ABSTRACT
The choice of developing thymocytes to become CD8+ cytotoxic or CD4+ helper T cells has been intensely studied, but many of the underlying mechanisms remain to be elucidated. Recent multiomics approaches have provided much higher resolution analysis of gene expression in developing thymocytes than was previously achievable, thereby offering a fresh perspective on this question. Focusing on our recent studies using CITE-seq (cellular indexing of transcriptomes and epitopes) analyses of mouse thymocytes, we present a detailed timeline of RNA and protein expression changes during CD8 versus CD4 T cell differentiation. We also revisit our current understanding of the links between T cell receptor signaling and expression of the lineage-defining transcription factors ThPOK and RUNX3. Finally, we propose a sequential selection model to explain the tight linkage between MHC-I versus MHC-II recognition and T cell lineage choice. This model incorporates key aspects of previously proposed kinetic signaling, instructive, and stochastic/selection models.
Subject(s)
CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Cell Differentiation , Cell Lineage , Animals , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Humans , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Receptors, Antigen, T-Cell/metabolism , Signal Transduction , Core Binding Factor Alpha 3 Subunit/metabolism , Core Binding Factor Alpha 3 Subunit/genetics , Mice , Transcription Factors/metabolism , Transcriptome , MultiomicsABSTRACT
The development of CD4+ T cells and CD8+ T cells in the thymus is critical to adaptive immunity and is widely studied as a model of lineage commitment. Recognition of self-peptide major histocompatibility complex (MHC) class I or II by the T cell antigen receptor (TCR) determines the CD8+ or CD4+ T cell lineage choice, respectively, but how distinct TCR signals drive transcriptional programs of lineage commitment remains largely unknown. Here we applied CITE-seq to measure RNA and surface proteins in thymocytes from wild-type and T cell lineage-restricted mice to generate a comprehensive timeline of cell states for each T cell lineage. These analyses identified a sequential process whereby all thymocytes initiate CD4+ T cell lineage differentiation during a first wave of TCR signaling, followed by a second TCR signaling wave that coincides with CD8+ T cell lineage specification. CITE-seq and pharmaceutical inhibition experiments implicated a TCR-calcineurin-NFAT-GATA3 axis in driving the CD4+ T cell fate. Our data provide a resource for understanding cell fate decisions and implicate a sequential selection process in guiding lineage choice.
Subject(s)
CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Mice , Animals , Cell Lineage , Thymocytes , Multiomics , Mice, Transgenic , Cell Differentiation , Receptors, Antigen, T-Cell/metabolism , Thymus Gland , Histocompatibility Antigens Class I , CD4 AntigensABSTRACT
Oxygen is critical for a multitude of metabolic processes that are essential for human life. Biological processes can be identified by treating cells with 18O2 or other isotopically labelled gases and systematically identifying biomolecules incorporating labeled atoms. Here we labelled cell lines of distinct tissue origins with 18O2 to identify the polar oxy-metabolome, defined as polar metabolites labelled with 18O under different physiological O2 tensions. The most highly 18O-labelled feature was 4-hydroxymandelate (4-HMA). We demonstrate that 4-HMA is produced by hydroxyphenylpyruvate dioxygenase-like (HPDL), a protein of previously unknown function in human cells. We identify 4-HMA as an intermediate involved in the biosynthesis of the coenzyme Q10 (CoQ10) headgroup in human cells. The connection of HPDL to CoQ10 biosynthesis provides crucial insights into the mechanisms underlying recently described neurological diseases related to HPDL deficiencies1-4 and cancers with HPDL overexpression5.
Subject(s)
4-Hydroxyphenylpyruvate Dioxygenase/metabolism , Mandelic Acids/metabolism , Metabolome , Ubiquinone/analogs & derivatives , Animals , Cell Line , Female , Humans , Mandelic Acids/analysis , Mice , Mice, Nude , Tyrosine/metabolism , Ubiquinone/biosynthesisABSTRACT
AIM: The "2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease" provides recommendations to guide clinicians in the treatment of patients with lower extremity peripheral artery disease across its multiple clinical presentation subsets (ie, asymptomatic, chronic symptomatic, chronic limb-threatening ischemia, and acute limb ischemia). METHODS: A comprehensive literature search was conducted from October 2020 to June 2022, encompassing studies, reviews, and other evidence conducted on human subjects that was published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through May 2023 during the peer review process, were also considered by the writing committee and added to the evidence tables where appropriate. STRUCTURE: Recommendations from the "2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with peripheral artery disease have been developed.
