An Integrated Experimental-Computational Study of Vocal Fold Vibration in Type I Thyroplasty.

Subject-specific computational modeling of vocal fold (VF) vibration was integrated with an ex vivo animal experiment of type 1 thyroplasty to study the effect of the implant on the vocal fold vibration. In the experiment, a rabbit larynx was used to simulate type 1 thyroplasty, where one side of the vocal fold was medialized with a trans-muscular suture while the other side was medialized with a silastic implant. Vocal fold vibration was then achieved by flowing air through the larynx and was filmed with a high-speed camera. The three-dimensional computational model was built upon the pre-operative scan of the laryngeal anatomy. This subject-specific model was used to simulate the vocal fold medialization and then the fluid-structure interaction (FSI) of the vocal fold. Model validation was done by comparing the vocal fold displacement with postoperative scan (for medialization), and by comparing the vibratory characteristics with the high-speed images (for vibration). These comparisons showed the computational model successfully captured the effect of the implant and thus has the potential for presurgical planning.

A Comparison of Long-Term Outcomes in Patients Managed With Venovenous Extracorporeal Membrane Oxygenation in the First and Second Waves of the COVID-19 Pandemic in the United Kingdom.

OBJECTIVES: Early studies of venovenous extracorporeal membrane oxygenation (ECMO) in COVID-19 have revealed similar outcomes to historical cohorts. Changes in the disease and treatments have led to differences in the patients supported on venovenous ECMO in the first and second waves. We aimed to compare these two groups in both the acute and follow-up phase. DESIGN: Retrospective single-center cohort study comparing mortality at censoring date (November 30, 2021) and decannulation, patient characteristics, complications and lung function and quality of life (QOL-by European Quality of Life 5 Dimensions 3 Level Version) at first follow-up in patients supported on venovenous ECMO between wave 1 and wave 2 of the COVID-19 pandemic. SETTING: Critical care department of a severe acute respiratory failure service. PATIENTS: Patients supported on ECMO for COVID-19 between wave 1 (March 17, 2020, to August 31, 2020) and wave 2 (January 9, 2020, to May 25, 2021). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred twenty-three patients were included in our analysis. Survival at censoring date (χ 2 , 6.35; p = 0.012) and decannulation (90.4% vs 70.0%; p < 0.001) was significantly lower in the second wave, while duration of ECMO run was longer (12.0 d [18.0-30.0 d] vs 29.5 d [15.5-58.3 d]; p = 0.005). Wave 2 patients had longer application of noninvasive ventilation (NIV) prior to ECMO and a higher frequency of barotrauma. Patient age and NIV use were independently associated with increased mortality (odds ratio 1.07 [1.01-1.14]; p = 0.025 and 3.37 [1.12-12.60]; p = 0.043, respectively). QOL and lung function apart from transfer coefficient of carbon monoxide corrected for hemoglobin was similar at follow-up across the waves. CONCLUSIONS: Most patients with COVID-19 supported on ECMO in both waves survived in the short and longer term. At follow-up patients had similar lung function and QOL across the two waves. This suggests that ECMO has an ongoing role in the management of a carefully selected group of patients with COVID-19.

Continuous renal replacement therapy in patients receiving extracorporeal membrane oxygenation therapy.

Methods of continuous renal replacement therapy (CRRT) in extracorporeal membrane oxygenation (ECMO) patients include dedicated central venous cannula (CVC) (vCRRT), in-series with filter connected to ECMO circuit (eCRRT) or in-line with haemodiafilter incorporated within ECMO circuit. We assessed the efficacy and safety of eCRRT versus vCRRT in 20 ECMO-CRRT patients. Average filter lifespan was 42 vs 28 hours and filter runs completing 72hours were 40% vs 13.8% (eCRRT vs vCRRT, respectively). One incidence of ECMO circuit air embolus occurred (vCRRT). eCRRT achieved adequate filtration and increased filter lifespan, and has become our default for ECMO-CRRT if a pre-existing dialysis CVC is not present.

Genetic Interactions of Progranulin Across the ALS-FTD Spectrum and Beyond.

