Novel Populations of Lung Capillary Endothelial Cells and Their Functional Significance.

The role of the lung's microcirculation and capillary endothelial cells in normal physiology and the pathobiology of pulmonary diseases is unequivocally vital. The recent discovery of molecularly distinct aerocytes and general capillary (gCaps) endothelial cells by single-cell transcriptomics (scRNAseq) advanced the field in understanding microcirculatory milieu and cellular communications. However, increasing evidence from different groups indicated the possibility of more heterogenic structures of lung capillaries. Therefore, we investigated enriched lung endothelial cells by scRNAseq and identified five novel populations of gCaps with distinct molecular signatures and roles. Our analysis suggests that two populations of gCaps that express Scn7a(Na+) and Clic4(Cl-) ion transporters form the arterial-to-vein zonation and establish the capillary barrier. We also discovered and named mitotically-active "root" cells (Flot1+) on the interface between arterial, Scn7a+, and Clic4 + endothelium, responsible for the regeneration and repair of the adjacent endothelial populations. Furthermore, the transition of gCaps to a vein requires a venous-capillary endothelium expressing Lingo2. Finally, gCaps detached from the zonation represent a high level of Fabp4, other metabolically active genes, and tip-cell markers showing angiogenesis-regulating capacity. The discovery of these populations will translate into a better understanding of the involvement of capillary phenotypes and their communications in lung disease pathogenesis.

A systematic review and meta-analysis of e-cigarette use among cancer survivors.

PURPOSE: We conducted a systematic review and meta-analysis to determine the use of e-cigarettes among cancer survivors, factors associated with their use, and prevalence of e-cigarette use as a quit attempt. METHODS: We searched five electronic databases until June 2022. Two authors independently selected studies, appraised their quality, and collected data. RESULTS: Twenty-three publications from eight data sources (national surveys) met our eligibility criteria. The pooled rate of lifetime e-cigarette use among cancer survivors was 15% (95% CI 6-27%); current use was 3% (95% CI 0-8%). Among survivors who currently used traditional cigarettes, 63% (95% CI 57-69%) also used e-cigarettes. The reported rates of weighted lifetime e-cigarette use differed between age groups (18-44 years, up to 46.7%; 45-64, up to 27.2%; ≥65, up to 24.8%). Nine publications reported factors associated with lifetime e-cigarette use (i.e., active use of traditional cigarettes; heavy drinking; poor mental health; younger age; being male, non-Hispanic White, or single; having less than high school education or income ≤$25,000 USD; and living in the South regions of the US or urban areas). E-cigarettes were used as a quit resource by 75% of survivors reporting dual use of electronic and traditional cigarettes (95% CI 63%, 85%). CONCLUSION: More than two-thirds of survivors currently using traditional cigarettes also use e-cigarettes. Higher use rates of e-cigarettes were reported among young cancer survivors compared to older survivors. Future studies are needed to assess the impact of e-cigarettes on long-term health and improve screening of smoking behaviors. IMPLICATIONS FOR CANCER SURVIVORS: Our study provides an overview of the prevalence of e-cigarette use and sociodemographic risk factors associated with e-cigarette use among cancer survivors. The findings can assist providers in supporting attempts to quit among cancer survivors.

Thinking Beyond the Temporal Bone Lab: A Systematic Process for Expanding Surgical Simulation in Otolaryngology Training.

The COVID-19 pandemic led to a temporary lapse in the development of otolaryngology trainee operative skills due to the cancellation of elective procedures and redeployment of trainees and attendings to COVID-19 units. Although transient, this disruption provided an opportunity for otolaryngology programs to develop contingency plans and formalize nascent simulation training curricula. Integration of formal simulation training alongside current didactic and surgical education may offset lost exposure during surgically lean times while providing the framework and resources for enhanced baseline training. Here, we provide an up-to-date overview of surgical simulation models in otolaryngology and identify easily implementable, low-cost, low fidelity models for junior trainees. By taking advantage of rapid advancements in technology and a paradigm shift to a more hands-on approach in medical education, formal simulation training may prove to be a beneficial tool at all stages of residency training, allowing for expanded peer-mentored skill development and providing a safe haven during unforeseen disruptions in surgical case volume.

Burden of diabetic foot syndrome in rural community: Need for screening and health promotion.

