Airway clearance physiotherapy is recommended in cystic fibrosis, but limited evidence exists to suggest how much treatment is enough. As a secondary analysis of a prior study investigating the safety, efficacy, and participants’ perceptions of a novel airway clearance technique, specific cough technique (SCT) compared to forced expiration technique (FET), we aimed to evaluate whether the intervention was associated with changes in health-related quality of life (HRQoL).We conducted randomised, controlled individual trials with six adults (N-of-1 RCTs). Each trial included eight weeks of treatment, twice a week, using saline inhalation in horizontal positions, one with SCT and one with FET, in random order. Efficacy was measured by sputum wet weight (g) after each session. Perceived usefulness and preference were self-reported at the end of the study. Lung function was assessed at baseline and at the end of study. HRQoL was measured using the Cystic Fibrosis Questionnaire-Revised (CFQ-R) at baseline (week 1) and at completion of the study (week 8). Individual HRQoL scores (0–100) were coded and analysed using CFQ-R Software Program, version 2.0.Patient-reported outcomes were completed by all subjects. Individual CFQ-R-Respiratory Symptoms Scores (CFQ-R-RSS) showed a positive change, meeting the minimal important difference (MID) ≥ 4 points in five participants and a negative change in one individual. A strong correlation (r = 0.94 (p<0.01) was found between total sputum weight (g) and the positive changes in CFQ-R-RSS, and between changes in lung function and CFQ-R-RSS (r = 0.84 (p = 0.04).The airway clearance intervention was associated with clinically meaningful changes in patient-reported symptoms on the CFQ-R in the majority of the participants. This finding warrants further investigation regarding treatment, duration and frequency. A long-term study may reveal beneficial effects on other clinically meaningful endpoints, such as pulmonary exacerbations, high-resolution computed tomography scores and HRQoL.NCT0 1266473.The study was registered in ClinicalTrials.gov, under the number  Lung disease in cystic fibrosis (CF) is characterized by increased mucus production and reduced mucus clearance, leading to a process of inflammation, infection, structural changes, and potentially reduced participation in everyday activities and quality of life –3. AirwaAirway Clearance Physiotherapy (ACP) comprises use of different airway clearance techniques (ACTs)  interactIn a previous study we performed a series of N-of-1 randomized, controlled trials and have reported on the individual efficacy, safety and participants’ perceptions of a novel ACT–Specific Cough Technique (SCT) compared to Forced Expiration Technique (FET) .As individuals with CF live longer due to better care and treatment, HRQoL has been commonly studied  to assesDisease-specific instruments are needed to evaluate the effectiveness of interventions , 14 and ACP focuses on reducing respiratory symptoms, pulmonary infections, and preventing loss of function and health. Thus, ACP has the potential to positively impact on HRQoL. The CFQ-R can be used in research or clinical practice to measure the effects of ACP interventions . HoweverThe objective of the present secondary analysis of the prior study  was to aWe conducted a pre-planned secondary analysis to a series of randomized controlled, individual trials (N-of-1 RCT) in adults with CF using a multiple crossover sequence in eight pairs of treatment periods . The ratEach participant performed treatment in pairs, serving as their own control with two interventions in each pair, one with SCT and one with FET in randomized order. Thus, performing 16 treatments during eight treatment periods. The treatment pairs were performed on two consecutive days separated by 24 hours. Perceived usefulness and preference were self-reported at the end of study. Further details were reported previously . HRQoL wCFQ-RThe present trial was designed to cover defined quality criteria for treatment and learning: Gentle, Efficient, Motivating, and Self-supporting (GEMS) , 20. TarThe intervention included use of a nebulized bronchodilator followed by either nebulized hypertonic or isotonic saline, depending on the study subject’s routine treatments.The interactive value of using mucoactive therapy as part of ACP probably increases efficacy and improves airway clearance since the therapies work together to optimize outcomes. Participants used nebulised saline during treatment in side-lying horizontal positions to facilitate mobilization of mucus to larger airways alternating with sputum removal using either FET or SCT in random order . The breImportantly, perceived efficacy and usefulness with treatment is a prerequisite for expecting adherence with maintenance treatment and thus impact on perceived health and HRQoL in a positive direction. The treatment method is visualised as a presupposition for expecting adherence with treatment and impact on HRQoL .Participants were recruited consecutively from the patient directory at the regional Oslo CF Centre. The CF diagnosis of the participants was based on clinical symptoms, sweat chloride levels > 59 mmol/L and two CF mutations in Cystic fibrosis transmembrane conductance regulator. Inclusion criteria were: CF diagnosis, age ≥ 18 years, sputum expectorated more than five ml in a treatment session, either isotonic or hypertonic saline inhalation as part of treatment, or dornase alpha. Exclusion criteria were: respiratory failure, active haemoptysis, pregnancy and acquisition with multiresistant Pseudomonas aeruginosa, Burkholderia cepacia, atypical Mycobacteria or Methicillin-Resistant Staphylococcus aureus. All participants were clinically stable at the time of entry, i.e., required no treatment for a pulmonary exacerbation within past two weeks. None were listed for transplant evaluation. The study was performed from August 2010 until April 2011 at the location and premises of the Department of Lung Medicine at Oslo University Hospital. The Regional Ethics Committee in Oslo approved this study (2010/802). All participants provided written informed consent. The study was registered in ClinicalTrials.gov, under the number NCT0 1266473.In the previously reported clinical trial  sputum wHRQoL was measured at baseline (week 1) and completion of the study (week 8) using the CFQ-R for adolescents and adults (CFQ-R 14 +). The CFQ-R was developed to assess disease-specific HRQoL domains. CFQ-R consists of 49 items on 12 domains: 9 quality-of-life domains, an overall Health Perceptions Scale and three symptom scales . The instrument is validated in Denmark (2008), Sweden (2017) and translated into Norwegian .The general domains encompass Physical Functioning, Vitality, Health Perceptions, Emotional, Social and Role Functioning. CF specific domains encompass Body Image, Eating Disturbances, Treatment Burden, and Respiratory and Digestive Symptoms . PatientLung function. Spirometry was performed by blinded assessor using a SensorMedicsVMax 20c . Lung function was assessed at baseline and at the end of the study using forced expiratory flow volumes according to the European Respiratory Society/American Thoracic Society guidelines using reference values from Knudson et.al (1983) [l (1983) . Forced Sputum weight. Sputum was collected throughout each treatment using pre-weighed transparent and gradated specimen tubes , one for each side-lying horizontal position, which was changed at the halfway point of the intervention. Sputum was weighed wet (g) after each session by a blinded assessor, using a Mettler TOLEDO weighing Balance . The balance was calibrated before each measurement and sputum weight was derived from the total weight minus the pre-use tube weight.The original protocol was based on a sample size of 10 participants and 10 interventions. However, a recalculation by the statistican before study start found that six participants and 16 interventions gave a sufficient and more feasible sample size . In the The data were checked and found to be normally distributed. Thus, linear regression was used. Multiple linear regression analyses using a backward elimination procedure was performed with both sputum weight and lung function in the model to examine which outcome was most strongly associated with HRQoL scores . Analyse2. Three had a chronic infection with Pseudomonas aeruginosa and three with Staphylococcus aureus. Median FEV1% predicted, (min-max) was 74.0 (29.0–95.0) median FEF 50% predicted, (min-max) was 49.0 (9.0–98.0) and median FEF25–75% predicted (min–max) was 40.5 (10.0–86.0). Further details are provided in a previous publication [Six participants  with CF were recruited. Median age was 35.3 years and they had a median BMI of 23.0 kg/m9.0 9.0–9.0 and meBefore study entry, all participants used their usual airway clearance therapy as reported at baseline. The majority of the participants used bronchodilators and saline inhalation (5 of 6) as part of the treatment and physical activity/exercise (3 of 6). One used DNase, and autogenic drainage when feeling tight. They were asked to continue with their usual self-administered treatment at home and not to perform treatment prior to interventions. During the study, all participants used bronchodilators, two inhaled isotonic saline and four inhaled hypertonic saline. Four participants used DNAse (Pulmozyme®) and two participants had regular treatment with inhaled antibiotics.Participant-reported outcomes were completed by all study subjects. The data were analyzed for change from baseline. Individual CFQ-R-Respiratory Symptoms Scores (0–100), showed a positive change with an MID ≥ 4 points in 5 of 6 participants . . A negatDomains that showed a positive change, no change or a negative change in individual participants were Weight (3/3/0), Role Functioning (2/3/1), Vitality (4/1/1), and Eating (0/5/1). The treatment burden domain showed a positive change in three participants and negative in two (3/1/2). Domains that showed a negative individual change were Physical Functioning (1/1/4), one due to another illness in week 7, Social Functioning (0/1/5), and