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To assess the incidence and risk factors for heart failure in patients with psoriatic disease and to describe their electrocardiographic and echocardiographic findings.A cohort analysis was conducted involving patients with psoriatic disease followed prospectively from 1978 to 2018. Participants were assessed according to a standard protocol every 6 to 12 months. The primary outcome was the time to first event of heart failure, further classified into ischemic and nonischemic heart failure (secondary outcomes). The association between cardiovascular risk factors, measures of disease activity, and heart failure events was assessed using Cox proportional hazards regression. Electrocardiographic and echocardiographic findings associated with heart failure events were described.A total of 1,994 patients with psoriatic disease were analyzed, with 64 incident heart failure events (38 ischemic, 26 nonischemic). The incidence rate of first heart failure event was 2.85 per 1,000 patient-years. In all events, the most common electrocardiographic findings were atrial fibrillation (22%) and bundle branch blocks (29%). Echocardiogram revealed 37% reduced ejection fraction and 63% preserved ejection fraction. In multivariable analysis, independent risk factors for all heart failure events were ischemic heart disease, adjusted mean tender joint count, adjusted mean swollen joint count, adjusted mean erythrocyte sedimentation rate, adjusted mean C-reactive protein level, and physical function (by Health Assessment Questionnaire) (all P 0.05). Minimal disease activity state was protective for all heart failure (P 0.05).Increased risk of heart failure is associated with a combination of known cardiovascular risk factors and measures of disease activity, particularly in nonischemic heart failure. The effect of inflammation on heart failure may be partially independent of atherosclerotic disease.

Organophosphate (OP) nerve agents and pesticides are a class of neurotoxic compounds that can cause status epilepticus (SE), and death following acute high-dose exposures. While the standard of care for acute OP intoxication (atropine, oxime, and high-dose benzodiazepine) can prevent mortality, survivors of OP poisoning often experience long-term brain damage and cognitive deficits. Preclinical studies of acute OP intoxication have primarily used rat models to identify candidate medical countermeasures. However, the mouse offers the advantage of readily available knockout strains for mechanistic studies of acute and chronic consequences of OP-induced SE. Therefore, the main objective of this study was to determine whether a mouse model of acute diisopropylfluorophosphate (DFP) intoxication would produce acute and chronic neurotoxicity similar to that observed in rat models and humans following acute OP intoxication. Adult male C57BL/6J mice injected with DFP (9.5 mg/kg, s.c.) followed 1 min later with atropine sulfate (0.1 mg/kg, i.m.) and 2-pralidoxime (25 mg/kg, i.m.) developed behavioral and electrographic signs of SE within minutes that continued for at least 4 h. Acetylcholinesterase inhibition persisted for at least 3 d in the blood and 14 d in the brain of DFP mice relative to vehicle (VEH) controls. Immunohistochemical analyses revealed significant neurodegeneration and neuroinflammation in multiple brain regions at 1, 7, and 28 d post-exposure in the brains of DFP mice relative to VEH controls. Deficits in locomotor and home-cage behavior were observed in DFP mice at 28 d post-exposure. These findings demonstrate that this mouse model replicates many of the outcomes observed in rats and humans acutely intoxicated with OPs, suggesting the feasibility of using this model for mechanistic studies and therapeutic screening.

Massive segmental bone defects (SBD) are mostly treated by removing the fibula and transplanting it complete with blood supply. While revolutionary 50 years ago, this remains the standard treatment. This review considers different strategies to repair SBD and emerging potential replacements for this highly invasive procedure. Prior to the technical breakthrough of microsurgery, researchers in the 1960s and 1970s had begun to make considerable progress in developing non autologous routes to repairing SBD. While the breaktthrough of vascularised bone transplantation solved the immediate problem of a lack of reliable repair strategies, much of their prior work is still relevant today. We challenge the assumption that mimicry is necessary or likely to be successful and instead point to the utility of quite crude (from a materials technology perspective), approaches. Together there are quite compelling indications that the body can regenerate entire bone segments with few or no exogenous factors. This is important, as there is a limit to how expensive a bone repair can be and still be widely available to all patients since cost restraints within healthcare systems are not likely to diminish in the near future. Statement of Significance This review is significant because it is a multidisciplinary view of several surgeons and scientists as to what is driving improvement in segmental bone defect repair, why many approaches to date have not succeeded and why some quite basic approaches can be as effective as they are. While there are many reviews of the literature of grafting and bone repair the relative lack of substantial improvement and slow rate of progress in clinical translation is often overlooked and we seek to challenge the reader to consider the issue more broadly.

We aimed to evaluate the value of ATN biomarker classification system (amyloid beta [A], pathologic tau [T], and neurodegeneration [N]) for predicting conversion from mild cognitive impairment (MCI) to dementia. In a sample of people with MCI (n = 415) we assessed predictive performance of ATN classification using empirical knowledge-based cut-offs for each component of ATN and compared it to two data-driven approaches, logistic regression and RUSBoost machine learning classifiers, which used continuous clinical or biomarker scores. In data-driven approaches, we identified ATN features that distinguish normals from individuals with dementia and used them to classify persons with MCI into dementia-like and normal groups. Both data-driven classification methods performed better than the empirical cut-offs for ATN biomarkers in predicting conversion to dementia. Classifiers that used clinical features performed as well as classifiers that used ATN biomarkers for prediction of progression to dementia. We discuss that data-driven modeling approaches can improve our ability to predict disease progression and might have implications in future clinical trials.

What, precisely, are we seeking to achieve in offering 'life-saving' treatment to patients with cancer? Research funding agencies and pharmaceutical industry media releases, and government cancer screening programs all promise that their cancer programs save lives. But everybody dies. The nature of life and death from cancer is explored philosophically in this essay, with particular reference to the quality of life, and its meaning, during the period of prolongation of survival by 'life-saving' cancer care.

PURPOSE This study assessed the economic impact of increased use of comprehensive genomic profiling (CGP) versus conventional testing strategies among patients with advanced non–small-cell lung cancer (aNSCLC) from a US commercial health plan perspective. METHODS A decision analytic model was developed to estimate the incremental benefits and costs across testing methodologies (CGP v non-CGP), as well as across sample types (tissue-based and liquid-based), for patients with newly diagnosed aNSCLC. Model outcomes included total direct costs, testing costs, and per member per month budget impact. Secondary model outcomes included the number of patients needed to test with CGP to add 1 life-year, and the number of patients needed to test with CGP to treat one individual with a biomarker-matched therapy. RESULTS In a hypothetical 2,000,000-member health plan, 790 members were estimated to have incident aNSCLC; 609 underwent molecular diagnostic testing with 122 (20%) tested with CGP (109 tissue-based and 13 liquid) in the base-case. An increase in CGP from 20% to 30% (an additional 61 patients tested with CGP) was associated with 3.11 additional life-years gained and a $0.01 in US dollars per member per month budget impact. Approximately 19.6 patients would need to be tested with CGP versus non-CGP to add one life-year and 5.9 patients would need to be tested with CGP to treat at least one patient with a biomarker-matched therapy. CONCLUSION An increase in CGP from 20% to 30% among patients with aNSCLC undergoing molecular diagnostic testing was associated with modest budget impact, most of which was attributable to prolonged survival associated with increased use of more effective treatments.

