System reset: topoisomerase 1 clears mitotic DNA for transcriptional memory.

Topoisomerase 1 (Top1) relieves torsional stress on DNA, including from RNA Polymerase II (Pol II) transcription. A new study by Wiegard et al. uncovers an unexpected role of Top1 in the appropriate clearance of Pol II from mitotic DNA, allowing for a reset of transcriptional memory in the daughter cells.

Heat shock transcription factors demonstrate a distinct mode of interaction with mitotic chromosomes.

A large number of transcription factors have been shown to bind and interact with mitotic chromosomes, which may promote the efficient reactivation of transcriptional programs following cell division. Although the DNA-binding domain (DBD) contributes strongly to TF behavior, the mitotic behaviors of TFs from the same DBD family may vary. To define the mechanisms governing TF behavior during mitosis in mouse embryonic stem cells, we examined two related TFs: Heat Shock Factor 1 and 2 (HSF1 and HSF2). We found that HSF2 maintains site-specific binding genome-wide during mitosis, whereas HSF1 binding is somewhat decreased. Surprisingly, live-cell imaging shows that both factors appear excluded from mitotic chromosomes to the same degree, and are similarly more dynamic in mitosis than in interphase. Exclusion from mitotic DNA is not due to extrinsic factors like nuclear import and export mechanisms. Rather, we found that the HSF DBDs can coat mitotic chromosomes, and that HSF2 DBD is able to establish site-specific binding. These data further confirm that site-specific binding and chromosome coating are independent properties, and that for some TFs, mitotic behavior is largely determined by the non-DBD regions.

Electrochemical modulation enhances the selectivity of peripheral neurostimulation in vivo.

Electrical nerve stimulation serves an expanding list of clinical applications, but it faces persistent challenges in selectively activating bundled nerve fibers. In this study, we investigated electrochemical modulation with an ion-selective membrane (ISM) and whether it, used together with electrical stimulation, may provide an approach for selective control of peripheral nerves. Guided by theoretical transport modeling and direct concentration measurements, we developed an implantable, multimodal ISM cuff capable of simultaneous electrical stimulation and focused Ca2+ depletion. Acutely implanting it on the sciatic nerve of a rat in vivo, we demonstrated that Ca2+ depletion could increase the sensitivity of the nerve to electrical stimulation. Furthermore, we found evidence that the effect of ion modulation would selectively influence functional components of the nerve, allowing selective activation by electrical current. Our results raise possibilities for improving functional selectivity of new and existing bioelectronic therapies, such as vagus nerve stimulation.

Aortic valve replacement versus conservative treatment in asymptomatic severe aortic stenosis: long-term follow-up of the AVATAR trial.

BACKGROUND AND AIMS: The question of when and how to treat truly asymptomatic patients with severe aortic stenosis (AS) and normal left ventricular (LV) systolic function is still subject to debate and ongoing research. Here, the results of extended follow-up of the AVATAR trial are reported (NCT02436655, clinical trials.gov). METHODS: The AVATAR trial randomly assigned patients with severe, asymptomatic AS and LV ejection fraction ≥50% to undergo either early surgical aortic valve replacement (AVR) or conservative treatment with watchful waiting strategy. All patients had negative exercise stress testing. The primary hypothesis was that early AVR will reduce a primary composite endpoint comprising all-cause death, acute myocardial infarction, stroke or unplanned hospitalization for heart failure (HF), as compared to conservative treatment strategy. RESULTS: A total of 157 low-risk patients (mean age 67 years, 57% men, mean Society of Thoracic Surgeons score 1.7%) were randomly allocated to either early AVR group (n=78) or conservative treatment group (n=79). In an intention-to-treat analysis, after a median follow-up of 63 months, the primary composite endpoint outcome event occurred in 18/78 patients (23.1%) in the early surgery group and in 37/79 patients (46.8%) in the conservative treatment group (hazard ratio [HR] early surgery vs. conservative treatment 0.42; 95% confidence interval [CI] 0.24-0.73, p=0.002). The Kaplan-Meier estimates for individual endpoints of all-cause death and HF hospitalization were significantly lower in the early surgery compared with the conservative group (HR 0.44; 95% CI 0.23-0.85, p=0.012 for all-cause death, and HR 0.21; 95% CI 0.06-0.73, p=0.007 for HF hospitalizations). CONCLUSIONS: The extended follow-up of the AVATAR trial demonstrates better clinical outcomes with early surgical AVR in truly asymptomatic patients with severe AS and normal LV ejection fraction compared with patients treated with conservative management on watchful waiting. TRIAL REGISTRATION NUMBER: NCT02436655 (ClinicalTrials.gov).

