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Background Asthma is a risk factor for mental illness, but few studies have explored this association around the time of pregnancy. We studied the association between asthma and perinatal mental illness and explored the modifying effects of social and medical complexities. Methods In a population-based cohort of 846 155 women in Ontario, Canada, with a singleton live birth in 2005–2015 and no recent history of mental illness, modified Poisson regression models were constructed to examine the association between asthma diagnosed before pregnancy and perinatal mental illness, controlling for socio-demographics and medical history. We explored the modifying effects of social and medical complexities using relative excess risk due to interaction. Additional analyses examined the association between asthma and perinatal mental illness by timing and type of mental illness. Results Women with asthma were more likely than those without asthma to have perinatal mental illness [adjusted relative risk (aRR) 1.14; 95% (confidence interval) CI: 1.13, 1.16]. Asthma was associated with increased risk of diagnosis of mental illness prenatally (aRR 1.11; 95% CI: 1.08, 1.13) and post-partum (aRR 1.17; 95% CI: 1.15, 1.19) and specifically diagnoses of mood and anxiety disorders (aRR 1.14; 95% CI: 1.13, 1.16), psychotic disorders (aRR 1.20; 95% CI: 1.10, 1.31) and substance- or alcohol-use disorders (aRR 1.24; 95% CI: 1.14, 1.36). There was no effect modification related to social or medical complexity for these outcomes. Conclusions Women with asthma predating pregnancy are at slightly increased risk of mental illness in pregnancy and post-partum. A multidisciplinary management strategy may be required to ensure timely identification and treatment.

ObjectivesEvidence suggests that B cell-depleting therapy with rituximab (RTX) affects humoral immune response after vaccination. It remains unclear whether RTX-treated patients can develop a humoral and T-cell-mediated immune response against SARS-CoV-2 after immunisation.MethodsPatients under RTX treatment (n=74) were vaccinated twice with either mRNA-1273 or BNT162b2. Antibodies were quantified using the Elecsys Anti-SARS-CoV-2 S immunoassay against the receptor-binding domain (RBD) of the spike protein and neutralisation tests. SARS-CoV-2-specific T-cell responses were quantified by IFN-γ enzyme-linked immunosorbent spot assays. Prepandemic healthy individuals (n=5), as well as healthy individuals (n=10) vaccinated with BNT162b2, served as controls.ResultsAll healthy controls developed antibodies against the SARS-CoV-2 RBD of the spike protein, but only 39% of the patients under RTX treatment seroconverted. Antibodies against SARS-CoV-2 RBD significantly correlated with neutralising antibodies (τ=0.74, p+ peripheral B cells (n=36) did not develop specific antibodies, except for one patient. Circulating B cells correlated with the levels of antibodies (τ=0.4, pConclusionsThe data suggest that vaccination can induce SARS-CoV-2-specific antibodies in RTX-treated patients, once peripheral B cells at least partially repopulate. Moreover, SARS-CoV-2-specific T cells that evolved in more than half of the vaccinated patients may exert protective effects independent of humoral immune responses.

Background At the individual level, it is well known that pregnancies have a short-term effect on a woman’s cardiovascular system and blood pressure. The long-term effect of having children on maternal blood pressure, however, is unknown. We thus estimated the causal effect of having children on blood pressure among mothers in India, a country with a history of high fertility rates. Methods We used nationally representative cross-sectional data from the 2015–16 India National Family and Health Survey (NFHS-4). The study population comprised 444 611 mothers aged 15–49 years. We used the sex of the first-born child as an instrumental variable (IV) for the total number of a woman’s children. We estimated the effect of an additional child on systolic and diastolic blood pressure in IV (two-stage least squares) regressions. In additional analyses, we stratified the IV regressions by time since a mother last gave birth. Furthermore, we repeated our analyses using mothers' husbands and partners as the regression sample. Results On average, mothers had 2.7 children [standard deviation (SD): 1.5], a systolic blood pressure of 116.4 mmHg (SD: 14.4) and diastolic blood pressure of 78.5 mmHg (SD: 9.4). One in seven mothers was hypertensive. In conventional ordinary least squares regression, each child was associated with 0.42 mmHg lower systolic [95% confidence interval (CI): –0.46 to –0.39, P Conclusions Bearing and rearing a child decreases blood pressure among mothers in India.

Purpose To identify areas of critical otolaryngology contributions to inpatient care resistant to disruption by the COVID-19 pandemic. Methods Medical records of 614 otolaryngology consults seen between January and June of 2019 and 602 seen between January and June of 2020 were reviewed. Extracted data included patient demographics, SARS-CoV-2 status, medical comorbidities, consult location, consult category, reason for consult, procedures performed, and overall outcome. Prevalence of data items was compared using t tests and Chi-squared tests. Results The number of monthly consults to the otolaryngology service remained approximately stable after the onset of the COVID-19 pandemic. However, there was a substantial increase in ICU consults and a decrease in ER and floor consults. The proportion of otology, rhinology, and head and neck consults decreased while that of airway consults—most of which were tracheostomy-related—greatly increased. While the top ten reasons for consult remained essentially the same, they dramatically increased as a percentage of consults during COVID-19 (55–92%), whereas there was a dramatic decrease in the proportion of less frequent consults. Conclusion The changes in otolaryngology consultation patterns seen after the onset of the pandemic are multifactorial, but may be attributed to novel pathologies, attitudes, and policies. Nonetheless, these patterns reveal that a set of core otolaryngologic issues, including acute airway issues, head and neck lesions, severe sinusitis and epistaxis, are essential and need to be addressed in the inpatient setting, whereas the significant drop in other consults suggests that they may be appropriately managed on an outpatient basis. Supplementary Information The online version contains supplementary material available at 10.1007/s00405-021-06963-7.

