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Heart failure with reduced left ventricular (LV) ejection fraction (HFrEF) is a morbid and life-threatening disease, arising secondary to abnormalities of cardiac structure and function that lead to adverse LV remodeling. Implementation of medical and device therapies results in significant improvements in patient outcomes that are associated with reverse LV remodeling and improved LV ejection fraction. This review provides an overview of the pathobiology of reverse LV remodeling in animal models and in HFrEF patients. We emphasize the differences between myocardial recovery and remission as well as the fragile nature of maintaining a state of myocardial remission., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Background: Patients undergoing tonsillectomy/ adenotonsillectomy (T/AT) can experience substantial postoperative pain. The aims of this study are to assess perioperative pain management in high-risk children (children with severe obstructive sleep apnea and other complex medical comorbidities or age younger than 2 years) undergoing T/AT, and the impact on oxygen levels and pain during extended Post-Anesthesia Care Unit (PACU) admission., Methods: A retrospective case series study at a tertiary care children's hospital., Results: There were 278 children enrolled in the study. The Apnea-Hypopnea index and mean oxygen nadir on preoperative polysomnography were 31.3 ± 25.76/h and 79.5 ± 9.5 % respectively. Overall, 246 (89 %) patients received intraoperative opioids alone (n = 35, 13 %) or in combination with non-opioid analgesia (n = 209, 75 %). While the median dose of opioid-free medications (acetaminophen, ibuprofen) ranged from 93 to 100 % of standard maximal dosing by weight and age, the median dose of opioids was significantly lower and ranged from 54 to 63 % of standard maximal dosing by weight and age, with 43 % of the patients receiving less than half the recommended maximum dose. Oxygen desaturation was charted in 21 patients (8 %) during their PACU admission. Patients who received opioid-free analgesia were as likely to develop oxygen desaturations (n = 17 (81 %) vs. n = 228 (89.4 %), p = 0.27) and to receive rescue pain medication during their PACU stay as patients who received opioids intraoperatively (n = 18 (56 %) vs. n = 167 (68 %), p = 0.23)., Conclusions: Intraoperative pain management varies across high-risk pediatric tonsillectomies. Opioid-free analgesia was not associated with an increased need for pain medications during PACU admission, or with a decreased likelihood of oxygen desaturations compared to intra-operative opioid analgesia use., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest and that this study did not receive financial support. All authors have seen and approved the manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To investigate the association of social determinants of health (SDoH) in squamous cell carcinoma of the tongue in the United States and to evaluate the real-world contribution of specific disparities., Study Design: Retrospective cohort study., Setting: United States., Methods: The Centers for Disease Control and Prevention-Social Vulnerability Index (SVI) and National Cancer Institute-Surveillance, Epidemiology, and End Results Program database were used to study 62,103 adult tongue squamous cell carcinoma patients from 1975 to 2017. Regression analysis assessed trends in months of follow-up and survival across social vulnerability and 4 subcategories of social vulnerability., Results: As overall SVI score increases (increased social vulnerability), there is a significant decrease in the average length of follow-up (22.95% decrease from 63.99 to 49.31 months; P < .001) across patients from the lowest and highest social vulnerability groups. As overall SVI score increases, there is a significant decrease in the average months of survival (28.00% decrease from 49.20 to 35.43 months; P < .001). There is also a significantly greater odds ratio (OR = 1.05; P < .001) of advanced cancer staging upon presentation at higher SVI scores. Patients with higher SVI scores have a lower OR (0.93; P < .001) of receiving surgery as their primary treatment when compared to patients with lower SVI scores. Patients with higher SVI scores also have a significantly greater OR (OR = 1.05; P < .001) of receiving chemotherapy as their primary treatment when compared to patients with lower SVI scores., Conclusion: Increased social vulnerability is shown to have a detrimental impact on the treatment and prognosis of patients with squamous cell carcinoma of the tongue., (© 2024 The Authors. Otolaryngology–Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology‐Head and Neck Surgery Foundation.)