A dynamic role for transcription factors in restoring transcription through mitosis.

Mitosis involves intricate steps, such as DNA condensation, nuclear membrane disassembly, and phosphorylation cascades that temporarily halt gene transcription. Despite this disruption, daughter cells remarkably retain the parent cell's gene expression pattern, allowing for efficient transcriptional memory after division. Early studies in mammalian cells suggested that transcription factors (TFs) mark genes for swift reactivation, a phenomenon termed 'mitotic bookmarking', but conflicting data emerged regarding TF presence on mitotic chromosomes. Recent advancements in live-cell imaging and fixation-free genomics challenge the conventional belief in universal formaldehyde fixation, revealing dynamic TF interactions during mitosis. Here, we review recent studies that provide examples of at least four modes of TF-DNA interaction during mitosis and the molecular mechanisms that govern these interactions. Additionally, we explore the impact of these interactions on transcription initiation post-mitosis. Taken together, these recent studies call for a paradigm shift toward a dynamic model of TF behavior during mitosis, underscoring the need for incorporating dynamics in mechanistic models for re-establishing transcription post-mitosis.

Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis: The AVATAR Trial.

BACKGROUND: Surgical aortic valve replacement (SAVR) represents a class I indication in symptomatic patients with severe aortic stenosis (AS). However, indications for early SAVR in asymptomatic patients with severe AS and normal left ventricular function remain debated. METHODS: The AVATAR trial (Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis) is an investigator-initiated international prospective randomized controlled trial that evaluated the safety and efficacy of early SAVR in the treatment of asymptomatic patients with severe AS, according to common criteria (valve area ≤1 cm2 with aortic jet velocity >4 m/s or a mean transaortic gradient ≥40 mm Hg), and with normal left ventricular function. Negative exercise testing was mandatory for inclusion. The primary hypothesis was that early SAVR would reduce the primary composite end point of all-cause death, acute myocardial infarction, stroke, or unplanned hospitalization for heart failure compared with a conservative strategy according to guidelines. The trial was designed as event-driven to reach a minimum of 35 prespecified events. The study was performed in 9 centers in 7 European countries. RESULTS: Between June 2015 and September 2020, 157 patients (mean age, 67 years; 57% men) were randomly allocated to early surgery (n=78) or conservative treatment (n=79). Follow-up was completed in May 2021. Overall median follow-up was 32 months: 28 months in the early surgery group and 35 months in the conservative treatment group. There was a total of 39 events, 13 in early surgery and 26 in the conservative treatment group. In the early surgery group, 72 patients (92.3%) underwent SAVR with operative mortality of 1.4%. In an intention-to-treat analysis, patients randomized to early surgery had a significantly lower incidence of primary composite end point than those in the conservative arm (hazard ratio, 0.46 [95% CI, 0.23-0.90]; P=0.02). There was no statistical difference in secondary end points, including all-cause mortality, first heart failure hospitalizations, major bleeding, or thromboembolic complications, but trends were consistent with the primary outcome. CONCLUSIONS: In asymptomatic patients with severe AS, early surgery reduced a primary composite of all-cause death, acute myocardial infarction, stroke, or unplanned hospitalization for heart failure compared with conservative treatment. This randomized trial provides preliminary support for early SAVR once AS becomes severe, regardless of symptoms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02436655.

Dielectric switching in correlation with the structural phase transitions in tetrapropylammonium perchlorate.

