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Loan No. 2542-BAN (SF): Participatory Small Scale Water Resources Sector Project [LGED/PSSW/PD/Ukhia/Cox/R-4/2013]




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Key Indicators for Asia and the Pacific 2024: Data for Climate Action

This publication provides updated statistics on a comprehensive set of economic, financial, social, and environmental measures as well as select indicators for the Sustainable Development Goals (SDGs).




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Sea lion cameras record amazing predator's view of the ocean

Eight Australian sea lions were fitted with cameras and trackers to capture unprecedented insights into their behaviour and the marine habitats where they hunt




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Migratory birds can use Earth's magnetic field like a GPS

Eurasian reed warblers don’t just get a sense of direction from Earth’s magnetic field – they can also calculate their coordinates on a mental map




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Single atoms captured morphing into quantum waves in startling image

In the 1920s, Erwin Schrödinger wrote an equation that predicts how particles-turned-waves should behave. Now, researchers are perfectly recreating those predictions in the lab




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Atoms at temperatures beyond absolute zero may be a new form of matter

Physicists have coaxed a cloud of atoms into having a temperature beyond absolute zero and placed them in a geometric structure that could produce an unknown form of matter




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This antimatter version of an atomic nucleus is the heaviest yet

Smashing gold nuclei together at high speeds billions of times has resulted in 16 particles of antihyperhydrogen-4, a very exotic and heavy form of antimatter




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Light has been seen leaving an atom cloud before it entered

Particles of light can spend "negative time" passing through a cloud of extremely cold atoms – without breaking the laws of physics




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Tiniest 'ruler' ever measures distances as small as an atom's width

A new technique uses glowing molecules, laser light and microscopes to measure distances as minuscule as 0.1 nanometres – the width of a typical atom




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Eerie green sunsets after 1883 Krakatoa eruption finally explained

Mysterious green sunsets were reported after the massive eruption of Krakatoa in 1883 – now simulations show how they were created and just how rare they are




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Deadly upwellings of cold water pose threat to migratory sharks

Climate change is making extreme cold upwellings more common in certain regions of the world, and these events can be catastrophic for animals such as bull sharks




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Migratory birds can use Earth's magnetic field like a GPS

Eurasian reed warblers don’t just get a sense of direction from Earth’s magnetic field – they can also calculate their coordinates on a mental map




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Egyptian pyramid may have been built using a water-powered elevator

Ancient Egyptians may have relied on a vertical shaft that could be filled with water, along with a network of water channels and filtration structures, to build the Step Pyramid of Djoser 4500 years ago




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Mandatory COVID-19 Tests Lifted for Vaccinated Travelers to Britain

Title: Mandatory COVID-19 Tests Lifted for Vaccinated Travelers to Britain
Category: Health News
Created: 2/11/2022 12:00:00 AM
Last Editorial Review: 2/14/2022 12:00:00 AM




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How Does Melatonin Make You Feel, and Are There Side Effects?

Title: How Does Melatonin Make You Feel, and Are There Side Effects?
Category: Health and Living
Created: 7/15/2022 12:00:00 AM
Last Editorial Review: 7/15/2022 12:00:00 AM




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Couch-Potato Kids Are Top U.S. Child Health Problem: Poll

Title: Couch-Potato Kids Are Top U.S. Child Health Problem: Poll
Category: Health News
Created: 8/24/2012 6:05:00 PM
Last Editorial Review: 8/27/2012 12:00:00 AM




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New Defibrillator Works Without Wires Touching Heart

Title: New Defibrillator Works Without Wires Touching Heart
Category: Health News
Created: 8/26/2013 4:36:00 PM
Last Editorial Review: 8/27/2013 12:00:00 AM




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VA Hospital Delays Didn't Cause Deaths, Investigators Say

Title: VA Hospital Delays Didn't Cause Deaths, Investigators Say
Category: Health News
Created: 8/26/2014 12:35:00 PM
Last Editorial Review: 8/27/2014 12:00:00 AM




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Mandatory Life Jacket Laws Could Reduce Boating Deaths

Title: Mandatory Life Jacket Laws Could Reduce Boating Deaths
Category: Health News
Created: 8/21/2015 12:00:00 AM
Last Editorial Review: 8/24/2015 12:00:00 AM




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Could Oral Contraceptives Help Ease Rheumatoid Arthritis?

