Greenhouse gas emissions associated with suboptimal asthma care in the UK: the SABINA healthCARe-Based envirONmental cost of treatment (CARBON) study.

BACKGROUND: Poorly controlled asthma is associated with increased morbidity and healthcare resource utilisation (HCRU). Therefore, to quantify the environmental impact of asthma care, this retrospective, cohort, healthCARe-Based envirONmental cost of treatment (CARBON) study estimated greenhouse gas (GHG) emissions in the UK associated with the management of well-controlled versus poorly controlled asthma. METHODS: Patients with current asthma (aged ≥12 years) registered with the Clinical Practice Research Datalink (2008‒2019) were included. GHG emissions, measured as carbon dioxide equivalent (CO2e), were estimated for asthma-related medication use, HCRU and exacerbations during follow-up of patients with asthma classified at baseline as well-controlled (<3 short-acting ß2-agonist (SABA) canisters/year and no exacerbations) or poorly controlled (≥3 SABA canisters/year or ≥1 exacerbation). Excess GHG emissions due to suboptimal asthma control included ≥3 SABA canister prescriptions/year, exacerbations and any general practitioner and outpatient visits within 10 days of hospitalisation or an emergency department visit. RESULTS: Of the 236 506 patients analysed, 47.3% had poorly controlled asthma at baseline. Scaled to the national level, the overall carbon footprint of asthma care in the UK was 750 540 tonnes CO2e/year, with poorly controlled asthma contributing excess GHG emissions of 303 874 tonnes CO2e/year, which is equivalent to emissions from >124 000 houses in the UK. Poorly controlled versus well-controlled asthma generated 3.1-fold higher overall and 8.1-fold higher excess per capita carbon footprint, largely SABA-induced, with smaller contributions from HCRU. CONCLUSIONS: These findings suggest that addressing the high burden of poorly controlled asthma, including curbing high SABA use and its associated risk of exacerbations, may significantly alleviate asthma care-related carbon emissions.

COVID-19 and pneumothorax: a multicentre retrospective case series.

INTRODUCTION: Pneumothorax and pneumomediastinum have both been noted to complicate cases of coronavirus disease 2019 (COVID-19) requiring hospital admission. We report the largest case series yet described of patients with both these pathologies (including nonventilated patients). METHODS: Cases were collected retrospectively from UK hospitals with inclusion criteria limited to a diagnosis of COVID-19 and the presence of either pneumothorax or pneumomediastinum. Patients included in the study presented between March and June 2020. Details obtained from the medical record included demographics, radiology, laboratory investigations, clinical management and survival. RESULTS: 71 patients from 16 centres were included in the study, of whom 60 had pneumothoraces (six with pneumomediastinum in addition) and 11 had pneumomediastinum alone. Two of these patients had two distinct episodes of pneumothorax, occurring bilaterally in sequential fashion, bringing the total number of pneumothoraces included to 62. Clinical scenarios included patients who had presented to hospital with pneumothorax, patients who had developed pneumothorax or pneumomediastinum during their inpatient admission with COVID-19 and patients who developed their complication while intubated and ventilated, either with or without concurrent extracorporeal membrane oxygenation. Survival at 28 days was not significantly different following pneumothorax (63.1±6.5%) or isolated pneumomediastinum (53.0±18.7%; p=0.854). The incidence of pneumothorax was higher in males. 28-day survival was not different between the sexes (males 62.5±7.7% versus females 68.4±10.7%; p=0.619). Patients aged ≥70 years had a significantly lower 28-day survival than younger individuals (≥70 years 41.7±13.5% survival versus <70 years 70.9±6.8% survival; p=0.018 log-rank). CONCLUSION: These cases suggest that pneumothorax is a complication of COVID-19. Pneumothorax does not seem to be an independent marker of poor prognosis and we encourage continuation of active treatment where clinically possible.

Sustainability in Inhaled Drug Delivery.