The crystals of the tetrapropylammonium perchlorate ([(CH3CH2CH2)4N]ClO4, TePrAClO4) compound undergo two reversible phase transitions: at ca. T1 = 284 K and at ca. T2 = 445 K. The observed phase transitions and distinct dielectric and relaxation effects are due to the dynamic motions of the organic cations and anionic framework. The crystals become ordered at low temperatures, then disordered at room temperature (propyl chains of the organic part as well as perchlorate ions are disordered over the mirror plane at c = 1/4 and 3/4) and highly disordered at high temperatures. The comparable changes in the wavenumber and FWHM shifts (IR and Raman spectroscopy) in the case of tetrapropylammonium and perchlorate ions in the phase transition at T1 and slightly more significant changes for organic cations (juxtaposed with perchlorate ions) in the phase transition at T2 lead to a conclusion that the phase transition at T1 is equally driven by motions of the two ions, while the phase transition at T2 is more influenced by the motions of organic cations. The phase transition at T2 with its large entropy change resembles the behavior found in liquid crystals. The dielectric function values can be switched and tuned in the low- and high-dielectric states, which may indicate the potential application of this material in sensors or actuators.

Extracorporeal life support in mitral papillary muscle rupture: Outcome of multicenter study.

BACKGROUND: Post-acute myocardial infarction papillary muscle rupture (post-AMI PMR) may present variable clinical scenarios and degree of emergency due to result of cardiogenic shock. Veno-arterial extracorporeal life support (V-A ECLS) has been proposed to improve extremely poor pre- or postoperative conditions. Information in this respect is scarce. METHODS: From the CAUTION (meChanical complicAtion of acUte myocardial infarcTion: an InternatiOnal multiceNter cohort study) database (16 different Centers, data from 2001 to 2018), we extracted adult patients who were surgically treated for post-AMI PMR and underwent pre- or/and postoperative V-A ECLS support. The end-points of this study were in-hospital survival and ECLS complications. RESULTS: From a total of 214 post-AMI PMR patients submitted to surgery, V-A ECLS was instituted in 23 (11%) patients. The median age was 61.7 years (range 46-81 years). Preoperatively, ECLS was commenced in 10 patients (43.5%), whereas intra/postoperative in the remaining 13. The most common V-A ECLS indication was post-cardiotomy shock, followed by preoperative cardiogenic shock and cardiac arrest. The median duration of V-A ECLS was 4 days. V-A ECLS complications occurred in more than half of the patients. Overall, in-hospital mortality was 39.2% (9/23), compared to 22% (42/219) for the non-ECLS group. CONCLUSIONS: In post-AMI PMR patients, V-A ECLS was used in almost 10% of the patients either to promote bridge to surgery or as postoperative support. Further investigations are required to better evaluate a potential for increased use and its effects of V-A ECLS in such a context based on the still high perioperative mortality.

Influence of prior knowledge on eye movements to scenes as revealed by hidden Markov models.

Human visual experience usually provides ample opportunity to accumulate knowledge about events unfolding in the environment. In typical scene perception experiments, however, participants view images that are unrelated to each other and, therefore, they cannot accumulate knowledge relevant to the upcoming visual input. Consequently, the influence of such knowledge on how this input is processed remains underexplored. Here, we investigated this influence in the context of gaze control. We used sequences of static film frames arranged in a way that allowed us to compare eye movements to identical frames between two groups: a group that accumulated prior knowledge relevant to the situations depicted in these frames and a group that did not. We used a machine learning approach based on hidden Markov models fitted to individual scanpaths to demonstrate that the gaze patterns from the two groups differed systematically and, thereby, showed that recently accumulated prior knowledge contributes to gaze control. Next, we leveraged the interpretability of hidden Markov models to characterize these differences. Additionally, we report two unexpected and interesting caveats of our approach. Overall, our results highlight the importance of recently acquired prior knowledge for oculomotor control and the potential of hidden Markov models as a tool for investigating it.

Long-Term Outcomes After External Maxillary Distraction Surgery in Patients With Down Syndrome.

BACKGROUND: Patients with Down syndrome have severe facial deformities that can precipitate functional consequences and social stigmatization. Craniofacial surgical intervention can play a role in improving these symptoms and patient quality of life. The objective of this study was to investigate the long-term outcomes of distraction osteogenesis and orthognathic surgical intervention in patients with Down syndrome. MATERIALS AND METHODS: Charts of 3 patients with Down syndrome who were treated with external maxillary distraction osteogenesis were retrospectively reviewed. The patients' caregivers were prospectively interviewed between 10 and 15 years after surgery to determine surgical stability, long-term function, and quality of life status. RESULTS: All patients and their caregivers reported excellent results with improvements in function and quality of life. Facial skeletal changes have been stable over time. The cephalometric analysis demonstrated significant maxillary advancement in all 3 patients and mandibular changes to correct mandibular prognathism and asymmetry in the patient who underwent finishing orthognathic surgery. CONCLUSIONS: External maxillary distraction osteogenesis and orthognathic surgery may be considered in select patients with Down syndrome as part of their multidisciplinary health care. These interventions can result in long-term improvements in patient function and quality of life.

