Fibroblasts: Origins, definitions, and functions in health and disease.

Fibroblasts are diverse mesenchymal cells that participate in tissue homeostasis and disease by producing complex extracellular matrix and creating signaling niches through biophysical and biochemical cues. Transcriptionally and functionally heterogeneous across and within organs, fibroblasts encode regional positional information and maintain distinct cellular progeny. We summarize their development, lineages, functions, and contributions to fibrosis in four fibroblast-rich organs: skin, lung, skeletal muscle, and heart. We propose that fibroblasts are uniquely poised for tissue repair by easily reentering the cell cycle and exhibiting a reversible plasticity in phenotype and cell fate. These properties, when activated aberrantly, drive fibrotic disorders in humans.

Lineage commitment of dermal fibroblast progenitors is controlled by Kdm6b-mediated chromatin demethylation.

Dermal Fibroblast Progenitors (DFPs) differentiate into distinct fibroblast lineages during skin development. However, the epigenetic mechanisms that regulate DFP differentiation are not known. Our objective was to use multimodal single-cell approaches, epigenetic assays, and allografting techniques to define a DFP state and the mechanism that governs its differentiation potential. Our initial results indicated that the overall transcription profile of DFPs is repressed by H3K27me3 and has inaccessible chromatin at lineage-specific genes. Surprisingly, the repressive chromatin profile of DFPs renders them unable to reform the skin in allograft assays despite their multipotent potential. We hypothesized that chromatin derepression was modulated by the H3K27me3 demethylase, Kdm6b/Jmjd3. Dermal fibroblast-specific deletion of Kdm6b/Jmjd3 in mice resulted in adipocyte compartment ablation and inhibition of mature dermal papilla functions, confirmed by additional single-cell RNA-seq, ChIP-seq, and allografting assays. We conclude that DFPs are functionally derepressed during murine skin development by Kdm6b/Jmjd3. Our studies therefore reveal a multimodal understanding of how DFPs differentiate into distinct fibroblast lineages and provide a novel publicly available multiomics search tool.

Higher Dose Noninvasive Transcutaneous Auricular Vagus Nerve Stimulation Increases Feeding Volumes and White Matter Microstructural Complexity in Open-Label Study of Infants Slated for Gastrostomy Tube.

OBJECTIVE: To determine whether transcutaneous auricular vagus nerve stimulation (taVNS) paired with twice daily bottle feeding increases the volume of oral feeds and white matter neuroplasticity in term-age-equivalent infants failing oral feeds and determined to need a gastrostomy tube. STUDY DESIGN: In this prospective, open-label study, 21 infants received taVNS paired with 2 bottle feeds for 2 - 3 weeks (2x). We compared 1) increase oral feeding volumes with 2x taVNS and previously reported once daily taVNS (1x) to determine a dose response, 2) number of infants who attained full oral feeding volumes, and 3) diffusional kurtosis imaging and magnetic resonance spectroscopy before and after treatment by paired t tests. RESULTS: All 2x taVNS treated infants significantly increased their feeding volumes compared with 10 days before treatment. Over 50% of 2x taVNS infants achieved full oral feeds but in a shorter time than 1x cohort (median 7 days [2x], 12.5 days [1x], P < .05). Infants attaining full oral feeds showed greater increase in radial kurtosis in the right corticospinal tract at the cerebellar peduncle and external capsule. Notably, 75% of infants of diabetic mothers failed full oral feeds, and their glutathione concentrations in the basal ganglia, a measure of central nervous system oxidative stress, were significantly associated with feeding outcome. CONCLUSIONS: In infants with feeding difficulty, increasing the number of daily taVNS-paired feeding sessions to twice-daily significantly accelerates response time but not the overall response rate of treatment. taVNS was associated with white matter motor tract plasticity in infants able to attain full oral feeds. TRIAL REGISTRATION: Clinicaltrials.gov (NCT04643808).

The Association Between COVID-19 and Febrile Seizure: A Retrospective Case-Control Study.