Improper disposal and burning of agricultural residues are commonly practiced in some developing countries in which harmful gaseous products released into the atmosphere and some are depleted and reacted with the soil causing environmental pollution. Renewable technology can therefore be introduced for the utilization of the residues and ensure proper storage medium of the residues. An investigation was carried out on the pollution potential of oil palm residues on surface and underground water resources at the processing centre. Oil palm residues and water samples from the stream and well located near the oil processing site were used for the experiment. Water samples were collected during the raining and dry season to determine the level of pollution caused by the residues. Physical, chemical and bacteriological parameters of the water samples were determined. The chemical compounds of the palm residues were investigated. Results showed that aromatics compounds are mainly dominant of the palm fruit fiber which was characterized for bio-fuel production. It is revealed that effect of pollution on water bodies is significant at p

The pathophysiology of empty nose syndrome (ENS) remains unclear despite significant research. The pathophysiologic mechanism of ENS was systematically reviewed.MEDLINE and Embase.Data were systematically reviewed for studies that provided original data on pathophysiology.A total of 2476 studies were screened, and 19 met the inclusion criteria: 13 case-control and 6 cross-sectional. Nine pathophysiologic themes were identified.• Demographics: ENS symptoms had no relationship with climatic factors.• Symptomatology: ENS patients demonstrated high symptom severity.• Mental health: Anxiety and depression including hyperventilation were reported in50% of ENS patients and correlated with ENS symptom severity.• Anatomic features: Structural changes in response to turbinate surgery were similar between ENS and non-ENS patients.• Airflow analysis: Airflow parameters were similar between ENS and non-ENS patients after turbinate surgery. On computational fluid dynamic analysis, differences were found on multiple outcomes.• Diagnostic testing: The menthol detection test was impaired in ENS, and cotton placement in the airway improved ENS symptoms.• Cognitive function: Functional magnetic resonance imaging showed activation in emotional processing area during breathing.• Olfactory function: Subjective impairment was reported in ENS, but quantitative measures were similar to non-ENS patients.• Mucosal physiology/innate immunity: Turbinate histopathology in ENS showed a tissue-remodeling pattern. Nasal nitric oxide level was lower in ENS patients.There is evidence of high comorbid mental health disorders in ENS patients. An abnormal trigeminal-thermoreceptor response may be present in some patients. The influence of altered airflow and the evidence of surgery as the cause for ENS are unclear.

The landscape of nuclear oncology is rapidly changing. The advent of molecular radionuclide theranostics, multidisciplinary tumor board decision making, artificial intelligence and radiomics interpretation of diagnostic imaging, evolution of pharmacogenomics prediction of tumor response, and regulatory requirements for prospective individual dosimetry are just some of the elements which are broadening the essence of physician responsibility. The burgeoning knowledge base essential for mastering the emergent technologies, and their profound effect on moral philosophic aspects of provision of cancer care, are challenging. The new relationship of the theranostic nuclear physician with respect to shared care of the individual patient, particularly with regard to transparency, accountability, and responsibility for targeted radionuclide diagnosis and therapy of cancer, will be explored in this update.

INTRODUCTION The Alzheimer's Disease Neuroimaging Initiative (ADNI) has accumulated 15 years of clinical, neuroimaging, cognitive, biofluid biomarker and genetic data, and biofluid samples available to researchers, resulting in more than 3500 publications. This review covers studies from 2018 to 2020. METHODS We identified 1442 publications using ADNI data by conventional search methods and selected impactful studies for inclusion. RESULTS Disease progression studies supported pivotal roles for regional amyloid beta (Aβ) and tau deposition, and identified underlying genetic contributions to Alzheimer's disease (AD). Vascular disease, immune response, inflammation, resilience, and sex modulated disease course. Biologically coherent subgroups were identified at all clinical stages. Practical algorithms and methodological changes improved determination of Aβ status. Plasma Aβ, phosphorylated tau181, and neurofilament light were promising noninvasive biomarkers. Prognostic and diagnostic models were externally validated in ADNI but studies are limited by lack of ethnocultural cohort diversity. DISCUSSION ADNI has had a profound impact in improving clinical trials for AD.

To determine the range of incidental mucosal changes in a general sinonasally asymptomatic population on radiology.Medline (1996-present) and Embase (1974-present) were searched on March 14, 2020, to identify articles that reported radiological sinus mucosal findings in asymptomatic population groups. Bibliographic search of included studies was conducted to identify additional articles.The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and Cochrane Handbook for Systematic Reviews of Interventions. A comprehensive search strategy was formulated and articles screened to extract data reporting Lund-Mackay (LM) score, presence of mucous retention cysts, and maxillary mucosal thickening. A random-effects model was used in meta-analysis.A total of 950 articles were identified, of which 33 manuscripts met the inclusion criteria. The included studies involved 16,966 sinonasally asymptomatic subjects. The mean LM score was 2.24 (95% CI, 1.61-2.87), and an LM score of ≥4 in 14.71% (95% CI, 6.86-24.82%) was present across all general asymptomatic population groups. Mucous retention cysts were noted in 13% (95% CI, 8.33-18.55%) and maxillary mucosal thickening of ≥2 mm in 17.73% (95% CI, 8.67-29.08%).The prevalence of incidental mucosal changes in a general asymptomatic population on radiology needs to be considered when making a diagnosis of chronic rhinosinusitis.