Context: Living with diabetes can be difficult since it can affect the patient in many ways. Diabetic foot syndrome (DFS) is described as a group of symptoms where neuropathy reduced blood supply and infection leads to tissue breakdown and morbidity. Aim: This study aims to determine the prevalence of DFS and associated sociodemographic and treatment-related factors among adults living with type 2 diabetes mellitus in a rural community. Setting and Design: A cross-sectional study was conducted in an area under the rural health training centre of department of Community Medicine. Methods and Material: The study was conducted to determine DFS by measuring neuropathy, peripheral vascular disease using Michigan neuropathy screening instrument, and clinical examination. Statistical Analysis Used: The data collected was analyzed using SPSS 25. Results: The prevalence of DFS among those with type 2 diabetes mellitus was high (51.7%). DFS was associated with advanced age (>75 years), duration of diabetes for more than 5 years and with foot ulcer. Smoking and alcohol consumption were not associated with DFS. Conclusion: Half of those with diabetes had DFS. People with DFS were more likely to be older and living with diabetes for longer duration. This underscores the need for early identification of DFS by the primary care physicians. Further research on the role of health professionals at the primary care level in educating and screening DFS in people with diabetes are required.

Beyond aroma: A scoping review on the impact of chronic rhinosinusitis on retronasal olfaction.

Background: Retronasal olfaction (RNO) refers to the perception of odorants inhaled through the mouth and carried through the nasopharynx to olfactory receptors within the olfactory cleft, enabling the perception of flavor. Although orthonasal olfactory dysfunction in chronic rhinosinusitis (CRS) has been widely described, the impact of CRS on RNO is less clear. In this study, we systematically review available literature to provide an update on RNO in the setting of CRS. Methods: We systematically searched PubMed, Ovid Embase, Web of Science, and the Cochrane Library for studies examining RNO in patients with documented CRS. The primary outcome of interest was objective psychophysical measurement of olfaction, including characterization of RNO. Results: We identified 404 unique references that underwent title and abstract review by two independent reviewers, with 52 articles undergoing full-text review, where 10 relevant studies underwent data extraction. Although outcome measures varied, all included studies demonstrated diminished RNO in patients with CRS. Of six studies evaluating the relationship between retronasal and orthonasal olfactory test scores in CRS patients two out of six (33%) demonstrated a correlation between both forms of olfaction and CRS, and two out of six studies (33%) found significantly lower orthonasal olfactory test scores compared to retronasal olfactory test scores. Two of three found significant improvement in RNO with treatment of underlying CRS. Of three studies examining patient reported outcome measures (PROMs) in CRS, two found significant associations between retronasal olfactory test scores and PROMs. Conclusions: Based on the current literature, CRS patients appear to have diminished RNO, which may be associated with orthonasal olfactory dysfunction and decreased quality of life in this population. Higher level of evidence studies are required to further elucidate these relationships and the impact of medical and surgical CRS management on RNO.

Simulation training in endoscopic skull base surgery: A scoping review.

Objective: Proficiency in endoscopic endonasal skull base surgery requires both substantial baseline training and progressive lifelong learning. Endoscopic simulation models continue to evolve in an effort to optimize trainee education and preoperative preparation and improve surgical outcomes. The current scoping review systematically reviews all available literature and synthesizes the current paradigms of simulation models for endoscopic skull base surgery training and skill enhancement. Methods: In accordance with Preferred Reporting Items for Systemic Review and Meta-Analyses guidelines, we systematically searched PubMed, Embase, CINAHL, and Cochrane databases. Studies were categorized according to the type of simulation models investigated. Results: We identified 238 unique references, with 55 studies ultimately meeting inclusion criteria. Of these, 19 studies described cadaveric dissection models, 17 discussed three-dimensional (3D) printed models, 14 examined virtual surgical planning and augmented reality-based models, and five 5 articles described task trainers. Conclusions: There are a wide variety of simulation models for endoscopic skull base surgery, including high-fidelity cadaveric, virtual reality, and 3D-printed models. These models are an asset for trainee development and preoperative surgical preparation.

Redox-dependent loss of flavin by mitochondria complex I is different in brain and heart.