Background Right- and left-side throwers in baseball may have different shoulder conditions and throwing biomechanics. This study aimed to compare the passive range of motion, humeral torsion, and clinical findings between right- and left-handed throwers who sustained throwing shoulder injuries and confirm the differences in the characteristics between throwing sides. Methods A total of 52 pitchers diagnosed with throwing shoulder injuries were included in this study: 27 patients were right-side throwers (R group), and 25 were left-side throwers (L group). We measured the bilateral passive external and internal rotation angles in abduction position (ABIR) and total arc at their first visit. To assess posterior shoulder tightness, the internal rotation angles in forward flexion (FIR), and the abduction angle (AA) and horizontal flexion angle (HFA) without scapula motion were measured. The bilateral humeral torsion angles were also measured using ultrasonography. These values were compared between the participants' throwing and non-throwing sides and between the R and L groups' throwing sides. Furthermore, several physical findings in the shoulders were assessed, and the positive ratio was compared between the R and L groups. Results On comparing the throwing and non-throwing sides, the R group had significantly greater external rotation angles in the abduction position and humeral torsion angle, and smaller ABIR, total arc, FIR, AA, and HFA in the throwing side, while the L group showed no significant differences, except for a smaller ABIR and larger HFA in the throwing side. On comparing the throwing side between the R and L groups, the R group had a smaller FIR, AA, and FHA than the L group. Regarding the physical findings, the posterior jerk test, Kim test, anterior and posterior drawer sign, sulcus sign, and scapular winging in the L group were significantly more positive than in the R group. Conclusion The range of motion and humeral torsions differed between the left- and right-side throwers, as did the pathology between their throwing sides. Clinicians should consider the possibility that the pathological condition differs between left- and right-side throwers.

Purpose The COVID-19 pandemic has affected healthcare systems worldwide. Data on the impact on otolaryngological clinics and private practices is sparse. This study aimed to present data on healthcare worker (HCW) screening, status of HCW, pre-interventional testing, the use of personal protective equipment (PPE) and the economic impact of the pandemic. Methods Otolaryngological private practices and hospital-based departments were surveyed nationwide using an online questionnaire. Participating facilities were recruited via the German Society for Oto-Rhino-Laryngology and the German Association for Otolaryngologists in Bavaria. Results 365 private practices (2776 employees) and 65 hospitals (2333 employees) were included. Significantly more hospitals (68.7%) than practices (40.5%) performed pre-interventional testing in their outpatients (p

Purpose No standardized treatment regimen exists for juvenile recurrent parotitis (JRP). The investigators hypothesized that irrigation with saline only without local anesthesia will be an effective and beneficial option. Methods Using a retrospective study design, a series of children with typical symptoms of JRP who were treated with at least one irrigation therapy were evaluated. This treatment consisted of irrigation of the affected gland with 3–10 ml saline solution without any type of anesthesia. The outcome variables were patient/parent satisfaction, frequency and duration of acute JRP episodes, and the need for antibiotics before and after irrigation therapy. Results The case series was composed of six boys aged 3.3–7.7 years who experienced one to eight sessions of irrigation therapy. The period of follow-up was 9–64 months. We observed a total resolution of symptoms in two children and an improvement in the other four. No relevant side effects were seen. Conclusion Our results suggest that irrigation therapy is a reasonable, simple, and minimally invasive treatment alternative for JRP. In contrast to sialendoscopy or sialography, there is no need for general anesthesia or radiation exposure.

Aims. With the ever-increasing survey speed of optical wide-field telescopes and the importance of discovering transients when they are still young, rapid and reliable source localization is paramount. We present AutoSourceID-Light (ASID-L), an innovative framework that uses computer vision techniques that can naturally deal with large amounts of data and rapidly localize sources in optical images. Methods. We show that the ASID-L algorithm based on U-shaped networks and enhanced with a Laplacian of Gaussian filter provides outstanding performance in the localization of sources. A U-Net network discerns the sources in the images from many different artifacts and passes the result to a Laplacian of Gaussian filter that then estimates the exact location. Results. Using ASID-L on the optical images of the MeerLICHT telescope demonstrates the great speed and localization power of the method. We compare the results with SExtractor and show that our method outperforms this more widely used method. ASID-L rapidly detects more sources not only in low- and mid-density fields, but particularly in areas with more than 150 sources per square arcminute. The training set and code used in this paper are publicly available.