Thirty-seven patients with advanced gastroenteropancreatic neuroendocrine tumors (GEPNETs) were treated on a prospective phase II single-center study with four cycles of 7.8 GBq 177Lu-octreotate combined with capecitabine and temozolomide chemotherapy (CAPTEM). Each 8-week cycle combined radiopeptide therapy with 14 days of capecitabine (1500 mg/m2) and 5 days of temozolomide (200 mg/m2). The incidence of grade ≥ 3 hematologic toxicity was analyzed. At a median follow-up of 7-years (range 1–10), six (16%) patients developed persistent hematologic toxicity (PHT) (defined as sustained grade ≥ 3 hematologic toxicity beyond 36-months follow-up) and three (8%) developed MDS/AL with a median time-to-event of 46 and 34 months, respectively. The estimated cumulative incidence of MDS/AL was 11% (95% CI: 3.45–24.01). Development of PHT was the only significant risk factor for secondary MDS/AL (RR, 16; 95% CI: 2.53 to 99.55; P < 0.001). The median PFS was 48 months (95% CI: 40.80–55.20), and the median OS was 86 months (95% CI: 56.90–115.13). Twenty-one deaths were recorded, including 13 (62%) due to progressive disease and all 3 (14%) patients with MDS/AL. 177Lu-octreotate CAPTEM therapy for GEPNETs is associated with a risk of long-term hematologic toxicity. The rising cumulative incidence of MDS/AL > 10% mandates the long-term monitoring of treated patients. However, time to onset is unpredictable, and incidence does not correlate with conventional baseline risk factors. Novel methods are required for the stratification of prospective patients based on genetic risk.

A new urology curriculum has been approved by the General Medical Council and will be rolled out from August 2021. Major changes include phasing of training with a hard checkpoint at ST5 that facilitates focussed development on core skills during phase 2 (ST3–5) and the development of a special interest during phase 3 (ST6–7). While the syllabus remains unchanged, supervision levels will replace many of the workplace-based assessments currently used in wider clinical practice, learning agreements will transition from placement to placement, and indicative numbers have been replaced with index procedures, in a move from box-ticking to a professional assessment of competency and totality of practice. While change can be daunting, the 2021 urology curriculum can be viewed positively as a move away from the arbitrary collection of records of workplace-based assessments and exposure to indicative numbers, and towards the holistic professional judgements of competency that are more in keeping with lifelong consultant practice. Level of evidence: Not applicable.

Background Biologic therapies such as mepolizumab and benralizumab are currently utilised in the treatment of eosinophilic asthma, and are emerging in the management of eosinophilic chronic rhinosinusitis (eCRS). These biologics inhibit the interaction of IL-5 with its receptor, thus impairing cytokine signalling and eosinophil inflammation. Mepolizumab does so by targeting IL-5, whereas benralizumab targets the α chain of the IL-5 receptor. This study compares the sinonasal tissue response to anti-IL-5 biologic therapies in patients with eCRS. Methods A cross-sectional study of adult eCRS patients who had completed at least 2 cycles of biologic therapy and underwent endoscopic sinus surgery as part of their management were included. Sinonasal mucosal tissue biopsies were obtained intraoperatively and assessed with structured histopathological examination. Comparisons of tissue histopathology outcomes following treatment with mepolizumab or benralizumab were performed. Results 18 patients (age 49.6 ± 14.2 years, 47% female, 100% co-morbid asthma) were included in this study, comprising 10 patients managed with mepolizumab and 8 patients managed with benralizumab. Even after mepolizumab, the tissue had predominantly eosinophilic inflammation compared to benralizumab (90% v 0%, p 2(2) = 14.53, p 10 eosinophils/HPF, τb = −8.47, p b = −2.37, p = 0.02). Conclusion Tissue histopathologic outcomes reflect the differing mechanism of action of mepolizumab and benralizumab in eCRS. Further analysis at the tissue level will provide further information to guide application of mAbs in type 2 inflammatory diseases.

Objective The clinical utility and prognostic value of WHO 2017 lineage-based classification of pituitary tumours have not been assessed. This study aimed to (1) determine the clinical utility of transcription factor analysis for classification of pituitary tumours and (2) determine the prognostic value of improved lineage-based classification of pituitary tumours. Methods This was a retrospective evaluation of patients who underwent surgical resection of pituitary tumours at St Vincent’s Public and Private Hospitals, Sydney, Australia between 1990 and 2016. Included patients were at least 18 years of age and had complete histopathological data, forming the 'histological cohort'. Patients with at least 12 months of post-surgical follow-up were included in the subgroup 'clinical cohort'. The diagnostic efficacy of transcription factor immunohistochemistry in conjunction with hormone immunohistochemistry was compared with hormone immunohistochemistry alone. The prognostic value of identifying 'higher-risk' histological subtypes was assessed. Results There were 171 patient tumour samples analyzed in the histological cohort. Of these, there were 95 patients forming the clinical cohort. Subtype diagnosis was changed in 20/171 (12%) of tumours. Within the clinical cohort, there were 21/95 (22%) patients identified with higher-risk histological subtype tumours. These were associated with tumour invasiveness (P = 0.050), early recurrence (12–24 months, P = 0.013), shorter median time to recurrence (49 (IQR: 22.5–73.0) vs 15 (IQR: 12.0–25.0) months, P = 0.005) and reduced recurrence-free survival (P = 0.031). Conclusions Application of transcription factor analysis, in addition to hormone immunohistochemistry, allows for refined pituitary tumour classification and may facilitate an improved approach to prognostication.

Background Periconceptional folic acid (FA) supplementation is recommended to prevent the occurrence of neural tube defects. Currently, most over-the-counter FA supplements in Canada and the United States contain 1 mg FA and some women are prescribed 5 mg FA/d. High-dose FA is hypothesized to impair 1-carbon metabolism. We aimed to determine folate and 1-carbon metabolism biomarkers in pregnant women exposed to 1 mg or 5 mg FA. Objectives This was an ancillary study within the Folic Acid Clinical Trial (FACT), a randomized, double-blinded, placebo-controlled, phase III trial designed to assess the efficacy of high-dose FA to prevent preeclampsia. Methods For FACT, women were randomized at 8-16 gestational weeks to receive daily 4.0 mg FA (high dose) or placebo (low dose) plus their usual supplementation (≤1.1 mg). Women were recruited from 3 Canadian FACT centers and provided nonfasting blood samples at 24-26 gestational weeks for measurement of RBC and serum total folate, serum unmetabolized FA (UMFA), tetrahydrofolate (THF), 5-methylTHF, 5-formylTHF, 5,10-methenylTHF, and MeFox (pyrazino-s-triazine derivative of 4α-hydroxy-5-methylTHF, a 5-methylTHF oxidation product); total vitamins B-12 and B-6; and plasma total homocysteine. Group differences were determined using χ2, Fisher exact, and Wilcoxon rank-sum tests. Results Nineteen (38%) women received high-dose FA and 31 (62%) received low-dose FA. The median RBC folate concentration was 2701 (IQR: 2243-3032) nmol/L and did not differ between groups. The high-dose group had higher serum total folate (median: 148.4 nmol/L, IQR: 110.4-181.2; P = 0.007), UMFA (median: 4.6 nmol/L, IQR: 2.5-33.8; P = 0.008), and 5-methylTHF (median: 126.6 nmol/L, IQR: 98.8-158.6; P = 0.03) compared with the low-dose group (median: 122.8 nmol/L, IQR: 99.5-136.0; median: 1.9 nmol/L, IQR: 0.9-4.1; median: 108.6 nmol/L, IQR: 96.4-123.2, respectively). Other biomarkers of 1-carbon metabolism did not differ. Conclusions High-dose FA supplementation in early pregnancy increases maternal serum folate but not RBC folate concentrations, suggesting tissue saturation. Higher UMFA concentrations in women receiving high-dose FA supplements suggest that these doses are supraphysiologic but with no evidence of altered 1-carbon metabolism.

