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.

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.

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.

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.

Interventions for improving outcomes in acute kidney injury.

PURPOSE OF REVIEW: Since the adoption of the classification of acute kidney injury (AKI) through changes in serum creatinine and/or urine output, much data have accumulated as to the associated risks in terms of morbidity and mortality after the development of AKI. However, until recently, a nihilistic approach persisted which implied that little could be done to alter the clinical course of a patient with AKI even where early identification was achieved. This view is reinforced by the opinion that given the broad cause underlying the syndrome of AKI, a 'one size fits all' approach is unlikely to be successful. RECENT FINDINGS: Recent evidence suggests that the management of AKI may be improved somewhat by simple measures, such as the use of care bundles particularly in the intensive care setting. Moreover, there are other interventions using common treatments, which may prove to be of benefit as well as some early evidence that specific therapeutics may be on the horizon. SUMMARY: Although a syndrome of significantly differing causes, the application of standardized care bundles appears promising and this approach may be improved by the use of specific therapies, including recombinant alkaline phosphatase, the use of intravenous bicarbonate and remote ischaemic preconditioning may also ameliorate the effects of AKI.

How deep is the conflict between molecular and fossil evidence on the age of angiosperms?

The timing of the origin of angiosperms is a hotly debated topic in plant evolution. Molecular dating analyses that consistently retrieve pre-Cretaceous ages for crown-group angiosperms have eroded confidence in the fossil record, which indicates a radiation and possibly also origin in the Early Cretaceous. Here, we evaluate paleobotanical evidence on the age of the angiosperms, showing how fossils provide crucial data for clarifying the situation. Pollen floras document a Northern Gondwanan appearance of monosulcate angiosperms in the Valanginian and subsequent poleward spread of monosulcates and tricolpate eudicots, accelerating in the Albian. The sequence of pollen types agrees with molecular phylogenetic inferences on the course of pollen evolution, but it conflicts strongly with Triassic and early Jurassic molecular ages, and the discrepancy is difficult to explain by geographic or taphonomic biases. Critical scrutiny shows that supposed pre-Cretaceous angiosperms either represent other plant groups or lack features that might confidently assign them to the angiosperms. However, the record may allow the Late Jurassic existence of ecologically restricted angiosperms, like those seen in the basal ANITA grade. Finally, we examine recently recognized biases in molecular dating and argue that a thoughtful integration of fossil and molecular evidence could help resolve these conflicts.

Perianesthetic and Anesthesia-Related Mortality in a Southeastern United States Population: A Longitudinal Review of a Prospectively Collected Quality Assurance Data Base.

BACKGROUND: Perianesthetic mortality (death occurring within 48 hours of an anesthetic) continues to vary widely depending on the study population examined. The authors study in a private practice physician group that covers multiple anesthetizing locations in the Southeastern United States. This group has in place a robust quality assurance (QA) database to follow all patients undergoing anesthesia. With this study, we estimate the incidence of anesthesia-related and perianesthetic mortality in this QA database. METHODS: Following institutional review board approval, data from 2011 to 2016 were obtained from the QA database of a large, community-based anesthesiology group practice. The physician practice covers 233 anesthetizing locations across 20 facilities in 2 US states. All detected cases of perianesthetic death were extracted from the database and compared to the patients' electronic medical record. These cases were further examined by a committee of 3 anesthesiologists to determine whether the death was anesthesia related (a perioperative death solely attributable to either the anesthesia provider or anesthetic technique), anesthetic contributory (a perioperative death in which anesthesia role could not be entirely excluded), or not due to anesthesia. RESULTS: A total of 785,467 anesthesia procedures were examined from the study period. A total of 592 cases of perianesthetic deaths were detected, giving an overall death rate of 75.37 in 100,000 cases (95% CI, 69.5-81.7). Mortality judged to be anesthesia related was found in 4 cases, giving a mortality rate of 0.509 in 100,000 (95% CI, 0.198-1.31). Mortality judged to be anesthesia contributory were found in 18 cases, giving a mortality of 2.29 in 100,000 patients (95% CI, 1.45-3.7). A total of 570 cases were judged to be nonanesthesia related, giving an incidence of 72.6 per 100,000 anesthetics (95% CI, 69.3-75.7). CONCLUSIONS: In a large, comprehensive database representing the full range of anesthesia practices and locations in the Southeastern United States, the rate of perianesthestic death was 0.509 in 100,000 (95% CI, 0.198-1.31). Future in-depth analysis of the epidemiology of perianesthetic deaths will be reported in later studies.

