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Anticipatory stress can prospectively and negatively influence diverse outcomes, including cognitive performance and emotional well-being. It has been suggested that perseverative cognitions (e.g., worry, rumination) during the anticipation period constitute a key mechanism driving these effects. The present study investigated the temporal dynamics among stressor anticipation, perseverative cognitions, and affective well-being. To accurately test the suggested mechanism, we focused on how these dynamics unfold within individuals over time. To that end, we analyzed data from an ecological momentary assessment study in an ethnically diverse sample (N = 243, 25-65 year olds, 68.7% Hispanic or non-Hispanic Black; 14 days, 5 measurement occasions per day) using dynamic structural equation modeling. Anticipating an upcoming stressor was linked to higher levels of perseverative cognitions approximately 3 hours later. At times when individuals reported higher levels of recent perseverative cognitions than typical for them, they also reported higher levels of negative affect and lower levels of positive affect. Mediational modeling indicated that perseverative cognitions accounted for the persistent effects of previous stressor anticipation on negative as well as positive affect several hours later. These findings suggest that perseverative cognitions may play an important role in explaining the detrimental effects of anticipatory stress on subsequent emotional well-being. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Dietary supplementation with 0.4 or 0.8% l-arginine (Arg) to gilts between days 14 and 25 of gestation enhances embryonic survival and vascular development in placentae; however, the underlying mechanisms are largely unknown. This study tested the hypothesis that Arg supplementation stimulated placental expression of mRNAs and proteins that enhance angiogenesis, including endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), placental growth factor (PGF), GTP cyclohydrolase-I (GTP-CH1), ornithine decarboxylase (ODC1), and vascular endothelial growth factor receptors 1 and 2 (VEGFR1 and VEGFR2). Beginning on the day of breeding, gilts were fed daily 2 kg of a corn–soybean meal-based diet supplemented with 0.0 (control), 0.4, or 0.8% Arg. On day 25 of gestation, gilts were hysterectomized to obtain uteri and conceptuses for histochemical and biochemical analyses. eNOS and VEGFR1 proteins were localized to endothelial cells of maternal uterine blood vessels and to the uterine luminal epithelium, respectively. Compared with the control, dietary supplementation with 0.4 or 0.8% Arg increased (P

Secreted phosphoprotein 1 (SPP1, also known as osteopontin) binds integrins to mediate cell–cell and cell–extracellular matrix communication to promote cell adhesion, migration, and differentiation. Considerable evidence links SPP1 to pregnancy in several species. Current evidence suggests that SPP1 is involved in implantation and placentation in mice, but in vivo localization of SPP1 and in vivo mechanistic studies to substantiate these roles are incomplete and contradictory. We localized Spp1 mRNA and protein in the endometrium and placenta of mice throughout gestation, and utilized delayed implantation of mouse blastocysts to link SPP1 expression to the implantation chamber. Spp1 mRNA and protein localized to the endometrial luminal (LE), but not glandular epithelia (GE) in interimplantation regions of the uterus throughout gestation. Spp1 mRNA and protein also localized to uterine naturel killer (uNK) cells of the decidua. Within the implantation chamber, Spp1 mRNA localized only to intermittent LE cells, and to the inner cell mass. SPP1 protein localized to intermittent trophoblast cells, and to the parietal endoderm. These results suggest that SPP1: (1) is secreted by the LE at interimplantation sites for closure of the uterine lumen to form the implantation chamber; (2) is secreted by LE adjacent to the attaching trophoblast cells for attachment and invasion of the blastocyst; and (3) is not a component of histotroph secreted from the GE, but is secreted from uNK cells in the decidua to increase angiogenesis within the decidua to augment hemotrophic support of embryonic/fetal development of the conceptus. Summary sentence Through utilization of delayed implantation, SPP1 mRNA and protein are localized in high levels to the luminal epithelium of interimplantation sites, to focal regions of the implantation chamber and to uterine natural killer cells in the decidua, suggesting roles for implantation in mice.

Objectives: This study investigated how COVID-19-related media exposure during the COVID-19 crisis was related to same-day and next-day COVID-19-related worries. Design: A 21-day diary study was conducted between late March and late April 2020 in Germany. Main Outcome Measures: Hypotheses were tested in a sample of 561 participants (Mage = 42.79, SDage = 6.12). Every evening, participants indicated their exposure to COVID-19-related media (e.g., TV, print, online) and their COVID-19-related worries. Results: Same-day analyses showed that participants reported more COVID-19-related worries on days with higher exposure to COVID-19-related media. Dynamical structural equation models provided evidence for a reciprocal cycle across days: Higher media exposure at one day predicted higher worries the next day, and higher worries at one day also predicted higher media exposure the next day. Individuals with high trait anxiety reported an enhanced general level of media exposure during the 21 days of assessment, and individuals high in neuroticism and anxiety reported an enhanced level of worries.Conclusion: These findings suggest a self-reinforcing cycle whereby consuming crisis-related media and worrying reciprocally influence each other across days, possibly amplifying adverse effects of the COVID-19 crisis and other crises alike on mental and physical health.

Objectives To determine whether dental maturity (dental development) was delayed in patients with Muenke syndrome, Saethre-Chotzen syndrome, and TCF12-related craniosynostosis, compared with a Dutch control group without syndromes. Materials and methods This study included 60 patients (38 patients with Muenke syndrome, 17 patients with Saethre-Chotzen syndrome, and 5 with TCF12-related craniosynostosis), aged 5.8–16.8 years that were treated at the Department of Oral Maxillofacial Surgery, Special Dental Care, and Orthodontics, in Sophia Children’s Hospital, Erasmus University Medical Center, Rotterdam, the Netherlands. Dental age was calculated according to Demirjian’s index of dental maturity. The control group included 451 children without a syndrome. Results Compared with the control group, dental development was delayed by an average of one year in 5- to 8-year-old patients with Muenke syndrome (P = 0.007) and in 8- to 10-year-old patients with Saethre-Chotzen syndrome (P = 0.044), but not in patients with TCF12-related craniosynostosis. Conclusions Our results indicated that dental development was delayed by one year, on average, in patients with Muenke syndrome and Saethre-Chotzen syndrome, compared with a Dutch control group without syndromes. Implications Our findings have improved the understanding of dental development in patients with Muenke and Saethre-Chotzen syndrome. These results can provide guidance on whether the orthodontist needs to consider growth disturbances related to dental development.

Introduction: The effect of pelvic fixation on postoperative medical complications, blood transfusion, length of hospital stay, and discharge disposition is poorly understood. Determining factors that predispose patients to increased complications after spinopelvic fusion will help surgeons to plan these complex procedures and optimize patients preoperatively. Methods: We conducted a retrospective cohort study using data from the ACS-NSQIP database between 2006 and 2016 of patients who underwent lumbar fusion with and without spinopelvic fixation. Data regarding demographics, complications, hospital stay, and discharge disposition were collected. Results: A total of 57,417 (98.5%) cases of lumbar fusion without spinopelvic fixation (LF) and 887 (1.5%) cases of lumbar fusion with spinopelvic fixation (SPF) were analyzed. The transfusion rate in the SPF group was 59.3% vs 13% in the LF group (p < 0.001). The mean length of stay (LOS) and discharge to skilled nursing facility (SNF) were significantly different (LOS: SPF 6.5 days vs LF 3.5 days p < 0.001; SNF: SPF 21.3% vs LF 10.4% p < 0.001). After controlling for demographic differences, the overall complication rates were not significantly different between the groups (p = 0.531). The odds ratio for transfusion in the SPF group was 2.9 (p < 0.001). The odds ratio for increased LOS and increased care discharge disposition were elevated in the SPF group (LOS OR: 1.3, p < 0.012, Discharge disposition OR: 1.8, p < 0.001). Conclusions: Patients who underwent SPF had increased complications, transfusion rate, LOS, and discharge to SNF or subacute rehab facilities as compared with patients who underwent LF. SPF remains an effective technique for achieving lumbosacral arthrodesis. Surgeons should consider the implications of the associated complication profile for SPF and the value of preoperative optimization in a select cohort of patients.