Progranulin (PGRN) is a growth factor in which mutations are one of the leading causes of frontotemporal dementia (FTD), and has been implicated in an assortment of neurodegenerative diseases. Conversely, higher levels of the protein have shown potential as a general neuronal protective factor. While examining its neuroprotective applications on a broader scale would be unfeasible in mammalian models, we turned to the nematode C. elegans to map the interactions of PGRN across multiple genetic models of neurodegenerative diseases. Our results indicate that while the overexpression of PGRN appears to be protective across all models tested, the loss of PGRN exacerbated the disease phenotypes of all but three of the models tested. Given the ease of genetic analysis in nematodes, we propose this model organism as an efficient tool to build a comprehensive map of PGRN's genetic interactions.

Cefazolin-induced hypoprothrombinemia.

Long-term antibiotic use can be associated with a myriad of side effects, ranging from relatively benign to life-threatening. The most common side effects of cephalosporins include dermatologic reactions and diarrhea. Here, we present a rarer side effect: a spontaneous retroperitoneal hematoma in the setting of cefazolin administration for vertebral osteomyelitis. Several cephalosporins have been implicated in coagulopathy secondary to hypoprothrombinemia. However, only a few case reports have implicated cefazolin, and all have occurred in the context of acute or chronic renal failure. Our case of cefazolin-induced coagulopathy occurred in a patient with normal renal function.

Metastasis of Renal Cell Carcinoma to the Stomach Twenty One Years from Initial Diagnosis.

A female in her 80's presented to our Emergency Department following a fall. She reported general malaise, weight loss and raised inflammatory markers. Background included renal cell carcinoma 21 years previous, managed with radical nephrectomy. During her inpatient stay she had an episode of haematemesis. Upper GI endoscopy revealed a 3cm polypoidal lesion on the greater curve of the upper stomach. This had an irregular pit pattern endoscopically and was friable. Multiple biopsies revealed metastatic clear cell carcinoma of renal origin; the same sub-type as her previous renal tumour. This is a rare manifestation of metastatic renal cell carcinoma and from literature review, is only the 2nd case we can find with a lag time of >20 years from the initial diagnosis to presenting with metastatic gastric disease.

Modeling the Morphodynamics of Coastal Responses to Extreme Events: What Shape Are We In?

This review focuses on recent advances in process-based numerical models of the impact of extreme storms on sandy coasts. Driven by larger-scale models of meteorology and hydrodynamics, these models simulate morphodynamics across the Sallenger storm-impact scale, including swash,collision, overwash, and inundation. Models are becoming both wider (as more processes are added) and deeper (as detailed physics replaces earlier parameterizations). Algorithms for wave-induced flows and sediment transport under shoaling waves are among the recent developments. Community and open-source models have become the norm. Observations of initial conditions (topography, land cover, and sediment characteristics) have become more detailed, and improvements in tropical cyclone and wave models provide forcing (winds, waves, surge, and upland flow) that is better resolved and more accurate, yielding commensurate improvements in model skill. We foresee that future storm-impact models will increasingly resolve individual waves, apply data assimilation, and be used in ensemble modeling modes to predict uncertainties.

An olfactory neuroblastoma presenting as posterior reversible leukoencephalopathy syndrome.

Olfactory neuroblastomas are rare malignancies of the nasal and sinus cavities. They have been associated with paraneoplastic syndromes due to secretion of adrenocorticotropin hormone (ACTH) or antidiuretic hormone. These associated paraneoplastic syndromes can present with a wide variety of symptoms that can make diagnosis of the underlying tumor difficult. Here we present the case of a 23-year-old woman who had a seizure due to the development of posterior reversible leukoencephalopathy syndrome because of secondary hypertension due to Cushing's syndrome, which was in turn found to be due to ectopic ACTH production from a metastatic olfactory neuroblastoma.

Hemophagocytic lymphohistiocytosis due to pembrolizumab therapy for adenocarcinoma of the lung.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder of dysregulated inflammation. It is most commonly seen in children who have a predisposing genetic mutation. However, adults can contract an acquired version of the disorder secondary to an infectious, neoplastic, or other inflammatory insult. There have been several documented cases of HLH being induced by treatment with immunotherapy. Here, we present the case of a 71-year-old man who was receiving pembrolizumab for lung adenocarcinoma when he developed HLH following his 14th cycle of therapy. Although bone marrow biopsy was negative, he nevertheless fulfilled the diagnostic criteria of the HLH 2004 report and was treated with high-dose steroids followed by a prolonged taper, with resolution of his symptoms and normalization of his blood counts.