Subject(s)
American Heart Association , Lower Extremity , Peripheral Arterial Disease , Humans , Peripheral Arterial Disease/therapy , Peripheral Arterial Disease/diagnosis , Lower Extremity/blood supply , United States , Cardiology/standardsABSTRACT
Development entails patterned emergence of diverse cell types within the embryo. In mammals, cells positioned inside the embryo give rise to the inner cell mass (ICM), which eventually forms the embryo itself. Yet, the molecular basis of how these cells recognise their 'inside' position to instruct their fate is unknown. Here, we show that provision of extracellular matrix (ECM) to isolated embryonic cells induces ICM specification and alters the subsequent spatial arrangement between epiblast (EPI) and primitive endoderm (PrE) cells that emerge within the ICM. Notably, this effect is dependent on integrin ß1 activity and involves apical-to-basal conversion of cell polarity. We demonstrate that ECM-integrin activity is sufficient for 'inside' positional signalling and is required for correct EPI/PrE patterning. Thus, our findings highlight the significance of ECM-integrin adhesion in enabling position sensing by cells to achieve tissue patterning.
Subject(s)
Body Patterning , Ectoderm/metabolism , Endoderm/metabolism , Extracellular Matrix/metabolism , Integrin beta1/metabolism , Signal Transduction , Animals , Cell Differentiation , Cell Polarity , Cells, Cultured , Ectoderm/cytology , Endoderm/cytology , Mice , Mice, Inbred C57BL , Mouse Embryonic Stem Cells/cytology , Mouse Embryonic Stem Cells/metabolismABSTRACT
L-3,4-dihydroxyphenylalanine (L-DOPA) is the main treatment for Parkinson's disease (PD) but with long term administration, motor complications such as dyskinesia are induced. Glycine transporter 1 (GlyT1) inhibition was shown to produce an anti-dyskinetic effect in parkinsonian rats and primates, coupled with an improvement in the anti-parkinsonian action of L-DOPA. The expression of GlyT1 in the brain in the dyskinetic state remains to be investigated. Here, we quantified the levels of GlyT1 across different brain regions using [3H]-NFPS in the presence of Org-25,935. Brain sections were chosen from sham-lesioned rats, L-DOPA-naïve 6-hydroxydopamine (6-OHDA)-lesioned rats and 6-OHDA-lesioned rats exhibiting mild or severe abnormal involuntary movements (AIMs). [3H]-NFPS binding decreased in the ipsilateral and contralateral thalamus, by 28% and 41%, in 6-OHDA-lesioned rats with severe AIMs compared to sham-lesioned animals (P < 0.01 and 0.001). [3H]-NFPS binding increased by 21% in the ipsilateral substantia nigra of 6-OHDA-lesioned rats with severe AIMs compared to 6-OHDA-lesioned rats with mild AIMs (P < 0.05). [3H]-NFPS binding was lower by 19% in the contralateral primary motor cortex and by 20% in the contralateral subthalamic nucleus of 6-OHDA-lesioned rats with mild AIMs animals compared to rats with severe AIMs (both P < 0.05). The severity of AIMs scores positively correlated with [3H]-NFPS binding in the ipsilateral substantia nigra (P < 0.05), ipsilateral entopeduncular nucleus (P < 0.05) and contralateral primary motor cortex (P < 0.05). These data provide an anatomical basis to explain the efficacy of GlyT1 inhibitors in dyskinesia in PD.