The emerging paradigm in the immunology of pregnancy is that implantation of conceptuses does not progress in an immunologically suppressed environment. Rather, the endometrium undergoes a controlled inflammatory response during implantation as trophectoderm of elongating and implanting pig conceptuses secrete the pro-inflammatory cytokine interferon gamma (IFNG). Results of this study with pigs revealed: (1) accumulation of immune cells and apoptosis of stromal cells within the endometrium at sites of implantation during the period of IFNG secretion by conceptuses; (2) accumulation of proliferating cell nuclear antigen (PCNA)-positive T cells within the endometrium at sites of implantation; (3) significant increases in expression of T cell co-signaling receptors including programmed cell death 1 (PDCD1), CD28, cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and inducible T cell co-stimulator (ICOS), as well as chemokines CXCL9, 10, and 11 within the endometrium at sites of implantation; (4) significant increases in T cell co-signaling receptors, PDCD1 and ICOS, and chemokine CXCL9 in the endometrium of cyclic gilts infused with IFNG; and (5) identification of CD4+ (22.59%) as the major T cell subpopulation, with minor subpopulations of CD8+ (1.38%), CD4+CD25+ (1.08%), and CD4+CD8+ (0.61%) T cells within the endometrium at sites of implantation. Our results provide new insights into the immunology of implantation to suggest that trophectoderm cells of pigs secrete IFNG to recruit various subpopulations of T cells to the endometrium to contribute to a controlled inflammatory environment that supports the active breakdown and restructuring of the endometrium in response to implantation of the conceptus.

Spinal epidural abscess (SEA) is a rare condition associated with significant morbidity and mortality. Despite advances in diagnostic medicine, early recognition of SEAs remains elusive. The vague presentation of the disease, coupled with its numerous risk factors, the diagnostic requirement for obtaining advanced imaging, and the necessity of specialized care constitute extraordinary challenges to both diagnosis and treatment of SEA. Once diagnosed, SEAs require urgent or emergent medical and/or surgical management. As SEAs are a relatively rare pathology, high-quality data are limited and there is no consensus on their optimal management. This paper focuses on presenting the treatment modalities that have been successful in the management of SEAs and providing a critical assessment of how specific SEA characteristics may render one infection more amenable to primary surgical or medical interventions. This paper reviews the relevant history, epidemiology, clinical presentation, radiology, microbiology, and treatment of SEAs and concludes by addressing the medicolegal implications of delayed treatment of the disease.

Summary The DNA methylation regulators DNMT3A and TET2 are recurrently mutated in hematological disorders. Despite possessing antagonistic biochemical activities, loss-of-function murine models show overlapping phenotypes in terms of increased hematopoietic stem cell (HSC) fitness. Here, we directly compared the effects of these mutations on hematopoietic progenitor function and disease initiation. In contrast to Dnmt3a-null HSCs, which possess limitless self-renewal in vivo, Tet2-null HSCs unexpectedly exhaust at the same rate as control HSCs in serial transplantation assays despite an initial increase in self-renewal. Moreover, loss of Tet2 more acutely sensitizes hematopoietic cells to the addition of a common co-operating mutation (Flt3ITD) than loss of Dnmt3a, which is associated with a more rapid expansion of committed progenitor cells. The effect of Tet2 mutation manifests more profound myeloid lineage skewing in committed hematopoietic progenitor cells rather than long-term HSCs. Molecular characterization revealed divergent transcriptomes and chromatin accessibility underlying these functional differences., Highlights • Tet2-null HSCs exhaust at the same rate as wild-type HSCs in serial transplantation • Loss of Tet2 sensitizes cells to Flt3ITD mutation more dramatically than Dnmt3a • Loss of Dnmt3a permits epigenetic plasticity between hematopoietic progenitors • Tet2 deficiency manifests profound myeloid lineage skewing in progenitor cells, Challen and colleagues show that Dnmt3a and Tet2 loss-of-function mutations manifest distinct molecular and functional consequences in different hematopoietic stem and progenitor cell compartments. Despite producing superficially similar phenotypes in terms of stem cell function and disease initiation, we show here divergent influences on progenitor cell lineage skewing, stem cell self-renewal, and predisposition to malignant transformation.

The period of conceptus (embryo and extraembryonic membrane) development between fertilization and implantation in mammalian species is critical as it sets the stage for placental and fetal development. The trophectoderm and endoderm of pre-implantation ovine and porcine conceptuses undergo elongation, which requires rapid proliferation, migration, and morphological modification of the trophectoderm cells. These complex events occur in a hypoxic intrauterine environment and are supported through the transport of secretions from maternal endometrial glands to the conceptus required for the biochemical processes of cell proliferation, migration, and differentiation. The conceptus utilizes glucose provided by the mother to initiate metabolic pathways that provide energy and substrates for other metabolic pathways. Fructose, however, is in much greater abundance than glucose in amniotic and allantoic fluids, and fetal blood during pregnancy. Despite this, the role(s) of fructose is largely unknown even though a switch to fructosedriven metabolism in subterranean rodents and some cancers are key to their adaptation to hypoxic environments.

This paper concerns the design and rigorous in silico evaluation of a closed-loop hemorrhage resuscitation algorithm with blood pressure (BP) as controlled variable. A lumped-parameter control design model relating volume resuscitation input to blood volume (BV) and BP responses was developed and experimentally validated. Then, three alternative adaptive control algorithms were developed using the control design model: (i) model reference adaptive control (MRAC) with BP feedback, (ii) composite adaptive control (CAC) with BP feedback, and (iii) CAC with BV and BP feedback. To the best of our knowledge, this is the first work to demonstrate model-based control design for hemorrhage resuscitation with readily available BP as feedback. The efficacy of these closed-loop control algorithms was comparatively evaluated as well as compared with an empiric expert knowledge-based algorithm based on 100 realistic virtual patients created using a well-established physiological model of cardiovascular (CV) hemodynamics. The in silico evaluation results suggested that the adaptive control algorithms outperformed the knowledge-based algorithm in terms of both accuracy and robustness in BP set point tracking: the average median performance error (MDPE) and median absolute performance error (MDAPE) were significantly smaller by >99% and >91%, and as well, their interindividual variability was significantly smaller by >88% and >94%. Pending in vivo evaluation, model-based control design may advance the medical autonomy in closed-loop hemorrhage resuscitation.

Introduction/Background* Recently 3 Phase III first-line studies, PAOLA-1/ENGOT-ov25 (Ray-Coquard et al. NEJM 2019). PRIMA/ENGOT-ov26/GOG-3012 (Gonzales Martin et al. NEJM 2019) and VELIA/GOG-3005 (Coleman et al. NEJM 2019) have demonstrated that the addition of a PARP inhibitor (PARPi) to platinum-based therapy+/-bevacizumab improved progression-free survival (PFS) in advanced ovarian cancer (AOC) patients. The benefit was greater when the tumor was homologous recombination deficient (HRD) according to Myriad myChoice test, independently of BRCA status. The PAOLA-1 olaparib+bevacizumab maintenance regimen was approved in USA/Europe/Japan for HRD positive patients. The European initiative aims at evaluating various HRD tests on PAOLA-1 tumor samples to identify new reliable and feasible HRD tests Methodology The HRD initiative has 2 components; one based on artificial intelligence with various partners and the other, the European HRD ENGOT initiative (EHEI), is led by academic research laboratories (RL) from ENGOT groups. The HRD test evaluation protocol for the EHEI RL includes 3 phases. The phase 1 (2019/12) brought together European RL. Because non-BRCA Homologous Recombination Repair (HRR) mutations have not been found predictive of PARPi activity in PAOLA-1 (Pujade-Lauraine et al, SGO 2021)) RL tests based on these mutations were not selected for the next phases. Phase 2 evaluated the correlation between RL tests and the Myriad myChoice test on tumor samples from 85 PAOLA-1 BRCA wild type patients using the KAPPA statistics. Phase 3 is the final PFS evaluation on more than 350 additional patient samples. Result(s)* A total of 20 RL from 21 ENGOT groups participated to the EHEI phase 1. Half of them had a test mainly based on an HRR gene panel. Three RL did not pursue for various reasons (capacity, financial or regulatory). The remaining 7 RL from 6 countries (table 1) completed the phase 2 in May 2021 and may proceed to phase 3. Conclusion* The EHEI is a unique collaboration of European academic laboratories involved in gynecologic oncology translational research with the aim of providing a reliable biomarker (HRD) for selecting AOC patients who could benefit most from PARPi+/-bevacizumab in first-line therapy. HRD tests performance will be described after their phase 3 is completed.

