Patterns of Discordance Between Clinical and Pathologic Stage in Head and Neck Cancer.

OBJECTIVE: To enhance understanding in patterns of discordance between clinical and pathological T and N staging in multiple sites of head and neck squamous cell cancer. METHODS: A retrospective cohort of 580 newly diagnosed and surgically treated head and neck squamous cell carcinoma patients from a single institution over a 10-year period are presented. Clinical and pathologic staging are compared. RESULTS: Notably, 33% of cases had staging discordance. Overall Cohen's kappa agreement was κ = 0.55 (moderate agreement). Highly discordant site stages with κ < 0.45 included: T2 oral cavity, T2 oropharynx, T3 larynx, and N1 lymph node. T2-4 oral cavity cancers were often overstaged, and more than one-third of T3 larynx cancers were understaged. Highly concordant site stages with κ>0.65 included: T1 larynx, T4 oropharynx, N0 lymph node, and N3 lymph node. CONCLUSION: There exists a quantifiable and, in certain sites, clinically relevant pattern of discordance between clinical and pathologic staging. Tumor board multidisciplinary evaluation can highlight these discrepancies and aide in limiting effects on treatment decisions. However, discordant staging can affect the interpretation and application of prognostication, treatment, and data accuracy. Further investigation is warranted to improve clinical staging accuracy in areas of highest discordance. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Atlantic bonito (Sarda) genomic analysis reveals population differentiation across Northeast Atlantic and mediterranean locations: Implications for fishery management.

The Atlantic bonito (Sarda, family Scombridae) is a pelagic species and one of the most exploited small tuna species. Despite its economic importance, biological information is scarce with no associated management directives. In this study, using a population genomic approach resulted in a lack of panmixia of two genetic pools with different effective population sizes (east central-tropical Atlantic and northeast Atlantic-Mediterranean) and an intermixing zone in Atlantic Morocco. The absence of genetic heterogeneity between the locations in Atlantic - Mediterranean transitional zone adds new evidence that challenges the Strait of Gibraltar as a phylogeographic barrier for marine pelagic species. These results are proposed to the ICCAT Commission to establish management areas for this species, although they are not consistent with the recently adopted pelagic ecoregions. Finally, a panel of highly informative SNPs was developed for efficient and low-cost population assignment and the analysis of unresolved population structures.

Assessing juvenile swordfish (Xiphias gladius) diet as an indicator of marine ecosystem changes in the northwestern Mediterranean Sea.

To preserve marine biodiversity, we need reliable early warning indicators that inform changes in marine ecosystems. As reliable samplers of mid-trophic level communities, studying the trophodynamics of large pelagic fish can contribute to monitoring these changes. Here, we combined stomach content and stable isotope analyses to reconstruct the diet of juvenile swordfish (Xiphias gladius) in the northwestern Mediterranean Sea, in a time-lapse of almost a decade (2012 and 2020). Overall, our study showed that swordfish fed on a wide range of fish and cephalopod species from both pelagic and demersal habitats. A dietary shift towards increasing consumption of cephalopods and decreasing consumption of Gadiformes had been observed between 2012 and 2020. Stable isotope approaches revealed that gelatinous organisms were also important prey, particularly for smaller-sized swordfish. We underline the importance of combining multiple and complementary approaches to better reconstruct the diet of generalist species. Our findings highlight the generalist and opportunistic diet of Mediterranean swordfish, which makes them good candidates for monitoring changes in the ecosystem.

Oocyte dynamics for Atlantic bluefin tuna (Thunnus thynnus) in the southern Gulf of Mexico: A comparative assessment of Mediterranean spawners using two stereological methods.