BACKGROUND/OBJECTIVE: Throughout the pandemic, febrile seizures have resulted from infection secondary to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The objective of this study is to determine if there is an increased association between COVID-19 and febrile seizures as compared with other causes of febrile seizures. METHODS: This was a retrospective case control study. Data were collected from the National Institute of Health (NIH) supported National COVID Cohort Collaborative (N3C). Patients from 6 to 60 months who were tested for COVID-19 were included; cases were defined as COVID-19-positive patients whereas controls were defined as COVID-19-negative patients. Febrile seizures diagnosed within 48 hours of the COVID-19 test were considered to be associated with the test result. Patients were subjected to a stratified gender and date matching design followed by a logistic regression controlling for age and race. RESULTS: During the study period, 27,692 patients were included. Of those, 6923 patients were COVID-19-positive, among which 189 had febrile seizures (2.7%). After logistic regression, the likelihood of having febrile seizures concurrently with COVID-19 as compared with other causes was 0.96 ( P = 0.949; confidence interval, 0.81, 1.14). CONCLUSIONS: There were 2.7% of the patients with COVID-19 that were diagnosed with a febrile seizure. However, when subjected to a matched case control design with logistic regression controlling for confounding variables, there does not appear to be an increased risk of febrile seizures secondary to COVID-19 as compared with other causes.

A Comprehensive Review of Vagus Nerve Stimulation for Depression.

OBJECTIVES: Vagus nerve stimulation (VNS) is reemerging as an exciting form of brain stimulation, due in part to the development of its noninvasive counterpart transcutaneous auricular VNS. As the field grows, it is important to understand where VNS emerged from, including its history and the studies that were conducted over the past four decades. Here, we offer a comprehensive review of the history of VNS in the treatment of major depression. MATERIALS AND METHODS: Using PubMed, we reviewed the history of VNS and aggregated the literature into a narrative review of four key VNS epochs: 1) early invention and development of VNS, 2) path to Food and Drug Administration (FDA) approval for depression, 3) refinement of VNS treatment parameters, and 4) neuroimaging of VNS. RESULTS: VNS was described in the literature in the early 1900s; however, gained traction in the 1980s as Zabara and colleagues developed an implantable neurocybernetic prosthesis to treat epilepsy. As epilepsy trials proceed in the 1990s, promising mood effects emerged and were studied, ultimately leading to the approval of VNS for depression in 2005. Since then, there have been advances in understanding the mechanism of action. Imaging techniques like functional magnetic resonance imaging and positron emission tomography further aid in understanding direct brain effects of VNS. CONCLUSIONS: The mood effects of VNS were discovered from clinical trials investigating the use of VNS for reducing seizures in epileptic patients. Since then, VNS has gone on to be FDA approved for depression. The field of VNS is growing, and as noninvasive VNS quickly advances, it is important to consider a historical perspective to develop future brain stimulation therapies.

Evaluation of a Portable Wavefront Aberrometer for Community Screening Refraction in the Elderly.

SIGNIFICANCE: The SVOne may prove useful to quickly and easily assess refractive correction needs in community screenings and low-resource settings, but not all subjects were testable with the device. PURPOSE: This study aimed to compare the SVOne handheld, smartphone-based wavefront aberrometer with a tabletop autorefractor in identifying refractive errors in elderly subjects. METHODS: Participants 50 years or older at community eye screenings with visual acuity worse than 20/40 in either eye underwent autorefraction followed by two SVOne trials. Power vectors of right eye data were analyzed. RESULTS: Of 84 subjects who underwent autorefraction, 67 (79.8%) were successfully autorefracted with the SVOne, of whom 82.1% (55/67) had a successful repeat reading. Mean M (spherical equivalent) values from tabletop and handheld autorefraction were -0.21 D (95% confidence interval [CI], -0.71 to +0.29 D) and -0.29 D (95% CI, -0.79 to +0.21 D), respectively (P > .05). Mean astigmatism values from tabletop and handheld devices were +1.06 D (95% CI, 0.87 to 1.26 D) and +1.21 D (95% CI, 0.99 to 1.43 D), respectively (P > .05). Intraclass correlation coefficients between devices were 0.95 (95% CI, 0.93 to 0.97) for M, 0.78 (95% CI, 0.66 to 0.86) for J0, and 0.45 (95% CI, 0.24 to 0.63) for J45 (P < .05 for all). Excellent test-retest correlation between SVOne measurements was noted for M (Pearson correlation [r] = 0.96; P < .05), but a weaker correlation was noted for J0 and J45 (r = 0.67 and r = 0.63 [P < .05 for both], respectively). CONCLUSIONS: The SVOne provided strong agreement for M, with the majority of readings within ±1.00 D of each other, when compared with the tabletop autorefractor. A weaker but still good correlation was noted for astigmatism. Similar findings were noted when assessing repeatability.

