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A realistic tight-binding model is developed and employed to elucidate the resistivity size effect due to steps on Ru thin films. The resistivity of two different film orientations, (0001) and (1 1 ¯ 00) , is computed for transport along the [ 11 2 ¯ 0 ] direction both for smooth surfaces and for surfaces with monolayer-high steps. In the case of smooth films, the systems are also studied using solutions to the Boltzmann transport equation. Interestingly, the resistivity of (1 1 ¯ 00) surfaces exhibits a significant size effect even in the absence of surface steps. When monolayer-high steps are spaced ∼ 10 nm apart, the resistivity is shown to increase due to scattering from the steps. However, only a small increase was found which cannot explain the large effect seen in recent experiments with Ru thin films. This highlights the need for further elucidation of the resistivity size effect. Theoretical analysis suggests that films made from materials with a relatively large ballistic conductance per area like Ru should exhibit a reduced resistivity size effect. This result points to Ru as a promising interconnect material. Finally, because a very efficient algorithm for computing resistivity based on the kernel polynomial method is used, the approach fulfills a need for realistic models that can span length scales directly relevant to experimental results. The calculations described here include films approaching 5 nm in thickness, with in-plane distances up to ∼ 160 nm and 3.8 × 10 5 atomic sites. [ABSTRACT FROM AUTHOR]

Burnout is most commonly defined as a syndrome characterized by emotional exhaustion, cynicism, and ineffectiveness, which occurs in response to chronic stressors at work. It can adversely affect health workers' physical and mental health, and the quality of care provided. The COVID-19 pandemic increased stressors and could impact burnout prevalence in this group. There is a lack of information regarding the prevalence of burnout among hospital health workers in Brazil. A newer definition of burnout has been proposed that considers three different clinical profiles: the frenetic, underchallenged and worn-out subtypes. This differentiation could lead to interventions tailored for each subtype. The present study aimed to estimate the prevalence of burnout, its subtypes, and associated factors in workers of a public hospital network in Brazil, during the pandemic. A total of 143 randomly selected participants answered an online form that included sociodemographic and occupational items, and the Burnout Clinical Subtypes Questionnaire, a summarized version. This questionnaire evaluates three burnout dimensions (overload, lack of development, neglect) that can be used to discriminate the three burnout subtypes (frenetic, underchallenged, worn-out, respectively); higher scores indicate higher burnout levels. The prevalence of burnout was high (53.85%), similar to other studies during the pandemic. The most common subtypes were 'frenetic' (34.97%), characterized by increased efforts to meet work demands, to the point of neglecting personal needs, and 'lack of development' (23.78%), characterized by a sense that work is uninteresting and does not contribute to personal development, and a perfunctory behavior towards tasks. Age was associated with burnout: workers with less than 51 years presented higher levels of burnout. These findings indicate the need for effective interventions to prevent and/or treat burnout. The assessment of burnout subtypes can allow managers to better understand the processes affecting employees, and inform actions to improve workforce health.

RESUMO O objetivo deste estudo foi relatar a experiência dos alunos do mestrado profissional em gestão de serviços de saúde acerca da utilização de conceitos da Análise Institucional, para analisar as resistências ao trabalho interprofissional e interdisciplinar na saúde, localizando-as como um analisador do processo e das relações de trabalho. O estudo foi elaborado a partir da vivência e da análise dos diários institucionais, escritos pelos alunos e analisados com base no referencial teórico da Análise Institucional. Observou-se que a resistência ao trabalho interprofissional e interdisciplinar, principalmente por parte dos médicos, atravessa as organizações de saúde, as relações de trabalho e a assistência aos usuários. Entretanto, essa resistência também é exercida por outros profissionais e pelos usuários, o que limita a interdisciplinaridade e a integralidade da assistência à saúde. Todavia, se, por um lado, ainda, há certa predominância do modelo biomédico, por outro, também se observam resistências a esse modelo nas organizações de saúde, necessitando ampliar os espaços de análise coletiva capazes de enunciar o reducionismo desse paradigma. Conclui-se que analisar coletivamente essas resistências possibilita aos profissionais da saúde ampliar as condições de sair de seus lugares instituídos e perceber os movimentos instituintes nos serviços em que atuam.

The NRF2-KEAP1 interaction is central for cytoprotection against stresses, giving it high clinical significance. Covalent modification of KEAP1 is an efficient approach, but the covalent inhibitors used in the clinic carry undesired side effects originating in their moderate selectivity. Starting with a phenotypic screen, we identified a new covalent inhibitor chemotype that was optimized to deliver a series of potent and highly selective KEAP1 binders. While the developed compounds showed both cellular and in vivo activity, upregulating antioxidant response element-dependent target genes, they showed no genotoxicity in vitro. The lead compound exhibited broad selectivity in activity-based protein profiling and showed no significant interaction with a panel of commonly studied receptors nor with a broad panel of kinases. The nature of its interaction with KEAP1 and the origin of its selectivity were revealed by X-ray crystallography.