This study aims to identify the epidemiology and effects of facial fractures on return to play (RTP) in Major League Soccer (MLS) and the English Premier League (EPL). A total of 39 MLS players and 40 EPL players who sustained facial fractures from 2007 to 2019 were identified. Data on player demographics, the injury, and the impact of their injury on RTP were collected. Elbow-to-head was the most common mechanism of injury (20.3%). The most common fracture involved the nasal bone (48.3%). Most players (90%) RTP the same season. Players who sustained nasal fractures missed significantly fewer games ( p  < 0.001) than those who suffered other craniofacial fractures. Players treated surgically missed significantly more games (3.21 vs. 0.71, p  = 0.006) and days (30.1 vs. 8.70, p  = 0.002) than those managed nonoperatively. Significantly more EPL players who sustained facial fractures wore headgear upon RTP compared to MLS players (82% vs. 56%, p <0 .01). Most professional soccer players who sustain a facial fracture RTP the same season, but their recovery time can vary depending on the type of fracture, injury management, or injury severity. Our findings can help inform future craniofacial injury management as well as guidelines on player safety and fracture prevention., Competing Interests: None declared., (Thieme. All rights reserved.)

Background & Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common complication of obesity with a hallmark feature of hepatic steatosis. Recent data from animal models of MAFLD have demonstrated substantial changes in macrophage composition in the fatty liver. In humans, the relationship between liver macrophage heterogeneity and liver steatosis is less clear., Methods: Liver tissue from 21 participants was collected at time of bariatric surgery and analysed using flow cytometry, immunofluorescence, and H&E microscopy. Single-cell RNA sequencing was also conducted on a subset of samples (n = 3). Intrahepatic triglyceride content was assessed via MRI and tissue histology. Mouse models of hepatic steatosis were used to investigate observations made from human liver tissue., Results: We observed variable degrees of liver steatosis with minimal fibrosis in our participants. Single-cell RNA sequencing revealed four macrophage clusters that exist in the human fatty liver encompassing Kupffer cells and monocyte-derived macrophages (MdMs). The genes expressed in these macrophage subsets were similar to those observed in mouse models of MAFLD. Hepatic CD14 + monocyte/macrophage number correlated with the degree of steatosis. Using mouse models of early liver steatosis, we demonstrate that recruitment of MdMs precedes Kupffer cell loss and liver damage. Electron microscopy of isolated macrophages revealed increased lipid accumulation in MdMs, and ex vivo lipid transfer experiments suggested that MdMs may serve a distinct role in lipid uptake during MAFLD., Conclusions: The human liver in MAFLD contains macrophage subsets that align well with those that appear in mouse models of fatty liver disease. Recruited myeloid cells correlate well with the degree of liver steatosis in humans. MdMs appear to participate in lipid uptake during early stages of MALFD., Impact and Implications: Metabolic dysfunction associated fatty liver disease (MAFLD) is extremely common; however, the early inflammatory responses that occur in human disease are not well understood. In this study, we investigated macrophage heterogeneity in human livers during early MAFLD and demonstrated that similar shifts in macrophage subsets occur in human disease that are similar to those seen in preclinical models. These findings are important as they establish a translational link between mouse and human models of disease, which is important for the development and testing of new therapeutic approaches for MAFLD., Competing Interests: BF is a member of the Scientific Advisory Board and owns stock in Cirius Therapeutics, which is developing an MPC inhibitor for clinical use in treating NASH. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Background: Right heart failure (RHF) is associated with worse clinical outcomes. In addition to hemodynamic perturbations, the syndrome of RHF involves liver congestion and dysfunction. The mechanisms that underlie heart-liver interactions are poorly understood and may involve secreted factors. As a first step to understand the cardiohepatic axis, we sought to elucidate the circulating inflammatory milieu in patients with RHF., Methods: Blood samples were collected from the inferior vena cava and hepatic veins during right heart catheterization from 3 groups of patients: (1) controls with normal cardiac function, (2) patients with heart failure who did not meet all criteria of RHF, and (3) patients who met prespecified criteria for RHF defined by hemodynamic and echocardiographic parameters. We performed a multiplex protein assay to survey levels of several circulating markers and analyzed their association with mortality and the need for a left ventricular assist device or heart transplant. Finally, we leveraged publicly available single-cell RNA sequencing data and performed tissue imaging to evaluate the expression of these factors in the liver., Results: In this study, RHF was associated with elevated levels of a subset of cytokines/chemokines/growth factors compared with controls. In particular, soluble CD163 (cluster of differentiation 163) and CXCL12 (chemokine [C-X-C motif] ligand 12) were higher in RHF and predicted left ventricular assist device/transplant-free survival in an independent validation cohort. Furthermore, single-cell RNA sequencing and immunohistochemistry of human liver biopsies suggest that these factors are expressed by Kupffer cells and may be liver derived., Conclusions: RHF is associated with a distinct circulating inflammatory profile. Soluble CD163 and CXCL12 are novel biomarkers that can prognosticate patient outcomes. Future studies to define how these molecules influence heart failure phenotypes and disease progression may lead to new approaches to the management of patients with RHF., Competing Interests: Disclosures None.