Emergency Department Provider Survey Regarding Acute Sickle Cell Pain Management.

Sickle cell disease (SCD) can lead to potentially devastating complications that occur secondary to vaso-occlusion. Current national clinical guidelines are largely based on expert opinion, resulting in significant variation of management. Provider awareness regarding emergency department (ED) management of vaso-occlusive crises (VOC) remains unknown. A 23-question assessment of VOC management was administered to all eligible ED providers at Riley Hospital for Children between September and November 2018. Univariate analyses were performed to evaluate responses between groups. Of 52 respondents comprised of ED staff attendings (27%), resident trainees (58%), and ED nurses (15%), the majority were not aware of SCD management guidelines being available. Approximately 54% of providers endorsed a high comfort level in managing VOC, with staff and nurses more likely to report this than trainees (P=0.02). Less than 10% of all providers knew the recommended timeframe from triage to initial medication administration. Prolonged time between pain assessments was reported by 25% of providers with a high comfort level in managing VOC, which was similar to providers with a lower comfort level (13%, P=0.217). Only one fourth of all respondents appropriately did not use vital signs as an indication of a patient's pain level, and >10% reported not utilizing patient-reported pain scores. This was not significantly different between provider comfort levels (P=0.285 and 0.412, relatively). Our results suggest education regarding recommended practices was inadequate regardless of reported provider comfort. Further provider education and/or standardized ED VOC management guidelines may serve as areas for improvement in SCD care.

In Planta Response of Arabidopsis to Photothermal Impact Mediated by Gold Nanoparticles.

Biological responses to photothermal effects of gold nanoparticles (GNPs) have been demonstrated and employed for various applications in diverse systems except for one important class - plants. Here, the uptake of GNPs through Arabidopsis thaliana roots and translocation to leaves are reported. Successful plasmonic nanobubble generation and acoustic signal detection in planta is demonstrated. Furthermore, Arabidopsis leaves harboring GNPs and exposed to continuous laser or noncoherent light show elevated temperatures across the leaf surface and induced expression of heat-shock regulated genes. Overall, these results demonstrate that Arabidopsis can readily take up GNPs through the roots and translocate the particles to leaf tissues. Once within leaves, GNPs can act as photothermal agents for on-demand remote activation of localized biological processes in plants.

Redox-reversible siderophore-based catalyst anchoring within cross-linked artificial metalloenzyme aggregates enables enantioselectivity switching.

The immobilisation of artificial metalloenzymes (ArMs) holds promise for the implementation of new biocatalytic reactions. We present the synthesis of cross-linked artificial metalloenzyme aggregates (CLArMAs) with excellent recyclability, as an alternative to carrier-based immobilisation strategies. Furthermore, iron-siderophore supramolecular anchoring facilitates redox-triggered cofactor release, enabling CLArMAs to be recharged with alternative cofactors for diverse selectivity.

Strategies used by teens growing up in families with Huntington disease.

The purpose of this study was to identify helpfulness of strategies used by teens growing up in families with Huntington disease (HD). Forty-four participants responded to a mailed HD Family Survey-Teens Strategies. Strategies were those with strong positive correlation between use and perceived helpfulness, and those with negative or inverse relationships. Obtaining information, thinking about or doing something else, and actions on behalf of the parent with HD were rated as highest use and perceived helpfulness. Emotional suppression had high use but low helpfulness. Participants reported using numerous helpful strategies. Social support was often unavailable to help manage teen concerns.

Lineage Commitment of Dermal Fibroblast Progenitors is Mediated by Chromatin De-repression.

