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Early neurovascular coupling (NVC) changes in Alzheimer's disease can potentially provide imaging biomarkers to assist with diagnosis and treatment. Previous efforts to quantify NVC with intrinsic signal imaging have required assumptions of baseline optical pathlength to calculate changes in oxy- and deoxy-hemoglobin concentrations during evoked stimuli. In this work, we present an economical spatial frequency domain imaging (SFDI) platform utilizing a commercially available LED projector, camera, and off-the-shelf optical components suitable for imaging dynamic optical properties. The fast acquisition platform described in this work is validated on silicone phantoms and demonstrated in neuroimaging of a mouse model. © 2012 SPIE.

Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs. How the maternal as well as the fetal immune system affect human neurodevelopment and contribute to NDDs remains unclear. An important reason for this knowledge gap is the fact that the impact of exposure to prenatal risk factors has been challenging to study in the human context. Here, we characterized a model of cerebral organoids (CO) with integrated microglia (COiMg). These organoids express typical microglial markers and respond to inflammatory stimuli. The presence of microglia influences cerebral organoid development, including cell density and neural differentiation, and regulates the expression of several ciliated and mesenchymal cell markers. Moreover, COiMg and organoids without microglia show similar but also distinct responses to inflammatory stimuli. Additionally, IFN-γ induced significant transcriptional and structural changes in the cerebral organoids, that appear to be regulated by the presence of microglia. Specifically, interferon-gamma (IFN-γ) was found to alter the expression of genes linked to autism. This model provides a valuable tool to study how inflammatory perturbations and microglial presence affect neurodevelopmental processes., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Physicians other than dermatologists evaluate nearly 60% of all skin diseases, and 22% of these physicians are family physicians. Dermatology education is therefore an important aspect of Family Medicine training. Dermatologic procedural training in Family Medicine residency is not standardized, however, so family physicians graduate with highly variable skills. This study describes the scope and diagnostic outcomes of skin biopsies performed by residents at a multisite Family Medicine residency network in comparison with those performed by attendings at a Family Medicine faculty community practice., Methods: We performed a retrospective chart review of patients evaluated at eight Family Medicine residency training sites and one Family Medicine faculty community practice within a regional academic health system between January 2020 and October 2022. Patients with a skin finding who underwent at least one skin biopsy during their visit were included in the study., Results: Among all of the skin findings, the incidence of skin biopsy was 3.6% (258/7104) for residents and 1.8% (175/9917) for attendings ( P < 0.001). Family Medicine residents performed fewer shave biopsies (57.8% vs 77.7%, P < 0.001) and more punch biopsies (25.6% vs 11.4%, P < 0.001) compared with attendings. Most biopsies performed by residents and attendings were benign, although residents biopsied significantly more benign (79.1% vs 64.6%, P < 0.001) and malignant lesions (11.2% vs 5.7%, P = 0.049). Attendings biopsied significantly more low-to-moderate-grade dysplastic (22.3% vs 5.0%, P < 0.001) and high-grade atypical lesions (4.0% vs 0.8%, P = 0.034)., Conclusions: Family Medicine residents at this residency network receive training in a variety of skin biopsy types. Distinct skin biopsy practices and outcomes between residents and attendings may reflect differences in patient populations, clinical expertise, and dermatology referral patterns.

Purpose: This study aims to evaluate how student performance and perspectives changed when the Objective Structured Clinical Exam (OSCE) assessment system was changed from a composite score to discipline-specific grading at the Harvard School of Dental Medicine., Methods: The retrospective study population consisted of all students (n = 349) who completed three OSCEs (OSCE 1, 2, and 3) as part of the predoctoral program during the years 2014-2023. Data on the students' OSCE scores were obtained from the Office of Dental Education, and data on students' race/ethnicity and gender were obtained from their admissions data., Results: The likelihood of a student failing the OSCE after the assessment system change significantly increased with an adjusted odds ratio of 20.12. After the change, the number of failed subjects per student decreased with an adjusted mean ratio of 0.48. Students perceived the OSCE as being less useful after the change. Independent of the grading change, OSCEs 1 and 2 were seen as more useful compared to OSCE 3, which is administered in the last year of the Doctor of Dental Medicine program., Conclusion: The discipline-specific nature of the new assessment system helps focus on specific areas of remediation, rather than blanket remediation used previously, in order to isolate the actual areas of deficiency and to focus remediation efforts so that students can align their learning needs appropriately. Therefore, although the actual number of fails identified increased for the course, the assessment change has allowed for more directed, actionable information to be gained from the OSCE to prepare students to work toward competency standards., (© 2024 American Dental Education Association.)

Competing Interests: Conflicts of interest The authors declare no conflicts of interest.

Background: Children with neuromuscular early onset scoliosis (EOS) receive numerous radiographic studies both from orthopaedic and other specialties. Ionizing radiation doses delivered by computed tomography (CT) are reportedly 100 times higher than conventional radiography. The purpose of this study was to evaluate the number of radiographic studies ordered for neuromuscular EOS patients during their care., Methods: Retrospective review at a tertiary children's hospital from January 2010 to June 2021 included all patients with neuromuscular EOS followed by an orthopaedic specialist for a minimum of 3 years. Patients were excluded if the majority of their nonorthopaedic care was provided by outside institutions., Results: Eighteen patients met inclusion criteria with mean follow up of 6.4±2.3 years. A total of 1312 plain radiographs and 35 CT scans were performed. Of the plain radiographs, 34.7% were ordered by orthopaedic providers and 65.3% (857/1312) were ordered by other providers. Of the CT scans, 4 were ordered by orthopaedic providers, while 88.5% (21/35) were ordered by other providers. An average of 74.7 (range: 29 to 124) radiographs and 1.9 (range: 0 to 9) CT scans ordered over the course of each patient's treatment for an average of 13.0±6.0 radiographs and 0.3 CT scans per year., Conclusions: With an average of 75 radiographs and 1.9 CT scans performed per patient, consideration for steps to limit exposure to ionizing radiation should be made a particularly high priority in this unique subset of patients. This requires interdisciplinary coordination as 65% of the radiographs and over 80% of the CT scans were ordered by nonorthopaedic providers., Level of Evidence: Level III., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose/objective: A career in healthcare is built on the foundations of continuous self-reflection and self-assessment. Previous studies have solely compared student self-assessment to faculty grades in a single discipline. The objective of this study was to investigate whether associations of a student's self-assessment skills exist across multiple disciplines in the predoctoral setting., Methods: Sixty-five students from two class years at the Harvard School of Dental Medicine completed preclinical competency exams in dental anatomy waxing and operative dentistry. The difference between the student's self-assessment score and average faculty grade for each exercise was calculated as the student‒faculty (S-F) gap, which served as a proxy to determine how students evaluate their work. Regression analysis was performed to assess associations between wax-up and preclinical operative S-F gaps., Results: Mean S-F gaps for waxing and preclinical operative procedures were positive (5.7 ± 6.1 and 7.6 ± 6.7, respectively). Additionally, students in the lower quartile tended to overestimate performance to a greater degree than their peers in the upper quartile. Furthermore, the waxing S-F gaps were positively associated with S-F gaps of each operative procedure, particularly with the combined operative exercise S-F gaps, where a statistically significant association was seen (coefficient = 0.28; p = 0.04)., Conclusion(s): Previously, we identified a negative correlation between students' self-assessment skills (S-F gaps) and their preclinical performance. In this study, we further demonstrated an association of S-F gaps in two fundamental exercises: wax-up and operative dentistry. This underscores the roles of S-F gaps as possible indicators of students' preclinical and clinical performance, and it holds potential to become a widely standardized and applicable calculation that may help evaluate the effectiveness of the dental curricula and optimize student learning., (© 2024 American Dental Education Association.)