Pathologies associated with tissue ischemia/reperfusion (I/R) in highly metabolizing organs such as the brain and heart are leading causes of death and disability in humans. Molecular mechanisms underlying mitochondrial dysfunction during acute injury in I/R are tissue-specific, but their details are not completely understood. A metabolic shift and accumulation of substrates of reverse electron transfer (RET) such as succinate are observed in tissue ischemia, making mitochondrial complex I of the respiratory chain (NADH:ubiquinone oxidoreductase) the most vulnerable enzyme to the following reperfusion. It has been shown that brain complex I is predisposed to losing its flavin mononucleotide (FMN) cofactor when maintained in the reduced state in conditions of RET both in vitro and in vivo. Here we investigated the process of redox-dependent dissociation of FMN from mitochondrial complex I in brain and heart mitochondria. In contrast to the brain enzyme, cardiac complex I does not lose FMN when reduced in RET conditions. We proposed that the different kinetics of FMN loss during RET is due to the presence of brain-specific long 50 kDa isoform of the NDUFV3 subunit of complex I, which is absent in the heart where only the canonical 10 kDa short isoform is found. Our simulation studies suggest that the long NDUFV3 isoform can reach toward the FMN binding pocket and affect the nucleotide affinity to the apoenzyme. For the first time, we demonstrated a potential functional role of tissue-specific isoforms of complex I, providing the distinct molecular mechanism of I/R-induced mitochondrial impairment in cardiac and cerebral tissues. By combining functional studies of intact complex I and molecular structure simulations, we defined the critical difference between the brain and heart enzyme and suggested insights into the redox-dependent inactivation mechanisms of complex I during I/R injury in both tissues.

Hypertension, diabetes, and corresponding annual clinical testing utilization: Comparison between Asian Indians and other races/ethnicities.

Asian Indians are at increased risk of developing cardiometabolic diseases. We sought to determine differences between Asian Indians and other races/ethnicities in hypertension and diabetes prevalence and associated annual blood pressure (BP) and fasting blood glucose (FBG) testing. A total of 257,652 adults ≥18 years from the 2011-2018 U.S. National Health Interview Surveys (NHIS) were included. BP and FBG testing in the past 12 months was defined dichotomously (yes/not yes). Racial/ethnic groups included non-Hispanic White (NHW), non-Hispanic Black (NHB), Asian Indian, Other Asians, and Hispanic/Multiracial. We used logistic regression, adjusting for covariates and the survey design. Analyses were completed from 08/2020-06/2021. Asian Indians (N = 3049) had 21% and 99% higher odds of hypertension and diabetes, respectively, than NHWs (aOR [95% CI]; hypertension: 1.21[1.04,1.40], diabetes: 1.99[1.64,2.41]). Accordingly, Asian Indians without diabetes had significantly higher odds of FBG screening than NHWs (Asian Indian: 1.41[1.25,1.59], NHB: 0.99 [0.95,1.04], Other Asian: 1.07[0.98, 1.18], Hispanic: 1.13[1.07,1.20]). Asian Indians without hypertension had a 14% insignificant increase in BP testing compared to NHWs (1.14[0.97,1.33]). Predictors of testing in Asian Indians included older age, doctor's visit, graduate-level education, insurance coverage, and history of hypertension or diabetes. NHBs with diabetes and Hispanics with hypertension had lower odds of FBG testing (0.75[0.66,0.84]) and BP testing (0.85[0.79,0.92]), respectively, than NHWs. Asian Indians have higher odds of diabetes and hypertension than NHWs and higher, but relatively lower, odds of FBG and BP testing. Increasing routine BP and FBG testing in Asian Indians in younger adults may allow for earlier detection of high-risk individuals.

Association between social determinants of health and olfactory function: a scoping review.