KCTD family proteins typically assemble into cullin-RING E3 ligases. KCTD1 is an atypical member that functions instead as a transcriptional repressor. Mutations in KCTD1 cause developmental abnormalities and kidney fibrosis in scalp-ear-nipple syndrome. Here, we present unexpected mechanistic insights from the structure of human KCTD1. Disease-causing mutation P20S maps to an unrecognized extension of the BTB domain that contributes to both its pentameric structure and TFAP2A binding. The C-terminal domain (CTD) shares its fold and pentameric assembly with the GTP cyclohydrolase I feedback regulatory protein (GFRP) despite lacking discernible sequence similarity. Most surprisingly, the KCTD1 CTD establishes a central channel occupied by alternating sodium and iodide ions that restrict TFAP2A dissociation. The elucidation of the structure redefines the KCTD1 BTB domain fold and identifies an unexpected ion-binding site for future study of KCTD1's function in the ectoderm, neural crest, and kidney., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Decreased myocardial capillary density has been reported as an important histopathological feature associated with various heart disorders. Quantitative assessment of cardiac capillarization typically involves double immunostaining of cardiomyocytes (CMs) and capillaries in myocardial slices. In contrast, single immunostaining of basement membrane protein is a straightforward approach to simultaneously label CMs and capillaries, presenting fewer challenges in background staining. However, subsequent image analysis always requires expertise and laborious manual work to identify and segment CMs/capillaries. Here, we developed an image analysis tool, AutoQC, for automatic identification and segmentation of CMs and capillaries in immunofluorescence images of basement membrane. Commonly used capillarization-related measurements can be derived from segmentation results. By leveraging the power of a pre-trained segmentation model (Segment Anything Model, SAM) via prompt engineering, the training of AutoQC required only a small dataset with bounding box annotations instead of pixel-wise annotations. AutoQC outperformed SAM (without prompt engineering) and YOLOv8-Seg, a state-of-the-art instance segmentation model, in both instance segmentation and capillarization assessment. Thus, AutoQC, featuring a weakly supervised algorithm, enables automatic segmentation and high-throughput, high-accuracy capillarization assessment in basement-membrane-immunostained myocardial slices. This approach reduces the training workload and eliminates the need for manual image analysis once AutoQC is trained., (© 2024. The Author(s).)

Introduction: Prompt bystander cardiopulmonary resuscitation (CPR) can double the chance of cardiac arrest survival. Rural and remote communities experience longer emergency service wait times and have lower rates of bystander-CPR compared to their urban counterparts. Our study addresses this disparity., Methods: We designed a 1.5-h free hands-only CPR course tailored to secondary school students in rural and remote communities taught by medical students. We evaluated our course using pre-test and post-test surveys., Results: We taught over 300 secondary students in 5 days. Less than one-third of students had previously taken a CPR course. We found that brief CPR instruction taught by medical students was effective in both improving students' knowledge of CPR (t[528] = -26, P < 0.01) and perceived comfort in performing CPR (t[548] = -12, P < 0.01)., Conclusion: CPR courses taught by medical students are effective, low cost, and may help address regional health care disparities. Teaching CPR to rural/remote communities may have secondary benefits such as promoting health care careers to rural youth. We encourage other health professional programmes to consider engaging students in CPR outreach projects., Introduction: Une réanimation cardio-pulmonaire rapide peut doubler les chances de survie en cas d'arrêt cardiaque. Les communautés rurales et éloignées connaissent des temps d'attente plus longs dans les services d'urgence et ont des taux plus faibles de RCP par rapport à leurs homologues urbains. Notre étude porte sur cette disparité., Mthodes: Nous avons conçu un cours de RCP pratique et gratuit d'une heure et demie, adapté aux élèves du secondaire des communautés rurales et isolées et dispensé par des étudiants en médecine. Nous avons évalué notre cours à l'aide d'enquêtes pré-test et post-test., Rsultats: En 5 jours, nous avons enseigné à plus de 300 élèves du secondaire. Moins d'un tiers des élèves avaient déjà suivi un cours de RCP. Nous avons constaté qu'une brève formation à la RCP dispensée par des étudiants en médecine était efficace pour améliorer les connaissances des élèves en matière de RCP (t[528] = -26, P < 0,01) et la perception de leur aisance à pratiquer la RCP (t[548] = -12, P < 0,01)., Conclusion: Les cours de RCP dispensés par les étudiants en médecine sont efficaces, peu coûteux et peuvent contribuer à lutter contre les disparités régionales en matière de soins de santé. L'enseignement de la RCP aux communautés rurales/éloignées peut avoir des avantages secondaires tels que la promotion des carrières dans le domaine de la santé auprès des jeunes ruraux. Nous encourageons d'autres programmes professionnels de santé à envisager d'engager leurs étudiants dans des projets de sensibilisation à la RCP., (Copyright © 2024 Copyright: © 2024 Society of Rural Physicians of Canada.)