Cardiac troponin I (cTnI) is a key regulator of cardiomyocyte contraction. However, its role in mitochondria is unknown. Here we show that cTnI localized to mitochondria in the heart, inhibited mitochondrial functions when stably expressed in noncardiac cells and increased the opening of the mitochondrial permeability transition pore under oxidative stress. Direct, specific and saturable binding of cTnI to F 1 F O -ATP synthase was demonstrated in vitro using immune-captured ATP synthase and in cells using proximity ligation assay. cTnI binding doubled ATPase activity, whereas skeletal troponin I and several human pathogenic cTnI variants associated with familial hypertrophic cardiomyopathy did not. A rationally designed peptide, P888, inhibited cTnI binding to ATP synthase, inhibited cTnI-induced increase in ATPase activity in vitro and reduced cardiac injury following transient ischemia in vivo. We suggest that cTnI-bound ATP synthase results in lower ATP levels, and releasing this interaction during cardiac ischemia-reperfusion may increase the reservoir of functional mitochondria to reduce cardiac injury., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Peak alpha frequency (PAF), the dominant oscillatory frequency within the alpha range (8-12 Hz), is associated with cognitive function and several neurological conditions, including chronic pain. Manipulating PAF could offer valuable insight into the relationship between PAF and various functions and conditions, potentially providing new treatment avenues. This systematic review aimed to comprehensively synthesise effects of non-invasive brain stimulation (NIBS) on PAF speed. Relevant studies assessing PAF pre- and post-NIBS in healthy adults were identified through systematic searches of electronic databases (Embase, PubMed, PsychINFO, Scopus, The Cochrane Library) and trial registers. The Cochrane risk-of-bias tool was employed for assessing study quality. Quantitative analysis was conducted through pairwise meta-analysis when possible; otherwise, qualitative synthesis was performed. The review protocol was registered with PROSPERO (CRD42020190512) and the Open Science Framework (https://osf.io/2yaxz/). Eleven NIBS studies were included, all with a low risk-of-bias, comprising seven transcranial alternating current stimulation (tACS), three repetitive transcranial magnetic stimulation (rTMS), and one transcranial direct current stimulation (tDCS) study. Meta-analysis of active tACS conditions (eight conditions from five studies) revealed no significant effects on PAF (mean difference [MD] = -0.12, 95% CI = -0.32 to 0.08, p = 0.24). Qualitative synthesis provided no evidence that tDCS altered PAF and moderate evidence for transient increases in PAF with 10 Hz rTMS. However, it is crucial to note that small sample sizes were used, there was substantial variation in stimulation protocols, and most studies did not specifically target PAF alteration. Further studies are needed to determine NIBS's potential for modulating PAF., (© 2024 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background/purpose: Self-assessment in dental education is considered a fundamental skill for proficient oral healthcare providers. While previous studies looked at self-assessment in education, few have done so at Japanese institutions. This study aimed to assess potential associations between gender and self-assessment skills in Japanese dental students., Materials and Methods: Dental students from Niigata University (n = 301) completed preclinical prosthodontic exercises and self-assessed their practical exam performance. Three calibrated faculty evaluated students' work using the same rubric. The difference between student self-assessment score and mean faculty grade was defined as the student-faculty (S-F) gap, indicating how accurately students evaluated their work. The gap scores were stratified by quartiles by faculty grade and by gender. Regression analysis was used to investigate potential associations., Results: Students mean S-F gap was 2.9 ± 10.5 % with a significant negative association to faculty grades (coefficient, -0.32; P  < 0.001). There was no significant difference between male and female students for faculty grades, self-assessment scores, and S-F gaps. When stratified by quartile, mean S-F gaps of bottom quartile students (5.7 ± 11.9 %) were significantly higher than the rest of the class (1.9 ± 9.8 %; P  = 0.01), while the mean S-F gaps of students in the top quartile (-0.8 ± 10.2 %) were significantly lower than the rest of the class (4.2 ± 10.3 %; P  < 0.001)., Conclusion: Niigata University students generally overestimated their performance. Students with higher faculty grades self-assessed themselves more accurately than students with lower faculty grades. Gender did not influence S-F gaps, despite dentistry in Japan shifting toward a female-dominated field., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2024 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Janus kinase 2 (JAK2) V617F mutation is present in most patients with polycythemia vera (PV). One persistently puzzling aspect unresolved is the association between JAK2V617F allele burden (also known as variant allele frequency) and the relevant clinical characteristics. Numerous studies have reported associations between allele burden and both hematologic and clinical features. While there are strong indications linking high allele burden in PV patients with symptoms and clinical characteristics, not all associations are definitive, and disparate and contradictory findings have been reported. Hence, this study aimed to synthesize existing data from the literature to better understand the association between JAK2V617F allele burden and relevant clinical correlates. Out of the 1,851 studies identified, 39 studies provided evidence related to the association between JAK2V617F allele burden and clinical correlates, and 21 studies were included in meta-analyses. Meta-analyses of correlation demonstrated that leucocyte and erythrocyte counts were significantly and positively correlated with JAK2V617F allele burden, whereas platelet count was not. Meta-analyses of standardized mean difference demonstrated that leucocyte and hematocrit were significantly higher in patients with higher JAK2V617F allele burden, whereas platelet count was significantly lower. Meta-analyses of odds ratio demonstrated that patients who had higher JAK2V617F allele burden had a significantly greater odds ratio for developing pruritus, splenomegaly, thrombosis, myelofibrosis, and acute myeloid leukemia. Our study integrates data from approximately 5,462 patients, contributing insights into the association between JAK2V617F allele burden and various hematological parameters, symptomatic manifestations, and complications. However, varied methods of data presentation and statistical analyses prevented the execution of high-quality meta-analyses., (© 2024. The Author(s).)

