This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2021. Other selected articles can be found online at ...https://www.biomedcentral.com/collections/annualupdate2021 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from https://link.springer.com/bookseries/8901 .
The utility of an electron-deficient, air stable, and commercially available Lewis acid tris(pentafluorophenyl)borane has recently been comprehensively explored. While being as reactive as its ...distant cousin boron trichloride, it has been shown to be much more stable and capable of catalyzing a variety of powerful transformations, even in the presence of water. The focus of this review will be to highlight those catalytic reactions that utilize a silane as a stoichiometric reductant in conjunction with tris(pentafluorophenyl) borane in the reduction of alcohols, carbonyls, or carbonyl-like derivatives.
The Liver Imaging Reporting and Data System (LI-RADS) categorizes observations from imaging analyses of high-risk patients based on the level of suspicion for hepatocellular carcinoma (HCC) and ...overall malignancy. The categories range from definitely benign (LR-1) to definitely HCC (LR-5), malignancy (LR-M), or tumor in vein (LR-TIV) based on findings from computed tomography or magnetic resonance imaging. However, the actual percentage of HCC and overall malignancy within each LI-RADS category is not known. We performed a systematic review to determine the percentage of observations in each LI-RADS category for computed tomography and magnetic resonance imaging that are HCCs or malignancies.
We searched the MEDLINE, Embase, Cochrane CENTRAL, and Scopus databases from 2014 through 2018 for studies that reported the percentage of observations in each LI-RADS v2014 and v2017 category that were confirmed as HCCs or other malignancies based on pathology, follow-up imaging analyses, or response to treatment (reference standard). Data were assessed on a per-observation basis. Random-effects models were used to determine the pooled percentages of HCC and overall malignancy for each LI-RADS category. Differences between categories were compared by analysis of variance of logit-transformed percentage of HCC and overall malignancy. Risk of bias and concerns about applicability were assessed with the Quality Assessment of Diagnostic Accuracy Studies 2 tool.
Of 454 studies identified, 17 (all retrospective studies) were included in the final analysis, consisting of 2760 patients, 3556 observations, and 2482 HCCs. The pooled percentages of observations confirmed as HCC and overall malignancy, respectively, were 94% (95% confidence interval CI 92%–96%) and 97% (95% CI 95%–99%) for LR-5, 74% (95% CI 67%–80%) and 80% (95% CI 75%–85%) for LR-4, 38% (95% CI 31%–45%) and 40% (95% CI 31%–50%) for LR-3, 13% (95% CI 8%–22%) and 14% (95% CI 9%–21%) for LR-2, 79% (95% CI 63%–89%) and 92% (95% CI 77%–98%) for LR-TIV, and 36% (95% CI 26%–48%) and 93% (95% CI 87%–97%) for LR-M. No malignancies were found in the LR-1 group. The percentage of HCCs and overall malignancies confirmed differed significantly among LR groups 2–5 (P < .00001). Patient selection was the most frequent factor that affected bias risk, because of verification bias and case–control study design.
In a systematic review, we found that increasing LI-RADS categories contained increasing percentages of HCCs and overall malignancy based on reference standard confirmation. Of observations categorized as LR-M, 93% were malignancies and 36% were confirmed as HCCs. The percentage of HCCs found in the LR-2 and LR-3 categories indicate the need for a more active management strategy than currently recommended. Prospective studies are needed to validate these findings. PROSPERO number CRD42018087441.
Rheumatoid arthritis (RA) is a chronic autoimmune disease in which imbalances in pro- and anti-inflammatory cytokines promote the induction of autoimmunity, inflammation and joint destruction. The ...importance of inflammatory cytokines in the pathogenesis of RA has been underscored by the success of biologics that act to block the effects of cytokines, such as tumour necrosis factor-α, interleukin (IL)-1 or IL-6, in treating disease. Mitogen-activated protein kinases (MAPKs) have been implicated as playing key regulatory roles in the production of these pro-inflammatory cytokines and downstream signalling events leading to joint inflammation and destruction. This article reviews the evidence that MAPKs play important roles in the pathogenesis of RA and discusses their therapeutic potential as drug targets.
Respiratory disease is unfortunately common in preterm infants with the archetype being bronchopulmonary dysplasia (BPD). BPD affects approximately 50,000 preterm infants in the U.S. annually with ...substantial morbidity and mortality related to its pathology (alveolar, airway, and pulmonary vasculature maldevelopment). Predicting the likelihood and severity of chronic respiratory disease in these children as they age is difficult and compounded by the lack of consistent phenotyping. Barriers to understanding the actual scope of this problem include few longitudinal studies, information limited by small retrospective studies and the ever‐changing landscape of therapies in the NICU that affect long‐term respiratory outcomes. Thus, the true burden of adult respiratory disease caused by premature birth is currently unknown. Nevertheless, limited data suggest that a substantial percentage of children with a history of BPD have long‐term respiratory symptoms and persistent airflow obstruction associated with altered lung function trajectories into adult life. Small airway disease with variable bronchodilator responsiveness, is the most common manifestation of lung dysfunction in adults with a history of BPD. The etiology of this is unclear however, developmental dysanapsis may underlie the airflow obstruction in some adults with a history of BPD. This type of flow limitation resembles that of aging adults with chronic obstructive lung disease with no history of smoking. It is also unclear whether lung function abnormalities in people with a history of BPD are static or if these individuals with BPD have a more accelerated decline in lung function as they age compared to controls. While some of the more significant mediators of lung function, such as tobacco smoke and respiratory infections have been identified, more work is necessary to identify the best means of preserving lung function for individuals born prematurely throughout their lifespan.