Purpose The scope of this research endeavor was the determination of the applicability of over the counter mouthwash solutions in reducing the viral load in the saliva of COVID-19 patients and hence decreasing their infectivity. Beyond that, new experimental mouthwashes were investigated in terms of a possible positive immune modulation, which might offer an additional opportunity for a positive pharmaceutical effect. Methods The effectivity of the mouth washing solution was determined on 34 hospitalized COVID-19 patients by measuring the viral load by RT-qPCR in pharyngeal swabs, which were taken before and after rinsing. The inflammatory modulation thru the experimental solutions was assayed in an in vitro model of virus infected nasopharyngeal epithelium cells. Results The clinical pilot study demonstrated that the mouth rinsing solution was able to reduce the viral load by about 90% in the saliva of most patients. This reduction was determined to persist for about 6 h. In the experimental solutions, the ingredients dexpanthenol and zinc were able to reduce the expression of proinflammatory cytokines in the cell culture model, while the antiviral response was not altered significantly. Conclusion We recommend the application of mouth wash solutions to COVID-19 patients, since our results indicate a reduction in infectivity and might govern the protection of health care professionals. Further improvement to the over the counter formulation can be made by utilizing zinc and dexpanthenol, as they which might be beneficial for the patients’ health.

Background Little is known about the time course of mortality reduction following smoking cessation in Asians who have smoking behaviours distinct from their Western counterparts. We evaluated the level of reduction in all-cause, cardiovascular disease (CVD) and lung cancer mortality by years since quitting smoking, in Asia. Methods Using Cox regression, we analysed individual participant data (n = 709 151) from 16 prospective cohorts conducted in China, Japan, Korea/Singapore, and India/Bangladesh, separately by cohorts. Cohort-specific hazard ratios (HRs) were combined using a random-effects meta-analysis. Results During a mean follow-up of 12.0 years, 108 287 deaths were ascertained—35 658 from CVD and 7546 from lung cancer. Among Asian men, a dose-response relationship of risk reduction in deaths from all causes, CVD and lung cancer was observed with an increase in years after smoking cessation. Compared with never smokers, however, all-cause and CVD mortality among former smokers remained elevated 10–14 years after quitting [multivariable-adjusted HR (95% confidence interval (CI) = 1.25 (1.13–1.37) and 1.20 (1.02–1.41), respectively]. Lung cancer mortality stayed almost 2-fold higher than among never smokers 15–19 years after smoking cessation [1.97 (1.41–2.73)], particularly among former heavy smokers [2.62 (1.71–4.00)]. Women who quitted for ≥5 years retained a significantly elevated mortality from all causes, CVD and lung cancer. Overall patterns of the cessation-mortality associations were similar across countries. Conclusions Our findings suggest that adverse effects of tobacco smoking persist for an extended time period, even for more than two decades, which is beyond the time windows defined in current clinical guidelines for risk assessment of lung cancer and CVD.

Background Prolonged opioid use can lead to suboptimal outcomes after total shoulder arthroplasty (TSA), and thus, reduced consumption is desirable. Our primary aims were to determine if differences in total morphine equivalent doses existed owing to (1) age less than or greater than 65 years, (2) sex, and (3) TSA type – reverse or anatomic total shoulder arthroplasty. We also characterized potential risk factors for (1) visiting another provider for pain, (2) pain control 6 weeks postoperatively, and (3) needing an opioid refill. Methods A retrospective cohort study of 100 patients who underwent TSA (reverse total shoulder arthroplasty N1 = 50; anatomic total shoulder arthroplasty N2 = 50) between 1 July 2018 and 31 December 2018 was performed. Demographics, perioperative treatments, and postoperative opioid prescriptions were recorded. Primary hypotheses were evaluated with Wilcoxon-Mann-Whitney testing. Univariate and multivariate analyses assessed potential risk factors for the 3 outcomes of interest. Results were given in adjusted odds ratios (aORs), 95% confidence intervals (CIs), and P values. Results There was a difference (P = .009) in total morphine equivalent doses used (in 5-milligram oxycodone tablets) between patients who were younger than 65 years of age (median: 83 tablets, interquartile range: 62-140) and those who were older than 65 years of age (median: 65 tablets, interquartile range: 52-90). Unemployment (aOR = 4.68, CI: 1.5-14.2, P = .006) and age less than 65 years (aOR = 4.18, CI: 1.6-11.2, P = .004) were independent risk factors for inadequate pain control 6 weeks postoperatively. Two independent risk factors for needing an opiate prescription refill after discharge were unemployment (aOR = 4.56, CI: 1.5-13.8, P = .007) and preoperative opiate use (aOR = 3.95, CI: 1.4-11.0, P = .009). Conclusion After TSA, morphine equivalent dose usage is higher for patients younger than 65 years of age, and several risk factors exist for requiring a refill and having inadequate pain control 6 weeks postoperatively. Prospective studies using these data to guide interventions may be beneficial.