Background: Rhinoplasty osteotomes can be sharpened in various ways: professional sharpening or hand sharpening using whetstones or rotary powered devices. Objective: To compare the effectiveness of sharpening osteotomes using various sharpening methods with that of professional sharpening as measured by a custom edge tester. Materials and Methods: We performed repeated serial osteotome impacts on bovine femoral cortical bone. These dull osteotomes were sharpened using preidentified sharpening techniques. Edge morphology was evaluated. Sharpness was tested using a custom mechanical testing platform. Optimized sharpness was achieved with a whetstone sharpening method wherein the osteotome is flipped after every stroke. Results: Seven distinct sharpening methods were tested for sharpness five times each to determine the optimal sharpening method versus professional sharpening (control). The two sharpening methods, 5 (5.51 ± 0.32) and 6 (5.55 ± 0.32), that used this flipping technique were significantly sharper than other methods. Methods 5 ( p  = 1.0) and 6 ( p  = 1.0) were the only methods that were not significantly different from control. Conclusion: Single stroke with successively alternating surfaces created the sharpest blades that achieved results similar to professional sharpening.

The coronavirus disease 2019 pandemic has led to innovation in the way scientific advancements are disseminated and the structure of physician continuing medical education. With in-person medical conferences and meetings throughout the world impacted by travel restrictions and many geographically confined, virtual teleconferences with exceptional attendance have become an integral part of medical education. Our group has successfully produced >50 virtual educational seminars, including multiple global webinar conferences ranging between 24 and 55 h of continuous lectures each. In this special communication, we discuss some of the challenges we overcame in learning "on the job" and share key elements to successful implementation of long-format virtual teleconference events. We hope our experience will guide future online continuing medical education efforts and assist others in planning their own online initiatives.

Objectives: Assessing the prognostic utility of lymph node status in pediatric rhabdomyosarcoma (RMS) patients and identifying demographic and clinical predictors of positive lymph node status among pediatric rhabdomyosarcoma patients., Study Design: Retrospective cohort study of head and neck RMS in patients with and without positive lymph node metastasis., Methods: National Cancer Database (NCDB) was queried for patients of young (0-11 years) and adolescent (12-21 years) ages with head and neck RMS and confirmed positive or negative lymph node metastasis status. Descriptive analyses, Kaplan-Meier survival analyses, and multivariate logistic regressions were performed on extracted demographic and clinical characteristics., Results: Among 272 head and neck RMS patients, 146 (54%) were found to have positive lymph node metastasis. Alveolar RMS (n = 147, 54%) followed by embryonal RMS (n = 74, 27%) were the most represented histology types. Positive lymph node metastasis conferred significantly decreased survivability (p < 0.001) with a median survival period of 36.42 months compared to negative lymph node metastasis with a period of 53.47 months. Older age showed markedly increased odds (OR-2.02; 95%CI 1.22-3.38) of having lymph node metastasis when controlling for sex, race, insurance status, and Charlson-Comorbidity score. Alveolar histologies showed markedly increased odds of having lymph node metastasis (OR-3.21; 95%CI 1.96-5.31); embryonal histologies showed markedly decreased odds of having lymph node metastasis (OR-0.32; 95%CI 0.18-0.56) CONCLUSIONS: This study highlights the significant prognostic value of lymph node status among pediatric head and neck rhabdomyosarcoma patients while showcasing crucial demographic and pathological predictors of lymph node metastasis in said patients. Use of lymph node status in pediatric head and neck rhabdomyosarcoma will present future steps towards improving its clinical course., (Copyright © 2022. Published by Elsevier B.V.)

