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Tumor Treating Fields (TTFields), an approved therapy for glioblastoma (GBM) and malignant mesothelioma, employ noninvasive application of low-intensity, intermediate-frequency, alternating electric fields to disrupt the mitotic spindle, leading to chromosome missegregation and apoptosis. Emerging evidence suggests that TTFields may also induce inflammation. However, the mechanism underlying this property and whether it can be harnessed therapeutically are unclear. Here, we report that TTFields induced focal disruption of the nuclear envelope, leading to cytosolic release of large micronuclei clusters that intensely recruited and activated 2 major DNA sensors — cyclic GMP-AMP synthase (cGAS) and absent in melanoma 2 (AIM2) — and their cognate cGAS/stimulator of interferon genes (STING) and AIM2/caspase 1 inflammasomes to produce proinflammatory cytokines, type 1 interferons (T1IFNs), and T1IFN-responsive genes. In syngeneic murine GBM models, TTFields-treated GBM cells induced antitumor memory immunity and a cure rate of 42% to 66% in a STING- and AIM2-dependent manner. Using single-cell and bulk RNA sequencing of peripheral blood mononuclear cells, we detected robust post-TTFields activation of adaptive immunity in patients with GBM via a T1IFN-based trajectory and identified a gene panel signature of TTFields effects on T cell activation and clonal expansion. Collectively, these studies defined a therapeutic strategy using TTFields as cancer immunotherapy in GBM and potentially other solid tumors.

Advances in biofabrication technology enable 3D printed constructs to resemble real tissues, but it remains unclear how cell-generated forces deform these constructs. Here the authors investigate mechanical behaviours of 3D printed “microbeams” made from mixtures of living cells and extracellular matrix.

BackgroundThe COVID-19 pandemic has placed excessive strain on health care systems and is especially evident in treatment decision-making for cancer patients. Glioblastoma (GBM) patients are among the most vulnerable due to increased incidence in the elderly and the short survival time. A virtual meeting was convened on May 9, 2020 with a panel of neuro-oncology experts with experience using Tumor Treating Fields (TTFields). The objective was to assess the risk-to-benefit ratio and provide guidance for using TTFields in GBM during the COVID-19 pandemic.Panel DiscussionTopics discussed included support and delivery of TTFields during the COVID-19 pandemic, concomitant use of TTFields with chemotherapy, and any potential impact of TTFields on the immune system in an intrinsically immunosuppressed GBM population. Special consideration was given to TTFields' use in elderly patients and in combination with radiotherapy regimens. Finally, the panel discussed the need to better capture data on COVID-19–positive brain tumor patients to analyze longitudinal outcomes and changes in treatment decision-making during the pandemic.Expert OpinionTTFields is a portable home-use device which can be managed via telemedicine and safely used in GBM patients during the COVID-19 pandemic. TTFields has no known immunosuppressive effects which is important during a crisis where other treatment methods might be limited, especially for elderly patients with multiple co-morbidities. It is too early to estimate the full impact of COVID-19 on the global healthcare system and on patient outcomes and the panel strongly recommended collaboration with existing cancer COVID-19 registries to follow CNS tumor patients.

Abstract Background Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. Methods After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). Results For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. Conclusions Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1; initially registered 19 September 2002

Summary: Accurately predicting cardioactive effects of new molecular entities for therapeutics remains a daunting challenge. Immense research effort has been focused toward creating new screening platforms that utilize human pluripotent stem cell (hPSC)-derived cardiomyocytes and three-dimensional engineered cardiac tissue constructs to better recapitulate human heart function and drug responses. As these new platforms become increasingly sophisticated and high throughput, the drug screens result in larger multidimensional datasets. Improved automated analysis methods must therefore be developed in parallel to fully comprehend the cellular response across a multidimensional parameter space. Here, we describe the use of machine learning to comprehensively analyze 17 functional parameters derived from force readouts of hPSC-derived ventricular cardiac tissue strips (hvCTS) electrically paced at a range of frequencies and exposed to a library of compounds. A generated metric is effective for then determining the cardioactivity of a given drug. Furthermore, we demonstrate a classification model that can automatically predict the mechanistic action of an unknown cardioactive drug. : Analysis methods must be improved in parallel with advancements in drug screening platforms. Machine learning principles are used here to analyze multidimensional datasets to determine cardioactivity of unknown drugs. Furthermore, this study describes the use of multiclassification algorithms to classify unknown drugs based on their mechanistic action and compare their potency with related drugs. Keywords: human pluripotent stem cell-derived cardiomyocytes, drug-induced cardiotoxicity, machine learning, human engineered cardiac tissue, drug classification library

Patients with bevacizumab-refractory recurrent glioblastoma multiforme (GBM) have a poor prognosis. We propose that instead of continuing on bevacizumab, patients should switch to treatment with Optune™, a novel antimitotic Tumor-Treating Fields (TTFields) therapy approved in the United States for newly diagnosed and recurrent GBM. This would reserve bevacizumab for subsequent disease progression. In this case series, we describe 8 patients with recurrent GBM who had disease progression on bevacizumab, discontinued bevacizumab treatment, and were treated with TTFields therapy alone. After subsequent radiographic or clinical progression, 5 patients were rechallenged with bevacizumab in a ‘pulse dose' fashion, an approach not previously described. Following treatment with TTFields therapy, median overall survival (OS) was 216 days (7.2 months). Median OS from last dose of initial bevacizumab was 237 days (7.9 months), twice that of historical controls for bevacizumab failures, and median OS from the first dose of bevacizumab rechallenge was 172 days (5.7 months). TTFields therapy was well tolerated, with a mean adherence rate of 74.2% (range, 48.2-92.9%). These results support the use of TTFields therapy with pulse dose bevacizumab as an option in patients with refractory GBM.

Glioblastoma harbors a dynamic subpopulation of glioblastoma stem-like cells (GSCs) that can propagate tumors in vivo and is resistant to standard chemoradiation. Identification of the cell-intrinsic mechanisms governing this clinically important cell state may lead to the discovery of therapeutic strategies for this challenging malignancy. Here, we demonstrate that the mitotic E3 ubiquitin ligase CDC20-anaphase-promoting complex (CDC20-APC) drives invasiveness and self-renewal in patient tumor-derived GSCs. Moreover, CDC20 knockdown inhibited and CDC20 overexpression increased the ability of human GSCs to generate brain tumors in an orthotopic xenograft model in vivo. CDC20-APC control of GSC invasion and self-renewal operates through pluripotency-related transcription factor SOX2. Our results identify a CDC20-APC/SOX2 signaling axis that controls key biological properties of GSCs, with implications for CDC20-APC-targeted strategies in the treatment of glioblastoma.

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.

Cyclin-dependent kinases 4 and 6 (CDK4/6) play critical roles in the G1 to S checkpoint of the cell cycle and have been shown to be overactive in several human cancers. Small-molecule inhibitors of CDK4/6 have demonstrated significant efficacy against many solid tumors. Since CDK4/6 inhibition is thought to induce cell cycle arrest at the G1/S checkpoint, much interest has been focused on combining CDK4/6 inhibitors with cytotoxic agents active against the S or M phase of the cell cycle to enhance therapeutic efficacy. However, it remains unclear how best to combine these two classes of drugs to avoid their potentially antagonistic effects. Here, we test various combinations of highly selective and potent CDK4/6 inhibitors with commonly used cytotoxic drugs in several cancer cell lines derived from lung, breast and brain cancers, for their cell-killing effects as compared to monotherapy. All combinations, either concurrent or sequential, failed to enhance cell-killing effects. Importantly, in certain schedules, especially pre-treatment with a CDK4/6 inhibitor, combining these drugs resulted in reduced cytotoxicity of cytotoxic agents. These findings urge cautions when combining these two classes of agents in clinical settings.