I. Executive summary BACKGROUND: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR-RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR-RS-2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence-based findings of the document. Methods ICAR-RS presents over 180 topics in the forms of evidence-based reviews with recommendations (EBRRs), evidence-based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results ICAR-RS-2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence-based management algorithm is provided. Conclusion This ICAR-RS-2021 executive summary provides a compilation of the evidence-based recommendations for medical and surgical treatment of the most common forms of RS.

Background Approximately one in five pregnant women have obesity. Obesity is associated with an increased risk of antenatal, intrapartum, and perinatal complications, but many women with obesity have uncomplicated pregnancies. At a time where maternity services are advocating for women to make informed choices, knowledge of the chance of having an uncomplicated (healthy) pregnancy is essential. The objective of this study was to calculate the rate of uncomplicated pregnancy in women with obesity and evaluate factors associated with this outcome. Methods This prospective cohort study was conducted using the Ontario birth registry dataset in Canada (703,115 women, April 2012–March 2017). The rate of uncomplicated or complicated composite pregnancy outcomes (hypertensive disorders of pregnancy, gestational diabetes, preterm birth, neonate small- or large- for gestational age at birth, congenital anomaly, fetal death, antepartum bleeding or preterm prelabour membrane rupture) were calculated for women with and without obesity. Associations between uncomplicated pregnancy and maternal characteristics were explored in a population of women with obesity but without other pre-existing co-morbidities (e.g., essential hypertension) or obstetric risks identified in the first trimester (e.g., multiple pregnancy), using log binomial regression analysis. Results Of the studied Ontario maternity population (body mass index not missing) 17·7% (n = 117,236) were obese. Of these 20·6% had pre-existing co-morbidities or early obstetric complicating factors. Amongst women with obesity but without early complicating factors, 58·2% (n = 54,191) experienced pregnancy without complication; this is in comparison to 72·7% of women of healthy weight and no early complicating factors. Women with obesity and no early pregnancy complicating factors are more likely to have an uncomplicated pregnancy if they are multiparous, younger, more affluent, of White or Black ethnicity, of lower weight, with normal placental-associated plasma protein-A and/or spontaneously conceived pregnancies. Conclusions The study demonstrates that over half of women with obesity but no other pre-existing medical or early obstetric complicating factors, proceed through pregnancy without adverse obstetric complication. Care in lower-risk settings can be considered as their outcomes appear similar to those reported for low-risk nulliparous women. Further research and predictive tools are needed to inform stratification of women with obesity.

Pharmaceutical industry clinical trials are ethically problematic: human research subjects are being used as a means to the end of demonstrating statistically significant efficacy of novel anticancer agents to achieve regulatory registration and marketing approval. Randomized controlled trial design is inequitable since control arm patients are denied access to the postulated best treatment. Most pharma studies do not provide clinically meaningful benefit of increased overall survival and enhanced quality of life (QOL) to cohorts and are not reliably generalizable to real-world patients. Precision oncology now enables prospective identification of patients expressing a specific cancer biomarker to determine their particular eligibility for evaluation of efficiency of molecular-targeted treatments. A patient-centered approach, collecting prospective real-world data in large populations, could provide real-world evidence of cost-effective, sustained clinical benefits of survival and QOL, while preserving the ethical beneficent compact between patient and doctor.

Developing a comprehensive portfolio of theoretically sound indicators is fundamental to effective place-based management of coastal ecosystems at a wide range of scales. We reviewed indicator deve...

Science-based natural resource management is necessary for agencies to effectively meet their goals and mandates. However, this scientific basis needs to be advanced and evolved with ecosystems exp...

In the marine science community of practice, the concept of ecosystem-based management (EBM) is a management strategy that incorporates the entire ecosystem, including humans, into resource managem...

Purpose of review The application of robotic surgery to anterior skull base disease has yet to be defined despite the potential for improved tumour resection with less morbidity in this region. Complex anatomy and restricted access have limited the development of robotic anterior skull base surgery. Recent findings A limited number of transoral robotic surgical anterior skull base procedures have been undertaken; however, there are significant limitations to the utilization of this technology in the anterior skull base. In this article, the advantages, disadvantages and limitations of robotic anterior skull base surgery are discussed. Currently, the major limitation is the size of the robotic endoscope and of the available instrumentation. Technological advancements that provide promise for the future development of robotic anterior skull base surgery are in development, such as single-port robots, flexible instrument systems and miniaturization and growth of minimally invasive platforms. Summary Although transnasal access to the skull base is not possible with the currently available robotic systems, promising technology does exist and is in development. Robotic anterior skull base surgery promises to provide greater access to skull base disease, improve oncologic results, reduce morbidity and to reduce the ergonomic burden on the surgeon.

In response to calls for marine ecosystem-based management (EBM), the U.S. National Oceanic and Atmospheric Administration (NOAA) developed a multidisciplinary science support framework called inte...

The Wnt/β-catenin signaling pathway is critical for bone differentiation and regeneration. Tideglusib, a selective FDA approved glycogen synthase kinase-3β (GSK-3β) inhibitor, has been shown to promote dentine formation, but its effect on bone has not been examined. Our objective was to study the effect of localized Tideglusib administration on bone repair. Bone healing between Tideglusib treated and control mice was analysed at 7, 14 and 28 days postoperative (PO) with microCT, dynamic histomorphometry and immunohistology. There was a local downregulation of GSK-3β in Tideglusib animals, resulting in a significant increase in the amount of new bone formation with both enhanced cortical bone bridging and medullary bone deposition. The bone formation in the Tideglusib group was characterized by early osteoblast differentiation with down-regulation of GSK-3β at day 7 and 14, and higher accumulation of active β-catenin at day 14. Here, for the first time, we show a positive effect of Tideglusib on bone formation through the inactivation of GSK-3β. Furthermore, the findings suggest that Tideglusib does not interfere with precursor cell recruitment and commitment, contrary to other GSK-3β antagonists such as lithium chloride. Taken together, the results indicate that Tideglusib could be used directly at a fracture site during the initial intraoperative internal fixation without the need for further surgery, injection or drug delivery system. This FDA-approved drug may be useful in the future for the prevention of non-union in patients presenting with a high risk for fracture-healing.