Title: Could Oral Contraceptives Help Ease Rheumatoid Arthritis?
Category: Health News
Created: 8/28/2015 12:00:00 AM
Last Editorial Review: 8/28/2015 12:00:00 AM




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Senator John McCain Dies From Brain Tumor

Title: Senator John McCain Dies From Brain Tumor
Category: Health News
Created: 8/26/2018 12:00:00 AM
Last Editorial Review: 8/27/2018 12:00:00 AM




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Pentagon to Make COVID Vaccination Mandatory for Military

Title: Pentagon to Make COVID Vaccination Mandatory for Military
Category: Health News
Created: 8/23/2021 12:00:00 AM
Last Editorial Review: 8/24/2021 12:00:00 AM




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11 Home Remedies for Rheumatoid Arthritis

Title: 11 Home Remedies for Rheumatoid Arthritis
Category: Diseases and Conditions
Created: 12/7/2020 12:00:00 AM
Last Editorial Review: 8/2/2022 12:00:00 AM




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Rheumatoid Factor (RF)

Title: Rheumatoid Factor (RF)
Category: Procedures and Tests
Created: 1/28/2002 12:00:00 AM
Last Editorial Review: 8/25/2022 12:00:00 AM




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Here Are the Top 15 Anti-Inflammatory Foods for Your Diet To Reduce Inflammation

Title: Here Are the Top 15 Anti-Inflammatory Foods for Your Diet To Reduce Inflammation
Category: Health and Living
Created: 8/26/2022 12:00:00 AM
Last Editorial Review: 8/26/2022 12:00:00 AM




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How Long Do Potatoes Last? Raw, Cooked, and More

Title: How Long Do Potatoes Last? Raw, Cooked, and More
Category: Health and Living
Created: 8/26/2022 12:00:00 AM
Last Editorial Review: 8/26/2022 12:00:00 AM




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Evidence-based management of symptoms in serious respiratory illness: what is in our toolbox?

Extract

Living with a respiratory illness requires patients to manage a wide range of symptoms, many of which will worsen as a disease progresses. Breathlessness is a hallmark feature of respiratory conditions, occurring in almost all individuals with COPD and interstitial lung disease (ILD) [1, 2]. Cough is present in 78% of people with ILD and is frequently distressing, with physical, social and emotional impacts [1, 3].




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Antibody-mediated protection against respiratory syncytial virus in children

Respiratory syncytial virus (RSV) is a major global pathogen, causing lower respiratory tract disease in at-risk populations including young children. Antibodies form a crucial layer of protection from RSV disease, particularly in immunologically naïve infants. Such antibodies are derived from the mother via transplacental transfer and breast milk, but may be particularly low in high-risk infants such as those born preterm. Maternally derived antibodies can now be supplemented by the administration of anti-RSV monoclonal antibodies, while a rising wave of maternal and paediatric vaccine strategies are approaching. The implementation of these prophylactics may profoundly decrease the healthcare burden of RSV. In this article, we review the role of antibody-mediated immunity in protecting children from RSV. We focus on maternally derived antibodies as the main source of protection against RSV and study factors that influence the scale of this transfer. The role of passive and active prophylactic approaches in protecting infants against RSV are discussed and knowledge gaps in our understanding of antibody-mediated protection against RSV are identified.




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Multicomponent services for symptoms in serious respiratory illness: a systematic review and meta-analysis

Background

People living with serious respiratory illness experience a high burden of symptoms. This review aimed to determine whether multicomponent services reduce symptoms in people with serious illness related to respiratory disease.

Methods

Electronic databases were searched to identify randomised controlled trials (RCTs) evaluating multicomponent services that enrolled patients due to symptoms, rather than underlying disease, and provided at least one nonpharmacological intervention. The primary outcome was chronic breathlessness and secondary outcomes were health-related quality of life (HRQoL), cough, fatigue and adverse events. At least two authors independently screened studies, assessed risk of bias and extracted data.

Results

Five RCTs, involving 439 patients, were included. In comparison to usual care, multicomponent services improved breathlessness mastery (Chronic Respiratory Questionnaire (CRQ) mastery scale, mean difference (MD) 0.43 points, 95% CI 0.20–0.67, three RCTs, 327 participants) and HRQoL (CRQ total score, MD 0.24 points, 95% CI 0.04–0.40, two RCTs, 237 participants). Fatigue did not improve with multicomponent services and no studies evaluated cough. No serious adverse events were reported. The one study evaluating mortality found increased survival in those accessing a multicomponent service. The certainty of evidence was very low, mainly due to detection and reporting bias.