Subject(s)
Brain , Glycine Plasma Membrane Transport Proteins , Oxidopamine , Sarcosine/analogs & derivatives , Animals , Glycine Plasma Membrane Transport Proteins/metabolism , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Rats , Male , Oxidopamine/pharmacology , Brain/metabolism , Brain/drug effects , Parkinsonian Disorders/metabolism , Rats, Sprague-Dawley , Disease Models, Animal , Tritium , Functional Laterality/physiologyABSTRACT
INTRODUCTION: Spontaneous coronary artery dissection (SCAD) is a nonatherosclerotic cause of myocardial infarction. Migraine headache has been reported to be common among patients with SCAD, but the degree of migraine-related disability has not been quantified. METHODS: Clinical data and headache variables were obtained from the baseline assessment of the prospective, multicenter iSCAD Registry. Migraine-related disability was quantified using the self-reported Migraine Disability Assessment (MIDAS). Demographic, clinical, psychosocial, and medical characteristics from data entry forms were compared between patients with and without migraine. RESULTS: Of the 773 patients with available data, 46% reported previous or current migraines. Those with migraines were more likely to be women (96.9% vs 90.3%, p = 0.0003). The presence of underlying carotid fibromuscular dysplasia was associated with migraine (35% vs 27%, p = 0.0175). There was not a significant association with carotid artery dissection and migraine. Current migraine frequency was less than monthly (58%), monthly (24%), weekly (16%), and daily (3%). Triptan use was reported in 32.5% of patients, and 17.5% used daily migraine prophylactic medications. Using the MIDAS to quantify disability related to migraine, 60.2% reported little or no disability, 14.4% mild, 12.7% moderate, and 12.7% severe. The mean MIDAS score was 9.9 (mild to moderate disability). Patients with SCAD had higher rates of depression and anxiety (28.2% vs 17.7% [p = 0.0004] and 35.3% vs 26.7% [p = 0.0099], respectively). CONCLUSIONS: Migraines are common, frequent, and a source of disability in patients with SCAD. The association between female sex, anxiety, and depression may provide some insight for potential treatment modalities.
Subject(s)
Coronary Vessel Anomalies , Migraine Disorders , Registries , Vascular Diseases , Humans , Female , Male , Migraine Disorders/epidemiology , Migraine Disorders/diagnosis , Middle Aged , Vascular Diseases/epidemiology , Vascular Diseases/congenital , Vascular Diseases/diagnosis , Coronary Vessel Anomalies/epidemiology , Coronary Vessel Anomalies/complications , Coronary Vessel Anomalies/diagnosis , Adult , Prospective Studies , Risk Factors , Disability Evaluation , Aged , Fibromuscular Dysplasia/epidemiology , Fibromuscular Dysplasia/complications , Fibromuscular Dysplasia/diagnosis , Fibromuscular Dysplasia/diagnostic imaging , Depression/epidemiology , Depression/diagnosisABSTRACT
OBJECTIVES: Data driven strategies for acute pancreatitis (AP) in pediatrics are limited; adult data suggests lactated ringers (LR) compared to normal saline (NS) resulted in favorable outcomes, but has not been studied in pediatrics. Our objective was to evaluate the efficacy of LR during the first 48 h of an AP episode compared with NS. STUDY DESIGN: A multisite randomized controlled clinical trial, from 2015 to 2020 (Clinical Trials.gov NCT03242473). Patients were randomized to exclusively LR or NS for the first 48 h. Primary outcomes were serial C-reactive protein (CRP) values. Secondary outcomes included other lab values, time to feeds, length of stay (LOS), systemic inflammatory response syndrome (SIRS) development, and progression to severe AP (SAP). RESULTS: We studied 76 patients (38 LR, 38 NS). CRP at 24 and 48 h were not significantly different between LR or NS group. Additionally, there were no differences in trends of BUN, amylase, lipase, SIRS status, or SAP development between the LR and NS group at 24 and 48 h. A higher proportion of LR patients (32%, 12/38) were discharged before 48 h compared to NS (13%, 5/38). The LR group had a significantly higher rate of discharge within the first 72 h compared to the NS group (p = 0.02). CONCLUSION: The use of LR was associated with a faster rate of discharge during the intervention period and in the first 72 h, but no other differences compared to NS. This reduction in length of hospitalization has significant implications for patients and healthcare costs.
Subject(s)
Fluid Therapy , Pancreatitis , Patient Discharge , Child , Humans , Acute Disease , Fluid Therapy/methods , Pancreatitis/therapy , Ringer's Lactate/therapeutic use , Saline Solution/therapeutic use , Systemic Inflammatory Response Syndrome/therapyABSTRACT
PURPOSE: The use of visuals to inquire about gender in the clinical setting has been rare. We developed a survey that included a visual spectrum to assess perceptions about the most and least inclusive ways of inquiring about gender in patients with gender dysphoria. METHODS: The survey included a multiple-choice question (MCQ), free-response question, and a visual spectrum on which respondents were asked to select one box that best depicts their gender. The survey was administered to all patients diagnosed with gender dysphoria at our institution between April and June 2022. RESULTS: A total of 223 of 856 patients responded. Those with more masculine gender identities selected boxes near the visual spectrum corner of "man," whereas responses were more variable for more feminine genders. The free-response question was identified by 59% of respondents as the most inclusive. The MCQ was identified as least inclusive by 70.4%. The visual spectrum was considered the most inclusive method by the majority of patients who self-identified as woman and demiwoman/demifemale. Being asked about pronouns was extremely or very important in the health care setting for 52% of respondents, but 68.6% indicated that they are rarely or sometimes asked about their pronouns in this setting. CONCLUSIONS: The traditional MCQ format for self-identifying gender may be lacking in inclusivity and fails to represent the nuances of gender identity. Free response was considered the most inclusive way to inquire about gender among our respondents. These findings highlight the importance of formatting gender identity questionnaires to foster inclusivity for transgender patients.