BACKGROUND:Poor central nervous system penetration of cytotoxic drugs due to the blood brain barrier (BBB) is a major limiting factor in the treatment of brain tumors. Most recurrent glioblastomas (GBM) occur within the peritumoral region. In this study, we describe a hyperthemic method to induce temporary disruption of the peritumoral BBB that can potentially be used to enhance drug delivery. METHODS:Twenty patients with probable recurrent GBM were enrolled in this study. Fourteen patients were evaluable. MRI-guided laser interstitial thermal therapy was applied to achieve both tumor cytoreduction and disruption of the peritumoral BBB. To determine the degree and timing of peritumoral BBB disruption, dynamic contrast-enhancement brain MRI was used to calculate the vascular transfer constant (Ktrans) in the peritumoral region as direct measures of BBB permeability before and after laser ablation. Serum levels of brain-specific enolase, also known as neuron-specific enolase, were also measured and used as an independent quantification of BBB disruption. RESULTS:In all 14 evaluable patients, Ktrans levels peaked immediately post laser ablation, followed by a gradual decline over the following 4 weeks. Serum BSE concentrations increased shortly after laser ablation and peaked in 1-3 weeks before decreasing to baseline by 6 weeks. CONCLUSIONS:The data from our pilot research support that disruption of the peritumoral BBB was induced by hyperthemia with the peak of high permeability occurring within 1-2 weeks after laser ablation and resolving by 4-6 weeks. This provides a therapeutic window of opportunity during which delivery of BBB-impermeant therapeutic agents may be enhanced. TRIAL REGISTRATION:ClinicalTrials.gov NCT01851733.

Objective: Facial feminization surgery (FFS) treats gender dysphoria in transfeminine patients by addressing the facial bony and soft tissue components. Individuals seeking FFS may be taking gender-affirming hormone replacement therapy [gender-affirming hormone therapy (GAHT)]. This study aims to better characterize the GAHT's impact on venous thromboembolism (VTE) risk, surgical planning, and outcomes., Methods: A systematic review and meta-analysis of the literature were carried out to assess the effect of perioperative GAHT continuation on VTE. Cochrane Q and I2 statistics measured study heterogeneity with the following meta-regression exploring these results. Simultaneously, a retrospective review of the senior author's FFS cohort was conducted to investigate GAHT duration's impact on FFS revision rate, complication incidence, and facial structures operated on., Results: Eleven articles were included: 602 patients stopped GAHT, of whom 3 VTEs were recorded (0.49%). This is compared with one episode among the 925 who continued GAHT perioperatively (0.11%). Study heterogeneity was low (0%), but limited VTE sample size precluded meta-analytic conclusions. Gender-affirming hormone therapy duration does not impact the incidence of all-cause complications (P = 0.478), wound infection (P = 0.283), hematoma (P = 0.283), or VTE (P = 1). The only procedures significantly less associated with higher GAHT were tracheal shaving (P = 0.002) and mandibuloplasty (P = 0.003). Finally, the FFS revision rate was not associated with GAHT duration (P = 0.06)., Conclusion: There is a paucity of data to assess the safety or harm of continuing GAHT in the FFS perioperative period. Thus, a shared provider-patient decision-making process examining the risks and benefits of GAHT perioperative continuation is warranted. As patients seeking gender-affirming care are diverse, a "one-protocol-fits-all" is not appropriate., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Purpose: To report two patient cases demonstrating the management of refractory macular holes through the application of temporary thin amniotic membrane grafts, followed by subsequent graft removal upon achieving hole closure., Methods: Comprehensive chart and literature review was conducted utilizing the PubMed database., Results: We describe two patients who underwent repeat pars plana vitrectomy for treatment of refractory macular holes. In both cases, the epi-retinal placement of a thin amniotic membrane graft (AMG) was done to achieve hole closure. Following a period of retinal stabilization, the amniotic membranes were removed due to the healthy appearance of the outer retinal layers and the ellipsoid zone, ultimately resulting in an improved final visual acuity in both patients., Conclusion: This case series demonstrates a new approach of using a temporary AMG to close refractory macular holes. After graft removal, both patients reported enhanced visual acuity and subjective visual improvement, accompanied by the stable closure of macular holes on serial OCT scans., Competing Interests: Conflicts of Interest: All authors of this work have no financial disclosures.