BACKGROUND: Social determinants of health (SDoH) include the socioeconomic, demographic, and social conditions that influence differences in health status among individuals and groups. The impact of these conditions on olfactory function remains poorly understood. In this scoping review, we systematically review the available literature to synthesize the association between SDoH and olfactory function. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Review (PRISMA-ScR) guidelines, we performed systematic search queries in PubMed, Embase, and Ovid databases and categorized articles according to themes that emerged regarding SDoH. The primary outcomes included self-reported and objective measurements of smell. RESULTS: We identified 722 unique references that underwent title and abstract review by two independent reviewers, with 70 articles undergoing full-text review and 57 relevant for data extraction. Six themes emerged in our review, under which we categorized the studies and synthesized respective associations with olfactory function. These include studies exploring socioeconomic status (n = 19, 33%), education status (n = 27, 47%), occupational exposures (n = 26, 46%), racial/ethnic disparities (n = 12, 21%), and lifestyle/behavioral factors (n = 33, 58%). CONCLUSIONS: Within the context of this scoping review, olfactory dysfunction is significantly more prevalent in patients with lower socioeconomic status, exposure to environmental and occupational toxins, and of minority race/ethnicity, whereas the associations between olfactory dysfunction and education level and lifestyle factors such as smoking and drinking seem to be much more elusive. This review highlights the importance of accounting for SDoH in observational studies examining olfactory outcomes. Given the increased awareness of olfactory loss, special consideration should be given to understanding olfactory dysfunction in the context of these factors.

Glucose-6-phosphate dehydrogenase deficiency contributes to metabolic abnormality and pulmonary hypertension.

We have previously reported that several patients with idiopathic pulmonary hypertension (PH) had different types of G6PD deficiency. However, the role of G6PD in PH is multifactorial because G6PD is involved in controlling oxidative stress, metabolic switch, and red blood cell fragility. To delineate the contribution of G6PD to PH pathogenesis, we utilized a mouse line with decreased expression of G6PD (10% from wild-type level). We confirmed that mice with G6PD deficiency develop spontaneous pulmonary hypertension with pulmonary artery and right heart remodeling. G6PD deficiency resulted in increased free hemoglobin and activation of the p38 pathway, which we recently reported induces the development of PH in the sugen/hypoxia model via endothelial barrier dysfunction. Metabolomics analysis of G6PD deficient mice indicates the switch to alternative metabolic fluxes that feed into the pentose phosphate pathway (PPP), resulting in the upregulation of oxidative stress, fatty acid pathway, and reduction in pyruvate production. Thus, G6PD deficiency did not reduce PPP flux that is important for proliferation but activated collateral pathways at the cost of increased oxidative stress. Indeed, we found the upregulation of myo-inositol oxidase, reduction in GSH/GSSG ratio, and increased nitration in the lungs of G6PD-deficient mice. Increased oxidative stress also results in the activation of PI3K, ERK1/2, and AMPK that contribute to the proliferation of pulmonary vasculature. Therefore, G6PD deficiency has a multimodal effect, including hemolysis, metabolic reprogramming, and oxidative stress leading to the PH phenotype in mice.

Delayed Bleeding After Endoscopic Resection of Colorectal Polyps: Identifying High-Risk Patients.

Delayed post-polypectomy bleeding (DPPB) is a potentially severe complication of therapeutic colonoscopy which can result in hospital readmission and re-intervention. Over the last decade, rates of DPPB reported in the literature have fallen from over 2% to 0.3-1.2%, largely due to improvements in resection technique, a shift towards cold snare polypectomy, better training, adherence to guidelines on periprocedural antithrombotic management, and the use of antithrombotics with more favourable bleeding profiles. However, as the complexity of polypectomy undertaken worldwide increases, so does the importance of identifying patients at increased risk of DPPB. Risk factors can be categorised according to patient, polyp and personnel related factors, and their integration together to provide an individualised risk score is an evolving field. Strategies to reduce DPPB include safe practices relevant to all patients undergoing colonoscopy, as well as specific considerations for patients identified to be high risk. This narrative review sets out an evidence-based summary of factors that contribute to the risk of DPPB before discussing pragmatic interventions to mitigate their risk and improve patient safety.

Single Mutation in the NFU1 Gene Metabolically Reprograms Pulmonary Artery Smooth Muscle Cells.