Subject(s)
Gender Dysphoria , Gender Identity , Humans , Male , Female , Gender Dysphoria/psychology , Surveys and Questionnaires , Adult , Middle Aged , Transgender Persons/psychologyABSTRACT
PURPOSE: The benefits of paraspinous flaps in adult complex spine surgery patients are established in the literature; however, their use in pediatric patients has not been well described. This study compares clinical outcomes with and without paraspinous muscle flap closure in pediatric patients who have undergone spine surgery. METHODS: We conducted a retrospective review of all pediatric spine surgeries at the University of California, San Francisco from 2011 to 2022. Patients were divided into 2 cohorts based on whether the plastic surgery service closed or did not close the wound with paraspinous muscle flaps. We matched patients by age, American Society of Anesthesiology classification, prior spinal surgical history, and diagnosis. Surgical outcomes were compared between the 2 cohorts. RESULTS: We identified 226 pediatric patients who underwent at least one spinal surgery, 14 of whom received paraspinous flap closure by plastic surgery. They were matched in a 1:4 ratio with controls (n = 56) that did not have plastic surgery closure. The most common indication for plastic surgery involvement was perceived complexity of disease by the spine surgeon with concern for inadequate healthy tissue coverage (78.6%), followed by infection (21.4%). Postoperative complications were similar between the two groups. The plastic surgery cohort had a higher rate of patients who were underweight (57.1% vs 14.3%, P < 0.01) and had positive preoperative wound cultures (28.6% vs 8.9%, P = 0.05), as well as a higher rate of postoperative antibiotic usage (78.6 vs 17.9%, P < 0.01). There was no difference in recorded postoperative outcomes. CONCLUSIONS: Spine surgeons requested paraspinous flap closure for patients with more complex disease, preoperative infections, history of chemotherapy, or if they were underweight. Patients with paraspinous flap coverage did not have increased postoperative complications despite their elevated risk profile. Our findings suggest that paraspinous muscle flaps should be considered in high-risk pediatric patients who undergo spine surgery.
Subject(s)
Paraspinal Muscles , Plastic Surgery Procedures , Surgical Flaps , Humans , Retrospective Studies , Female , Male , Child , Adolescent , Plastic Surgery Procedures/methods , Surgical Flaps/transplantation , Child, Preschool , Postoperative Complications/epidemiology , Treatment Outcome , Spinal Diseases/surgeryABSTRACT
BACKGROUND/IMPORTANCE: Dietary interventions, vitamins, and nutritional supplementation are playing an increasingly important role in the management of neuropathic pain. Current pharmacological treatments are poorly tolerated and ineffective in many cases. OBJECTIVE: This systematic review aims to study the efficacy of dietary interventions, vitamins, and nutritional supplementation in the management of chronic neuropathic pain in adults. EVIDENCE REVIEW: The review followed PRISMA guidelines and was registered with PROSPERO (#CRD42022300312). Ten databases and gray literature, including Embase.com, MEDLINE and Web of Science, were systematically searched using a combination of keywords and controlled vocabulary related to chronic neuropathic pain and oral non-pharmacological supplements. Studies on adult humans published between 2000 and 2021 were considered for inclusion. The Cochrane Handbook was used to assess risk of bias, and Grading of Recommendations Assessment, Development, and Evaluation was used to determine overall quality of evidence. FINDINGS: Forty studies were included in the final review, and results were categorized according to pain type including pain related to chemotherapy-induced peripheral neuropathy (CIPN, 22 studies, including 3 prospective cohorts), diabetic peripheral neuropathy (DPN, 13 studies, including 2 prospective), complex regional pain syndrome (CRPS-I, 3 studies, including 1 prospective), and other (2 studies, both RCT). The CIPN studies used various interventions including goshajinkigan (4 studies), vitamin E (5), vitamin B12 (3), glutamine (3), N-acetyl-cysteine (2), acetyl-l-carnitine (2), guilongtonluofang (1), ninjin'yoeito (1), alpha-lipoic acid (1), l-carnosine (1), magnesium and calcium (1), crocin (1), and antioxidants (1), with some studies involving multiple interventions. All CIPN studies involved varying cancers and/or chemotherapies, advising caution for generalizability of results. Interventions for DPN included alpha-lipoic acid (5 studies), vitamin B12 (3), acetyl-l-carnitine (3), vitamin E (1), vitamin D (2), and a low-fat plant-based diet (1). Vitamin C was studied to treat CRPS-I (3 studies, including 1 prospective). Magnesium (1) and St. John's wort (1) were studied for other or mixed neuropathologies. CONCLUSIONS: Based on the review, we cannot recommend any supplement use for the management of CIPN, although further research into N-acetyl-cysteine, l-carnosine, crocin, and magnesium is warranted. Acetyl-l-carnitine was found to be likely ineffective or harmful. Alpha-lipoic acid was not found effective. Studies with goshajinkigan, vitamin B12, vitamin E, and glutamine had conflicting results regarding efficacy, with one goshajinkigan study finding it harmful. Guilongtonluofang, ninjin'yoeito, and antioxidants showed various degrees of potential effectiveness. Regarding DPN, our review supports the use of alpha-lipoic acid, acetyl-l-carnitine, and vitamin D. The early use of vitamin C prophylaxis for the development of CRPS-I also seems promising. Further research is warranted to confirm these findings.
Subject(s)
Carnosine , Complex Regional Pain Syndromes , Neuralgia , Thioctic Acid , Humans , Adult , Acetylcarnitine/therapeutic use , Magnesium/therapeutic use , Thioctic Acid/therapeutic use , Carnosine/therapeutic use , Glutamine/therapeutic use , Cysteine/therapeutic use , Prospective Studies , Dietary Supplements , Vitamins/therapeutic use , Neuralgia/drug therapy , Vitamin E/therapeutic use , Ascorbic Acid/therapeutic use , Diet , Antioxidants/therapeutic use , Vitamin B 12 , Vitamin D/therapeutic useABSTRACT
The reform of derogatory access authorisations (DAs) on 1st July 2021 has distorted the routine of the hospital pharmacists dealing with innovative medicines that are waiting for marketing authorization or approval. There are two distinct categories of DAs: Compassionate Access Authorisations (CAAs) are granted by the French National Agency for the Safety of Medicines (ANSM) while Early Access Authorisations (EAPs) are granted at the request of pharmaceutical companies by the French National Authority for Health (HAS). All AAPs and a majority of the AACs are supported by a Protocol for Therapeutic Use and Data Collection (PTU-DC). The aim of this study is to assess the impact of the reform on pharmacy process one year following its implementation, and to identify the risks related to the new circuits. The working group, composed of three pharmacists carried out an initial assessment of the effects first measured the impact of the reform on medicine processes in DAs. They performed a comparison of the changes in their management methods: 3 months prior to the reform (M0), and 3 (M3) and 12 months (M12) post-reform. Risks analysis was conducted using the Failure Modes, Effects and Criticality Analysis (FMEA) method. The analysis was limited to the process steps specific related to DAs drugs were analyzed. The critical severity of the risk situations identified was rated. A critical hierarchy matrix was used to establish priority actions. The priority actions to be taken were determined using the critical hierarchy matrix. Over the span of one year, the number of DAs in our establishment showed a 31.7% increase, from 41 at M0 to 54 at M12. At M0, the proportion of drugs needed inclusion via a drug-specific digital platform, specific to each drug, stood at 27% (11/41) of drugs at M0 while at M12, it rose to 52% (28/54). The percentage of PTU-DCs therefore increased by a factor of 1.7, rising from 29% (12/41) at M0 to 47% (21/45) at M3 and 60% (32/54) at M12. For orders, which are always nominative, approval depends on both the presence of the PTU-DC tracking sheet being present in 12% of PAAs, and the inclusion number in 26% of PAAs. The risk analysis shows 49 failure modes leading to risk situations. Among the failure modes, 36 have a consequence of acceptable or tolerable criticality under control, whilst 13 are deemed of unacceptable criticality. A suitable control method exists has been identifies for 5 of them. Finally, the ranking evaluation of criticalities has highlighted 4 situations which require immediate action as a priority: delivery times, obtaining completed tracking sheets and ordering procedures. The aim of the DAs reform is to simplify access to innovative medicines. However, the reform has significant and damaging repercussions on pharmaceutical activities. Corrective measures need to be taken in conjunction with all parties involved in the circuits including laboratories and service providers (CROs), authorities and healthcare professionals.