Although most research focused on the northern Gulf of Mexico for western Atlantic bluefin tuna, the histological records of reproductive activity of this species in the southern Gulf of Mexico (Mexican waters) have been presented for the first time. This work is the first to study oocyte dynamics in Atlantic bluefin tuna caught in the southern Gulf of Mexico by assessing and comparing them with Mediterranean stock (BFT-E) through stereology using two different methods. Regardless of Atlantic bluefin tuna females returning to their respective spawning grounds at different months in the southern Gulf of Mexico and the Mediterranean, both stocks arrived reproductively inactive and remained in these zones during periods of similar length; they were reproductively active until March for the southern Gulf of Mexico and May for the Mediterranean females. The comparison of the size structure between the two stocks examined using kernel density estimators demonstrated a quite remarkable difference in mean fork lengths between stocks. The ovarian oocyte density, that is, the number of oocytes per gram of ovary, for each gonad stage predicted using the Weibel and Gomez and oocyte packing density (OPD) methods did not significantly differ between stocks and showed that advanced vitellogenic oocytes from spawning-capable females are an appropriate indicator to estimate potential fecundity, presenting values of c. 1273 and ~1355 eggs per gram for the southern Gulf of Mexico and Mediterranean females, respectively. Females caught in Mexican waters (southern Gulf of Mexico) were larger than those caught in the Mediterranean; however, it was demonstrated that the length and weight of females did not affect ovarian oocyte density production. In addition, densities estimated for each gonad stage using W&G and OPD methods did not differ between stocks and presented equal patterns in their oocyte dynamics. These findings contribute to a better understanding of the reproductive biology of Atlantic bluefin tuna, especially in the southern Gulf of Mexico, due to the lack of information regarding this zone, and may allow to support strategies for proper assessment, management, and conservation.

Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer.

The accumulation of senescent cells in the tumor microenvironment can drive tumorigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse line, we show that macrophages and endothelial cells are the predominant senescent cell types in murine KRAS-driven lung tumors. Through single cell transcriptomics, we identify a population of tumor-associated macrophages that express a unique array of pro-tumorigenic SASP factors and surface proteins and are also present in normal aged lungs. Genetic or senolytic ablation of senescent cells, or macrophage depletion, result in a significant decrease in tumor burden and increased survival in KRAS-driven lung cancer models. Moreover, we reveal the presence of macrophages with senescent features in human lung pre-malignant lesions, but not in adenocarcinomas. Taken together, our results have uncovered the important role of senescent macrophages in the initiation and progression of lung cancer, highlighting potential therapeutic avenues and cancer preventative strategies.

The relative importance of biological and environmental factors on the trophodynamics of a pelagic marine predator, the blue shark (Prionace glauca).

Marine ecosystems have been significantly altered by the cumulative impacts of human activities. Pelagic sharks have become vulnerable to increases in mortality rates caused by fishing. The decrease in number of these top predators could have substantial cascading effects on wider marine communities. Concerns about these potential impacts, and the critical need for effective management, have led to an increased interest in assessing the trophic ecology of sharks. While stable isotope analyses have been used to provide relevant insights about the trophic ecology of sharks, the causal factors leading to trophic variation between individuals has been largely overlooked. Here, we investigated the relative effect of biological factors, geographic location, and environmental factors on the spatial trophodynamics of the blue shark (Prionace glauca). Specifically, stable isotope values of δ15N and δ13C, and the estimated trophic position (TP) were analysed for 180 blue sharks collected from south of the Canary Islands in the Atlantic Ocean, to the north-western Mediterranean Sea. The results showed that models which included combined variables explained the variation in δ15N, TP and δ13C values better than models which considered only stand-alone predictors. The independent contributions of environmental variables and biological factors seemed to be more important than geographic location for δ15N and TP. δ15N and TP increased in a curvilinear fashion with body size, and TP was higher for females. In the case of δ13C values, only an effect from sex was observed. Among environmental variables, chlorophyll-a, pelagic productivity, and sea-surface temperature proved to be reliable predictors, particularly for δ15N and TP, most likely due to their relationship with productivity and prey availability. This study provides new information on ranking the factors that influence the trophodynamics of the blue shark, namely the environment, the geographic location, and the biological factors of the species.

Comparison of the Capacitance of a Cyclically Fatigued Stretch Sensor to a Non-Fatigued Stretch Sensor When Performing Static and Dynamic Foot-Ankle Motions.