The Association Between H-Index and Publication of Plastic Surgery Meeting Presenters From 2014 to 2017.

BACKGROUND: Plastic surgery is a competitive specialty that values research productivity among members of the field. The Hirsch index has been shown to measure a researcher's scientific impact. This study sought to determine whether an association exists between H-indices and the probability of and speed to publication. METHODS: Using Scopus, Google Scholar, PubMed, and the Plastic Surgery the Meeting (PSTM) website, first author (FAHi) and senior author (SAHi) H-indices (n = 1048) from Plastic Surgery the Meeting (PSTM) abstracts from 2014 to 2017 were collected. Whether or not an abstract was ultimately published in a peer-reviewed journal was noted. If published, number of days between PSTM presentation and publication date were recorded. Logistic regression model was used for statistical analysis. RESULTS: In total, 592 out of 1048 total abstracts were published as manuscripts. FAHi and SAHi had significant positive correlations with odds of publication. Both FAHi and SAHi showed positive correlation with the odds of abstract publication (P < 0.001 and P = 0.033). Impact of FAHi on likelihood of publication was greater than that of SAHi. The correlation between FAHi and SAHi with the number of days until abstract publication was not significant (P = 0.333 and P = 0.856). For abstracts published before the PSTM presentation date (15.9% of published), only FAHi (P = 0.008) showed positive correlation of publication before presentation. CONCLUSIONS: The Hirsch index provides an objective method for evaluating the probability that an abstract will lead to manuscript publication, in addition to its traditional application in gauging the impact of research. The findings of this study support that both FAHi and SAHi have a positive, direct correlation with the probability of publication.

Prehospital Ultrasound: A Narrative Review.

Background: Point-of-care ultrasound is rapidly becoming more prevalent in the prehospital environment. Though considered a relatively new intervention in this setting, there is growing literature that aims to explore the use of prehospital ultrasound by EMS personnel.Methods: To better understand and report the state of the science on prehospital ultrasound, we conducted a narrative review of the literature.Results: Following a keyword search of MEDLINE in Ovid from inception to August 2, 2022, 2,564 records were identified and screened. Based on review of abstracts and full texts, with addition of seven articles via bibliography review, 193 records were included. Many included studies detail usage in air medical and other critical care transport environments. Clinicians performing prehospital ultrasound are often physicians or other advanced practice personnel who have previous ultrasound experience, which facilitates implementation in the prehospital setting. Emerging literature details training programs for prehospital personnel who are novices to ultrasound, and implementation for some study types appears feasible without prior experience. Unique use scenarios that show promise include during critical care transport, for triage in austere settings, and for thoracic evaluation of patients at risk of life-threatening pathology.Conclusion: There is a growing mostly observational body of literature describing the use of ultrasound by prehospital personnel. Prehospital ultrasound has demonstrated feasibility for specific conditions, yet interventional studies evaluating benefit to patient outcomes are absent.

The Year of the Rat: The Rat Genome Database at 20: a multi-species knowledgebase and analysis platform.

Formed in late 1999, the Rat Genome Database (RGD, https://rgd.mcw.edu) will be 20 in 2020, the Year of the Rat. Because the laboratory rat, Rattus norvegicus, has been used as a model for complex human diseases such as cardiovascular disease, diabetes, cancer, neurological disorders and arthritis, among others, for >150 years, RGD has always been disease-focused and committed to providing data and tools for researchers doing comparative genomics and translational studies. At its inception, before the sequencing of the rat genome, RGD started with only a few data types localized on genetic and radiation hybrid (RH) maps and offered only a few tools for querying and consolidating that data. Since that time, RGD has expanded to include a wealth of structured and standardized genetic, genomic, phenotypic, and disease-related data for eight species, and a suite of innovative tools for querying, analyzing and visualizing this data. This article provides an overview of recent substantial additions and improvements to RGD's data and tools that can assist researchers in finding and utilizing the data they need, whether their goal is to develop new precision models of disease or to more fully explore emerging details within a system or across multiple systems.