Body Image (0/2/4). The results regarding HRQoL are presented in full detail in Lung function data from before and after each intervention in week 2 and sputum production data were reported on previously . To be a2 = 0.881  produced by the participants during the study and positive changes in CFQ-R-Respiratory Symptoms scores (CFQ-R-RSS) r = 0.94  0.54  (p = 0.006), implying that 10 grams increase in sputum weight improve CFQ-R-RSS by 0.54 points.1 and CFQ-R-RSS r = 0.82 . The correlation is presented in There was a positive correlation for the relation between delta FEVThere was also a positive correlation between delta FEF50 and CFQ-R-RSS r = 0.84  .There was no significant correlation between change in lung function and other CFQ-R domains.We found in multiple linear regression analyses with backward elimination technique that delta FEF50 was more strongly associated with CFQ-R-RSS than delta FEV1.The relation between CFQ-R-RSS (dependent variable) and delta FEF50 in univariate linear regression analyses was Beta 0.95  (p = 0.037), implying that an increase in FEF50 of 1 percent predicted improves CFQR-RSS with 0.95 points. In a multiple linear regression model with both sputum weight and delta FEF50 in the analysis, only sputum weight remained significantly associated with CFQ-R-RSS.CFQ-R respiratory symptoms scores in individuals with CF were improved after the airway clearance intervention period. We found a clinically important change in respiratory symptoms score in the majority of the participants, which clearly exceeded MID ≥ 4 p. This is an important finding with relevance to the airway clearance management of CF pulmonary disease. In addition, a positive change was found in the CFQ-R Health Perceptions in all participants. Further, a significant positive correlation was found between total sputum weight (g) produced by the participants during the study (week 1–8), and change in CFQ-R Respiratory Symptoms Scores, and a positive correlation was found between change in lung function and CFQ-R-Respiratory Symptoms Scores.The CFQ-R was designed and validated for use as a clinical endpoint to evaluate the effect of interventions in CF. However, to our knowledge, few studies have demonstrated impact of ACP on HRQoL , 18.In a recent overview of six Cochrane Reviews, the authors reported no definitive conclusions on the effectiveness and safety of ACTs in relation to HRQoL in CF . Two revOne long-term study by Pryor et al assessed five ACTs in adults with CF and found no difference in HRQoL as measured with Short Form-36 (SF-36) and Chronic Respiratory Questionnaire (CRQ) . HoweverIn the present trial, the CFQ-R Respiratory Symptoms Scores were improved after the intervention. Clinically meaningful changes were documented in the majority of participants, with improvements clearly exceeding the MID. Thus, these results may reflect the experience of clinical response to treatment in individual participants. Participation in the study implied that participants removed more sputum than usual due to the intervention. Hence, the changes in HRQoL may be related to increased sputum removal, thereby also improving lung function parametres.The main rationale for ACP in CF is to improve ventilation and deposition of inhaled medication and to enhance mucus clearance and expectoration of bronchial secretions when needed . The ultHowever, while some previous studies have favoured one technique over another, other studies have not found significant differences in sputum production . Pryor eTo our knowledge, this is the first trial to assess HRQoL and the association with sputum clearance in CF. This trial found a significant, positive correlation between total sputum weight and the changes in CFQ-R Respiratory Symptoms Scores. The explanation for this finding may likely be due to the original trial design and the intervention as a whole addressing sputum removal, that is, techniques and treatment method, duration and frequency .1% predicted is commonly used as outcome measure in clinical trials to assess the effectiveness of interventions [1 has been considered an appropriate surrogate outcome for clinical trials since it reflects disease status, and low lung function is strongly associated with decreased HRQOL [As ACP may improve lung function, FEVventions . FEV1 haed HRQOL .1 and there were no clear differences in terms of FVC, FEF25-75 [Several studies have used pulmonary function measures to assess comparative effects in ACT studies . HoweverFEF25-75 .The suitability and reliability of lung function as outcome measure for treatment efficacy has been questioned in three previous long-term studies . The autBy addressing sputum removal, results demonstrated improvement in HRQoL and lung function. Not surprisingly, the benefit observed in respiratory symptoms reflects the higher amount of sputum that was expectorated during the intervention, which was associated with a benefit in lung function. It was anticipated a priori that increased sputum production might impact on lung function and HRQoL by way of improvement in respiratory symptoms.Thus, the CFQ-R Respiratory Symptoms Scale was found to be a valid domain for this study and was sensitive to change.It has been questioned whether participating in clinical trials influences perceptions of HRQoL due to increased attention and better treatment during the study period , which iThe present intervention used nebulised saline in horizontal positions during treatment alternating with either SCT or FET in random order . The sigTo date, no clear evidence for the optimal duration and frequency of ACP exists , 18. PreThe present study used a treatment duration of approximately 60 minutes, twice a week over eight weeks. Thus, the benefits observed may reflect that longer treatment duration adds greater benefit due to increased sputum clearance. Hence, the clearance effect of the intervention may explain the positive changes seen in CFQ-R Respiratory Symptoms and lung function from their baseline values, and the associations found between HRQoL, sputum production and lung function.The relationship between clinical variables and measures of HRQoL can be illustrated by the conceptual model from Wilson and Cleary The model classifies different measures of health outcomes and can be used to identify measures, evaluate interventions, and improve quality of patient care . The relThis study has demonstrated a linkage between different types of outcomes and a relationship between clinical variables and HRQoL .By addressing the need for airway clearance in the intervention, we have demonstrated a clinically relevant change in CFQ-R-RSS and associations with sputum weight and lung function. Thus, sputum may be considered as a risk factor and a key factor, which can be modified in treatment strategies. By emphasizing sputum removal, respiratory symptoms improved, and so did health perceptions. In addition, improvement in respiratory symptoms was associated with critical clinical variables (lung function). Thus, a clinical intervention that reduces symptoms may also improve HRQoL in chronic diseases . Hence, Long-term randomized controlled trials using clinical meaningful outcome measures have been suggested for future research , 18. HowThe strength of our study was the excellent adherence to the original trial design  with parAdditional benefits may be enhanced skills and self-management, which in turn may influence adherence to maintenance treatment  and impaOur results have also highlighted a relationship between sputum production and dimensions of HRQoL that are linked to other key health outcomes. Thus, this study has provided new research questions and insight into the effect of this new treatment method on HRQoL in CF, which may be of value in future ACP studies. The focus should be on target group and optimised intervention according to need, and outcome measures that are likely to change, such as the CFQ-R.A limitation was the small sample size. However, this study was performed as part of a previously described pilot study of a series of N-of-1 randomised controlled trials . CompariThe clinical implication of our study is that the intervention as a whole has demonstrated clinically meaningful changes in the CFQ-R respiratory symptoms domain in the majority of the participants. The strong and positive association between primary and secondary outcome measures highlights the relationships between symptoms, clinical variables and HRQoL. Further, the role of sputum clearance as an intervening variable that likely mediate the effects should be explored both in clinical settings and in future studies.It remains important to establish individualized and optimized maintenance treatment, ensure performance skills and involve patients in shared-decision making. Importantly, surveillance and follow-up are essential to adjust treatment and treatment goals to avoid growing treatment complexity. Individual issues and needs demand different interventions. In the era of CFTR-modulators, this is especially important. Hence, the treatment in less sputum producers might address optimized ventilation and drug deposition more than airway clearance.Participation in the present study led to improvement in HRQoL and MID ≥ 4 in the CFQ-R Respiratory Symptoms domain in the majority of participants. Based on this finding, we conclude our results to be of clinical relevance. Further, a significant correlation was found between total sputum weight (g) and the positive changes in CFQ-R Respiratory Symptoms Scores, and between the changes in lung function and the CFQ-R Respiratory Symptoms Scores. These findings warrant further investigation with regard to ACP and its content, duration and frequency. A long-term trial adapted to the target group with appropriate outcome measures may further reveal information of importance to maintenance treatment. More studies are needed to investigate ACP and ACTs and possible beneficial effects on HRQoL, and to explore the use of HRQoL in clinical trials.S1 TableDetails data on CFQ-R domains, as measured at baseline (week 1) and at the end of study (week 8).(PDF)Click here for additional data file.