Dermal Fibroblast Progenitors (DFPs) differentiate into distinct fibroblast lineages during skin development. However, the mechanisms that regulate lineage commitment of naive dermal progenitors to form niches around the hair follicle, dermis, and hypodermis, are unknown. In our study, we used multimodal single-cell approaches, epigenetic assays, and allografting techniques to define a DFP state and the mechanisms that govern its differentiation potential. Our results indicate that the overall chromatin profile of DFPs is repressed by H3K27me3 and has inaccessible chromatin at lineage specific genes. Surprisingly, the repressed chromatin profile of DFPs renders them unable to reform skin in allograft assays despite their multipotent potential. Distinct fibroblast lineages, such as the dermal papilla and adipocytes contained specific chromatin profiles that were de-repressed during late embryogenesis by the H3K27-me3 demethylase, Kdm6b/Jmjd3. Tissue-specific deletion of Kdm6b/Jmjd3 resulted in ablating the adipocyte compartment and inhibiting mature dermal papilla functions in single-cell-RNA-seq, ChIPseq, and allografting assays. Altogether our studies reveal a mechanistic multimodal understanding of how DFPs differentiate into distinct fibroblast lineages, and we provide a novel multiomic search-tool within skinregeneration.org.

Impacts of commingling preconditioned and auction-derived beef calves on bovine respiratory disease related morbidity, mortality, and weight gain.

Introduction: Stressors predisposing to bovine respiratory disease (BRD) upon arrival in the feedlot, include the ranch to feedlot transition and mixing cattle from multiple sources. Preconditioning (PC) reduces multiple stressors, but commingling PC and auction-derived (AD) calves in a feedlot may increase BRD risk. Our objective was to evaluate PC calf performance over the first 40 days in the feedlot and determine impacts of commingling with varying proportions of AD calves (25, 50, and 75%). Methods: Calves were either preconditioned at one ranch (n = 250) or mixed-source and bought from a local auction (n = 250). At arrival, calves were assigned into 1 of 5 pens: 100 PC, 75 PC, 50 PC, 25 PC, and 0 PC, reflecting the percentage of PC calves in a 100-head pen. Results: Over 40 days, morbidity in pen 100 PC was lower compared to 0 PC (24 vs. 50%, P < 0.001) and varied in commingled pens, being highest (63%) in 25 PC and least (21%) in 50 PC (P < 0.05). There were 3 AD deaths in 0 PC and 2 deaths in 25 PC. The AD calves in 0 PC were 3 times more likely to get BRD than PC calves in 100 PC; however, AD calves gained 0.49 kg/d more than PC calves (P < 0.0001). Ignoring pen placement, AD calves were 2.76 times more likely to get BRD but gained 0.27 kg/d more than PC calves (P < 0.0001). Commingling did not affect morbidity of PC (P = 0.5) or AD calves (P = 0.96), implying commingling did not affect health. Calves in 25 PC were 3.39 times more likely to get BRD than those in the 100 PC (P < 0.001). Furthermore, 25 PC calves gained the most (1.08 kg/d), followed by 50 PC (0.62 kg/d) and 75 PC (0.61 kg/d), compared to 100 PC (P < 0.05). Calf weight at arrival modified ADG (P < 0.05). Discussion: In conclusion, PC calves had lower morbidity over the first 40 days, irrespective of commingling. With larger variations in arrival weight, there was no advantage of PC for ADG in the first 40 days. The unknown weaning strategies and comparable arrival weights of AD calves may have contributed to greater ADG in AD calves.

Arabidopsis monothiol glutaredoxin, AtGRXS17, is critical for temperature-dependent postembryonic growth and development via modulating auxin response.

Global environmental temperature changes threaten innumerable plant species. Although various signaling networks regulate plant responses to temperature fluctuations, the mechanisms unifying these diverse processes are largely unknown. Here, we demonstrate that an Arabidopsis monothiol glutaredoxin, AtGRXS17 (At4g04950), plays a critical role in redox homeostasis and hormone perception to mediate temperature-dependent postembryonic growth. AtGRXS17 expression was induced by elevated temperatures. Lines altered in AtGRXS17 expression were hypersensitive to elevated temperatures and phenocopied mutants altered in the perception of the phytohormone auxin. We show that auxin sensitivity and polar auxin transport were perturbed in these mutants, whereas auxin biosynthesis was not altered. In addition, atgrxs17 plants displayed phenotypes consistent with defects in proliferation and/or cell cycle control while accumulating higher levels of reactive oxygen species and cellular membrane damage under high temperature. Together, our findings provide a nexus between reactive oxygen species homeostasis, auxin signaling, and temperature responses.