Semantic object-scene inconsistencies affect eye movements, but not in the way predicted by contextualized meaning maps.

Semantic information is important in eye movement control. An important semantic influence on gaze guidance relates to object-scene relationships: objects that are semantically inconsistent with the scene attract more fixations than consistent objects. One interpretation of this effect is that fixations are driven toward inconsistent objects because they are semantically more informative. We tested this explanation using contextualized meaning maps, a method that is based on crowd-sourced ratings to quantify the spatial distribution of context-sensitive "meaning" in images. In Experiment 1, we compared gaze data and contextualized meaning maps for images, in which objects-scene consistency was manipulated. Observers fixated more on inconsistent versus consistent objects. However, contextualized meaning maps did not assign higher meaning to image regions that contained semantic inconsistencies. In Experiment 2, a large number of raters evaluated image-regions, which were deliberately selected for their content and expected meaningfulness. The results suggest that the same scene locations were experienced as slightly less meaningful when they contained inconsistent compared to consistent objects. In summary, we demonstrated that - in the context of our rating task - semantically inconsistent objects are experienced as less meaningful than their consistent counterparts and that contextualized meaning maps do not capture prototypical influences of image meaning on gaze guidance.

Alloplastic Temporomandibular Joint Reconstruction Following Recurrent Ameloblastoma Resection.

ABSTRACT: Ameloblastomas are benign tumors that most commonly affecting the mandible. The current standard of treatment for ameloblastomas is resection followed by reconstruction that has historically been accomplished through the use of a microsurgical vascularized flaps taken from the iliac crest or fibula. Alloplastic reconstruction methods have gained popularity over recent years with success reported in the reconstruction of many pathologies, including ankylosis, condylar fracture, neoplasia involving extensive resection, severe inflammatory/degenerative temporomandibular joint (TMJ) disease, and congenital TMJ abnormalities. The authors present a patient who successfully underwent ameloblastoma resection and TMJ reconstruction with a custom TMJ Concepts alloplastic implant. The authors also present a review of the literature on alloplastic TMJ reconstruction following ameloblastoma resection. To our knowledge, this is the second report in the literature on the use of a TMJ Concepts implant after ameloblastoma resection.

Adjusting the Stiffness of Supports during Milling of a Large-Size Workpiece Using the Salp Swarm Algorithm.

This paper concerns the problem of vibration reduction during milling. For this purpose, it is proposed that the standard supports of the workpiece be replaced with adjustable stiffness supports. This affects the modal parameters of the whole system, i.e., object and its supports, which is essential from the point of view of the relative tool-workpiece vibrations. To reduce the vibration level during milling, it is necessary to appropriately set the support stiffness coefficients, which are obtained from numerous milling process simulations. The simulations utilize the model of the workpiece with adjustable supports in the convention of a Finite Element Model (FEM) and a dynamic model of the milling process. The FEM parameters are tuned based on modal tests of the actual workpiece. For assessing simulation results, the proper indicator of vibration level must be selected, which is also discussed in the paper. However, simulating the milling process is time consuming and the total number of simulations needed to search the entire available range of support stiffness coefficients is large. To overcome this issue, the artificial intelligence salp swarm algorithm is used. Finally, for the best combination of stiffness coefficients, the vibration reduction is obtained and a significant reduction in search time for determining the support settings makes the approach proposed in the paper attractive from the point of view of practical applications.

Advances in visualizing transcription factor - DNA interactions.

At the heart of the transcription process is the specific interaction between transcription factors (TFs) and their target DNA sequences. Decades of molecular biology research have led to unprecedented insights into how TFs access the genome to regulate transcription. In the last 20 years, advances in microscopy have enabled scientists to add imaging as a powerful tool in probing two specific aspects of TF-DNA interactions: structure and dynamics. In this review, we examine how applications of diverse imaging technologies can provide structural and dynamic information that complements insights gained from molecular biology assays. As a case study, we discuss how applications of advanced imaging techniques have reshaped our understanding of TF behavior across the cell cycle, leading to a rethinking in the field of mitotic bookmarking.