Objective: To analyze the extant literature describing the application of gene therapy to spinal fusion., Methods: A systematic review of the English-language literature was performed. The search query was designed to include all published studies examining gene therapy approaches to promote spinal fusion. Approaches were classified as ex vivo (delivery of genetically modified cells) or in vivo (delivery of growth factors via vectors). The primary endpoint was fusion rate. Random effects meta-analyses were performed to calculate the overall odds ratio (OR) of fusion using a gene therapy approach and overall fusion rate. Subgroup analyses of fusion rate were also performed for each gene therapy approach., Results: Of 1179 results, 35 articles met criteria for inclusion (all preclinical), of which 26 utilized ex vivo approaches and 9 utilized in vivo approaches. Twenty-seven articles (431 animals) were included in the meta-analysis. Gene therapy use was associated with significantly higher fusion rates (OR 77; 95% confidence interval {CI}: [31, 192]; P < 0.001); ex vivo strategies had a greater effect (OR 136) relative to in vivo strategies (OR 18) (P = 0.017). The overall fusion rate using a gene therapy approach was 80% (95% CI: [62%, 93%]; P < 0.001); overall fusion rates were significantly higher in subjects treated with ex vivo compared to in vivo strategies (90% vs. 42%; P = 0.011). For both ex vivo and in vivo approaches, the effect of gene therapy on fusion was independent of animal model., Conclusions: Gene therapy may augment spinal fusion; however, future investigation in clinical populations is necessary., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: KCTD15 encodes an oligomeric BTB domain protein reported to inhibit neural crest formation through repression of Wnt/beta-catenin signalling, as well as transactivation by TFAP2. Heterozygous missense variants in the closely related paralogue KCTD1 cause scalp-ear-nipple syndrome., Methods: Exome sequencing was performed on a two-generation family affected by a distinctive phenotype comprising a lipomatous frontonasal malformation, anosmia, cutis aplasia of the scalp and/or sparse hair, and congenital heart disease. Identification of a de novo missense substitution within KCTD15 led to targeted sequencing of DNA from a similarly affected sporadic patient, revealing a different missense mutation. Structural and biophysical analyses were performed to assess the effects of both amino acid substitutions on the KCTD15 protein., Results: A heterozygous c.310G>C variant encoding p.(Asp104His) within the BTB domain of KCTD15 was identified in an affected father and daughter and segregated with the phenotype. In the sporadically affected patient, a de novo heterozygous c.263G>A variant encoding p.(Gly88Asp) was present in KCTD15. Both substitutions were found to perturb the pentameric assembly of the BTB domain. A crystal structure of the BTB domain variant p.(Gly88Asp) revealed a closed hexameric assembly, whereas biophysical analyses showed that the p.(Asp104His) substitution resulted in a monomeric BTB domain likely to be partially unfolded at physiological temperatures., Conclusion: BTB domain substitutions in KCTD1 and KCTD15 cause clinically overlapping phenotypes involving craniofacial abnormalities and cutis aplasia. The structural analyses demonstrate that missense substitutions act through a dominant negative mechanism by disrupting the higher order structure of the KCTD15 protein complex., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Competing Interests: The authors declare no conflict of interest.

Pseudomonas aeruginosa is one of the top priority pathogens that requires immediate attention according to the World Health Organisation (WHO). Due to the alarming shortage of novel antimicrobials, targeting quorum sensing (QS), a bacterial cell to cell signaling system controlling virulence, has emerged as a promising approach as an antibiotic adjuvant therapy. Interference with the pqs system, one of three QS systems in P. aeruginosa , results in reduction of bacterial virulence gene expression and biofilm maturation. Herein, we report a hit to lead process to fine-tune the potency of our previously reported inhibitor 1 (IC 50 3.2 μM in P. aeruginosa PAO1-L), which led to the discovery of 2-(4-(3-((6-chloro-1-isopropyl-1 H -benzo[ d ]imidazol-2-yl)amino)-2-hydroxypropoxy)phenyl)acetonitrile ( 6f ) as a potent PqsR antagonist. Compound 6f inhibited the PqsR-controlled P pqsA - lux transcriptional reporter fusion in P. aeruginosa at low submicromolar concentrations. Moreover, 6f showed improved efficacy against P. aeruginosa CF isolates with significant inhibition of pyocyanin, 2-alkyl-4(1 H )-quinolones production.

Groundwater dependent systems are extremely important habitats for a wide variety of taxa in the Great Basin of North America. The impacts of grazing on these habitats cause shifts in resources and subsequent change in species composition. The Greater sage-grouse, a keystone species of Great Basin ecosystems, rear offspring in these areas during spring and summer months using forbs and arthropods. To examine the impact of grazing on arthropod abundance in these ecosystems, seven meadows, each made up of three unique vegetative communities, were grazed at three intensities across two years (2019-2020) and monitored for environmental variables and abundance of arthropods during peak sage-grouse utilization periods. Additionally, the relationship of field measurements and near-surface digital cameras (phenocams) was examined to better understand how remote sensing technologies can be used to monitor these insect abundance shifts on larger scales. Arthropod taxa abundance responded differently to grazing management and environmental variables. Coleoptera abundance during peak sage-grouse usage periods increased roughly 50% in some meadows with increased grazing intensity. For year-to-year environmental variability in precipitation, Lepidoptera abundance was 114% higher in the drier year, while Coleoptera was 39% lower. Near-surface cameras had varied success with predicting peak insect abundance levels. Lepidoptera and Coleoptera capture rates had strong correlations with phenological indices derived from phenocams, while Formicidae had much weaker relationships., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Tamzen Stringham reports financial support was provided by Bureau of Land Management, Nevada State Offices. Tamzen Stringham reports financial support was provided by Bureau of Land Management Carson City, NV District. Tamzen Stringham reports financial support was provided by UNR Great Basin Restoration Fund., (Published by Elsevier Ltd.)