Study Design: Systematic review. The purpose of this study was to compare the top 25 articles on pediatric spine surgery by number of citations and Altmetric score. All published articles pertaining to pediatric spine surgery from 2010 to 2021 were assessed for: Altmetric scores, Altmetric score breakdown (e.g. Twitter, News), citation counts, and article topics. The top 25 Altmetric articles and top 25 cited articles were identified. Out of the 50 total articles, only 3 (6.0%) overlapped between the two groups. The top Altmetric articles had averages (mean ± SD) of 167 ± 130 Altmetric score and 66 ± 135 citations, while the top citation articles had averages of 22 ± 45 Altmetric score and 196 ± 114 citations. When evaluating article topics, articles on 'back pain' (36% vs. 4%; P  = 0.003) and 'backpacks' (16% vs. 0%; P  = 0.030) were published significantly more in the top Altmetric group, while articles on 'scoliosis' (93% vs. 36%; P  < 0.001) and 'growth friendly surgery' (24% vs. 4%; P  = 0.041) were published significantly more in the top citation group. The total number of citations and online mentions for both groups are presented in Table 2. The biggest differences were the top Altmetric score articles receiving greater percentages of Twitter mentions relative to overall mentions (87% vs. 57%). The most socially popular articles focused on back pain and backpacks, and the most cited articles focused on scoliosis and growth-friendly surgery. Twitter had the most mentions of all social media for both the top cited articles and the top Altmetric articles., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

In metazoans, living cells achieve capabilities beyond individual cell functionality by assembling into multicellular tissue structures. These higher-order structures represent dynamic, heterogeneous, and responsive systems that have evolved to regenerate and coordinate their actions over large distances. Recent advances in constructing micrometer-sized vesicles, or synthetic cells, now point to a future where construction of synthetic tissue can be pursued, a boon to pressing material needs in biomedical implants, drug delivery systems, adhesives, filters, and storage devices, among others. To fully realize the potential of synthetic tissue, inspiration has been and will continue to be drawn from new molecular findings on its natural counterpart. In this review, we describe advances in introducing tissue-scale features into synthetic cell assemblies. Beyond mere complexation, synthetic cells have been fashioned with a variety of natural and engineered molecular components that serve as initial steps toward morphological control and patterning, intercellular communication, replication, and responsiveness in synthetic tissue. Particular attention has been paid to the dynamics, spatial constraints, and mechanical strengths of interactions that drive the synthesis of this next-generation material, describing how multiple synthetic cells can act as one.

Background: Polycythemia vera (PV) patients often experience constitutional symptoms and are at risk of thromboembolism as well as disease progression to myelofibrosis or acute myeloid leukemia. Not only is PV often overlooked but treatment options are also limited, however., Objectives: To explore the patient characteristics and treatment pattern of PV patients in Taiwan, and compare with other countries reported in the literature., Design: This is a nationwide cross-sectional study., Methods: The National Health Insurance Research Database in Taiwan, which covers 99% of the population, was utilized. Patients were identified during the cross-sectional period between 2016 and 2017, and their retrospective data were retrieved from 2001 to 2017., Results: A total of 2647 PV patients were identified between 1 January 2016 and 31 December 2017. This study described the demographic information of these patients, including number of patients by risk stratification and by sex, age at diagnosis, age at cross-sectional period, rate of bone marrow aspiration/biopsy at diagnosis, comorbidities, number of postdiagnosis thrombosis, number of disease progression, and death. The mortality rate of PV patients (4.1%) over 60 of age was higher than the general population of the same age group (2.8%). This study also compared the different treatment patterns between sexes and risk groups. Hydroxyurea was deferred to an older age, but conversely was prescribed at higher dose to younger patients. Alarmingly, a high proportion of patients did not receive phlebotomy or hydroxyurea for at least 2 years. Furthermore, discrepancies in prevalence, age at diagnosis, sex ratio, incidence of thrombosis and mortality were also found when compared with data reported in other countries., Conclusion: The clinical landscape of PV in Taiwan between 2016 and 2017 was examined. Distinctive patterns of phlebotomy and hydroxyurea were identified. Overall, these findings highlight the importance of understanding the patient characteristics and treatment patterns of PV in different regions to better inform clinical practice and improve patient outcomes., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Mr A.J.-H.L. and Dr L.H.-L.Y. have declared their employment status with Panco Healthcare Co., Ltd., a subsidiary of PharmaEssentia Corporation and Dr M.-S.Y. and Prof. M.-C.C. are consultants for Panco Healthcare Co., Ltd., (© The Author(s), 2023.)

Physical activity is associated with beneficial adaptations in human and rodent metabolism. We studied over 50 complex traits before and after exercise intervention in middle-aged men and a panel of 100 diverse strains of female mice. Candidate gene analyses in three brain regions, muscle, liver, heart, and adipose tissue of mice indicate genetic drivers of clinically relevant traits, including volitional exercise volume, muscle metabolism, adiposity, and hepatic lipids. Although ∼33% of genes differentially expressed in skeletal muscle following the exercise intervention are similar in mice and humans independent of BMI, responsiveness of adipose tissue to exercise-stimulated weight loss appears controlled by species and underlying genotype. We leveraged genetic diversity to generate prediction models of metabolic trait responsiveness to volitional activity offering a framework for advancing personalized exercise prescription. The human and mouse data are publicly available via a user-friendly Web-based application to enhance data mining and hypothesis development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Pediatric hip disorders represent a broad range of pathology and remain a significant source of morbidity for children and young adults. Surgical intervention is often required for joint preservation, but when salvage is not possible, joint replacement may be indicated to eliminate pain and preserve function. Although there have been significant updates in the management of both pediatric hip disease and the field of total hip arthroplasty (THA), there is a paucity of literature reflecting advancements in the area of pediatric and young adult (PYA) arthroplasty. No study has investigated the impact of approach on outcomes after PYA THA. The purpose of this study is to describe the indications, techniques, and early outcomes of THA in the PYA population in a modern practice setting., Methods: We performed a retrospective descriptive analysis of all patients undergoing primary THA performed at a tertiary care children's hospital from 2004 to 2019. Ninety-three hips in 76 patients were evaluated. Demographics, intraoperative variables, postoperative pain and function ratings, and complication and revision rates were collected., Results: Eighty-five hips in 69 patients were included. Patients were aged 12 to 23 years old, with males and females represented equally (33 vs. 36, respectively). The most common cause of hip pain was avascular necrosis (AVN, 56/85, 66%), most commonly due to slipped capital femoral epiphysis (13/56, 23%) idiopathic AVN (12/56, 21%), and chemotherapy (12/56, 21%). Half of all hips had been previously operated before THA (43/85). Thirty-six procedures were performed via the posterolateral approach (36/85, 42%), 33 were performed via direct anterior approach (33/85, 39%), and 16 were performed via the lateral approach (LAT, 16/85, 19%). At final follow-up, 98% (83/85) of patients had complete resolution of pain, 82% (70/85) had no notable limp, and 95% (81/85) had returned to all activities. There were 6 complications and 1 early revision. Average Hip disability and Osteoarthritis Outcomes Score for Joint Replacement scores increased by 37 points from 56 to 93. The overall revision-free survival rate for PYA THA was 98.8% (at average 19-mo follow-up)., Conclusions: Modern PYA THA is dissimilar in indications and surgical techniques to historic cohorts, and conclusions from prior studies should not be generalized to modern practice. In our practice, PYA patients most commonly carry a diagnosis of AVN, and THA can be performed with modern cementless fixation with large cup and head sizes and ceramic-on-cross-linked polyethylene bearings utilizing any approach. Further study is required to better characterize middle-term and long-term results and patient-reported outcomes., Level of Evidence: Therapeutic Level IV-retrospective case series., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Treatment of acute pediatric Monteggia fractures requires ulnar length stability to maintain reduction of the radiocapitellar joint. When operative care is indicated, intramedullary ulna fixation can be buried or left temporarily exposed through the skin while under a cast. The authors hypothesized that treatment with exposed fixation yields equivalent results to buried fixation for Monteggia fractures while avoiding secondary surgery for hardware removal., Methods: A retrospective review of children with acute Monteggia fractures at our Level 1 pediatric trauma center was performed. Patient charts and radiographs were evaluated for age, fracture type, fracture location, Bado classification, type of treatment, complications, cast duration, time to fracture union, time to hardware removal, and range of motion., Results: Out of 59 acute Monteggia fractures surgically treated (average age 6 y, range 2 to 14), 15 (25%) patients were fixed with buried intramedullary fixation and 44 (75%) with exposed intramedullary fixation under a cast. There were no significant differences between buried and exposed intramedullary fixation in cast time after surgery (39 vs. 37 d; P =0.55), time to fracture union (37 vs. 35 d; P =0.67), pronation/supination (137 vs. 134 degrees; P =0.68) or flexion/extension (115 vs. 114 degrees; P =0.81) range of motion. The exposed fixation had a return to OR of 4.5% (2 out of 44), and the buried fixation returned to the OR for removal on all patients., Conclusion: Exposed intramedullary fixation yielded equivalent clinical outcomes to buried devices in the treatment of acute pediatric Monteggia fractures while eliminating the need for a second surgery to remove hardware, reducing the associated risks and costs of surgery and anesthesia, but had a higher complication rate. Open Monteggia fractures or patterns with a known risk of delayed union may benefit from buried instead of exposed intramedullary fixation for earlier mobilization., Level of Evidence: III., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