OBJECTIVE: NFU1 is a mitochondrial iron-sulfur scaffold protein, involved in iron-sulfur assembly and transfer to complex II and LAS (lipoic acid synthase). Patients with the point mutation NFU1G208C and CRISPR/CAS9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9)-generated rats develop mitochondrial dysfunction leading to pulmonary arterial hypertension. However, the mechanistic understanding of pulmonary vascular proliferation due to a single mutation in NFU1 remains unresolved. Approach and Results: Quantitative proteomics of isolated mitochondria showed the entire phenotypic transformation of NFU1G206C rats with a disturbed mitochondrial proteomic landscape, involving significant changes in the expression of 208 mitochondrial proteins. The NFU1 mutation deranged the expression pattern of electron transport proteins, resulting in a significant decrease in mitochondrial respiration. Reduced reliance on mitochondrial respiration amplified glycolysis in pulmonary artery smooth muscle cell (PASMC) and activated GPD (glycerol-3-phosphate dehydrogenase), linking glycolysis to oxidative phosphorylation and lipid metabolism. Decreased PDH (pyruvate dehydrogenase) activity due to the lipoic acid shortage is compensated by increased fatty acid metabolism and oxidation. PASMC became dependent on extracellular fatty acid sources due to upregulated transporters such as CD36 (cluster of differentiation 36) and CPT (carnitine palmitoyltransferase)-1. Finally, the NFU1 mutation produced a dysregulated antioxidant system in the mitochondria, leading to increased reactive oxygen species levels. PASMC from NFU1 rats showed apoptosis resistance, increased anaplerosis, and attained a highly proliferative phenotype. Attenuation of mitochondrial reactive oxygen species by mitochondrial-targeted antioxidant significantly decreased PASMC proliferation. CONCLUSIONS: The alteration in iron-sulfur metabolism completely transforms the proteomic landscape of the mitochondria, leading toward metabolic plasticity and redistribution of energy sources to the acquisition of a proliferative phenotype by the PASMC.

Use of Nonmedicated Control Substances in Randomized Clinical Trials of Patients With Chronic Rhinosinusitis: A Systematic Review and Single-Arm Meta-analysis.

Importance: The effect of nonmedicated control substances in chronic rhinosinusitis remains unclear. Objective: To assess the association of nonmedicated control substances in randomized clinical trials with disease outcomes in patients diagnosed with chronic rhinosinusitis. Data Sources and Study Selection: In this single-arm systematic review and meta-analysis, the Cochrane Library of Systematic Reviews, Ovid MEDLINE, Embase, PubMed, and ClinicalTrials.gov databases were searched for randomized clinical trials with a preintervention and postintervention design for chronic rhinosinusitis that were published between 1946 and January 23, 2019. Data Extraction and Synthesis: Paired reviewers independently extracted data. The analyses used random-effects models and the Cochrane risk of bias assessment to rate the quality of the evidence. Main Outcomes and Measures: The primary outcomes were the association of nonmedicated control substances with 22-item Sinonasal Outcome Test (SNOT-22) scores or nasal symptom scores when SNOT-22 was not available. Results: A total of 2305 abstracts were identified and screened, 725 articles were reviewed in full text, and 38 articles met the study criteria and were included in the meta-analysis. Among the 38 included studies, a total of 2258 adults (mean age range, 27-53 years; 20.0%-72.5% women) were randomized to receive nonmedicated control substances or sham interventions. Topical nonmedicated control substances were associated with significant reduction in SNOT-22 scores (mean difference [MD], -8.81; 95% CI, -12.60 to -5.03). A subgroup analysis of topical therapies, limited to saline irrigation and nasal spray diluents, found that topical diluents were associated with a greater reduction in SNOT-22 scores (MD, -11.45; 95% CI, -13.50 to -9.41) compared with saline irrigation (MD, -13.60; 95% CI, -19.95 to -7.25). Nonmedicated control substances were associated with a significant reduction in nasal obstruction scores (standardized MD [SMD], -0.42; 95% CI, -0.81 to -0.03). No significant change was found in rhinorrhea scores (SMD, -0.34; 95% CI, -1.37 to 0.69), postnasal drip scores (SMD, -0.96; 95% CI, -2.18 to 0.25), facial pain scores (SMD, -0.57; 95% CI, -1.68 to 0.55), or loss of smell scores (SMD, -0.18; 95% CI, -0.68 to 0.32). Conclusions and Relevance: This systematic review and meta-analysis of the use of nonmedicated control substances in randomized clinical trials of chronic rhinosinusitis outcomes suggests that the use of nonmedicated control substances is associated with limited improvements in SNOT-22 and nasal obstruction scores. These findings highlight potential areas of future research directions and the importance of randomized clinical trials to accurately estimate treatment effect.

