Polyunsaturated fatty acids (PUFAs) undergo cytochrome P450 (CYP)-dependent oxidation to epoxides that modulate important physiological functions, including vasoactivity, inflammation, nociception, ...proliferation and viability. One of the most important human CYP epoxygenases is human CYP2J2 that is widely expressed in tissues, especially heart, vascular smooth muscle, salivary glands and placenta. Recent studies have shown that overexpression of CYP2J2 in vivo reverses several pathological processes in animals, including hypertension and other cardiovascular pathologies and insulin resistance. Information on the molecular regulation of CYP2J2 is sparse but supports roles for specificity protein-1 (Sp1) and activator protein-1 (AP-1) in transcription and the micro-RNA Let-7b in post-transcriptional regulation. Exposure to stress stimuli, including pro- and antioxidant factors and pro-inflammatory cytokines regulates CYP2J2, possibly in a cell-specific fashion. CYP2J2 is also subject to genetic variation and the promoter region SNP (CYP2J2-76G > T; *7 allele) reportedly decreases epoxygenase activity in vivo. Several studies have suggested that carriers of the *7 allele may be predisposed to adverse cardiovascular and related health outcomes, although other studies report different findings. Greater understanding of the mechanisms by which CYP2J2 is regulated could provide insights into important pathogenic processes in complex disease states. Such studies may also lead to the development of novel therapeutic strategies that seek to activate CYP2J2 expression in tissues. Additionally, the development of agents that promote fatty acid epoxide production, or stable analogs that retain the activities of the epoxides, offer promising new avenues for utilizing the beneficial actions of these molecules.
Archimedes said, “Give me the place to stand, and a lever long enough, and I will move the Earth.” Economists have their own powerful lever: the instrumental variable estimator. The instrumental ...variable estimator can avoid the bias that ordinary least squares suffers when an explanatory variable in a regression is correlated with the regression's disturbance term. But, like Archimedes' lever, instrumental variable estimation requires both a valid instrument on which to stand and an instrument that isn't too short (or “too weak”). This paper briefly reviews instrumental variable estimation, discusses classic strategies for avoiding invalid instruments (instruments themselves correlated with the regression's disturbances), and describes recently developed strategies for coping with weak instruments (instruments only weakly correlated with the offending explanator).
The time-dependent stock of PBDEs contained in in-use products (excluding building materials and large vehicles) was estimated for the U.S. and Canada from 1970 to 2020 based on product consumption ...patterns, PBDE contents, and product lifespan. The stocks of penta- and octaBDE peaked in in-use products at 17 000 (95% confidence interval: 6000–70 000) and 4000 (1000–50 000) tonnes in 2004, respectively, and for decaBDE at 140 000 (40 000–300 000) tonnes in 2008. Products dominating PBDE usage were polyurethane foam used in furniture (65% of pentaBDE), casings of electrical and electronic equipment or EEE (80% of octaBDE), and EEE and automotive seating (35% of decaBDE for each category). The largest flow of PBDEs in products, excluding automotive sector, to the waste phase occurred between 2005 and 2008 at ∼10 000 tonnes per year. Total consumption of penta-, octa-, and decaBDE from 1970 to 2020 in products considered was estimated at ∼46 000, ∼25 000, and ∼380 000 tonnes, respectively. Per capita usage was estimated at 10–250, 10–150, and 200–2000 g·capita–1·y–1 for penta-, octa-, and decaBDE, respectively, over the time span. Considering only the first use (no reuse and/or storage) of PBDE-containing products, approximately 60% of the stock of PBDEs in 2014 or ∼70 000 tonnes, of which 95% is decaBDE, will remain in the use phase in 2020. Total emissions to air of all PBDEs from the in-use product stock was estimated at 70–700 tonnes between 1970 and 2020, with annual emissions of 0.4–4 tonnes·y–1 for each of penta- and octaBDE and 0.35–3.5 tonnes·y–1 for decaBDE in 2014.
Ebola virus, the virus responsible for Ebola virus disease, has spawned several epidemics during the past 38 years. In 2014, an Ebola epidemic spread from Africa to other continents, becoming a ...pandemic. The virus's relatively unique structure, its infectivity and lethality, the difficulty in stopping its spread, and the lack of an effective treatment captured the world's attention. This article provides a brief review of the known history of Ebola virus disease, its etiology, epidemiology, and pathophysiology and a review of the limited information on managing patients with Ebola virus disease.
To update the 2002 version of "Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient."
A Task Force comprising 17 members of the Society of Critical ...Medicine with particular expertise in the use of neuromuscular-blocking agents; a Grading of Recommendations Assessment, Development, and Evaluation expert; and a medical writer met via teleconference and three face-to-face meetings and communicated via e-mail to examine the evidence and develop these practice guidelines. Annually, all members completed conflict of interest statements; no conflicts were identified. This activity was funded by the Society for Critical Care Medicine, and no industry support was provided.