Consumption of a 5-mg Melatonin Supplement Does Not Affect 32.2-km Cycling Time Trial Performance.

Brandenberger, KJ, Ingalls, CP, Rupp, JC, and Doyle, JA. Consumption of a 5-mg melatonin supplement does not affect 32.2-km cycling time trial performance. J Strength Cond Res 32(10): 2872-2877, 2018-Some studies suggest that exogenous melatonin supplementation may improve athletic performance in hot humid environments because of its precooling effect. However, melatonin is also consumed as a sleep aid for its depressive effects on the central nervous system (CNS), which may hinder performance. Therefore, this study was conducted to determine whether consuming a 5-mg supplement of melatonin would affect performance in a laboratory-simulated 32.2-km cycling time trial. The time trial was conducted in a thermoneutral environment to separate CNS depressive effects of the melatonin from the cooling effects. Trained male subjects (n = 10; V[Combining Dot Above]O2max = 62.7 ± 6.3 ml·kg·min; age = 25.1 ± 4.0 years; mass = 69.9 ± 9.1 kg; height = 176.0 ± 7.1 cm) performed three 32.2-km time trials on an electronically braked cycle ergometer. The first trial was a familiarization. During the 2 experimental trials, subjects received in a random order either a placebo or a 5-mg melatonin supplement 15 minutes before exercise in a double-blind, crossover design. Variables were measured before exercise and at 8-km intervals. The mean 32.2-km time trial completion times for the melatonin (64.94 ± 5.95 minutes) and placebo (65.26 ± 6.85 minutes) trials were not different (p = 0.682). The mean time trial power output for the melatonin (190.4 ± 40.4 watts) and placebo (190.0 ± 45.7 watts) trials was not different (p = 0.927). Rectal temperature was not significantly different for melatonin compared with placebo (p = 0.827). These results suggest that a 5-mg melatonin supplement administered 15 minutes before exercise does not measurably impact the performance of a 32.2-km cycling time trial in a thermoneutral environment.

Wrong guidelines: why and how often they occur.

Evidence-based guidelines are considered an essential tool in assisting physicians, policymakers and patients when choosing among alternative care options and are considered unbiased standards of care. Unfortunately, depending on how their reliability is measured, up to 50% of guidelines can be considered untrustworthy. This carries serious consequences for patients' safety, resource use and health economics burden. Although conflict of interests, panel composition and methodological flaws are traditionally thought to be the main reasons undermining their untrustworthiness, corruption and waste of biomedical research also contribute. We discuss these issues in the hope for a wider awareness of the limits of guidelines.

Wrong guidelines: how to detect them and what to do in the case of flawed recommendations.

Any evidence-based recommendation needs careful assessment of its methodological background as well as of its content trustworthiness, especially given that following it will not necessarily produce the intended clinical outcomes. There are no established instruments to evaluate guidelines for their content, while useful tools assessing the quality of methods followed are well recognised and adopted. We suggest a 'safety bundle' considering methodological aspects and content trustworthiness of guidelines, by adopting the GRADE method in a backward fashion. Sharing the critical analysis of the guidelines with patients, including any eventual uncertainty about them, is of key importance in order to avoid the possible adverse effects derived from following the wrong guidelines. Such critical approach is also helpful and beneficial in producing better care pathways, health policy decisions and more relevant and ethical research.

Acute kidney injury: short-term and long-term effects.

Acute kidney injury (AKI) is the most common cause of organ dysfunction in critically ill adults, with a single episode of AKI, regardless of stage, carrying a significant morbidity and mortality risk. Since the consensus on AKI nomenclature has been reached, data reflecting outcomes have become more apparent allowing investigation of both short- and long-term outcomes.Classically the short-term effects of AKI can be thought of as those reflecting an acute deterioration in renal function per se. However, the effects of AKI, especially with regard to distant organ function ("organ cross-talk"), are being elucidated as is the increased susceptibility to other conditions. With regards to the long-term effects, the consideration that outcome is a simple binary endpoint of dialysis or not, or survival or not, is overly simplistic, with the reality being much more complex.Also discussed are currently available treatment strategies to mitigate these adverse effects, as they have the potential to improve patient outcome and provide considerable economic health savings. Moving forward, an agreement for defining renal recovery is warranted if we are to assess and extrapolate the efficacy of novel therapies. Future research should focus on targeted therapies assessed by measure of long-term outcomes.