Características clínicas de la neurocisticercosis en un hospital referencial del norte del Perú. 2016-2018 / Clinical characteristics of neurocysticercosis from a reference hospital of the northern of Peru. 2016-2018

INTRODUCCIÓN: La neurocisticercosis (NCC) es la parasitosis más común del sistema nervioso central, siendo una causa muy importante de epilepsia. OBJETIVO: Describir las características de pacientes con NCC atendidos en un hospital de alta complejidad de Lambayeque durante el período 2016-2018. PACIENTES Y MÉTODOS: Se revisaron las historias clínicas de pacientes con diagnóstico de NCC y se recolectó su información en una ficha de datos. RESULTADOS: 46 historias cumplieron criterios de inclusión; 23 correspondían a varones, la mediana de edad fue 46,5 años (RIC: 26,5-63), el paciente más joven tuvo 7 años, el más longevo 85 años; 30 procedían de la región Lambayeque. Epilepsia se presentó en 24 pacientes, hipertensión endocraneal en 10, síndrome psíquico en dos, déficit neurológico focal en 1, síndrome visual en 1, un paciente fue asintomático. Siete pacientes tuvieron epilepsia y otro síndrome simultáneamente. En las neuroimágenes, las calcificaciones cerebrales fueron las lesiones más comunes; 9 tuvieron quistes sub-aracnoideos. En 20 pacientes se efectuó serología por western blot, siendo positiva en 11; 38 fueron clasificados como NCC definitiva y 8 probable. Recibieron solamente tratamiento sintomático18 pacientes, 27 tratamiento antiparasitario y 6 adicionalmente tratamiento neuroquirúrgico. Falleció un paciente. CONCLUSIONES: La sintomatología y los hallazgos de neuroimágenes fueron proteiformes y la mortalidad fue baja.

BACKGROUND: Neurocysticercosis (NCC) is the most common parasitosis of the central nervous system, and a very important cause of epilepsy. AIM: To describe the clinical features of patients with NCC attending a high level hospital from Lambayeque during: 2016-2018. METHODS: The medical records of patients with NCC were reviewed, and their information was collected on a data sheet. RESULTS: 46 stories met the inclusion criteria; 23 patients were male, the median age was 46.5 years (IQR: 26.5-63), the youngest patient was 7 years old, and the longest 85. Thirty patients were from Lambayeque. Epilepsy occurred in 24 patients, intracranial hypertension in 10, psychic syndrome in 2 and focal neurological deficit and visual syndrome in 1; there was one asymptomatic patient and seven had epilepsy and another syndrome. In neuroimaging, cerebral calcifications were the most common lesions; 9 patients had subarachnoid cysts. Serology (western blot) was performed in 20 patients being positive in 11; 38 were definitive NCC and 8 probable. Eighteen patients received only symptomatic treatment, 27 antiparasitic treatment and 6, additionally neurosurgical treatment. Only one patient died. CONCLUSIONS: The symptoms and neuroimaging findings were proteiform and the mortality found was low.

Necrosis-Released HMGB1 (High Mobility Group Box 1) in the Progressive Pulmonary Arterial Hypertension Associated With Male Sex.

Damage-associated molecular patterns, such as HMGB1 (high mobility group box 1), play a well-recognized role in the development of pulmonary arterial hypertension (PAH), a progressive fatal disease of the pulmonary vasculature. However, the contribution of the particular type of vascular cells, type of cell death, or the form of released HMGB1 in PAH remains unclear. Moreover, although male patients with PAH show a higher level of circulating HMGB1, its involvement in the severe PAH phenotype reported in males is unknown. In this study, we aimed to investigate the sources and active forms of HMGB1 released from damaged vascular cells and their contribution to the progressive type of PAH in males. Our results showed that HMGB1 is released by either pulmonary artery human endothelial cells or human pulmonary artery smooth muscle cells that underwent necrotic cell death, although only human pulmonary artery smooth muscle cells produce HMGB1 during apoptosis. Moreover, only human pulmonary artery smooth muscle cell death induced a release of dimeric HMGB1, found to be mitochondrial reactive oxygen species dependent, and TLR4 (toll-like receptor 4) activation. The modified Sugen/Hypoxia rat model replicates the human sexual dimorphism in PAH severity (right ventricle systolic pressure in males versus females 54.7±2.3 versus 44.6±2 mm Hg). By using this model, we confirmed that necroptosis and necrosis are the primary sources of circulating HMGB1 in the male rats, although only necrosis increased circulation of HMGB1 dimers. Attenuation of necrosis but not apoptosis or necroptosis prevented TLR4 activation in males and blunted the sex differences in PAH severity. We conclude that necrosis, through the release of HMGB1 dimers, predisposes males to a progressive form of PAH.