Background: Primary hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM) represent the liver's two most common malignant neoplasms. Liver-directed therapies such as ablation have become part of multidisciplinary therapies despite a paucity of data. Therefore, an expert panel was convened to develop evidence-based recommendations regarding the use of microwave ablation (MWA) and radiofrequency ablation (RFA) for HCC or CRLM less than 5 cm in diameter in patients ineligible for other therapies., Methods: A systematic review was conducted for six key questions (KQ) regarding MWA or RFA for solitary liver tumors in patients deemed poor candidates for first-line therapy. Subject experts used the GRADE methodology to formulate evidence-based recommendations and future research recommendations., Results: The panel addressed six KQs pertaining to MWA vs. RFA outcomes and laparoscopic vs. percutaneous MWA. The available evidence was poor quality and individual studies included both HCC and CRLM. Therefore, the six KQs were condensed into two, recognizing that these were two disparate tumor groups and this grouping was somewhat arbitrary. With this significant limitation, the panel suggested that in appropriately selected patients, either MWA or RFA can be safe and feasible. However, this recommendation must be implemented cautiously when simultaneously considering patients with two disparate tumor biologies. The limited data suggested that laparoscopic MWA of anatomically more difficult tumors has a compensatory higher morbidity profile compared to percutaneous MWA, while achieving similar overall 1-year survival. Thus, either approach can be appropriate depending on patient-specific factors (very low certainty of evidence)., Conclusion: Given the weak evidence, these guidelines provide modest guidance regarding liver ablative therapies for HCC and CRLM. Liver ablation is just one component of a multimodal approach and its use is currently limited to a highly selected population. The quality of the existing data is very low and therefore limits the strength of the guidelines., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Autofluorescence (AF) poses challenges for detecting proteins of interest in situ when employing immunofluorescence (IF) microscopy. This interference is particularly pronounced in strongly autofluorescent tissues such as myocardium, where tissue AF can be comparable to IF. Although various histochemical methods have been developed to achieve effective AF suppression in different types of tissue, their applications on myocardial  samples have not been well validated. Due to inconsistency across different autofluorescent structures in sometypes of tissue, it is unclear if these methods can effectively suppress AF across all autofluorescent structures within the myocardium. Here, we quantitatively evaluated the performance of several commonly used quenching treatments on formaldehyde-fixed myocardial samples, including 0.3 M glycine, 0.3% Sudan Black B (SBB), 0.1% and 1% sodium borohydride (NaBH4), TrueVIEW® and TrueBlack®. We further assessed their quenching performance by employing the pre-treatment and post-treatment protocols, designed to cover two common IF staining scenarios where buffers contained detergents or not. The results suggest that SBB and TrueBlack® outperform other reagents in AF suppression on formaldehyde-fixed myocardial samples in both protocols. Furthermore, we inspected the quenching performance of SBB and TrueBlack® on major autofluorescent myocardial structures and evaluated their influence on IF imaging. The results suggest that SBB outperforms TrueBlack® in quenching major autofluorescent structures, while TrueBlack® excels in preserving IF labeling signal. Surprisingly, we found the treatment of NaBH4 increased AF signal and enhanced the AF contrast of major autofluorescent structures. This finding suggests that NaBH4 has the potential to act as an AF enhancer and may facilitate the interpretation of myocardial structures without the need for counterstaining.