Background: Radiotherapy is a common treatment option for lung or esophageal cancer, particularly when surgery is not feasible for patients with poor lung function. However, radiotherapy can affect pulmonary function and thereby induce pneumonitis or pneumonia, which can be fatal in patients with respiratory impairment. The purpose of this study is to evaluate if reductions in pulmonary function after radiotherapy can be minimized through simultaneous pulmonary rehabilitation (PR). Methods: In this matched case control study, we retrospectively analyzed patients who had undergone radiotherapy for thoracic malignant disease between January 2018 and June 2019. We analyzed results from pulmonary function tests and 6-minute walking tests (6MWT) conducted within the six months before and after radiotherapy treatment. Results: In total, results from 144 patients were analyzed, with 11 of the patients receiving PR and radiotherapy simultaneously. Of the 133 patients in the control group, 33 were matched with 11 patients in the PR group. Changes in forced expiratory volume in one second (FEV1) and FEV1/forced vital capacity were significantly different between the PR group and the matched control group (240 mL vs. -10 mL, p=0.017 and 5.5% vs. 1.0%, p=0.038, respectively). The median distance of 6MWT in the PR group also increased significantly, from 407.5 m to 493.0 m after radiotherapy (p=0.017). Conclusion: Simultaneous PR improved pulmonary function, particularly in measures of FEV1, and exercise capacity for patients with lung or esophageal cancer even after radiotherapy treatment. These findings may provide an important base of knowledge for further large population studies with long-term follow-up analysis in the identification of the PR’s effects during thoracic radiotherapy.

Background Shoulder surgery results in several months of rehabilitation, which is often underestimated by patients preoperatively. Currently, there is little written about this process of recovery. Information on this would help patients to anticipate the trajectory of their recovery. This would also provide a reference point allowing surgeons to compare a patient's progress in their recovery. The purpose of our study was to analyze and document the expected rate of recovery for the most common shoulder operations. Methods A retrospective analysis of all patients who underwent total shoulder arthroplasty (TSA), reverse total shoulder arthroplasty (RTSA), arthroscopic rotator cuff repair (ARCR), and arthroscopic biceps tenodesis (BT) using prospectively collected data from the Surgical Outcomes System registry was performed. All patients included had a complete 2-year follow-up data set. The pain score (visual analog scale) was measured preoperatively at 2, 6, and 12 weeks and 6, 12, and 24 months. The American Shoulder and Elbow Surgeons (ASES) and Single Assessment Numeric Evaluation (SANE) score were recorded preoperatively and after 6, 12, and 24 months. The speed of recovery, defined as the percentage of total improvement, for each procedure was assessed as the primary outcome parameter at all time points. Results All shoulder interventions resulted in significant improvement of the pain, SANE, and ASES scores 2 years after shoulder surgery. The speed of recovery of all 3 scores was highest after TSA at all measured time points and slowest after ARCR and BT. Measured by the pain score, 90% and 82% of the total improvement after TSA and RTSA was completed after 6 weeks compared to 58% and 59% after ARCR and BT, respectively. Six months postoperatively the ASES recovery rate was significantly higher after arthroplasty (TSA 96% and RTSA 85%) compared to ARCR and BT (76% and 77%, respectively). The SANE score recovery rate was between 82% and 92% (TSA 92%, RTSA 89%, ARCR 87%, BT 82%) 6 months after surgery. After 1 year all patient groups reached 89% or more of the total improvement in all scores, except for the pain after ARCR (89%). Conclusion The improvement in pain is fastest after TSA and slowest after ARCR and BT. After TSA and RTSA, >80% of the total pain reduction is achieved 6 weeks postoperatively, whereas after ARCR and BT, >80% of the pain reduction is achieved only 6 months postoperatively. At 12 months postoperatively, the differences in recovery curves were not significant.

Background For generations, cigarette smoking has presented an important public health concern. This study aimed to compare the health-promoting behavior, exercise capacity, physical activity level, health literacy, and knowledge level of smoking-related diseases between smokers and non-smokers. Methods The study included 71 smokers (mean age, 32.69±8.55 years) and 72 non-smokers (mean age, 31.88±9.94 years) between the ages of 20 and 60 years. Assessments included a 6-minute walking test (6MWT), Godin Leisure-Time Physical Activity Questionnaire, Health-Promoting Lifestyle Profile II (HPLP-II), Cardiovascular Risk Factors Knowledge Level Scale (CARRF-KL), Asthma/COPD Awareness Questionnaire, the World Health Organization Quality of Life-Bref questionnaire (WHOQoL-Bref [TR]), and Health Literacy Questionnaire (HLQ). Results The results from the study show that the number of coronary artery disease risk factors measured significantly higher among the smoker group members when compared to that of the non-smoker group members (p=0.001). Smokers had significantly lower %6MWT distance than non-smokers (84.83±4.72 and 93.45±7.16, respectively; p0.05). Additionally, while only forty-one smokers (57.7%) were active, 48 of the non-smoker group was active (66.7%). Conclusion Smokers suffer greater negative effects to their exercise capacity in comparison to non-smokers. Although smokers and non-smokers have similar levels of health literacy and similar levels of knowledge about cardiovascular disease risk factors and obstructive lung diseases, health professionals could continue to further increase individuals’ awareness of smoking-related risk factors and continue to emphasize the importance of physical activity and exercise for protecting cardiopulmonary health.

Purpose Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) replicates predominantly in the upper respiratory tract and is primarily transmitted by droplets and aerosols. Taking the medical history for typical COVID-19 symptoms and PCR-based SARS-CoV-2 testing have become established as screening procedures. The aim of this work was to describe the clinical appearance of SARS-CoV-2-PCR positive patients and to determine the SARS-CoV-2 contact risk for health care workers (HCW). Methods The retrospective study included n = 2283 SARS-CoV-2 PCR tests from n = 1725 patients with otorhinolaryngological (ORL) diseases performed from March to November 2020 prior to inpatient treatment. In addition, demographic data and medical history were assessed. Results n = 13 PCR tests (0.6%) were positive for SARS-CoV-2 RNA. The positive rate showed a significant increase during the observation period (p n = 4) or had symptoms that were interpreted as symptoms typical of the ORL disease or secondary diagnoses (n = 9). Conclusion The identification of SARS-CoV-2-positive patients is a considerable challenge in clinical practice. Our findings illustrate that taking a medical history alone is of limited value and cannot replace molecular SARS-CoV-2 testing, especially for patients with ORL diseases. Our data also demonstrate that there is a high probability of contact with SARS-CoV-2-positive patients in everyday clinical practice, so that the use of personal protective equipment, even in apparently “routine cases”, is highly recommended.

ObjectivesThis integrated analysis presents the safety profile of upadacitinib, a Janus kinase inhibitor, at 15 mg and 30 mg once daily in patients with moderately to severely active rheumatoid arthritis (RA).MethodsTreatment-emergent adverse events (TEAEs) and laboratory data from five randomised, placebo- or active-controlled phase III trials of upadacitinib for patients with RA were analysed and summarised. Exposure-adjusted event rates are shown for placebo (three trials; 12/14 weeks), methotrexate (two trials; mean exposure: 36 weeks), adalimumab (one trial; mean exposure: 42 weeks), upadacitinib 15 mg (five trials; mean exposure: 53 weeks) and upadacitinib 30 mg (four trials; mean exposure: 59 weeks).Results3834 patients received one or more doses of upadacitinib 15 mg (n=2630) or 30 mg (n=1204), for a total of 4020.1 patient-years of exposure. Upper respiratory tract infection, nasopharyngitis and urinary tract infection were the most commonly reported TEAEs with upadacitinib. Rates of serious infection were similar between upadacitinib 15 mg and adalimumab but higher compared with methotrexate. Rates of herpes zoster and creatine phosphokinase (CPK) elevations were higher in both upadacitinib groups versus methotrexate and adalimumab, and rates of gastrointestinal perforations were higher with upadacitinib 30 mg. Rates of deaths, malignancies, adjudicated major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs) were similar across treatment groups.ConclusionIn the phase III clinical programme for RA, patients receiving upadacitinib had an increased risk of herpes zoster and CPK elevation versus adalimumab. Rates of malignancies, MACEs and VTEs were similar among patients receiving upadacitinib, methotrexate or adalimumab.Trial registration numbersSELECT-EARLY:NCT02706873; SELECT-NEXT:NCT02675426; SELECT-COMPARE:NCT02629159; SELECT-MONOTHERAPY:NCT02706951; SELECT-BEYOND:NCT02706847.

ObjectivesIncreasing evidence suggests that inflammatory mechanisms play a key role in chronic tendon disease. After observing T cell signatures in human tendinopathy, we explored the interaction between T cells and tendon stromal cells or tenocytes to define their functional contribution to tissue remodelling and inflammation amplification and hence disease perpetuation.MethodsT cells were quantified and characterised in healthy and tendinopathic tissues by flow cytometry (FACS), imaging mass cytometry (IMC) and single cell RNA-seq. Tenocyte activation induced by conditioned media from primary damaged tendon or interleukin-1β was evaluated by qPCR. The role of tenocytes in regulating T cell migration was interrogated in a standard transwell membrane system. T cell activation (cell surface markers by FACS and cytokine release by ELISA) and changes in gene expression in tenocytes (qPCR) were assessed in cocultures of T cells and explanted tenocytes.ResultsSignificant quantitative differences were observed in healthy compared with tendinopathic tissues. IMC showed T cells in close proximity to tenocytes, suggesting tenocyte–T cell interactions. On activation, tenocytes upregulated inflammatory cytokines, chemokines and adhesion molecules implicated in T cell recruitment and activation. Conditioned media from activated tenocytes induced T cell migration and coculture of tenocytes with T cells resulted in reciprocal activation of T cells. In turn, these activated T cells upregulated production of inflammatory mediators in tenocytes, while increasing the pathogenic collagen 3/collagen 1 ratio.ConclusionsInteraction between T cells and tenocytes induces the expression of inflammatory cytokines/chemokines in tenocytes, alters collagen composition favouring collagen 3 and self-amplifies T cell activation via an auto-regulatory feedback loop. Selectively targeting this adaptive/stromal interface may provide novel translational strategies in the management of human tendon disorders.

The Copernican principle, the notion that we are not at a special location in the Universe, is one of the cornerstones of modern cosmology and its violation would invalidate the Friedmann-Lema\^{\i}tre-Robertson-Walker (FLRW) metric, causing a major change in our understanding of the Universe. Thus, it is of fundamental importance to perform observational tests of this principle. We determine the precision with which future surveys will be able to test the Copernican principle and their ability to detect any possible violations. We forecast constraints on the inhomogeneous Lema\^{\i}tre-Tolman-Bondi model with a cosmological constant $\Lambda$ ($\Lambda$LTB), basically a cosmological constant $\Lambda$ and cold dark matter ($\Lambda$CDM) model, but endowed with a spherical inhomogeneity. We consider combinations of currently available data and simulated Euclid data, together with external data products, based on both $\Lambda$CDM and $\Lambda$LTB fiducial models. These constraints are compared to the expectations from the Copernican principle. When considering the $\Lambda$CDM fiducial model, we find that Euclid data, in combination with other current and forthcoming surveys, will improve the constraints on the Copernican principle by about $30\%$, with $\pm10\%$ variations depending on the observables and scales considered. On the other hand, when considering a $\Lambda$LTB fiducial model, we find that future Euclid data, combined with other current and forthcoming data sets, will be able to detect Gpc-scale inhomogeneities of contrast $-0.1$. Next-generation surveys, such as Euclid, will thoroughly test homogeneity at large scales, tightening the constraints on possible violations of the Copernican principle., Comment: 15 pages, 5 figures, 3 tables, v2 reflects version accepted for publication in A&A

Patients with type 2 diabetes mellitus are at a higher risk of developing heart failure compared with the healthy population. In recent landmark clinical trials, sodium-glucose co-transporter 2 (SGLT2) inhibitor therapies improve blood glucose control and also reduce cardiovascular events and heart failure hospitalisations in patients with type 2 diabetes. Intriguingly, such clinical benefits have also been seen in patients with heart failure in the absence of type 2 diabetes although the underlying mechanisms are not clearly understood. Potential pathways include improved glycaemic control, diuresis, weight reduction and reduction in blood pressure, but none fully explain the observed improvements in clinical outcomes. More recently, novel mechanisms have been proposed to explain these benefits that include improved cardiomyocyte calcium handling, enhanced myocardial energetics, induced autophagy and reduced epicardial fat. We provide an up-to-date review of cardiac-specific SGLT2 inhibitor–mediated mechanisms and highlight studies currently underway investigating some of the proposed mechanisms of action in cardiovascular health and disease.

ObjectiveTo establish the feasibility of a multicentre randomised controlled trial to assess the effectiveness and cost-effectiveness of a non-operative treatment pathway compared with appendicectomy in children with uncomplicated acute appendicitis.DesignFeasibility randomised controlled trial with embedded qualitative study to inform recruiter training to optimise recruitment and the design of a future definitive trial.SettingThree specialist paediatric surgery centres in the UK.PatientsChildren (aged 4–15 years) with a clinical diagnosis of uncomplicated acute appendicitis.InterventionsAppendicectomy or a non-operative treatment pathway (comprising broad-spectrum antibiotics and active observation).Main outcome measuresPrimary outcome measure was the proportion of eligible patients recruited. Secondary outcomes evaluated adherence to interventions, data collection during follow-up, safety of treatment pathways and clinical course.ResultsFifty per cent of eligible participants (95% CI 40 to 59) approached about the trial agreed to participate and were randomised. Repeated bespoke recruiter training was associated with an increase in recruitment rate over the course of the trial from 38% to 72%. There was high acceptance of randomisation, good patient and surgeon adherence to trial procedures and satisfactory completion of follow-up. Although more participants had perforated appendicitis than had been anticipated, treatment pathways were found to be safe and adverse event profiles acceptable.ConclusionRecruitment to a randomised controlled trial examining the effectiveness and cost-effectiveness of a non-operative treatment pathway compared with appendicectomy for the treatment of uncomplicated acute appendicitis in children is feasible.Trial registration numberNCT15830435.