Subject(s)
Pharmacists , Pharmacy Service, Hospital , Workload , France , Humans , Pharmacy Service, Hospital/organization & administration , Risk Assessment , Compassionate Use Trials , Drug ApprovalABSTRACT
Primary progressive aphasia (PPA) and primary progressive apraxia of speech (PPAOS) are neurodegenerative syndromes characterized by progressive decline in language or speech. There is a growing number of studies investigating speech-language interventions for PPA/PPAOS. An updated systematic evaluation of the treatment evidence is warranted to inform best clinical practice and guide future treatment research. We systematically reviewed the evidence for behavioral treatment for speech and language in this population. Reviewed articles were published in peer-reviewed journals through 31 May 2021. We evaluated level of evidence, reporting quality, and risk of bias using a modified version of the American Speech-Language Hearing Association (ASHA) Levels of Evidence, an appraisal point system, additional reporting quality and internal/external validity items, and, as appropriate, the Single Case Experimental Design Scale or the Physiotherapy Evidence Database - PsycBITE Rating Scale for Randomized and Non-Randomized Controlled Trials. Results were synthesized using quantitative summaries and narrative review. A total of 103 studies reported treatment outcomes for 626 individuals with PPA; no studies used the diagnostic label PPAOS. Most studies evaluated interventions for word retrieval. The highest-quality evidence was provided by 45 experimental and quasi-experimental studies (16 controlled group studies, 29 single-subject designs). All (k = 45/45) reported improvement on a primary outcome measure; most reported generalization (k = 34/43), maintenance (k = 34/39), or social validity (k = 17/19) of treatment for at least one participant. The available evidence supports speech-language intervention for persons with PPA; however, treatment for PPAOS awaits systematic investigation. Implications and limitations of the evidence and the review are discussed.
ABSTRACT
Multifocal fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection are both sex-biased diseases disproportionately affecting women over men in a 9:1 ratio. Traditionally known in the context of renovascular hypertension, recent advances in knowledge about FMD have demonstrated that FMD is a systemic arteriopathy presenting as arterial stenosis, aneurysm, and dissection in virtually any arterial bed. FMD is also characterized by major cardiovascular presentations including hypertension, stroke, and myocardial infarction. Similar to FMD, spontaneous coronary artery dissection is associated with a high prevalence of extracoronary vascular abnormalities, including FMD, aneurysm, and extracoronary dissection, and recent studies have also found genetic associations between the two diseases. This review will summarize the relationship between FMD and spontaneous coronary artery dissection with a focus on common clinical associations, histopathologic mechanisms, genetic susceptibilities, and the biology of these diseases. The current status of disease models and critical future research directions will also be addressed.
Subject(s)
Coronary Vessel Anomalies , Fibromuscular Dysplasia , Sex Factors , Vascular Diseases/congenital , Aneurysm/etiology , Aortic Dissection/etiology , Angiography , Constriction, Pathologic/etiology , Coronary Vessel Anomalies/diagnostic imaging , Coronary Vessel Anomalies/epidemiology , Coronary Vessel Anomalies/genetics , Coronary Vessel Anomalies/pathology , Female , Fibromuscular Dysplasia/diagnostic imaging , Fibromuscular Dysplasia/epidemiology , Fibromuscular Dysplasia/genetics , Fibromuscular Dysplasia/pathology , Genetic Predisposition to Disease , Genetic Variation , Humans , Hypertension/etiology , Male , Myocardial Infarction/etiology , Stroke/etiology , Vascular Diseases/diagnostic imaging , Vascular Diseases/epidemiology , Vascular Diseases/genetics , Vascular Diseases/pathologyABSTRACT
Regulatory T cells (Tregs) reside in nonlymphoid tissues where they carry out unique functions. The molecular mechanisms responsible for Treg accumulation and maintenance in these tissues are relatively unknown. Using an unbiased discovery approach, we identified LAYN (layilin), a C-type lectin-like receptor, to be preferentially and highly expressed on a subset of activated Tregs in healthy and diseased human skin. Expression of layilin on Tregs was induced by TCR-mediated activation in the presence of IL-2 or TGF-ß. Mice with a conditional deletion of layilin in Tregs had reduced accumulation of these cells in tumors. However, these animals somewhat paradoxically had enhanced immune regulation in the tumor microenvironment, resulting in increased tumor growth. Mechanistically, layilin expression on Tregs had a minimal effect on their activation and suppressive capacity in vitro. However, expression of this molecule resulted in a cumulative anchoring effect on Treg dynamic motility in vivo. Taken together, our results suggest a model whereby layilin facilitates Treg adhesion in skin and, in doing so, limits their suppressive capacity. These findings uncover a unique mechanism whereby reduced Treg motility acts to limit immune regulation in nonlymphoid organs and may help guide strategies to exploit this phenomenon for therapeutic benefit.