Using the Grading of Recommendations Assessment, Development, and Evaluation system, the Grading of Recommendations Assessment, Development, and Evaluation expert on the Task Force created profiles for the evidence related to six of the 21 questions and assigned quality-of-evidence scores to these and the additional 15 questions for which insufficient evidence was available to create a profile. Task Force members reviewed this material and all available evidence and provided recommendations, suggestions, or good practice statements for these 21 questions.
The Task Force developed a single strong recommendation: we recommend scheduled eye care that includes lubricating drops or gel and eyelid closure for patients receiving continuous infusions of neuromuscular-blocking agents. The Task Force developed 10 weak recommendations. 1) We suggest that a neuromuscular-blocking agent be administered by continuous intravenous infusion early in the course of acute respiratory distress syndrome for patients with a PaO2/FIO2 less than 150. 2) We suggest against the routine administration of an neuromuscular-blocking agents to mechanically ventilated patients with status asthmaticus. 3) We suggest a trial of a neuromuscular-blocking agents in life-threatening situations associated with profound hypoxemia, respiratory acidosis, or hemodynamic compromise. 4) We suggest that neuromuscular-blocking agents may be used to manage overt shivering in therapeutic hypothermia. 5) We suggest that peripheral nerve stimulation with train-of-four monitoring may be a useful tool for monitoring the depth of neuromuscular blockade but only if it is incorporated into a more inclusive assessment of the patient that includes clinical assessment. 6) We suggest against the use of peripheral nerve stimulation with train of four alone for monitoring the depth of neuromuscular blockade in patients receiving continuous infusion of neuromuscular-blocking agents. 7) We suggest that patients receiving a continuous infusion of neuromuscular-blocking agent receive a structured physiotherapy regimen. 8) We suggest that clinicians target a blood glucose level of less than 180 mg/dL in patients receiving neuromuscular-blocking agents. 9) We suggest that clinicians not use actual body weight and instead use a consistent weight (ideal body weight or adjusted body weight) when calculating neuromuscular-blocking agents doses for obese patients. 10) We suggest that neuromuscular-blocking agents be discontinued at the end of life or when life support is withdrawn. In situations in which evidence was lacking or insufficient and the study results were equivocal or optimal clinical practice varies, the Task Force made no recommendations for nine of the topics. 1) We make no recommendation as to whether neuromuscular blockade is beneficial or harmful when used in patients with acute brain injury and raised intracranial pressure. 2) We make no recommendation on the routine use of neuromuscular-blocking agents for patients undergoing therapeutic hypothermia following cardiac arrest. 3) We make no recommendation on the use of peripheral nerve stimulation to monitor degree of block in patients undergoing therapeutic hypothermia. 4) We make no recommendation on the use of neuromuscular blockade to improve the accuracy of intravascular-volume assessment in mechanically ventilated patients. 5) We make no recommendation concerning the use of electroencephalogram-derived parameters as a measure of sedation during continuous administration of neuromuscular-blocking agents. 6) We make no recommendation regarding nutritional requirements specific to patients receiving infusions of neuromuscular-blocking agents. 7) We make no recommendation concerning the use of one measure of consistent weight over another when calculating neuromuscular-blocking agent doses in obese patients. 8) We make no recommendation on the use of neuromuscular-blocking agents in pregnant patients. 9) We make no recommendation on which muscle group should be monitored in patients with myasthenia gravis receiving neuromuscular-blocking agents. Finally, in situations in which evidence was lacking or insufficient but expert consensus was unanimous, the Task Force developed six good practice statements. 1) If peripheral nerve stimulation is used, optimal clinical practice suggests that it should be done in conjunction with assessment of other clinical findings (e.g., triggering of the ventilator and degree of shivering) to assess the degree of neuromuscular blockade in patients undergoing therapeutic hypothermia. 2) Optimal clinical practice suggests that a protocol should include guidance on neuromuscular-blocking agent administration in patients undergoing therapeutic hypothermia. 3) Optimal clinical practice suggests that analgesic and sedative drugs should be used prior to and during neuromuscular blockade, with the goal of achieving deep sedation. 4) Optimal clinical practice suggests that clinicians at the bedside implement measure to attenuate the risk of unintended extubation in patients receiving neuromuscular-blocking agents. 5) Optimal clinical practice suggests that a reduced dose of an neuromuscular-blocking agent be used for patients with myasthenia gravis and that the dose should be based on peripheral nerve stimulation with train-of-four monitoring. 6) Optimal clinical practice suggests that neuromuscular-blocking agents be discontinued prior to the clinical determination of brain death.
The COVID-19 infectious disease pandemic has caused significant fear and uncertainty around the world and had significant adverse psychological impact. Children, adolescents and adults with autism ...spectrum disorder (ASD) are a particularly vulnerable population, impacted by stay-at-home orders, closures at nonessential services, and social distancing standards. This commentary describes various challenges faced by individuals with ASD in the United States including disruptions caused by educational and vocational changes, challenges to home and leisure routines, limited access to behavioral health services and changes in health services delivery due to the pandemic. We highlight the need for ongoing skills development for individuals and development within systems to better respond to needs of the ASD population in future emergencies.