Conclusion

Multicomponent services improve breathlessness mastery and HRQoL, with minimal risk. These findings support the use of multicomponent symptom-directed services for people living with serious respiratory illness.




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The effect of graded exercise therapy on fatigue in people with serious respiratory illness: a systematic review

Background

In adults with serious respiratory illness, fatigue is prevalent and under-recognised, with few treatment options. The aim of this review was to assess the impact of graded exercise therapy (GET) on fatigue in adults with serious respiratory illness.

Methods

Electronic databases were searched to identify randomised controlled trials (RCTs) testing GET (involving incremental increases in exercise from an established baseline) in adults with serious respiratory illness. The primary outcome was fatigue and secondary outcomes were health-related quality of life (HRQoL) and adverse events. Two authors independently screened for inclusion, evaluated risk of bias and extracted data.

Results

76 RCTs were included with 3309 participants, most with a diagnosis of COPD or asthma. Reductions in fatigue measured by the Chronic Respiratory Disease Questionnaire fatigue domain score were demonstrated following GET consisting of aerobic with/without resistance training (mean difference (MD) 0.53 points, 95% CI 0.41–0.65, 11 RCTs, 624 participants) and GET using resistance training alone (MD 0.58 points, 95% CI 0.21–0.96, two RCTs, 82 participants) compared with usual care. Although the mean effect exceeded the minimal important difference, the lower end of the confidence intervals did not always exceed this threshold so the clinical significance could not be confirmed. GET consistently improved HRQoL in people with a range of chronic respiratory diseases on multiple HRQoL measures. No serious adverse events related to GET were reported.

Conclusion

GET may improve fatigue alongside consistent improvements in HRQoL in people with serious respiratory illness. These findings support the use of GET in the care of people with serious respiratory illness.




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Breathing techniques to reduce symptoms in people with serious respiratory illness: a systematic review

Background

In adults with serious respiratory illness, breathlessness is prevalent and associated with reduced health-related quality of life. The aim of this review was to assess the impact of breathing techniques on breathlessness in adults with serious respiratory illness.

Methods

Electronic databases were searched to identify randomised controlled trials testing breathing techniques (techniques that aim to alter the respiratory pattern, excluding respiratory muscle training) in people with serious respiratory illness. The primary outcome was breathlessness and secondary outcomes were health-related quality of life and adverse events. Two authors independently screened for inclusion, evaluated risk of bias and extracted data.

Results

73 randomised controlled trials were included with 5479 participants, most with COPD or asthma. Breathing exercises (pursed lip and/or diaphragmatic breathing) reduced breathlessness measured by the modified Medical Research Council scale compared to usual care (mean difference (MD) –0.40 points, 95% CI –0.70– –0.11, eight studies, n=323), although the effect did not exceed the minimal important difference. Yoga breathing also improved modified Medical Research Council score compared to usual care (MD –1.05 points, 95% CI –2.45–0.35, three studies, n=175). Breathing techniques consistently improved health-related quality of life in people with COPD and asthma on multiple health-related quality of life measures in comparison to usual care, with effects that generally exceeded the minimal important difference. No adverse events related to breathing techniques were reported.

Conclusion

Breathing techniques may improve breathlessness, and consistently improve health-related quality of life, in people with serious respiratory illness. These findings support the use of breathing exercises in the care of people with serious respiratory illness.




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Opioids for the palliation of symptoms in people with serious respiratory illness: a systematic review and meta-analysis

Background

People living with serious respiratory illness experience a high burden of distressing symptoms. Although opioids are prescribed for symptom management, they generate adverse events, and their benefits are unclear.

Methods

We examined the efficacy and safety of opioids for symptom management in people with serious respiratory illness. Embase, MEDLINE and the Cochrane Central Register of Controlled Trials were searched up to 11 July 2022. Reports of randomised controlled trials administering opioids to treat symptoms in people with serious respiratory illness were included. Key exclusion criteria included <80% of participants having a nonmalignant lung disease. Data were extracted regarding study characteristics, outcomes of breathlessness, cough, health-related quality of life (HRQoL) and adverse events. Treatment effects were pooled using a generic inverse variance model with random effects. Risk of bias was assessed using the Cochrane Risk of Bias tool version 1.