Objective: The objective of this investigation was to demonstrate that in vivo induction of hypertension (HTN) and in vitro cyclic stretch of aortic vascular smooth muscle cells (VSMCs) can cause serum and glucocorticoid-inducible kinase (SGK-1)-dependent production of cytokines to promote macrophage accumulation that may promote vascular pathology., Methods: HTN was induced in C57Bl/6 mice with angiotensin II infusion (1.46 mg/kg/day × 21 days) with or without systemic infusion of EMD638683 (2.5 mg/kg/day × 21 days), a selective SGK-1 inhibitor. Systolic blood pressure was recorded. Abdominal aortas were harvested to quantify SGK-1 activity (pSGK-1/SGK-1) by immunoblot. Flow cytometry quantified the abundance of CD11b + /F480 + cells (macrophages). Plasma interleukin (IL)-6 and monocyte chemoattractant protein-1 (MCP-1) was assessed by enzyme-linked immunosorbent assay. Aortic VSMCs from wild-type mice were subjected to 12% biaxial cyclic stretch (Stretch) for 3 or 12 hours with or without EMD638683 (10 μM) and with or without SGK-1 small interfering RNA with subsequent quantitative polymerase chain reaction for IL-6 and MCP-1 expression. IL-6 and MCP-1 in culture media were analyzed by enzyme-linked immunosorbent assay. Aortic VSMCs from SGK-1 flox+/+ mice were transfected with Cre-Adenovirus to knockdown SGK-1 (SGK-1KD VSMCs) and underwent parallel tension experimentation. Computational modeling was used to simulate VSMC signaling. Statistical analysis included analysis of variance with significance at a P value of <.05., Results: SGK-1 activity, abundance of CD11b + /F4-80 + cells, and plasma IL-6 were increased in the abdominal aorta of mice with HTN and significantly reduced by treatment with EMD638683. This outcome mirrored the increased abundance of IL-6 in media from Stretch C57Bl/6 VSMCs and attenuation of the effect with EMD638683 or SGK-1 small interfering RNA. C57Bl/6 VSMCs also responded to Stretch with increased MCP-1 expression and secretion into the culture media. Further supporting the integral role of mechanical signaling through SGK-1, target gene expression and cytokine secretion was unchanged in SGK-1KD VSMCs with Stretch, and computer modeling confirmed SGK-1 as an intersecting node of signaling owing to mechanical strain and angiotensin II., Conclusions: Mechanical activation of SGK-1 in aortic VSMCs can promote inflammatory signaling and increased macrophage abundance, therefore this kinase warrants further exploration as a pharmacotherapeutic target to abrogate hypertensive vascular pathology., Competing Interests: J.M.R. is a surgical proctor for CVRx, outside the scope of the submitted work.

Objective: The goal of this study is to discuss our initial experience with a multimodal opioid-sparing cocktail containing ropivacaine, epinephrine, clonidine, and ketorolac (RECK) in the postoperative management of lumbar decompression surgeries., Methods: Patients were either administered no local anesthetic at the incision site or were administered a weight-based amount of RECK into the paraspinal musculature and subdermal space surrounding the operative site once the fascia was closed. We performed a retrospective chart review of all patients 18 years of age or older undergoing lumbar laminectomy and lumbar diskectomy surgeries between December 2019 and April 2021. Outcomes including total opioid use, measured as morphine milligram equivalent, length of stay, and postoperative visual analog scores for pain, were collected. Relationships between variables were analyzed with Student's t-test, chi-square tests, and Fisher exact tests., Results: A total of 121 patients undergoing 52 lumbar laminectomy and 69 lumbar diskectomy surgeries were identified. For lumbar laminectomy, patients who were administered RECK had decreased opioid use in the postoperative period (11.47 ± 12.32 vs. 78.51 ± 106.10 morphine milligram equivalents, P = 0.019). For patients undergoing lumbar diskectomies, RECK administration led to a shorter length of stay (0.17 ± 0.51 vs. 0.79 ± 1.45 days, P = 0.019) and a lower 2-hour postoperative pain score (3.69 ± 2.56 vs. 5.41 ± 2.28, P = 0.006)., Conclusions: The RECK cocktail has potential to be an effective therapeutic option for the postoperative management of lumbar decompression surgeries., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 ( CDKL5 ) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual, and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD has indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3β, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3β activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3β activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3β. These compounds are very soluble in water but blood-brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces postsynaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity, and human neuropathology., Competing Interests: AC, MS, CW, JS, CF, HO, YL, WR, JS, FB, JS, IG, KD, DD, NP, AB, SU No competing interests declared, TB Consultancy for AveXis, Ovid, GW Pharmaceuticals, International Rett Syndrome Foundation, Takeda, Taysha, CureGRIN, GRIN Therapeutics, Alcyone, Neurogene, and Marinus; Clinical Trials with Acadia, Ovid, GW Pharmaceuticals, Marinus and RSRT; all remuneration has been made to his department, AA Advisor for Proteic Bioscience Inc, (© 2023, Castano, Silvestre et al.)

Despite mediating several essential processes in the brain, including during development, cyclin-dependent kinase-like 5 (CDKL5) remains a poorly characterized human protein kinase. Accordingly, its substrates, functions, and regulatory mechanisms have not been fully described. We realized that availability of a potent and selective small molecule probe targeting CDKL5 could enable illumination of its roles in normal development as well as in diseases where it has become aberrant due to mutation. We prepared analogs of AT-7519, a compound that has advanced to phase II clinical trials and is a known inhibitor of several cyclin-dependent kinases (CDKs) and cyclin-dependent kinase-like kinases (CDKLs). We identified analog 2 as a highly potent and cell-active chemical probe for CDKL5/GSK3 (glycogen synthase kinase 3). Evaluation of its kinome-wide selectivity confirmed that analog 2 demonstrates excellent selectivity and only retains GSK3α/β affinity. We next demonstrated the inhibition of downstream CDKL5 and GSK3α/β signaling and solved a co-crystal structure of analog 2 bound to human CDKL5. A structurally similar analog ( 4 ) proved to lack CDKL5 affinity and maintain potent and selective inhibition of GSK3α/β, making it a suitable negative control. Finally, we used our chemical probe pair ( 2 and 4 ) to demonstrate that inhibition of CDKL5 and/or GSK3α/β promotes the survival of human motor neurons exposed to endoplasmic reticulum stress. We have demonstrated a neuroprotective phenotype elicited by our chemical probe pair and exemplified the utility of our compounds to characterize the role of CDKL5/GSK3 in neurons and beyond.