During developmental processes and wound healing, activation of living cells occurs with spatiotemporal precision and leads to rapid release of soluble molecular signals, allowing communication and coordination between neighbors. Nonliving systems capable of similar responsive release hold great promise for information transfer in materials and site-specific drug delivery. One nonliving system that offers a tunable platform for programming release is synthetic cells. Encased in a lipid bilayer structure, synthetic cells can be outfitted with molecular conduits that span the bilayer and lead to material exchange. While previous work expressing membrane pore proteins in synthetic cells demonstrated content exchange, user-defined control over release has remained elusive. In mammalian cells, connexon nanopore structures drive content release and have garnered significant interest since they can direct material exchange through intercellular contacts. Here, we focus on connexon nanopores and present activated release of material from synthetic cells in a light-sensitive fashion. To do this, we re-engineer connexon nanopores to assemble after post-translational processing by a protease. By encapsulating proteases in light-sensitive liposomes, we show that assembly of nanopores can be triggered by illumination, resulting in rapid release of molecules encapsulated within synthetic cells. Controlling connexon nanopore activity provides an opportunity for initiating communication with extracellular signals and for transferring molecular agents to the cytoplasm of living cells in a rapid, light-guided manner.

Encouraged by the dependence of drug-resistant, metastatic cancers on GPX4, we examined biophysical mechanisms of GPX4 inhibition, which revealed an unexpected allosteric site. We found that this site was involved in native regeneration of GPX4 under low glutathione conditions. Covalent binding of inhibitors to this allosteric site caused a conformational change, inhibition of activity, and subsequent cellular GPX4 protein degradation. To verify this site in an unbiased manner, we screened a library of compounds and identified and validated that an additional compound can covalently bind in this allosteric site, inhibiting and degrading GPX4. We determined co-crystal structures of six different inhibitors bound in this site. We have thus identified an allosteric mechanism for small molecules targeting aggressive cancers dependent on GPX4., Competing Interests: Declaration of interests B.R.S. is an inventor on patents and patent applications involving small-molecule drug discovery, ferroptosis, and GPX4; co-founded and serves as a consultant to Inzen Therapeutics, Exarta Therapeutics, and ProJenX, Inc.; serves as a consultant to Weatherwax Biotechnologies Corporation and Akin Gump Strauss Hauer & Feld LLP; and receives sponsored research support from Sumitomo Dainippon Pharma Oncology., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

There have been few clinically useful targetable biomarkers in uterine cervical carcinomas. Estrogen receptor (ER), HER2, and fibroblast activation protein (FAP) are potential therapeutic or theranostic targets in other gynecologic and genitourinary carcinoma types. We determined the immunohistochemical expression patterns of these markers in treatment-naive cervical carcinoma, and whether expression correlated with clinical outcomes after definitive chemoradiation therapy. Tissue microarrays were created from 71 patient samples taken before therapy (57 squamous cell carcinomas and 14 nonsquamous cell carcinomas) and stained for ER, HER2, and FAP. ER was positive in 25/70 cases (36%). Of 66 tumors with evaluable HER2 staining, only 1 had positive (3+) staining (3%, positive for HER2 amplification by fluorescence in situ hybridization), and 1 had equivocal (2+) staining (negative for amplification by fluorescence in situ hybridization). The remainder were negative for HER2 overexpression. FAP expression was widely variably in the tumor stroma. ER positivity and FAP expression did not correlate with cervical recurrence, pelvic recurrence, distant recurrence, or cancer death. In conclusion, HER2 amplification is very rare in nonmetastatic treatment-naive cervical carcinomas, but if present, could represent a target for antibody therapy. ER and FAP were expressed in a subset of tumors, but expression did not correlate with clinical outcomes. These immunohistochemical markers do not demonstrate prognostic significance in treatment-naive cervical cancer, but they may have utility in targeted therapy or imaging., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)