Reviewing the Outcomes of Different Treatment Approaches in Elderly Pancreatic Cancer Patients.

OBJECTIVES: The incidence of pancreatic cancer is age dependent. Ninety percent of new diagnoses occur in patients older than 55 years. Despite the association with age and cancer, elderly patients are historically underrepresented in clinical trials. Thus, optimal management of elderly patients has a lack of data. The purpose of this retrospective study was to investigate the outcomes of palliative chemotherapy in elderly patients with pancreatic cancer compared with supportive care alone. METHODS: Unicentric data were reviewed on all elderly patients (defined as age >65 years) with a diagnosis of pancreatic cancer from 2008 through 2019 to compare outcomes in those who received chemotherapy versus supportive care alone. RESULTS: The study reviewed 665 patients with a median age of 75 years (mean, 75.7 years) and average Charlson Comorbidity Score of 5.74. Of them, 291 received chemotherapy and 363 received supportive care only. Chemotherapy was associated with a median overall survival of 250 versus 93 days with supportive care (P < 0.0001). Analysis showed improved survival for all age ranges, cancer stages, and Charlson Comorbidity Scores. CONCLUSIONS: Elderly pancreatic cancer patients can benefit from palliative chemotherapy, and it should be considered, especially in patients with fewer medical comorbidities and better functional status.

A single copy transgenic mutant FUS strain reproduces age-dependent ALS phenotypes in C. elegans.

Mutations in the human DNA/RNA binding protein FUS are associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration, including some aggressive and juvenile onset forms. Cytoplasmic inclusions of human FUS proteins are observed in various neurodegenerative disorders, such as Huntington's disease or spinocerebellar ataxia, suggesting that FUS proteinopathy may be a key player in neurodegeneration. To better understand the pathogenic mechanisms of FUS, we created single copy transgenic Caenorhabditis elegans strains expressing full-length, untagged human FUS in the worm's GABAergic neurons. These transgenic worms expressing human mutant FUS (mFUS) display the same ALS-associated phenotypes than our previous multiple copy transgenic model, including adult-onset age-dependent loss of motility, progressive paralysis and GABAergic neurodegeneration. These phenotypes are distinct from the transgenic worms expressing human wild-type FUS (wtFUS). We introduce here our C. elegans single copy transgenic for human mutant FUS motor neuron toxicity that may be used for rapid genetic and pharmacological suppressor screening.

Six Month Mortality in Patients with COVID-19 and Non-COVID-19 Viral Pneumonitis Managed with Veno-Venous Extracorporeal Membrane Oxygenation.

A significant proportion of patients with COVID-19 develop acute respiratory distress syndrome (ARDS) with high risk of death. The efficacy of veno-venous extracorporeal membrane oxygenation (VV-ECMO) for COVID-19 on longer-term outcomes, unlike in other viral pneumonias, is unknown. In this study, we aimed to compare the 6 month mortality of patients receiving VV-ECMO support for COVID-19 with a historical viral ARDS cohort. Fifty-three consecutive patients with COVID-19 ARDS admitted for VV-ECMO to the Royal Brompton Hospital between March 17, 2020 and May 30, 2020 were identified. Mortality, patient characteristics, complications, and ECMO parameters were then compared to a historical cohort of patients with non-COVID-19 viral pneumonia. At 6 months survival was significantly higher in the COVID-19 than in the non-COVID-19 viral pneumonia cohort (84.9% vs. 66.0%, p = 0.040). Patients with COVID-19 had an increased Murray score (3.50 vs. 3.25, p = 0.005), a decreased burden of organ dysfunction (sequential organ failure score score [8.76 vs. 10.42, p = 0.004]), an increased incidence of pulmonary embolism (69.8% vs. 24.5%, p < 0.001) and in those who survived to decannulation longer ECMO runs (19 vs. 11 days, p = 0.001). Our results suggest that survival in patients supported with EMCO for COVID-19 are at least as good as those treated for non-COVID-19 viral ARDS.

Chemical and genetic rescue of in vivo progranulin-deficient lysosomal and autophagic defects.