Geometrical modification of three electrode Clark sensor is performed to enhance the sensing amperometric current. Two types of implantable microsensors are designed and characterized for measuring dissolved oxygen (DO 2 ). For type I sensor, the area of the reference electrode (RE) conventionally sandwiched between working electrode (WE) and counter electrode (CE), is optimized. In contrast to the conventional Clark sensors, the CE is sandwiched between WE and RE in type II sensor. Both type microsensors are fabricated using simple processes of silicon-based microfabrication technology. Electrochemical characterizations are performed on both sensors. For 96% DO 2 , type I and type II microsensors demonstrate a sensing current of -0.87 μA and -2.35 μA as compared to a sensing current of -0.27 μA for the conventional Clark microsensor of same size. A sensitivity of 0.0094 μA/%DO 2 and 0.024 μA/%DO 2 are achieved with type I and type II microsensor, respectively in contrast to a sensitivity of 0.0027 μA/%DO 2 of the conventional Clark microsensor of same size. The sensors show a lifetime of 48 hours. With its miniature size and enhanced sensing current the sensors have potentials for clinical and biomedical applications.

© 2020 The Authors., Fire is a powerful ecological and evolutionary force that regulates organismal traits, population sizes, species interactions, community composition, carbon and nutrient cycling and ecosystem function. It also presents a rapidly growing societal challenge, due to both increasingly destructive wildfires and fire exclusion in fire‐dependent ecosystems. As an ecological process, fire integrates complex feedbacks among biological, social and geophysical processes, requiring coordination across several fields and scales of study. Here, we describe the diversity of ways in which fire operates as a fundamental ecological and evolutionary process on Earth. We explore research priorities in six categories of fire ecology: (a) characteristics of fire regimes, (b) changing fire regimes, (c) fire effects on above‐ground ecology, (d) fire effects on below‐ground ecology, (e) fire behaviour and (f) fire ecology modelling. We identify three emergent themes: the need to study fire across temporal scales, to assess the mechanisms underlying a variety of ecological feedbacks involving fire and to improve representation of fire in a range of modelling contexts. Synthesis: As fire regimes and our relationships with fire continue to change, prioritizing these research areas will facilitate understanding of the ecological causes and consequences of future fires and rethinking fire management alternatives., Support was provided by NSF‐DEB‐1743681 to K.K.M. and A.J.T. We thank Shalin Hai‐Jew for helpful discussion of the survey and qualitative methods.

Importance: Nasal valve dysfunction can be addressed by various valve reinforcement techniques. There is no consensus on which technique is most efficacious. Objective: To evaluate lateral crural t...

The Spanish conquest of the Cuchumatanes Highlands (1524–1541 ce) led to dramatic land use changes adhering to colonial practices and values, which included the rearing of livestock, agriculture, timber extraction, mining, and the relocation of indigenous populations to new settlements. These changes are often recorded in historical accounts and official records; however, these are sparse, incomplete, and have been lost over the passage of time. Here, we present a high-resolution palaeoenvironmental reconstruction for Cenote Kail (Guatemala) since the Spanish Conquest, to provide additional evidence of land use changes from an integrated multi-proxy perspective. We analysed: (i) fossil pollen; (ii) macroscopic and microscopic charcoal; and (iii) dung fungal spores (Sporormiella) from a lake sediment core extracted from Cenote Kail in the Cuchumatanes highlands, combining these analyses with remotely sensed satellite data. We reconstructed: (i) forest composition and dynamics; (ii) burning, (iii) fauna abundance, and (iv) agricultural activities. High resolution age-depth modelling was conducted using a combination of 210Pb and 14C dates. The high temporal resolution enabled a novel integrated validation of the charcoal data sets with remotely sensed satellite data and the historical record. Three stages of floral compositional change were discerned from the palynological assemblage data encompassing: (i) the decline of mixed hard wood forests (MHWF), associated with the building of new settlements, agriculture and timber extraction for fuel (1550–1675 ce); (ii) pastoral expansions involving the rearing of livestock (1700–1800 ce); and (iii) the expansions of urban settlements and increasing management of the land (1821–2015 ce). Seed predation is suggested as the dominant factor preventing MHWF from re-establishing in the Cuchumatanes Highlands over the past 500 years. Burning is limited locally and regionally and in line with the modern regime, which suggests that fire has been managed and controlled since European contact.

Traumatic brain injury (TBI) is a major public health concern due to its growing incidence and resulting long-term or lifelong impairments. Exercise is a non-stigmatising approach proposed to allev...

OBJECTIVES Oral corticosteroid (OCS) as a part of appropriate medical therapy (AMT) (formerly maximal medical therapy) in chronic rhinosinusitis remains controversial. While the risks of OCS are well known, the benefit remains unclear due the absence of a standardized prescribing regimen. Consequently, it is difficult to characterize whether the risks of OCS and its ability to avert endoscopic sinus surgery (ESS) are helpful in AMT. When OCS is highly effective at averting surgery, the lesser risks of OCS would be justified because it can avoid the greater risks of ESS. When OCS is poorly effective at averting ESS, the risks of OCS would not be justified because many patients will be exposed to both risks. This study seeks to identify the threshold effectiveness of OCS at averting ESS that would minimize risk exposure to patients. METHODS A probabilistic risks-based decision analysis was constructed from literature reported incidences and impacts of adverse events of OCS and ESS. Monte Carlo analysis was performed to identify the minimum effectiveness required to avoid further intervention (MERAFI) for chronic sinusitis without nasal polyp (CRSsNP) and chronic sinusitis with nasal polyp (CRSwNP). RESULTS The analysis showed MERAFI results of 20.8% (95% CI 20.7-20.9%) for CRSsNP and 16.8% (95% CI 16.7-16.9%) for CRSwNP. CONCLUSIONS Given reported OCS effectiveness in the range of 34-71% in CRSsNP and 46-63% in CRSwNP, this analysis suggests that the inclusion of OCS in AMT may be the lower risk strategy. LEVEL OF EVIDENCE N/A Laryngoscope, 131:473-481, 2021.