Background: Primary hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM) represent the two most common malignant neoplasms of the liver. The objective of this study was to assess outcomes of surgical approaches to liver ablation comparing laparoscopic versus percutaneous microwave ablation (MWA), and MWA versus radiofrequency ablation (RFA) in patients with HCC or CRLM lesions smaller than 5 cm., Methods: A systematic review was conducted across seven databases, including PubMed, Embase, and Cochrane, to identify all comparative studies between 1937 and 2021. Two independent reviewers screened for eligibility, extracted data for selected studies, and assessed study bias using the modified Newcastle Ottawa Scale. Random effects meta-analyses were subsequently performed on all available comparative data., Results: From 1066 records screened, 11 studies were deemed relevant to the study and warranted inclusion. Eight of the 11 studies were at high or uncertain risk for bias. Our meta-analyses of two studies revealed that laparoscopic MW ablation had significantly higher complication rates compared to a percutaneous approach (risk ratio = 4.66; 95% confidence interval = [1.23, 17.22]), but otherwise similar incomplete ablation rates, local recurrence, and oncologic outcomes. The remaining nine studies demonstrated similar efficacy of MWA and RFA, as measured by incomplete ablation, complication rates, local/regional recurrence, and oncologic outcomes, for both HCC and CRLM lesions less than 5 cm (p > 0.05 for all outcomes). There was no statistical subgroup interaction in the analysis of tumors < 3 cm., Conclusion: The available comparative evidence regarding both laparoscopic versus percutaneous MWA and MWA versus RFA is limited, evident by the few studies that suffer from high/uncertain risk of bias. Additional high-quality randomized trials or statistically matched cohort studies with sufficient granularity of patient variables, institutional experience, and physician specialty/training will be useful in informing clinical decision making for the ablative treatment of HCC or CRLM., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Colorectal liver metastases (CRLM) occur in roughly half of patients with colorectal cancer. Minimally invasive surgery (MIS) has become an increasingly acceptable and utilized technique for resection in these patients, but there is a lack of specific guidelines on the use of MIS hepatectomy in this setting. A multidisciplinary expert panel was convened to develop evidence-based recommendations regarding the decision between MIS and open techniques for the resection of CRLM., Methods: Systematic review was conducted for two key questions (KQ) regarding the use of MIS versus open surgery for the resection of isolated liver metastases from colon and rectal cancer. Evidence-based recommendations were formulated using the GRADE methodology by subject experts. Additionally, the panel developed recommendations for future research., Results: The panel addressed two KQs, which pertained to staged or simultaneous resection of resectable colon or rectal metastases. The panel made conditional recommendations for the use of MIS hepatectomy for both staged and simultaneous resection when deemed safe, feasible, and oncologically effective by the surgeon based on the individual patient characteristics. These recommendations were based on low and very low certainty of evidence., Conclusions: These evidence-based recommendations should provide guidance regarding surgical decision-making in the treatment of CRLM and highlight the importance of individual considerations of each case. Pursuing the identified research needs may help further refine the evidence and improve future versions of guidelines for the use of MIS techniques in the treatment of CRLM., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: While surgical resection has a demonstrated utility for patients with colorectal liver metastases (CRLM), it is unclear whether minimally invasive surgery (MIS) or an open approach should be used. This review sought to assess the efficacy and safety of MIS versus open hepatectomy for isolated, resectable CRLM when performed separately from (Key Question (KQ) 1) or simultaneously with (KQ2) the resection of the primary tumor., Methods: PubMed, Embase, Google Scholar, Cochrane CENTRAL, International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov databases were searched to identify both randomized controlled trials (RCTs) and non-randomized comparative studies published during January 2000-September 2020. Two independent reviewers screened literature for eligibility, extracted data from included studies, and assessed internal validity using the Cochrane Risk of Bias 2.0 Tool and the Newcastle-Ottawa Scale. A random-effects meta-analysis was performed using risk ratios (RR) and mean differences (MD)., Results: From 2304 publications, 35 studies were included for meta-analysis. For staged resections, three RCTs and 20 observational studies were included. Data from RCTs indicated MIS having similar disease-free survival (DFS) at 1-year (RR 1.03, 95%CI 0.70-1.50), overall survival (OS) at 5-years (RR 1.04, 95%CI 0.84-1.28), fewer complications of Clavien-Dindo Grade III (RR 0.62, 95%CI 0.38-1.00), and shorter hospital length of stay (LOS) (MD -6.6 days, 95%CI -10.2, -3.0). For simultaneous resections, 12 observational studies were included. There was no evidence of a difference between MIS and the open group for DFS-1-year, OS-5-year, complications, R0 resections, blood transfusions, along with lower blood loss (MD -177.35 mL, 95%CI -273.17, -81.53) and shorter LOS (MD -3.0 days, 95%CI -3.82, -2.17)., Conclusions: Current evidence regarding the optimal approach for CRLM resection demonstrates similar oncologic outcomes between MIS and open techniques, however MIS hepatectomy had a shorter LOS, lower blood loss and complication rate, for both staged and simultaneous resections., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The biomass of microalgae and cyanobacteria yields a variety of products. Outdoor pilot plant trials typically grow a single species at circumneutral pH and provide CO 2 by gas sparging. Here a cyanobacterial consortium was grown at high pH (beyond 11) and high dissolved carbonate concentrations (0.5 M) in an outdoor 1,150 L tubular photobioreactor for 130 days in Calgary, Canada. The aim was to assess the productivity and robustness of the consortium. Importantly, the system was designed to enable future integration of air capture of CO 2 . Productivity was between 3.1 and 5.8 g ash-free dry weight per square metre per day, depending on biomass density and month. 16S rRNA amplicon sequencing showed that cyanobacterium Candidatus "Phormidium alkaliphilum" made up 80% of the consortium. The consortium displayed robust growth and adapted to environmental conditions. Bicarbonate uptake pushed medium pH past 11, demonstrating the ability to achieve CO 2 delivery by air capture., (Copyright © 2022. Published by Elsevier Ltd.)