There is growing experimental evidence that many respiratory viruses—including influenza and SARS-CoV-2—can interact, such that their epidemiological dynamics may not be independent. To assess these interactions, standard statistical tests of independence suggest that the prevalence ratio—defined as the ratio of co-infection prevalence to the product of single-infection prevalences—should equal unity for non-interacting pathogens. As a result, earlier epidemiological studies aimed to estimate the prevalence ratio from co-detection prevalence data, under the assumption that deviations from unity implied interaction. To examine the validity of this assumption, we designed a simulation study that built on a broadly applicable epidemiological model of co-circulation of two respiratory viruses causing seasonal epidemics. By focusing on the pair influenza–SARS-CoV-2, we first demonstrate that the prevalence ratio systematically under-estimates the strength of interaction, and can even misclassify antagonistic or synergistic interactions that persist after clearance of infection. In a global sensitivity analysis, we further identify properties of viral infection—such as a high reproduction number or a short infectious period—that blur the interaction inferred from the prevalence ratio. Altogether, our results suggest that epidemiological studies based on co-detection prevalence data provide a poor guide to assess interactions among respiratory viruses.

Objective: To evaluate the effectiveness of the WhiteTeeth mobile app, a theory-based mobile health (mHealth) program for promoting oral hygiene in adolescent orthodontic patients. Methods: In this parallel randomized controlled trial, the data of 132 adolescents were collected during three orthodontic check-ups: at baseline (T0), at 6-week follow-up (T1) and at 12-week follow-up (T2). The intervention group was given access to the WhiteTeeth app in addition to usual care (n = 67). The control group received usual care only (n = 65). The oral hygiene outcomes were the presence and the amount of dental plaque (Al-Anezi and Harradine plaque index), and the total number of sites with gingival bleeding (Bleeding on Marginal Probing Index). Oral health behaviour and its psychosocial factors were measured through a digital questionnaire. We performed linear mixed-model analyses to determine the intervention effects. Results: At 6-week follow-up, the intervention led to a significant decrease in gingival bleeding (B = −3.74; 95% CI −6.84 to −0.65) and an increase in the use of fluoride mouth rinse (B = 1.93; 95% CI 0.36 to 3.50). At 12-week follow-up, dental plaque accumulation (B = −11.32; 95% CI −20.57 to −2.07) and the number of sites covered with plaque (B = −6.77; 95% CI −11.67 to −1.87) had been reduced significantly more in the intervention group than in the control group. Conclusions: The results show that adolescents with fixed orthodontic appliances can be helped to improve their oral hygiene when usual care is combined with a mobile app that provides oral health education and automatic coaching. Netherlands Trial Registry Identifier: NTR6206: 20 February 2017.

Introduction ‘Fluid creep’ or excessive fluid delivered to burn patients during early resuscitation has been suggested by several studies from individual burn centers. Methods We performed a Medline search from 1980 to 2015 in order to identify studies of burn patients predominantly resuscitated with lactated Ringers with infusion adjusted per urinary output. Data was abstracted for 48 publications (3196 patients) that met entry criteria. Results Higher resuscitation volumes compared to Parkland estimates were reported, but the trend of increasing resuscitation volumes over the last 30 years is not supported by regression of total fluid infused versus year of study. Mean 24 h fluid infused for all studies was 5.2 ± 1.1 mL/kg per %TBSA. The mean 24 h urinary output reported in 30 studies was 1.2 ± 0.5 mL/kg per hr. Burns with inhalation injuries (5 studies) received significantly more fluid than non-inhalation injured burn patients (5.0 ± 1.3 versus 3.9 ± 0.9 mL/kg per %TBSA). Fluid infused and urinary outputs were similar for adults and pediatric patients. The most striking finding of our analyses was the great ranges of the means and high standard deviations of volumes infused compared to the original Baxter publication that introduced the Parkland formula Conclusions These analyses suggest that burn units currently administer volumes larger than Parkland formula with great patient variability. Individual patient hourly data is needed to better understand the record of burn resuscitation and Fluid Creep.

The histone demethylase KDM6B (JMJD3) is upregulated in blood disorders, suggesting that it may have important pathogenic functions. Here we examined the function of Kdm6b in hematopoietic stem cells (HSC) to evaluate its potential as a therapeutic target. Loss of Kdm6b lead to depletion of phenotypic and functional HSCs in adult mice, and Kdm6b is necessary for HSC self-renewal in response to inflammatory and proliferative stress. Loss of Kdm6b leads to a pro-differentiation poised state in HSCs due to the increased expression of the AP-1 transcription factor complex (Fos and Jun) and immediate early response (IER) genes. These gene expression changes occurred independently of chromatin modifications. Targeting AP-1 restored function of Kdm6b-deficient HSCs, suggesting that Kdm6b regulates this complex during HSC stress response. We also show Kdm6b supports developmental context-dependent leukemogenesis for T-cell acute lymphoblastic leukemia (T-ALL) and M5 acute myeloid leukemia (AML). Kdm6b is required for effective fetal-derived T-ALL and adult-derived AML, but not vice versa. These studies identify a crucial role for Kdm6b in regulating HSC self-renewal in different contexts, and highlight the potential of KDM6B as a therapeutic target in different hematopoietic malignancies.

Hematopoietic cell homing after hematopoietic cell transplant (HCT) is governed by several pathways involving marrow niche cells that are evoked after pre-HCT conditioning. To understand the factors that play a role in homing, we performed expression analysis on zebrafish marrow niche cells following conditioning. We determined that the noncollagenous protein extracellular matrix related protein dermatopontin (Dpt) was upregulated sevenfold in response to irradiation. Studies in mice revealed DPT induction with radiation and lipopolysaccharide exposure. Interestingly, we found that coincubation of zebrafish or murine hematopoietic cells with recombinant DPT impedes hematopoietic stem and progenitor cell homing by 50% and 86%, respectively. Similarly, this translated into a 24% reduction in long-term engraftment (vs control; P = .01). We found DPT to interact with VLA-4 and block hematopoietic cell–endothelial cell adhesion and transendothelial migration. Finally, a DPT-knockout mouse displayed a 60% increase in the homing of hematopoietic cells vs wild-type mice (P = .03) with a slight improvement in long-term lin−SCA1+cKIT+-SLAM cell engraftment (twofold; P = .04). These data show that the extracellular matrix–related protein DPT increases with radiation and transiently impedes the transendothelial migration of hematopoietic cells to the marrow.