Background Breast implant illness (BII) after aesthetic breast augmentation remains a poorly defined syndrome encompassing a wide spectrum of symptoms. While previously published series have observed overall symptomatic improvement after breast implant removal,1–3 there is a lack of studies evaluating changes in specific symptoms over time. The purpose of this study was to gain an understanding of symptoms associated with BII, and to evaluate how these symptoms change after removal of breast implants and total capsulectomy (explantation). We hypothesized that patients presenting with BII would experience both immediate and sustained improvement in constitutional symptoms after explantation. Methods A retrospective study of all patients who underwent explantation by a single surgeon over 2 years was conducted. Repeated-measures analysis of variance accounting for dependency was used to compare symptoms before and after surgery. Multivariate analyses and linear regression models were used to examine the impact of patient- and implant-related factors on changes in symptoms. Results Seven hundred fifty patients met inclusion criteria. Mean preoperative survey score (26.19 ± 11.24) was significantly different from mean postoperative survey score at less than 30 days (9.49 ± 7.56) and greater than 30 days (9.46 ± 7.82, P < 0.001). Patients with a BMI greater than 30 or those with clinically detectable contracture on examination showed greater improvement on their survey scores (P = 0.039, 0.034, respectively). Conclusions Although BII encompasses a large range of symptoms, subjects in this study demonstrated significant and sustained improvement in 11 common symptom domains. This improvement was demonstrable within the first 30 days postoperatively and was maintained beyond 30 days. The study demonstrated a strong association of explantation and specific symptom improvement within the patient population studied. Future investigation will further elucidate possible biologic phenomena to better characterize the pathophysiology and mechanism of BII.

Multiple measurements of serum human chorionic gonadotropin (hCG) are used to predict the final pregnancy outcome for women with a pregnancy of unknown location (PUL) and monitor the management of ectopic pregnancy (EP). Urine-based testing would be more convenient and economical. This prospective cohort study involving 80 women assessed the degree of correlation between serum and urine hCG levels and whether urine hCG levels have the potential to impact clinical decision making in the management of women with a PUL. Paired urine and serum hCG measurements differed quite widely but were well correlated and the degree of correlation improved after creatinine correction. Although serial serum hCG measurements appear to be better for the overall prediction of pregnancy outcome in PUL (AUC 0.77-0.94 compared to corrected urine AUC 0.69-0.84), serial urine hCG measurements may have a role in identifying subtypes of low-risk PUL (AUC 0.83-0.84).

A new approach is proposed to enhance sensing amperometric current in three-electrode Clark dissolved oxygen (DO2) Microelectromechanical systems (MEMS) sensors. In the proposed approach, the counter electrode (CE) in a conventional concentric three-electrode sensor is modified to admit a large ratio of static electric current in an electrochemical solution. The typically large CE of a conventional sensor is replaced with an array of narrow-width electrodes. The modified CE is expected to reduce the inductive coupling and simultaneously increase the capacitive coupling of the structure. The overall changes of inductive and capacitive couplings are shown to enhance the sensing amperometric current of the sensor. Two μ-sensors are developed and fabricated based on MEMS technology including a conventional, as the reference and a new modified μ-sensors. The experimental results confirm an enhancement of 3.2:1 (0.352 μA:0.112 μA for 23% of DO2) in the sensing amperometric current of the developed MEMS μ-sensor compared to the conventional same-sized counterpart.

DEAP-3600 is a liquid-argon scintillation detector looking for dark matter. Scintillation events in the liquid argon (LAr) are registered by 255 photomultiplier tubes (PMTs), and pulseshape discrimination (PSD) is used to suppress electromagnetic background events. The excellent PSD performance of LAr makes it a viable target for dark matter searches, and the LAr scintillation pulseshape discussed here is the basis of PSD. The observed pulseshape is a combination of LAr scintillation physics with detector effects. We present a model for the pulseshape of electromagnetic background events in the energy region of interest for dark matter searches. The model is composed of (a) LAr scintillation physics, including the so-called intermediate component, (b) the time response of the TPB wavelength shifter, including delayed TPB emission at $${\mathcal {O}}$$O(ms) time-scales, and c) PMT response. TPB is the wavelength shifter of choice in most LAr detectors. We find that approximately 10% of the intensity of the wavelength-shifted light is in a long-lived state of TPB. This causes light from an event to spill into subsequent events to an extent not usually accounted for in the design and data analysis of LAr-based detectors.

Introduction We investigated plasma proteomic markers of astrocytopathy, brain degeneration, plasticity, and inflammation in sporadic early-onset versus late-onset Alzheimer's disease (EOAD and LOAD). Methods Plasma was analyzed using ultra-sensitive immuno-based assays from 33 EOAD, 30 LOAD, and 36 functionally normal older adults. Results Principle component analyses identified 3 factors: trophic (BDNF, VEGF, TGFβ), degenerative (GFAP, NfL), and inflammatory (TNFα, IL-6, IP-10, IL-10). Trophic factor was elevated in both AD groups and associated with cognition and gray matter volumes. Degenerative factor was elevated in EOAD, with higher levels associated with worse functioning in this group. Biomarkers of inflammation were not significantly different between groups and were only associated with age. Disucssion Plasma proteomic biomarkers provide novel means of investigating molecular processes in vivo and their contributions to clinical outcomes. We present initial investigations of several of these fluid biomarkers, capturing aspects of astrocytopathy, neuronal injury, cellular plasticity, and inflammation in EOAD versus LOAD.

BACKGROUND Hypoestrogenemia due to menopause is associated with increased cardiovascular disease risk, in part due to elevated indexes of aortic wave reflection (AWRI) and central (aortic) blood pressure. We sought to investigate whether AWRI and central blood pressure are also augmented in hypoestrogenic exercise-trained premenopausal women with functional hypothalamic amenorrhea (ExFHA). METHODS In age- (pooled mean ± SEM, 24 ± 1 years), BMI- (21 ± 1 kg/m2 ), and cardiorespiratory fitness-matched (45 ± 2 ml/kg/min) eumenorrheic ovulatory (ExOv; n = 11) and ExFHA women (n = 10), we assessed aortic blood pressure and waveform characteristics (augmentation index and wave reflection amplitude) obtained from radial pressure waves (applanation tonometry). Doppler ultrasound determined cardiac output (CO) and total peripheral resistance (TPR). Measures were recorded before and 1 hour after 45 minutes of moderate intensity exercise to determine the influence of exercise-induced increases in nitric oxide. RESULTS Pre-exercise, AIx75, central systolic BP (SBPc), and CO were lower (P .05) in ExFHA but was lowered (P

The current definition of postural orthostatic tachycardia syndrome (POTS) dates back to a small case series of patients with a subacute illness who presented with excessive orthostatic tachycardia and orthostatic intolerance, in the absence of another recognized disease. Conventional POTS criteria require an excessive orthostatic tachycardia in the absence of substantial orthostatic hypotension, and predominant symptoms of orthostatic intolerance, worse with upright posture and better with recumbence. POTS is a heterogeneous syndrome with likely several underlying pathophysiological processes, and not a specific disease. The primary panel for this Canadian Cardiovascular Society position statement sought to provide a contemporary update of the best evidence for the evaluation and treatment of POTS. We performed a systemic review of evidence for the evaluation of treatment of POTS using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, and developed recommendations on the basis of the Canadian Cardiovascular Society approach to position statements. One identified problem was that numerous patients who did not meet criteria for POTS would still be given that diagnoses by providers to validate the illness even though this diagnosis is incorrect. This includes patients with postural symptoms without tachycardia, orthostatic tachycardia without symptoms, and those with orthostatic tachycardia but another overt cause for excessive tachycardia. We developed a novel nomenclature ecosystem for orthostatic intolerance syndromes to increase clarity. We also provide more clarity on how to interpret the orthostatic vital signs. These concepts will need to be prospectively assessed.