Subject(s)
Carrier Proteins/metabolism , Membrane Glycoproteins/metabolism , Receptors, Lymphocyte Homing/metabolism , Skin/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Carrier Proteins/genetics , Cell Movement , Cells, Cultured , Humans , Immune Tolerance , Lymphocyte Activation , Membrane Glycoproteins/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Immunological , Organ Specificity , Receptors, Lymphocyte Homing/genetics , Transforming Growth Factor beta/metabolismABSTRACT
Lacrimal gland cysts are rare clinical entities in the pediatric population. Herein is described a 6-year-old male patient presenting with progressive left upper lid ptosis, found to have a large ipsilateral superotemporal orbital mass. Diagnosis of a giant lacrimal gland cyst was confirmed excisional biopsy. Despite the resolution of mechanical blepharoptosis, the patient maintained visual acuity limitation due to suspected deprivation amblyopia. The pathophysiology and clinical manifestations of lacrimal gland cysts in the pediatric population are reviewed to emphasize the importance of expedited identification and management in this patient cohort.
Subject(s)
Blepharoptosis , Cysts , Eye Neoplasms , Lacrimal Apparatus Diseases , Lacrimal Apparatus , Orbital Diseases , Male , Humans , Child , Lacrimal Apparatus/pathology , Cysts/diagnosis , Blepharoptosis/diagnosis , Orbital Diseases/complications , Lacrimal Apparatus Diseases/diagnosisABSTRACT
BACKGROUND: To continue education during the COVID-19 pandemic, we implemented a Virtual Education Platform (VEP) and Virtual Visiting Professorship (VVP) in March 2020 into our plastic surgery residency curriculum. This study investigated resident and guest speaker perceptions of the VEP since the start of the pandemic. METHODS: The VEP consists of weekly VVP lectures and usual conferences held over Zoom. In May 2020, residents and speakers completed surveys that assessed the perceptions of the VEP using a 5-point Likert scale and open-ended responses. In August 2021, residents also completed follow-up surveys. RESULTS: A total of 19 (100%) residents and 10 (100%) speakers responded to the 2020 surveys and 15 (88.2%) residents responded to the 2021 follow-up survey. Speakers represented nine academic institutions, one international. 74% of residents responded that they learned a lot or a great deal from the VVP. In 2021, 100% of residents agreed that virtual conferences should remain a core component in PRS residency education, even after social distancing requirements subside. The VVP lectures were mentioned as the most helpful lectures in both years. Easy accessibility without travel time was the most mentioned advantage of the VEP in both years, with significantly more residents citing this benefit in 2021 (p = 0.0076). The most reported disadvantage for residents was the lack of social interaction and community in both years, with significantly more residents in 2021 citing this as a disadvantage (p = 0.0307). Residents' attitudes also shifted such that significantly more residents liked and were satisfied with the VVP lectures from 2020 to 2021 (p = 0.04). CONCLUSION: Over a year into the COVID-19 pandemic, resident perceptions of a virtual education platform and virtual visiting professorship were very positive. The quick development, implementation, and high efficacy of these educational experiences underscore that learning is possible in alternative forms in unprecedented times.