Following photoreceptors ablation by intense light exposure, adult zebrafish are capable of complete regeneration due to the ability of their Müller glia (MG) to re-enter the cell cycle, creating progenitors that differentiate into new photoreceptors. The majority of previous reports on retinal regeneration focused on the first few days of the regenerative response, which include MG cell-cycle re-entry and progenitor cell proliferation. With this study, we analyzed the full 28-day time-course of regeneration by pairing a detailed morphological/immunological analysis with RNA-seq transcriptional profiling at 8 key time points during retinal regeneration. We observed several novel findings. First, we provide evidence for two separate peaks of MG gliosis, with the secondary gliotic peak occurring after MG cell-cycle re-entry. Second, we highlight a distinct transcriptional shift between 5- and 10-days post lesion that highlights the transition from progenitor proliferation to differentiation into new photoreceptors. Third, we show distinctly different patterns of transcriptional recovery of the photoreceptor opsins at 28 days post lesion. Finally, using differential gene expression analysis, we revealed that the established functional recovery of the retina at 28 days post lesion does not, in fact, return to an undamaged transcriptional state, potentially redefining what the field considers complete regeneration. Together, to our knowledge, this work represents the first histological and transcriptomic map of a 28-day time-course of retinal regeneration in adult zebrafish.

Existing burn resuscitation protocols exhibit large variability in treatment efficacy. Hence, they must be further optimized based on comprehensive knowledge of burn pathophysiology. A physics-based mathematical model that can replicate physiological responses in diverse burn patients can serve as an attractive basis to perform non-clinical testing of burn resuscitation protocols and to expand knowledge on burn pathophysiology. We intend to develop, optimize, validate, and analyze a mathematical model to replicate physiological responses in burn patients. Using clinical datasets collected from 233 burn patients receiving burn resuscitation, we developed and validated a mathematical model applicable to computer-aided in-human burn resuscitation trial and knowledge expansion. Using the validated mathematical model, we examined possible physiological mechanisms responsible for the cohort-dependent differences in burn pathophysiology between younger versus older patients, female versus male patients, and patients with versus without inhalational injury. We demonstrated that the mathematical model could replicate physiological responses in burn patients associated with wide demographic characteristics and injury severity and that an increased inflammatory response to injury may be a key contributing factor in increasing the mortality risk of older patients and patients with inhalation injury via an increase in the fluid retention. The mathematical model may provide an attractive platform to conduct non-clinical testing of burn resuscitation protocols and test new hypotheses on burn pathophysiology., 24 pages The final version of this paper has been accepted for publication in the IEEE Journal of Transactions on Biomedical Engineering (2021) and is available for early access at https://ieeexplore.ieee.org/document/9478222

This paper presents a mathematical model of blood volume kinetics and renal function in response to burn injury and resuscitation, which is applicable to the development and non-clinical testing of burn resuscitation protocols and algorithms. Prior mathematical models of burn injury and resuscitation are not ideally suited to such applications due to their limited credibility in predicting blood volume and urinary output observed in wide-ranging burn patients as well as in incorporating contemporary knowledge of burn pathophysiology. Our mathematical model consists of an established multi-compartmental model of blood volume kinetics, a hybrid mechanistic-phenomenological model of renal function, and novel lumped-parameter models of burn-induced perturbations in volume kinetics and renal function equipped with contemporary knowledge on burn-related physiology and pathophysiology. Using the dataset collected from 16 sheep, we showed that our mathematical model can be characterized with physiologically plausible parameter values to accurately predict blood volume kinetic and renal function responses to burn injury and resuscitation on an individual basis against a wide range of pathophysiological variability. Pending validation in humans, our mathematical model may serve as an effective basis for an in-depth understanding of complex burn-induced volume kinetic and renal function responses as well as development and non-clinical testing of burn resuscitation protocols and algorithms. Keywords: Mathematical Model, Burn Injury, Burn Resuscitation, Non-Clinical Testing, Burn Resuscitation Protocols, and Algorithms, Comment: Published in the Journal of Burns 24 Pages

Physiological closed-loop controlled (PCLC) medical devices are complex systems integrating one or more medical devices with a patient’s physiology through closed-loop control algorithms; introducing many failure modes and parameters that impact performance. These control algorithms should be tested through safety and efficacy trials to compare their performance to the standard of care and determine whether there is sufficient evidence of safety for their use in real care setting. With this aim, credible mathematical models have been constructed and used throughout the development and evaluation phases of a PCLC medical device to support the engineering design and improve safety aspects. Uncertainties about the fidelity of these models and ambiguities about the choice of measures for modeling performance need to be addressed before a reliable PCLC evaluation can be achieved. This research develops tools for evaluating the accuracy of physiological models and establishes fundamental measures for predictive capability assessment across different physiological models. As a case study, we built a refined physiological model of blood volume (BV) response by expanding an original model we developed in our prior work. Using experimental data collected from 16 sheep undergoing hemorrhage and fluid resuscitation, first, we compared the calibration performance of the two candidate physiological models, i.e., original and refined, using root-mean-squared error (RMSE), Akiake information criterion (AIC), and a new multi-dimensional approach utilizing normalized features extracted from the fitting error. Compared to the original model, the refined model demonstrated a significant improvement in calibration performance in terms of RMSE (9%, P = 0.03) and multi-dimensional measure (48%, P = 0.02), while a comparable AIC between the two models verified that the enhanced calibration performance in the refined model is not due to data over-fitting. Second, we compared the physiological predictive capability of the two models under three different scenarios: prediction of subject-specific steady-state BV response, subject-specific transient BV response to hemorrhage perturbation, and leave-one-out inter-subject BV response. Results indicated enhanced accuracy and predictive capability for the refined physiological model with significantly larger proportion of measurements that were within the prediction envelope in the transient and leave-one-out prediction scenarios (P < 0.02). All together, this study helps to identify and merge new methods for credibility assessment and physiological model selection, leading to a more efficient process for PCLC medical device evaluation.

Objectives The objective of this study was to compare maxillary dimensions and growth in newborns with Complete Unilateral Cleft Lip and Palate (UCLP) to healthy newborns before and after cheiloplasty. Additionally, a palatal growth curve is constructed to give more information about the natural growth before surgical intervention. Methods Twenty-eight newborns with complete UCLP were enrolled in this study. Multiple plaster-casts of each child during their first year were collected and grouped in before and after cheiloplasty. A previous developed semi-automatic segmentation tool was used to assess the maxillary dimensions and were compared to a healthy control group. Z-scores were calculated to indicate differences between the two populations and if cheiloplasty had influence on maxillary growth. Furthermore, the prediction model created in a previous study was used to indicate differences between predictions and the outcome in UCLP measurements. The analysis was tested for inter- and intra-observer variability. Results Results show differences in alveolar and palatal shape in UCLP patients in comparison with healthy controls. Prior to cheiloplasty an increased width and alveolar length was observed while the palatal depth was decreased. After cheiloplasty the widths moved towards normal but were still significantly larger. Conclusion Infants with unilateral cleft lip and palate show a wider maxillary arch in comparison with the control population. Initial treatment has most influence on the width of the arch, which decreased towards normal.

The conceptuses (embryo/fetus and placental membranes) of pigs require energy to support elongation and implantation, and amounts of glucose and fructose increase in the uterine lumen during the peri-implantation period. Conceptuses from day 16 of pregnancy were incubated with either 14C-glucose or 14C-fructose and amounts of radiolabeled CO2 released from the conceptuses measured to determine rates of oxidation of glucose and fructose. Glucose and fructose both transport into conceptuses, and glucose is preferentially metabolized in the presence of fructose, whereas fructose is actively metabolized in the absence of glucose and to a lesser extent in the presence of glucose. Endometrial and placental expression of glucose transporters SLC2A1, SLC2A2, SCL2A3, and SLC2A4 were determined. SLC2A1 messenger RNA (mRNA) and protein, and SLC2A4 mRNA were abundant in the uterine luminal epithelium of pregnant compared to cycling gilts, and increased in response to progesterone and conceptus-secreted estrogen. SLC2A2 mRNA was expressed weakly by conceptus trophectoderm on day 15 of pregnancy, whereas SLC2A3 mRNA was abundant in trophectoderm/chorion throughout pregnancy. Therefore, glucose can be transported into the uterine lumen by SLC2A1, and then into conceptuses by SLC2A3. On day 60 of gestation, the cell-specific expression of these transporters was more complex, suggesting that glucose and fructose transporters are precisely regulated in a spatial-temporal pattern along the uterine-placental interface of pigs to maximize hexose sugar transport to the pig conceptus/placenta.