Background: The role of age and sex in mediating coagulation characteristics in injured children is not well defined. We hypothesize that thromboelastography (TEG) profiles are equivalent across sex in younger children and diverge after puberty., Methods: Consecutive trauma patients younger than 18 years were identified from a university-affiliated, Level I, pediatric trauma center (2016-2020) database. Demographics, injury characteristics, and TEG parameters were recorded. Children were categorized by sex and age (younger, ≤10 years; older, ≥11 years). Baseline characteristics, outcomes, and TEG parameters were compared using nonparametric tests as appropriate. To account for the effects of confounding variables, analysis of covariance was performed controlling for Injury Severity Score (ISS), admission Glasgow Coma Scale score, and pediatric age-adjusted shock index., Results: Six hundred forty-seven subjects were identified (70.2% male, median ISS, 10; interquartile range, 5-24; blunt mechanism, 75.4%). Among 395 younger children (≤10 years), there were no differences in TEG characteristics between sexes. Among 252 adolescents (≥11 years), males had greater kinetic times (1.8 vs. 1.4 min; p < 0.001), decreased alpha angles (69.6° vs73.7°; p < 0.001), and lower maximum amplitudes (59.4 vs. 61.5 mm; p = 0.01). Fibrinolysis was significantly lower in older females compared with younger females (0.4% vs. 1.5%, p < 0.001) and age-matched males (0.4% vs. 1.0%, p = 0.02). Compared with younger male children, adolescent males had greater kinetic times (1.8 vs. 1.4 min; p < 0.001), decreased alpha angles (73.5° vs. 69.6°, p < 0.001), lower maximum amplitudes (59.4 vs. 62 mm, p < 0.001), and less fibrinolysis (1.0% vs. 1.3%, p = 0.03). This interaction persisted after controlling for ISS, Glasgow Coma Scale, and pediatric age-adjusted shock index., Conclusion: Sex dimorphisms in TEG coagulation profiles appear after puberty. This divergence appears to be driven by a shift in male coagulation profiles to a relatively hypocoagulable state and female coagulation profiles to a relatively hypercoagulable state after puberty., Level of Evidence: Prognostic and Epidemiologic, Level III., (Copyright © 2021 American Association for the Surgery of Trauma.)

Engineered replacement materials have tremendous potential for vascular applications where over 400,000 damaged and diseased blood vessels are replaced annually in the United States alone. Unlike large diameter blood vessels, which are effectively replaced by synthetic materials, prosthetic small-diameter vessels are prone to early failure, restenosis, and reintervention surgery. We investigated the differential response of varying 0%-6% sodium dodecyl sulfate and sodium deoxycholate anionic detergent concentrations after 24 and 72 h in the presence of DNase using biochemical, histological, and biaxial mechanical analyses to optimize the decellularization process for xenogeneic vascular tissue sources, specifically the porcine internal thoracic artery (ITA). Detergent concentrations greater than 1% were successful at removing cytoplasmic and cell surface proteins but not DNA content after 24 h. A progressive increase in porosity and decrease in glycosaminoglycan (GAG) content was observed with detergent concentration. Augmented porosity was likely due to the removal of both cells and GAGs and could influence recellularization strategies. The treatment duration on the other hand, significantly improved decellularization by reducing DNA content to trace amounts after 72 h. Prolonged treatment times reduced laminin content and influenced the vessel's mechanical behavior in terms of altered circumferential stress and stretch while further increasing porosity. Collectively, DNase with 1% detergent for 72 h provided an effective and efficient decellularization strategy to be employed in the preparation of porcine ITAs as bypass graft scaffolding materials with minor biomechanical and histological penalties., (© 2021 Wiley Periodicals LLC.)