Results

Out of 17 included trials, six were laboratory-based exercise trials (n=70), 10 were home studies measuring breathlessness in daily life (n=788) and one (n=18) was conducted in both settings. Overall certainty of evidence was "very low" to "low". Opioids reduced breathlessness intensity during laboratory exercise testing (standardised mean difference (SMD) –0.37, 95% CI –0.67– –0.07), but not breathlessness measured in daily life (SMD –0.10, 95% CI –0.64–0.44). No effects on HRQoL (SMD –0.42, 95% CI –0.98–0.13) or cough (SMD –1.42, 95% CI –3.99–1.16) were detected. In at-home studies, opioids led to increased frequency of nausea/vomiting (OR 3.32, 95% CI 1.70–6.51), constipation (OR 3.08, 95% CI 1.69–5.61) and drowsiness (OR 1.37, 95% CI 1.01–1.86), with serious adverse events including hospitalisation and death identified.

Conclusions

Opioids improved exertional breathlessness in laboratory exercise studies, but did not improve breathlessness, cough or HRQoL measured in daily life at home. There were significant adverse events, which may outweigh any benefits.




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Evidence for compensatory evolution within pleiotropic regulatory elements [RESEARCH]

Pleiotropy, measured as expression breadth across tissues, is one of the best predictors for protein sequence and expression conservation. In this study, we investigated its effect on the evolution of cis-regulatory elements (CREs). To this end, we carefully reanalyzed the Epigenomics Roadmap data for nine fetal tissues, assigning a measure of pleiotropic degree to nearly half a million CREs. To assess the functional conservation of CREs, we generated ATAC-seq and RNA-seq data from humans and macaques. We found that more pleiotropic CREs exhibit greater conservation in accessibility, and the mRNA expression levels of the associated genes are more conserved. This trend of higher conservation for higher degrees of pleiotropy persists when analyzing the transcription factor binding repertoire. In contrast, simple DNA sequence conservation of orthologous sites between species tends to be even lower for pleiotropic CREs than for species-specific CREs. Combining various lines of evidence, we propose that the lack of sequence conservation in functionally conserved pleiotropic CREs is owing to within-element compensatory evolution. In summary, our findings suggest that pleiotropy is also a good predictor for the functional conservation of CREs, even though this is not reflected in the sequence conservation of pleiotropic CREs.




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Impact of COVID-19 on Chronic Ambulatory-Care-Sensitive Condition Emergency Department Use Among Older Adults

Background:

The COVID-19 pandemic social distancing requirements encouraged patients to avoid public spaces including in-office health care visits. Ambulatory-care-sensitive conditions (ACSCs) represent conditions that can be managed with quality primary care and when access is limited, these conditions can lead to avoidable emergency department (ED) visits.

Methods:

Using national data on ED visits from 2019 to 2021 in the National Hospital Ambulatory Care Survey, we examined the impact of COVID-19 pandemic on ACSC ED visits among older adults (aged ≥65).

Results:

The proportion of ED visits among older adults that were for ACSCs increased between 2019 (17.4%) and 2021 (18.5%). The trend in both rural (26.4%–28.6%) and urban areas (15.4%–16.8%) shows a significant jump from 2019 to 2021 (P < .001).

Conclusions:

This rise in ACSC ED use is consistent with a delay in normal primary care during the pandemic.




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A Qualitative Analysis of a Primary Care Medical-Legal Partnership: Impact, Barriers, and Facilitators

Background:

Certain health-related risk factors require legal interventions. Medical-legal partnerships (MLPs) are collaborations between clinics and lawyers that address these health-harming legal needs (HHLNs) and have been shown to improve health and reduce utilization.

Objective:

The objective of this study is to explore the impact, barriers, and facilitators of MLP implementation in primary care clinics.

Methods:

A qualitative design using a semistructured interview assessed the perceived impact, barriers, and facilitators of an MLP, among clinicians, clinic and MLP staff, and clinic patients. Open AI software (otter.ai) was used to transcribe interviews, and NVivo was used to code the data. Braun & Clarke’s framework was used to identify themes and subthemes.

Results:

Sixteen (n = 16) participants were included in this study. Most respondents were women (81%) and white (56%). Four respondents were clinic staff, and 4 were MLP staff while 8 were clinic patients. Several primary themes emerged including: Patients experienced legal issues that were pernicious, pervasive, and complex; through trusting relationships, the MLP was able to improve health and resolve legal issues, for some; mistrust, communication gaps, and inconsistent staffing limited the impact of the MLP; and, the MLP identified coordination and communication strategies to enhance trust and amplify its impact.

