GCIG groups is not considered on a regular basis and is predominantly limited to operational aspects of research activities. The lack of resources and expertize, as well as the missing well-organized and structured process of some groups, combined with their ability to ensure process sustainability, are among the main factors affecting implementation and adoption of patient involvement within GCIG research activities., Competing Interests: The authors declare no conflict of interest. The authors declare that they did not use any supporting source and have no financial relationship that may have influenced the work presented in this article., (© 2023 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

A widespread sense of the unsustainability of the food system has taken hold in recent years, leading to calls for fundamental change. The role of animal agriculture is central to many of these debates, leading to interest in the possibility of a "protein transition," whereby the production and consumption of animal-derived foods is replaced with plant-based substitutes or "alternative proteins." Despite the potential sustainability implications of this transition, the developmental trajectories and transformative potential of the associated technologies remain underexplored. This article sheds light on these dynamics by addressing two questions: 1) how have alternative protein innovations developed over the past three decades, and 2) what explains their more recent acceleration? To answer these questions, the article makes an empirical analysis of four alternative protein innovations, and the partial destabilization of the animal agriculture system between 1990 and 2021, guided by the multi-level perspective. The analysis highlights an intensification in corporate engagement with alternative protein development and diffusion. This intensification is judged to be consistent with the beginnings of a wider corporate reorientation, occurring alongside a rise in pressures on the animal agriculture system, notably an increasing scientific consensus and societal awareness of the links between climate change and meat-intensive diets. The paper demonstrates how differences in technological maturity across the niche innovations have resulted in potentially transformative pressures, which are consistent with an emerging sustainability transition, manifesting differently in terms of the extent of diffusion of the alternative protein niches.

Problem: Medical education must evolve to meet the changing needs of patients and communities. Innovation is a critical component of that evolution. As medical educators pursue innovative curricula, assessments, and evaluation techniques, the impact of innovations may be limited by minimal funding. The American Medical Association (AMA) Innovation Grant Program, launched in 2018, seeks to address the gap in funding and stimulate educational innovation and research in medical education., Approach: In 2018 and 2019, the Innovation Grant Program targeted innovation in content areas including health systems science, competency-based medical education, coaching, learning environment, and emerging technology. The authors reviewed the content of applications and final reports for the 27 projects completed during the first 2 years of the program. They also noted measures of success (completion of project, achievement of grant objectives, development of transferrable educational product, dissemination)., Outcomes: In 2018, the AMA received 52 submissions and funded 13 proposals, dispersing $290,000 ($10,000 and $30,000 grants). In 2019, the AMA received 80 submissions and funded 15 proposals, dispersing $345,000. Among the 27 completed grants, 17 (63%) supported innovations related to health systems science. Fifteen (56%) were used to create educational products that could be shared, such as new assessment tools, curricula, and teaching modules. Five grant recipients (29%) published articles and 15 (56%) presented at national conferences., Next Steps: The grant program advanced educational innovations, particularly in health systems science. The next steps will involve examining the long-term outcomes and impact of the completed projects on medical students, patients, and the health system; the professional development of the grantees; and the adoption and dissemination of the innovations., (Copyright © 2023 by the Association of American Medical Colleges.)

Objective: Intraventricular meningiomas (IVMs) of the lateral ventricle are rare tumors that present surgical challenges because of their deep location. Visual field deficits (VFDs) are one risk associated with these tumors and their treatment. VFDs may be present preoperatively due to the tumor and mass effect (tumor VFDs) or may develop postoperatively due to the surgical approach (surgical VFDs). This institutional series aimed to review surgical outcomes following resection of IVMs, with a focus on VFDs., Methods: Patients who received IVM resection at one academic institution between the years 1996 and 2021 were retrospectively reviewed. Diffusion tensor imaging (DTI) reconstructions of the optic radiations around the tumor were performed from preoperative IVM imaging. The VFD course and resolution were documented., Results: Thirty-two adult patients underwent IVM resection, with gross-total resection in 30 patients (93.8%). Preoperatively, tumor VFDs were present in 6 patients, resolving after surgery in 5 patients. Five other patients (without preoperative VFD) had new persistent surgical VFDs postoperatively (5/32, 15.6%) that persisted to the most recent follow-up. Of the 5 patients with persistent surgical VFDs, 4 received a transtemporal approach and 1 received a transparietal approach, and all these deficits occurred prior to regular use of DTI in preoperative imaging., Conclusions: New surgical VFDs are a common neurological deficit after IVM resection. Preoperative DTI may demonstrate distortion of the optic radiations around the tumor, thus revealing safe operative corridors to prevent surgical VFDs.

Use of e-cigarettes is increasing, alongside an expanding variety of devices and e-liquids. To match this growth and in line with the expanding legal and regulatory requirements applicable to manufacturers of e-cigarettes (e.g. disclosure of list of ingredients and quantities thereof in a product), rapid methods for determining levels of the main e-liquid constituents-namely, propylene glycol (PG), vegetable glycerol (VG), water and nicotine-are needed. We have assessed the ability of near infrared (NIR) spectroscopy, coupled with partial least squares (PLS) regression, to predict the levels of these constituents in e-liquid formulations. Using NIR spectral data from a large set of reference e-liquids incorporating working concentration ranges, flavourings, and other ingredients, linear calibration models were established for PG, VG, water and nicotine (predicted vs theoretical values, all R 2  > 0.995). The performance of these models was then evaluated on commercial e-liquids using NIR and compared to results obtained by gas chromatography (GC). A strong correlation was observed between NIR-predicted values and measured values for PG, VG and nicotine (all R 2  > 0.955). There was less consistency between predicted and GC measured values for water due to the relatively high limit of quantification (LOQ) of the GC method (2.6% w/w) versus the e-liquid content (0-18% w/w). The LOQ of the NIR method for water was 0.6% w/w, suggesting that NIR may be a more accurate method than GC to predict water concentration in e-liquids, especially at low levels (< 2.6% w/w). Collectively, although limitations of the technique have been identified, specifically for e-liquids containing compounds that might interfere with the set calibrations, our findings suggest that NIR combined with PLS regression is a suitable tool for rapid, simultaneous and high-throughput measurement of PG, VG, water and nicotine levels in most commercial e-liquids., (© 2023. Springer Nature Limited.)