Background: Interprofessional communication is fundamental to the delivery of healthcare and can be taught in medical school and other health professional schools through interprofessional education (IPE) activities. Simulation centers have become a predominant location for simulation IPE activities with infrastructure able to support high fidelity activities in a controlled environment. In this secondary analysis of a scoping review conducted on simulation-based IPE, we describe the characteristics of previously reported simulation IPE activities involving undergraduate medical students in a simulation center focused on interprofessional communication., Methods: Electronic searches of PubMed, CINAHL, and ERIC databases in accordance with PRISMA-ScR guidelines were conducted to isolate relevant articles from 2016-2020. In total, 165 peer-reviewed articles met inclusion criteria and data extraction linked to four research questions was applied by one individual and the accuracy was confirmed by a second individual. A secondary analysis was performed to describe what existing approaches for simulation IPE in simulation center settings have been used to explicitly achieve interprofessional communication competencies in undergraduate medical education. A sub-dataset was developed from the original scoping review and identified 21 studies describing simulation IPE activities that took place in dedicated simulation centers, targeted the IPEC interprofessional communication domain, and involved undergraduate medical students., Results: Though diverse, the majority of simulation IPE activities described high-fidelity approaches involving standardized patients and utilized assessment tools with established validity evidence in IPE activities to measure learning outcomes. A minority of simulation IPE activities were described as hybrid and utilized more than one resource or equipment for the activity and only two were longitudinal in nature. Learning outcomes were focused predominantly on modification of attitudes/perceptions and few targeted higher levels of assessment., Conclusions: Educators charged with developing simulation IPE activities for medical students focused on interprofessional communication should incorporate assessment tools that have validity evidence from similar activities, target higher level learning outcomes, and leverage hybrid models to develop longitudinal simulation IPE activities. Though an ideal environment to achieve higher level learning outcomes, simulation centers are not required for meaningful simulation IPE activities., (© 2022. The Author(s).)

Background: Post-surgical invasive Staphylococcus aureus infections among spinal fusion patients are serious complications that can worsen clinical outcomes and increase healthcare utilization. Risk of such infections at the population level remains unknown. This study assessed the post-surgical risk of invasive Staphylococcus aureus infections among patients undergoing elective posterior instrumented spinal fusion surgeries in 129 U.S. hospitals. Patients and Methods: This retrospective cohort study analyzed adult patients ≥18 years of age who underwent thoracolumbar/lumbar and cervical fusion surgeries during 2010 - 2014 using the Premier Healthcare Database, the largest hospital discharge database in the United States. Risks of blood stream infection (BSI), deep or organ/space surgical site infections (SSI) caused by Staphylococcus aureus during 90 and 180 days post-index surgery were estimated. Infections were identified based on positive culture results, related International Classification of Diseases, Ninth Revision (ICD-9) procedure codes, and specific claims information. Results: Among 11,236 patients with thoracolumbar/lumbar fusion, 90- and 180-day BSI/SSI infection risks were higher for multilevel than single level fusion (90-day, 1.52% vs. 1.07%, p = 0.05; 180-day, 1.66% vs. 1.07%, p = 0.014). Among 1,641 patients with cervical fusion, 90- and 180-day BSI/SSI infection risks were also higher in multilevel fusions but not statistically significant (90-day, 1.66% vs. 0.52%, p = 0.350; 180-day, 1.80% vs. 0.51%, p = 0.241). The risk for SSI/BSI was more than twice as high among multilevel thoracolumbar/lumbar fusion patients with more than two comorbidities than those with no comorbidity at both 90-day (2.78% vs. 1.00%, p < 0.05) and 180-day (3.01% vs. 1.10%, p < 0.05). Similar trend without statistical significance was seen in multilevel cervical fusion cohort (90-day, 2.91% vs. 1.25%, p > 0.05; 180-day, 3.88% vs. 1.41%, p > 0.05). Conclusions: The risk of BSI/SSI infection for elective posterior instrumented spinal fusions ranged between 0.5% and 2%. Higher risk was observed in multilevel thoracolumbar/lumbar surgery, with infection risk greatest in patients with more than two comorbidities. These real-world findings highlight the need for additional measures, in addition to antibiotic prophylaxis, to reduce invasive Staphylococcus aureus infections in this setting.

Objective: The objective of this scoping review is to identify, collate, and map the evidence on simulation interprofessional education activities in any setting for the education of health professional students., Introduction: Simulation interprofessional education activities comprise in-person and collaborative online learning embedded in formal curricula. Though the number of simulation interprofessional education activities has increased with the knowledge of the importance of effective interprofessional collaboration, the literature still lacks a description of the characteristics of existing activities., Inclusion Criteria: This scoping review will consider interprofessional education activities taking place within a simulation environment. Included papers will report on activities with two or more types of learners in health professional programs., Methods: The proposed scoping review will be conducted in accordance with the JBI methodology for scoping reviews. Databases searched will include PubMed, CINAHL, and ERIC. Results will be limited to English-language publications from 2016 to the present year. Data extraction will be performed using a purposefully developed data extraction tool. Teams of reviewers will screen abstracts and full texts of articles for potential inclusion, and decisions will be determined via consensus of two out of three reviewers. Extracted data will be presented in diagrammatic or tabular form in a manner that aligns with the objective of this scoping review. A narrative summary will accompany the tabulated and/or charted results and will describe how the results relate to the review's objective and questions, and how the results might inform future simulation interprofessional education activities in health professions education., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 JBI.)