In March 2021, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by four families (Aliusviridae, Crepuscuviridae, Myriaviridae, and Natareviridae), three subfamilies (Alpharhabdovirinae, Betarhabdovirinae, and Gammarhabdovirinae), 42 genera, and 200 species. Thirty-nine species were renamed and/or moved and seven species were abolished. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Smoking and human immunodeficiency virus 1 (HIV-1) infection are risk factors for chronic obstructive pulmonary disease (COPD), which is among the most common comorbid conditions in people living with HIV-1. HIV-1 infection leads to persistent expansion of CD8 + T cells, and CD8 + T cell-mediated inflammation has been implicated in COPD pathogenesis. In this study, we investigated the effects of HIV-1 infection and smoking on T-cell dynamics in patients at risk of COPD. BAL fluid, endobronchial brushings, and blood from HIV-1 infected and uninfected nonsmokers and smokers were analyzed by flow cytometry, and lungs were imaged by computed tomography. Chemokines were measured in BAL fluid, and CD8 + T-cell chemotaxis in the presence of cigarette smoke extract was assessed in vitro . HIV-1 infection increased CD8 + T cells in the BAL fluid, but this increase was abrogated by smoking. Smokers had reduced BAL fluid concentrations of the T cell-recruiting chemokines CXCL10 and CCL5, and cigarette smoke extract inhibited CXCL10 and CCL5 production by macrophages and CD8 + T-cell transmigration in vitro . In contrast to the T cells in BAL fluid, CD8 + T cells in endobronchial brushings were increased in HIV-1-infected smokers, which was driven by an accumulation of effector memory T cells in the airway mucosa and an increase in tissue-resident memory T cells. Mucosal CD8 + T-cell numbers inversely correlated with lung aeration, suggesting an association with inflammation and remodeling. HIV-1 infection and smoking lead to retention of CD8 + T cells within the airway mucosa.

Large-scale genetic studies revealed SCN2A as one of the most frequently mutated genes in patients with neurodevelopmental disorders. SCN2A encodes for the voltage-gated sodium channel isoform 1.2 (Na v 1.2) expressed in the neurons of the central nervous system. Homozygous knockout (null) of Scn2a in mice is perinatal lethal, whereas heterozygous knockout of Scn2a (Scn2a +/- ) results in mild behavior abnormalities. The Na v 1.2 expression level in Scn2a +/- mice is reported to be around 50-60% of the wild-type (WT) level, which indicates that a close to 50% reduction of Na v 1.2 expression may not be sufficient to lead to major behavioral phenotypes in mice. To overcome this barrier, we characterized a novel mouse model of severe Scn2a deficiency using a targeted gene-trap knockout (gtKO) strategy. This approach produces viable homozygous mice (Scn2a gtKO/gtKO ) that can survive to adulthood, with about a quarter of Na v 1.2 expression compared to WT mice. Innate behaviors like nesting and mating were profoundly disrupted in Scn2a gtKO/gtKO mice. Notably, Scn2a gtKO/gtKO mice have a significantly decreased center duration compared to WT in the open field test, suggesting anxiety-like behaviors in a novel, open space. These mice also have decreased thermal and cold tolerance. Additionally, Scn2a gtKO/gtKO mice have increased fix-pattern exploration in the novel object exploration test and a slight increase in grooming, indicating a detectable level of repetitive behaviors. They bury little to no marbles and have decreased interaction with novel objects. These Scn2a gene-trap knockout mice thus provide a unique model to study pathophysiology associated with severe Scn2a deficiency., (© 2020 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

CAR (Chimeric Antigen Receptor) T cells have demonstrated clinical success for the treatment of multiple lymphomas and leukaemias, but not for various solid tumours, despite promising data from murine models. Lower effective CAR T-cell delivery rates to human solid tumours compared to haematological malignancies in humans and solid tumours in mice might partially explain these divergent outcomes. We used anatomical and physiological data for human and rodent circulatory systems to calculate the typical perfusion of healthy and tumour tissues, and estimated the upper limits of immune cell delivery rates across different organs, tumour types and species. Estimated maximum delivery rates were up to 10 000-fold greater in mice than humans yet reported CAR T-cell doses are typically only 10-100-fold lower in mice, suggesting that the effective delivery rates of CAR T cells into tumours in clinical trials are far lower than in corresponding mouse models. Estimated delivery rates were found to be consistent with published positron emission tomography data. Results suggest that higher effective human doses may be needed to drive efficacy comparable to mouse solid tumour models, and that lower doses should be tested in mice. We posit that quantitation of species and organ-specific delivery and homing of engineered T cells will be key to unlocking their potential for solid tumours.