The resilience of serotinous obligate-seeding plants to fire may be compromised if increasing fire frequency curtails time available for canopy seed bank accumulation (i.e., immaturity risk), but how various drivers affect seed availability at the time of fire is poorly understood. Using field data from California closed-cone pine (Pinus attenuata and P. muricata) stands, we assess two critical demographic processes during the inter-fire period—reproductive capacity and mortality. At tree- and stand-levels, we test how these processes are affected by stand age and are mediated by biotic and abiotic factors. We found that stand age was the key driver of reproductive capacity; older stands had a greater proportion of reproductively mature individuals and greater closed cone density. Stand density mediated the effect of age; greater stand density resulted in greater closed cone density and a lower proportion of reproductively mature individuals, but reproductive capacity in low- and high-density stands converged over time. Increased moisture stress reduced the stand-level proportion reproductively mature but had no effect on closed cone density. Mortality was strongly associated with density-dependent thinning and increased in stands with high moisture stress. Reproductive capacity began to increase sharply 10 years after fire and by 20 years immaturity risk is low. However, prior to 20 years, low-density stands with high moisture stress may be more susceptible to immaturity risk. Understanding these relationships is critical to predicting serotinous population persistence under changing climate and disturbance conditions.

Background:. Acute compartment syndrome of the foot is a controversial topic. Release of the foot has been seen as complicated because of large incisions and postoperative morbidity, and there has been debate over whether this procedure is actually effective for releasing all areas of increased pressure. New sensor technology affords the opportunity to advance our understanding of acute compartment syndrome of the foot and its treatment. The purpose of the present study was to determine whether percutaneous decompression could be performed for the treatment of compartment syndrome in a forefoot model. Methods:. The present study utilized a validated continuous pressure sensor to model compartment syndrome in human cadaveric feet. We utilized a pressure-controlled saline solution infusion system to induce increased pressure. A novel percutaneous release of the forefoot was investigated to assess its efficacy in achieving decompression. Results:. For all cadaveric specimens, continuous pressure monitoring was accomplished with use of a continuous pressure sensor. There were 4 discrete compartment areas that could be reliably pressurized in all feet. The average baseline, pressurized, and post-release pressures (and standard deviations) were 4.5 ± 2.9, 43.8 ± 7.7, and 9.5 ± 3.6 mm Hg, respectively. Percutaneous decompression produced a significant decrease in pressure in all 4 compartments (p < 0.05). Conclusions:. With use of continuous compartment pressure monitoring, 4 consistent areas were established as discrete compartments in the foot. All 4 compartments were pressurized with a standard pump system. With use of 2 small dorsal incisions, all 4 compartments were successfully released, with no injuries identified in the cutaneous nerve branches, extensor tendons, or arteries. These results have strong implications for the future of modeling compartment syndrome as well as for guiding clinical studies. Clinical Relevance:. A reproducible and accurate method of continuous pressure monitoring of foot compartments after trauma is needed (1) to reliably identify patients who are likely to benefit from compartment release and (2) to help avoid missed or evolving cases of acute compartment syndrome. In addition, a reproducible method for percutaneous compartment release that minimizes collateral structural damage and the need for secondary surgical procedures is needed.

Background Persistent organic pollutants (POPs) are toxic chemicals with demonstrable effects on pregnancy and neonatal outcomes. The associations of early pregnancy body mass index (BMI) and antenatal weight changes with circulating POP concentrations are poorly understood in the Canadian context. The objective of this study is thus to examine the relationships between first trimester maternal BMI, weight change from pre-pregnancy to 6-13 weeks of pregnancy (early gestational weight change), and first trimester plasma POP concentrations among Canadian pregnant women. Methods We conducted a secondary analysis of data collected as part of the Maternal-Infant Research on Environmental Chemicals (MIREC) Study. We determined the POP concentrations across first trimester BMI category (underweight/normal weight, overweight, class I & II obese, and class III obese) and early gestational weight change categories (weight loss, weight neutral/gain) and tested for overall differences using Kruskal-Wallis tests. Associations between first trimester maternal BMI and early gestational weight changes with the plasma concentrations of 41 POPs measured in the first trimester were further evaluated using unadjusted and adjusted censored regression models. Results Eleven of 41 POPs were detectable in at least 50% of the MIREC participants and could be analyzed for their relationships with first trimester BMI and weight change. The majority of POPs were inversely associated with first trimester BMI after controlling for the main confounding variables. Although not statistically significant, POP plasma concentrations tended to be generally higher in participants who lost weight compared to those who gained weight or whose weight stayed relatively stable from pre-pregnancy into the first trimester. Conclusions Our findings lend support to the hypothesis that pregnant women with obesity may have higher bioaccumulation of POPs within their adipose tissues than normal weight pregnant women. Additionally, early gestational weight loss appears to be associated with the highest circulating POP levels. Future studies should focus on the effect of weight changes on POPs concentrations across trimesters.

Magnetized Liner Inertial Fusion (MagLIF) is a magneto-inertial fusion concept that relies on fuel magnetization, laser preheat, and a magnetically driven implosion to produce fusion conditions. In MagLIF, the target is a roughly 10 mm long, 5 mm diameter, 0.5 mm thick, cylindrical beryllium shell containing ~1 mg/cm 3 D 2 gas. An axial magnetic field on the order of 10 T is applied to the target, and several kJ of laser energy is deposited into the fuel. Up to 20 MA of current is driven axially through the beryllium target, causing it to implode over approximately 100 ns. The implosion produces a ~100-μm diameter, ~8-mm tall fuel column with a burn-averaged ion temperature of several keV, that generates 10 11 -10 13 DD neutrons.