In 2006, GRN mutations were first linked to frontotemporal dementia (FTD), the leading cause of non-Alzheimer dementias. While much research has been dedicated to understanding the genetic causes of the disease, our understanding of the mechanistic impacts of GRN deficiency has only recently begun to take shape. With no known cure or treatment available for GRN-related FTD, there is a growing need to rapidly advance genetic and/or small-molecule therapeutics for this disease. This issue is complicated by the fact that, while lysosomal dysfunction seems to be a key driver of pathology, the mechanisms linking a loss of GRN to a pathogenic state remain unclear. In our attempt to address these key issues, we have turned to the nematode, Caenorhabditis elegans, to model, study, and find potential therapies for GRN-deficient FTD. First, we show that the loss of the nematode GRN ortholog, pgrn-1, results in several behavioral and molecular defects, including lysosomal dysfunction and defects in autophagic flux. Our investigations implicate the sphingolipid metabolic pathway in the regulation of many of the in vivo defects associated with pgrn-1 loss. Finally, we utilized these nematodes as an in vivo tool for high-throughput drug screening and identified two small molecules with potential therapeutic applications against GRN/pgrn-1 deficiency. These compounds reverse the biochemical, cellular, and functional phenotypes of GRN deficiency. Together, our results open avenues for mechanistic and therapeutic research into the outcomes of GRN-related neurodegeneration, both genetic and molecular.

Veno-venous extracorporeal membrane oxygenation for the acute respiratory distress syndrome: a bridge too far?

Veno-Venous Extracorporeal Membrane Oxygenation (VV-ECMO) provides a bridge to recovery in patients with acute respiratory failure due to the acute respiratory distress syndrome (ARDS). Survival in ARDS has improved over 15 years, and VV-ECMO may rescue even the most severe of these patients. Predictors of survival on ICU are based upon the principles of reversibility of the inciting aetiology, and premorbid 'reserve' - an imprecise term encompassing comorbidities and frailty. ECMO can support failing organs for prolonged periods, thus sometimes masking trajectories of decline, or unmasking irretrievable intrinsic conditions at a later time point in the critical illness. Clinicians are confronted with new on-treatment dilemmas: how long should we continue this high level of care? Will the patient's limited respiratory reserve manage off ECMO? Or are we hastening their demise? How long is it justifiable to keep someone on ECMO, if the predicted survival off is ultimately poor, but they are in a stable state whilst supported? The palliative withdrawal from ECMO is unchartered territory that requires further study. We describe two representative cases and discuss the wide ethical issues surrounding the initiation and withdrawal of ECMO.

Modulating the endoplasmic reticulum stress response attenuates neurodegeneration in a Caenorhabditiselegans model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a devastating autosomal recessive neuromuscular disease resulting in muscle atrophy and neurodegeneration, and is the leading genetic cause of infant death. SMA arises when there are homozygous deletion mutations in the human SMN1 gene, leading to a decrease in corresponding SMN1 protein. Although SMN1 is expressed across multiple tissue types, much of the previous research into SMA focused on the neuronal aspect of the disease, overlooking many of the potential non-neuronal aspects of the disease. Therefore, we sought to address this gap in knowledge by modeling SMA in the nematode Caenorhabditis elegans We mutated a previously uncharacterized allele, which resulted in the onset of mild SMA-like phenotypes, allowing us to monitor the onset of phenotypes at different stages. We observed that these mutant animals recapitulated many key features of the human disease, and most importantly, we observed that muscle dysfunction preceded neurodegeneration. Furthermore, we tested the therapeutic efficacy of targeting endoplasmic reticulum (ER) stress in non-neuronal cells and found it to be more effective than targeting ER stress in neuronal cells. We also found that the most potent therapeutic potential came from a combination of ER- and neuromuscular junction-targeted drugs. Together, our results suggest an important non-neuronal component of SMA pathology and highlight new considerations for therapeutic intervention.

Pulmonary Angiopathy in Severe COVID-19: Physiologic, Imaging, and Hematologic Observations.