The aim of this study was to develop an accurate and intuitive semi-automatic segmentation technique to calculate an average maxillary arch and palatal growth profile for healthy newborns in their first year of life. Seventy babies born between 1985 and 1988 were included in this study. Each child had five impressions made in the first year after birth that were digitalized. A semi-automatic segmentation tool was developed and used to assess the maxillary dimensions. Finally, random effect models were built to describe the growth and build a simulation population of 10,000 newborns. The segmentation was tested for inter- and intra-observer variability. The Pearson correlation coefficient for each of the variables was between 0.94 and 1.00, indicating high inter-observer agreement. The paired sample t test showed that, except for the tuberosity distance, there were small, but significant differences in the landmark placements between observers. Intra-observer repeatability was high, with Pearson correlation coefficients ranging from 0.87 to 1.00 for all measurements, and the mean differences were not significant. A third or second degree growth curve could be successfully made for each parameter. These findings indicated this method could be used for objective clinical evaluation of maxillary growth. The resulting growth models can be used for growth studies in healthy newborns and for growth and treatment outcome studies in children with cleft lip and palate or other craniofacial anomalies.

In this paper we describe a data set of multivariate physiological measurements recorded from conscious sheep (N = 8; 37.4 ± 1.1 kg) during hemorrhage. Hemorrhage was experimentally induced in each animal by withdrawing blood from a femoral artery at two different rates (fast: 1.25 mL/kg/min; and slow: 0.25 mL/kg/min). Data, including physiological waveforms and continuous/intermittent measurements, were transformed to digital file formats (European Data Format [EDF] for waveforms and Comma-Separated Values [CSV] for continuous and intermittent measurements) as a comprehensive data set and stored and publicly shared here (Appendix A). The data set comprises experimental information (e.g., hemorrhage rate, animal weight, event times), physiological waveforms (arterial and central venous blood pressure, electrocardiogram), time-series records of non-invasive physiological measurements (SpO2, tissue oximetry), intermittent arterial and venous blood gas analyses (e.g., hemoglobin, lactate, SaO2, SvO2) and intermittent thermodilution cardiac output measurements. A detailed explanation of the hemodynamic and pulmonary changes during hemorrhage is available in a previous publication (Scully et al., 2016) [1] .

Intra-atrial reentrant tachycardia (IART) is a common sequela in the congenital heart disease (CHD) population, and it significantly increases morbidity and mortality. Atrial antitachycardia devices (ATDs) capable of atrial antitachycardia pacing (ATP) therapy have been used to manage IART in the CHD population, but there are limited data on their safety and efficacy.To determine whether ATD implantation was associated with reduced direct current (DC) cardioversions and to compare ATP success between different CHD diagnoses and ATP programs.A single-center retrospective chart review was performed on CHD patients with ATDs. Demographic data were collected in addition to the number of DC cardioversions required before and after ATD implantation; data on ATP efficacy and the specific ATP program utilized; and adverse events related to ATD implantation or subsequent ATP treatments.ATD implantation in 91 CHD patients was associated with a significant reduction in DC cardioversions (P.01). Overall, 72% of IART episodes were successfully terminated by ATP. Patients with levo-transposition of the great arteries experienced lower rates of ATP success than the remainder of the cohort (P.01). There was no evidence of degeneration to ventricular arrhythmia or death directly attributed to ATP.ATD implantation was associated with reduced DC cardioversion burden. Patients with levo-transposition of the great arteries may experience lower ATP efficacy than patients with other CHDs; however, a larger patient population is required to better determine subgroup efficacy. These results support the safety and efficacy of ATP in the CHD population.

Closed-loop automation of critical care therapy has the potential to reduce the workload of clinical personnel while maintaining the quality of care. In the real-world clinical arena, critically ill patients receive multiple medical treatments. However, existing body of work has predominantly focused on closed-loop automation of isolated individual treatments. How these individual treatment loops interact with each other has not been investigated. The goal of this work is to garner insights on the safety of critical care therapy and potential deleterious conflicts therein when multiple isolated and individually closed-loop controlled medical treatments act upon a patient, using a case study of hemorrhage resuscitation and intravenous propofol sedation. For this purpose, a physiological model of a critically ill patient was developed and experimentally validated to describe the collective cardiovascular and pharmacological effects of these treatments. Then, isolated and individually closed-loop controlled hemorrhage resuscitation and intravenous propofol sedation treatments were simultaneously applied to the physiological model and their interactive behavior was investigated. The results showed that (i) the influence of one treatment on the other must be taken into account in selecting treatment set point to maintain the safety of overall therapy, and that (ii) information sharing between control loops may enhance the efficacy and robustness of individual treatment loops. In sum, it was concluded that hemorrhage resuscitation and intravenous propofol sedation treatments may benefit from coordination both at the set point and the loop levels. The conclusion may generalize to a wide spectrum of multiple closed-loop controlled medical treatments.

Among the congenital heart disease (CHD) population, intra-atrial reentrant tachycardia (IART) is a common sequela resulting from anatomical anomalies and surgical scars that significantly increases morbidity and mortality. Atrial antitachycardia pacing (ATP) delivered by atrial antitachycardia devices (ATDs) has been used to treat IART in the CHD population. However, there remains limited data on the safety and efficacy of ATP, as well as on comparisons of its effects amongst different CHD subtypes. The purpose of the current study is to describe the clinical history and ATP efficacy in three patients with unique forms of complex CHD. During this study, a single-center review of three patients with ATDs was performed. One patient with each of the following CHD anomalies was selected for inclusion: systemic left ventricle, systemic right ventricle, and single ventricle. Data collected included ATP success rates, medications in use, direct current (DC) cardioversions, and any complications related to the ATDs. Study findings revealed the patient with a systemic left ventricle had an ATD implanted for approximately 9.5 years, with 695 of 956 (73%) episodes successfully converted. Unsuccessfully treated episodes were generally asymptomatic and self-terminating in this patient. The patient with a systemic right ventricle had an ATD implanted for approximately 16 years, with 333 of 348 (96%) episodes being successfully converted. The patient with a single ventricle had an ATD implanted for approximately 12.5 years, with 404 of 416 (97%) episodes successfully converted. The patients with biventricular physiology were able to forgo DC cardioversion after receiving their ATDs. However, due to medical noncompliance as well as multiple episodes of IART, which presented with 1:1 conduction or low rates, the single-ventricle patient still required DC cardioversions post-ATD implantation. In conclusion, this study’s findings demonstrate that, while ATP can be effective in a wide variety of CHDs, experiences can vary based on individual arrhythmia substrates, cardiac anatomy, and medical compliance. Additionally, challenges remain in IART detection in patients with especially complex CHD anatomies.

Genome sequencing efforts have identified virtually all of the important mutations in adult myeloid malignancies. More recently, population studies have identified cancer-associated variants in the blood of otherwise healthy individuals as they age, a phenomenon termed clonal hematopoiesis of indeterminate potential (CHIP). This suggests that these mutations may occur in hematopoietic stem cells (HSCs) long before any clinical presentation but are not necessarily harbingers of transformation because only a fraction of individuals with CHIP develop hematopoietic pathologies. Delineation between CHIP variants that predispose for disease versus those that are more benign could be used as a prognostic factor to identify individuals at greater risk for transformation. To achieve this, the biological impact of CHIP variants on HSC function must be validated. One variant that has been identified recurrently in CHIP is a gain-of-function missense mutation in the imprinted gene GNAS (Guanine Nucleotide Binding Protein, Alpha Stimulating). In this study, we examined the effect of the GNASR201C variant on HSC function. Ectopic expression of GNASR201C supported transplantable HSC activity and improved lymphoid output in secondary recipients. Because declining lymphoid output is a hallmark of aging, GNASR201C mutations may sustain lymphoid-biased HSCs over time and maintain them in a developmental state favorable for transformation.