Background: The proximal femur is a common location for pathologic fractures in children, yet there is little published information regarding this injury. The purpose of this study was to investigate the outcomes of pediatric pathologic proximal femur fractures due to benign bone tumors., Methods: A retrospective review of patients treated for pathologic proximal femur fractures from 2004 to 2018 was conducted. Inclusion criteria were age below 18 years and pathologic proximal femur fracture secondary to a benign bone tumor. Patients were excluded if they had <1 year of follow-up. Medical charts and serial radiographs were reviewed for fracture classification, underlying pathology, treatment, complications, and time to fracture healing., Results: A total of 14 patients were included. Mean age was 6±3 (3 to 11) years, and mean follow-up was 44±21 (22 to 86) months. Index treatment was spica casting in 9/14 (68%) patients, while 5/14 (32%) were treated with internal fixation. Of the 9 patients initially treated with casting, 22% (2/9) required repeat spica casting at a mean of 0.6 months after index treatment, 67% (6/9) required internal fixation at a mean of 20.3 months after index treatment, and 11% (1/9) did not require revision treatment. Eighty-eight percent (8/9) of patients treated with casting required revision treatment compared with 40% (2/5) of those treated with internal fixation (P=0.05). Nonunion occurred after 1 refracture, malunion with coxa vara occurred in 2 fractures, and the remaining 11/14 (84%) fractures had a union at a mean of 4.9±3.0 months All cases of malunion occurred in patients initially treated nonoperatively. There were 19 distinct complications in 10/14 (71%) patients. The incidence of any revision surgery was 64% (9/14)., Conclusions: In this series, pediatric pathologic proximal femur fractures demonstrated prolonged time to union, high incidence of revision surgery (64%), and substantial complication rate (71%). In children with pathologic proximal femur fractures, treatment with internal fixation is recommended as this series showed a 78% failure rate of initial conservative management., Level of Evidence: Level IV., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To report long-term results of an outpatient template-based high-dose-rate interstitial brachytherapy (HDR ISBT) program for the treatment of gynecologic malignancies., Methods: Patients treated between 2006 and 2020 at an academic hospital with outpatient template based HDR ISBT without spinal or general anesthesia were reviewed. Patients who had previously received HDR ISBT were excluded. Baseline patient, tumor, and treatment characteristics, such as tumor size, histology, and/or total EQD2 including prior external beam radiation therapy (EBRT) were recorded. Local control and overall survival were estimated using the Kaplan-Meier method, and factors associated with local control and overall survival were evaluated using Cox regression analyses., Results: 150 patients received HDR ISBT for a gynecologic tumor and the median follow-up time was 2.98 years (0.89-4.82). Of those, 74/150 (49%) were treated definitively, 69/150 (46%) were treated for tumor recurrence/persistence, and 7/150 (5%) were treated for durable palliation. Median tumor size was 3.00 cm (1.50-4.00). 124/150 (83%) patients received EBRT prior to HDR ISBT. Median HDR ISBT dose was 18 Gy delivered in eight fractions. Local control was 71% (64%-79%), 58% (50%-68%), and 57% (48%-67%) at one, three, and five years, respectively. On multivariate analysis, non-endometrial adenocarcinoma histology (HR = 2.423, 95% CI = 1.011-5.808, p = 0.047) and tumor size ≥ 3 cm (HR = 2.903, 95% CI 1.053-3.441, p = 0.033) were associated with lower local control., Conclusions: The majority of patients who received outpatient-based twice daily HDR ISBT had long-term local control. Larger tumor size and non-endometrial adenocarcinoma histology were detrimental to local control., Competing Interests: Declaration of Competing Interest We have no conflicts of interest to disclose which specifically pertain to the creation of this manuscript. Conflicts of interest unrelated to this manuscript are summarized in the supplied ICJME forms., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Recent studies have demonstrated that alterations in mitochondrial dynamics can impact innate immune function. However, the upstream mechanisms that link mitochondrial dynamics to innate immune phenotypes have not been completely elucidated. This study asks if Protein Kinase C, subunit delta (δPKC)-mediated phosphorylation of dynamin-related protein 1 (Drp1), a key driver of mitochondrial fission, impacts macrophage pro-inflammatory response following bacterial-derived lipopolysaccharide (LPS) stimulation., Methods: Using RAW 264.7 cells, bone marrow-derived macrophages from C57BL/6J mice, as well as human monocyte-derived macrophages, we first characterized changes in δPKC-mediated phosphorylation of Drp1 following LPS stimulation. Next, using rationally designed peptides that inhibit δPKC activation (δV1-1) and δPKC-Drp1 interaction (ψDrp1), we determined whether δPKC-mediated phosphorylation of Drp1 impacts LPS-induced changes in mitochondrial morphology, mitochondrial function, and inflammatory response., Results: Our results demonstrated that δPKC-dependent Drp1 activation is associated with increased mitochondrial fission, impaired cellular respiration, and increased mitochondrial reactive oxygen species in LPS-treated macrophages. This is reversed using a rationally designed peptide that selectively inhibits δPKC phosphorylation of Drp1 (ψDrp1). Interestingly, limiting excessive mitochondrial fission using ψDrp1 reduced LPS-triggered pro-inflammatory response, including a decrease in NF-κB nuclear localization, decreased iNOS induction, and a reduction in pro-inflammatory cytokines (IL-1β, TNFα, IL-6)., Conclusion: These data suggest that inhibiting Drp1 phosphorylation by δPKC abates the excessive mitochondrial fragmentation and mitochondrial dysfunction that is seen following LPS treatment. Furthermore, these data suggest that limiting δPKC-dependent Drp1 activation decreases the pro-inflammatory response following LPS treatment. Altogether, δPKC-dependent Drp1 phosphorylation might be an upstream mechanistic link between alterations in mitochondrial dynamics and innate immune phenotypes, and may have therapeutic potential., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

Background: Oncoplastic breast reconstruction improves cosmetic outcomes when compared to standard breast conservation therapy alone. The authors studied whether tailoring a breast reduction to a cancer resection affects complication rates by comparing (1) outcomes between oncoplastic and benign macromastia patients and (2) complication rates between the cancer side and the symmetrizing side of an oncoplastic reduction., Methods: A retrospective chart review was performed on female patients who underwent either oncoplastic or benign breast reduction over 9 years by a single surgeon. Patient demographics, intraoperative data, and postoperative outcomes were gathered from the electronic medical record. Chi-square and t tests were performed when appropriate to determine significance., Results: Of the 211 patients included in the study, 62 (29.4 percent) underwent oncoplastic breast reduction and 149 (70.6 percent) underwent breast reduction for benign macromastia. Total resection weight was greater in the benign group (p = 0.00). There was a higher rate of loss of nipple sensation in the oncoplastic group (p = 0.005) but no differences in any other complication. There was a higher complication rate in the oncologic breast when compared to the symmetrizing breast within the oncoplastic cohort (p = 0.039), but no differences in the rates of individual complications., Conclusions: Although the loss of nipple sensation was increased in patients undergoing oncoplastic breast reduction, all other outcomes were not significantly different between the two groups. The authors' findings indicate that oncoplastic breast reduction can be performed with a safety profile similar to that of a standard breast reduction., Clinical Question/level of Evidence: Therapeutic, III., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Background: Cast injuries can occur during application, throughout immobilization, and during removal, with common morbidities being pressure ulcers and cast saw burns. The incidence rate of cast injuries in generalized and diagnosis specific pediatric populations is not known. The goal of this study is to accurately quantify the rate of incidence of cast injuries at a large pediatric orthopaedic practice and identify potentially modifiable risk factors to guide quality of care improvement., Methods: A retrospective review was performed at our institution between July 2019 and October 2020. Inclusion criteria was all pediatric patients (below 21 y old) with an orthopaedic diagnosis that was treated with casting. The child's diagnosis, specific type of cast, and training level of the person applying the cast was recorded. Patient injuries were identified through cast technicians' documentation regarding cast removal. The primary outcome was the incidence of casting injuries from July 2019 through October 2020. Additional outcomes included the association between diagnosis of neuromuscular disease and training level of individual applying the cast with casting injuries. χ2 tests were used to compare categorical variables and post hoc comparisons using Bonferroni correction. Injury incidence rates were calculated as number of injuries per 1000 casts., Results: There were 2239 casts placed on children at this institution between July 2019 and October 2020 and a total of 28 injuries for an incidence rate of 12.5 per 1000. Of the 28 total injuries reported, there were 5 cast saw burns (2.2 per 1000) and 23 pressure ulcers (10.3 per 1000). Incidence of cast injury was not significantly correlated with timing of application during the academic year or training level of the individual applying the cast (P=0.21 and 0.86). Notably, there was a significantly higher incidence of cast injuries in individuals with a diagnosis of a neuromuscular disorder (37.4 per 1000) than those without (7.5 per 1000) (P<0.01)., Conclusion: The incidence of cast injuries is 12.5 per 1000 children at our level I trauma tertiary referral pediatric clinic. Training level of the individual applying the cast or timing during the academic year did not correlate with cast injuries. Patients with neuromuscular disorders are at significantly higher risk for experiencing cast injuries., Level of Evidence: Level III., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Myocardial infarction is the leading cause of cardiovascular mortality, with myocardial injury occurring during ischemia and subsequent reperfusion (IR). We previously showed that the inhibition of protein kinase C delta (δPKC) with a pan-inhibitor (δV1-1) mitigates myocardial injury and improves mitochondrial function in animal models of IR, and in humans with acute myocardial infarction, when treated at the time of opening of the occluded blood vessel, at reperfusion. Cardiac troponin I (cTnI), a key sarcomeric protein in cardiomyocyte contraction, is phosphorylated by δPKC during reperfusion. Here, we describe a rationally-designed, selective, high-affinity, eight amino acid peptide that inhibits cTnI's interaction with, and phosphorylation by, δPKC (ψTnI), and prevents tissue injury in a Langendorff model of myocardial infarction, ex vivo. Unexpectedly, we also found that this treatment attenuates IR-induced mitochondrial dysfunction. These data suggest that δPKC phosphorylation of cTnI is critical in IR injury, and that a cTnI/δPKC interaction inhibitor should be considered as a therapeutic target to reduce cardiac injury after myocardial infarction.