The prognosis of idiopathic chronic fibrotic interstitial pneumonitis (CFIP) in patients with acute exacerbation (AE) is variable. We examined whether the imaging pattern on thoracic computed tomography (CT) or the severity of respiratory failure with AE-CFIP is associated with short-term prognosis.Patients admitted to two university hospitals were retrospectively analyzed and divided into derivation and validation cohorts. The distribution of newly appearing parenchymal abnormalities on thoracic CT was classified into peripheral, multifocal, and diffuse patterns. Respiratory failure was defined as severe if a fraction of inspired oxygen ≥ 0.5 was required to maintain percutaneous oxygen saturation ≥ 90% on admission. Factors associated with 90 day-mortality were analyzed using univariate and Cox proportional hazard regression.In 59 patients with AE-CFIP of the derivation cohort, diffuse pattern on CT was associated with higher mortality within 90 days (43%) than peripheral/multifocal pattern . Additionally, compared with non-severe failure, severe respiratory failure was associated with higher mortality . Cox proportional hazard regression analysis demonstrated that a combination of diffuse pattern on CT and severe respiratory failure was associated with the poorest prognosis  in the derivation cohort, which was confirmed in the validation cohort .The combination of imaging pattern on thoracic CT and severity of respiratory failure was associated with the prognosis of idiopathic AE-CFIP. Acute exacerbation (AE) accompanied by new ground-glass opacity and consolidation in the lungs along with rapid acceleration of respiratory failure are the major causes of mortality in patients with idiopathic pulmonary fibrosis (IPF). Approximately half of the deaths of IPF patients are associated with AE, and the estimated median survival time of IPF patients who have developed AE is 3–4 months –5. AE alSeveral studies have shown that thoracic computed tomography (CT) imaging patterns and distribution are useful for predicting the prognosis of AE in patients with IPF. Akira et al.  defined 2)/ fraction of inspired oxygen (FiO2) < 200, have been reported to be associated with poor prognosis [2/FiO2 ratio is also a well-established parameter for classification of the severity of acute respiratory distress syndrome (ARDS) [2/FiO2 ratio < 100 is considered severe and is associated with a poor prognosis regardless of the treatment [In contrast, several other studies have shown that oxygenation status is a prognostic factor for AE in patients with IPF. Parameters for oxygenation during AE, particularly partial pressure of oxygen in arterial blood PaO/ fractiorognosis , 10–19. Though several biomarkers, including concentration of lactate dehydrogenase, C-reactive protein, Krebs von Lungen-6 (KL-6) in serum, and neutrophil and lymphocyte counts in bronchoalveolar lavage fluid (BALF) have also been linked to poor prognosis of AE-IPF , 21–23, Patients who were admitted to Tokai University Hospital, a tertiary university hospital in Japan, due to AE-CFIP between April 2006 and March 2018, were retrospectively analyzed as a derivation cohort. Patients who were admitted to Tokai University Oiso Hospital during the same period and those who were admitted to Tokai University Hospital due to AE-CFIP between April 2018 and August 2020 were retrospectively analyzed as a validation cohort.Idiopathic CFIP, including IPF, unclassifiable interstitial pneumonia, and non-specific interstitial pneumonia, was diagnosed based on multidisciplinary discussion (MDD) with multiple pulmonologists and a radiologist to assess patients’ clinical history, physical examination, laboratory data, and radiographic findings on high-resolution CT (HRCT). Patients with secondary conditions due to connective tissue disease, hypersensitivity pneumonitis, and sarcoidosis were excluded; those with neoplasms undergoing active treatments, including cytotoxic chemotherapy, molecular-targeted drugs, or immune checkpoint inhibitors were also excluded.AE-CFIP was diagnosed based on modified AE-IPF criteria , which wThis study was reviewed and approved by the Institutional Review Board of Tokai University Hospital (17R-198/18R-241/20R-230) and Tokai University Oiso Hospital (18R-241), implemented in compliance with the Declaration of Helsinki. Informed consent was obtained in the form of opt-out on the website. No patient declined to participate in the study.1) were calculated using equations proposed by the Japanese Respiratory Society [Data associated with clinical and laboratory parameters within 12 months prior to and after the onset of AE-CFIP were collected from medical charts. The systemic inflammatory response syndrome (SIRS) score at the time of admission for AE-CFIP was determined based on body temperature, heart rate, respiratory rate, and white blood cell counts, as previously reported . While t Society .2 required to maintain percutaneous oxygen saturation (SpO2) ≥ 90% on admission. The FiO2 during oxygen therapy was estimated using the conversion formula described below [Respiratory failure severity at admission was defined according to the minimum FiOed below .2 < 0.5 or ≥ 0.5, respectively, to maintain SpO2 ≥ 90%. As per the Berlin definition, the severe group corresponds to moderate or severe oxygenation disorder (PaO2/FiO2 < 200) [Respiratory failure was defined as non-severe or severe when the patients required FiOThoracic HRCT with 1.5 mm-thick axial sections was obtained at 1-cm intervals throughout the entire thorax in the inspiratory phase prior to the onset of AE. CT images were classified according to the consensus reading by three pulmonologists blinded to the prognosis of each case as usual interstitial pneumonia (UIP)/probable UIP/indeterminate for UIP/alternative diagnosis based on the 2018 ATS/ERS/JRS/ALAT international diagnostic guidelines .Newly appeared ground-glass attenuation (GGA) and consolidation in the lungs on CT at AE-CFIP were classified into three patterns, namely peripheral, multifocal, and diffuse, according to the definition by Akira et al. . The IchData are presented as mean ± standard deviation for continuous variables and as numbers and percentages for categorical data. Group comparisons were made using the Mann-Whitney U test for continuous variables and Fisher’s exact test for categorical variables. Kaplan-Meier survival curves and log-rank tests were employed to evaluate survival. In addition, a log-rank trend test was conducted to confirm the changes in trends related to 90-day mortality. When the severity of respiratory failure and CT pattern were analyzed in combination, patients were categorized into three groups: cases with non-severe respiratory failure and non-diffuse CT pattern, those with severe respiratory failure and diffuse pattern, and the discordant group with either non-severe respiratory failure and diffuse CT pattern or severe respiratory failure and non-diffuse CT pattern. Cox proportional hazard regression analysis for 90-day survival in the derivation cohort was performed using the parameters identified by p < 0.1 in the univariate analyses and no missing data. Hazard ratios (HRs) were presented as median and interquartile range (IQR). Statistically significant parameters in the analysis of the derivation cohort were applied to the validation cohort. Patients with IPF in the derivation and validation cohorts (an IPF cohort) were also used for the sensitivity analysis. All analyses were performed using the IBM SPSS Statistics software ver. 27 . The level of statistical significance was set at p < 0.05.We identified 59 patients  admitted due to AE-CFIP during the study period in the derivation cohort. For the validation cohort, 34 patients with AE-CFIP were found to be eligible in the two institutes. Two patients, one each from in the derivation and validation cohorts were lost to follow-up within 90 days, and were excluded from the univariate analysis of 90-day mortality.2 required to maintain SpO2 ≥ 90% on admission, there were 19 (32%) and 7 (21%) subjects with severe respiratory failure requiring FiO2 ≥ 0.5, in the derivation and validation cohorts, respectively. In 12 patients (13%), the respiratory failure grade changed within 24 hours after hospitalization. Specifically, eight patients worsened and four improved  in the derivation cohort and 9 (26%) in the validation cohort, high-flow nasal cannula or invasive positive-pressure ventilation was used for the treatment of respiratory failure. There were no significant differences in pharmacotherapy or oxygen therapy between the groups .Seventeen patients (29%) died within 90 days after AE (non-survivors), including 8 patients (21%) with non-severe respiratory failure and 9 patients (47%) with severe respiratory failure  died within 90 days after AE. The association demonstrated in the derivation cohort between 90-day mortality and severe respiratory failure or diffuse pattern on CT was replicated in the validation cohort  of the respiratory failure grade and the combination of the respiratory failure grade and CT pattern, to predict 90-day mortality/survival using the combined dataset of derivation and validation cohorts n = 91, . The PPVCox proportional hazard regression analysis adjusted for age and sex was performed using the parameters identified by p < 0.1 in univariate analyses of the derivation cohort with no missing data, including smoking history, UIP/probable UIP, severity of respiratory failure, CT pattern on AE-CFIP, and their combinations. Smoking status and the combination of severe respiratory failure and diffuse pattern were the predictive factors of 90-day mortality . In the validation cohort, a combination of severe respiratory failure and diffuse pattern was also predictive for 90-day mortality .Sixty-two cases of IPF were identified in the combined dataset of the derivation and validation cohorts. Twenty-eight patients (45%) died within 90 days of admission due to AE-IPF. The respiratory failure grade, CT pattern, and combination of two were predictive of survival within 90 days , as was 2 required to maintain SpO2 ≥ 90% at hospitalization and diffuse distribution of newly developed ground-glass opacity or consolidation on thoracic HRCT images was significantly associated with 90-day mortality. This was especially noted when the two were analyzed in combination. However, post-AE Ichicado scores that reflect the extent of fibroproliferative changes were not associated with the outcome of AE-CFIP. These findings were confirmed by an additional analysis of 31 cases in the validation cohort. This suggests that the intensity and extent of lung injury during AE at the site where gas exchange can be maintained without structural remodeling is essential for the prognosis of AE-CFIP.In our retrospective analysis of 54 cases with AE-CFIP, the severity of respiratory failure defined by FiOTwo methods have been used to evaluate CT patterns in the lungs during AE-IPF; one which focuses on the distribution pattern of newly developed opacities, and the other that evaluates the extent of fibroproliferative changes in greater detail. Our data confirmed the findings of a previous report which documented that diffuse patterns of new lung opacities are associated with poorer prognosis as compared with peripheral or multifocal patterns . The IchThe severity of respiratory failure on admission was not significantly associated with the distribution of newly developed ground-glass opacity or consolidation on thoracic CT images; a diffuse pattern being observed in 49% and 53% of cases with non-severe and severe respiratory failure, respectively, in the derivation cohort (p = 0.99). A substantial proportion of patients  demonstrated discordance between the severity of respiratory failure and the extent of lung opacities. The prognosis of patients with discordant features was better than those with concordant severe respiratory failure and diffuse CT pattern, suggesting that the severity of respiratory failure was determined not only by the area of the damaged lung, but also by the pathological changes in the injured lung. This hypothesis is supported by observations in cases of ARDS as reported earlier. A post-mortem analysis of 356 cases of ARDS had demonstrated that 56%, 40%, and 12% of the cases with severe, moderate, and mild respiratory failure presented with diffuse alveolar damage, whereas others suffered from organizing pneumonia . AlthougThere are a few limitations to the present study. First, it was a retrospective study conducted in two clinical centers with a small sample size, especially in the validation cohort. However, the obtained results are reliable as data from the first cohort were confirmed in an independent cohort. Second, this study examined a population with mixed backgrounds, including cases of IPF and non-IPF. However, severe respiratory failure and diffuse patterns on CT was associated with a poor prognosis, independent of the presence of UIP/probable UIP. Therefore, in future studies, cases of interstitial pneumonia secondary to collagen vascular diseases and chronic hypersensitivity pneumonia should also be examined.Short-term mortality in idiopathic AE-CFIP patients was dependent on the intensity, quality, and area of lung injury, which can be clinically assessed based on the severity of respiratory failure and the distribution of new opacities on HRCT.