Conclusion:

HHLNs can have a significant, negative impact on the physical and mental health of patients. Respondents perceived that MLPs improved health and resolved these needs, for some. Despite perceived successes, integration between the clinical and legal organizations was elusive.




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The Evolution of Intermittent Mandatory Ventilation: Update and Implications for Home Care




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Comparing Highs and Flows in Patients With COPD With Chronic Hypercapnic Respiratory Failure




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Home Respiratory Strategies in Patients With COPD With Chronic Hypercapnic Respiratory Failure

BACKGROUND:Home noninvasive ventilation (NIV) may improve chronic hypercarbia in COPD and patient-important outcomes. The efficacy of home high-flow nasal cannula (HFNC) as an alternative is unclear.METHODS:We searched MEDLINE, Embase, Cochrane CENTRAL, Scopus, and ClinicalTrials.gov for randomized trials of subjects from inception to March 31, 2023, and updated the search on July 14, 2023. We performed a frequentist network meta-analysis and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We analyzed randomized controlled trials (RCTs) comparing NIV, HFNC, or standard care in adult subjects with COPD with chronic hypercapnic respiratory failure. Outcomes included mortality, COPD exacerbations, hospitalizations, and quality of life (St George Respiratory Questionnaire [SGRQ]).RESULTS:We analyzed 24 RCTs (1,850 subjects). We found that NIV may reduce the risk of death compared to standard care (relative risk 0.82 [95% CI 0.66–1.00]) and probably reduces exacerbations (relative risk 0.71 [95% CI 0.58–0.87]). HFNC probably reduces exacerbations compared to standard care (relative risk 0.77 [0.68–0.88]), but its effect on mortality is uncertain (relative risk 1.20 [95% CI 0.63–2.28]). HFNC probably improves SGRQ scores (mean difference −7.01 [95% CI −12.27 to −1.77]) and may reduce hospitalizations (relative risk 0.87 [0.69–1.09]) compared to standard care. No significant difference was observed between HFNC and NIV in reducing exacerbations.CONCLUSIONS:Both NIV and HFNC reduce exacerbation risks in subjects with COPD compared to standard care. HFNC may offer advantages in improving quality of life.




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Exploring the Impact of Varied Design Approaches and Materials in Respiratory Therapy Education




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Effects of Lung Injury and Abdominal Insufflation on Respiratory Mechanics and Lung Volume During Time-Controlled Adaptive Ventilation

BACKGROUD:Lung volume measurements are important for monitoring functional aeration and recruitment and may help guide adjustments in ventilator settings. The expiratory phase of airway pressure release ventilation (APRV) may provide physiologic information about lung volume based on the expiratory flow-time slope, angle, and time to approach a no-flow state (expiratory time [TE]). We hypothesized that expiratory flow would correlate with estimated lung volume (ELV) as measured using a modified nitrogen washout/washin technique in a large-animal lung injury model.METHODS:Eight pigs (35.2 ± 1.0 kg) were mechanically ventilated using an Engström Carescape R860 on the APRV mode. All settings were held constant except the expiratory duration, which was adjusted based on the expiratory flow curve. Abdominal pressure was increased to 15 mm Hg in normal and injured lungs to replicate a combination of pulmonary and extrapulmonary lung injury. ELV was estimated using the Carescape FRC INview tool. The expiratory flow-time slope and TE were measured from the expiratory flow profile.RESULTS:Lung elastance increased with induced lung injury from 29.3 ± 7.3 cm H2O/L to 39.9 ± 15.1cm H2O/L, and chest wall elastance increased with increasing intra-abdominal pressures (IAPs) from 15.3 ± 4.1 cm H2O/L to 25.7 ± 10.0 cm H2O/L in the normal lung and 15.8 ± 6.0 cm H2O/L to 33.0 ± 6.2 cm H2O/L in the injured lung (P = .39). ELV decreased from 1.90 ± 0.83 L in the injured lung to 0.67 ± 0.10 L by increasing IAP to 15 mm Hg. This had a significant correlation with a TE decrease from 2.3 ± 0.8 s to 1.0 ± 0.1 s in the injured group with increasing insufflation pressures (ρ = 0.95) and with the expiratory flow-time slope, which increased from 0.29 ± 0.06 L/s2 to 0.63 ± 0.05 L/s2 (ρ = 0.78).CONCLUSIONS:Changes in ELV over time, and the TE and flow-time slope, could be used to demonstrate evolving lung injury during APRV. Using the slope to infer changes in functional lung volume represents a unique, reproducible, real-time, bedside technique that does not interrupt ventilation and may be used for clinical interpretation.