Our reaction on the letter of Yosiko Myoken et al.(2020): Yosiko Myoken et al. commented on our article about the effect of using a mobile application ("WhiteTeeth") on improving oral hygiene 2 . Although they commended our article, they raised some questions that we would like to respond to. First, Myoken et al. believed that we should have evaluated the effectiveness of our intervention over a longer study period of at least six months to obtain accurate results.

To determine the effectiveness of colonic fluid absorption as a route for fluid resuscitation of a major burn. In order to assess the feasibility and performance of colonic resuscitation, the authors compared plasma volume expansion and hemodynamic parameters of animals submitted to colonic or intravenous fluid resuscitation. Twelve anesthetized swine were submitted to a 40% full thickness flame burn. Thirty minutes later fluid resuscitation was initiated with either intravenous or colonic infusion of crystalloid based on the Parkland formula. This treatment lasted 4.5 hours. The volume of fluid infused was 86 ± 18 ml/kg for the intravenous treatment and 89 ± 14 ml/kg for the colonic treatment. The percentage of fluid absorbed by the colon at the end of the protocol was 30 ± 13% of the infused fluid. Enteral resuscitation was equally effective in expanding plasma volume at the end of the protocol. Laboratorial and hemodynamic parameters were similar between the two resuscitation strategies throughout the study. Urine output was significantly higher in the intravenous group (7.9 ± 4.2 ml/kg/hr vs 0.9 ± 0.3 ml/kg/hr, P = .03). This study demonstrates that colonic infusion of normal saline in a severe burn injury model can restore hemodynamic stability and expand plasma volume to a degree that rivals the effect of direct intravenous infusion for early burn resuscitation in a swine model.

Summary The hematopoietic marrow microenvironment is composed of multiple cell types embedded in an extracellular matrix (ECM). We have explored marrow ECM using mass spectrometry and found dermatopontin (DPT), a small non-collagenous ECM protein, to be present. We found that DPT cooperates with other ECM proteins to promote hematopoietic cell adherence in vitro on plastic as well as OP9 stromal cells. We generated constitutional DPT−/− mice that were viable and had no peripheral lympho-hematopoietic abnormalities. The composition of the marrow of wild-type and DPT−/− mice was equivalent in terms of cellularity, CFU-C, LSK (Lineage−, SCA-1+, KIT+), and LSK-SLAM (LSK, CD48−, CD150+) frequencies. These data suggest that DPT fosters adherence but is not required for steady-state hematopoiesis in vivo. There are likely overlapping cellular adhesion mechanisms that can compensate to maintain the hematopoietic niche in the absence of DPT., Highlights • Murine marrow can be decellularized to reveal the ECM • Dermatopontin is a component of the marrow ECM • DPT can promote HSPC adherence in vitro • DPT is dispensable for native hematopoiesis, In this article, Lund and colleagues show that dermatopontin is a component of murine bone marrow, binds to hematopoietic cells, and plays a role in in vitro cell attachment. Constitutional deletion of dermatopontin did not result in hematopoietic abnormalities, although HSPC mobilization with AMD3100 was improved, suggesting an in vivo role in cell retention within the bone marrow microenvironment.

Vasopressors provide a rapid and effective approach to correct hypotension in the perioperative setting. Our group developed a closed-loop control (CLC) system that titrates phenylephrine (PHP) based on the mean arterial pressure (MAP) during general anesthesia. As a means of evaluating system competence, we compared the performance of the automated CLC with physicians. We hypothesized that our CLC algorithm more effectively maintains blood pressure at a specified target with less blood pressure variability and reduces the dose of PHP required. In a crossover study design, 6 swine under general anesthesia were subjected to a normovolemic hypotensive challenge induced by sodium nitroprusside. The physicians (MD) manually changed the PHP infusion rate, and the CLC system performed this task autonomously, adjusted every 3 seconds to achieve a predetermined MAP. The CLC maintained MAP within 5 mm Hg of the target for (mean ± standard deviation) 93.5% ± 3.9% of the time versus 72.4% ± 26.8% for the MD treatment (P = .054). The mean (standard deviation) percentage of time that the CLC and MD interventions were above target range was 2.1% ± 3.3% and 25.8% ± 27.4% (P = .06), respectively. Control statistics, performance error, median performance error, and median absolute performance error were not different between CLC and MD interventions. PHP infusion rate adjustments by the physician were performed 12 to 80 times in individual studies over a 60-minute period. The total dose of PHP used was not different between the 2 interventions. The CLC system performed as well as an anesthesiologist totally focused on MAP control by infusing PHP. Computerized CLC infusion of PHP provided tight blood pressure control under conditions of experimental vasodilation.

Introduction This review was designed to make recommendations on future educational needs, principles of curricular development, and how the International Society for Sexual Medicine (ISSM) should address the need to enhance and promote human sexuality education around the world. Aim To explore the ways in which graduate and postgraduate medical education in human sexuality has evolved and is currently delivered. Methods We reviewed existing literature concerning sexuality education, curriculum development, learning strategies, educational formats, evaluation of programs, evaluation of students, and faculty development. We reviewed literature relating to four main areas: (i) the current status of the international regulation of training in sexual medicine; (ii) the current delivery of education and training in sexual medicine; (iii) resident and postgraduate education in sexual medicine surgery; and (iv) education and training for allied health professionals. Results The main findings in these four areas are as follows. Sexual medicine has grown considerably as a specialty during the past 20 years, with many drivers being identified. However, the regulatory aspects of training, assessment, and certification are currently in the early stages of development and are in many ways lagging behind the scientific and clinical knowledge in the field. However, there are examples of the development of curricula with accompanying assessments that have attempted to set standards of education and training that might underlie the delivery of high-quality care to patients in sexual medicine. The development of competence assessment has been applied to surgical training in sexual medicine, and there is increasing interest in simulation as a means of enhancing technical skills training. Although the focus of curriculum development has largely been the medical profession, there is early interest in the development of standards for training and education of allied health professionals. Conclusion Organizations of professionals in sexual health, such as the ISSM, have an opportunity, and indeed a responsibility, to provide and disseminate learning opportunities, curricula, and standards of training for doctors and allied health professionals in sexual medicine.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors, and comprises approximately 15% and 25% of pediatric and adult ALL cases respectively. It is well-established that activating NOTCH1 mutations are the major genetic lesions driving T-ALL in most patients, but efforts to develop targeted therapies against this pathway have produced limited success in decreasing leukemic burden and come with significant clinical side effects. A finer detailed understanding of the genetic and molecular mechanisms underlying T-ALL is required identify patients at increased risk for treatment failure and the development of precision medicine strategies. Generation of genetic models that more accurately reflect the normal developmental history of T-ALL are necessary to identify new avenues for treatment. The DNA methyltransferase enzyme DNMT3A is also recurrently mutated in T-ALL patients, and we show here that inactivation of Dnmt3a combined with Notch1 gain-of-function leads to an aggressive T-ALL in mouse models. Moreover, conditional inactivation of Dnmt3a in mouse hematopoietic cells leads to an accumulation of immature progenitors in the thymus which are less apoptotic. These data demonstrate that Dnmt3a is required for normal T-cell development, and acts as a T-ALL tumor suppressor.

Purpose of Review Probiotics are promising remedial treatments for symptoms of small intestine (SI) diseases and promoters of overall good health. Probiotics play an important role in supporting a healthy SI microbiome (eubiosis), and in preventing establishment of unhealthy microbiota. SI eubiosis promotes optimal nutrient uptake, and optimal nutritional status maintains a healthy SI, reducing the likelihood of SI diseases. It is important to understand the advantages and limitations of probiotic therapies. Recent Findings Microbial dysbiosis decreases the capacity of the small bowel to utilize and absorb dietary compounds. In some studies, probiotic supplements containing lactic acid bacteria and Bifidobacterium have been demonstrated effective in supporting beneficial microbes in the SI while improving barrier integrity and reducing nutrient malabsorption and SI disease-related pathology. Summary Strain-specific probiotic therapy may be a natural and effective approach to restoring SI barrier integrity and eubiosis, resulting in improved nutrient absorption and better health, including reducing the incidence of and severity of SI diseases.