Understanding geographic disparities in Coronavirus Disease 2019 (COVID-19) testing and outcomes at the local level during the early stages of the pandemic can guide policies, inform allocation of control and prevention resources, and provide valuable baseline data to evaluate the effectiveness of interventions for mitigating health, economic and social impacts. Therefore, the objective of this study was to identify geographic disparities in COVID-19 testing, incidence, hospitalizations, and deaths during the first five months of the pandemic in Florida. Florida county-level COVID-19 data for the time period March-July 2020 were used to compute various COVID-19 metrics including testing rates, positivity rates, incidence risks, percent of hospitalized cases, hospitalization risks, case-fatality rates, and mortality risks. High or low risk clusters were identified using either Kulldorff’s circular spatial scan statistics or Tango’s flexible spatial scan statistics and their locations were visually displayed using QGIS.Visual examination of spatial patterns showed high estimates of all COVID-19 metrics for Southern Florida. Similar to the spatial patterns, high-risk clusters for testing and positivity rates and all COVID-19 outcomes  were concentrated in Southern Florida. The distributions of these metrics in the other parts of Florida were more heterogeneous. For instance, testing rates for parts of Northwest Florida were well below the state median  but they were above the state median for North Central Florida. The incidence risks for Northwest Florida were equal to or above the state median incidence risk , but the converse was true for parts of North Central Florida. Consequently, a cluster of high testing rates was identified in North Central Florida, while a cluster of low testing rate and 1–3 clusters of high incidence risks, percent of hospitalized cases, hospitalization risks, and case fatality rates were identified in Northwest Florida. Central Florida had low-rate clusters of testing and positivity rates but it had a high-risk cluster of percent of hospitalized cases.Substantial disparities in the spatial distribution of COVID-19 outcomes and testing and positivity rates exist in Florida, with Southern Florida counties generally having higher testing and positivity rates and more severe outcomes  compared to Northern Florida. These findings provide valuable baseline data that is useful for assessing the effectiveness of preventive interventions, such as vaccinations, in various geographic locations in the state. Future studies will need to assess changes in spatial patterns over time at lower geographical scales and determinants of any identified patterns.The online version contains supplementary material available at 10.1186/s12889-022-14450-9. The coronavirus disease 2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), is currently the most serious challenge to global health. In the U.S, the first COVID-19 infections were reported in the West Coast . The U.SThe spread of the disease to Southeastern U.S. is particularly concerning due to the higher prevalence of several pre-existing health conditions that places many individuals in this region at higher risk of both COVID-19 infection and more severe outcomes compared to those in the rest of the country , 7. The This study was reviewed and approved by the University of Tennessee Institutional Review Board (IRB). The IRB number is UTK IRB-20–06,105.rd most populous state in the U.S., with approximately 20.9 million people distributed as follows; 49% male, 22.3% (0–19 years old), 57.7% (20–64 years old), and 20% (≥ 65 years old) . The majority (77.4%) of the population are White, 16.9% are Black, and all other races comprise 5.7% of the population. By ethnicity, 25.7% of the population is Hispanic-Latino and the rest is non-Hispanic [This is a retrospective ecological study conducted at the county level in the state of Florida using publicly available COVID-19 data collected from March 1 to July 15, 2020. Florida is the 3Hispanic . These dHispanic . ApproxiCounty-level data for total number of: persons who tested positive for COVID-19, persons who tested negative for COVID-19, hospitalized cases, and deaths among Florida residents were extracted from Florida Department of Health (DOH) COVID-19 dashboard . Total n(a) Testing rate = no. COVID-19 tests/2018 county population*100,000;(b) Positivity rate = no. positive COVID-19 tests/all people tested in the county*100;(c) Incidence risk = no. COVID-19 cases/all people at risk in the county (i.e. 2018 county population) *100,000;(d) Percent of hospitalized COVID-19 cases = no. COVID-19 cases hospitalized/no. COVID-19 cases in the county*100;(e) Hospitalization risks = no. COVID-19 cases hospitalized/all people at risk in the county (i.e. 2018 county population) *100,000;(f) Case-fatality rates = no. COVID-19 deaths/no. COVID-19 cases in the county*100;(g) COVID-19 mortality risks = no. COVID-19 deaths/all people at risk in the county (i.e. 2018 county population) *100,000.The following COVID-19 metrics were computed cumulatively for the study period for each county:All descriptive analyses-including mean, standard deviation, median, lower quartile, upper quartile, and interquartile range were performed in SAS 9.4 . All varClusters of testing rates and positivity rates were investigated using Kulldorff’s circular spatial scan statistics (CSSS), a spatial epidemiological tool for detecting and identifying circular clusters. This was implemented in SaTScan version 9.6 . A discrp-value of 0.05.Clusters for COVID-19 outcomes were investigated using Tango’s flexible spatial scan statistics (FSSS), a spatial epidemiological tool for detecting and identifying circular and irregularly shaped high-risk clusters. This was implemented in FleXScan v 3.1.2 , 28. PoiQGIS version 3.22.0 was used to display the geographic distribution of all COVID-19 metrics and the location of spatial clusters . Jenk’s The median testing rate for the state of Florida was 11,697 tests per 100,000 persons, and testing rates varied from 6,071 to 30,133 per 100,000 persons across the state Fig. a. The liTwo clusters of high testing rates and three clusters of low testing rates were identified Fig. a. High tThe percent of persons with positive tests also varied widely across the state, ranging from 2.7% to 26.6% Fig. . A totalOnly one cluster with a high positivity rate  was identified, and it was located in Miami-Dade County in Southern Florida   Fig. , Table 1A total of 4 high-risk clusters of percentage of hospitalized cases were identified. The largest high-risk cluster was located in South Florida and smaller clusters were identified in North Florida Fig. . AdditioHospitalization risks varied from 17 to 282 cases/100,000 (Median = 66)  in Southern Florida counties  across the state Fig. g.The locations of high mortality risk clusters generally mirrored those of high case fatality rates, with all high mortality risks clusters being located in Southern Florida Figs. . The relIn summary, estimates of all COVID-19 metrics for Southern Florida counties were generally above the state average or median. However, while testing rates, positivity rates and percent of hospitalized cases for a number of rural counties in Northern Florida were above the state average, the incidence risks, hospitalization risks, case fatality rates, and mortality risks for most counties in that region were below the state average. Both circular and irregularly-shaped high-risk clusters for all COVID-19 metrics were concentrated in Southern Florida, with a few clusters of high incidence risks, percent of hospitalized cases, hospitalization risks and case fatality rates in the Northwest and Central Florida. A single high-risk cluster of percent of hospitalized cases was identified in Central Florida. Low testing and positivity rate clusters were concentrated in predominantly rural counties in Northern Florida.This study retrospectively investigated geographic disparities in COVID-19 testing and positivity rates; incidence, hospitalization and mortality risks; and percent of hospitalized and fatal cases in Florida during the first five months of the pandemic. Study findings will provide useful baseline data to advance our understanding of the spatial dynamics of the pandemic because these findings could be compared to the findings of similar studies using the recent data in Florida. Study findings will also help public health officials gauge the impact of mitigation efforts on the disease burden. Furthermore, Florida’s current age structure and ethnic/racial composition  foreshadIdentification of low testing rate clusters in rural counties of Northwest Florida and high testing rate clusters in the predominantly urban Miami-Dade county is consistent with findings from other studies that reported lowest COVID-19 testing rates in rural areas, areas with high poverty levels, and/or large proportions of Black and Hispanic populations, particularly during the early stages of the pandemic –34.The location of COVID-19 testing sites in the U.S. was initially based on the location of existing healthcare infrastructure, which resulted in communities with already low access to healthcare having fewer COVID-19 testing sites per capita , 36. ForThe results of this study showing geographic disparities in positivity rates across Florida are in agreement with those of other ecologic studies , 41. TheHigh-density living settings and high population density have been associated with high SARS-CoV-2 infection rates –52. ConsSouthern Florida, on the other hand, has large proportions of Hispanic and non-White immigrant populations, a large proportion of whom live in multigenerational overcrowded households in densely populated areas , 54–60. It has been postulated that a high incidence of COVID-19 in certain areas could be due to high testing rates in those areas . HoweverThe identified high-risk hospitalization and mortality clusters in this study parallel reports from other studies examining placed-based inequities in these COVID-19 outcomes both in the US , 68, 72 2 and PM 2.5, due