Rationale: Clinical and epidemiologic data in coronavirus disease (COVID-19) have accrued rapidly since the outbreak, but few address the underlying pathophysiology.Objectives: To ascertain the physiologic, hematologic, and imaging basis of lung injury in severe COVID-19 pneumonia.Methods: Clinical, physiologic, and laboratory data were collated. Radiologic (computed tomography (CT) pulmonary angiography [n = 39] and dual-energy CT [DECT, n = 20]) studies were evaluated: observers quantified CT patterns (including the extent of abnormal lung and the presence and extent of dilated peripheral vessels) and perfusion defects on DECT. Coagulation status was assessed using thromboelastography.Measurements and Results: In 39 consecutive patients (male:female, 32:7; mean age, 53 ± 10 yr [range, 29-79 yr]; Black and minority ethnic, n = 25 [64%]), there was a significant vascular perfusion abnormality and increased physiologic dead space (dynamic compliance, 33.7 ± 14.7 ml/cm H2O; Murray lung injury score, 3.14 ± 0.53; mean ventilatory ratios, 2.6 ± 0.8) with evidence of hypercoagulability and fibrinolytic "shutdown". The mean CT extent (±SD) of normally aerated lung, ground-glass opacification, and dense parenchymal opacification were 23.5 ± 16.7%, 36.3 ± 24.7%, and 42.7 ± 27.1%, respectively. Dilated peripheral vessels were present in 21/33 (63.6%) patients with at least two assessable lobes (including 10/21 [47.6%] with no evidence of acute pulmonary emboli). Perfusion defects on DECT (assessable in 18/20 [90%]) were present in all patients (wedge-shaped, n = 3; mottled, n = 9; mixed pattern, n = 6).Conclusions: Physiologic, hematologic, and imaging data show not only the presence of a hypercoagulable phenotype in severe COVID-19 pneumonia but also markedly impaired pulmonary perfusion likely caused by pulmonary angiopathy and thrombosis.

Evidence for an extinct lineage of angiosperms from the Early Cretaceous of Patagonia and implications for the early radiation of flowering plants.

The pinnately lobed Aptian leaf fossil Mesodescolea plicata was originally described as a cycad, but new evidence from cuticle structure suggests that it is an angiosperm. Here we document the morphology and cuticle anatomy of Mesodescolea and explore its significance for early angiosperm evolution. We observed macrofossils and cuticles of Mesodescolea with light, scanning electron and transmission electron microscopy, and used phylogenetic methods to test its relationships among extant angiosperms. Mesodescolea has chloranthoid teeth and tertiary veins forming elongate areoles. Its cuticular morphology and ultrastructure reject cycadalean affinities, whereas its guard cell shape and stomatal ledges are angiospermous. It shares variable stomatal complexes and epidermal oil cells with angiosperm leaves from the lower Potomac Group. Phylogenetic analyses and hypothesis testing support its placement within the basal ANITA grade, most likely in Austrobaileyales, but it diverges markedly in leaf form and venation. Although many Early Cretaceous angiosperms fall within the morphological range of extant taxa, Mesodescolea reveals unexpected early morphological and ecophysiological trends. Its similarity to other Early Cretaceous lobate leaves, many identified previously as eudicots but in some cases pre-dating the appearance of tricolpate pollen, may indicate that Mesodescolea is part of a larger extinct lineage of angiosperms.

Waist-to-Hip Ratio as Supernormal Stimuli: Effect of Contrapposto Pose and Viewing Angle.

In women, the waist-to-hip ratio (WHR) is an indicator of attractiveness, health, youthfulness, and reproductive potential. In the current study, we hypothesized that viewing angle and body postures influence the attractiveness of these forms based on the view dependency of WHR stimuli (vdWHR). Using eye tracking, we quantified the number of fixations and dwell time on 3D images of a female avatar in two different poses (standing and contrapposto) from eight viewing angles incrementing in 45 degrees of rotation. A total of 68 heterosexual individuals (25 men and 43 women) participated in the study. Results showed that the contrapposto pose was perceived as more attractive than the standing pose and that lower vdWHR sides of the stimuli attracted more first fixation, total fixations, and dwell time. Overall, the results supported that WHR is view-dependent and vdWHRs lower than optimal WHRs are supernormal stimuli that may generate peak shifts in responding. Results are discussed in terms of the attractiveness of women's movements (gaits and dance) and augmented artistic presentations.