Complex III Inhibition-Induced Pulmonary Hypertension Affects the Mitochondrial Proteomic Landscape.

The mitochondria play a vital role in controlling cell metabolism and regulating crucial cellular outcomes. We previously demonstrated that chronic inhibition of the mitochondrial complex III in rats by Antimycin A (AA) induced sustained pulmonary vasoconstriction. On the metabolic level, AA-induced mitochondrial dysfunction resulted in a glycolytic shift that was reported as the primary contributor to pulmonary hypertension pathogenesis. However, the regulatory proteins driving this metabolic shift with complex III inhibition are yet to be explored. Therefore, to delineate the mechanisms, we followed changes in the rat lung mitochondrial proteome throughout AA treatment. Rats treated with AA for up to 24 days showed a disturbed mitochondrial proteome with significant changes in 28 proteins (p < 0.05). We observed a time-dependent decrease in the expression of key proteins that regulate fatty acid oxidation, the tricarboxylic acid cycle, the electron transport chain, and amino acid metabolism, indicating a correlation with diminished mitochondrial function. We also found a significant dysregulation in proteins that controls the protein import machinery and the clearance and detoxification of oxidatively damaged peptides via proteolysis and mitophagy. This could potentially lead to the onset of mitochondrial toxicity due to misfolded protein stress. We propose that chronic inhibition of mitochondrial complex III attenuates mitochondrial function by disruption of the global mitochondrial metabolism. This potentially aggravates cellular proliferation by initiating a glycolytic switch and thereby leads to pulmonary hypertension.

Diagnostic dilemma - sinonasal organizing hematoma.

Sinonasal organizing hematomas are benign lesions often mistaken for malignancy due to their aggressive appearance on diagnostic imaging and endoscopic findings that favor advanced disease. The destructive nature of this pathology paired with the rarity of the presentation often results in diagnostic deception that may escalate intervention planning and affect discussion of prognosis with patients. Herein, we present a case of a 56-year-old male with left-sided nasal obstruction and daily epistaxis, where computed tomography imaging revealed heterogeneous opacification of the left maxillary sinus, erosion of the left inferior orbital wall and extension into the nasal cavity. Although clinical and radiographic presentations of sinonasal organizing hematomas can be managed definitively with endoscopic intervention, there is a need to increase awareness of this entity among clinicians to improve our prognostic counseling with patients.

​False-positive paracetamol levels in a patient with hyperbilirubinaemia: clinical perspectives.

​Serum concentrations of paracetamol are measured to investigate the cause of acute hepatitis, monitor the clearance of paracetamol from the body and to determine if supratherapeutic levels warrant treatment with N-acetylcysteine (NAC). ​A 49-year-old man treated for ischaemic colitis developed worsening renal and liver function tests. As part of the investigation of hepatorenal failure, paracetamol levels were requested, which were elevated at 14 mg/L (normal <4 mg/L) resulting in treatment with NAC. Despite treatment, levels of paracetamol remained elevated and the link between hyperbilirubinemia and false-positive paracetamol levels was identified. ​Bilirubin and its by-products have intense absorbance in the ultraviolet and visible regions of the electromagnetic spectrum, causing interference in the enzymatic colorimetric assay most commonly used to measure paracetamol concentration, resulting in false-positive paracetamol levels. Laboratories correct for this interference above a predetermined bilirubin concentration, termed the Icteric Index; however, in our case this interference occurred at a lower level of hyperbilirubinaemia than previously identified as significant. This interaction was found to be more significant at lower bilirubin levels when low or no paracetamol levels were present in the serum, resulting in a change to laboratory practice and development of a 'Sliding Scale' approach to analysis. ​Concurrent bilirubin or Icteric Index measurement is recommended for all laboratories that use the enzymatic colorimetric assay for paracetamol measurement. Lower Icteric Index or bilirubin thresholds are required when low or no paracetamol levels are present in the serum to prevent false-positive paracetamol results. We describe a new 'Sliding Scale' approach to analysis, and highlight an important interaction for clinicians to be aware of.