Background: Individuals with chronic obstructive pulmonary disease (COPD) often experience high health-care utilization following pulmonary rehabilitation, suggesting suboptimal transitions to home., Objective: To understand the experiences of persons with COPD and health-care professionals regarding transitions from pulmonary rehabilitation to home, including factors impacting these transitions., Design: A descriptive qualitative study., Setting and Participants: Health-care professionals working at, and persons with COPD who attended, an inpatient or outpatient pulmonary rehabilitation programme at one large, urban health-care centre. The centre is located in Ontario, Canada., Main Variable Studied: Experiences of participants with care transitions between pulmonary rehabilitation and home. Semi-structured interviews were audio-recorded, transcribed verbatim, and thematically analysed., Results: Ten patients and eight health-care professionals participated. Four main themes were identified around the overall experiences with pulmonary rehabilitation and transitions to home: (a) pulmonary rehabilitation as a safe environment; (b) pulmonary rehabilitation as a highly structured environment; (c) contrasting perceptions of the role of pulmonary rehabilitation; and (d) dependency on pulmonary rehabilitation programmes. Persons with COPD and health-care professionals identified three key factors that influenced this transition: (a) patients' social support, (b) application of self-management strategies prior to discharge, and (c) patients' physical and mental health., Conclusion: Participants agreed that some patients with COPD experienced suboptimal transitions from pulmonary rehabilitation to home that were characterized by suboptimal self-management. Further research is needed to develop and evaluate interventions to improve transitions. Such interventions should include strategies to elicit long-term behaviour change to assist patients when they return into the community., (© 2019 The Authors Health Expectations published by John Wiley & Sons Ltd.)

Purpose: The purpose of this paper is to illustrate delirium as a possible consequence of the application of symptom-triggered therapy for alcohol withdrawal and to explore alternative treatment modalities. In the management of alcohol withdrawal syndrome, symptom-triggered therapy directs nursing staff to regularly assess patients using standardized instruments, such as the Clinical Institute for Withdrawal Assessment of Alcohol, Revised (CIWA-Ar), and administer benzodiazepines at symptom severity thresholds. Symptom-triggered therapy has been shown to lower total benzodiazepine dosage and treatment duration relative to fixed dosage tapers (Daeppen et al. , 2002). However, CIWA-Ar has important limitations. Because of its reliance on patient reporting, it is inappropriate for nonverbal patients, non-English speakers (in the absence of readily available translators) and patients in confusional states including delirium and psychosis. Importantly, it also relies on the appropriate selection of patients and considering alternate etiologies for signs and symptoms also associated with alcohol withdrawal., Design/methodology/approach: The authors report a case of a 47-year-old male admitted for cardiac arrest because of benzodiazepine and alcohol overdose who developed worsening delirium on CIWA-Ar protocol., Findings: While symptom-triggered therapy through instruments such as the CIWA-Ar protocol has shown to lower total benzodiazepine dosage and treatment duration in patients in alcohol withdrawal, over-reliance on such tools may also lead providers to overlook other causes of delirium., Originality/value: This case illustrates the necessity for providers to consider using other available assessment and treatment options including objective alcohol withdrawal scales, fixed benzodiazepine dosage tapers and even antiepileptic medications in select patients., (© Andrew Chunkil Park, Leigh Goodrich, Bobak Hedayati, Ralph Albert, Kyle Dornhofer and Erin Danielle Knox.)

Purpose: To investigate the influence of abutment material properties on the fracture resistance and failure mode of lithium disilicate (IPS e.max) CAD/CAM (computer-aided design/manufacturing) crowns on traditionally and minimally prepared simulated tooth substrates., Materials and Methods: Thirty lithium disilicate (IPS e.max) CAD/CAM crowns were divided into three groups (n = 10): TD: traditional thickness crowns cemented on Paradigm MZ100 abutments; MD: minimal thickness crowns cemented on Paradigm MZ100 abutments; ME: minimal thickness crowns cemented on e.max abutments. The 3Shape system was used to scan, design and mill all abutments and crowns with a die space set to 40 µm. Traditional thickness crowns were designed based on manufacturer guidelines with 1.5 mm occlusal thickness and 1.0 mm margins. Minimal thickness crowns were designed with 0.7 mm occlusal thickness and 0.5 mm margins. MZ100 composite and e.max abutments were selected to simulate dentin and enamel substrates, respectively, based on their elastic-modulus. Variolink Esthetic was used to cement all samples following manufacturer's instructions. A universal testing machine was used to load all specimens to fracture with a 3 mm radius stainless steel hemispherical tip at a crosshead speed 0.5 mm/minute along the longitudinal axis of the abutment with a 1 mm thermoplastic film placed between the loading tip and crown surface. Data was analyzed using ANOVA and Bonferroni post hoc assessment. Fractographic analysis was performed with scanning electron microscopy (SEM)., Results: The mean fracture load (standard deviation) was 1499 (241) N for TD; 1228 (287) N for MD; and 1377 (96) N for ME. Statistically significant difference between groups did not exist (p = 0.157, F = 1.995). In groups TD and MD with low e-modulus abutments, the dispersion of a probability distribution (coefficient of variation: CV) was statistically higher than that of group ME with high e-modulus abutments. SEM illustrated larger micro-fracture dimensions in Group MD than Group ME., Conclusion: Minimal thickness e.max crowns did not demonstrate statistical difference in fracture resistance from traditional thickness crowns. Fracture mechanisms of minimal thickness e.max crowns may be affected by the e-modulus of the substrate. Minimal thickness e.max crowns may be a viable restorative option when supported by high e-modulus materials., (© 2019 by the American College of Prosthodontists.)