18 pags., 21 figs., 5 tabs, 1 app., Strong winds and ultraviolet (UV) radiation from O-type stars disrupt and ionize their molecular core birthplaces, sweeping up material into parsec-size shells. Owing to dissociation by starlight, the thinnest shells are expected to host low molecular abundances and therefore little star formation. Here, we expand previous maps made with observations using the IRAM 30 m telescope (at 11″ ≃ 4500 AU resolution) and present square-degree 12CO and 13CO (J = 2-1) maps of the wind-driven "Veil bubble"that surrounds the Trapezium cluster and its natal Orion molecular core (OMC). Although widespread and extended CO emission is largely absent from the Veil, we show that several CO "globules"exist that are blueshifted in velocity with respect to OMC and are embedded in the [C » II] 158 μm-bright shell that confines the bubble. This includes the first detection of quiescent CO at negative local standard of rest velocities in Orion. Given the harsh UV irradiation conditions in this translucent material, the detection of CO globules is surprising. These globules are small (Rg = 7100 AU), not massive (Mg = 0.3 M⊙ ), and are moderately dense: nH = 4 × 104 cm-3 (median values). They are confined by the external pressure of the shell, Pext∕ k ≳ 107 cm-3 K, and are likely magnetically supported. They are either transient objects formed by instabilities or have detached from pre-existing molecular structures, sculpted by the passing shock associated with the expanding shell and by UV radiation from the Trapezium. Some represent the first stages in the formation of small pillars, others of isolated small globules. Although their masses (Mg, We warmly thank the operators, AoDs, and chefs at the IRAM 30 m telescope for their support while the CO observations were conducted. This work is also based on observations made with the NASA/DLR Stratospheric Observatory for Infrared Astronomy (SOFIA). SOFIA is jointly operated by the Universities Space Research Association, Inc. (USRA), under NASA contract NNA17BF53C, and the Deutsches SOFIA Institut (DSI) under DLR contract 50 OK 0901 to the University of Stuttgart. We acknowledge the work, during the C+ upGREAT square degree survey of Orion, of the USRA and NASA staff of the Armstrong Flight Research Center in Palmdale, the Ames Research Center in Mountain View (California), and the Deutsches SOFIA Institut. We thank the Spanish MICIU for funding support under grant AYA2017-85111-P. Research on the ISM at Leiden Observatory is supported through a Spinoza award.

Dissatisfaction with current methods of burn resuscitation exclusively using Lactated Ringer’s and physician-directed adjustments in hourly fluid infusions are based on a record of excessive total fluid volume infused and complications of fluid overload. Alternative approaches to current standard of care include early use of albumin, supplements of high dose vitamin C and nurse-driven, protocolized care. However, electronic urinary output monitors and computerized decision support technologies are emerging. The efficacy of these approaches of different fluids and computerized solutions remains to be proven with current multicenter trials.

There is a scarcity of literature exploring the consequences of Failure To Extubate (FTE) and Delayed Reintubation (DRI) in spine surgery. While it is reasonable to believe that patients who FTE or undergo DRI after Posterior Lumbar Fusion (PLF) and Transforaminal Lumbar Interbody Fusion (TLIF) are at risk for graver outcomes, there is minimal data to explicitly support that. The goal of this study was to investigate the morbidity and mortality associated with FTE and DRI after lumbar spine surgery in a large pool of patients.We conducted a retrospective multicenter study of patients that underwent elective posterior lumbar fusion (PLF) and transforaminal lumbar interbody fusion (TLIF) using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database from 2006 to 2016. We excluded patients with disseminated cancer, metastatic disease to the neural axis, patient with spinal epidural abscess, and patients with ventilator dependency prior to the operation.57,677 patients from 2006 to 2016 were identified; 55 patients (0.1 %) had FTE and 262 patients (0.46 %) had DRI. The incidence of pneumonia was 27.2-fold greater in the FTE group and septic shock was 63.5-fold greater. All complications listed below are significance to p 0.001. Deep vein thrombosis, pulmonary embolism, myocardial infarction and cardiac arrest were respectively, 10.4-, 12.2-, 22.8-, and 45.5- fold greater in the FTE group. Overall complication rate differed significantly between the two groups and were 9.8-fold greater in the FTE group. FTE was associated with increased, length of stay and all complications except DVT and pulmonary embolism. FTE was profoundly associated with severe complications (OR 13.0, 95 % CI 7.2-23.5) and mortality (OR = 21.5, CI = 7.5-61.0). The DRI group had a significantly higher morbidity (OR = 71.0, CI = 44.1-114.4), including overall complication (OR = 21.2, CI = 16.0-28.0) and severe complications (OR = 34.4, CI = 26.1-45.3). The DRI group had significantly higher rates of pneumonia (OR = 37.0), DVT (OR = 9.6) and pulmonary embolism (OR = 7.0), septic shock (OR = 60.5), myocardial infarction (OR = 32.1,) and cardiac arrest (OR = 236.4).FTE and DRI were highly predictive of morbidity and mortality. Overall, investigations of the effects of FTE and DRI following spine procedures are lacking. This large multi-center national database review is one of the first to provide insight into the consequences of FTE and DRI in lumbar fusion cases. Future investigation into the consequences and predictors of FTE and DRI in spine surgery are required.

An 11-year-old girl presented at an orthodontist asking for the correction of the crooked position of her upper and lower front teeth. In addition, the patient was concerned about the abnormal shape and size of tooth 21. There was a disto-occlusion, crowding and tooth gemination of tooth 21 with the shape of a dens invaginatus. The tooth, moreover, was infected. Teeth 21 and 14 were extracted as part of the treatment. By means of a guided transposition, tooth 23 was brought to the extraction site of tooth 21. Treatment was performed with hybrid fixed appliance techniques.Een 11-jarig meisje meldde zich bij een orthodontist met het verzoek de scheefstand van haar boven- en onderfront te corrigeren. Daarnaast stoorde de patiënt zich aan de afwijkende vorm en grootte van gebitselement 21. Er was sprake van een disto-occlusie, ruimtegebrek, geminatio dentis van gebitselement 21 met de vorm van een dens invaginatus. Het gebitselement was bovendien ontstoken. Gebitselementen 21 en 14 werden in het kader van de behandeling geëxtraheerd. Op plek van het verwijderde gebitselement 21 werd gebitselement 23 gebracht door middel van geforceerde transpositie. Er is gebruikgemaakt van hybride orthodontische technieken.

Cortical injury elicits long-term cytotoxic and cytoprotective mechanisms within the brain and the balance of these pathways can determine the functional outcome for the individual. Cytotoxicity is exacerbated by production of reactive oxygen species, accumulation of iron, and peroxidation of cell membranes and myelin. There are currently no neurorestorative treatments to aid in balancing the cytotoxic and cytoprotective mechanisms following cortical injury. Cell based therapies are an emerging treatment that may function in immunomodulation, reduction of secondary damage, and reorganization of surviving structures. We previously evaluated human umbilical tissue-derived cells (hUTC) in our non-human primate model of cortical injury restricted to the hand area of primary motor cortex. Systemic hUTC treatment resulted in significantly greater recovery of fine motor function compared to vehicle controls. Here we investigate the hypothesis that hUTC treatment reduces oxidative damage and iron accumulation and increases the extent of the microglial response to cortical injury. To test this, brain sections from these monkeys were processed using immunohistochemistry to quantify oxidative damage (4-HNE) and activated microglia (LN3), and Prussian Blue to quantify iron. hUTC treated subjects exhibited significantly reduced oxidative damage in the sublesional white matter and iron accumulation in the perilesional area as well as a significant increase in the extent of activated microglia along white matter pathways. Increased perilesional iron accumulation was associated with greater perilesional oxidative damage and larger reconstructed lesion volume. These findings support the hypothesis that systemic hUTC administered 24 h after cortical damage decreases the cytotoxic response while increasing the extent of microglial activation.