Asthma and chronic obstructive pulmonary disease (COPD) are amongst the most common chronic diseases worldwide, and are largely preventable by improving the quality of the air we breathe. The most commonly deployed treatment, the metered dose inhaler (MDI), uses hydrofluorocarbon propellants, which are powerful greenhouse gases that contribute disproportionately to the climate crisis. Alternative treatment strategies are required if we are to avoid contributing to the worst effects of climate change. These strategies include promoting non-pharmacological therapies like smoking cessation and pulmonary rehabilitation; empowering patients to gain better disease control through written management plans and encouraging preventer, rather than reliever therapies. Pharmacological strategies include: improving inhaler technique and spacer use; minimising propellant release by using smaller volume MDIs and simpler dosing regimes; dose counters to prevent waste; switching to low global warming potential inhalers; and inhaler recycling. There are also opportunities to improve disease control alongside reduced greenhouse gas emissions, including better matching of patients' devices to inhaler technique rather than defaulting to MDIs, stopping unnecessary inhaled steroids in COPD and maintenance and reliever therapy in asthma. New, lower global warming potential propellants are on the horizon, and their introduction could offer a golden opportunity to enhance MDIs usability and sustainability by making them refillable, integrating whistles to optimise inhalation technique, adding integrated caps, optimising materials for recycling and adding dose counters to all MDIs.

Carbon footprint impact of the choice of inhalers for asthma and COPD.

In the 1990s, metered dose inhalers (MDIs) containing chlorofluorocarbons were replaced with dry-powder inhalers (DPIs) and MDIs containing hydrofluorocarbons (HFCs). While HFCs are not ozone depleting, they are potent greenhouse gases. Annual carbon footprint (CO2e), per patient were 17 kg for Relvar-Ellipta/Ventolin-Accuhaler; and 439 kg for Seretide-Evohaler/Ventolin-Evohaler. In 2017, 70% of all inhalers sold in England were MDI, versus 13% in Sweden. Applying the Swedish DPI and MDI distribution to England would result in an annual reduction of 550 kt CO2e. The lower carbon footprint of DPIs should be considered alongside other factors when choosing inhalation devices.

Costs of switching to low global warming potential inhalers. An economic and carbon footprint analysis of NHS prescription data in England.

OBJECTIVES: Metered-dose inhalers (MDIs) contain propellants which are potent greenhouse gases. Many agencies propose a switch to alternative, low global warming potential (GWP) inhalers, such as dry powder inhalers (DPIs). We aimed to analyse the impact on greenhouse gas emissions and drug costs of making this switch. SETTING: We studied National Health Service prescription data from England in 2017 and collated carbon footprint data on inhalers commonly used in England. DESIGN: Inhalers were separated into different categories according to their mechanisms of action (eg, short-acting beta-agonist). Within each category we identified low and high GWP inhalers and calculated the cost and carbon impact of changing to low GWP inhalers. We modelled scenarios for swapping proportionally according to the current market share of each equivalent DPI (model 1) and switching to the lowest cost pharmaceutically equivalent DPI (model 2). We also reviewed available data on the carbon footprint of inhalers from scientific publications, independently certified reports and patents to provide more accurate carbon footprint information on different types of inhalers. RESULTS: If MDIs using HFA propellant are replaced with the cheapest equivalent DPI, then for every 10% of MDIs changed to DPIs, drug costs decrease by £8.2M annually. However if the brands of DPIs stay the same as 2017 prescribing patterns, for every 10% of MDIs changed to DPIs, drug costs increase by £12.7M annually. Most potential savings are due to less expensive long-acting beta-agonist (LABA)/inhaled corticosteroids (ICS) inhalers. Some reliever inhalers (eg, Ventolin) have a carbon footprint over 25 kg CO2e per inhaler, while others use far less 1,1,1,2-tetrafluoroethane (HFA134a) (eg, Salamol) with a carbon footprint of <10 kg CO2e per inhaler. 1,1,1,2,3,3,3-Heptafluoropropane (HFA227ea) LABA/ICS inhalers (eg, Flutiform) have a carbon footprint over 36 kg CO2e, compared with an equivalent HFA134a combination inhaler (eg, Fostair) at <20 kg CO2e. For every 10% of MDIs changed to DPIs, 58 kt CO2e could be saved annually in England. CONCLUSIONS: Switching to DPIs would result in large carbon savings and can be achieved alongside reduced drug costs by using less expensive brands. Substantial carbon savings can be made by using small volume HFA134a MDIs, in preference to large volume HFA134a MDIs, or those containing HFA227ea as a propellant.

Monolithically integrated low linewidth comb source using gain switched slotted Fabry-Perot lasers.