to residence in close proximity to sources of air pollution and longer distance from regulatory air quality monitoring compared to white communities [The clustering of high COVID-19 hospitalization and mortality risks in Southern Florida may be a reflection of the disproportionate burden of COVID-19 borne by Black and non-white Hispanic/Latino communities , 76. Themunities –87. Thismunities –93. Socimunities , 94–96 mmunities . Since omunities . TherefoThe fact that Miami-Dade, Collier, and Lee Counties were not included in the high-risk cluster in Southern Florida when hospitalized cases were divided by total cases, but the converse was true when incident and hospitalized cases were divided by county population suggests that a large proportion of the incident cases were not severe enough to warrant hospitalization. These urban counties have a relatively younger population, implying that a large proportion of the cases were less susceptible to severe disease compared to the rest of Florida. This explanation is bolstered by the absence of clusters of high case fatality rates in those counties. Surprisingly, the opposite trend was observed for St. Lucie County, which is also an urban county in Southeast Florida. Potential reasons for high susceptibility to more adverse COVID-19 outcomes in St. Lucie County include high percentage of individuals living below the federal poverty limit, low healthcare accessibility, and high burden of comorbidities. Not surprisingly, the average life expectancy in St. Lucie is consistently lower than that for Miami-Dade, Collier, and Lee counties . The cluThe identification of high-risk clusters in Calhoun, Gadsden, and Jackson counties in Northwest Florida both when hospitalized cases were -divided by the total number of cases and by the county population suggests that despite the lower COVID-19 incidence risks in Northwest Florida compared to Southern Florida, a large proportion of the cases in Northwest Florida were severe enough to warrant hospitalization. Northwest Florida is a predominantly rural region with large proportions of black and older residents, and high burdens of comorbidities such as diabetes, hypertension and cardiovascular disease , 100–102The identification of a high-risk cluster of percent of hospitalized COVID-19 cases in parts of Central Florida around Gainesville may be due to higher level of accessibility of healthcare facilities equipped with ICU beds in that region , 84. AddThe identification of low-risk clusters of percent of positive tests and only a few high-risk clusters of incidence, hospitalization, and mortality risks in rural counties in Northern Florida suggests that the impact of COVID-19 was lower in rural areas than in urban areas during the study period. These results are consistent with those of other area-level studies reporting lower COVID-19 incidence and deaths in the most socioeconomically vulnerable counties during the early stage of the pandemic –113. TheIt is worth noting that despite reduced opportunities for the SARS-COV-2 virus to spread in the sparsely populated rural Florida counties, these locales have, on average, larger proportions of older (> 65 years) residents and higher burdens of underlying chronic health conditions such as obesity  diabetesThe use of rigorous spatial epidemiological tools (FSSS and CSSS) coupled with the investigation of disparities in COVID-19 testing and positivity rates and several of its outcomes enabled this study to obtain a more comprehensive picture of the burden of COVID-19 in Florida during the early stage of the pandemic. The FSSS method identified irregularly shaped local clusters that would otherwise be missed by the CSSS method, which is used by most studies for identifying local spatial clusters. A limitation of the study is the potential for an underreporting of COVID-19 incidence, hospitalization, and mortality risks and an overestimation of case fatality rates. This is because the number of cases diagnosed was contingent on local SARS-CoV-2 testing availability and guidelines, which varied across the state and evolved during the study period as the understanding of COVID-19 clinical presentations and its risk factors improved. Additionally, we did not identify the contextual factors that may be associated with the identified disparities. Therefore, our discussion is based on our knowledge of the underlying population groups in areas with high COVID-19 incidence and death risks and low testing. Identifying determinants may aid in the development of novel approaches to reduce the disproportionate burden of COVID-19 in some populations to achieve greater health equity. Additionally, the FSSS analysis failed to run when we attempted to detect high testing rate clusters, hence it is likely that irregularly shaped clusters were missed.Finally, aggregating data by county may obscure substantial local heterogeneities that may be present at a lower spatial scale , 127. ThSubstantial geographic disparities in COVID-19 testing and positivity rates; incidence, hospitalization and mortality risks; and percent of hospitalized and fatal cases exist across Florida early in the pandemic, with counties in Southern Florida generally having higher testing rates and poorer outcomes compared to those in the Northern Florida. These findings may provide baseline data to evaluate the effectiveness of interventions aimed at controlling the pandemic and reducing health disparities in Florida. Future studies will need to assess changes in spatial patterns over time at lower geographical scales and determinants of any identified patterns.Additional file 1:Supplementary File 1. Raw COVID-19 data for Florida counties, March 1 to July 15, 2020.


The COVID-19 pandemic seems endless with the regular emergence of new variants. Is the SARS-CoV-2 virus particularly evasive to the immune system, or is it merely disrupting communication between the body and the brain, thus pre-empting homeostasis? Retrospective analysis of the COVID-19 and AIDS pandemics, as well as prion disease, emphasizes the pivotal but little-known role of the 10th cranial nerve in health. Considering neuroimmunometabolism from the point of view of the vagus nerve, non-invasive bioengineering solutions aiming at monitoring and stimulating the vagal tone are subsequently discussed as the next optimal and global preventive treatments, far beyond pandemics. In the context of globalization, it is crucial to rapidly protect the world population against new pathogens. Despite major advances in medical research, the last pandemic has underscored the limits of our societies in overcoming atypical viruses, compelling us to use ancestral methods such as lockdowns.In the race against time during pandemics, two main strategies usually prevail : drug reEffector-triggered immunity (ETI) is a conserved mechanism of pathogen sensing, based on the detection of combinations of critical host molecules signaling the presence of pathogens, subsequently activating innate immune signaling pathways and, ultimately, driving inflammatory responses  pandemics—namely, COVID-19 and AIDS—in order to upgrade future therapeutic strategies worldwide.Interestingly, SARS-CoV-2 and HIV-1 do share similarities ,8. IndeeThe nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout the nervous and immune systems  and the digestive organs to the brainstem . Thus, fRemarkably, the constant bidirectional communication within the microbiota–gut–brain axis, mediated by the vagus nerve, is essential for maintaining homeostasis . Indeed,As a consequence, vagus nerve stimulation is a powerful anti-inflammatory tool  . unsurprAlthough various therapeutic approaches have been developed in light of the AIDS and COVID-19 pandemics, remarkably, none  has eradicated infection so far. Conversely, retrograde axonal transport of pathogens—most notably through the vagus nerve—has been suggested for more than 10 years in order to protect against neurotropic viruses . LikewisR device to provide two consecutive 2-min doses of cervical non-invasive VNS, three times daily . Seitz et al. [R device) inserted into vagally supplied regions of one auricle. The device delivered intermittent electrical stimulation (3 h on/3 h off) with a 1 Hz frequency, 0.5–0.9 mA peak current (1.5 mA maximum), 1 ms pulse width, and 3.8 V fixed amplitude. No study at all was able to show a significant improvement in the clinical outcomes of the COVID-19-positive inpatients  was created during spring 2020 in order to support the rapid deployment and clinical validation of neuromodulation technologies—especially VNS devices—through multiple modalities, including electricity , ultrasound , and focused ultrasound   (see  for a reer)  , for instance. In 2016, Koopman et al. demonstrated that in RA patients, an implantable vagus-nerve-stimulating device significantly inhibited tumor necrosis factor production for up to 84 days and was able to significantly improve the clinical disease severity . VNS hasAs diseases are already or soon to be diagnosed earlier, minimally invasive VNS modalities should also be proposed as a first-line treatment in several indications ,105. RemAs many common  , uncommoThe analysis of the last two pandemics underlines the central role of the vagus nerve in maintaining homeostasis, most notably via regulation of neuroimmunometabolism. Many viruses or pathogens invade and hijack the vagus nerve, presumably after co-binding to nicotinic acetylcholine receptors, in order to enter the brain, resulting in brain lesions and poor outcomes. The rapidity and the scale of SARS-CoV-2 infection in particular urge the repurposing of drugs and/or therapeutic solutions.The efficiency of non-invasive vagus nerve stimulation—either cervical or auricular—definitely ought to be assessed in larger clinical trials involving severely infected patients, in order to be able to react faster in the event of another pandemic or beyond. Indeed, the impact of such clinical trials is also likely to be useful for the prevention and treatment of diseases that have been poorly managed so far. “What doesn’t kill us makes us stronger…”.