Zebrafish (Danio rerio) have become a highly-utilized model system in the field of regenerative biology because of their endogenous ability to regenerate many tissues and organs, including the retina. The vast majority of previous research on retinal regeneration in adult zebrafish utilizes acute methodologies for retinal damage. Acute retinal cell death triggers a reactive gliosis response of Müller glia (MG), the resident macroglia of the retina. In addition, each activated MG undergoes asymmetric cell division to produce a neuronal progenitor, which continues to divide and ultimately gives rise to new retinal neurons. Studies using these approaches have uncovered many crucial mechanisms by which MG respond to acute damage. However, they may not adequately mimic the chronic neuronal degeneration observed in many human retinal degenerative diseases. The current study aimed to develop a new long-term, chronic photoreceptor damage and degeneration model in adult zebrafish. Comparing the subsequent cellular responses to that of the commonly-used acute high-intensity model, we found that low, continuous light exposure damaged the outer segments of both rod and cone photoreceptors, but did not result in significant apoptotic cell death, MG gliosis, or MG cell-cycle re-entry. Instead, chronic light nearly completely truncated photoreceptor outer segments and resulted in a recruitment of microglia to the area. Together, these studies present a chronic photoreceptor model that can be performed in a relatively short time frame (21 days), that may lend insight into the cellular events underlying non-regenerative photoreceptor degeneration observed in other model systems.

Introduction Patients supported with left ventricular assist devices (LVADs) are burdened by frequent hemocompatibility-related adverse events related to patient-pump interactions. These predominantly vascular events include stroke, gastrointestinal bleeding, and pump thrombosis. Our center performs routine, invasive hemodynamic ramp speed titrations in LVAD patients to determine the optimal rotational speed after implantation. We sought to interrogate changes in vascular hemodynamics during an exercise ramp study to understand the influence of pump speed and exercise on outflow graft and cerebrovascular flow. Case Report A 71-year-old male patient supported by Heartware HVAD operating at a baseline speed of 2700 RPM presented for LVAD ramp and exercise study with vascular imaging. A right heart catheterization, echocardiography with Doppler imaging of the patient's LVAD outflow graft, and vascular Doppler of the left common carotid artery and middle cerebral artery were performed. The patient's LVAD operating speed was reduced to 2400 RPM and then increased stepwise to a maximum speed of 3000 RPM. At each increment of operating speed, Doppler imaging was attempted and right heart catheterization was repeated. After reviewing data from the ramp study, the patient's operating speed was set to 2900 RPM and then a staged exercise protocol with bicycle ergometer was performed. Pertinent findings of vascular imaging include a blunting of peak systolic to end-diastolic velocity ratio in vascular beds with incremental speed increase and partial recovery of pulsatility with exercise (Figure). Summary This case demonstrates the influence LVAD speed adjustment and exercise have on carotid artery and outflow graft pulsatility. With exercise the outflow graft and carotid artery peak systolic and end-diastolic velocities were similar to those at the lowest LVAD pump speed, suggesting that intrinsic contractility and native LV unloading was restored with exercise despite a higher pump speed.

Summary Metabolism of oxidative stress is necessary for cellular survival. We have previously utilized the zebrafish as a model of the oxidative stress response. In this study, we found that gata1-expressing erythroid cells contributed to a significant proportion of total-body oxidative stress when animals were exposed to a strong pro-oxidant. RNA-seq of zebrafish under oxidative stress revealed the induction of tp53. Zebrafish carrying tp53 with a mutation in its DNA-binding domain were acutely sensitive to pro-oxidant exposure and displayed significant reactive oxygen species (ROS) and tp53-independent erythroid cell death resulting in an edematous phenotype. We found that a major contributing factor to ROS was increased basal mitochondrial respiratory rate without reserve. These data add to the concept that tp53, while classically a tumor suppressor and cell-cycle regulator, has additional roles in controlling cellular oxidative stress., Highlights • Erythroid precursors contribute significantly to total ROS after oxidative challenge • Tp53 is induced after pro-oxidant challenge • Mutated tp53 is associated with an increased mitochondrial oxygen consumption rate • Decreased mitochondrial reserve leads to overwhelming ROS and erythroid cell death, In this article, Lund and colleagues show that Gata1+ erythroid precursors contribute to total reactive oxygen species (ROS) in the zebrafish. Disruption of Tp53 increases ROS and overall sensitivity to pro-oxidant challenge, involving dysregulation of mitochondrial respiration.

The Special Interest Groups of the American Burn Association provide a forum for interested members of the multidisciplinary burn team to congregate and discuss matters of mutual interest. At the 47th Annual Meeting of the American Burn Association in Chicago, IL, the Fluid Resuscitation Special Interest Group sponsored a special symposium on burn resuscitation. The purpose of the symposium was to review the history, current status, and future direction of fluid resuscitation of patients with burn shock. The reader will note several themes running through the following presentations. One is the perennial question of the proper role for albumin or other fluid-sparing strategies. Another is the unique characteristics of the pediatric burn patient. A third is the need for multicenter trials of burn resuscitation, while recognizing the obstacles to conducting randomized controlled trials in this setting.

Highly proliferative tissues such as the gut, skin, and bone marrow lose millions of cells each day to normal attrition and challenge from different biological adversities. To achieve a lifespan beyond the longevity of individual cell types, tissue-specific stem cells sustain these tissues throughout the life of a human. For example, the lifespan of erythrocytes is about 100 days and adults make about two million new erythrocytes every second. A small pool of hematopoietic stem cells (HSCs) in the bone marrow is responsible for the lifetime maintenance of these populations. However, there are changes that occur within the HSC pool during aging. Biologically, these changes manifest as blunted immune responses, decreased bone marrow cellularity, and increased risk of myeloid diseases. Understanding the molecular mechanisms underlying dysfunction of aging HSCs is an important focus of biomedical research. With advances in modern health care, the average age of the general population is ever increasing. If molecular or pharmacological interventions could be discovered that rejuvenate aging HSCs, it could reduce the burden of age related immune system compromise as well as open up new opportunities for treatment of hematological disorders with regenerative therapy.

Electronic urinary output monitors, intended to provide urine output information to guide fluid therapy during burn resuscitation, can be inaccurate because of airlocks causing urine retention in the drainage tube and bladder. In this study, the authors explore the effects of airlock formation on urine output measured using an electronic urinary output monitor connected to either a standard commercial drainage tubing system or a drainage tubing system with an automated airlock clearing mechanism. In a multicenter study in the burn intensive care unit, urine output was compared between 10 control patients with a standard commercial drainage tubing system and 10 test patients with a novel automated airlock clearing drainage tubing system. The comparison was focused on identifying the number and magnitude of surges in urinary output because of airlocks and associated periods of false oliguria. In the control group, 5 of 10 (50%) patients had drainage line flow impediments from 8 airlocks. In addition, control patients experienced six associated periods of false oliguria. Airlock surge volumes ranged from 50 to 329 ml, and false oliguria duration ranged from 39.4 to 185.2 minutes. In the test group, 0 of 10 (0%) patients had drainage line impediments from airlocks (P < .01), and hence, there were no periods of false oliguria. Airlocks and associated periods of false oliguria occur with standard commercial drainage tubing and are eliminated using an automated airlock clearing drainage tube. Electronic urinary output monitoring with self-clearing drainage has the potential to improve tracking of real-time urine output and decrease caregiver workload.