Recent studies have identified an association between perturbed type I interferon (IFN) responses and the severity of coronavirus disease 2019 (COVID-19). IFNα intervention may normalize the dysregulated innate immunity of COVID-19. However, details regarding its utilization and therapeutic evidence have yet to be systematically evaluated. The aim of this comprehensive review was to summarize the current utilization of IFNα for COVID-19 treatment and to explore the evidence on safety and efficacy. A comprehensive review of clinical studies in the literature prior to December 1st , 2021, was performed to identify the current utilization of IFNα, which included details on the route of administration, the number of patients who received the treatment, the severity at the initiation of treatment, age range, the time from the onset of symptoms to treatment, dose, frequency, and duration as well as safety and efficacy. Encouragingly, no evidence was found against the safety of IFNα treatment for COVID-19. Early intervention, either within five days from the onset of symptoms or at hospital admission, confers better clinical outcomes, whereas late intervention may result in prolonged hospitalization., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: A major obstacle in the clinical translation of engineered auricular scaffolds is the significant contraction and loss of topography that occur during maturation of the soft collagen-chondrocyte matrix into elastic cartilage. We hypothesized that 3-dimensional-printed, biocompatible scaffolds would "protect" maturing hydrogel constructs from contraction and loss of topography., Design: External disc-shaped and "ridged" scaffolds were designed and 3D-printed using polylactic acid (PLA). Acellular type I collagen constructs were cultured in vitro for up to 3 months. Collagen constructs seeded with bovine auricular chondrocytes (BAuCs) were prepared in 3 groups and implanted subcutaneously in vivo for 3 months: preformed discs with ("Scaffolded/S") or without ("Naked/N") an external scaffold and discs that were formed within an external scaffold via injection molding ("Injection Molded/SInj")., Results: The presence of an external scaffold or use of injection molding methodology did not affect the acellular construct volume or base area loss. In vivo , the presence of an external scaffold significantly improved preservation of volume and base area at 3 months compared to the naked group ( P < 0.05). Construct contraction was mitigated even further in the injection molded group, and topography of the ridged constructs was maintained with greater fidelity ( P < 0.05). Histology verified the development of mature auricular cartilage in the constructs within external scaffolds after 3 months., Conclusion: Custom-designed, 3D-printed, biocompatible external scaffolds significantly mitigate BAuC-seeded construct contraction and maintain complex topography. Further refinement and scaling of this approach in conjunction with construct fabrication utilizing injection molding may aid in the development of full-scale auricular scaffolds.

The metabolic syndrome is a cluster of conditions that increase an individual's risk of developing diseases. Being physically active throughout life is known to reduce the prevalence and onset of some aspects of the metabolic syndrome. Furthermore, previous studies have demonstrated that an individual's gut microbiome composition has a large influence on several aspects of the metabolic syndrome. However, the mechanism(s) by which physical activity may improve metabolic health are not well understood. We sought to determine if endurance exercise is sufficient to prevent or ameliorate the development of the metabolic syndrome and its associated diseases. We also analyzed the impact of physical activity under metabolic syndrome progression upon the gut microbiome composition. Utilizing whole-body low-density lipoprotein receptor (LDLR) knockout mice on a "Western Diet," we show that long-term exercise acts favorably upon glucose tolerance, adiposity, and liver lipids. Exercise increased mitochondrial abundance in skeletal muscle but did not reduce liver fibrosis, aortic lesion area, or plasma lipids. Lastly, we observed several changes in gut bacteria and their novel associations with metabolic parameters of clinical importance. Altogether, our results indicate that exercise can ameliorate some aspects of the metabolic syndrome progression and alter the gut microbiome composition., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Radiotherapy plays an important role in the definitive and adjuvant treatment of head and neck squamous cell carcinoma (HNSCC). However, standard courses of radiation therapy may contribute to the depletion of circulating lymphocytes and potentially attenuate optimal tumor antigen presentation that may be detrimental to the efficacy of novel immunotherapeutic agents. This review explores the advantages of restricting radiation to the primary tumor/tumor bed and ipsilateral elective neck as it pertains to the evolving field of immunotherapy.