Primary rhegmatogenous retinal detachment is an acute threat to visual impairment due to a retinal break that allows the passage of vitreous fluid into the subretinal space. Although it is clear that functional results are influenced by retinal detachment extension and surgical timing, we do not have definitive indications on post-operative changes in macular microcirculation and how they might affect visual performance. The study aims to evaluate the long-term macular vascular changes and their correlation with functional recovery in patients successfully treated for rhegmatogenous retinal detachment. We found a reduction of the vascular density in the operated eyes, not influenced by surgical techniques, independently from the pre-operative detachment extension. However, we found that functional recovery is influenced by different intraoperative choices. In conclusion, such visual acuity and microvascular changes can be considered biomarkers that highlight the relevance of careful management of this sight-threatening disease.p < 0.05) in both the Macula-ON and Macula-OFF groups. Vessel length density (VLD) decrease in SCP was more extended in the Macula-OFF group. No difference in the DCP perfusion parameters was found, compared to controls. Subgroup analysis dependent on the type of surgery or tamponade showed no significant differences of VD and VLD. An inverse correlation was found between the SCP VD and the duration of silicone oil (SO) tamponade (p = 0.039). A significant correlation was observed between parafoveal SCP VD and final best corrected visual acuity (BCVA) (p = 0.028). The multivariate linear regression analysis showed that only the type of tamponade was significantly correlated with the final BCVA in the Macula-ON group (p = 0.004). Conclusions: Our study described long-term perfusion changes in RRD after surgery, with lower SCP VD and VLD in the operated eyes compared to the fellow ones, not influenced by type of surgery or tamponade. The choice of tamponade and SO removal timing may affect functional outcomes, especially in Macula-ON RRD. In conclusion, such functional and perfusion changes can be considered biomarkers that highlight the relevance of careful management of this sight-threatening disease.Background: The aim of this study was to assess long-term macular vascular changes and their correlation with functional recovery in patients successfully treated for Macula-ON and Macula-OFF rhegmatogenous retinal detachment (RRD). Methods: This retrospective observational study included 82 eyes of 82 patients who received primary successful retinal detachment surgery, 33 Macula-ON and 49 Macula-OFF. Superficial and deep capillary plexuses (SCP and DCP) were evaluated by optical coherence tomography angiography (OCTA), and were correlated with visual acuity (VA), surgical technique and tamponade at 12 months after surgery. The fellow eyes were used as controls. Results: At 12-month follow-up, there was a significant decrease in the vessel density (VD) in the SCP in the operated eyes compared to control eyes ( Rhegmatogenous retinal detachment (RRD) is defined as the separation of the neurosensory retina from the retinal pigment epithelium (RPE), triggered by retinal breaks which allows vitreous fluid to escape into the subretinal space. RRD is an acute threat to visual impairment which requires early surgical management. The surgical techniques can be different, including scleral buckling (SB) and pars plana vitrectomy (PPV) with internal tamponade such as gas or silicone oil (SO). Despite the high anatomical restoration after vitreoretinal surgery, some patients continue to have poor visual recovery . The maiOptical coherence tomography angiography (OCTA) is a non-invasive method to study the macular microcirculation, with good reproducibility and repeatability ,5,6. It The aim of this study was to evaluate foveal microvascular structure and investigate the significance of long-term vascular changes in the eyes with successfully reattached RRD with different surgical techniques (SB or PPV and gas or SO tamponade). We have also compared perfusion/architectural parameters with functional findings.This retrospective observational study was conducted at the Ophthalmology Clinic of University of Modena and Reggio Emilia . This work was approved by the Ethics Committee of the Vasta Emilia Nord Area  and was conducted following the principles of the Declaration of Helsinki. The study sample consisted of patients who underwent RRD surgery in the period between June 2018 and March 2021. Inclusion criteria were primary unilateral RRD, presence of successful retinal reattachment after single surgical intervention (SB or PPV with gas or SO tamponade), and absence of macular pathologies that could potentially impair visual function. We defined patients with an RRD not involving the fovea as the Macula-ON group and those with an RRD with foveal detachment as the Macula-OFF group. Successful retinal reattachment was considered if all the breaks were supported and adequately sealed with retinal laser and the macula was adequately attached. Patients with severe proliferative vitreoretinopathy (PVR) were excluded. Other exclusion criteria were previous surgical interventions (other than uneventful cataract surgery), re-detachment, persistent subretinal fluid and prior retinal detachment in the fellow eye. Patients who met the inclusion criteria underwent a complete ophthalmic examination for both eyes, including BCVA, intraocular pressure, slit-lamp biomicroscopy, fundoscopy, spectral-domain (SD)-OCT and OCTA, along with a complete medical history. For all patients, the fellow eyes were considered as the control group. Pre-operative and intra-operative data collected from the medical records were age, sex, hypertension, diabetes, BCVA, retinal detachment extension and surgical procedure information (such as combined phaco-vitrectomy) and intra-operative retinal photocoagulation laser application.25G 3-port pars plana vitrectomy was performed in 70 eyes (PPV) by the same expert surgeon (RM). After core vitrectomy, a complete vitreous base removal was performed. The surgeon removed as much of the peripheral vitreous as possible, thus releasing vitreous traction on the retinal break. Subretinal fluid was aspirated using a flute needle during the fluid/air exchange. Endolaser photocoagulation was applied around the break(s) or 360° retinal photocoagulation was performed in the presence of multiple breaks in many quadrants. After that, gas (SF6 or C3F8) or SO tamponade was injected in vitreous chambers.Scleral buckle (SB) was performed in 12 eyes (SB group) by the same surgeon (RM). Segmental radial or circumferential buckles were sutured above the retinal breaks and external subretinal fluid drainage was performed. Finally, an intravitreal expansible gas injection was performed.Young phakic patients, without posterior vitreous detachment, preferably underwent episcleral surgery, otherwise PPV was the first choice for surgical management. Combined phacoemulsification, aspiration, and intraocular lens implantation were performed at the discretion of the surgeon in cases of phakic patientsAt the time of data collection, all eyes underwent silicone oil removal surgery, or complete resorption of the gas bubble was ascertained.The best-corrected visual acuity (BCVA) was assessed using Snellen’s visual acuity chart. The recording of BCVA was performed preoperatively and during the postoperative visit. The BCVA was converted from Snellen’s scale to the logarithm of the minimum angle of resolution (logMAR) units for the purpose of statistical analysis. ® trough-dilated pupils. The OCTA images of the SCP and DCP were binarized and then, skeletonized by integrated-images-processing system software. Vessel density (VD) calculated on binarized image was considered as the percentage of white pixels in the region by percent (%). On skeletonized images, the lines of a binary image were transformed into thin lines (1 pixel of thickness) and the value obtained by dividing the sum of the length of the thin lines in the region by the area by “mm-1” to represent the vessel length density (VLD). All the above-mentioned image processing was performed by the software (OCT-HS100 Angio Expert AX®). Predefined automatic segmentation for the retinal vascular plexuses was performed by the integrated software (RX Capture for OCT-HS100®). (3 × 3 mm OCTA scans of SCP and DCP were performed using Canon OCT HS100 angiographyHS100®).  An all-it test) was used to compare ocular parameters of RRD eyes with the fellow eyes. Analysis of variance (ANOVA) was performed. Bivariate correlations and possible associations between vascular parameters and post-operative BCVA were analyzed by applying Pearson correlations. To identify the factors related to BCVA in the studied eyes, the potential determinants were tested using univariate and multivariate linear regression analyses. All the p values were considered statistically significant when the values were <0.05. Statistical analyses were performed with SPSS  and STATA14 .Continuous variables were presented as mean values ± standard deviation (SD). The categorical data were described as the frequency counts and percentages. The quantitative data fitted a normal distribution, and a paired t-test  with mean age of 63 ± 12 years were included in the study. Demographics, ocular data and characteristics of study group are reported in SB was performed in 12 eyes and PPV in 70 eyes. All the patients in the PPV group patients were pseudophakic at the time of study recruitment. The mean follow-up period was 13.1 ± 2 months. In the PPV group the mean duration of SO tamponade was 4.81 ± 1.8 months. Eight eyes (9.8%) experienced increased IOP during the post-operative period; thus, requiring topical anti-glaucoma eyedrops. No eyes required glaucoma surgery. p = 0.00). The Macula-ON group had a non-significant improvement of BCVA at follow-up (p = 0.245).The Macula-ON group’s pre-operative and post-operative visual acuity were significantly better than in the Macula-OFF group. A post-operative significant improvement in terms of BCVA was observed in the Macula-OFF RRD group . The multivariate linear regression analysis showed that only the type of tamponade (p = 0.004) was significantly correlated with the final BCVA in the Macula-ON group, as showed in A surgical technique-based subgroup analysis showed that final BCVA was not influenced by type of surgery. The sub-analysis dependent on macula involvement and tamponade has shown that the Macula-ON group’s eyes filled with gas had a better final BCVA (0.058 ± 0.10 logMAR) than those with SO  for all quadrants, but no statistically significant difference in DCP.Compared to healthy fellow eyes, RRD eyes had a significant lower SCP VD and VLD (p = 0.028)  .Compared to healthy fellow eyes, RRD eyes had a lower SCP VD in the central, nasal, and superior quadrant and a lower SCP VLD only in the central quadrant. There was no statistically significant difference in VD between treated eyes and controls in all DCP segments .Compared to healthy fellow eyes, RRD eyes had a lower SCP VD and VLD in all the segments. There was no statistically significant difference in VD and VLD between treated eyes and controls in the DCP.  