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•Lake Erie is heavily impacted by urban and agricultural nutrient loading.•The timing and bioavailability of these nutrient inputs favour toxic cyanobacteria.•High organic production ...exacerbates bottom hypoxia and sediment release of phosphorus, which will delay the lake's response to nutrient management.•Modelling has generated soluble and total P reduction targets for Lake Erie.•Many best management options were identified; their performance should be verified on a watershed basis.
Lake Erie supplies drinking water to more than 11 million consumers, processes millions of gallons of wastewater, provides important species habitat and supports a substantial industrial sector, with >$50 billion annual income to tourism, recreational boating, shipping, fisheries, and other industries. These and other key ecosystem services are currently threatened by an excess supply of nutrients, manifested in particular by increases in the magnitude and extent of harmful planktonic and benthic algal blooms (HABs) and hypoxia. Widespread concern for this important international waterbody has been manifested in a strong focus of scientific and public material on the subject, and commitments for Canada-US remedial actions in recent agreements among Federal, Provincial and State agencies. This review provides a retrospective synthesis of past and current nutrient inputs, impairments by planktonic and benthic HABs and hypoxia, modelling and Best Management Practices in the Lake Erie basin. The results demonstrate that phosphorus reduction is of primary importance, but the effects of climate, nitrogen and other factors should also be considered in the context of adaptive management. Actions to reduce nutrient levels by targeted Best Management Practices will likely need to be tailored for soil types, topography, and farming practices.
Analgesia and sedation in patients with ARDS Chanques, Gerald; Constantin, Jean-Michel; Devlin, John W. ...
Intensive care medicine,
12/2020, Letnik:
46, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Acute Respiratory Distress Syndrome (ARDS) is one of the most demanding conditions in an Intensive Care Unit (ICU). Management of analgesia and sedation in ARDS is particularly challenging. An expert ...panel was convened to produce a “state-of-the-art” article to support clinicians in the optimal management of analgesia/sedation in mechanically ventilated adults with ARDS, including those with COVID-19. Current ICU analgesia/sedation guidelines promote analgesia first and minimization of sedation, wakefulness, delirium prevention and early rehabilitation to facilitate ventilator and ICU liberation. However, these strategies cannot always be applied to patients with ARDS who sometimes require deep sedation and/or paralysis. Patients with severe ARDS may be under-represented in analgesia/sedation studies and currently recommended strategies may not be feasible. With lightened sedation, distress-related symptoms (e.g., pain and discomfort, anxiety, dyspnea) and patient-ventilator asynchrony should be systematically assessed and managed through interprofessional collaboration, prioritizing analgesia and anxiolysis. Adaptation of ventilator settings (e.g., use of a pressure-set mode, spontaneous breathing, sensitive inspiratory trigger) should be systematically considered before additional medications are administered. Managing the mechanical ventilator is of paramount importance to avoid the unnecessary use of deep sedation and/or paralysis. Therefore, applying an “ABCDEF-R” bundle (R = Respiratory-drive-control) may be beneficial in ARDS patients. Further studies are needed, especially regarding the use and long-term effects of fast-offset drugs (e.g., remifentanil, volatile anesthetics) and the electrophysiological assessment of analgesia/sedation (e.g., electroencephalogram devices, heart-rate variability, and video pupillometry). This review is particularly relevant during the COVID-19 pandemic given drug shortages and limited ICU-bed capacity.
With advances in genomic sequencing technology, the number of reported gene-disease relationships has rapidly expanded. However, the evidence supporting these claims varies widely, confounding ...accurate evaluation of genomic variation in a clinical setting. Despite the critical need to differentiate clinically valid relationships from less well-substantiated relationships, standard guidelines for such evaluation do not currently exist. The NIH-funded Clinical Genome Resource (ClinGen) has developed a framework to define and evaluate the clinical validity of gene-disease pairs across a variety of Mendelian disorders. In this manuscript we describe a proposed framework to evaluate relevant genetic and experimental evidence supporting or contradicting a gene-disease relationship and the subsequent validation of this framework using a set of representative gene-disease pairs. The framework provides a semiquantitative measurement for the strength of evidence of a gene-disease relationship that correlates to a qualitative classification: “Definitive,” “Strong,” “Moderate,” “Limited,” “No Reported Evidence,” or “Conflicting Evidence.” Within the ClinGen structure, classifications derived with this framework are reviewed and confirmed or adjusted based on clinical expertise of appropriate disease experts. Detailed guidance for utilizing this framework and access to the curation interface is available on our website. This evidence-based, systematic method to assess the strength of gene-disease relationships will facilitate more knowledgeable utilization of genomic variants in clinical and research settings.
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