Motion capture is the current gold standard for assessing movement of the human body, but laboratory settings do not always mimic the natural terrains and movements encountered by humans. To overcome such limitations, a smart sock that is equipped with stretch sensors is being developed to record movement data outside of the laboratory. For the smart sock stretch sensors to provide valuable feedback, the sensors should have durability of both materials and signal. To test the durability of the stretch sensors, the sensors were exposed to high-cycle fatigue testing with simultaneous capture of the capacitance. Following randomization, either the fatigued sensor or an unfatigued sensor was placed in the plantarflexion position on the smart sock, and participants were asked to complete the following static movements: dorsiflexion, inversion, eversion, and plantarflexion. Participants were then asked to complete gait trials. The sensor was then exchanged for either an unfatigued or fatigued plantarflexion sensor, depending upon which sensor the trials began with, and each trial was repeated by the participant using the opposite sensor. Results of the tests show that for both the static and dynamic movements, the capacitive output of the fatigued sensor was consistently higher than that of the unfatigued sensor suggesting that an upwards drift of the capacitance was occurring in the fatigued sensors. More research is needed to determine whether stretch sensors should be pre-stretched prior to data collection, and to also determine whether the drift stabilizes once the cyclic softening of the materials comprising the sensor has stabilized.

Trends and Outcomes of Fungal Temporal Bone Osteomyelitis: A Scoping Review.

INTRODUCTION: Temporal bone osteomyelitis is an invasive infection most often caused by bacteria and associated with high mortality. Fungal etiologies are rare and little is known of the predictors of disease severity and outcomes in fungal temporal bone osteomyelitis. MATERIALS AND METHODS: A scoping review was performed to determine what is known from the literature on how clinical, diagnostic, and treatment characteristics relate to patient outcomes in fungal temporal bone osteomyelitis. Using PRISMA guidelines, three databases were searched to identify all published cases of fungal temporal bone osteomyelitis. Data were extracted from each study, including clinical, diagnostic, and treatment characteristics, and outcomes. RESULTS: Sixty-eight studies comprising 74 individual cases of fungal temporal bone osteomyelitis were included. All studies were case reports. There were high rates of diabetes, facial nerve palsy, infectious complications, and need for surgical intervention, as well as a significant delay in the evaluation and diagnosis of fungal temporal bone osteomyelitis. Disease recovery was greater in patients presenting with otorrhea, comorbid diabetes, and in those without facial nerve palsy. DISCUSSION: Many of the defining characteristics of fungal temporal bone osteomyelitis remain unknown, and future reports should focus on determining factors that improve timely diagnosis and treatment of fungal TBO in addition to identifying prognostic indicators for outcomes and survival.

Factors associated with the differential distribution of cetaceans linked with deep habitats in the Western Mediterranean Sea.

Deep-habitat cetaceans are generally difficult to study, leading to a limited knowledge of their population. This paper assesses the differential distribution patterns of three deep-habitat cetaceans (Sperm whale-Physeter macrocephalus, Risso's dolphin-Grampus griseus & Cuvier's beaked whale-Ziphius cavirostris). We used data of 842 opportunistic sightings of cetaceans in the western Mediterranean sea. We inferred environmental and spatio-temporal factors that affect their distribution. Binary logistic regression models were generated to compare the presence of deep-habitat cetaceans with the presence of other cetacean species in the dataset. Then, the favourability function was applied, allowing for comparison between all the models. Sperm whale and Risso's dolphin presence was differentially favoured by the distance to towns in the eastern part of the western Mediterranean sea. The differential distribution of sperm whale was also influenced by the stability of SST, and that of the Risso's dolphin by lower mean salinity and higher mean Chlorophyll A concentration. When modelling the three deep-habitat cetaceans (including Cuvier's beaked whale), the variable distance to towns had a negative influence on the presence of any of them more than it did to other cetaceans, being more favourable far from towns, so this issue should be further investigated.

Species-specific heavy metal concentrations of tuna species: the case of Thunnus alalunga and Katsuwonus pelamis in the Western Mediterranean.