Introduction
Although prolonged respiratory symptoms following severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection have been described in adults, data are emerging that children ...also experience long‐term sequelae of coronavirus disease 2019 (COVID‐19). The respiratory sequelae of COVID‐19 in children remain poorly characterized. In this study we describe health data and respiratory findings in pediatric patients presenting with persistent respiratory symptoms following COVID‐19.
Methods
This study included patients referred to Pulmonary Clinic at the Children's Hospital of Philadelphia between December 2020 and April 2021 (n = 29). Inclusion criteria included a history of SARS‐CoV‐2 RNA positivity or confirmed close household contact and suggestive symptoms. A retrospective chart review was performed and demographic, clinical, imaging, and functional test data were collected.
Results
The mean age at presentation to clinic was 13.1 years (range: 4–19 years). Patients had persistent respiratory symptoms ranging from 1.3 to 6.7 months postacute infection. Persistent dyspnea and/or exertional dyspnea were present in nearly all (96.6%) patients at the time of clinic presentation. Other reported chronic symptoms included cough (51.7%) and exercise intolerance (48.3%). Fatigue was reported in 13.8% of subjects. Many subjects were overweight or obese (62.1%) and 11 subjects (37.9%) had a prior history of asthma. Spirometry and plethysmography were normal in most patients. The six‐minute walk test (6MWT) revealed exercise intolerance and significant tachycardia in two‐thirds of the nine children tested.
Conclusion
Exertional dyspnea, cough and exercise intolerance were the most common respiratory symptoms in children with postacute COVID‐19 respiratory symptoms seen in an outpatient pulmonary clinic. Spirometry (and plethysmography when available), however, was mostly normal, and exertional intolerance was frequently demonstrated using the 6MWT.
•Autoinflammatory keratinization diseases have autoinflammatory pathomechanisms.•The clinical entity “autoinflammatory keratinization diseases” includes IL36Ra-related pustulosis.•CARD14-mediated ...pustular psoriasis falls within the concept of autoinflammatory keratinization diseases.•Pityriasis rubra pilaris type V and keratosis lichenoides chronica are included in autoinflammatory keratinization diseases.•Improved understanding of disease pathophysiology may lead to innovative targeted therapies.
Classifying inflammatory skin diseases is challenging, especially for the expanding group of disorders triggered by genetic factors resulting in hyperactivated innate immunity that result in overlapping patterns of dermal and epidermal inflammation with hyperkeratosis. For such conditions, the umbrella term “autoinflammatory keratinization diseases” (AIKD) has been proposed. AIKD encompasses diseases with mixed pathomechanisms of autoinflammation and autoimmunity, and includes IL-36 receptor antagonist (IL-36Ra)-related pustulosis, CARD14-mediated pustular psoriasis, pityriasis rubra pilaris (PRP) type V, and familial keratosis lichenoides chronica (KLC). Mechanistically, the entities include generalized pustular psoriasis (GPP) without psoriasis vulgaris, impetigo herpetiformis and acrodermatitis continua, which are IL-36Ra-related pustuloses caused by loss-of-function mutations in IL36RN; GPP with psoriasis vulgaris and palmoplantar pustular psoriasis which are CARD14-mediated pustular psoriasiform dermatoses with gain-of-function variants of CARD14; PRP type V which is caused by gain-of-function mutations in CARD14; and, familial KLC in which mutations in NLRP1, an inflammasome sensor protein predominantly expressed in skin, have been identified. It is likely that further inflammatory keratinization disorders will also fall within the concept of AIKD, as elucidation of novel pathogenic mechanisms of inflammatory keratinization diseases emerges. A better understanding of the pathophysiology of AIKD is likely to lead to innovative, targeted therapies that benefit patients.
Tobacco smoke and nicotine exposure during prenatal and postnatal life can impair lung development, alter the immune response to viral infections, and increase the prevalence of wheezing during ...childhood. The following review examines recent discoveries in the fields of lung development and tobacco and nicotine exposure, emphasizing studies published within the last 5 years. In utero tobacco and nicotine exposure remains common, occurring in approximately 10% of pregnancies within the United States. Exposed neonates are at increased risk for diminished lung function, altered central and peripheral respiratory chemoreception, and increased asthma symptoms throughout childhood. Recently, genomic and epigenetic risk factors, such as alterations in DNA methylation, have been identified that may influence the risk for long-term disease. This review examines the impact of prenatal tobacco and nicotine exposure on lung development with a particular focus on nicotinic acetylcholine receptors. In addition, this review examines the role of prenatal and postnatal tobacco smoke and nicotine exposure and its association with augmenting infection risk, skewing the immune response toward a T-helper type 2 bias and increasing risk for developing an allergic phenotype and asthmalike symptoms during childhood. Finally, this review outlines the respiratory morbidities associated with childhood secondhand smoke and nicotine exposure and examines genetic and epigenetic modifiers that may influence respiratory health in infants and children exposed to in utero or postnatal tobacco smoke.
Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the ...inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition.
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•Germline, gain-of-function NLRP1 mutations cause MSPC and FKLC syndromes.•Mutant NLRP1 proteins have lower threshold for inflammasome activation.•The Pyrin (PYD) and LRR domains of NLRP1 inhibit its self-oligomerization.•NLRP1 mutants cause skin hyperplasia via paracrine inflammatory signaling.
Gain-of-function mutations in the inflammasome sensor NLRP1 increase susceptibility to skin cancer and unmask unique regulatory autoinhibition in the inflammasome.
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