The Macup = 0.039)  .p > 0.05).No differences were found between the two groups (Macula ON and OFF) in terms of CMT (p = 0.002). Patients who developed intraretinal cysts had a significantly greater CMT (367.58 ± 81.70 µm) in comparison to patients who did not develop cysts . In the Macula-OFF group eyes filled with SO the CMT was statistically greater than in those filled with gas. In the SO group 47% (8/17) of subjects developed CME, although CME was revealed only at 6% (4/65) in the gas group.Post-operatively, eyes filled with SO had a greater CMT (349.53 ± 76.58 µm) in comparison to eyes filled with gas  and different tamponade (gas or silicone oil).As expected in our cohort, a statistically significant post-operative improvement of BCVA was found in the Macula-OFF group ,11 givenIn detail, the multivariate regression analyses showed that only the type of tamponade was significantly correlated with the final BCVA in the Macula-ON group, as eyes filled with gas had a better final BCVA then those filled with SO and this is in line with some previous studies ,14. Moreover, visual acuity was negatively related to parafoveal SCP VD, suggesting that as the perfusion parameter decreased after surgery, a concomitant lowering of BCVA was detected, similarly to the RVO condition . These eOur study emphasizes the concept of a reduced retinal perfusion after RRD surgery, as we found a significant differences in SCP VD compared to control eyes at 12-month follow-up. The mechanism of retinal perfusion changes after RRD repair is still controversial. A fair number of studies with a follow-up no longer than 8 months were investigated. Reduction of VD in retinal capillary plexuses in comparison to fellow eyes at post-operative follow-up was usually reported in literature, with more significant evidence in Macula-OFF condition ,23,24,25We found also a reduced VLD in the SCP, in comparison to controls, more extensive in the Macula-OFF group than in the Macula-ON one. This discrepancy between the two groups may indicate that in the Macula-OFF group the smaller capillaries were more affected by RDD, in which the damage mainly manifests itself in a lower density of the VLD, probably due to a more extensive rarefaction of retinal vessels, if compared with the Macula-ON condition ,34,35. IIn our cohort of patients, we did not find any differences in terms of VD with respect to the type of tamponade, similarly to Resc M. et al.’s findings .We observed an inverse correlation between the SCP VD and the duration of SO tamponade; likewise previous studies showed that long-time SO tamponade could lead to a decrease in post-operative macular VD ,38. In aConsidering the absence of significant differences in OCTA-studied parameters in Macula-ON eyes between SO and gas groups, we could hypothesize a not primarily ischemic-pattern-retinal impairment for the explanation of the above-mentioned worst BCVA in SO filled eyes. Loss of retinal sensitivity might be led by toxic insult, photo-toxicity and failure of potassium siphoning by Muller cells ,43,44,45In addition, a significant CMT increase was observed in patients with intraretinal cysts, considering that half of the eyes filled with SO developed cysts. SO increases the accumulation of pro-inflammatory cytokines in the retro-silicone oil fluid. In fact, in the ocular tissues an inflammatory response happens since macrophages and giant cells with lipid vacuoles have been found . DiffusiThis study has some limitations. First, a selection bias may have been created because of its retrospective design and one single hospital’s data. There was no randomization for gas or SO tamponade groups. The choice of tamponade was established by the surgeon on the base of multiple aspects, comprising the estimated risk of re-detachment and size of retinal tear. However, the randomization of the choice of tamponade would not be feasible in current practice. We did not differentiate patients for different types of SO used as tamponade. Second, operative time and RD extension can impact on retinal capillary plexuses recovery; however, we did not consider these factors in our study. We did not evaluate the height and volume of the macular detachment, which probably might affect the post-operative macular perfusion outcomes. Third, some segmentation errors and artifacts can persist on the OCT and OCTA images, even though cases with poor quality were excluded. In addition, we did not evaluate OCT structural changes, as well as ellipsoid zone and external limiting-membrane integrity, which are known to be independent factors affecting visual acuity after vitreoretinal surgery.In conclusion, the results of this study showed a trend of reduction of macular vascular density in superficial plexus in eyes operated for RRD, with more impressive decreases for Macula-OFF, even following a successful anatomical repair. Despite neither the choice of type of surgery or tamponade differently influencing vascular parameters, in the Macula-ON RRD group the SO tamponade led to the worst final BCVA compared to gas. This suggests a non-ischemic pattern in retinal impairment induced by SO. In addition, the duration of the SO tamponade is correlated with a decrease in VD in the SCP. Therefore, the use of SO should be preferred only in the treatment of complicated retinal detachments with a great importance of an early SO removal, in order to prevent vascular insufficiency in retinal capillary plexuses, also in long-term follow-up. Further investigations are needed with a wider sample and proper randomization of patients to confirm the vascular microarchitecture modifications and to improve the knowledge about vascular relationship with functional recovery.


Nurses, as the largest group of health professionals, have a key role in recognising, mitigating and preventing domestic violence. However, studies demonstrating effective undergraduate educational interventions are lacking. The research aim was to compare undergraduate nursing students’ knowledge and attitudes about domestic violence before and after an educational intervention on domestic violence and explore their views on the most useful teaching strategies.A quasi-experimental pre and post design was used to determine the impact of an educational intervention. Australian nursing students enrolled in a first-year undergraduate subject were invited to participate. The educational intervention included a 40-min pre-recorded lecture on domestic violence, and a two-hour face-to-face workshop facilitated by an expert, supported by readings. Students completed a pre- and post-intervention online anonymous survey using a validated instrument, the Inventory on Beliefs and Attitudes towards Domestic Violence. Wilcoxon signed rank tests were used to compare pre and post intervention results.p = .001, CI -.206—-0.067) post intervention. Of the 173 students who indicated post intervention which forms of education they found useful, 38.2% considered face-to-face tutorials to be the most useful education modality.Approximately 400 students completed the voluntary workshop; 198 students completed the pre survey, 176 completed the post survey and 59 (13.1%) completed both. Post intervention, participants indicated stronger agreement on 15 of 22 items. The inventory score became significantly more positive (Z = -3.196, This study demonstrates the effectiveness of even a small educational intervention in changing attitudes, and creating awareness and knowledge of the context, prevalence, perpetrators, and significant associated burden of illness related to domestic violence, and nurses’ responsibility to support victims. Internationally, domestic violence (DV), also called intimate partner violence, is violence that occurs between current or former intimate partners , 2, and Domestic violence occurs in all settings and among all socioeconomic, religious and cultural groups, and genders . IndigenDomestic violence is associated with significant negative health, economic, social, and emotional consequences, contributing to 5.1% of the burden of disease for Australian women aged 15–44 and 11% for indigenous women . In 2016Victims who receive an initial positive response to DV disclosure are more likely to seek further help to escape violence . Yet an Despite global support for the integration of DV content into undergraduate health professional degrees , 18, appIn Australia, less than 1% of nursing subject outlines specifically refer to DV , and undSeveral studies have reported on specific DV educational interventions in undergraduate health professional curricula. A meta-analysis on DV digital education for pre and post-registration health professionals indicated improved outcomes compared to no intervention or traditional teaching methods, although the level of evidence was poor . Only onSeveral studies have examined DV training delivered via simulation, however, most examined self-reported knowledge or attitudes post training , 31 withThis review demonstrates a lack of DV education in undergraduate nursing programs coupled with limited evaluation of the influence of specific education strategies on nursing students’ attitudes towards, and knowledge of DV. Our study aimed to evaluate the influence of an educational intervention on nursing students’ DV knowledge and attitudes and ascertain student perceptions on the most useful DV teaching strategies.A quasi-experimental pre- and post-intervention design was used to explore the impact of an educational workshop on undergraduate nursing students’ knowledge of, and attitudes towards, DV. The educational intervention included a 40-min pre-recorded lecture on DV, and a two-hour face-to-face workshop facilitated by a DV expert, supported by readings, and covered behaviours included in DV; its health impacts, prevalence, and contributing factors; the role of the nurse and importance of screening, and the use of appropriate language with DV victims. Four hundred and fifty-two nursing students enrolled in a first-year undergraduate subject were invited to participate by the Primary Investigator via an online announcement on their subject website where they were directed to a link to the pre- and post-workshop anonymous online surveys hosted on Qualtrics. Data were collected between August and October, 2019.The research was approved by the Southern Cross University Human Research Ethics Committee (ECN-17–009). Students were provided with information about the study, including ethical considerations and what participation would involve. Participation was voluntary and the survey was anonymous. Survey completion was considered to indicate consent.The Inventory on Beliefs and Attitudes towards DV, a validated tool , was useA student generated anonymous code was used to match pre- and post-intervention responses. Within-subject pre- and post-intervention statistical analysis involved self-reported ratings in response to statements about DV. Data were analysed in SPSS 25 . DiffereThe same facilitator delivered 15 workshops across three campuses to approximately 400 nursing students . One hundred and ninety-eight (198) students completed the pre-intervention survey, 176 completed the post-intervention survey and 59 (13.1%) completed both. Attendance was not compulsory. On average 26 nursing students attended each workshop. The majority were female (86.4%), aged 18–29 years (67.8%) and non-indigenous (93.2%)  post intervention. Items that were statistically more positive are noted in Table Cronbach’s alpha was 0.882 on both pre and post versions indicating good reliability. After the intervention, participants indicated stronger agreement on 15 of 22 items. The inventory score mean overall became significantly more positive  indicated post intervention which forms of DV education they found most useful  , didactiViolence against women is a global public health problem of epidemic proportions, requiring urgent action from the health sector to integrate issues related to violence into clinical training . To be aNursing students are best supported to do this in safe environments within their undergraduate teaching so they can practice their skills and develop confidence to effectively intervene in real peoples’ lives once they graduate and enter the health workforce. This is fundamental given the high rates of access to health care services by women who experience DV. Nurses are the biggest professional group of the health workforce and are the most preferred health professional women feel comfortable making a disclosure of DV to .Study limitations included the low numbers responding to both surveys and implementation at one university, which limit the ability to generalise the results. Even on anonymous online surveys, participants may also display socially desirable responding , which mThis study demonstrates the effectiveness of a small DV educational intervention in changing attitudes, and creating awareness and knowledge of the context, prevalence, perpetrators, significant associated burden of illness of DV, and nurses’ responsibility to support victims. Nurses need to feel comfortable to ask questions to identify DV and support women and children with interventions to reduce the burden of illness and save lives. Further research may identify the best combination of educational practices at undergraduate level to achieve this outcome.