Ti ringspot is an emerging foliar disease of the ti plant ( Cordyline fruticosa ) in Hawaii that is quickly spreading throughout the islands. Symptoms include small chlorotic ringspots on leaves that often coalesce to form larger lesions. Although several virus species have been discovered in symptomatic plants, none have been associated with these symptoms. Here, we report and characterize a novel virus closely associated with ti ringspot symptoms in Hawaii. The presence of double membrane bodies approximately 85 nm in diameter in symptomatic cells and sequence analyses of five genomic RNA segments obtained by high-throughput sequencing indicate that this virus is most closely related to members of the plant virus genus Emaravirus . Phylogenetic and sequence homology analyses place this virus on a distinct clade within the Emaravirus genus along with High Plains wheat mosaic emaravirus , blue palo verde broom virus, and Raspberry leaf blotch emaravirus . Sequence identity values with taxonomically relevant proteins indicate that this represents a new virus species, which we are tentatively naming ti ringspot-associated virus (TiRSaV). TiRSaV-specific reverse transcription PCR assays detected the virus in several experimental herbaceous host species following mechanical inoculation. TiRSaV was also detected in eriophyid mites collected from symptomatic ti plants, which may represent a putative arthropod vector of the virus.

Lung interstitial CD4+ T cells are critical for protection against pulmonary infections, but the fate of this population during HIV-1 infection is not well described. We studied CD4+ T cells in the setting of HIV-1 infection in human lung tissue, humanized mice, and a Mycobacterium tuberculosis (Mtb)/simian immunodeficiency virus (SIV) nonhuman primate co-infection model. Infection with a CCR5-tropic strain of HIV-1 or SIV results in severe and rapid loss of lung interstitial CD4+ T cells but not blood or lung alveolar CD4+ T cells. This is accompanied by high HIV-1 production in these cells in vitro and in vivo. Importantly, during early SIV infection, loss of lung interstitial CD4+ T cells is associated with increased dissemination of pulmonary Mtb infection. We show that lung interstitial CD4+ T cells serve as an efficient target for HIV-1 and SIV infection that leads to their early depletion and an increased risk of disseminated tuberculosis., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The foundational concept of habitat lies at the very root of the entire science of ecology, but inaccurate use of the term compromises scientific rigor and communication among scientists and nonscientists. In 1997, Hall, Krausman & Morrison showed that 'habitat' was used correctly in only 55% of articles. We ask whether use of the term has been more accurate since their plea for standardization and whether use varies across the broader range of journals and taxa in the contemporary literature (1998-2012). We searched contemporary literature for 'habitat' and habitat-related terms, ranking usage as either correct or incorrect, following a simplified version of Hall et al.'s definitions. We used generalized linear models to compare use of the term in contemporary literature with the papers reviewed by Hall et al. and to test the effects of taxa, journal impact in the contemporary articles and effects due to authors that cited Hall et al. Use of the term 'habitat' has not improved; it was still only used correctly about 55% of the time in the contemporary data. Proportionately more correct uses occurred in articles that focused on animals compared to ones that included plants, and papers that cited Hall et al. did use the term correctly more often. However, journal impact had no effect. Some habitat terms are more likely to be misused than others, notably 'habitat type', usually used to refer to vegetation type, and 'suitable habitat' or 'unsuitable habitat', which are either redundant or nonsensical by definition. Inaccurate and inconsistent use of the term can lead to (1) misinterpretation of scientific findings; (2) inefficient use of conservation resources; (3) ineffective identification and prioritization of protected areas; (4) limited comparability among studies; and (5) miscommunication of science-based findings. Correct usage would improve communication with scientists and nonscientists, thereby benefiting conservation efforts, and ecology as a science.