Introduction: The failure rate of Pavlik harness treatment for developmental dysplasia of the hip (DDH) has been reported as high as 55%. The purpose of this study is to investigate the effect of an inverted acetabular labrum on outcomes of Pavlik harness treatment for DDH., Methods: A retrospective review was conducted on DDH patients at a tertiary care pediatric hospital from 2004 to 2016. DDH patients that underwent index treatment with Pavlik harness and had minimum 12 months follow-up were included. Medical charts were reviewed for demographics, treatment, and outcomes. Outcomes were compared between patients with an inverted labrum versus those without an inverted labrum., Results: A total of 156 patients with 229 dysplastic hips were included. The mean age at initiation of Pavlik harness treatment was 1.9±1.4 months and mean follow-up was 37.7±23.0 months. Bilateral DDH was diagnosed in 46% (73/156) of patients. In all, 37% (75/229) of hips failed Pavlik harness index treatment. Second-line treatment was rigid hip abduction bracing in 91% (68/75) of hips, closed reduction in 5% (4/75) of hips, and open reduction in 4% (3/75) of hips. An inverted labrum was present in 10% (22/229) of all hips. The incidence of Pavlik harness treatment failure was 91% (20/22) in the inverted labrum group compared with 27% (55/207) in the control group (P<0.001). Closed or open reduction was required in 86% (15/22) of the inverted labrum group compared with 3% (7/207) of hips in the control group (P<0.001). The incidence of avascular necrosis was 18% (4/22) in hips with an inverted labrum compared with 0.4% (1/207) in the control group (P<0.001)., Conclusions: In children with DDH undergoing index treatment in a Pavlik harness, the presence of an inverted acetabular labrum is strongly predictive of treatment failure. Dysplastic hips with an inverted labrum also have a significantly higher risk of requiring closed or open reduction and developing avascular necrosis compared with those without an inverted labrum., Level of Evidence: Level III., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: In order to solve the problem of accurate and effective segmentation of the patient's lung computed tomography (CT) images, so as to improve the efficiency of treating lung cancer., Method: We propose a U-Net network (DC-U-Net) fused with dilated convolution, and compare the results of segmented lung CT with DC-U-Net, Otsu and region growth. We use Intersection over Union (IOU), Dice coefficient, Precision and Recall to evaluate the performance of the three algorithms., Results: Compared with the common segmentation algorithm Otsu and region growing, the segmented image of DC-U-Net is closer to the Ground truth. The IOU of DC-U-Net is 0.9627, and the Dice coefficient is 0.9743, which is close to 1 and much higher than the other two algorithms., Conclusion: We propose that the model can directly segment the original image automatically, and the segmentation effect is good. This model speeds up the segmentation, simplifies the steps of medical image segmentation, and provides better segmentation for subsequent lung blood vessels, trachea and other tissues., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Methylnaltrexone, a peripheral opioid antagonist, is used to decrease opioid-induced constipation; however, there is limited evidence for its use in children. The primary objective of the study is to assess the efficacy of per os (PO) methylnaltrexone in inducing bowel movements (BMs) in patients with adolescent idiopathic scoliosis who underwent a posterior spinal fusion and instrumentation (PSFI). Secondary outcomes include hospital length of stay, postoperative pain scores, and postoperative opioid usage., Methods: Retrospective chart review identified all adolescent idiopathic scoliosis patients above 10 years of age who underwent PSFI with a minimum of 24 hours of postoperative opioid analgesia after the initiation of the new bowel regimen protocol. The bowel regimen included daily administration of PO methylnaltrexone starting on postoperative day 1 until BM is achieved. A case-matched cohort was obtained with patients who did not receive PO methylnaltrexone and otherwise had the same bowel function regimen. Case-matched controls were also matched for age, sex, body mass index, and curve severity. t Tests and Pearson χ2 tests were used for statistical analysis., Results: Fifty-two patients received oral methylnaltrexone (14±2.6 y) and 52 patients were included in the case-matched control group (14±2.1 y). The methylnaltrexone group had a significantly shorter hospital length of stay (3.09±0.66) compared with controls (3.69±0.80) (P<0.01). 59% (31 of 52) of the methylnaltrexone group had a BM by postoperative day postoperative day 2, compared with 30% (16 of 52) of the control group (P<0.01). In the methylnaltrexone group, 44% (23 of 52) of the patients required a Dulcolax (bisacodyl) suppository and 11% (6 of 52) required an enema, compared with 50% (26 of 52) and 33% (12 of 52) of the control group respectively (P=0.43 and 0.12). In addition, significantly less patients had abdominal distension during their postoperative stay in the methylnaltrexone group (17%, 9 of 52) compared with the control group (40%, 21 of 52) (P<0.01). There was no significant difference in self-reported average FACES pain score (P=0.39) or in opioid morphine equivalents required per hour (P=0.18)., Conclusions: Patients who received PO methylnaltrexone after PSFI had decreased length of stay and improved bowel function. Administration of methylnaltrexone did not increase maximum self-reported FACES pain values or opioid consumption compared with controls. The use of oral methylnaltrexone after PSFI reduces postoperative constipation, which has implications for reducing hospital length of stay and overall morbidity., Level of Evidence: Level III-retrospective comparative study., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Esophageal cancer is a common malignant tumor in life, which seriously affects human health. In order to reduce the work intensity of doctors and improve detection accuracy, we proposed esophageal cancer detection using deep learning. The characteristics of deep learning: association and structure, activity and experience, essence and variation, migration and application, value and evaluation., Method: The improved Faster RCNN esophageal cancer detection in this paper introduces the online hard example mining (OHEM) mechanism into the system, and the experiment used 1520 gastrointestinal CT images from 421 patients. Then, we compare the overall performance of Inception-v2, Faster RCNN, and improved Faster RCNN through F-1 measure, mean average precision (mAP), and detection time., Results: The experiment shows that the overall performance of the improved Faster RCNN is higher than the other two networks. The F-1 measure of our method reaches 95.71%, the mAP reaches 92.15%, and the detection time per CT is only 5.3s., Conclusion: Through comparative analysis on the esophageal cancer image data set, the experimental results show that the introduction of online hard example mining mechanism in the Faster RCNN algorithm can improve the detection accuracy to a certain extent., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interests in this article., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: Chemoradiotherapy for locally advanced cervical cancer fails in over a third of patients. Biomarkers with therapeutic implications are therefore needed. We investigated the relationship between an established prognostic marker, maximum standardized uptake value (SUV max ) on 18 F-fluorodeoxyglucose positron emission tomography, and the inflammatory and immune state of cervical cancers., Experimental Design: An SUV max most prognostic for freedom from progression (FFP) was identified and compared with known prognostic clinical variables in a cohort of 318 patients treated with definitive radiation with prospectively collected clinical data. Gene set enrichment analysis (GSEA) and CIBERSORT of whole-transcriptome data from 68 patients were used to identify biological pathways and immune cell subpopulations associated with high SUV max . IHC using a tissue microarray (TMA, N = 82) was used to validate the CIBERSORT findings. The impact of macrophages on cervical cancer glucose metabolism was investigated in coculture experiments., Results: SUV max <11.4 was most prognostic for FFP ( P = 0.001). The GSEA showed that high SUV max is associated with increased gene expression of inflammatory pathways, including JAK/STAT3 signaling. CIBERSORT and CD68 staining of the TMA showed high SUV max tumors are characterized by a monocyte-predominant immune infiltrate. Coculture of cervical cancer cells with macrophages or macrophage-conditioned media altered glucose uptake, and IL6 and JAK/STAT3 signaling contribute to this effect., Conclusions: SUV max is a prognostic marker in cervical cancer that is associated with activation of inflammatory pathways and tumor infiltration of myeloid-derived immune cells, particularly macrophages. Macrophages contribute to changes in cervical cancer glucose metabolism. See related commentary by Williamson et al., p. 4136 ., (©2021 American Association for Cancer Research.)

Chemotherapy remains the primary treatment of advanced solid cancer, including lung cancer. However, as first-line treatment, cisplatin-based therapy is restricted by the frequent development of drug resistance. Increasing data showed that the programmed cell death protein ligand 1 (PD-L1) plays a vital role in regulating cisplatin resistance. However, the underlying mechanisms are not fully understood. We found that miR-526b-3p expression declined while PD-L1 was elevated in cisplatin-resistant lung cancer compared to that in cisplatin-sensitive lung cancer by analyzing clinical samples. Significantly, miR-526b-3p was associated with response to cisplatin negatively. We further demonstrated that miR-526b-3p reversed cisplatin resistance, suppressed metastasis, and activated CD8+ T cells in a STAT3/PD-L1-dependent manner. Thus, our findings extended the knowledge of PD-L1-mediated cisplatin resistance of lung cancer. In addition, the introduction of miR-526b-3p provided a new clue to improve the anti-tumor effects of the combination of immunotherapy and chemotherapy., (© 2021. The Author(s).)

Sample barcoding is essential in mass cytometry analysis, since it can eliminate potential procedural variations, enhance throughput, and allow simultaneous sample processing and acquisition. Sample pooling after prior surface staining termed live-cell barcoding is more desirable than intracellular barcoding, where samples are pooled after fixation and permeabilization, since it does not depend on fixation-sensitive antigenic epitopes. In live-cell barcoding, the general approach uses two tags per sample out of a pool of antibodies paired with five palladium (Pd) isotopes in order to preserve appreciable signal-to-noise ratios and achieve higher yields after sample deconvolution. The number of samples that can be pooled in an experiment using live-cell barcoding is limited, due to weak signal intensities associated with Pd isotopes and the relatively low number of available tags. Here, we describe a novel barcoding technique utilizing 10 different tags, seven cadmium (Cd) tags and three Pd tags, with superior signal intensities that do not impinge on lanthanide detection, which enables enhanced pooling of samples with multiple experimental conditions and markedly enhances sample throughput.