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The Impact of Increased PEEP on Hemodynamics, Respiratory Mechanics, and Oxygenation in Pediatric ARDS

BACKGROUND:PEEP is a cornerstone treatment for children with pediatric ARDS. Unfortunately, its titration is often performed solely by evaluating oxygen saturation, which can lead to inadequate PEEP level settings and consequent adverse effects. This study aimed to assess the impact of increasing PEEP on hemodynamics, respiratory system mechanics, and oxygenation in children with ARDS.METHODS:Children receiving mechanical ventilation and on pressure-controlled volume-guaranteed mode were prospectively assessed for inclusion. PEEP was sequentially changed to 5, 12, 10, 8 cm H2O, and again to 5 cm H2O. After 10 min at each PEEP level, hemodynamic, ventilatory, and oxygenation variables were collected.RESULTS:A total of 31 subjects were included, with median age and weight of 6 months and 6.3 kg, respectively. The main reasons for pediatric ICU admission were respiratory failure caused by acute viral bronchiolitis (45%) and community-acquired pneumonia (32%). Most subjects had mild or moderate ARDS (45% and 42%, respectively), with a median (interquartile range) oxygenation index of 8.4 (5.8–12.7). Oxygen saturation improved significantly when PEEP was increased. However, although no significant changes in blood pressure were observed, the median cardiac index at PEEP of 12 cm H2O was significantly lower than that observed at any other PEEP level (P = .001). Fourteen participants (45%) experienced a reduction in cardiac index of > 10% when PEEP was increased to 12 cm H2O. Also, the estimated oxygen delivery was significantly lower, at 12 cm H2O PEEP. Finally, respiratory system compliance significantly reduced when PEEP was increased. At a PEEP of 12 cm H2O, static compliance had a median reduction of 25% in relation to the initial assessment (PEEP of 5 cm H2O).CONCLUSIONS:Although it may improve arterial oxygen saturation, inappropriately high PEEP levels may reduce cardiac output, oxygen delivery, and respiratory system compliance in pediatric subjects with ARDS with low potential for lung recruitability.




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Comparison of Web-Based and On-Site Lung Simulators for Education in Mechanical Ventilation

BACKGROUND:Training in mechanical ventilation is a key goal in critical care fellowship education. Web-based simulators offer a cost-effective and readily available alternative to traditional on-site simulators. However, it is unclear how effective they are as teaching tools. In this study, we evaluated the test scores of fellows who underwent mechanical ventilation training by using a web-based simulator compared with fellows who used an on-site simulator during a mechanical ventilation course.METHODS:This was a nonrandomized controlled trial conducted as part of a mechanical ventilation course that involved 70 first-year critical care fellows. The course was identical except for the simulation technology used. One group of instructors used a traditional on-site simulator, the ASL 5000 Lung Solution (n = 39). The second group was instructed in using a web-based simulator, VentSim (n = 31). Each fellow completed a pre-course test and a post-course test by using a validated, case-based ventilator waveform examination that consisted of 5 questions with a total possible score of 100. The primary outcome was a comparison of the mean scores on the posttest between the 2 groups. The study was designed as a non-inferiority trial with a predetermined margin of 10 points.RESULTS:There was no significant difference in the mean ± SD pretest scores between the web-based and the on-site groups (21.1 ± 12.6 and 26.9 ± 13.6 respectively; P = .11). The mean ± SD posttest scores were 45.6 ± 25.0 for the web-based simulator and 43.4 ± 16.5 for on-site simulator (mean difference 2.2; one-sided 95% CI –7.0 to ∞; Pnon-inferiority = .02 [non-inferiority confirmed]). Changes in mean ± SD scores (posttest – pretest) were 25.9 ± 20.9 for the web-based simulator and 16.5 ± 15.9 for the on-site simulator (mean difference 9.4, one-sided 95% CI 0.9 to ∞; Pnon-inferiority < .001 [non-inferiority confirmed]).CONCLUSIONS:In the education of first-year critical care fellows on mechanical ventilation waveform analysis, a web-based mechanical ventilation simulator was non-inferior to a traditional on-site mechanical ventilation simulator.