Classic Ehlers-Danlos syndrome (cEDS) is characterized by fragile, hyperextensible skin and hypermobile joints. cEDS can be caused by heterozygosity for missense mutations in genes COL5A2 and COL5A1, which encode the α2(V) and α1(V) chains, respectively, of collagen V, and is most often caused by COL5A1 null alleles. However, COL5A2 null alleles have yet to be associated with cEDS or other human pathologies. We previously showed that mice homozygous null for the α2(V) gene Col5a2 are early embryonic lethal, whereas haploinsufficiency caused aberrancies of adult skin, but not a frank cEDS-like phenotype, as skin hyperextensibility at low strain and dermal cauliflower-contoured collagen fibril aggregates, two cEDS hallmarks, were absent. Herein, we show that ubiquitous postnatal Col5a2 knockdown results in pathognomonic dermal cauliflower-contoured collagen fibril aggregates, but absence of skin hyperextensibility, demonstrating these cEDS hallmarks to arise separately from loss of collagen V roles in control of collagen fibril growth and nucleation events, respectively. Col5a2 knockdown also led to loss of dermal white adipose tissue (WAT) and markedly decreased abdominal WAT that was characterized by miniadipocytes and increased collagen deposition, suggesting α2(V) to be important to WAT development/maintenance. More important, Col5a2 haploinsufficiency markedly increased the incidence and severity of abdominal aortic aneurysms, and caused aortic arch ruptures and dissections, indicating that α2(V) chain deficits may play roles in these pathologies in humans., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

T helper 17 (Th17)-dependent autoimmune responses can develop after heart or lung transplantation and are associated with fibro-obliterative forms of chronic rejection; however, the specific self-antigens involved are typically different from those associated with autoimmune disease. To investigate the basis of these responses, we investigated whether removal of regulatory T cells or blockade of function reveals a similar autoantigen bias. We found that Th17 cells specific for collagen type V (Col V), kα1-tubulin, and vimentin were present in healthy adult peripheral blood mononuclear cells, cord blood, and fetal thymus. Using synthetic peptides and recombinant fragments of the Col V triple helical region (α1[V]), we compared Th17 cells from healthy donors with Th17 cells from Col V-reactive heart and lung patients. Although the latter responded well to α1(V) fragments and peptides in an HLA-DR-restricted fashion, Th17 cells from healthy persons responded in an HLA-DR-restricted fashion to fragments but not to peptides. Col V, kα1-tubulin, and vimentin are preferred targets of a highly conserved, hitherto unknown, preexisting Th17 response that is MHC class II restricted. These data suggest that autoimmunity after heart and lung transplantation may result from dysregulation of an intrinsic mechanism controlling airway and vascular homeostasis., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