A monolithically integrated low linewidth optical comb is demonstrated by gain switching of a three-section laser device. The device consists of a slave and master section separated by a shared slotted mirror section. Wavelength tunability has been demonstrated by varying the electrical bias of each section. The number of comb lines is shown to almost double with the addition of optical injection from the master section into the slave. The unmodulated device has a full width half max linewidth of ∼ 500 kHz, while the comb line set were measured to be ∼ 600 kHz, with little degradation as a result of gain switching. The FSR (free spectral range) of the demonstrated comb is 4 GHz, which is tunable within the bandwidth of the device, with a central wavelength of 1580.3 nm.

Palmitoylation of nicotinic acetylcholine receptors.

It is well established that nicotinic acetylcholine receptors (nAChRs) undergo a number of different posttranslational modifications, such as disulfide bond formation, glycosylation, and phosphorylation. Recently, our laboratory has developed more sensitive assays of protein palmitoylation that have allowed us and others to detect the palmitoylation of relatively low abundant proteins such as ligand-gated ion channels. Here, we present evidence that palmitoylation is prevalent on many subunits of different nAChR subtypes, both muscle-type nAChRs and the neuronal "alpha(4)beta(2)" and "alpha(7)" subtypes most abundant in brain. The loss of ligand binding sites that occurs when palmitoylation is blocked with the inhibitor bromopalmitate suggests that palmitoylation of alpha(4)beta(2) and alpha(7) subtypes occurs during subunit assembly and regulates the formation of ligand binding sites. However, additional experiments are needed to test whether nAChR subunit palmitoylation is involved in other aspects of nAChR trafficking or whether palmitoylation regulates nAChR function. Further investigation would be aided by identifying the sites of palmitoylation on the subunits, and here we propose a mass spectrometry strategy for identification of these sites.

Obesity and coronary heart disease.

Obesity is commonly cited as a risk factor for the development of coronary heart disease (CHD). Epidemiologic studies tend to support this contention, particularly those focusing on patients with central obesity. Such studies however, are imprecise and prone to misclassification bias. Angiographic and post mortem studies have demonstrated little or no correlation of total fat mass and coronary atherosclerosis except in those with abdominal obesity. There is a strong association of obesity, particularly central obesity, and traditional risk factors for CHD such as hypertension, type II diabetes mellitus, and dyslipidemia. There may also be an association between obesity and several nontraditional risk factors such as hyperhomocystinemia, elevated Lp(a) levels and factors that increase thrombogenesis. Obesity may also alter endothelial function. Weight loss, although associated with favorable modification of multiple risk factors for CHD, has not been shown to independently and definitively reduce CHD risk.

Cardiac arrhythmia at high altitude: the progressive effect of aging.

To evaluate the effects of aging on cardiac rhythm at high altitude, I wore a Holter monitor at age 75 during a climb to 5,100 m on Mt. Kilimanjaro, then compared findings with those from my climb to 5,895 m at age 65. Holter leads were placed to identify left or right ventricular source of ectopy, and on the 2nd ascent arterial oxygen saturation was monitored by finger oximetry. Sea-level testing revealed no evidence of cardiac disease. During ascent from 4,710 to 5,100 m, when arterial oxygen saturation reached 70%, heart rate was higher (123 vs 116 beats per minute), and frequency of left ventricular premature complexes was greater (56 vs 50 per hour) than on the earlier ascent. Nine 3- to 5-complex runs of left ventricular tachycardia were recorded during climbing, resting, or sleeping, and there was 1 run of 14 complexes at 250 beats per minute during the climb near 5,100 m. These observations suggest that aging increases sympathetic response or sensitivity, or both, to hypoxia during exercise, and even during sleep. Also, our focus should perhaps be on sympathetic stimulation rather than on pulmonary hypertension as a cause of arrhythmia in unacclimatized older persons at high altitude.

Coronary problems associated with altitude and air travel.

Hypoxia accompanying acute exposure to high altitude engenders augmented sympathetic nervous activity, thus increasing heart rate and blood pressure and the risk of effort angina and dysrhythmia in coronary patients. This risk is highest during the first 1 to 3 days and diminishes in 5 to 7 days as sympathetic activity subsides. Protective effects may result from 1. Gradual ascent. 2. Attention to blood pressure control. 3. Limitation of activity to less than the symptom-limiting degree at sea level, especially during the first 1 to 3 days. 4. Preexisting exercise tolerance of modest-to-moderate degree. 5. Ability of patient to appraise heart rate and blood pressure. Ascent by high-risk patients can be recommended to no more than moderate altitude, where adequate facilities for cardiovascular care are proximate. The risk of acute mountain sickness is not increased in older coronary patients. Strong contraindications to air travel by coronary patients would appear to be 1. New-onset angina. 2. Unstable angina. 3. Frequent or high-grade ventricular ectopy. 4. Severe or poorly controlled hypertension. Myocardial infarction within several weeks or months constitutes a relative contraindication, with persistent angina, ventricular ectopy, and poor ventricular function as the factors of greatest concern.