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Respiratory Care




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YY1 knockout in pro-B cells impairs lineage commitment, enabling unusual hematopoietic lineage plasticity [Research Papers]

During B-cell development, cells progress through multiple developmental stages, with the pro-B-cell stage defining commitment to the B-cell lineage. YY1 is a ubiquitous transcription factor that is capable of both activation and repression functions. We found here that knockout of YY1 at the pro-B-cell stage eliminates B lineage commitment. YY1 knockout pro-B cells can generate T lineage cells in vitro using the OP9-DL4 feeder system and in vivo after injection into sublethally irradiated Rag1–/– mice. These T lineage-like cells lose their B lineage transcript profile and gain a T-cell lineage profile. Single-cell RNA-seq experiments showed that as YY1 knockout pro-B cells transition into T lineage cells in vitro, various cell clusters adopt transcript profiles representing a multiplicity of hematopoietic lineages, indicating unusual lineage plasticity. In addition, YY1 KO pro-B cells in vivo can give rise to other hematopoietic lineages in vivo. Evaluation of RNA-seq, scRNA-seq, ChIP-seq, and scATAC-seq data indicates that YY1 controls numerous chromatin-modifying proteins leading to increased accessibility of alternative lineage genes in YY1 knockout pro-B cells. Given the ubiquitous nature of YY1 and its dual activation and repression functions, YY1 may regulate commitment in multiple cell lineages.




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Temperature matters: the potential impact of thermoregulatory mechanisms in brain-body physiology [Special Section: Symposium Outlook]

Thermoregulation, responsible for maintaining a stable core temperature during wide fluctuations in external and internal thermal environments, is an iconic homeostatic process. However, we suggest that despite its fundamental physiological significance, the potential for required cool housing temperatures and thermoregulatory mechanisms to influence the interpretation of experimental data is not sufficiently appreciated. Moreover, although it is generally assumed that the major thermoregulatory pathways are well understood, here we discuss new research that suggests otherwise and reveals the emergence of a new wave of exciting ideas for this "old" field of research.




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The area postrema: a critical mediator of brain-body interactions [Special Section: Symposium Outlook]

The dorsal vagal complex contains three structures: the area postrema, the nucleus tractus solitarii, and the dorsal motor nucleus of the vagus. These structures are tightly linked, both anatomically and functionally, and have important yet distinct roles in not only conveying peripheral bodily signals to the rest of the brain but in the generation of behavioral and physiological responses. Reports on the new discoveries in these structures were highlights of the symposium. In this outlook, we focus on the roles of the area postrema in mediating brain–body interactions and its potential utility as a therapeutic target, especially in cancer cachexia.




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Characteristics of exacerbators in the US Bronchiectasis and NTM Research Registry: a cross-sectional study

Background

Exacerbations of noncystic fibrosis bronchiectasis (bronchiectasis) are associated with reduced health-related quality of life and increased mortality, likelihood of hospitalisation and lung function decline. This study investigated patient clinical characteristics associated with exacerbation frequency.

Methods

A cross-sectional cohort study of patients ≥18 years with bronchiectasis enrolled in the US Bronchiectasis and Nontuberculous Mycobacteria (NTM) Research Registry (BRR) September 2008–March 2020. Patients were stratified by exacerbation frequency in their 2 years before enrolment. Patient demographics, respiratory symptoms, healthcare resource utilisation, microbiology, modified bronchiectasis severity index (mBSI) and select comorbidities were collected at enrolment. Patient characteristics associated with exacerbation frequency were assessed using a negative binomial model.

Results

The study included 2950 patients (mean age 65.6 years; 79.1% female). Frequency of moderate to severe airway obstruction (forced expiratory volume in 1 s (FEV1) % predicted <50%; most recent measure) was 15.9%, 17.8%, and 24.6% in patients with 1, 2, and ≥3 exacerbations versus 8.9% in patients with 0 exacerbations; severe disease (mBSI) was 27.8%, 24.2% and 51.1% versus 13.2%; respiratory hospitalisation was 24.5%, 33.0% and 36.5% versus 4.1%; and Pseudomonas aeruginosa infection was 18.8%, 23.4% and 35.2% versus 11.9%. In multivariable model analysis, respiratory hospitalisation, cough, haemoptysis, P.  aeruginosa, younger age, lower FEV1% predicted, asthma, and gastro-oesophageal reflux disease were associated with more exacerbations.