Objective: This posthoc analysis investigated the relationship between paraoxonase-1 (PON1) genotype and activity, and risk of major adverse cardiovascular events (MACE) and malignancies in clinical studies of tofacitinib in patients with rheumatoid arthritis (RA)., Methods: Data were pooled from 9 phase II/III studies and the associated long-term extension studies (all completed by October 2017). PON1 activities in plasma were measured using paraoxon (paraoxonase activity), dihydrocoumarin (lactonase activity), and phenylacetate (arylesterase activity) as substrates. PON1 Q192R genotype effect on baseline PON1 activity was assessed using linear regression for each study, with fixed-effects metaanalysis across studies. MACE and malignancy risk by time-varying enzyme activity was determined using Cox proportional hazards regression., Results: The analysis included 1969 patients with RA. Compared with the QQ genotype, the RR genotype had a significant positive association with baseline paraoxonase activity and a significant negative association with baseline lactonase and arylesterase activity (all P < 0.001). Time-varying models demonstrated a significant association of increased paraoxonase activity over time with lower risk of MACE ( P < 0.001) and malignancies (excluding nonmelanoma skin cancer [NMSC]; P ≤ 0.05), even after controlling for risk factors identified in univariate analysis and RA disease activity. A similar trend was observed for lactonase and arylesterase for MACE., Conclusion: Higher paraoxonase activity over time was associated with significantly reduced risk of future MACE and malignancies (excluding NMSC), but not NMSC, in patients with RA receiving tofacitinib. Further investigation of PON1 as a novel functional lipid biomarker of MACE/malignancy risk in patients with RA is warranted. (ClinicalTrials.gov: NCT01059864, NCT00550446, NCT00687193, NCT00960440, NCT00814307, NCT00856544, NCT00853385, NCT00847613, NCT01039688, NCT00413699, NCT00661661).

Long-term sustainability of ex-situ animal populations is important for zoos and aquariums, but challenging due to inconsistent compliance with Breeding and Transfer Plans. Transfer recommendations are key to promoting the sustainability of ex-situ animal populations by ensuring cohesive populations, genetic diversity, and demographic stability, but factors affecting their fulfillment are poorly understood. We used a network analysis framework to analyze data compiled from PMCTrack from 2011 to 2019 for three taxonomic classes (mammals, birds, and reptiles/amphibians) within the Association of Zoos and Aquariums to assess factors affecting transfer recommendation fulfillment. Of 2505 compiled transfer recommendations spanning 330 Species Survival Plan® (SSP) Programs and 156 institutions, 1628 (65%) of them were fulfilled. Transfers were most likely to be fulfilled between institutions in close proximity with an established relationship. Annual operating budget, SSP Coordinator experience, number of staff, and diversity of Taxonomic Advisory Groups in which an institution participates also influenced transfer recommendations and/or fulfillment, but effects varied with taxonomic class. Our results suggest that current practices of focusing on transfers between institutions in close proximity are working to maximize transfer success and that institutions with larger budgets and some degree of taxonomic specialization play important roles in promoting success. Success could be further enhanced by building reciprocal transfer relationships and encouraging further development of relationships between smaller institutions and larger ones. These results emphasize the utility of examining animal transfers using a network approach, which accounts for attributes of both sending and receiving institutions, describing novel patterns otherwise left undetected., (© 2023 The Authors. Zoo Biology published by Wiley Periodicals LLC.)

Background: Mild traumatic brain injury (MTBI) causes morbidity and disability worldwide. Pediatric patients are uniquely vulnerable due to developmental and psychosocial factors. Reduced healthcare access in rural/underserved communities impair management and outcome. A knowledge update relevant to current gaps in care is critically needed to develop targeted solutions., Methods: The National Library of Medicine PubMed database was queried using comprehensive search terms (("mild traumatic brain injury" or "concussion") and ("rural" or "low-income" or "underserved") and ("pediatric" or "child/children")) in the title, abstract, and Medical Subject Headings through December 2022. Fifteen articles on rural/underserved pediatric MTBI/concussion not covered in prior reviews were examined and organized into four topical categories: epidemiology, care practices, socioeconomic factors, and telehealth., Results: Incidences are higher for Individuals in rural regions, minorities, and those aged 0-4 years compared to their counterparts, and are increasing over time. Rural healthcare utilization rates generally exceed urban rates, and favor emergency departments (vs. primary care) for initial injury assessment. Management guidelines require customization to resource-constrained settings for implementation and adoption. Decreased community recognition of the seriousness of injury is a consensus challenge to care provision by clinicians. Low parental education and income were correlated with decreased MTBI knowledge and worse outcome. Telehealth protocols for triage/consultation and rehabilitation were feasible in improving care delivery to rural and remote settings., Conclusions: Pediatric MTBI/concussion patients in rural/underserved regions experience increased risks of injury, geographic and financial healthcare barriers, and poorer outcomes. Globally, under-reporting of injury has hindered epidemiological understanding. Ongoing MTBI education should be implemented for rural caregivers, schools, and low-income populations to improve community awareness. Telehealth can improve care delivery across acuity settings, and warrants judicious inclusion in triage and treatment protocols.

Introduction: Epidemiological evidence supports an association between higher levels of physical activity and improved cancer survival. Trial evidence is now needed to demonstrate the effect of exercise in a clinical setting. The E xercise during CH emotherapy for O varian cancer (ECHO) trial is a phase III, randomised controlled trial, designed to determine the effect of exercise on progression-free survival and physical well-being for patients receiving first-line chemotherapy for ovarian cancer., Methods and Analysis: Participants (target sample size: n=500) include women with newly diagnosed primary ovarian cancer, scheduled to receive first-line chemotherapy. Consenting participants are randomly allocated (1:1) to either the exercise intervention (plus usual care) or usual care alone, with stratification for recruitment site, age, stage of disease and chemotherapy delivery (neoadjuvant vs adjuvant). The exercise intervention involves individualised exercise prescription with a weekly target of 150 minutes of moderate-intensity, mixed-mode exercise (equivalent to 450 metabolic equivalent minutes per week), delivered for the duration of first-line chemotherapy through weekly telephone sessions with a trial-trained exercise professional. The primary outcomes are progression-free survival and physical well-being. Secondary outcomes include overall survival, physical function, body composition, quality of life, fatigue, sleep, lymphoedema, anxiety, depression, chemotherapy completion rate, chemotherapy-related adverse events, physical activity levels and healthcare usage., Ethics and Dissemination: Ethics approval for the ECHO trial (2019/ETH08923) was granted by the Sydney Local Health District Ethics Review Committee (Royal Prince Alfred Zone) on 21 November 2014. Subsequent approvals were granted for an additional 11 sites across Queensland, New South Wales, Victoria and the Australian Capital Territory. Findings from the ECHO trial are planned to be disseminated via peer-reviewed publications and international exercise and oncology conferences., Trial Registration Number: Australian New Zealand Clinical Trial Registry (ANZCTRN12614001311640; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=367123&isReview=true)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Women with advanced endometrial carcinoma (EC) with mismatch repair (MMR) deficiency have improved outcomes when treated with immune checkpoint inhibitors; however, additional biomarkers are needed to identify women most likely to respond. Scores for programmed death ligand 1 (PD-L1), immunohistochemical staining of tumor (TC+), immune cells (IC+) and presence of tumor-associated immune cells (ICP) on MMR deficient (n = 34) and proficient (n = 33) EC from women treated with durvalumab in the PHAEDRA trial (ANZGOG1601/CTC0144) (trial registration number ACTRN12617000106336, prospectively registered 19 January 2017) are reported and correlated with outcome. Receiver operating characteristic (ROC) analyses and area under the ROC curve were used to determine optimal cutpoints. Performance was compared with median cutpoints and two algorithms; a novel algorithm derived from optimal cutpoints (TC+ ≥ 1 or ICP ≥ 10 or IC+ ≥ 35) and the Ventana urothelial carcinoma (UC) algorithm (either TC+ ≥ 25, ICP > 1 and IC+ ≥ 25 or ICP = 1 and IC+ = 100). The cutpoint ICP ≥ 10 had highest sensitivity (53%) and specificity (82%), being prognostic for progression-free survival (PFS) (p = 0.01), while the optimal cutpoints algorithm was associated with overall survival (p = 0.02); these results were not significant after adjusting for MMR status. The optimal cutpoints algorithm identified non-responders (p = 0.02) with high sensitivity (88%) and negative predictive value (92%), remaining significant after adjustment for MMR. Although MMR status had the strongest association with response, further work to determine the significance of ICP ≥ 10 and the novel optimal cutpoint algorithm is needed.

Background: Epilepsy-associated psychoses are poorly understood, and management is focused on treating epilepsy. Chronic, interictal psychosis that persists despite seizure control is typically treated with antipsychotics. Whether resection of a mesial temporal lobe lesion may improve interictal psychotic symptoms that persist despite seizure control remains unknown., Observations: In a 52-year-old man with well-controlled epilepsy and persistent comorbid psychosis, brain magnetic resonance imaging (MRI) revealed an infiltrative, intraaxial, T2 fluid-attenuated inversion recovery intense mass of the left amygdala. The patient received an amygdalectomy for oncological diagnosis and surgical treatment of a presumed low-grade glioma. Pathology was ganglioglioma, World Health Organization grade I. Postoperatively, the patient reported immediate resolution of auditory hallucinations. Patient has remained seizure-free on 2 antiepileptic drugs and no antipsychotic pharmacotherapy and reported lasting improvement in his psychotic symptoms., Lessons: This report discusses improvement of psychosis symptoms after resection of an amygdalar glioma, independent of seizure outcome. This case supports a role of the amygdala in psychopathology and suggests that low-grade gliomas of the limbic system may represent, at minimum, partially reversible etiology of psychotic symptoms.

Background: Spinal granulomas form from infectious or noninfectious inflammatory processes and are rarely present intradurally. Intradural granulomas secondary to hematoma are unreported in the literature and present diagnostic and management challenges., Observations: A 70-year-old man receiving aspirin presented with encephalopathy, subacute malaise, and right lower extremity weakness and was diagnosed with polysubstance withdrawal and refractory hypertension requiring extended treatment. Seven days after admission, he reported increased bilateral lower extremity (BLE) weakness. Magnetic resonance imaging showed T2-3 and T7-8 masses abutting the pia, with spinal cord compression at T2-3. He was transferred to the authors' institution, and work-up showed no vascular shunting or malignancy. He underwent T2-3 laminectomies for biopsy/resection. A firm, xanthochromic mass was resected en bloc. Pathology showed organizing hematoma without infection, vascular malformation, or malignancy. Subsequent coagulopathy work-up was unremarkable. His BLE strength significantly improved, and he declined resection of the inferior mass. He completed physical therapy and was cleared for placement in a skilled nursing facility., Lessons: Spinal granulomas can mimic vascular lesions and malignancy. The authors present the first report of paraparesis caused by intradural granuloma secondary to organizing hematoma, preceded by severe refractory hypertension. Tissue diagnosis is critical, and resection is curative. These findings can inform the vigilant clinician for expeditious treatment.

Changes in temperature can significantly affect spectroscopic-based methods for in situ monitoring of processes. As varying temperature is inherent to many processes, associated temperature effects on spectra are unavoidable, which can hinder solute concentration determination. Ultraviolet (UV) and mid-infrared (IR) data were acquired for l-ascorbic acid (LAA) in MeCN/H 2 O (80:20 w/w) at different concentrations and temperatures. For both techniques, global partial least squares (PLS) models for prediction of LAA concentration constructed without preprocessing of the spectra required a high number of latent variables to account for the effects of temperature on the spectra (root mean square error of cross validation (RMSECV) of 0.18 and 0.16 g/100 g solvent, for UV and IR datasets, respectively). The PLS models constructed on the first derivative spectra required fewer latent variables, yielding variable results in accuracy (RMSECV of 0.23 and 0.06 g/100 g solvent, respectively). Corresponding isothermal local models constructed indicated improved model performance that required fewer latent variables in the absence of temperature effects (RMSECV of 0.01 and 0.04 g/100 g solvent, respectively). Temperature correction of the spectral data via loading space standardization (LSS) enabled the construction of global models using the same number of latent variables as the corresponding local model, which exhibited comparable model performance (RMSECV of 0.06 and 0.04 g/100 g solvent, respectively). The additional chemometric effort required for LSS is justified if prediction of solute concentration is required for in situ monitoring and control of cooling crystallization with an accuracy and precision approaching that attainable using an isothermal local model. However, the model performance with minimal preprocessing may be sufficient, for example, in the early phase development of a cooling crystallization process, where high accuracy is not always required. UV and IR spectrometries were used to determine solubility diagrams for LAA in MeCN/H 2 O (80:20 w/w), which were found to be accurate compared to those obtained using the traditional techniques of transmittance and gravimetric measurement. For both UV and IR spectrometries, solubility values obtained from models with LSS temperature correction were in better agreement with those determined gravimetrically. In this first example of the application of LSS to UV spectra, significant improvement in the predicted solute concentration is achieved with the additional chemometric effort. There is no extra experimental burden associated with the use of LSS if a structured approach is employed to acquire calibration data that account for both temperature and concentration., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Background: Urban malaria has received insufficient attention in the literature. The prevalence and clinical characteristics of Plasmodium falciparum infection amongst patients presenting with suspected malaria were investigated at a major urban hospital in Douala, Cameroon with a particular focus on anaemia., Methods: A cross-sectional, 18-week demographic and clinical survey was conducted of patients presenting to the Emergency Department of Douala Military Hospital with suspected malaria, largely defined by the presence or recent history of fever. Venous samples were tested for P. falciparum using rapid diagnostic tests and PCR, and anaemia was defined by haemoglobin level according to WHO definitions. Likelihood ratios (LR), odds ratios (OR), and population attributable risk percent (PARP) were calculated., Results: Participants were ages 8 months to 86 years, 51% were women (257/503), and all districts of Douala were represented. Overall, 38.0% (n = 189/497) were anaemic, including 5.2% (n = 26/497) with severe anaemia. Anaemia prevalence was significantly higher (OR: 2.20, 95% CI 1.41-3.45) among children < 15 years (53.1%, n = 52/98) compared to adults (34%, n = 133/392). Plasmodium falciparum was detected in 37.2% by nested PCR. Among all participants, several factors were associated with clinically significant LR for P. falciparum infection, including age 10-14 years (positive LR: 3.73), living in the island district of Douala VI (positive LR: 3.41), travel to any of three northern regions (positive LR: 5.11), and high fever > 40 °C at presentation (positive LR: 4.83). Among all participants, 8.7% of anaemia was associated with P. falciparum infection, while the PARP was 33.2% among those < 15 years of age and 81.0% among 10-14-year-olds., Conclusions: The prevalence of P. falciparum infection in the urban hospital was high. Mirroring trends in many rural African settings, older children had the highest positivity rate for P. falciparum infection. Anaemia was also common in all age groups, and for those 10-14 years of age, 80% of the risk for anaemia was associated with P. falciparum infection. Malaria rates in major urban population centres can be high, and more research into the multifactorial causes of anaemia across the age spectrum are needed., (© 2022. The Author(s).)

Objective: Broca's aphasia is a syndrome of impaired fluency with retained comprehension. The authors used an unbiased algorithm to examine which neuroanatomical areas are most likely to result in Broca's aphasia following surgical lesions., Methods: Patients were prospectively evaluated with standardized language batteries before and after surgery. Broca's area was defined anatomically as the pars opercularis and triangularis of the inferior frontal gyrus. Broca's aphasia was defined by the Western Aphasia Battery language assessment. Resections were outlined from MRI scans to construct 3D volumes of interest. These were aligned using a nonlinear transformation to Montreal Neurological Institute brain space. A voxel-based lesion-symptom mapping (VLSM) algorithm was used to test for areas statistically associated with Broca's aphasia when incorporated into a resection, as well as areas associated with deficits in fluency independent of Western Aphasia Battery classification. Postoperative MRI scans were reviewed in blinded fashion to estimate the percentage resection of Broca's area compared to areas identified using the VLSM algorithm., Results: A total of 289 patients had early language evaluations, of whom 19 had postoperative Broca's aphasia. VLSM analysis revealed an area that was highly correlated (p < 0.001) with Broca's aphasia, spanning ventral sensorimotor cortex and supramarginal gyri, as well as extending into subcortical white matter tracts. Reduced fluency scores were significantly associated with an overlapping region of interest. The fluency score was negatively correlated with fraction of resected precentral, postcentral, and supramarginal components of the VLSM area., Conclusions: Broca's aphasia does not typically arise from neurosurgical resections in Broca's area. When Broca's aphasia does occur after surgery, it is typically in the early postoperative period, improves by 1 month, and is associated with resections of ventral sensorimotor cortex and supramarginal gyri.

Globally, many populations suffer from a lack of access to basic sanitation facilities. This is partly caused by a combination of water resource shortages and the high cost of conventional centralised treatment systems. A novel decentralised treatment technology based on sub-critical hydrothermal processing of organic wastes at toilet-scale, contributes to addressing these economic and resource limitations. To be effective, this technology needs to satisfy a broad range of environmental and safety considerations, including the nature and quantity of formed gas products. We investigated the impact of four process parameters (temperature; O 2 : COD ratio (λ); time; feed solids content) on off-gas composition by quantifying volatile organic compounds (VOCs), CO, H 2 and CO 2 in factorial experiments. Temperature and λ influenced VOCs generation greatly. The lowest VOC emissions occurred at 200% λ and 300 °C. Aldehydes and ketones were mostly generated at 200% λ and intermediate temperatures, sulphur compounds in the absence of oxygen, and aromatics, furans, and pyrroles at intermediate oxygen levels and elevated temperatures. Most CO was created at 300 °C but its concentration decreased at longer processing times. Processing conditions have complex impacts and require careful consideration when designing for real world deployment., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Background: Domoic acid (DA) is a naturally occurring neurotoxin harmful to marine animals and humans. California sea lions exposed to DA in prey during algal blooms along the Pacific coast exhibit significant neurological symptoms, including epilepsy with hippocampal atrophy., Observations: Here the authors describe a xenotransplantation procedure to deliver interneuron progenitor cells into the damaged hippocampus of an epileptic sea lion with suspected DA toxicosis. The sea lion has had no evidence of seizures after the procedure, and clinical measures of well-being, including weight and feeding habits, have stabilized., Lessons: These preliminary results suggest xenotransplantation has improved the quality of life for this animal and holds tremendous therapeutic promise.

Competing Interests: Declaration of interests We declare no competing interests.

In addition to being required for protein synthesis, ribosomes and ribosomal proteins (RPs) also regulate messenger RNA translation in uninfected and virus-infected cells. By individually depleting 85 RPs using RNA interference, we found that overall protein synthesis in uninfected primary fibroblasts was more sensitive to RP depletion than those infected with herpes simplex virus-1 (HSV-1). Although representative RP depletion (uL3, uS4, uL5) inhibited protein synthesis in cells infected with two different DNA viruses (human cytomegalovirus, vaccinia virus), HSV-1-infected cell protein synthesis unexpectedly endured and required a single virus-encoded gene product, VP22. During individual RP insufficiency, VP22-expressing HSV-1 replicated better than a VP22-deficient variant. Furthermore, VP22 promotes polysome accumulation in virus-infected cells when uL3 or ribosome availability is limiting and cosediments with initiating and elongating ribosomes in infected and uninfected cells. This identifies VP22 as a virus-encoded, ribosome-associated protein that compensates for RP insufficiency to support viral protein synthesis and replication. Moreover, it reveals an unanticipated class of virus-encoded, ribosome-associated effectors that reduce the dependence of protein synthesis upon host RPs and broadly support translation during physiological stress such as infection., Competing Interests: The authors declare no competing interest.

Background/aims: Participants are integral to the success of any clinical research study, yet participant recruitment into clinical trials poses ongoing and complex challenges. It is widely accepted and recognised that clinical trial sites often find it difficult to meet recruitment goals, both in terms of accrual targets and timelines. This can impact the validity of trials or cause major delays for research. There are very few frameworks available to clinical trial sites to improve recruitment. The GREET project (Guidance to Recruitment: Examining Experiences at clinical Trial sites) sought to identify barriers to recruitment and produce formal guidance to optimise recruitment outcomes., Methods: Clinical Trials: Impact and Quality, a collaborative of sector stakeholders, convened a project team with comprehensive knowledge of the Australian clinical trials sector to undertake the GREET project. The project scope included exploration of recruitment issues at a site level across all phases of clinical trials and all types of trial sites. The scope excluded upstream issues such as protocol design and general public clinical trial awareness, participant retention and elements of recruitment outside a site's capacity to directly influence or control. The project team's extensive knowledge and experience conducting clinical trials in Australia was used to collaboratively identify a list of 24 key barriers and 12 enablers to site recruitment which formed the basis of the project. Key stakeholder groups were surveyed to challenge project team assumptions. A national and international environmental scan and literature review was conducted to identify best-practice recruitment solutions., Results: A total of 343 people responded to a survey sent to sites, sponsors, and contract research organisations, and 162 people responded to a survey sent to consumers via consumer networks. The key barriers and enablers initially identified by the project team aligned with the key outcomes of the surveys, which in turn assisted in the development of best-practice recommendations in the form of a Clinical Trial Site Recruitment Guide. Recommendations were grouped into four key themes; conducting accurate study feasibility; proactive planning during start-up; selecting optimal recruitment methods; and participant involvement. Early intervention was identified as a key facilitator in maximising improved recruitment outcomes. The GREET Clinical Trial Site Recruitment Guide is publicly accessible on the Clinical Trials: Impact and Quality website., Conclusion: Participant recruitment challenges experienced at a site level are widespread and varied, and there is no universal recruitment solution. However, this project identified that there are interventions and assessments that can be proactively implemented and selectively applied to facilitate improved recruitment outcomes.

Background: Millions have been exposed to SARS-CoV-2, but the severity of resultant infections has varied among adults and children, with adults presenting more serious symptomatic cases. Children may possess an immunity that adults lack, possibly from childhood vaccinations. This retrospective study suggests immunization against the poliovirus may provide an immunity to SARS-CoV-2. Methods: Publicly available data were analyzed for possible correlations between national median ages and epidemiological outbreak patterns across 100 countries. Sera from 204 adults and children, who were immunized with the poliovirus vaccine, were analyzed using an enzyme-linked immunosorbent assay. The effects of polio-immune serum on SARS-CoV-2-induced cytopathology in cell culture were then evaluated. Results: Analyses of median population age demonstrated a positive correlation between median age and SARS-CoV-2 prevalence and death rates. Countries with effective poliovirus immunization protocols and younger populations have fewer and less pathogenic cases of COVID-19. Antibodies to poliovirus and SARS-CoV-2 were found in pediatric sera and in sera from adults recently immunized with polio. Sera from polio-immunized individuals inhibited SARS-CoV-2 infection of Vero cell cultures. These results suggest the anti-D3-pol-antibody, induced by poliovirus vaccination, may provide a similar degree of protection from SARS-CoV-2 to adults as to children. Conclusions: Poliovirus vaccination induces an adaptive humoral immune response. Antibodies created by poliovirus vaccination bind the RNA-dependent RNA polymerase (RdRp) protein of both poliovirus and SARS-CoV-2, thereby preventing SARS-CoV-2 infection. These findings suggest proteins other than "spike" proteins may be suitable targets for immunity and vaccine development., Competing Interests: BC did not receive any personal fees from E-Mo Biology, Inc. while writing this manuscript, though is pending negotiations for future interests. JA and RC report personal fees from E-Mo Biology, Inc. YJ reports personal fees from GeneScan Diagnostics, LLC. QX holds an executive position in and reports personal fees from E-Mo Biology, Inc. E-Mo Biology, Inc. has a patent pending. 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 Comunale, Engineer, Jiang, Andrews, Liu, Ji, Yurkovich, Comunale and Xie.)

Muscle function and mass begin declining in adults long before evidence of sarcopenia and include reduced mitochondrial function, although much remains to be characterized. We found that mRNA decay factor AU-rich mRNA binding factor 1 (AUF1), which stimulates myogenesis, is strongly reduced in skeletal muscle of adult and older mice in the absence of evidence of sarcopenia. Muscle-specific adeno-associated virus (AAV)8-AUF1 gene therapy increased expression of AUF1, muscle function, and mass. AAV8 AUF1 muscle gene transfer in 12-month-old mice increased the levels of activated muscle stem (satellite) cells, increased muscle mass, reduced markers of muscle atrophy, increased markers of mitochondrial content and muscle fiber oxidative capacity, and enhanced exercise performance to levels of 3-month-old mice. With wild-type and AUF1 knockout mice and cultured myoblasts, AUF1 supplementation of muscle fibers was found to increase expression of Peroxisome Proliferator-activated Receptor Gamma Co-activator 1-alpha (PGC1α), a major effector of skeletal muscle mitochondrial oxidative metabolism. AUF1 stabilized and increased translation of the pgc1α mRNA, which is strongly reduced in adult muscle in the absence of AUF1 supplementation. Skeletal muscle-specific gene transfer of AUF1 therefore restores muscle mass, increases exercise endurance, and may provide a therapeutic strategy for age-related muscle loss., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

In the last two decades, prompted by the anticipated arrival of the 21st Century and on the centenary of the publication of the Flexner Report, many in medical education called for change to address the expanding chasm between the requirements of the health care system and the educational systems producing the health care workforce. Calls were uniform. Curricular content was missing. There was a mismatch in where people trained and where they were needed to practice, legacy approaches to pedagogical methods that needed to be challenged, an imbalance in diversity of trainees, and a lack of research on educational outcomes, resulting in a workforce that was described as ill-equipped to provide health care in the current and future environment. The Lancet Commission on Education of Health Professionals for the 21st Century published a widely acclaimed report in 2010 that called for a complete and authoritative re-examination of health professional education. This paper describes the innovations of the American Medical Association Accelerating Change in Medical Education Consortium schools as they relate to the recommendations of the Lancet Commission. We outline the successes, challenges, and lessons learned in working to deeply reform medical education.

Objective: The 2017 World Health Organization classification of pituitary adenomas identified the plurihormonal PIT-1-positive (PP1) adenoma as a distinct subtype. The reported data suggest that PP1 adenomas encompass the former class of silent subtype 3 (SS3) adenomas and might have an aggressive phenotype. In the present study, we summarized the current clinical data on PP1 and SS3 adenomas and compared the reported data with the data from a single institutional cohort., Methods: Medline and Google Scholar were searched from 1990 to 2020 for clinical series of PP1 and SS3 adenomas in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. Studies were included if they had reported pituitary pathology as PP1 or SS3 adenomas and had reported the clinical outcomes after surgical intervention. To better define the PP1 phenotype compared with non-PP1 adenomas, we also reviewed the adenomas treated surgically at our institution from 2012 to 2019., Results: Of all the tumors reported in the studies as PP1 or SS3, 99% were macroadenomas and 18% were giant adenomas (>4 cm). Of the reported patients, 31.8% had received radiotherapy, and 22.9% had undergone multiple surgeries for their pituitary tumor. In our single-center experience, 20 patients had an adenoma that met the criteria for a PP1 adenoma. Compared with the 1146 non-PP1 tumors, the PP1 tumors did not show statistically significant differences in the extent of resection, size, number of previous surgeries, future reoperations, rate of radiotherapy, p53 staining, or MIB-1 labeling index., Conclusions: The findings from the present large, single-center study comparing PP1 and non-PP1 adenomas do not suggest that PP1 tumors are more aggressive. Further work is warranted to identify the pathologic subtypes of pituitary adenomas that are consistently more clinically aggressive., (Copyright © 2021. Published by Elsevier Inc.)