How well do older persons tolerate moderate altitude?

We studied the physiologic and clinical responses to moderate altitude in 97 older men and women (aged 59 to 83 years) over 5 days in Vail, Colorado, at an elevation of 2,500 m (8,200 ft). The incidence of acute mountain sickness was 16%, which is slightly lower than that reported for younger persons. The occurrence of symptoms of acute mountain sickness did not parallel arterial oxygen saturation or spirometric or blood pressure measurements. Chronic diseases were present in percentages typical for ambulatory elderly persons: 19 (20%) had coronary artery disease, 33 (34%) had hypertension, and 9 (9%) had lung disease. Despite this, no adverse signs or symptoms occurred in our subjects during their stay at this altitude. Our findings suggest that persons with preexisting, generally asymptomatic, cardiovascular or pulmonary disease can safely visit moderate altitudes.

Age, altitude, and arrhythmia.

Continuous electrocardiographic recording by Holter monitor was carried out during a climb to 5,895 m by an unacclimatized 65-year-old man confirmed to be without cardiac disease on rigorous examination. During ascent, marked ventricular ectopy and multiple runs of left ventricular bigeminy developed in association with an increase in P-wave amplitude of lead V2, and unchanged QT interval. With the diminished aerobic stress of descent, bigeminy disappeared, although premature ventricular complexes, apparently of right ventricular origin, remained increased throughout the climb. Arrhythmogenic mechanisms activated by prolonged exercise under hypoxic conditions are reviewed in relation to age.

Coronary heart disease at altitude.

In the past, it has been assumed that some basic physiologic responses to altitude, exposure in coronary patients are comparable to those in normal young subjects. In fact there are similar changes in sympathetic activation, heart rate, and blood pressure early after ascent, with decrements in plasma volume, cardiac output, and stroke volume as acclimatization proceeds. These responses are described, and experience with coronary patients is reviewed. During the 1st 2 to 3 days at altitude, coronary patients are at greatest risk of untoward events. Gradual rather than abrupt ascent, a moderate degree of physical conditioning, early limitation of activity to a level tolerated at low altitude for somewhat less), and attention to blood pressure control all appear to have protective effects. Ascent to moderate altitude appears to entail little risk in coronary patients who are asymptomatic or have moderate exercise tolerance, provided that the above precautions are observed and that activity does not exceed levels at lower altitude. If activity is to be increased, pre-ascent treadmill exercise testing or Holter monitor data secured under conditions comparable to those anticipated at altitude may provide reasonable guidelines. For coronary patients previously evaluated and known to be in a high-risk category, indications for ascent should be examined more critically, and precautionary measures should be more rigorous. Advice for patients with known coronary disease who may desire to trek at very high altitude must involve individual evaluation, and guidelines remain elusive.

Oxygen transport and cardiovascular function at extreme altitude: lessons from Operation Everest II.

Operation Everest II was designed to examine the physiological responses to gradual decompression simulating an ascent of Mt Everest (8,848 m) to an inspired PO2 of 43 mmHg. The principal studies conducted were cardiovascular, respiratory, muscular-skeletal and metabolic responses to exercise. Eight healthy males aged 21-31 years began the "ascent" and six successfully reached the "summit", where their resting arterial blood gases were PO2 = 30 mmHg and PCO2 = 11 mmHg, pH = 7.56. Their maximal oxygen uptake decreased from 3.98 +/- 0.2 L/min at sea level to 1.17 +/- 0.08 L/min at PIO2 43 mmHg. The principal factors responsible for oxygen transport from the atmosphere to tissues were (1) Alveolar ventilation--a four fold increase. (2) Diffusion from the alveolus to end capillary blood--unchanged. (3) Cardiac function (assessed by hemodynamics, echocardiography and electrocardiography)--normal--although maximum cardiac output and heart rate were reduced. (4) Oxygen extraction--maximal with PvO2 14.8 +/- 1 mmHg. With increasing altitude maximal blood and muscle lactate progressively declined although at any submaximal intensity blood and muscle lactate was higher at higher altitudes.

An aid to the localisation of the mobilised premaxillary segment.