Conclusions

These findings demonstrate a high disease burden, including increased respiratory symptoms, healthcare resource utilisation, and P.  aeruginosa infection in patients with bronchiectasis and multiple exacerbations.




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Ensuring availability of respiratory medicines in times of European drug shortages

Extract

It is of utmost importance that medicines are available at all times for our patients. Historically, medication unavailability has typically, if not exclusively, affected low- and middle-income countries [1]. More recently however, drug shortages have also been reported in high-income European countries [2]. Drug shortages have negative health consequences for patients [3], and a profound economic impact, with the need to resort to more expensive alternatives and demands on healthcare professionals’ time to find, prescribe and dispense alternatives [4].




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Investigations into the Concentrations and Metabolite Profiles of Doping Agents and Antidepressants in Human Seminal Fluid Using Liquid Chromatography-Mass Spectrometry [Articles]

Exogenous substances, including drugs and chemicals, can transfer into human seminal fluid and influence male fertility and reproduction. In addition, substances relevant in the context of sports drug testing programs, can be transferred into the urine of a female athlete (after unprotected sexual intercourse) and trigger a so-called adverse analytical finding. Here, the question arises as to whether it is possible to distinguish analytically between intentional doping offenses and unintentional contamination of urine by seminal fluid. To this end, 480 seminal fluids from nonathletes were analyzed to identify concentration ranges and metabolite profiles of therapeutic drugs that are also classified as doping agents. Therefore, a screening procedure was developed using liquid chromatography connected to a triple quadrupole mass spectrometer, and suspect samples (i.e., samples indicating the presence of relevant compounds) were further subjected to liquid chromatography-high-resolution accurate mass (tandem) mass spectrometry. The screening method yielded 90 findings (including aromatase inhibitors, selective estrogen receptor modulators, diuretics, stimulants, glucocorticoids, beta-blockers, antidepressants, and the nonapproved proliferator-activated receptor delta agonist GW1516) in a total of 81 samples, with 91% of these suspected cases being verified by the confirmation method. In addition to the intact drug, phase-I and -II metabolites were also occasionally observed in the seminal fluid. This study demonstrated that various drugs including those categorized as doping agents partition into seminal fluid. Monitoring substances and metabolites may contribute to a better understanding of the distribution and metabolism of exogenous substances in seminal fluid that may be responsible for the impairment of male fertility.

SIGNIFICANCE STATEMENT

This study demonstrates that doping agents as well as clinically relevant substances are transferred/eliminated into seminal fluid to a substantial extent and that knowledge about drug levels (and potential consequences for the male fertility and female exposure) is limited. The herein generated new dataset provides new insights into an important and yet little explored area of drug deposition and elimination, and hereby a basis for the assessment of contamination cases by seminal fluid in sports drug testing.




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Characterizing the Distribution of a Stimulator of Interferon Genes Agonist and Its Metabolites in Mouse Liver by Matrix-Assisted Laser Desorption/Ionization Imaging Mass Spectrometry [Special Section on New and Emerging Areas and Technologies in Drug Met

A STING (stimulator of interferon genes) agonist GSK3996915 under investigation in early discovery for hepatitis B was orally dosed to a mouse model for understanding the parent drug distribution in liver, the target organ. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was used to quantify the distribution of GSK3996915 in liver collected from mice administered a single oral dose at 90 mg/kg. GSK3996915 was detected with a zonal distribution localized in the portal triad and highly concentrated in the main bile ducts, indicating clearance through biliary excretion. High spatial resolution imaging showed the distribution of the parent drug localized to the cellular populations in the sinusoids, including the Kupffer cells. Additionally, a series of drug-related metabolites were observed to be localized in the central zones of the liver. These results exemplify the potential of utilizing MALDI IMS for measuring not only quantitative drug distribution and target exposure but also drug metabolism and elimination in a single suite of experiments.

SIGNIFICANCE STATEMENT

An integrated imaging approach utilizing matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) complemented with immunohistochemistry (IHC) and histology was used to address the question of target exposure at the cellular level. Localized quantification of the parent drug in the target organ and identification of potential metabolites in the context of tissue histology were also achieved in one experimental suite to support characterization of pharmacokinetic properties of the drug in the early discovery stage.: