Recommendations for the recognition, diagnosis, and management of long COVID: a Delphi study.

BACKGROUND: In the absence of research into therapies and care pathways for long COVID, guidance based on 'emerging experience' is needed. AIM: To provide a rapid expert guide for GPs and long COVID clinical services. DESIGN AND SETTING: A Delphi study was conducted with a panel of primary and secondary care doctors. METHOD: Recommendations were generated relating to the investigation and management of long COVID. These were distributed online to a panel of UK doctors (any specialty) with an interest in, lived experience of, and/or experience treating long COVID. Over two rounds of Delphi testing, panellists indicated their agreement with each recommendation (using a five-point Likert scale) and provided comments. Recommendations eliciting a response of 'strongly agree', 'agree', or 'neither agree nor disagree' from 90% or more of responders were taken as showing consensus. RESULTS: Thirty-three clinicians representing 14 specialties reached consensus on 35 recommendations. Chiefly, GPs should consider long COVID in the presence of a wide range of presenting features (not limited to fatigue and breathlessness) and exclude differential diagnoses where appropriate. Detailed history and examination with baseline investigations should be conducted in primary care. Indications for further investigation and specific therapies (for myocarditis, postural tachycardia syndrome, mast cell disorder) include hypoxia/desaturation, chest pain, palpitations, and histamine-related symptoms. Rehabilitation should be individualised, with careful activity pacing (to avoid relapse) and multidisciplinary support. CONCLUSION: Long COVID clinics should operate as part of an integrated care system, with GPs playing a key role in the multidisciplinary team. Holistic care pathways, investigation of specific complications, management of potential symptom clusters, and tailored rehabilitation are needed.

The prevalence and nature of prescribing and monitoring errors in English general practice: a retrospective case note review.

BACKGROUND: Relatively little is known about prescribing errors in general practice, or the factors associated with error. AIM: To determine the prevalence and nature of prescribing and monitoring errors in general practices in England. DESIGN AND SETTING: Retrospective case-note review of unique medication items prescribed over a 12-month period to a 2% random sample of patients. Fifteen general practices across three primary care trusts in England. METHOD: A total of 6048 unique prescription items prescribed over the previous 12 months for 1777 patients were examined. The data were analysed by mixed effects logistic regression. The main outcome measures were prevalence of prescribing and monitoring errors, and severity of errors, using validated definitions. RESULTS: Prescribing and/or monitoring errors were detected in 4.9% (296/6048) of all prescription items (95% confidence interval [CI] = 4.4% to 5.5%). The vast majority of errors were of mild to moderate severity, with 0.2% (11/6048) of items having a severe error. After adjusting for covariates, patient-related factors associated with an increased risk of prescribing and/or monitoring errors were: age <15 years (odds ratio [OR] = 1.87, 95% CI = 1.19 to 2.94, P = 0.006) or >64 years (OR = 1.68, 95% CI = 1.04 to 2.73, P = 0.035), and higher numbers of unique medication items prescribed (OR = 1.16, 95% CI = 1.12 to 1.19, P<0.001). CONCLUSION: Prescribing and monitoring errors are common in English general practice, although severe errors are unusual. Many factors increase the risk of error. Having identified the most common and important errors, and the factors associated with these, strategies to prevent future errors should be developed, based on the study findings.

Detailed analyses of self-poisoning episodes presenting to a large regional teaching hospital in the UK.

AIMS: The primary aim of this paper is to provide comprehensive contemporaneous data on the demographics, patterns of presentation and management of all episodes of deliberate self-poisoning presenting to a large regional teaching hospital over a 12 month period. METHODS: We undertook detailed, retrospective analyses using information from electronic patient records and local patient-tracking, pathology and administrative databases. Statistical analyses were performed using Chi-squared tests, anova and two-tailed t-tests (Graphpad Prism). RESULTS: One thousand five hundred and ninety-eight episodes of deliberate self-poisoning presented over the year. Demographic data and information on the month, day and time of admission are provided. 70.7% presented to the emergency department (ED) within 4 h of ingestion. 76.3% of patients had only one episode in an extended 29 month follow-up period. A mean of 1.72 drugs were taken per episode with just over half of all episodes involving a single drug only. Paracetamol and ibuprofen were the two most commonly ingested drugs involved in 42.5% and 17.3% of all overdoses respectively. 56.3% of patients taking paracetamol reported ingesting over 8 g (one over the counter packet). Detailed mapping of the patients' pathway through the hospital allowed an estimation of the hospital cost of caring for this patient group at pound 1.6 million pounds per year. CONCLUSIONS: We present comprehensive and contemporary data on presentations to hospital resulting from deliberate self-poisoning. We include demographic information, presentation patterns, drugs used, a detailed analysis of episodes involving paracetamol and an estimate of the financial burden to hospitals of overdose presentations.

Pregnancy experiences among women with lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare lung disease affecting women. Following case reports that pregnancy exacerbates LAM, patients are frequently advised to avoid pregnancy. Our objective was to determine pregnancy and health outcomes in LAM to provide better evidence with which to council patients contemplating pregnancy. We surveyed 328 women with LAM regarding pregnancy outcomes, pulmonary function, subjective and psychological functioning, quality of life, dyspnoea and fatigue. Amongst childless women the main reason not to attempt pregnancy was based on concerns about potential effects of pregnancy on LAM. Almost two thirds of patients had been pregnant, the majority before LAM was diagnosed, in whom pregnancy outcome was generally favourable. Women diagnosed with LAM (n=15) during pregnancy had high rates of pneumothorax (67%), miscarriage (7%) and premature birth (47%). The group diagnosed with LAM before or during pregnancy (n=12) had lower mean FEV(1), FVC and DLCO after pregnancy compared with those diagnosed following pregnancy or never pregnant. There were no differences in subjective or psychological functioning, quality of life, dyspnoea or fatigue scores between groups. In newly diagnosed LAM patients there was a high incidence of premature birth and pneumothorax. These adverse outcomes may be a marker of aggressive LAM.

Bradykinin activates calcium-dependent potassium channels in cultured human airway smooth muscle cells.

Bradykinin (BK) is an inflammatory mediator that can cause bronchoconstriction. In this study, we investigated the membrane currents induced by BK in cultured human airway smooth muscle (ASM) cells. Depolarization of the cells induced outward currents, which were inhibited by tetraethylammonium (TEA) in a concentration-dependent manner with an IC50 of 0.33 microM. The currents were increased by elevating intracellular free Ca2+ concentration, suggesting they are calcium-activated potassium channels [I(K(Ca))]. Preexposure to inhibitor of I(K(Ca)) of large conductance (BKCa), iberiotoxin, and small conductance (SKCa), apamin, inhibited the increase of outward current induced by BK. The relative contribution of BKCa was greatest in early passage cells. Both nickel and SKF-96365 (10 microM) inhibited the increase of the I(K(Ca)) induced by BK; however, the l-type Ca2+ channel blocker, nifedipine, had no effect. Activation of the BK-induced current was inhibited by heparin, indicating dependence on intact inositol 1,4,5-triphosphate (IP3)-sensitive intracellular Ca2+ stores. BK also increased inositol phosphate accumulation and induced a transient Ca2+-activated chloride current (CACC) and a sustained nonselective cation current (I(CAT)). In summary, BK activates BKCa, SKCa, CACC, and I(CAT) via IP3-sensitive stores in human ASM.

Collagen I and thrombin activate MMP-2 by MMP-14-dependent and -independent pathways: implications for airway smooth muscle migration.

Increased proinflammatory mediators and ECM deposition are key features of the airways in asthma. Matrix metalloproteinases (MMPs) are produced by airway smooth muscle (ASM) cells and have multiple roles in inflammation and tissue remodeling. We hypothesized that components of the asthmatic airway would stimulate MMP production and activation by ASM and contribute to airway remodeling. We measured human ASM-derived MMP mRNA, protein, and activity by real-time RT-PCR, zymography, Western blotting, and MMP activity assay. Collagen I and thrombin caused a synergistic increase in MMP-2 protein and total MMP activity but paradoxically decreased MMP-2 mRNA. Additionally, collagen I activated MMP-2 in culture supernatants independent of the cell surface. Together, collagen I and thrombin strongly enhanced MMP-14 mRNA and protein but had no effect individually, suggesting increased MMP-14, the activating protease for MMP-2, may be partially responsible for MMP-2 activation. Furthermore, collagen I reduced tissue inhibitor of metalloproteinase-2 protein (TIMP-2). We examined the role of MMPs in functions of ASM related to airway remodeling and found migration and proliferation were MMP dependent, whereas adhesion and apoptosis were not. Ilomastat inhibited migration by 25%, which was also inhibited by TIMPs 1-4 and increased by the MMP-2 activator thrombin. These in vitro findings suggest that the environment within the airways of patients with asthma enhances MMP-2 and -14 protein and activity by a complex interaction of transcriptional and posttranscriptional mechanisms, which may contribute to ASM migration.

Extracellular matrix modulates beta2-adrenergic receptor signaling in human airway smooth muscle cells.

The airways of patients with chronic asthma commonly develop an element of fixed airway obstruction, which fails to reverse with inhaled beta2-adrenoceptor agonists. Airway remodeling refers to the structural changes of the bronchi in longstanding asthma and is characterized by increased deposition and altered ratios of extracellular matrix (ECM) proteins. We therefore assessed whether ECM proteins alter beta2-adrenoceptor signaling in human airway smooth muscle cells. We report that a fibronectin environment increases responses to beta2-adrenoceptor stimulation, whereas exposure to collagen V or laminin decreases accumulation of the second messenger cyclic AMP when compared with collagens I or IV. These differences are likely to be physiologically significant as they translate into altered phosphorylation of the downstream target VASP. The altered cAMP levels are due to differences in adenylyl cyclase activity, although expression of the relevant isoforms of enzyme appears unaltered. However, inhibition of Galphai abrogates the differences in beta2-adrenoceptor-mediated cAMP accumulation in cells exposed to different matrix factors. The difference in Galphai signaling is not due to altered Galphai expression. We conclude therefore that ECM modulates Galphai activity in human airway smooth muscle cells, and propose that these changes could contribute to the fixed airway obstruction seen in patients with chronic asthma.

Biosynthesized matrix provides a key role for survival signaling in bronchial epithelial cells.

The extracellular matrix (ECM) influences a variety of cellular functions, including survival, adhesion molecule expression, differentiation, and migration. The ECM composition of the epithelial basement membrane is altered in asthmatics. In this study, we elucidate the major survival signals received by bronchial epithelial cells in vitro by studying the effects of a variety of ECM factors and soluble growth factors on bronchial epithelial cell survival. Our findings indicate that the insulin family of soluble growth factors provides important survival signals but also that adhesion to ECM is a crucial determinant of bronchial epithelial cell survival. In the BEAS-2B bronchial epithelial cell line, collagens I and IV, laminin, fibronectin, and vitronectin provide significant levels of protection from apoptosis. Tenascin-C has no effect, whereas elastin and collagen V increase apoptosis to above control levels. BEAS-2B cells secrete their own biosynthesized matrix (BSM), which also provides rescue from apoptosis. Protection by collagen I, fibronectin, and vitronectin was found to be via an RGD domain. Laminin-, collagen IV-, and BSM-mediated survival is not RGD dependent. Primary bronchial epithelial cells exhibit a similar pattern of apoptosis rescue to the BEAS-2B cell line, although we did not observe any vitronectin-mediated protection in the primary cells. These data indicate that bronchial epithelial cell survival is dependent both on soluble growth factors and on a variety of ECM-derived signals.