Albacore Thunnus alalunga and skipjack tuna Katsuwonus pelamis are highly migratory species that are usually caught together in the Western Mediterranean. These species are top predators that are highly affected by the biomagnification process through the trophic chain. Bioaccumulation pattern of the main metal pollutants (mercury, Hg; lead, Pb; and cadmium, Cd) were analyzed in muscle tissues of 52 individuals (26 T. alalunga and 26 K. pelamis) of these highly consumed species in order to address two objectives: (1) compare the species-specific bioaccumulation between these large-pelagic species, and (2) assess the healthy properties of such valuable resources based on the trace metal limits established by the European Commission Regulation (ECR). Both generalized linear mixed models and redundancy analysis indicated a differential bioaccumulation between these two tuna species. While T. alalunga accumulates higher concentrations of Hg (0.1996 ± 0.0602 mg·kg-1 weight wet-ww), K. pelamis accumulates higher concentrations of Cd (0.0076 ± 0.0049 mg·kg-1 ww) and Pb (0.0031 ± 0.0017 mg·kg-1 ww). Size and trophic ecology support the differences detected in the bioaccumulation pattern. Heavy metal concentrations were below the tolerable limits considered by ECR (1, 0.1, and 0.3 mg·kg-1 ww for Hg, Cd, and Pb, respectively).

Prescripción potencialmente inapropiada y polifarmacia en adultos mayores con demencia moderada y severa / Potentially inappropriate prescription and polypharmacy in older adults with dementia moderate and severe

Objetivo: Determinar la prevalencia de polifarmacia y prescripciones potencialmente inapropiadas (PPI) en pacientes mayores con demencia moderada y grave. Material y métodos: Este estudio retrospectivo transversal incluyó 180 pacientes diagnosticados con demencia durante junio de 2018 a abril de 2019. Se analizaron variables demográficas, comorbilidades, tipo de demencia, número de fármacos prescritos y la prevalencia de prescripción inadecuada. Resultados: La edad media fue 80,5 (±7,4) años. La demencia más frecuente fue Alzheimer (50%). 150 (83%) y 90 (50%) pacientes fueron detectados con polifarmacia y PPI, respectivamente. Las PPI más frecuentes fueron: fármacos que afectan la probabilidad de caída (22%), el sistema nervioso central y cardiovascular (14%). El riesgo de PPI fue 2,29 veces mayor en aquellos con polifarmacia. Discusión: En pacientes con demencia moderada y severa la polifarmacia aumenta el riesgo de PPI, siendo ambas altamente prevalentes. Revisar constantemente la medicación en esta población es necesario para reducir los riesgos a la salud (AU)

Objective: To determine the prevalence of polypharmacy and potentially inappropriate prescriptions (PIP) in older patients with moderate and severe dementia. Methods: This retrospective, cross-sectional study included 180 patients diagnosed with dementia during June 2018 to April 2019. We analyzed demographic variables, comorbidities, type of dementia, number of drugs prescribed and the prevalence of inadequate prescription. Results: Mean age was 80.5 (±7.4) years. Alzheimer's disease was the most frequent dementia (50%). 150 (83%) and 90 (50%) patients were detected with polypharmacy and PIP, respectively. The most frequent PIP were about drugs that affect individual’s probability of falling (22%), the central nervous system and the cardiovascular system (14%). The risk of PIP was 2,29 times higher in those with polypharmacy. Discussion: Polypharmacy and PPI are highly prevalent in older adults with moderate and severe dementia. Polypharmacy increases the risk of PIP. A continuous evaluation of the medication in this population is necessary to reduce the risk of adverse events (AU)

Association of Inventory to Measure and Assess imaGe Disturbance - Head and Neck Scores With Clinically Meaningful Body Image-Related Distress Among Head and Neck Cancer Survivors.