Patients with systemic lupus erythematosus are often treated with antimalarial agents (AMs), including chloroquine and hydroxychloroquine, for prolonged periods of time because of their beneficial immunomodulatory effects. Although previously considered rare, AM-induced cardiomyopathy (AMIC) is

Among older adults who have recently sustained a fracture, there is substantial adoption of mobile technology. Furthermore, health and eHealth literacy level reported by participants supports the development of interactive eHealth interventions toward fostering better patient engagement in skeletal health management. Electronic health resources are increasingly used in the self-management of medical conditions. We aimed to identify the current level of technology adoption, health, and eHealth literacy among older adults with a recent fracture, to determine if the use of electronic interventions would be feasible and acceptable in this population. Adults ≥ 50 years with recent fractures were invited to complete a self-administered survey composed of 21 questions, including an 8-item perceived eHealth literacy scale. A total of 401 participants completed the survey (women, 64%; ≥ 65 years, 59%; university education, 32%). Most participants reported no difficulty in reading printed health material (67%) and felt confident in filling out medical forms (65%). Younger age and higher levels of education were associated with higher health literacy. Most respondents (81%) owned at least one mobile device (smartphone, 49%; tablet, 45%). eHEALS scores were similar among men (29, IQR 24–32) and women (29, IQR 25–33), and between younger age group categories (50–64 years, 30; IQR 26–33; and 65–74 years, 29; IQR 25–32), but lower in the oldest age group (≥ 75 years, 24; IQR 21–29; p

Eosinophilic chronic rhinosinusitis (eCRS) is an inflammatory endotype of CRS. Contemporary treatment includes creation of a "neo-sinus" cavity and postoperative corticosteroid irrigations. Not all patients gain control with local therapy. This study aims to determine, in patients with polyp recurrence, the most common sinuses involved.A prospective case-series was conducted on consecutive adult (≥18 years) post-FESS eCRS patients followed for a minimum of 12 months. All patients had a neo-sinus cavity created surgically and used corticosteroid irrigations daily for 3-6 months, then tapered to disease control. Sinus cavities were assessed by endoscopy on last follow-up. Polyp recurrence was defined as a score of 5 or 6 in the MLMES in ≥3 sinus cavities. Patient-reported outcomes based on SNOT22 and NSS, frequency of corticosteroid irrigations, and courses of systemic antibiotics and corticosteroid were collected. The pattern of sinus involvement was analyzed.A total of 342 sinus cavities were assessed (mean ± standard deviation, 54.9 ± 13.4 years, 43.2% female). Polyp recurrence occurred in 4.3% (6.4% of patients, n = 7 unilateral) of sinus cavities. Frontal and ethmoid sinus cavities were most affected in those with polyp recurrence, compared to the maxilla and sphenoid (100% vs 100% vs 53% vs 53%, p0.01). Although those patients with polyp recurrence utilized more systemic corticosteroids courses per year (0.4 ± 0.4 vs 0.1 ± 0.3, p0.01), the use of corticosteroid irrigations was similar (%4/week; 66.7% vs 48.9%, p = 0.13). Prior surgery was more common in patients with polyp recurrence (86.7% vs 53.5%, p = 0.01).The frontal and ethmoid sinuses were most affected in those patients with polyp recurrence. Whether the disease is more active in this location or topical therapy has limited access requires further evaluation.

To determine the efficacy of high-dose folic acid for the prevention of preeclampsia in twin pregnancies.Secondary analysis of a randomized controlled trial in 70 obstetrical sites in Argentina, Australia, Canada, Jamaica, and the UK between 2011 and 2015. Eligible women pregnant with twins who were aged 18 y or older and between 8 and 16 completed weeks' gestation were randomized between to receive daily high-dose folic acid (4.0-5.1 mg) or placebo. The primary outcome was preeclampsia, presenting as hypertension after 20 weeks' gestation with significant proteinuria. Secondary outcomes included severe preeclampsia, preterm birth, and adverse fetal and neonatal outcomes.Of 2464 participants randomized between 18 April 2011 and 14 December 2015, 462 (18.8%) had a confirmed twin pregnancy. Thirty-four of these participants withdrew consent or did not have primary outcome data available, and 428 women were analyzed. The rate of preeclampsia was significantly higher in the folic acid group compared to the placebo group in crude analyses (17.2 versus 9.9%; relative risk 1.75 [95% CI 1.06-2.88],High-dose folic acid supplementation was not significantly associated with preeclampsia in a subgroup of twin pregnancies. Although a suggested elevated risk cannot be confirmed, these results may help to gain novel insights in the etiology of preeclampsia, which continues to be poorly understood.ClinicalTrials.gov NCT01355159.

Background Respiratory epithelium is a key defense against inhaled pathogens. Vitamin D3 (VD) has been suggested to modulate airway inflammation; however, its effect on innate airway defenses, the physical barrier, mucociliary apparatus, and cytokine release remains unclear. Objective To investigate the outcomes of VD application prior to challenge in an in vitro model of human sinonasal epithelium, through assessment of epithelial transepithelial resistance (TER), cilia beat frequency (CBF), and interleukin (IL)-6 release, and secondarily to determine whether topical VD is beneficial to patients with inflammatory sinonasal pathology. Methods Primary human sinonasal epithelial cells from patients with eosinophilic chronic rhinosinusitis (eCRS) and healthy controls were cultured in air–liquid interface (ALI). Well-differentiated cultures from each patient were pretreated for 24 hours with 4 different VD doses. Toxicity was quantified at 24 hours in unchallenged ALI by lactate dehydrogenase (LDH) assay. Innate responses were assessed by measuring TER and CBF before and up to 24 hours after house dust mite Dermatophagoides pteronyssinus challenge. IL-6 release was evaluated 24-hour postchallenge. Results Fifteen patients (53 ± 13.5 years, 60% females, 53% eCRS) representing 120 ALI wells were assessed. VD (0, 25, 50, 150 IU/mL) released less LDH than vehicle, indicating noncytotoxicity (0.15 ± 0.02; 0.15 ± 0.00; 0.14 ± 0.02; 0.11 ± 0.01 vs 0.17 ± 0.03, P = .004). VD increased TER for eCRS wells at 5 minutes (50 IU/mL: Δ6.76 ± 3.93 vs Δ3.87 ± 2.46, P = .04) and 24 hours (50 IU/mL: Δ0.88 ± 0.49 vs Δ0.40 ± 0.42, P = .02; 150 IU/mL: Δ1.06 ± 0.58 vs Δ0.47 ± 0.46, P = .01). CBF increased at 1 hour for eCRS wells (50 IU/mL: Δ0.62 ± 0.14 vs Δ0.41 ± 0.13, P = .001; 150 IU/ml: Δ0.60 ± 0.13 vs Δ0.38 ± 0.11, P Conclusion Topical VD supplementation in eCRS patients may be beneficial for innate epithelial defenses. VD is noncytotoxic and does not adversely affect the physical barrier, mucociliary apparatus, or IL-6 release. Further studies should clarify its potential as a therapeutic agent.