Aims: A complete metabolic response (CMR) on early post-treatment 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a positive prognostic factor for cervical cancer patients treated with definitive chemoradiation, but long-term outcomes of this group of patients are unknown. Patterns of failure and risk subgroups are identified., Materials and Methods: Patients who received curative-intent chemoradiation from 1998 to 2018 for International Federation of Gynecology and Obstetrics (FIGO) stage IB1-IVA cervical cancer and had a CMR on post-treatment FDG-PET within 5 months of treatment completion were included. Cox proportional hazards models determined factors associated with locoregional and distant failure. Kaplan-Meier estimates of freedom from any recurrence (FFR) of patient subgroups were compared with Log-rank tests., Results: There were 402 patients with a CMR after chemoradiation on FDG-PET. Initial T stage was T1 (38%)/T2 (40%)/T3 (20%)/T4 (2%); initial FDG-avid nodal status was no nodes (50%)/pelvic lymph nodes (40%)/pelvic and para-aortic lymph nodes (10%). After a median follow-up of 6 years, 109 (27%) recurred. The pattern of recurrence was locoregional (27%), distant (61%) or both (12%). No factors were associated with locoregional failure. Distant recurrence was more likely in patients with T3-4 lesions (hazard ratio = 2.4, 95% confidence interval 1.5-3.8) and involvement of pelvic (hazard ratio = 1.6, 95% confidence interval 1.0-2.7) or para-aortic lymph nodes (hazard ratio = 2.7, 95% confidence interval 1.4-5.0) at diagnosis. The 5-year FFR rates for T1-2 patients with no nodes, pelvic nodes alone or para-aortic nodes at diagnosis were 85, 76 and 62%, respectively (P = 0.04, none versus para-aortic nodes). The 5-year FFR for T3-4 patients with no nodes, pelvic nodes alone or para-aortic nodes at diagnosis were 68, 56 and 25%, respectively (P = 0.09, none versus para-aortic nodes)., Conclusions: T3-4 tumours and para-aortic nodal involvement at diagnosis are poor prognostic factors, even after a CMR following chemoradiation., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Study Design: Retrospective., Objective: The aim of this study is to evaluate if standing in a Schroth trained position influences the radiographic assessment of Cobb angle and other radiographic parameters compared to a normal standing position. Schroth method has been associated with improved Cobb angle. This study aims to evaluate if standing in the Schroth trained position influences radiographic assessment of Cobb angle compared to a normal standing position., Methods: This is a retrospective review of patients with adolescent idiopathic scoliosis (AIS) who were participating in Schroth therapy at the time of radiographs. Ten pairs of radiographs were included in this study. Each pair consisted of two micro-dose biplanar PA thoracolumbar spine radiographs obtained on the same day, one with the patient standing in the Schroth trained position and one in their normal standing position. Each pair of radiographs was independently evaluated by three attending pediatric spine surgeons for Cobb angle, coronal balance, shoulder balance, and leg length discrepancy, for a total of 30 paired readings (3 readings for each of the 10 pairs of radiographs)., Results: Major Cobb angle was a mean of 6° less (p = 0.02) and the compensatory curve was 5° less (p = 0.03) in the Schroth trained position compared to their normal standing position. Neither coronal balance (p = 0.40) nor shoulder balance (p = 0.16) was significantly different. Mean leg length discrepancy was 6.8 mm greater in the Schroth trained versus normal position (p < 0.001)., Conclusion: Standing in a Schroth trained position for a PA spine radiograph was associated with a mean change in major Cobb angle of 6° compared to a normal standing position. If bracing was recommended for curves > 25° and surgery for curves > 45°, different treatment recommendations would have been made in 33% (10/30) of attendings' readings for the Schroth versus normally paired radiographs taken on the same day on the same patient. Studies evaluating the effect of Schroth therapy on Cobb angle must report if patients are standing in a normal or Schroth trained position during radiographs for conclusions to be valid, or differences may be due to a temporary, voluntary change in posture., Level of Evidence: III.

Mitochondrial dysfunction is frequently associated with impairment in metabolic homeostasis and insulin action, and is thought to underlie cellular aging. However, it is unclear whether mitochondrial dysfunction is a cause or consequence of insulin resistance in humans. To determine the impact of intrinsic mitochondrial dysfunction on metabolism and insulin action, we performed comprehensive metabolic phenotyping of the polymerase gamma (PolG) D257A "mutator" mouse, a model known to accumulate supraphysiological mitochondrial DNA (mtDNA) point mutations. We utilized the heterozygous PolG mutator mouse (PolG +/mut ) because it accumulates mtDNA point mutations ~ 500-fold > wild-type mice (WT), but fails to develop an overt progeria phenotype, unlike PolG mut/mut animals. To determine whether mtDNA point mutations induce metabolic dysfunction, we examined male PolG +/mut mice at 6 and 12 months of age during normal chow feeding, after 24-hr starvation, and following high-fat diet (HFD) feeding. No marked differences were observed in glucose homeostasis, adiposity, protein/gene markers of metabolism, or oxygen consumption in muscle between WT and PolG +/mut mice during any of the conditions or ages studied. However, proteomic analyses performed on isolated mitochondria from 12-month-old PolG +/mut mouse muscle revealed alterations in the expression of mitochondrial ribosomal proteins, electron transport chain components, and oxidative stress-related factors compared with WT. These findings suggest that mtDNA point mutations at levels observed in mammalian aging are insufficient to disrupt metabolic homeostasis and insulin action in male mice., (© 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Exposure to maternal stress during prenatal life is associated with an increased risk of neuropsychiatric disorders, such as depression and anxiety, in offspring. It has also been increasingly observed that prenatal stress alters the phenotype of offspring via immunological mechanisms and that immunological dysfunction, such as elevated interleukin-18 levels, has been reported in cultures of microglia. Prenatal restraint stress (PRS) in rats permits direct experimental investigation of the link between prenatal stress and adverse outcomes. However, the majority of studies have focused on the consequences of PRS delivered in the second half of pregnancy, while the effects of early prenatal stress have rarely been examined. Therefore, pregnant rats were subjected to PRS during early/middle and late gestation (days 8-14 and 15-21, respectively). PRS comprised restraint in a round plastic transparent cylinder under bright light (6500 lx) three times per day for 45 minutes. Differences in interleukin-18 expression in the hippocampus and in behavior were compared between offspring rats and control rats on postnatal day 75. We found that adult male offspring exposed to PRS during their late prenatal periods had higher levels of anxiety-related behavior and depression than control rats, and both male and female offspring exhibited higher levels of depression-related behavior, impaired recognition memory and diminished exploration of novel objects. Moreover, an elevated level of interleukin-18 was observed in the dorsal and ventral hippocampus of male and female early- and late-PRS offspring rats. The results indicate that PRS can cause anxiety and depression-related behaviors in adult offspring and affect the expression of interleukin-18 in the hippocampus. Thus, behavior and the molecular biology of the brain are affected by the timing of PRS exposure and the sex of the offspring. All experiments were approved by the Animal Experimentation Ethics Committee at Kunming Medical University, China (approval No. KMMU2019074) in January 2019., Competing Interests: None