The evaluation of annuloplasty in bicuspid aortic valve repair using cardiac magnetic resonance.

BACKGROUND: The incompetent bicuspid aortic valve (BAV) can be replaced or repaired using various surgical techniques. This study sought to assess the efficacy of external annuloplasty and postoperative reverse remodelling using cardiac magnetic resonance (CMR) and compare the results of external and subcommissural annuloplasty. METHODS: Out of a total of 200 BAV repair performed between 2004 and 2018, 21 consecutive patients (median age 54 years) with regurgitation requiring valve repair with annuloplasty without concomitant aortic root surgery were prospectively referred for CMR and transthoracic echocardiography (TTE) one year after the operation. Two aortic annulus stabilization techniques were used: external, circumferential annuloplasty (EA), and subcommissural annuloplasty (SCA). RESULTS: 11 patients received EA and 10 patients were treated using SCA. There was no in-hospital mortality and all patients survived the follow-up period (median: 12.6 months (first quartile: 6.6; third quartile: 14.1). CMR showed strong correlation between postoperative aortic recurrent regurgitant fraction and left ventricular end-diastolic volume (r = 0.62; p = 0.003) as well as left ventricular ejection fraction (r = -0.53; p = 0.01). Patients treated with EA as compared with SCA had larger anatomic aortic valve area measured by CMR (3.5 (2.5; 4.0) vs. 2.5 cm2 (2.0; 3.4); p = 0.04). In both EA and SCA group, aortic valve area below 3.5 cm2 correlated with no regurgitation recurrency. EA (vs. SCA) was associated with lower peak transvalvular aortic gradients (10 (6; 17) vs. 21 mmHg (15; 27); p = 0.04). CONCLUSIONS: The repair of the bicuspid aortic valve provides significant postoperative reverse remodelling, provided no recurrent regurgitation and durable reduction annuloplasty can be achieved. EA is associated with lower transvalvular gradients and higher aortic valve area assessed by CMR, compared to SCA.

The Most Disruptive Publications in Craniofacial Surgery (1954-2014).

BACKGROUND: Emphasis on the quantification and qualification of scientific literature has increased over recent years. The newly validated disruption score is a bibliometric measure that identifies groundbreaking research that eclipses prior research in a specific field of study. MATERIALS AND METHODS: The 100 most disruptive craniofacial surgery publications were identified through query of the 4 top craniofacial journals and 10 of the most prominent Plastic and Reconstructive Surgery journals, looking at craniofacial specific publications. RESULTS: Presented is the compilation and analysis of the 100 most disruptive publications in the field of craniofacial surgery compared to the 100 most cited publications between 1954 and 2014. Plastic and Reconstructive Surgery had the most papers in the top 100 (n = 56) followed by Journal of Oral and Maxillofacial Surgery (n = 22), and British Journal of Surgery (n = 12). The correlation coefficient between disruption scores and citation counts was -0.001 and -0.07 among all papers, and the top 100 most disruptive papers, respectively. For craniofacial journals, Journal of Craniofacial Surgery had the highest average disruption score for all published papers. The most common decade represented in the top 100 was the 1980's (n = 32) and the least common was the 2000's (n = 14). Randomized controlled trials did not comprise a large amount of either the most disruptive (n = 1) or most cited (n = 2) lists. CONCLUSIONS: This is the first use of disruption index score to describe craniofacial surgery research. The disruption score can help recognize paradigm shifts and innovative research in this unique surgical subspecialty.

What makes euthanasia justifiable? The role of symptoms' characteristics and interindividual differences.

The consideration of laypeople's views of conditions under which euthanasia is justifiable is important for policy decisions. In an online survey of US respondents, we examined how patient's symptoms influence justifiability of euthanasia. Euthanasia was judged more justifiable for conditions associated with physical suffering and negative impact on other people. The weight given to physical suffering and negative impact on others in evaluation of justifiability of euthanasia also differed based on personal characteristics. The results suggest that public discourse about medical assistance in dying should take into account differences in its perceived justifiability for patients with different conditions.