We have shown previously that collagen V (col(V)) autoimmunity is a consistent feature of atherosclerosis in human coronary artery disease and in the Apoe(-/-) mouse model. We have also shown sensitization of Apoe(-/-) mice with col(V) to markedly increase the atherosclerotic burden, providing evidence of a causative role for col(V) autoimmunity in atherosclerotic pathogenesis. Here we sought to determine whether induction of immune tolerance to col(V) might ameliorate atherosclerosis, providing further evidence for a causal role for col(V) autoimmunity in atherogenesis and providing insights into the potential for immunomodulatory therapeutic interventions. Mucosal inoculation successfully induced immune tolerance to col(V) with an accompanying reduction in plaque burden in Ldlr(-/-) mice on a high-cholesterol diet. The results therefore demonstrate that inoculation with col(V) can successfully ameliorate the atherosclerotic burden, suggesting novel approaches for therapeutic interventions. Surprisingly, tolerance and reduced atherosclerotic burden were both dependent on the recently described IL-35 and not on IL-10, the immunosuppressive cytokine usually studied in the context of induced tolerance and amelioration of atherosclerotic symptoms. In addition to the above, using recombinant protein fragments, we were able to localize two epitopes of the α1(V) chain involved in col(V) autoimmunity in atherosclerotic Ldlr(-/-) mice, suggesting future courses of experimentation for the characterization of such epitopes., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Null alleles for the COL5A1 gene and missense mutations for COL5A1 or the COL5A2 gene underlie cases of classic Ehlers-Danlos syndrome, characterized by fragile, hyperextensible skin and hypermobile joints. However, no classic Ehlers-Danlos syndrome case has yet been associated with COL5A2 null alleles, and phenotypes that might result from such alleles are unknown. We describe mice with null alleles for the Col5a2. Col5a2(-/-) homozygosity is embryonic lethal at approximately 12 days post conception. Unlike previously described mice null for Col5a1, which die at 10.5 days post conception and virtually lack collagen fibrils, Col5a2(-/-) embryos have readily detectable collagen fibrils, thicker than in wild-type controls. Differences in Col5a2(-/-) and Col5a1(-/-) fibril formation and embryonic survival suggest that α1(V)3 homotrimers, a rare collagen V isoform that occurs in the absence of sufficient levels of α2(V) chains, serve functional roles that partially compensate for loss of the most common collagen V isoform. Col5a2(+/-) adults have skin with marked hyperextensibility and reduced tensile strength at high strain but not at low strain. Col5a2(+/-) adults also have aortas with increased compliance and reduced tensile strength. Results thus suggest that COL5A2(+/-) humans, although unlikely to present with frank classic Ehlers-Danlos syndrome, are likely to have fragile connective tissues with increased susceptibility to trauma and certain chronic pathologic conditions., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: α1(V) is an extensively modified collagen chain important in disease., Results: Comprehensive mapping of α1(V) post-translational modifications reveals unexpectedly large numbers of X-position hydroxyprolines in Gly-X-Y amino acid triplets., Conclusion: The unexpected abundance of X-position hydroxyprolines suggests a mechanism for differential modification of collagen properties., Significance: Positions, numbers, and occupancy of modified sites can provide insights into α1(V) biological properties. Aberrant expression of the type V collagen α1(V) chain can underlie the connective tissue disorder classic Ehlers-Danlos syndrome, and autoimmune responses against the α1(V) chain are linked to lung transplant rejection and atherosclerosis. The α1(V) collagenous COL1 domain is thought to contain greater numbers of post-translational modifications (PTMs) than do similar domains of other fibrillar collagen chains, PTMs consisting of hydroxylated prolines and lysines, the latter of which can be glycosylated. These types of PTMs can contribute to epitopes that underlie immune responses against collagens, and the high level of PTMs may contribute to the unique biological properties of the α1(V) chain. Here we use high resolution mass spectrometry to map such PTMs in bovine placental α1(V) and human recombinant pro-α1(V) procollagen chains. Findings include the locations of those PTMs that vary and those PTMs that are invariant between these α1(V) chains from widely divergent sources. Notably, an unexpectedly large number of hydroxyproline residues were mapped to the X-positions of Gly-X-Y triplets, contrary to expectations based on previous amino acid analyses of hydrolyzed α1(V) chains from various tissues. We attribute this difference to the ability of tandem mass spectrometry coupled to nanoflow chromatographic separations to detect lower-level PTM combinations with superior sensitivity and specificity. The data are consistent with the presence of a relatively large number of 3-hydroxyproline sites with less than 100% occupancy, suggesting a previously unknown mechanism for the differential modification of α1(V) chain and type V collagen properties.

Cephazolin, the latest parenteral cephalosporin produced by substitution of heterocyclic groups on the 7-aminocephalosporanic acid (7-ACA) nucleus, became available for clinical use in the U.K. in 1974. Its history is traced from the original Sardinian mould (1945) through isolation of cephalosporin C (1953) and 7-ACA (1962) to its discovery (1969) and subsequent clinical use. Its mode of actionis examined and its bactericidal nature confirmed, MICs of over 500 common pathogens are used to define its spectrum. The cut-off point for sensitivity and resistance is taken as 20 mg. per l. With 30 mug. discs zone sizes less than or equal to 14mm. indicate resistance. The clinical relevance of MICs and attainable serum and urine levels is examined by relating them to clinical response in 12 patients. A disc study compares cephazolin with 4 other available cephalosporins, namely cephaloridine, cephalothinm cephalexin and cephradine. Many major discrepancies indicate that they are not interchangeable. The laboratory and clinical implications are discussed, including the need for local policy decisions regarding choice of preparation. The change from a parenteral to an oral form should be preceded by a sensitivity test against the causal organism. The validity of using a single representative disc is questioned and the use of phrases such as 'sensitive to the cephalosporins' deprecated. Cephazolin is potent, broad-spectrum and bactericidal and is potentially life-saving in serious hospital infections. The cephalosporins rival the aminoglycosides as 'best-guess' primary choice and are preferable in pregnancy, the puerperium and in pulmonary infections. Within the group cephazolin will seriously challenge or even oust cephaloridine and cephalothin.