ObjectivesTo quantify the prevalence and nature of adverse events in acute Irish hospitals in 2015 and to assess the impact of the National Clinical Programmes and the National Clinical Guidelines on the prevalence of adverse events by comparing these results with the previously published data from 2009.Design and methodsA retrospective chart review of 1605 admissions to eight Irish hospitals in 2015, using identical methods to those used in 2009.ResultsThe percentage of admissions associated with one or more adverse events was unchanged (p=0.48) at 14% (95% CI=10.4% to 18.4%) in 2015 compared with 12.2% (95% CI=9.5% to 15.5%) in 2009. Similarly, the prevalence of preventable adverse events was unchanged (p=0.3) at 7.4% (95% CI=5.3% to 10.5%) in 2015 compared with 9.1% (95% CI=6.9% to 11.9%) in 2009. The incidence densities of preventable adverse events were 5.6 adverse events per 100 admissions (95% CI=3.4 to 8.0) in 2015 and 7.7 adverse events per 100 admissions (95% CI=5.8 to 9.6) in 2009 (p=0.23). However, the percentage of preventable adverse events due to hospital-associated infections decreased to 22.2% (95% CI=15.2% to 31.1%) in 2015 from 33.1% (95% CI=25.6% to 41.6%) in 2009 (p=0.01).ConclusionAdverse event rates remained stable between 2009 and 2015. The percentage of preventable adverse events related to hospital-associated infection decreased, which may represent a positive impact of the related national programmes and guidelines.

Telehealth services are innovative healthcare strategies that utilize communication technologies to improve healthcare access for patients. Teleradiology is a form of telehealth service that involves the transmission of radiological images, such as x-rays, CTs and MRIs, from one location to another to share patient information with other physicians. The purpose of this study was to assess teleradiology consultations for orthopaedic patients at a paediatric tertiary care centre. A retrospective review was conducted of patients who received teleradiology consultations with a single orthopaedic surgeon from 2015 to 2018 through the paediatric orthopaedic hip clinic at our institution. Teleradiology consultations involved follow-up radiographic imaging at a local community facility for patients who initially received healthcare services at our institution, followed by a telephone consultation to review imaging results and communicate next steps in care. Data collected included patient demographics, imaging type, facility location and distance from our institution. Eighty patients (F = 66, M = 14) who received teleradiology services were reviewed. Mean age was 3.5 years [95% confidence interval (CI): 2.5-4.4] at time of imaging. The average distance from community facilities to our institution was 1167 km (95% confidence interval: 920-1414), a measure of the total distance saved in travel for each patient in a single direction. The travel distance saved was substantial. Paediatric orthopaedic teleradiology services provide families specialized consultations and care continuity without costly travel. With increased implementation of teleradiology services, more patients and families can remain in their home communities while receiving the same quality of care.

Coccidioidomycosis is a fungal infection of the Western hemisphere that is endemic to the soil in areas with limited rainfall. Human and animal infections result with inhalation of arthroconidia. Most often, this is an asymptomatic event. When illness occurs, it is primarily a pneumonic presentation. A small minority of infections eventuate in disseminated disease. Predominately, this presents as meningitis or osteoarticular or integumentary disease. Treatment may not be required for the mildest illness. Azoles are commonly prescribed. Severe infections may require amphotericin B.

Purpose The COVID-19 pandemic placed an unprecedented demand on critical care services for the provision of mechanical ventilation. Tracheostomy formation facilitates liberation from mechanical ventilation with advantages for both the patient and wider critical care resource, and can be performed using both percutaneous dilatational and surgical techniques. We compared outcomes in those patients undergoing percutaneous dilatational tracheostomy to those undergoing surgical tracheostomy and make recommendations for provision of tracheostomy services in any future surge. Methods Multicentre multidisciplinary retrospective observational cohort study including 201 patients with COVID-19 pneumonitis admitted to an ICU in one of five NHS Trusts within the South London Adult Critical Care Network who required mechanical ventilation and subsequent tracheostomy. Results Percutaneous dilatational tracheostomy was performed in 124 (62%) of patients, and surgical tracheostomy in 77 (38%) of patients. There was no difference between percutaneous dilatational tracheostomy and surgical tracheostomy in either the rate of peri-operative complications (16.9 vs. 22.1%, p = 0.46), median [IQR(range)] time to decannulation [19.0 (15.0–30.2 (5.0–65.0)] vs. 21.0 [15.5–36.0 (5.0–70.0) days] or mortality (13.7% vs. 15.6%, p = 0.84). Of the 172 patients that were alive at follow-up, two remained ventilated and 163 were decannulated. Conclusion In patients with COVID-19 pneumonitis that require tracheostomy to facilitate weaning from mechanical ventilation, there was no difference in outcomes between those patients that had percutaneous dilatational tracheostomy compared with those that had surgical tracheostomy. Planning for future surges in COVID-19-related critical care demands should utilise all available resource and expertise. Supplementary Information The online version contains supplementary material available at 10.1007/s00405-020-06597-1.