Objective: The Inventory to Measure and Assess imaGe disturbance - Head and Neck (IMAGE-HN) is a validated patient-reported outcome measure of head and neck cancer-related body image-related distress (BID). However, the IMAGE-HN score corresponding to clinically relevant BID is unknown. The study objective is to determine the IMAGE-HN cutoff score that identifies head and neck cancer patients with clinically relevant BID. Methods: We conducted a cross-sectional study at six academic medical centers. Individuals ≥18 years old with a history of head and neck cancer treated with definitive intent were included. The primary outcome measure was the IMAGE-HN. A Receiver Operating Characteristic curve analysis was performed to identify the IMAGE-HN score that maximized sensitivity and specificity relative to a Body Image Scale score of ≥10 (which indicates clinically relevant BID in a general oncology population). To confirm the validity of the IMAGE-HN cutoff score, we compared the severity of depressive [Patient Health Questionnaire-9 (PHQ-9)] and anxiety symptoms [Generalized Anxiety Disorder-7 (GAD-7)], and quality of life [University of Washington-QOL (UW-QOL)] in patients with IMAGE-HN scores above and below the cutoff. Results: Of the 250 patients, 70.4% were male and the mean age was 62.3 years. An IMAGE-HN score of ≥22 was the optimal cutoff score relative to a Body Image Scale score of ≥10 and represents a clinically relevant level of head and neck cancer-related BID. Relative to those with an IMAGE-HN score of <22, patients with IMAGE-HN scores of ≥22 had a clinically meaningful increase in symptoms of depression (mean PHQ-9 score difference = 5.8) and anxiety (mean GAD-7 score difference = 4.1) as well as worse physical (mean UW-QOL score difference = 18.9) and social-emotional QOL (mean UW-QOL score difference = 21.5). Using an IMAGE-HN cutoff score ≥22, 28% of patients had clinically relevant BID. Conclusion: An IMAGE-HN score of ≥22 identifies patients with clinically relevant head and neck cancer-related BID. This score may be used to detect patients who could benefit from strategies to manage their distress, select patients for studies evaluating interventions to manage head and neck cancer-related BID, and improve our understanding of the underlying epidemiology of the disorder.

Fatigue Testing of Wearable Sensing Technologies: Issues and Opportunities.

Standards for the fatigue testing of wearable sensing technologies are lacking. The majority of published fatigue tests for wearable sensors are performed on proof-of-concept stretch sensors fabricated from a variety of materials. Due to their flexibility and stretchability, polymers are often used in the fabrication of wearable sensors. Other materials, including textiles, carbon nanotubes, graphene, and conductive metals or inks, may be used in conjunction with polymers to fabricate wearable sensors. Depending on the combination of the materials used, the fatigue behaviors of wearable sensors can vary. Additionally, fatigue testing methodologies for the sensors also vary, with most tests focusing only on the low-cycle fatigue (LCF) regime, and few sensors are cycled until failure or runout are achieved. Fatigue life predictions of wearable sensors are also lacking. These issues make direct comparisons of wearable sensors difficult. To facilitate direct comparisons of wearable sensors and to move proof-of-concept sensors from "bench to bedside", fatigue testing standards should be established. Further, both high-cycle fatigue (HCF) and failure data are needed to determine the appropriateness in the use, modification, development, and validation of fatigue life prediction models and to further the understanding of how cracks initiate and propagate in wearable sensing technologies.

Factors Associated With Risk of Body Image-Related Distress in Patients With Head and Neck Cancer.