A device is described to aid localisation of the mobilised premaxillary segment during intermediate bone grafting of bilateral alveolar clefts.

Oxygen transport during exercise at extreme altitude: Operation Everest II.

Eight male volunteers had rest and exercise measurement to determine the mechanisms of oxygen transport during a 40-day chamber decompression simulating high-altitude exposure equivalent to the summit of Mt Everest. Five subjects completing the study decreased their maximum oxygen uptake by 72%. During maximal or near-maximal exercise, arterial PCO2 fell as low as 8 mm Hg, defending the alveolar PO2 and confirming marked hyperventilation. Alveolar-arterial diffusion did not improve and V/Q worsened. Cardiac function was unimpaired. Circulatory oxygen transport resembled that at sea level. The decrease in mixed venous PO2 was not enough to preserve fractional oxygen utilization "on the summit." The PO2 gradients from atmosphere to alveolus, alveolus to arterial blood, arterial to venous blood, and from venous (capillary) blood to mitochondria all decreased. However, hyperventilation appeared to be the primary adaptation that defended the maximum oxygen uptake.

Enhanced left ventricular systolic performance at high altitude during Operation Everest II.

Serial rest and upright cycle exercise 2-dimensional echocardiographic studies were performed in 7 healthy young men during acclimatization to a simulated altitude of 29,000 feet (barometric pressure [PB] 240 torr) in a chamber for 40 days. In all subjects left ventricular (LV) end-diastolic, end-systolic and stroke volumes progressively decreased, with mean reductions of 21%, 40% and 14%, respectively, on ascent to 25,000 feet (PB 282 torr) at rest, and reductions of 23%, 43% and 14% during 60-W exercise. At PB 282 torr, mean arterial blood O2 partial pressures were 37 torr (rest) and 32 torr (exercise), with corresponding O2 saturations of 68% and 59%. All 3 indexes of LV systolic function examined--ejection fraction, ratio of peak systolic pressure to end-systolic volume and mean normalized systolic ejection rate at rest--were sustained in all subjects at high altitude despite reduced preload, pulmonary hypertension and severe hypoxemia. Increases in ejection fraction of 6% at rest and 10% during exercise developed at PB 282 torr and a higher mean normalized systolic ejection rate in association with elevated circulating catecholamines reflecting enhanced sympathetic activity. LV systolic function is not a limiting factor in compromising the exercise capacity of normal humans on ascent to high altitude, even to the peak of Mt. Everest.

Effects of cholesterol and lipoproteins on endocytosis by a monocyte-like cell line.

The human monocyte/macrophage-like cell line U937 is a cholesterol auxotroph. Incubation of these cells in the growth medium in which delipidated fetal calf serum has been substituted for fetal calf serum depletes cellular cholesterol and inhibits growth. The cholesterol requirement of these cells for growth can be satisfied by human low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL), but not by high-density lipoprotein (HDL). U937 cells can bind and degrade LDL via a high-affinity site and this recognition is altered by acetylation of LDL. This indicates that these cells express relatively high LDL receptor activity and low levels of the acetyl-LDL receptor. The cells were used to study the role of cholesterol in lectin-mediated and fluid-phase endocytosis. Growth of the cells in the medium containing delipidated fetal calf serum results in impairment of both concanavalin A-mediated endocytosis of horseradish peroxidase and concanavalin A-independent endocytosis of Lucifer Yellow. Supplementation of the medium with cholesterol prevents cellular cholesterol depletion, supports growth and stimulates Lucifer Yellow endocytosis but fails to restore horseradish peroxidase endocytosis. However, if the cells are incubated in the presence of no less than 40 micrograms LDL protein/ml to maintain normal cell cholesterol levels, concanavalin A-mediated endocytosis of horseradish peroxidase is activated. The effect of LDL is specific since neither VLDL nor HDL3 at the same protein concentration activates horseradish peroxidase uptake by the cells. Furthermore, the activation of endocytosis by LDL is not inhibited by the inclusion of heparin or acetylation of the LDL indicating that binding of LDL to the LDL receptor is not required for these effects. The mediation of activation of horseradish peroxidase endocytosis by the lectin is presumed to involve binding of LDL to concanavalin A associated with the cell surface which in turn stimulates horseradish peroxidase binding and uptake by adsorptive endocytosis. The rate of fluid endocytosis and endosome formation seems to depend on cellular cholesterol content presumably because cholesterol is involved in maintaining the appropriate plasma membrane structure and fluidity.