Background: Facial feminization surgery (FFS) is an emerging practice that falls under the broader umbrella of gender-affirming surgery. Various approaches exist to feminize the face, yet few published articles describe in detail the techniques of each component procedure. Considering the diversity of interventions employed, the objective of this manuscript is to highlight FFS techniques utilized by the senior author and create a corresponding media gallery., Methods: All patients with the diagnosis of gender dysphoria that were referred to the senior author for FFS consultation between June 2017 and August 2022 were reviewed. Data were retrospectively collected from electronic medical records according to the institutional review board (IRB)-approved study protocol. Data collected and analyzed included demographics, operative documentation, and postoperative follow-up. Multimedia material was collected intraoperatively and postoperatively., Results: A total of 231 patients underwent 262 operations with a total of 1224 FFS procedures. The average follow-up time was 7.7 ± 11 months. Out of the 262 operations, 24 (9.2%) patients experienced minor complications, including 3 (1.1%) with wound dehiscence, 13 (5.0%) with hematomas, and 14 (5.3%) with postoperative infection requiring antibiotics. Of those, 3 (1.1%) required a return to the operating room for washout or removal of malar implants., Conclusion: Although there is a consensus on the fundamental surgical principles to achieve adequate feminization of the facial architecture, the specific techniques to do so differ according to individual practices. As techniques diverge, so do their risk profiles and outcomes; techniques must, thus, align with patients' interventional goals. The material presented here is one of many that can support trainees and junior surgeons as they build a gender-affirming practice., Competing Interests: Conflicts of interest and sources of funding: None of the authors have any conflicts of interest to declare and have financial interests in any of the products, devices, or drugs mentioned in this manuscript., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The pediatric craniofacial trauma literature is limited to single institutions or short study periods. Herein, this study analyzes a national database over 10 years to delineate the epidemiology of pediatric craniofacial fractures and to identify risk factors for acute-level hospital course in the largest series to date., Methods: Utilizing the National Trauma Data Bank, pediatric craniofacial fractures admitted between 2010 and 2019 were identified. Descriptive analyses and multivariable regression were performed to identify risk factors for acute-level hospital course., Results: A total of 155,136 pediatric craniofacial fracture cases were reviewed, including cranial vault (49.0%), nasal (22.4%), midface (21.0%), mandibular (20.2%), and orbital floor fractures (13.7%). Midface and orbital floor fractures occurred commonly as multicraniofacial fractures. Cranial vault fractures were the most common among all age groups, but frequency declined with age. In contrast, facial fractures increased with age. Despite the inherent complexity of multicraniofacial trauma, isolated fractures remained a concern for acute-level hospital course.Cranial vault and midface fractures had an increased risk of intracranial injury and intensive care unit admission (P<0.001). Mandibular and midface fractures had an increased risk for cervical spine fracture and tracheostomy (P<0.001). Patient and injury-specific risk factors among the fractures with the strongest association for each outcome-cranial vault and mandible-were identified., Conclusions: The inherent limitations of prior studies-geographical biases, small cohorts, and short-term study periods-were addressed. Describing the independent contribution of each craniofacial fracture to the risk of acute-level hospital course outcomes can be employed to better optimize risk stratification, counseling, and management., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Intraosseous basivertebral nerve ablation is indicated for the treatment of chronic vertebrogenic low back pain with failure of at least 6 months of conservative treatment. This article details patient positioning and setup, step-by-step instructions for the procedure, and postoperative management. Pearls and pitfalls are also discussed. In addition, an instructional procedure video accompanies this paper and can be found online (at https://vimeo.com/791578426/de0e90cfbe)., Competing Interests: Dr Schroeder has received funds to travel from AOSpine and Medtronic. The remaining authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: A study previously conducted in primary care practices found that implementation of an educational session and peer comparison feedback was associated with reduced antibiotic prescribing for respiratory tract diagnoses (RTDs). Here, we assess the long-term effects of this intervention on antibiotic prescribing following cessation of feedback., Methods: RTD encounters were grouped into tiers based on antibiotic prescribing appropriateness: tier 1, almost always indicated; tier 2, possibly indicated; and tier 3, rarely indicated. A χ2 test was used to compare prescribing between 3 time periods: pre-intervention, intervention, and post-intervention (14 months following cessation of feedback). A mixed-effects multivariable logistic regression analysis was performed to assess the association between period and prescribing., Results: We analyzed 260 900 RTD encounters from 29 practices. Antibiotic prescribing was more frequent in the post-intervention period than in the intervention period (28.9% vs 23.0%, P < .001) but remained lower than the 35.2% pre-intervention rate (P < .001). In multivariable analysis, the odds of prescribing were higher in the post-intervention period than the intervention period for tier 2 (odds ratio [OR], 1.19; 95% confidence interval [CI]: 1.10-1.30; P < .05) and tier 3 (OR, 1.20; 95% CI: 1.12-1.30) indications but was lower compared to the pre-intervention period for each tier (OR, 0.66; 95% CI: 0.59-0.73 tier 2; OR, 0.68; 95% CI: 0.61-0.75 tier 3)., Conclusions: The intervention effects appeared to last beyond the intervention period. However, without ongoing provider feedback, there was a trend toward increased prescribing. Future studies are needed to determine optimal strategies to sustain intervention effects., Competing Interests: Potential conflicts of interest. W. B. B. reports participation on multiple data and safety monitoring boards (DSMBs) for Genentech, all unrelated to this work. M. Z. D. reports grants to their institution for research projects from the National Institute of Allergy and Infectious Diseases, National Institutes of Health and the CDC; a grant to their institution for a research study from Contrafect; a contract with their institution for a research study from GSK; consulting fees paid to their institution for a scientific report from Johnson & Johnson; honorarium for a lecture and travel reimbursement from the University of Iowa; and paid participation on a DSMB or advisory board for GSK. L. D. reports contracts and grants paid to their institution from the CDC and a role with the Society for Healthcare Epidemiology of the America Public Policy and Government Affairs Committee (member 2019–2022). K. W. H. reports contracts and grants paid to their institution from the CDC. J. J. H. reports an ID Week 2022 Fellow Travel Award. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Purpose: This study investigates whether the intraoral approach to mandibular open reduction and internal fixation, through exposure to the oral cavity's microbiome, results in higher infection rates compared to the extraoral approach, thus addressing a critical public health concern, potentially offering an opportunity to reduce health-care costs, and aiming to guide effective clinical practice., Methods: In this systematic review with meta-analyses, a review of the literature was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. A comprehensive literature search was conducted using Embase and PubMed for articles published between 1989 and 2023. Inclusion criteria targeted studies on open reduction and internal fixation mandibular fractures comparing intraoral and extraoral approaches and reporting infection rates. Exclusion criteria eliminated non-English articles, case reports, and studies with insufficient approach-specific data. The primary outcome was the postoperative infection rate, with surgical approach as the predictor. Covariates such as age, sex, diabetes, and smoking status were included when reported. Data were analyzed using R software, employing random-effects models due to anticipated heterogeneity (I 2 statistics)., Results: From 61 studies, 11 provided direct comparisons involving 1,317 patients-937 intraoral and 380 extraoral. Infection rates were 5.9% for intraoral and 10% for extraoral approaches. Pooled relative risk was 0.94 [95% confidence interval, 0.63, 1.39], suggesting no significant risk difference. Prevalence of infections was estimated at 9% for intraoral and 6.1% for extraoral procedures, with significant heterogeneity (I 2  = 84% for intraoral and 56% for extraoral)., Conclusion: Our meta-analysis found no significant difference in infection rates between the two approaches. There is opportunity to expand on reporting complication rates comparing the various approaches to mandibular fixation. Until these data are presented, surgeon preference may dictate the operative approach to expose the mandible for reduction and fixation., (Copyright © 2024 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Oncoplastic breast-conserving surgery (OBCS) has demonstrated superior cosmetic outcomes to traditional breast-conserving surgery (BCS) while maintaining oncologic safety. While prior studies have compared OBCS to mastectomy, there is a scarcity of literature on the impact of social determinants of health on outcomes. Furthermore, although traditionally tumors larger than 5 cm and multifocal disease were treated with mastectomy, the literature has now shown OBCS to be safe in treating such disease. As a result, patients with large or multifocal tumors could be eligible for both mastectomy and OBCS, which prompts the need for comparison between the two. Thus, the aim of our study was to compare OBCS and mastectomy with reconstruction using BREAST-Q and oncologic outcome measures, as well as stratify these outcomes based on race, ethnicity, and body mass index (BMI)., Methods: A retrospective chart review was performed for 57 patients treated with OBCS and 204 patients treated with mastectomy with reconstruction from 2015 to 2021. Variables including age, race, ethnicity, BMI, insurance status, surgery type, pathology, recurrence, and complications were recorded. Patient-reported outcomes (PROs) were recorded using BREAST-Q pre- and post-operatively., Results: Despite having a higher BMI (P<0.001), OBCS yielded higher "satisfaction with breast" and "satisfaction with outcome" than mastectomy (P=0.02 and P=0.02, respectively). When stratified by race, there were no statistical differences in the PROs between the two surgeries for Hispanic nor African American patients. OBCS had a significantly lower rate of infection and fewer additional surgeries than mastectomy (P=0.004 and P<0.001, respectively). There were no differences in positive margin rate or recurrence rate between the groups., Conclusions: In our study, OBCS yielded better PROs than mastectomy while maintaining oncologic safety and resulting in fewer surgeries and complications. These excellent outcomes in a majority non-Caucasian cohort support the utilization of OBCS for underserved, minority populations. Larger studies evaluating PROs in diverse and uninsured groups are needed to reinforce these conclusions., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-23-403/coif). The authors have no conflicts of interest to declare., (2024 Gland Surgery. All rights reserved.)

Objectives: Patients at risk of adverse effects related to positive fluid balance could benefit from fluid intake optimization. Less attention is paid to nonresuscitation fluids. We aim to evaluate the heterogeneity of fluid intake at the initial phase of resuscitation., Design: Prospective multicenter cohort study., Setting: Thirty ICUs across France and one in Spain., Patients: Patients requiring vasopressors and/or invasive mechanical ventilation., Interventions: None., Measurements and Main Results: All fluids administered by vascular or enteral lines were recorded over 24 hours following admission and were classified in four main groups according to their predefined indication: fluids having a well-documented homeostasis goal (resuscitation fluids, rehydration, blood products, and nutrition), drug carriers, maintenance fluids, and fluids for technical needs. Models of regression were constructed to determine fluid intake predicted by patient characteristics. Centers were classified according to tertiles of fluid intake. The cohort included 296 patients. The median total volume of fluids was 3546 mL (interquartile range, 2441-4955 mL), with fluids indisputably required for body fluid homeostasis representing 36% of this total. Saline, glucose-containing high chloride crystalloids, and balanced crystalloids represented 43%, 27%, and 16% of total volume, respectively. Whatever the class of fluids, center of inclusion was the strongest factor associated with volumes. Compared with the first tertile, the difference between the volume predicted by patient characteristics and the volume given was +1.2 ± 2.0 L in tertile 2 and +3.0 ± 2.8 L in tertile 3., Conclusions: Fluids indisputably required for body fluid homeostasis represent the minority of fluid intake during the 24 hours after ICU admission. Center effect is the strongest factor associated with the volume of fluids. Heterogeneity in practices suggests that optimal strategies for volume and goals of common fluids administration need to be developed., Competing Interests: Dr. Constan’s institution received funding from the French Intensive Care Society/Société de Réanimation de Langue Française. Dr. Senay disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Abstract: Subarachnoid hemorrhage due to cerebral aneurysm rupture is a devastating event with a high mortality and significant morbidity. The safety of patients undergoing electroconvulsive therapy (ECT) in the presence of an aneurysm is not clear and is a cause of anxiety for both health care workers and patients. The present article collated the available evidence related to ECT in the presence of an aneurysm and found that there were no case reports where ECT directly led to the rupture of an aneurysm, although 1 case reported a rupture of an aneurysm between sessions of ECT. The epidemiology of cerebral aneurysms is discussed, as are key clinical considerations related to the care of patients with aneurysms who require ECT., Competing Interests: The authors have no conflicts of interest or financial disclosures to report., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Schrenkiella parvula, a leading extremophyte model in Brassicaceae, can grow and complete its lifecycle under multiple environmental stresses, including high salinity. Yet, the key physiological and structural traits underlying its stress-adapted lifestyle are unknown along with trade-offs when surviving salt stress at the expense of growth and reproduction. We aimed to identify the influential adaptive trait responses that lead to stress-resilient and uncompromised growth across developmental stages when treated with salt at levels known to inhibit growth in Arabidopsis and most crops. Its resilient growth was promoted by traits that synergistically allowed primary root growth in seedlings, the expansion of xylem vessels across the root-shoot continuum, and a high capacity to maintain tissue water levels by developing thicker succulent leaves while enabling photosynthesis during salt stress. A successful transition from vegetative to reproductive phase was initiated by salt-induced early flowering, resulting in viable seeds. Self-fertilization in salt-induced early flowering was dependent upon filament elongation in flowers otherwise aborted in the absence of salt during comparable plant ages. The maintenance of leaf water status promoting growth, and early flowering to ensure reproductive success in a changing environment, were among the most influential traits that contributed to the extremophytic lifestyle of S. parvula., (© 2023 Society for Experimental Biology and John Wiley & Sons Ltd.)

Objective: Stereotactic radiosurgery (SRS) for operative brain metastasis (BrM) is usually administered 1 to 6 weeks after resection. Preoperative versus postoperative timing of SRS delivery related to surgery remains a critical question, as a pattern of failure is the development of leptomeningeal disease (LMD) in as many as 35% of patients who undergo postoperative SRS or the occurrence of radiation necrosis. As they await level I clinical data from ongoing trials, the authors aimed to bridge the gap by comparing postoperative with simulated preoperative single-fraction SRS dosimetry plans for patients with surgically resected BrM., Methods: The authors queried their institutional database to retrospectively identify patients who underwent postoperative Gamma Knife SRS (GKSRS) after resection of BrM between January 2014 and January 2021. Exclusion criteria were prior radiation delivered to the lesion, age < 18 years, and prior diagnosis of LMD. Once identified, a simulated preoperative SRS plan was designed to treat the unresected BrM and compared with the standard postoperative treatment delivered to the resection cavity per Radiation Therapy Oncology Group (RTOG) 90-05 guidelines. Numerous comparisons between preoperative and postoperative GKSRS treatment parameters were then made using paired statistical analyses., Results: The authors' cohort included 45 patients with a median age of 59 years who were treated with GKSRS after resection of a BrM. Primary cancer origins included colorectal cancer (27%), non-small cell lung cancer (22%), breast cancer (11%), melanoma (11%), and others (29%). The mean tumor and cavity volumes were 15.06 cm3 and 12.61 cm3, respectively. In a paired comparison, there was no significant difference in the planned treatment volumes between the two groups. When the authors compared the volume of surrounding brain that received 12 Gy or more (V12Gy), an important predictor of radiation necrosis, 64% of patient plans in the postoperative SRS group (29/45, p = 0.008) recorded greater V12 volumes. Preoperative plans were more conformal (p < 0.001) and exhibited sharper dose drop-off at the lesion margins (p = 0.0018) when compared with postoperative plans., Conclusions: Comparison of simulated preoperative and delivered postoperative SRS plans administered to the BrM or resection cavity suggested that preoperative SRS allows for more highly conformal lesional coverage and sharper dose drop-off compared with postoperative plans. Furthermore, V12Gy was lower in the presurgical GKSRS plans, which may account for the decreased incidence of radiation necrosis seen in prior retrospective studies.

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Malar augmentation is a key procedure sought out by transfeminine individuals seeking to feminize their facial appearance. Different surgical techniques have been described in the literature including fat transfer to the cheeks and malar implant placement. Because of the paucity of information in the literature, there is no consensus on best practices for this procedure. The objective of our study is to determine the effectiveness and safety of malar implants as compared with fat transfer to the cheeks in transfeminine individuals., Methods: We examined all patients with the diagnosis of gender dysphoria that were referred to the senior author seeking consultation for feminizing facial procedures between June 2017 and August 2022. Patients who underwent fat transfer to the cheeks or malar implant placement were included in our study. We reviewed the electronic medical record of each patient, and we retrieved and analyzed data regarding demographics, medical and surgical history, operative dictations, clinic notes, and postoperative follow-up. Univariate analysis was used to assess for differences in postoperative complications between these 2 groups., Results: We identified 231 patients underwent feminizing facial gender affirming surgery, with 152 patients receiving malar augmentation through malar implants or fat grafting. One hundred twenty-nine patients (84.9%) underwent malar implant placement and 23 (15.1%) underwent fat grafting to the cheeks. The mean follow-up time was 3.6 ± 2.7 months. Patient satisfaction was greater in the malar implant group (126/129, 97.7%) compared with the fat transfer group (20/23, 87%, P < 0.045). Two patients who received implants (1.8%) experienced postoperative complications. No patient undergoing fat transfer experiences similar adverse outcomes. Nevertheless, the difference was not statistically significant (P = 1.00)., Conclusions: Our findings support the contention that malar implants are a safe alternative for malar augmentation among transfeminine individuals. While autologous fat transfer to the cheek is an indispensable option in patients requiring minor malar enhancement, malar implants offer a more permanent option with a better aesthetic outcome in patients requiring major malar enhancement. To minimize postoperative complications, surgeons should emphasize patient compliance with postoperative directions., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The benefit-risk ratio of prophylactic non-invasive ventilation (NIV) and high-flow nasal oxygen therapy (HFNC-O 2 ) during the early stage of blunt chest trauma remains controversial because of limited data. The main objective of this study was to compare the rate of endotracheal intubation between two NIV strategies in high-risk blunt chest trauma patients., Methods: The OptiTHO trial was a randomized, open-label, multicenter trial over a two-year period. Every adult patients admitted in intensive care unit within 48 h after a high-risk blunt chest trauma (Thoracic Trauma Severity Score ≥ 8), an estimated PaO 2 /FiO 2 ratio < 300 and no evidence of acute respiratory failure were eligible for study enrollment (Clinical Trial Registration: NCT03943914). The primary objective was to compare the rate of endotracheal intubation for delayed respiratory failure between two NIV strategies: i) a prompt association of HFNC-O 2 and "early" NIV in every patient for at least 48 h with vs. ii) the standard of care associating COT and "late" NIV, indicated in patients with respiratory deterioration and/or PaO 2 /FiO 2 ratio ≤ 200 mmHg. Secondary outcomes were the occurrence of chest trauma-related complications (pulmonary infection, delayed hemothorax or moderate-to-severe ARDS)., Results: Study enrollment was stopped for futility after a 2-year study period and randomization of 141 patients. Overall, 11 patients (7.8%) required endotracheal intubation for delayed respiratory failure. The rate of endotracheal intubation was not significantly lower in patients treated with the experimental strategy (7% [5/71]) when compared to the control group (8.6% [6/70]), with an adjusted OR = 0.72 (95%IC: 0.20-2.43), p = 0.60. The occurrence of pulmonary infection, delayed hemothorax or delayed ARDS was not significantly lower in patients treated by the experimental strategy (adjusted OR = 1.99 [95%IC: 0.73-5.89], p = 0.18, 0.85 [95%IC: 0.33-2.20], p = 0.74 and 2.14 [95%IC: 0.36-20.77], p = 0.41, respectively)., Conclusion: A prompt association of HFNC-O 2 with preventive NIV did not reduce the rate of endotracheal intubation or secondary respiratory complications when compared to COT and late NIV in high-risk blunt chest trauma patients with non-severe hypoxemia and no sign of acute respiratory failure., Clinical Trial Registration: NCT03943914, Registered 7 May 2019., (© 2023. The Author(s).)

There are over 43 million individuals in the world who are blind. As retinal ganglion cells are incapable of regeneration, treatment modalities for this condition are limited. Since first incepted in 1885, whole-eye transplantation (WET) has been proposed as the ultimate cure for blindness. As the field evolves, different aspects of the surgery have been individually explored, including allograft viability, retinal survival, and optic nerve regeneration. Due to the paucity in the WET literature, we aimed to systematically review proposed WET surgical techniques to assess surgical feasibility. Additionally, we hope to identify barriers to future clinical application and potential ethical concerns that could be raised with surgery., Methods: We conducted a systematic review of PubMed, Embase, Cochrane Library, and Scopus from inception to June 10, 2022, to identify articles pertaining to WET. Data collection included model organisms studied, surgical techniques utilized, and postoperative functional outcomes., Results: Our results yielded 33 articles, including 14 mammalian and 19 cold-blooded models. In studies performing microvascular anastomosis in mammals, 96% of allografts survived after surgery. With nervous coaptation, 82.9% of retinas had positive electroretinogram signals after surgery, indicating functional retinal cells after transplantation. Results on optic nerve function were inconclusive. Ocular-motor functionality was rarely addressed., Conclusions: Regarding allograft survival, WET appears feasible with no complications to the recipient recorded in previous literature. Functional restoration is potentially achievable with a demonstrated positive retinal survival in live models. Nevertheless, the potential of optic nerve regeneration remains undetermined., Competing Interests: The authors have no financial interest to declare in relation to the content of this article. Disclosure statements are at the end of this article, following the correspondence information., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Cholinergic antagonists interfere with synaptic transmission in the central nervous system and are involved in pathological processes in patients with neurocognitive disorders (NCD), such as behavioral and psychological symptoms of dementia (BPSD). In this commentary, we will briefly review the current knowledge on the impact of cholinergic burden on BPSD in persons with NCD, including the main pathophysiological mechanisms. Given the lack of clear consensus regarding symptomatic management of BPSD, special attention must be paid to this preventable, iatrogenic condition in patients with NCD, and de-prescription of cholinergic antagonists should be considered in patients with BPSD.

Objectives: To (a) identify rates of hospital readmission and emergency department (ED) re-presentation for asthma within a 12-month period, (b) estimate the effects of modifiable hospital, general practitioner (GP) and home environmental factors on hospital readmission, ED re-presentations and rescue oral corticosteroid use., Methods: We recruited 767 children aged 3-18 years who were admitted to 3 hospitals in Victoria, Australia between 2017 and 2018 with a validated diagnosis of asthma on chart review. Primary outcome was hospital readmission with asthma within 12 months of index admission. Secondary outcomes were ED re-presentation for asthma and rescue oral corticosteroid use. All outcomes were identified through linked administrative datasets. Their caregivers and 277 nominated GPs completed study surveys regarding the home environment and their usual asthma management practices respectively., Results: Within 12 months of an index admission for asthma 263 (34.3%) participants were readmitted to a hospital for asthma, with participants between the ages of 3-5 years accounting for 69.2% of those readmitted. The estimated effect of GP reported guideline discordant care on the odds of readmission was OR 1.57, 95% CI 1.00-2.47, p  = 0.05. None of the hospital or home environmental factors appeared to be associated with hospital readmissions., Conclusions: Hospital readmissions among Australian children with asthma are increasing, and linked datasets are important for objectively identifying the health services burden of asthma. They also confirm the important role of the GP in the management of pediatric asthma.

Introduction: Influenza vaccination of children with medical comorbidities is critical due their increased risks for severe influenza disease. In Australia, hospitals are an avenue for influenza vaccine delivery to children with comorbidities but are not always effectively utilised. Qualitative enquiry sought to ascertainment the barriers and enablers for influenza vaccination recommendation, delivery, and recording of these children at Australian hospitals., Methods: Semi-structured interviews and discussion group sessions were conducted with paediatricians and nurses at four tertiary paediatric specialist hospitals and two general community hospitals in three Australian states. Transcripts from interviews and group sessions were inductively analysed for themes. The Capability, Opportunity, Motivation, and Behaviour (COM-B) model was used to explore the elements of each theme and identify potential interventions to increase influenza vaccination recommendation and delivery behaviours by providers., Results: Fifteen discussion sessions with 28 paediatricians and 26 nurses, and nine in-depth interviews (five paediatricians and four nurses) were conducted. Two central thematic domains were identified: 1. The interaction between hospital staff and parents/patients for influenza vaccine recommendation, and 2. Vaccination delivery and recording in the hospital environment. Six themes across these domains emerged detailing the importance of dedicated immunisation services, hospital leadership, paediatricians' vaccine recommendation role, the impact of comorbidities, vaccination recording, and cocooning vaccinations. Supportive hospital leadership, engaged providers, and dedicated immunisation services were identified as essential for influenza vaccination of children with comorbidities in Australian hospital., Conclusion: Recommendation of influenza vaccination for Australian children with comorbidities is impacted by the beliefs of paediatricians and the perceived impact of influenza disease on children's comorbidities. Dedicated immunisation services and supportive hospital leadership were drivers for influenza vaccine delivery at hospitals. Future interventions targeting hospital-based influenza vaccine delivery for children with comorbidities should take a rounded approach targeting providers' attitudes, the hospital environment and leadership support., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: A/Prof Seale has previously received funding from vaccine manufactures for investigator driven research and for presenting at workshops. This funding was not associated with this research and this does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have no competing interests to declare. All authors have approved submission of the manuscript for publication to PLOS ONE., (Copyright: © 2022 Norman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Radiographic worsening in patients with glioblastoma undergoing treatment may be due to tumor recurrence or treatment effect. The overall prognosis of these patients based on histologic findings at the time of repeat resection is not well established., Methods: Patients with glioblastoma at our institution were identified. Patients who only had 1 surgery were excluded. Demographic and clinical data were recorded. The histologic diagnosis at the time of repeat surgery was recorded as either tumor recurrence or pseudoprogression. For this study, pseudoprogression was defined as absence of tumor histologic features and could show coagulative necrosis, reactive gliosis, and/or inflammatory infiltration., Results: A total of 115 patients were identified, 106 with tumor recurrence and 9 with pseudoprogression. The pseudoprogression group had a greater percentage of patients with O 6 -methylguanine DNA-methyltransferase (MGMT) methylation (37.7% vs. 66.7%), but these results did not reach statistical significance. The overall median survival was 23.1 months. The overall median survival was 22.0 months in the tumor recurrence group and 33.3 months in the pseudoprogression group (P = 0.0814). The overall median survival from the time of repeat surgery was 8.4 months for the entire cohort, 8.3 months for the tumor recurrence group and 18.4 months for the pseudoprogression group (P = 0.0063). In multivariable analysis, presence of tumor features was predictive of worse overall survival from the time of second surgery (hazards ratio 3.96, 95% confidence interval: 1.30-12.06, P = 0.0156)., Conclusions: In patients with worsening imaging, the absence of tumor on histologic diagnosis is associated with improved survival from the time of second surgery., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Conventionally, magnetism arises from the strong exchange interaction among the magnetic moments of d- or f-shell electrons. It can also emerge in perfect lattices from nonmagnetic elements, such as that exemplified by the Stoner criterion. Here we report tunable magnetism in suspended rhombohedral-stacked few-layer graphene (r-FLG) devices with flat bands. At small doping levels ( n ∼ 10 11 cm -2 ), we observe prominent conductance hysteresis and giant magnetoconductance that exceeds 1000% as a function of magnetic fields. Both phenomena are tunable by density and temperature and disappear at n > 10 12 cm -2 or T > 5 K. These results are confirmed by first-principles calculations, which indicate the formation of a half-metallic state in doped r-FLG, in which the magnetization is tunable by electric field. Our combined experimental and theoretical work demonstrate that magnetism and spin polarization, arising from the strong electronic interactions in flat bands, emerge in a system composed entirely of carbon atoms.

Canadian provinces routinely collect patient-level data for administrative purposes. These real-world data (RWD) can be used to generate real-world evidence (RWE) to inform clinical care and healthcare policy. The CanREValue Collaboration is developing a framework for the use of RWE in cancer drug funding decisions. A Data Working Group (WG) was established to identify data assets across Canada for generating RWE of oncology drugs. The mapping exercise was conducted using an iterative scan with informant surveys and teleconference. Data experts from ten provinces convened for a total of three teleconferences and two in-person meetings from March 2018 to September 2019. Following each meeting, surveys were developed and shared with the data experts which focused on identifying databases and data elements, as well as a feasibility assessment of conducting RWE studies using existing data elements and resources. Survey responses were compiled into an interim data report, which was used for public stakeholder consultation. The feedback from the public consultation was used to update the interim data report. We found that databases required to conduct real-world studies are often held by multiple different data custodians. Ninety-seven databases were identified across Canada. Provinces held on average 9 distinct databases (range: 8-11). An Essential RWD Table was compiled that contains data elements that are necessary, at a minimal, to conduct an RWE study. An Expanded RWD Table that contains a more comprehensive list of potentially relevant data elements was also compiled and the availabilities of these data elements were mapped. While most provinces have data on patient demographics (e.g., age, sex) and cancer-related variables (e.g., morphology, topography), the availability and linkability of data on cancer treatment, clinical characteristics (e.g., morphology and topography), and drug costs vary among provinces. Based on current resources, data availability, and access processes, data experts in most provinces noted that more than 12 months would be required to complete an RWE study. The CanREValue Collaboration's Data WG identified key data holdings, access considerations, as well as gaps in oncology treatment-specific data. This data catalogue can be used to facilitate future oncology-specific RWE analyses across Canada.

Background: Oral anticancer chemotherapy (OC) has been misperceived as being safer than intravenous chemotherapy, leading to its increased risk of improper handling and disposal. This survey study assessed the knowledge, practices and attitudes of pharmacists and patients regarding OC handling and disposal, gaps in knowledge and barriers to patient education., Methods: Surveys were developed based on literature review and pilot study validation results. Patients completed a 33-item paper or electronic survey whereas pharmacists completed a 38-item electronic survey. Descriptive statistics and Fisher's exact test computed using the R Project were used for analyses., Results: Pharmacist group (16/25, 62.5%) and patient group (14/29, 48.3%) believed that the oral route is safer than IV. Average overall correct response rates for pharmacist and patient groups were 78.3% and 61.9%, respectively. Significant gaps in knowledge between groups were observed in three sections (p < 0.05). Common barriers to providing patient education were insufficient training (70.8%) and insufficient time (50%)., Conclusion: Pharmacist and patient knowledge, awareness and practices of OC safe handling and disposal are suboptimal. Areas of knowledge gaps and barriers to patient education were identified. Enhanced supports are needed to empower pharmacists to assume an active role in patient education on safe handling and disposal of OC., Competing Interests: Conflict of Interest The authors report no conflicts of interest.

Alpha-synuclein (αSyn) pathology is a hallmark of Parkinson's disease. Here we show that lysophosphatidylcholine acyltransferase 1 (LPCAT1) is a regulator of αSyn pathology and cytotoxicity. LPCAT1 is upregulated by αSyn E35K E46K E61K (3K) in human M17 neuroblastoma cells and primary rat cortical neurons, and in postmortem brain tissue from PD patients with confirmed αSyn aggregate pathology. Suppression of LPCAT1 reduces αSyn accumulations and toxicity in our neuroblastoma αSyn 3K overexpression model. Further overexpression of LPCAT1 promotes pS129 αSyn positive aggregation in primary neurons in the αSyn pre-formed fibril (PFF) model. A phospholipid product of LPCAT1 enzymatic activity, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, similarly promotes neuronal PFF seeded aggregation. Using a pH sensitive PFF model we provide evidence that αSyn fibrils have altered endo-lysosomal processing under LPCAT1 enhancement, suggesting less aggregate degradation. Our data demonstrates that LPCAT1 and associated phospholipids can regulate αSyn pathology., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Liver transplant hepatic venous anastomoses are usually created using "bicaval" or "piggyback" techniques, which may result in unfavorable angulation between the inferior vena cava and hepatic veins, and makes hepatic vein catheterization and tissue sampling during transjugular liver biopsy (TLB) technically challenging., Purpose: To compare the technical successes and complications of TLBs for recipients of liver transplants with bicaval and piggyback hepatic vein anastomoses., Material and Methods: Information on type of hepatic vein surgical anastomosis was available for 190 adult patients in whom 306 consecutive TLBs were performed during 2009-2017: 158 with bicaval and 148 with piggyback anastomoses. The primary outcome of procedural success was defined as obtaining a tissue sample sufficient to make a pathologic diagnosis., Results: A technical success rate of 97% with adequate liver tissue for diagnosis was similar between the anastomotic groups ( P  = 0.50). TLB was unsuccessful in 3% of patients with piggyback anastomoses due to unfavorable hepatic venous anatomy whereas biopsy was successful in all patients with bicaval anastomoses ( P  = 0.02). Fluoroscopy times were not significantly different (12.1 vs. 13.9 min, P  = 0.08). Rates of major complication were similar between the two groups (3% vs. 3%, P  > 0.99)., Conclusion: TLB is safe and effective for liver transplant patients regardless of the type of hepatic vein anastomosis. While failure to catheterize or advance the stiffened biopsy cannula into the hepatic vein is more likely to occur in patients with piggyback anastomoses, this is a rare occurrence.

Opinion Statement: Laser interstitial thermal therapy (LITT) is a minimally invasive treatment option for brain tumors including glioblastoma, other primary central nervous system (CNS) neoplasms, metastases, and radiation necrosis. LITT employs a fiber optic coupled laser delivery probe stabilized via stereotaxis to deliver thermal energy that induces coagulative necrosis in tumors to achieve effective cytoreduction. LITT complements surgical resection, radiation treatment, tumor treating fields, and systemic therapy, especially in patients who are high risk for surgical resection due to tumor location in eloquent regions or poor functional status. These factors must be balanced with the increased rate of cerebral edema post LITT compared to surgical resection. LITT has also been shown to induce transient disruption of the blood-brain barrier (BBB), especially in the peritumoral region, which allows for enhanced CNS delivery of anti-neoplastic agents, thus greatly expanding the armamentarium against brain tumors to include highly effective anti-neoplastic agents that have poor BBB penetration. In addition, hyperthermia-induced immunogenic cell death is another secondary side effect of LITT that opens up immunotherapy as an attractive adjuvant treatment for brain tumors. Numerous large studies have demonstrated the safety and efficacy of LITT against various CNS tumors and as the literature continues to grow on this novel technique so will its indications., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Abstract: Traditional microbiological testing methods are slow, and many molecular-based techniques rely on culture-based enrichment to overcome low limits of detection. Recent advancements in sequencing technologies may make it possible to utilize machine learning to identify patterns in microbiome data to potentially predict the presence or absence of pathogens. In this study, 299 poultry rinsate samples from various points in the processing chain were analyzed to determine if microbiota could inform about a sample's risk for containing Salmonella. Samples were culture confirmed as Salmonella positive or negative following modified U.S. Department of Agriculture Microbiological Laboratory Guidebook protocols. The culture confirmation result was used as a reference to compare with 16S sequencing data. Prechill samples tested positive (71 of 82) at a higher frequency than postchill samples (30 of 217) and contained greater microbial diversity. Due to the larger sample size, postchill samples were analyzed more thoroughly. Analysis of variance identified a significant effect of chilling on the number of genera (P < 0.001), but analysis of similarities failed to provide evidence for microbial dissimilarity between pre- and postchill samples (P = 0.001, R = 0.443). Various machine learning models were trained by using postchill samples to predict if a sample contained Salmonella on the basis of the samples' microbiota preenrichment. The optimal model was a random forest-based model with a performance as follows: accuracy (88%), sensitivity (85%), and specificity (90%). Although the algorithms described in this article are prototypes, these risk-based algorithms demonstrate the potential and need for further studies to provide insight alongside diagnostic tests. Combining risk-based information with diagnostic tools can help poultry processors make informed decisions to help identify and prevent the spread of Salmonella. These data add to the growing body of literature exploring novel ways to utilize microbiome data for predictive food safety., (Published 2021 by the International Association for Food Protection. Not subject to U.S. Copyright.)

Here, we report the independent discovery and validation of stearoyl-CoA desaturase (SCD) as a modulator of α-synuclein (αSyn)-induced pathology and toxicity in cell-based Parkinson's disease (PD) models. We identified SCD as top altered gene from transcriptional profiling in primary neurons exogenously expressing αSyn with the amplified familial PD mutation 3K. Thus, we sought to further explore SCD as a therapeutic target in neurodegeneration. We report that SCD inhibitors are toxic to early human and rat neuron cultures while displaying minimal toxicity to late cultures. The fatty acid product of SCD, oleic acid (OLA), fully rescues this toxicity in early cultures, suggesting on-target toxicity. Furthermore, SCD inhibition rescues αSyn 3K-induced toxicity in late primary neurons. We also confirm that SCD inhibitors reduce formation of αSyn accumulations, while OLA increases these accumulations in an αSyn 3K neuroblastoma model. However, we identify a caveat with this model where αSyn 3K levels can be suppressed by high SCD inhibitor concentrations, obscuring true effect size. Further, we show that both SCD1 or SCD5 knock-down reduce αSyn 3K accumulations and toxicity, making both a putative drug target. Overall, we confirm key findings of published data on SCD inhibition and its benefits in αSyn accumulation and stress models. The differential neurotoxicity induced by SCD inhibition based on neuron culture age must be accounted for when researching SCD in neuron models and has potential clinical implications. Lastly, our gene profiling studies also revealed novel putative genes connected to αSyn neurotoxicity that are worth further study., (Copyright © 2021 Nicholatos et al.)

Background. Real-world evidence can be a valuable tool when clinical trial data are incomplete or uncertain. Bevacizumab was adopted as first-line therapy for metastatic colorectal cancer (mCRC) based on significant survival improvements in initial clinical trials; however, survival benefit diminished in subsequent analyses. Consequently, there is uncertainty surrounding the cost-effectiveness of bevacizumab therapy achieved in practice. Objective. To assess real-world cost-effectiveness of first-line bevacizumab with irinotecan-based chemotherapy versus irinotecan-based chemotherapy alone for mCRC in British Columbia (BC), Saskatchewan, and Ontario, Canada. Methods. Using provincial cancer registries and linked administrative databases, we identified mCRC patients who initiated publicly funded irinotecan-based chemotherapy, with or without bevacizumab, in 2000 to 2015. We compared bevacizumab-treated patients to historical controls (treated before bevacizumab funding) and contemporaneous controls (receiving chemotherapy without bevacizumab), using inverse-probability-of-treatment weighting with propensity scores to balance baseline covariates. We calculated incremental cost-effectiveness ratios (ICER) using 5-year cost and survival adjusted for censoring, with bootstrapping to characterize uncertainty. We also conducted one-way sensitivity analysis for key drivers of cost-effectiveness. Results. The cohorts included 12,112 (Ontario), 1,161 (Saskatchewan), and 2,977 (BC) patients. Bevacizumab significantly increased treatment costs, with mean ICERs between $78,000 and $84,000/LYG (life-year gained) in the contemporaneous comparisons and $75,000 and $101,000/LYG in the historical comparisons. Reducing the cost of bevacizumab by 50% brought ICERs in all comparisons below $61,000/LYG. Limitations. Residual confounding in observational data may bias results, while the use of original list prices overestimates current bevacizumab cost. Conclusion. The addition of bevacizumab to irinotecan-based chemotherapy extended survival for mCRC patients but at significant cost. At original list prices bevacizumab can only be considered cost-effective with certainty at a willingness-to-pay threshold over $100,000/LYG, but price reductions or discounts have a significant impact on cost-effectiveness., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Background Subclinical left ventricular dysfunction detected by 2-dimensional global longitudinal strain post breast radiotherapy has been described in patients with breast cancer. We hypothesized that left ventricular dysfunction postradiotherapy may be site specific, based on differential segmental radiotherapy dose received. Methods and Results Transthoracic echocardiograms were performed at baseline, 6 weeks, and 12 months postradiotherapy on 61 chemotherapy-naïve women with left-sided breast cancer undergoing tangential breast radiotherapy. Radiation received within basal, mid, and apical regions for the 6 left ventricular walls was quantified from the radiotherapy treatment planning system. Anterior, anteroseptal, and anterolateral walls received the highest radiation doses, while inferolateral and inferior walls received the lowest. There was a progressive increase in the radiation dose received from basal to apical regions. At 6 weeks, the most significant percentage deterioration in strain was seen in the apical region, with greatest reductions in the anterior wall followed by the anteroseptal and anterolateral walls, with a similar pattern persisting at 12 months. There was a within-patient dose-response association between the segment-specific percentage deterioration in strain at 6 weeks and 12 months and the radiation dose received. Conclusions Radiotherapy for left-sided breast cancer causes differential segmental dysfunction, with myocardial segments that receive the highest radiation dose demonstrating greatest strain impairment. Percentage deterioration in strain observed 6 weeks postradiotherapy persisted at 12 months and demonstrated a dose-response relationship with radiotherapy dose received. Radiotherapy-induced subclinical cardiac dysfunction is of importance because it could be additive to chemotherapy-related cardiotoxicity in patients with breast cancer. Long-term outcomes in patients with asymptomatic strain reduction require further investigation.

Metastatic triple-negative breast cancer (mTNBC) is the most aggressive breast cancer subtype. Programmed death ligand 1 (PD-L1) on immune cells (IC) using the VENTANA SP142 assay is linked to improved clinical outcome in atezolizumab plus nab-paclitaxel-treated patients with mTNBC in the IMpassion130 study. The goal of the current study was to evaluate prevalence of VENTANA SP142 PD-L1 assay by anatomic location in 670 histologically confirmed TNBC cases from subjects with metastatic disease screened for the phase 1 study PCD4989g (NCT01375842). PD-L1 immunohistochemistry was centrally tested on tumor cells (TC) and on tumor infiltrating IC, following manufacturer's instructions. At a 1% cutoff, tumor PD-L1 was more prevalent in IC than TC: 46% were PD-L1 IC+/TC-, 3% were PD-L1 IC-/TC+, and 10% were PD-L1 IC+/TC+. PD-L1 IC and TC immunostaining correlated with CD274 RNA expression, as assessed by fluidigm. Analyses of anatomic locations suggest that prevalence of PD-L1 IC+ was highest in lymph nodes (65.0%), lowest in liver metastases (26.9%), while breast tissue was intermediate (57.1%). Matched paired samples from the same subject collected synchronously or asynchronously showed a PD-L1 IC status agreement of 80% (8/10) and 75% (15/20), respectively. Our results suggest that the anatomic location of metastases and time of collection may influence the detection of PD-L1., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Molecular biologists rely on the use of fluorescent probes to take measurements of their model systems. These fluorophores fall into various classes (e.g. fluorescent dyes, fluorescent proteins, etc.), but they all share some general properties (such as excitation and emission spectra, brightness) and require similar equipment for data acquisition. Selecting an ideal set of fluorophores for a particular measurement technology or vice versa is a multidimensional problem that is difficult to solve with ad hoc methods due to the enormous solution space of possible fluorophore panels. Choosing sub-optimal fluorophore panels can result in unreliable or erroneous measurements of biochemical properties in model systems. Here, we describe a set of algorithms, implemented in an open-source software tool, for solving these problems efficiently to arrive at fluorophore panels optimized for maximal signal and minimal bleed-through.

Background: Bevacizumab has promising activity against recurrent glioblastoma (GBM). However, acquired resistance to this agent results in tumor recurrence. We hypothesized that vorinostat, a histone deacetylase (HDAC) inhibitor with anti-angiogenic effects, would prevent acquired resistance to bevacizumab., Methods: This multicenter phase II trial used a Bayesian adaptive design to randomize patients with recurrent GBM to bevacizumab alone or bevacizumab plus vorinostat with the primary endpoint of progression-free survival (PFS) and secondary endpoints of overall survival (OS) and clinical outcomes assessment (MD Anderson Symptom Inventory Brain Tumor module [MDASI-BT]). Eligible patients were adults (≥18 y) with histologically confirmed GBM recurrent after prior radiation therapy, with adequate organ function, KPS ≥60, and no prior bevacizumab or HDAC inhibitors., Results: Ninety patients (bevacizumab + vorinostat: 49, bevacizumab: 41) were enrolled, of whom 74 were evaluable for PFS (bevacizumab + vorinostat: 44, bevacizumab: 30). Median PFS (3.7 vs 3.9 mo, P = 0.94, hazard ratio [HR] 0.63 [95% CI: 0.38, 1.06, P = 0.08]), median OS (7.8 vs 9.3 mo, P = 0.64, HR 0.93 [95% CI: 0.5, 1.6, P = 0.79]) and clinical benefit were similar between the 2 arms. Toxicity (grade ≥3) in 85 evaluable patients included hypertension (n = 37), neurological changes (n = 2), anorexia (n = 2), infections (n = 9), wound dehiscence (n = 2), deep vein thrombosis/pulmonary embolism (n = 2), and colonic perforation (n = 1)., Conclusions: Bevacizumab combined with vorinostat did not yield improvement in PFS or OS or clinical benefit compared with bevacizumab alone or a clinical benefit in adults with recurrent GBM. This trial is the first to test a Bayesian adaptive design with adaptive randomization and Bayesian continuous monitoring in patients with primary brain tumor and demonstrates the feasibility of using complex Bayesian adaptive design in a multicenter setting., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Retronychia is an uncommonly reported condition among the category of nail pathologies. It often presents mimicking similar nail disorders, such as onychocryptosis, onychomycosis, and paronychia. This pathologic condition has recently seen an increased presence in the literature, mainly in the form of case studies. Literature on retronychia was collected using PubMed, the US National Library of Medicine, the National Institutes of Health's online database, life science journals, and online books. References cited by these articles were also reviewed for additional relevant publications. Reviews, case studies, and retrospective articles were compiled and analyzed for commonalities in cause, patient demographics, clinical signs, and treatment. Retronychia may be more common than previously suggested. Proper knowledge and education of this pathologic nail condition is important to health-care professionals to achieve early and correct diagnosis.

Objective: There are multiple treatment options to enhance a patient's smile, from conservative bleaching procedures to composite resins, porcelain veneers, or full-coverage crowns. Treating patients with porcelain veneers is a commonly used approach in esthetic dentistry. Provisional restorations for veneers can be time-consuming to make and difficult to retain. This article illustrates a technique for fabricating indirect snap-on provisional restorations for veneer cases, describing both analog and digital approaches., Clinical Considerations: The present article presents an alternative provisionalization technique using snap-on restorations for dental veneers. Application of these techniques will allow for ease of cleansability by the patient leading to healthier soft tissues before the final cementation. Delivery of veneers is more predictable with healthy soft tissue, as bleeding and inflammation may affect the bonding process., Conclusions: This technique is an effective provisionalization option in most veneer cases. This approach seems to be well accepted by patients and a good alternative in helping to maintain optimal gingival health with interim restorations before delivery., Clinical Significance: The use of snap-on provisionals for veneer restorations will allow the clinician to have an efficient technique with better tissue response before cementation. This prevents inflammation and facilitates a controlled delivery process., (© 2020 Wiley Periodicals, Inc.)

Background: Although lung protection with low tidal volume and limited plateau pressure (P plat ) improves survival in acute respiratory distress syndrome patients (ARDS), the best way to set positive end-expiratory pressure (PEEP) is still debated., Methods: This study aimed to compare two strategies using individual PEEP based on a maximum P plat (28-30 cmH 2 O, the Express group) or on keeping end-expiratory transpulmonary pressure positive (0-5 cmH 2 O, P Lexpi group). We estimated alveolar recruitment (Vrec), end-expiratory lung volume and alveolar distension based on elastance-related end-inspiratory transpulmonary pressure (P L,EL )., Results: Nineteen patients with moderate to severe ARDS (PaO 2 /FiO 2  < 150 mmHg) were included with a baseline PEEP of 7.0 ± 1.8 cmH 2 O and a PaO 2 /FiO 2 of 91.2 ± 31.2 mmHg. PEEP and oxygenation increased significantly from baseline with both protocols; PEEP Express group was 14.2 ± 3.6 cmH 2 O versus 16.7 ± 5.9 cmH 2 O in P Lexpi group. No patient had the same PEEP with the two protocols. Vrec was higher with the latter protocol (299 [0 to 875] vs. 222 [47 to 483] ml, p = 0.049) and correlated with improved oxygenation (R 2  = 0.45, p = 0.002). Two and seven patients in the Express and P L,expi groups, respectively, had P L,EL  > 25 cmH 2 O., Conclusions: There is a great heterogeneity of P Lexpi when P plat is used to titrate PEEP but with limited risk of over-distension. A PEEP titration for a moderate positive level of P Lexpi might slightly improve alveolar recruitment and oxygenation but increases the risk of over-distension in one-third of patients.

Cross-feeding on intermediary and end-point metabolites plays an important role in the dynamic interactions of host-associated microbial communities. While gut microbiota possess inherent resilience to perturbation, variations in the intake of certain nutrients may lead to changes in the community composition with potential consequences on host physiology. Syntrophic relationships and mutualism at the level of major carbon and energy sources have been documented, however, relatively little is known about metabolic interactions involving micronutrients, such as B-vitamins, biosynthetic precursors of essential cofactors in the mammalian host and numerous members of the gut microbiota alike. In silico genomic reconstruction and prediction of community-wide metabolic phenotypes for eight major B-vitamins (B1, B2, B3, B5, B6, B7, B9, and B12), suggests that a significant fraction of microbial gut communities (>20% by abundance) are represented by auxotrophic species whose viability is strictly dependent on acquiring one or more B-vitamins from diet and/or prototrophic microbes via committed salvage pathways. Here, we report the stability of gut microbiota using humanized gnotobiotic mice and in vitro anaerobic fecal culture in the context of extreme variations of dietary B-vitamin supply as revealed by phylotype-to-phenotype prediction from 16S rRNA profiling and metabolomic measurements. The observed nearly unaltered relative abundance of auxotrophic species in gut communities in the face of diet or media lacking B-vitamins or containing them in great excess (∼30-fold above normal) points to a strong contribution of metabolic cooperation (B-vitamin exchange and sharing) to the stability of gut bacterial populations.

Purpose: Subacute changes following breast radiotherapy have been demonstrated in discrete areas of the left ventricle (LV), with recent guidelines being developed to help determine dose to subvolumes of the LV. This study aims to determine doses to the 17 segments of the LV as per the American Heart Association (AHA) and other cardiac subvolumes, and to correlate mean heart (MHD) dose with various subvolume dosimetric indices. These results may direct focus to specific left ventricular segments in studies of radiation-related heart disease incorporating surveillance imaging, help to determine more precise dose response relationships, and potentially aid prediction of late radiation effects., Methods and Materials: The heart and cardiac subvolumes of 29 patients treated with tangential radiotherapy for left breast cancer were contoured. Delineation of cardiac subvolumes (cardiac chambers, cardiac valves and the 17 segments of the LV) was undertaken using a novel contouring method on planning CT data reformatted into the cardiac axis. Individual segments were then combined to determine doses to the basal, mid and apical left ventricular regions, and the anterior, septal, inferior and lateral ventricular walls. Radiotherapy doses (including maximum, mean, D1cc, V25) were determined. Correlation analyses were performed between MHD and various substructure dosimetric indices., Results: Twenty five patients received tangential breast free breathing radiotherapy alone, and four patients received regional nodal irradiation including the internal mammary chain with deep inspiration breath hold (DIBH). For patients receiving breast only radiation, the median mean heart radiation dose was 2.62 Gy (range 1.52-3.90 Gy), and a heterogeneous dose distribution to the LV was noted, with the apical region receiving the highest median mean dose (14.99 Gy) compared with the mid and basal regions (3.10 Gy and 1.51 Gy respectively). The anterior LV wall received the highest median mean dose (9.21 Gy) with the remaining walls receiving similar mean doses (range 1.79-3.05 Gy). The anterior LV apical segment (segment 13) and apex (segment 17) received the highest individual median mean segment doses (26.73 Gy and 30.02 Gy respectively). Apical segments received the highest median mean doses (segments 13, 14, 15, 16), followed by the mid anterior (segment 7) and anteroseptal (segment 8) segments. Segments receiving the highest doses remained unchanged between the DIBH cohort and free breathing cohort. MHD showed a high correlation with the anterior wall r = 0.71, p < 0.05 and entire left ventricle r = 0.82, p < 0.05, but correlations varied from weak to high when MHD was correlated with segments receiving highest doses (range r = 0.43-0.76), p < 0.05., Conclusions: In the setting of breast cancer radiotherapy, there are substantial RT dose variations within specific LV segments, with mid and apical anterior ventricular segments (segments 7, 13) and the apical region of the LV (segments 13, 14, 15, 16, 17) being consistently exposed to the highest radiation doses. Determining segmental and regional RT doses to the left ventricle may help guide focus in diagnostic cardiology in the post radiotherapy setting., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Aim: To examine refugee health assessments in Syrian and Iraqi children in the context of changes to offshore immigration screening, updated Australian refugee health guidelines and the primary care refugee health model in Victoria., Methods: This is a retrospective audit of Syrian and Iraqi children aged 0-17 years attending a specialist immigrant health service from January 2015 to September 2017., Results: We saw 128 children (7 months-16 years, 64.8% male). Prior to arrival, 58.9% of children had experienced trauma, and 67.9% had missed at least 1 year of school. Almost all children (93.3%) were linked with a regular general practitioner in Australia, and 23.6% children were linked with a refugee health nurse; offshore health records were infrequently available. Of school-aged children, 25% were not enrolled in school 3 months after arrival. Only 2 of 113 (1.8%) children had completed a recommended refugee health assessment, and 55.1% had commenced appropriate catch-up vaccination in primary care. After screening completion, the most prevalent conditions were low vitamin D (63.6%); growth/nutrition (24.2%), neurological/metabolic (16.4%), learning/behaviour (15.6%) and mental health (12.5%) concerns; latent tuberculosis infection (11.8%); and developmental delay (10.2%). Sixteen children required surgery after arrival, and six children had life-threatening medical conditions on arrival - only one had an offshore critical alert; care for the other five children resulted in 133 unanticipated hospital admission days., Conclusions: There are substantial challenges with the current primary care screening model in Victoria. Disability, developmental and mental health concerns were prominent in this cohort, and many children had delays in education access, compounding prior disadvantage., (© 2018 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)