Postoperative complication rates in the "super-obese" hip and knee arthroplasty population.

The effect of obesity on the outcomes of total joint arthroplasties is an ongoing concern. As obesity becomes more endemic, new categories emerge, such as the "super-obese." We conducted a retrospective study to determine the difference in outcomes among the super-obese. When categorized according to body mass index (BMI), the overall rate of complications was higher for patients with BMI of 45 or higher. Super-obese patients had an odds ratio (OR) of 8.44 for developing inhospital complications. Most importantly, each incremental 5-U increase in BMI above 45 was associated with an increased risk of inhospital (OR, 1.69) and outpatient complications (OR, 2.71), and readmission (OR, 2.0), compared with patients with BMI of 45 to 50. Length of stay was increased by 13.8% for each 5-U increase in BMI above 45. There is a significant increased risk for complications in the super-obese population, and this continues to increase with BMI increases above 45. These data are important when counseling super-obese patients and should be accounted for in reporting quality outcome measures in this population.

Parallel Single-Cell Multiomics Analysis of Neonatal Skin Reveals the Transitional Fibroblast States that Restrict Differentiation into Distinct Fates.

One of the keys to achieving skin regeneration lies within understanding the heterogeneity of neonatal fibroblasts, which support skin regeneration. However, the molecular underpinnings regulating the cellular states and fates of these cells are not fully understood. To investigate this, we performed a parallel multiomics analysis by processing neonatal murine skin for single-cell Assay for Transposase-Accessible Chromatin sequencing and single-cell RNA sequencing separately. Our approach revealed that fibroblast clusters could be sorted into papillary and reticular lineages on the basis of transcriptome profiling, as previously reported. However, single-cell Assay for Transposase-Accessible Chromatin sequencing analysis of neonatal fibroblast lineage markers, such as Dpp4/Cd26, Corin, and Dlk1 along with markers of myofibroblasts, revealed accessible chromatin in all fibroblast populations despite their lineage-specific transcriptome profiles. These results suggest that accessible chromatin does not always translate to gene expression and that many fibroblast lineage markers reflect a fibroblast state, which includes neonatal papillary fibroblasts, reticular fibroblasts, and myofibroblasts. This analysis also provides a possible explanation as to why these marker genes can be promiscuously expressed in different fibroblast populations under different conditions. Our single-cell Assay for Transposase-Accessible Chromatin sequencing analysis also revealed that the functional lineage restriction between dermal papilla and adipocyte fates is regulated by distinct chromatin landscapes. Finally, we have developed a webtool for our multiomics analysis: https://skinregeneration.org/scatacseq-and-scrnaseq-data-from-thompson-et-al-2021-2/.

A Quality Improvement Initiative to Decrease Time to Analgesia in Patients With Sickle Cell and Vaso-Occlusive Crisis: A Population With Disparities in Treatment.

INTRODUCTION: Vaso-occlusive crises (VOCs) are the leading cause of emergency department (ED) visits and hospitalizations in patients with sickle cell disease (SCD). Timely administration of analgesia, within 60 minutes of patient registration, is the standard of care for SCD patients with VOCs. Patients with VOCs have longer times to initial analgesia compared to similar painful conditions. The primary aim of the project is to have 75% of patients with VOCs receive initial analgesia within 60 minutes of being registered, the current recommended time frame from the National Heart, Lung, and Blood Institute (NHLBI). METHODS: A multi-disciplinary team used quality improvement (QI) methodology to develop a plan involving multiple Plan-Do-Study-Act (PDSA) cycles. A rapid evaluation process was employed which included notification of a patient with a VOC being placed in a room, rapid evaluation by all team members and use of an electronic order set. RESULTS: The aim was met 72% of the time during our intervention period, compared to 17% pre-intervention. Average time to initial analgesia was decreased from 61 minutes to 42 minutes (p-value < 0.001), while time to disposition was also decreased when time goals were achieved. CONCLUSION: Using a rapid evaluation process we were able to decrease time to initial analgesia in a patient population that has previously experienced delays in care and decrease overall time to disposition.