Background: E-cigarettes are steadily gaining popularity in Korea. However, the characteristics of e-cigarette smokers, especially nicotine dependence and stress susceptibility, have not been evaluated in comparison to those of nonsmokers or combustible cigarette smokers in Korea. Methods: In this study, 28,059 participants from the Korea National Health and Nutrition Examination Survey (2013-2017) were classified into the following three groups: non-smokers, smokers (current smokers and ex-smokers of combustible cigarettes only), and e-smokers (current smokers and ex-smokers of e-cigarettes regardless of combustible cigarette use). Results: Among the participants, 16,980 (60.5%), 9,247 (33.0%), and 1,832 (6.4%) subjects were non-smokers, smokers, and e-smokers, respectively. E-smokers were younger, more educated, and had a higher household income than nonsmokers or smokers. The number of e-smokers who smoked within 5 minutes of waking up (31.5% vs. 19.8%, p

Purpose Long total waiting times (TWT) experienced by patients during a clinic visit have a significant adverse effect on patient’s satisfaction. Our aim was to use big data simulations of a patient scheduling calendar and its effect on TWT in a general ophthalmology clinic. Based on the simulation, we implemented changes to the calendar and verified their effect on TWT in clinical practice. Design and methods For this retrospective simulation study, we generated a discrete event simulation (DES) model based on clinical timepoints of 4.401 visits to our clinic. All data points were exported from our clinical warehouse for further processing. If not available from the electronic health record, manual time measurements of the process were used. Various patient scheduling models were simulated and evaluated based on their reduction of TWT. The most promising model was implemented into clinical practice in 2017. Results During validation of our simulation model, we achieved a high agreement of mean TWT between the real data (229 ± 100 min) and the corresponding simulated data (225 ± 112 min). This indicates a high quality of the simulation model. Following the simulations, a patient scheduling calendar was introduced, which, compared with the old calendar, provided block intervals and extended time windows for patients. The simulated TWT of this model was 153 min. After implementation in clinical practice, TWT per patient in our general ophthalmology clinic has been reduced from 229 ± 100 to 183 ± 89 min. Conclusion By implementing a big data simulation model, we have achieved a cost-neutral reduction of the mean TWT by 21%. Big data simulation enables users to evaluate variations to an existing system before implementation into clinical practice. Various models for improving patient flow or reducing capacity loads can be evaluated cost-effectively.

Background: Particulate matter 10 (PM10; airborne particles

Ozone is known to cause bronchial inflammation and airway hyper-responsiveness via oxidative injury and inflammation. While other ambient air pollutants such as particulate matter (PM) and nitrogen dioxide showed decreasing trends in mean annual concentrations, ozone concentrations have not declined recently in most countries across the world. Short-term exposure to high concentrations of ozone has been associated with increased mortality and cardiovascular and respiratory morbidity in many regions of the world. However, the long-term effects of ozone have been less investigated than the short-term exposure due to the difficulty in modeling ozone exposure and linking between individual exposures and health outcome data. A recently developed model of ozone exposure enabled the investigation of long-term ozone effects on health outcomes. Recent findings suggested that long-term exposure to ozone was associated with an increased risk of cardiovascular and respiratory mortality. Longitudinal studies using large cohorts also revealed that long-term exposure to ozone was associated with a greater decline in lung function and the progression of emphysema. The development of long-term standards for ozone as well as PM should be considered to protect the respiratory health of the general population and people with chronic respiratory diseases.

Background Diet quality is a risk factor for chronic disease and mortality. Differential DNA methylation across the epigenome has been associated with chronic disease risk. Whether diet quality is associated with differential methylation is unknown. This study assessed whether diet quality was associated with differential DNA methylation measured across 445 548 loci in the Women’s Health Initiative (WHI) and the TwinsUK cohort. Design The discovery cohort consisted of 4355 women from the WHI. The replication cohort consisted of 571 mono- and dizygotic twins from the TwinsUK cohort. DNA methylation was measured in whole blood using the Illumina Infinium HumanMethylation450 Beadchip. Diet quality was assessed using the Alternative Healthy Eating Index 2010 (AHEI-2010). A meta-analysis, stratified by study cohort, was performed using generalized linear models that regressed methylation on AHEI-2010, adjusting for cell composition, chip number and location, study characteristics, principal components of genetic relatedness, age, smoking status, race/ethnicity and body mass index (BMI). Statistical significance was defined as a false discovery rate < 0.05. Significant sites were tested for replication in the TwinsUK cohort, with significant replication defined by P Results Diet quality was significantly associated with differential DNA methylation at 428 cytosine-phosphate-guanine (CpG) sites in the discovery cohort. A total of 24 CpG sites were consistent with replication in the TwinsUK cohort, more than would be expected by chance (P = 2.7x10-4), with one site replicated in both the blood and adipose tissue (cg16379999 located in the body of SEL1L). Conclusions Diet quality was associated with methylation at 24 CpG sites, several of which have been associated with adiposity, inflammation and dysglycaemia. These findings may provide insight into pathways through which diet influences chronic disease.

This publication is an English version of the Japanese Society for Radiation Oncology (JASTRO) and The Japanese Circulation Society official guidelines for patients with cardiac implantable electronic devices (CIEDs). Several radiotherapy-associated malfunctions have been reported for CIEDs such as pacemakers and implantable cardioverter-defibrillators. Accordingly, guidelines for radiotherapy in patients with CIEDs have been issued by other countries and societies. In August 2010, JASTRO published the ‘Radiotherapy Guidelines for Patients with Pacemakers and Implantable Defibrillators’ (hereafter referred to as the former guidelines). Given new findings in this decade, a multidisciplinary working group of radiation oncologists, medical physicists, radiation therapists and cardiologists jointly reviewed and revised the former guidelines.