A hundred years after the Flexner report laid the foundation for modern medical education, a number of authors commemorated the occasion by commenting on how the medical education system had to change once more to serve 21st century patients. Experts called for standardized outcomes and individualized learner pathways, integration of material across traditional areas, attention to an environment of inquiry, and professional identity formation. The medical education community responded and much has been achieved in the last decade, but much work remains to be done. In this paper we outline how the American Medical Association Accelerating Change in Medical Education Consortium, launched in 2013 through significant funding of transformation projects in undergraduate medical education, expanded its work into graduate medical education, and we look to the future of innovation in medical education.

Background: In this study, we assessed the activity of durvalumab, an antibody to programmed death ligand-1, in two cohorts of women with advanced endometrial cancers (AEC)-mismatch repair proficient (pMMR) and mismatch repair deficient (dMMR)., Methods: A multicenter phase two study was performed in women with AEC with pMMR tumor progressing after one to three lines of chemotherapy and women with AEC with dMMR tumor progressing after zero to three lines of chemotherapy. Mismatch repair status was based on immunohistochemistry expression. All women received durvalumab 1500 mg given every 4 weeks until progression or unacceptable toxicity. The primary endpoint was objective tumor response by RECIST V.1.1 modified for immune-based therapeutics., Results: Seventy-one women were recruited: 35 dMMR and 36 pMMR. Median follow-up was 19 vs 21 months in dMMR versus pMMR, respectively. Median age was 67 years. Histology in dMMR versus pMMR included endometrioid (94% vs 57%) and serous (0% vs 31%) and was high grade in 26% vs 74%. The objective tumor response rate (OTRR) in the dMMR cohort was 47% (17/36, 95% CI 32 to 63), including 6 complete responses and 11 partial responses (PRs)) vs 3% in the pMMR cohort (1/35, 95% CI 1 to 15, PR). In the dMMR cohort, durvalumab was the first-line therapy in 58% (OTRR 57%) and the second-line therapy in 39% (OTRR 38%). Median progression-free survival was 8.3 months in the dMMR cohort vs 1.8 months in the pMMR cohort. The 12-month overall survival (OS) rate was 71% in dMMR vs 51% in pMMR, with median OS not reached for dMMR vs 12 months for pMMR. Immune-related adverse events occurred in 14 women, mostly grades 1-2., Conclusion: Durvalumab monotherapy showed promising activity and acceptable safety in AEC with dMMR regardless of prior lines of chemotherapy, but activity was limited in AEC with pMMR., Trial Registration Numbers: ANZGOG1601, ACTRN12617000106336, and NCT03015129., Competing Interests: Competing interests: YA: honoraria from AstraZeneca and research funding from AstraZeneca. P-SK: research funding from AstraZeneca and honoraria from Pfizer. DS: stock or other ownership for SNP Pathology; honoraria from Mark Sharp & Dohme; and patents, royalties, and other intellectual property from Uniquest. MF: honoraria from Pfizer and AstraZeneca; and consulting or advisory role, or AstraZeneca and Pfizer. SB-H: consulting or advisory role from AstraZeneca, Novartis, and Pfizer; and travel and accommodation expenses from Novartis. CS: speakers’ bureau for AstraZeneca olaparib advisory board, Roche HER2+ breast cancer. JC: honoraria from Takeda, MSD; consulting or advisory role from Takeda, MSD; research funding from AstraZeneca; and travel, accommodation, and expenses from AMGEN-ESMO. PB: honoraria from Roche; consulting or advisory role from AstraZeneca; and travel and accommodation expenses from Astra Zeneca. TM: honoraria and research funding from AstraZeneca. MRS: research funding from Astra Zeneca., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This article reviews therapeutic drug monitoring (TDM) use for current inflammatory bowel disease (IBD) treatments. IBD comprises Crohn's disease and ulcerative colitis-chronic gastrointestinal inflammatory disorders. Treatment options for moderate to severe IBD include thiopurines; methotrexate; biologic agents targeting tumor necrosis factor, α4β7 integrin or interleukins 12 and 23; and Janus kinase inhibitors. TDM is recommended to guide treatment decisions for some of these agents. Published literature concerning TDM for IBD treatments was reviewed. S.D.L., R.S., and E.V.L. drew on their clinical experiences. Polymorphisms resulting in altered enzymatic activity inactivating thiopurine metabolites can lead to myelotoxicity and hepatotoxicity. Increased elimination of biologic agents can result from immunogenicity or higher disease activity, leading to low drug concentration and consequent nonresponse or loss of response. TDM may aid treatment and dose decisions for individual patients, based on monitoring metabolite levels for thiopurines, or serum drug trough concentration and antidrug antibody levels for biologic agents. Challenges remain around TDM implementation in IBD, including the lack of uniform assay methods and guidance for interpreting results. The Janus kinase inhibitor tofacitinib is not impacted by enzyme polymorphisms or disease activity, and is not expected to stimulate the formation of neutralizing antidrug antibodies. TDM is associated with implementation challenges, despite the recommendation of its use for guiding many IBD treatments. Newer small molecules with less susceptibility to patient variability factors may fulfill the unmet need of treatment options that do not require TDM, although further study is required to confirm this., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Arachnoid webs of the spine are a relatively rare entity with unique radiological findings, most notably the scalpel-sign on sagittal magnetic resonance imaging (MRI).1-4 To date there have been no videographic descriptions of the surgical treatment for this clinical entity. We present the case of a patient with progressive myelopathy and MRI showing a cervical and thoracic syrinx with a sharp transition point at the level of the T5 vertebral body. On computed tomography myelogram, there was preserved cerebrospinal fluid (CSF) in the ventral subarachnoid space-this space is often interrupted in ventral cord herniation, and preserved in dorsal arachnoid webs.5 A laminectomy with intradural excision of arachnoid web was offered and the patient consented for the procedure. Preoperatively, a fiducial screw was placed at T5. A T4-6 laminectomy was performed. A clearly compressive arachnoid web was encountered on exposure. Bands were dissected under an operating microscope, restoring normal CSF flow. Ventral dural defect was ruled out by passing a delicot beneath the cord and withdrawing it on the contralateral side. The patient did well and has shown improvement in myelopathic symptoms at 1- and 3-mo follow-up. Arachnoid webs of the spine can be treated effectively with a prudent, stepwise approach, and careful microsurgical technique. The neurosurgeon should consult closely with their neuroradiology colleagues to rule out other entities prior to the operation, such as ventral cord herniations, which can mimic dorsal arachnoid webs radiologically and clinically. We have received informed consent of the patient to submit this video., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Purple phototrophic bacteria (PPB) community, enriched from municipal wastewater, was characterized to assess their growth, tolerance, composition and potential for resource recovery from NH 4 + -rich medium. Batch experiments were conducted in tissue culture flasks and glass bottles under anaerobic conditions with infra-red lights. PPBs showed remarkable tolerance to high concentrations of NH 4 + -N and acetate. Below 1.5 g/L, growth was unaffected by NH 4 + -N with optical density at 590 nm (OD 590 ) reaching 2.6-2.9, while they could tolerate 4.5 g/L NH 4 + -N. Similarly, PPB growth was unaffected at acetate concentrations below 4 g/L and they could tolerate >20 g/L acetate. Taxonomic characterization showed that the community comprised of 37-52% PPBs (with 15-20% proteins) under different conditions, with Rhodobacter sp. over Rhodopseudomonas sp. dominating at higher NH 4 + -N concentrations. PPBs showed growth and removal rates in anaerobic digestate and accumulated 26% proteins. These results indicated the potential of PPBs in resource recovery from NH 4 + -rich wastewater., (Copyright © 2020. Published by Elsevier Ltd.)

Preclinical studies of PD-L1 and CTLA-4 blockade have relied heavily on mouse syngeneic tumor models with intact immune systems, which facilitate dissection of immunosuppressive mechanisms in the tumor microenvironment. Commercially developed monoclonal antibodies (mAbs) targeting human PD-L1, PD-1, and CTLA-4 may not demonstrate cross-reactive binding to their mouse orthologs, and surrogate anti-mouse antibodies are often used in their place to inhibit these immune checkpoints. In each case, multiple choices exist for surrogate antibodies, which differ with respect to species of origin, affinity, and effector function. To develop relevant murine surrogate antibodies for the anti-human PD-L1 mAb durvalumab and the anti-human CTLA-4 mAb tremelimumab, rat/mouse chimeric or fully murine mAbs engineered for reduced effector function were developed and compared with durvalumab and tremelimumab. Characterization included determination of target affinity, in vivo effector function, pharmacokinetic profile, and anti-tumor efficacy in mouse syngeneic tumor models. Results showed that anti-PD-L1 and anti-CTLA-4 murine surrogates with pharmacologic properties similar to those of durvalumab and tremelimumab demonstrated anti-tumor activity in a subset of commonly used mouse syngeneic tumor models. This activity was not entirely dependent on antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis effector function, or regulatory T-cell depletion, as antibodies engineered to lack these features showed activity in models historically sensitive to checkpoint inhibition, albeit at a significantly lower level than antibodies with intact effector function.

We report a systematic combinatorial exploration of affinity enhancement of antibodies by insertions and deletions (InDels). Transposon-based introduction of InDels via the method TRIAD (transposition-based random insertion and deletion mutagenesis) was used to generate large libraries with random in-frame InDels across the entire single-chain variable fragment gene that were further recombined and screened by ribosome display. Knowledge of potential insertion points from TRIAD libraries formed the basis of exploration of length and sequence diversity of novel insertions by insertional-scanning mutagenesis (InScaM). An overall 256-fold affinity improvement of an anti-IL-13 antibody BAK1 as a result of InDel mutagenesis and combination with known point mutations validates this approach, and suggests that the results of this InDel mutagenesis and conventional exploration of point mutations can synergize to generate antibodies with higher affinity., Competing Interests: Competing interest statement: M.C., J.A., D.G.R., D.C., B.P., A.B., and R.R.M. are employees of AstraZeneca.

Objective: A fundamental question in epilepsy surgery is how to delineate the margins of cortex that must be resected to result in seizure freedom. Whether and which areas showing seizure activity early in ictus must be removed to avoid postoperative recurrence of seizures is an area of ongoing research. Seizure spread dynamics in the initial seconds of ictus are often correlated with postoperative outcome; there is neither a consensus definition of early spread nor a concise summary of the existing literature linking seizure spread to postsurgical seizure outcomes. The present study is intended to summarize the literature that links seizure spread to postoperative seizure outcome and to provide a framework for quantitative assessment of early seizure spread., Methods: A systematic review was carried out according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A Medline search identified clinical studies reporting data on seizure spread measured by intracranial electrodes, having at least 10 subjects and reporting at least 1-year postoperative outcome in the English literature from 1990 to 2019. Studies were evaluated regarding support for a primary hypothesis: Areas of early seizure spread represent cortex with seizure-generating potential., Results: The search yielded 4562 studies: 15 studies met inclusion criteria and 7 studies supported the primary hypothesis. The methods and metrics used to describe seizure spread were heterogenous. The timeframe of seizure spread associated with seizure outcome ranged from 1-14 seconds, with large, well-designed, retrospective studies pointing to 3-10 seconds as most likely to provide meaningful correlates of postoperative seizure freedom., Significance: The complex correlation between electrophysiologic seizure spread and the potential for seizure generation needs further elucidation. Prospective cohort studies or trials are needed to evaluate epilepsy surgery targeting cortex involved in the first 3-10 seconds of ictus., (© 2020 International League Against Epilepsy.)

Construct: We investigated whether a situational judgment test (SJT) designed to measure professionalism in physicians predicts residents' performance on (a) Accreditation Council for Graduate Medical Education (ACGME) competencies and (b) a multisource professionalism assessment (MPA). Background: There is a consensus regarding the importance of assessing professionalism and interpersonal and communication skills in medical students, residents, and practicing physicians. Nonetheless, these noncognitive competencies are not well measured during medical education selection processes. One promising method for measuring these noncognitive competencies is the SJT. In a typical SJT, respondents are presented with written or video-based scenarios and asked to make choices from a set of alternative courses of action. Interpersonally oriented SJTs are commonly used for selection to medical schools in the United Kingdom and Belgium and for postgraduate selection of trainees to medical practice in Belgium, Singapore, Canada, and Australia. However, despite international evidence suggesting that SJTs are useful predictors of in-training performance, end-of-training performance, supervisory ratings of performance, and clinical skills licensing objective structured clinical examinations, the use of interpersonally oriented SJTs in residency settings in the United States has been infrequently investigated. The purpose of this study was to investigate whether residents' performance on an SJT designed to measure professionalism-related competencies-conscientiousness, integrity, accountability, aspiring to excellence, teamwork, stress tolerance, and patient-centered care-predicts both their current and future performance as residents on two important but conceptually distinct criteria: ACGME competencies and the MPA. Approach: We developed an SJT to measure seven dimensions of professionalism. During calendar year 2017, 21 residency programs from 2 institutions administered the SJT. We conducted analyses to determine the validity of SJT and USMLE scores in predicting milestone performance in ACGME core competency domains and the MPA in June 2017 and 3 months later in September 2017 for the MPA and 1 year later, in June 2018, for ACGME domains. Results: At both periods, the SJT score predicted overall ACGME milestone performance ( r = .13 and .17, respectively; p < .05) and MPA performance ( r = .19 and .21, respectively; p < .05). In addition, the SJT predicted ACGME patient care, systems-based practice, practice-based learning and improvement, interpersonal and communication skills, and professionalism competencies ( r = .16, .15, .15, .17, and .16, respectively; p < .05) 1 year later. The SJT score contributed incremental validity over USMLE scores in predicting overall ACGME milestone performance ( ΔR = .07) 1 year later and MPA performance ( ΔR = .05) 3 months later. Conclusions: SJTs show promise as a method for assessing noncognitive attributes in residency program applicants. The SJT's incremental validity to the USMLE series in this study underscores the importance of moving beyond these standardized tests to a more holistic review of candidates that includes both cognitive and noncognitive measures.

The postictal state following seizures is characterized by impaired consciousness and has a major negative impact on individuals with epilepsy. Previous work in disorders of consciousness including the postictal state suggests that bilateral deep brain stimulation (DBS) of the thalamic intralaminar central lateral nucleus (CL) may improve level of arousal. We tested the effects of postictal thalamic CL DBS in a rat model of secondarily generalized seizures elicited by electrical hippocampal stimulation. Thalamic CL DBS was delivered at 100 Hz during the postictal period in 21 female rats while measuring cortical electrophysiology and behavior. The postictal period was characterized by frontal cortical slow waves, like other states of depressed consciousness. In addition, rats exhibited severely impaired responses on two different behavioral tasks in the postictal state. Thalamic CL stimulation prevented postictal cortical slow wave activity but produced only modest behavioral improvement on a spontaneous licking sucrose reward task. We therefore also tested responses using a lever-press shock escape/avoidance (E/A) task. Rats achieved high success rates responding to the sound warning on the E/A task even during natural slow wave sleep but were severely impaired in the postictal state. Unlike the spontaneous licking task, thalamic CL DBS during the E/A task produced a marked improvement in behavior, with significant increases in lever-press shock avoidance with DBS compared with sham controls. These findings support the idea that DBS of subcortical arousal structures may be a novel therapeutic strategy benefitting patients with medically and surgically refractory epilepsy. SIGNIFICANCE STATEMENT The postictal state following seizures is characterized by impaired consciousness and has a major negative impact on individuals with epilepsy. For the first time, we developed two behavioral tasks and demonstrate that bilateral deep brain stimulation (DBS) of the thalamic intralaminar central lateral nucleus (CL) decreased cortical slow wave activity and improved task performance in the postictal period. Because preclinical task performance studies are crucial to explore the effectiveness and safety of DBS treatment, our work is clinically relevant as it could support and help set the foundations for a human neurostimulation trial to improve postictal responsiveness in patients with medically and surgically refractory epilepsy., (Copyright © 2020 the authors.)

Projecting landscape impacts from energy development is essential to land management decisions. We forecast landscape alteration resulting from oil and gas well-pad construction across the economically important Permian Basin of Texas and New Mexico, USA, by projecting current landscape trends through 2050. We modeled three landscape-impact scenarios (low, medium, and high) using recent (2008-2017) trends in well-pad construction and energy production. The results of low-, medium-, and high-impact scenarios suggest that ~60,000, ~180,000, and ~430,000 new well pads could be constructed, potentially causing ~1000, ~2800, and ~6700 km 2 of new direct landscape alteration. Almost two-thirds of all new well pads will be constructed within the geologic boundaries of the Delaware and Midland Basins. This translates into a 40, 120, and 300% increase in direct landscape alteration compared with direct alteration from existing well pads. We found that indirect effects (from edges) could increase by twofold, and that the ratio between indirect and direct alteration could decline by half as alteration intensifies and overlaps with existing alteration. The Chihuahuan Desert occupies the largest portion of the study area, and is projected to experience the largest area of alteration from future well-pad construction in the Permian Basin; the degree of direct alteration could increase by 70, 200, and 500% in this desert region, under low-, medium-, and high-impact scenarios. These scenarios can be used to design proactive conservation strategies to reduce landscape impacts from future oil and gas development.

Background and Importance: Apraxia of speech is a disorder of articulatory coordination and planning in speech sound production. Its diagnosis is based on deficits in articulation, prosody, and fluency. It is often described concurrent with aphasia or dysarthria, while pure apraxia of speech is a rare entity., Clinical Presentation: A right-handed man underwent focal surgical resection of a recurrent grade III astrocytoma in the left hemisphere dorsal premotor cortex located in the posterior middle frontal gyrus. After the procedure, he experienced significant long-term speech production difficulties. A battery of standard and custom language and articulatory assessments were administered, revealing intact comprehension and naming abilities, and preserved strength in orofacial articulators, but considerable deficits in articulatory coordination, fluency, and prosody-consistent with diagnosis of pure apraxia of speech. Tractography and resection volumes compared with publicly available imaging data from the Human Connectome Project suggest possible overlap with area 55b, an under-recognized language area in the dorsal premotor cortex and has white matter connectivity with the superior longitudinal fasciculus., Conclusion: The case reported here details a rare clinical entity, pure apraxia of speech resulting from resection of posterior middle frontal gyrus. While not a classical language area, emerging literature supports the role of this area in the production of fluent speech, and has implications for surgical planning and the general neurobiology of language., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Non-communicable diseases (NCDs) are medical conditions that, by definition, are non-infectious and non-transmissible among people. Much of current NCDs are generally due to genetic, behavioral, and metabolic risk factors that often include excessive alcohol consumption, smoking, obesity, and untreated elevated blood pressure, and share many common signal transduction pathways. Alterations in cell and physiological signaling and transcriptional control pathways have been well studied in several human NCDs, but these same pathways also regulate expression and function of the protein synthetic machinery and mRNA translation which have been less well investigated. Alterations in expression of specific translation factors, and disruption of canonical mRNA translational regulation, both contribute to the pathology of many NCDs. The two most common pathological alterations that contribute to NCDs discussed in this review will be the regulation of eukaryotic initiation factor 2 (eIF2) by the integrated stress response (ISR) and the mammalian target of rapamycin complex 1 (mTORC1) pathways. Both pathways integrally connect mRNA translation activity to external and internal physiological stimuli. Here, we review the role of ISR control of eIF2 activity and mTORC1 control of cap-mediated mRNA translation in some common NCDs, including Alzheimer's disease, Parkinson's disease, stroke, diabetes mellitus, liver cirrhosis, chronic obstructive pulmonary disease (COPD), and cardiac diseases. Our goal is to provide insights that further the understanding as to the important role of translational regulation in the pathogenesis of these diseases.

Recent work suggests an important role for cortical-subcortical networks in seizure-related loss of consciousness. Temporal lobe seizures disrupt subcortical arousal systems, which may lead to depressed cortical function and loss of consciousness. Extracellular recordings show ictal neocortical slow waves at about 1 Hz, but it is not known whether these simply represent seizure propagation or alternatively deep sleep-like activity, which should include cortical neuronal Up and Down states. In this study, using in vivo whole-cell recordings in a rat model of focal limbic seizures, we directly examine the electrophysiological properties of cortical neurons during seizures and deep anesthesia. We found that during seizures, the membrane potential of frontal cortical secondary motor cortex layer 5 neurons fluctuates between Up and Down states, with decreased input resistance and increased firing rate in Up states when compared to Down states. Importantly, Up and Down states in seizures are not significantly different from those in deep anesthesia, in terms of membrane potential, oscillation frequency, firing rate, and input resistance. By demonstrating these fundamental similarities in cortical electrophysiology between deep anesthesia and seizures, our results support the idea that a state of decreased cortical arousal may contribute to mechanisms of loss of consciousness during seizures., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)