Subject(s)
COVID-19 , Surgery, Plastic , Humans , Pandemics , COVID-19/epidemiology , Schools , Educational StatusABSTRACT
AIM: The aim of this study is to explore experiences and perspectives of nurses and providers (e.g., physicians, medical directors, fellows, and nurse practitioners) on reducing preventable hospitalizations of nursing home (NH) residents in relation to interprofessional relationship and hospitalization decision-making process. BACKGROUND: Preventable NH resident hospitalization continues to be a pressing public health issue. Studies show that improved interprofessional relationship may help reduce hospitalization, yet research on communication processes and interactions among different NH staff remains limited. METHODS: This is a qualitative descriptive study. Two focus groups were held with fourteen nurses and thirteen in-depth, qualitative interviews were conducted with providers from two Chicagoland NHs. Focus group sessions and interviews were transcribed, coded, and analyzed for common themes based on qualitative description method. RESULTS: All study participants agreed that providers have the ultimate responsibility for hospitalization decisions. However, nurses believed they could influence those decisions, depending on provider characteristics, trust, and resident conditions. Nurses and providers differed in the way they experienced and conveyed emotions, and differed in key elements affecting hospitalization decisions such as structural or environmental factors (e.g., lacking staff and equipment at the facility, poor communication between the NH and hospitals) and interpersonal factors (e.g., characteristics of effective nurses or providers and the effective interactions between them). CONCLUSIONS: Interpersonal factors, including perceived competence, respect, and trust, may influence NH hospitalization decisions and be targeted for reducing preventable hospitalizations of residents.
Subject(s)
Nursing Staff , Physicians , Humans , Hospitalization , Nursing Homes , Hospitals , Qualitative ResearchABSTRACT
BACKGROUND: Access to primary care was hindered by the coronavirus disease 2019 (COVID-19) pandemic. OBJECTIVE: Evaluate changes in health screening rates before and during the pandemic. DESIGN: Retrospective analysis of health maintenance and disease management screening rates among primary care patients before and during the pandemic. PARTICIPANTS: Over 150,000 patients of a large, academic health system. MAIN MEASURES: Six quality measures were analyzed: colon cancer, breast cancer, cervical cancer, diabetes Hgb A1C, diabetes eye, and diabetes nephropathy monitoring. Based on US Preventative Services Task Force screening guidelines, we determined which patients were due for at least one of the quality measures. We tracked completion rates during three time periods: pre-pandemic (January 1-March 3, 2020), stay-at-home (March 4-May 8, 2020), and phased reopening (May 9-July 8, 2020). Differences in quality measure completion rates were evaluated using mixed-effects logistic regression models. KEY RESULTS: Compared to pre-pandemic rates, completion of all health screenings declined during the stay-at-home period: mammograms (OR: 0.34; 95% CI: 0.31-0.37), cervical cancer (OR: 0.83; 95% CI: 0.76-0.91), colorectal cancer (OR: 0.25; 95% CI: 0.23-0.28), diabetes eye (OR: 0.34; 95% CI: 0.29-0.41), diabetes Hgb A1c (OR: 0.41; 95% CI: 0.37-0.46), and diabetes nephropathy (OR: 0.46, 95% CI: 0.41-0.53). During phased reopening, completion of all quality measures increased compared to the stay-at-home period, except for cervical cancer screening (OR: 0.83; 95% CI: 0.76-0.92). There was a persistent reduction in completion of all quality measures, except for diabetic nephropathy monitoring (OR: 0.99; 95% CI: 0.89-1.09), during phased reopening compared to pre-pandemic. CONCLUSIONS: Healthcare screening rates were reduced during the early part of the COVID-19 pandemic and did not fully recover to pre-pandemic rates by July 2020. Future research should aim to clarify the long-term impacts of delayed health screenings. New interventions should be considered for expanding remote preventative health services.
Subject(s)
COVID-19 , Delivery of Health Care, Integrated , Uterine Cervical Neoplasms , COVID-19/epidemiology , Early Detection of Cancer , Female , Humans , Pandemics/prevention & control , Primary Health Care , Quality Indicators, Health Care , Retrospective StudiesABSTRACT
Refugee and immigrant populations are extremely vulnerable to the consequences of the COVID-19 pandemic. COVID-19 vaccination is a critical tool in mitigating these consequences, but these same communities often lack access to COVID-19 vaccines. We describe the efforts of a community-based primary care clinic in Clarkston, Georgia to provide access to COVID-19 vaccines in a culturally sensitive manner to address this health disparity and vaccine hesitancy.