Should we treat pyrexia? And how do we do it?

The concept of pyrexia as a protective physiological response to aid in host defence has been challenged with the awareness of the severe metabolic stress induced by pyrexia. The host response to pyrexia varies, however, according to the disease profile and severity and, as such, the management of pyrexia should differ; for example, temperature control is safe and effective in septic shock but remains controversial in sepsis. From the reported findings discussed in this review, treating pyrexia appears to be beneficial in septic shock, out of hospital cardiac arrest and acute brain injury.Multiple therapeutic options are available for managing pyrexia, with precise targeted temperature management now possible. Notably, the use of pharmacotherapy versus surface cooling has not been shown to be advantageous. The importance of avoiding hypothermia in any treatment strategy is not to be understated.Whilst a great deal of progress has been made regarding optimal temperature management in recent years, further studies will be needed to determine which patients would benefit the most from control of pyrexia and by which means this should be implemented. This narrative review is part of a series on the pathophysiology and management of pyrexia.

Goal-directed therapy and acute kidney injury: as good as it gets?

The use of goal-directed therapy as part of an enhanced recovery programme is well established in terms of management of the modern high-risk surgical patient in order to reduce both morbidity and mortality. The mechanisms behind this improvement are debated, but a reduction in the development of post-operative complications including acute kidney injury may be relevant. A recent study examining this relationship has been reported and is discussed here.

Cancer risk to First Nations' people from exposure to polycyclic aromatic hydrocarbons near in-situ bitumen extraction in Cold Lake, Alberta.

BACKGROUND: The Alberta oil sands are an important economic resource in Canada, but there is growing concern over the environmental and health effects as a result of contaminant releases and exposures. Recent studies have shown a temporal and spatial trend of increased polycyclic aromatic hydrocarbon (PAH) concentrations in sediments and snowpack near the Athabasca oil sands operations (i.e., open pit mines), but thus far similar studies have not been done for the Cold Lake region where steam assisted gravity drainage (in situ) extraction is performed. METHODS: Many PAHs are known mutagenic carcinogens, and this study measured soil and atmospheric concentrations of PAHs in the Cold Lake region to assess the excess lifetime cancer risk posed to the First Nations' inhabitants of the region. Using both deterministic and probabilistic risk assessment methods, excess lifetime cancer risks were calculated for exposures from inhalation or inadvertent soil ingestion. RESULTS: The mean excess cancer risk for First Nations' people through ingestion who engage in traditional wilderness activities in the Cold Lake region was 0.02 new cases per 100,000 with an upper 95% risk level of 0.07 cases per 100,000. Exposure to PAHs via inhalation revealed a maximum excess lifetime cancer risk of less than 0.1 cases per 100,000. CONCLUSIONS: Excess lifetime risk values below 1 case per 100,000 is generally considered negligible, thus our analyses did not demonstrate any significant increases in cancer risks associated with PAH exposures for First Nations people inhabiting the Cold Lake region.

Hydatellaceae identified as a new branch near the base of the angiosperm phylogenetic tree.

Although the relationship of angiosperms to other seed plants remains controversial, great progress has been made in identifying the earliest extant splits in flowering-plant phylogeny, with the discovery that the New Caledonian shrub Amborella trichopoda, the water lilies (Nymphaeales), and the woody Austrobaileyales constitute a basal grade of lines that diverged before the main radiation in the clade. By focusing attention on these ancient lines, this finding has re-written our understanding of angiosperm structural and reproductive biology, physiology, ecology and taxonomy. The discovery of a new basal lineage would lead to further re-evaluation of the initial angiosperm radiation, but would also be unexpected, as nearly all of the approximately 460 flowering-plant families have been surveyed in molecular studies. Here we show that Hydatellaceae, a small family of dwarf aquatics that were formerly interpreted as monocots, are instead a highly modified and previously unrecognized ancient lineage of angiosperms. Molecular phylogenetic analyses of multiple plastid genes and associated noncoding regions from the two genera of Hydatellaceae identify this overlooked family as the sister group of Nymphaeales. This surprising result is further corroborated by evidence from the nuclear gene phytochrome C (PHYC), and by numerous morphological characters. This indicates that water lilies are part of a larger lineage that evolved more extreme and diverse modifications for life in an aquatic habitat than previously recognized.