Improved Perceptions of Education and Wellness Among General Surgery Residents and Faculty After the Implementation of Outpatient Scribes.

BACKGROUND: Recent studies have revealed a high rate of burnout among general surgery (GS) residents. Efforts to design and implement interventions to mitigate fatigue in surgical trainees are critical. Our aim was to assess the educational and wellness impact of outpatient scribe utilization at an academic GS residency program. METHODS: Electronic surveys were sent to 38 GS residents and 15 faculties who used outpatient scribes for at least 12 months. Questions were scored on a 5-point Likert scale with answers of "Strongly agree" or "Agree" representing affirmative responses. RESULTS: Thirty residents and 14 faculty completed the survey, resulting in an 83% overall response rate. Twenty-eight (93%) residents and 12 (86%) faculty believed that scribes decrease the daily workload of trainees. Twenty-seven (90%) residents felt that scribes allow them more time to focus on patient care and improve the quality of their surgical education. Ninety-three percent of residents (n = 28) and faculty (n = 13) believed that scribes enhance resident well-being. Twenty-four (80%) residents reported that scribes help improve adherence to duty hour restrictions. Twenty-five (83%) residents believed that utilizing scribes is an effective fatigue mitigation strategy for surgical training programs. CONCLUSION: Our findings demonstrate that the implementation of an outpatient scribe program at an academic GS residency program may enhance resident education and wellness.

Pulmonary Arteriovenous Malformation in a Patient with Suspected Hereditary Hemorrhagic Telangiectasia: A Case Report.

Hemoptysis is a common presenting symptom of hereditary hemorrhagic telangiectasia (HHT), an often overlooked diagnosis in the emergency setting. Patient history often includes telangiectasias, epistaxis, visceral lesions, and a family history of similar findings. Here, we review a case of HHT in a young woman, presenting initially with hemoptysis. Imaging was significant for large left upper lobe arteriovenous malformation (AVM), requiring patient admission and interventional radiology embolization of the AVM. The purpose of this report is to highlight a diagnosis that is important not to miss in the emergency department. Topics: Pulmonary arteriovenous malformation, hereditary hemorrhagic telangiectasia, Osler-Weber-Rendu syndrome.

Evaluating Applicant Perceptions of the Impact of Social Media on the 2020-2021 Residency Application Cycle Occurring During the COVID-19 Pandemic: Survey Study.

BACKGROUND: Due to challenges related to the COVID-19 pandemic, residency programs in the United States conducted virtual interviews during the 2020-2021 application season. As a result, programs and applicants may have relied more heavily on social media-based communication and dissemination of information. OBJECTIVE: We sought to determine social media's impact on residency applicants during an entirely virtual application cycle. METHODS: An anonymous electronic survey was distributed to 465 eligible 2021 Match applicants at 4 University of California Schools of Medicine in the United States. RESULTS: A total of 72 participants (15.5% of eligible respondents), applying to 16 specialties, responded. Of those who responded, 53% (n=38) reported following prospective residency accounts on social media, and 89% (n=34) of those respondents were positively or negatively influenced by these accounts. The top three digital methods by which applicants sought information about residency programs included the program website, digital conversations with residents and fellows of that program, and Instagram. Among respondents, 53% (n=38) attended virtual information sessions for prospective programs. A minority of applicants (n=19, 26%) adjusted the number of programs they applied to based on information found on social media, with most (n=14, 74%) increasing the number of programs to which they applied. Survey respondents ranked social media's effectiveness in allowing applicants to learn about programs at 6.7 (SD 2.1) on a visual analogue scale from 1-10. Most applicants (n=61, 86%) felt that programs should use social media in future application cycles even if they are nonvirtual. CONCLUSIONS: Social media appears to be an important tool for resident recruitment. Future studies should seek more information on its effect on later parts of the application cycle and the Match.