Importance: Body image-related distress (BID) is common among head and neck cancer (HNC) survivors and associated with significant morbidity. Risk factors for HNC-related BID remain poorly characterized because prior research has used outcome measures that fail to fully capture BID as experienced by HNC survivors. Objective: To assess the association of demographic and oncologic characteristics with HNC-related BID using the Inventory to Measure and Assess imaGe disturbancE-Head & Neck (IMAGE-HN), a validated, multidomain, patient-reported outcome measure of HNC-related BID. Design, Setting, and Participants: This cross-sectional study assessed 301 adult survivors of surgically managed HNC at 4 academic medical centers. Main Outcomes and Measures: The primary outcome measure was IMAGE-HN scores, for which higher scores reflect more severe HNC-related BID. Multivariable linear regression analyses were performed to evaluate the association of patient characteristics with IMAGE-HN global and 4 subdomain (other-oriented appearance concerns, personal dissatisfaction with appearance, distress with functional impairments, and social avoidance) scores. Results: Of the 301 participants (212 [70.4%] male; mean [SD] age, 65.3 [11.7] years), 181 (60.1%) underwent free flap reconstruction. Graduation from college (ß = -9.6; 95% CI, -17.5 to -1.7) or graduate school (ß = -12.6; 95% CI, -21.2 to -3.8) was associated with lower IMAGE-HN social avoidance scores compared with less than a high school education. Compared with paid work, unemployment was associated with higher IMAGE-HN other-oriented appearance (ß = 10.7; 95% CI, 2.0-19.3), personal dissatisfaction with appearance (ß = 12.5; 95% CI, 1.2-23.7), and global (ß = 8.0; 95% CI, 0.6-15.4) scores. Compared with no reconstruction, free flap reconstruction was associated with higher IMAGE-HN global scores (ß = 11.5; 95% CI, 7.9-15.0) and all subdomain scores (other-oriented appearance: ß = 13.1; 95% CI, 8.6-17.6; personal dissatisfaction with appearance: ß = 15.4; 95% CI, 10.0-20.7; distress with functional impairment: ß = 12.8; 95% CI, 8.1-17.4; and social avoidance and isolation: ß = 10.2; 95% CI, 5.8-14.6). Higher IMAGE-HN distress with functional impairment scores were found in those who received surgery and adjuvant radiation (ß = 7.8; 95% CI, 2.9-12.7) or chemoradiotherapy (ß = 6.5; 95% CI, 1.8-11.3) compared with surgery alone. The multivariable regression model accounted for a modest proportion of variance in IMAGE-HN global (R2 = 0.18) and subdomain scores (R2 = 0.20 for other-oriented appearance, 0.14 for personal dissatisfaction with appearance, 0.21 for distress with functional impairment, and 0.13 for social avoidance and isolation). Conclusions and Relevance: In this cross-sectional study, factors associated with risk of HNC-related BID included free flap reconstruction, lower educational attainment, unemployment, and multiple treatment modalities. These characteristics explain a modest proportion of variance in IMAGE-HN scores, suggesting that other characteristics may be the major risk factors for HNC-related BID and should be explored in future studies.

Genetic validation of the unexpected presence of a tropical tuna, bigeye tuna (Thunnus obesus), in the Mediterranean.

Bigeye tuna (Thunnus obesus, Lowe, 1839) is one of the eight recognized species of the genus Thunnus. It is considered a tropical species distributed in the Atlantic, Pacific and Indian Oceans. To date, no validated presence of this species has been reported inside the Mediterranean Sea. This study, however, confirms, for the first time, the presence of three young individuals of this species within the Mediterranean Sea.

Endothelial cell regulation of systemic haemodynamics and metabolism acts through the HIF transcription factors.

BACKGROUND: The vascular endothelium has important endocrine and paracrine roles, particularly in the regulation of vascular tone and immune function, and it has been implicated in the pathophysiology of a range of cardiovascular and inflammatory conditions. This study uses a series of transgenic murine models to explore for the first time the role of the hypoxia-inducible factors, HIF-1α and HIF-2α in the pulmonary and systemic circulations as potential regulators of systemic vascular function in normoxic or hypoxic conditions and in response to inflammatory stress. We developed a series of transgenic mouse models, the HIF-1α Tie2Cre, deficient in HIF1-α in the systemic and pulmonary vascular endothelium and the L1Cre, a pulmonary endothelium specific knockout of HIF-1α or HIF-2α. In vivo, arterial blood pressure and metabolic activity were monitored continuously in normal atmospheric conditions and following an acute stimulus with hypoxia (10%) or lipopolysaccharide (LPS). Ex vivo, femoral artery reactivity was assessed using wire myography. RESULTS: Under normoxia, the HIF-1α Tie2Cre mouse had increased systolic and diastolic arterial pressure compared to litter mate controls over the day-night cycle under normal environmental conditions. VO2 and VCO2 were also increased. Femoral arteries displayed impaired endothelial relaxation in response to acetylcholine mediated by a reduction in the nitric oxide dependent portion of the response. HIF-1α L1Cre mice displayed a similar pattern of increased systemic blood pressure, metabolic rate and impaired vascular relaxation without features of pulmonary hypertension, polycythaemia or renal dysfunction under normal conditions. In response to acute hypoxia, deficiency of HIF-1α was associated with faster resolution of hypoxia-induced haemodynamic and metabolic compromise. In addition, systemic haemodynamics were less compromised by LPS treatment. CONCLUSIONS: These data show that deficiency of HIF-1α in the systemic or pulmonary endothelium is associated with increased systemic blood pressure and metabolic rate, a pattern that persists in both normoxic conditions and in response to acute stress with potential implications for our understanding of the pathophysiology of vascular dysfunction in acute and chronic disease.

Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant hypoxia-inducible factor (HIF)2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades.Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH. Haemodynamic measurements were performed, followed by collection of heart, lung and blood for pathological, gene expression and biochemical analysis. Blood outgrowth endothelial cells from idiopathic PAH patients were used to determine the impact of HIF2α-inhibition on endothelial function.Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models. PT2567 intervention reduced the expression of PH-associated target genes in both lung and cardiac tissues and restored plasma nitrite concentration. Treatment of monocrotaline-exposed rodents with PT2567 reduced the impact on cardiovascular haemodynamics and promoted a survival advantage. In vitro, loss of HIF2α signalling in human pulmonary arterial endothelial cells suppresses target genes associated with inflammation, and PT2567 reduced the hyperproliferative phenotype and overactive arginase activity in blood outgrowth endothelial cells from idiopathic PAH patients. These data suggest that targeting HIF2α hetero-dimerisation with an orally bioavailable compound could offer a new therapeutic approach for PAH. Future studies are required to determine the role of HIF in the heterogeneous PAH population.

Duplication of the oral cavity and mandible: a rare congenital craniofacial anomaly.

A newborn girl was referred to the otolaryngology service after prenatal imaging showed a right mandibular mass. Physical examination revealed a 1-2 cm mass along the right mandible with the appearance of a vestigial oral cavity. Tissue resembling the vermillion and primitive tongue appeared innervated and moved in conjunction with oral movements. MRI and CT of the mandible after birth confirmed a partially ossified soft tissue mass of the right mandibular body, containing unerupted teeth. She was taken to the operating room at 6 months of age for mass excision and reconstruction. Postoperatively, she healed well and was feeding without difficulty. Craniofacial duplication, including duplication of stomatodeal structures or diprosopus, is a rare condition with a variety of phenotypes. In the case of suspected craniofacial duplication, associated syndromes should be ruled out and appropriate imaging employed to determine the extent of involvement of adjacent structures, which will ultimately guide surgical planning.

Low dose lung radiotherapy for COVID-19 pneumonia. The rationale for a cost-effective anti-inflammatory treatment.

The COVID-19 pandemia is affecting people worldwide. Most of the patients suffered of a respiratory disease that will progress to an acute respiratory distress syndrome (ARDS). SARS-CoV-2 pneumonia severely ill patients, develop a systemic inflammatory response with a Cytokine Release Syndrome (CRS), that is characterized by a sudden increase in several pro-inflammatory cytokines, mainly IL-1, IL-6 and TNF-alfa by activated macrophages (M1 phenotype). Blocking IL-6 with tocilizumab and using respirator equipment seems to be a very important issue in this (SARS-CoV-2) pneumonia, but not all patients are referred to such treatments. Low dose radiotherapy (0,5 Gy), is an evidence-based anti-inflammatory treatment, that could modify the immune landscape in the lung affected of SARS-CoV-2 pneumonia, through macrophages polarization to alternatively activated Macrophages (M2 phenotype). Radiation-induced cancer risk could be assumed due to the very low dose used, the advanced age of the patients and the life-threatening condition of SARS-Cov2 pneumonia. LDRT is a cost-effective non-toxic treatment already available in most general hospitals. This fact allows that it would be used for the large number of patients that will suffer this disease, and that would not receive specific anti-IL-6 treatments in ICUs in low and middle income countries.