Hypertension appears to be one of the commonest comorbidities in COVID-19 patients, although whether hypertensive individuals have a higher risk of severe COVID-19 compared with non-hypertensives is unclear. It is also unclear whether the absolute level of systolic blood pressure, or the type of anti-hypertensive medication is related to this risk. Analyses were conducted using data from the UK Biobank and linked health records. Logistic regression models were fitted to assess the impact of hypertension, systolic blood pressure (SBP) and medications on the risk of severe COVID-19. 16,134 individuals tested positive for severe acute respiratory syndrome-coronavirus, 22%  developed severe COVID-19 and 40%  were hypertensive. Hypertension was associated with 22% higher odds of severe COVID-19 (Odds ratio (OR) 1.22; 95% confidence interval (CI) 1.12, 1.33), compared with normotension after adjusting for confounding variables. In those taking anti-hypertensive medications, elevated SBP showed a dose-response relationship with severe COVID-19 , >180+mmHg versus 120-129mmHg ). SBP <120mmHg was associated with greater odds of severe COVID-19 . Angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers were not associated with altered risk of severe COVID-19. Hypertension is an important risk factor for COVID-19. A better understanding of the underlying mechanisms is warranted in case of more severe strains or other viruses in the future. A number of studies have reported that hypertension is one of the most common comorbidities amongst individuals with COVID-19. Moreover, the risk of developing severe COVID-19 is increased in hypertensive individuals compared with normotensives, possibly due to enhanced Angiotensin-converting enzyme-2 (ACE-2) receptor expression . Indeed,According to the 2018 Health Survey for England, 30% of males and 26% of females were living with hypertension in the UK, over 85% of whom were treated with blood pressure (BP) lowering medications . Of partTwo recent meta-analyses found no evidence of any effect of ACEi or ARBs on a range of COVID-19 outcomes, including severe disease and concluded that drugs targeting the RAAS should continue to be used , 15. MorParticipants from the UK Biobank, a large population-based cohort study, with linked primary health care records, death records and COVID-19 test results were included in these analyses. We used 04/04/2021 as the censor date for all records and test results used for these analyses. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations were used to guide the reporting of this analysis and the STROBE table made publically available.The UK Biobank is a longitudinal prospective study, initiated in 2006 and has recruited over 500,000 men and women aged between 40 and 69 years from the UK. It was established to investigate diseases in middle and older ages. At baseline (2006–2010) and over two further follow-up visits, a vast array of data, including physical measures, lifestyle data and biological samples, were collected. The UK Biobank additionally released primary care records for approximately 409,000 individuals for use solely in COVID-19 research, providing a wealth of further and longer-term health outcomes. This study was covered by the generic ethical approval for UK Biobank studies from the NHS National Research Ethics Service (Ref 11/NW/0382). This project is performed under project number 45885 and full written ethical approval has been granted via the UK Biobank.For the main analyses, hypertension status was determined using primary and secondary ICD10 codes for essential (primary) hypertension (I10) obtained from the UK Biobank cohort data including self-reported data, hospital episodes from Hospital Episode Statistics (HES) data as well as primary health care records for the individuals, where available. Read coded clinical terms (version 2 (V2) and clinical terms version 3 (CTV3), Systematised Nomenclature of Medicine–Clinical Terms (SNOMED—CT), The Phoenix Partnership (TPP) and TPP local codes via SystmOne and Egton Medical Information Systems (EMIS) local codes were mapped to ICD10 codes for linked health records where ICD10 codes were not provided. An individual was defined as taking BP lowering medication if they were prescribed BP lowering medications on their most recent prescription record. SBP, diastolic BP (DBP) and body mass index (BMI) were obtained from the primary care clinical records (see data supplement for code lists), where available, otherwise from the UK Biobank database, taking the BP reading closest to the analysis baseline (16/03/2020). Current smokers were those with a record of being a current smoker at their most recent UK Biobank visit. The Townsend deprivation index (TDI) calculated immediately prior to the UK Biobank baseline visit was used as a measure of socio-economic status (SES). Each individual was assigned a score corresponding to the output area in which their postcode was located, based on the national census output areas. The TDI consisted of z-scores calculated from the deprivation scores; a greater deprivation index represents a higher level of deprivation. Ethnicity was dichotomised into white and non-white  and sex was taken from the baseline UK Biobank visit. All data were assumed to be true at the analysis baseline. Comorbidity was defined as any of the following: peripheral vascular disease (PVD), myocardial infarction (MI), coronary heart disease (CHD) (excluding hypertension), angina, heart failure (HF) and arrhythmia or stroke at any one of the UK Biobank follow-up visits, prevalent at baseline or history of a CV comorbidity based on International Classification of Diseases 10 (ICD10) codes from hospital inpatient episodes or from primary health care records using primary or secondary positions of the diagnostic codes. Death due to COVID-19 was obtained using ICD10 codes from the death records, primary care records and hospital inpatient records. Further information including ICD10 code lists is included in the supplement.Medications were obtained from the UK Biobank database, defined using British National Formulary (BNF) codes and from primary care records using dictionary of medicines and devices (dm+d) codes and local healthcare codes (TPP/EMIS). Relevant medications included ACEi, ARBs and other anti-hypertensives, as well as statins, which are commonly taken in combination with anti-hypertensive medications. All antihypertensive medications not defined as ACEi or ARBs were defined as ‘other’. All medication lists were checked by a clinician. Further information on specific medication lists included in these analyses and code lists can be found in the supplement.th 2020, COVID-19 test results from SARS-COV2 polymerase chain reaction (PCR)-based swab tests, provided by Public Health England (PHE), were available to be linked to UK Biobank data. Our outcome of interest was severe COVID-19, defined as a positive test result requested from an in-patient unit  or a COVID-19 related cause of death based on primary ICD10 codes: U071 and U072, since 16 March 2020 from the PHE lab tests and HES data. On the World Health Organisation (WHO) clinical progression scale this was defined as score between 4 and 10  [From March 16or dead) . We also2, classified as normal, overweight, class 1 obesity and class 2 obesity, respectively. SBP was categorised by 10mmHg ranges, starting from <120mmHg up to 180+mmHg, with the reference category defined as: 120-129mmHg, based on data from the SPRINT study demonstrating that intensive SBP lowering to below 120mmHg, as compared with the traditional threshold of 140mmHg, is beneficial [Logistic regression was used to assess the association between hypertension, SBP or antihypertensive medication and the odds of severe COVID-19. All analyses were adjusted for age, sex, BMI, ethnicity, smoking status, diabetes status, SES and inflammation (C-reactive protein (CRP)) as these were proposed as potential confounders. To assess the direct effect of hypertension on COVID-19, we adjusted for intermediate variables on the causal pathway between hypertension and severe COVID-19, these included CV comorbidities and Stroke  broadening our classification of hypertension to additionally include any individual whose most recent BP measurement indicated SBP ≥140mmHg or DBP ≥90mmHg (ii) assessing the association between hypertension with death due to COVID-19 as the outcome, (iii) considering the effect of SBP on the odds of severe COVID-19 in both treated and untreated individuals with hypertension, (iv) using the average SBP since 2016, (v) considering treatment by mono- or combination therapy, as well as considering individuals who had not switched between ACEi and ARB treatment. We also looked at the association between DBP and severe COVID-19. When comparing ACEi and ARB treatments with other antihypertensive medications, individuals reported to have been treated with both ACEi and ARB drug classes concurrently in their most recent prescription were removed from the analyses. Rv4.0.0 for RStudio was used to perform all analyses.In all, 16,134 individuals who tested positive for, who were diagnosed with or who died due to COVID-19, with complete covariate data, were included in the analyses ). The chA total of 6,517 (40%) individuals had a diagnosis of essential hypertension, of whom 4,391 (67%) were treated , 59% combination therapy ) and 2,126 (33%) were untreated. The full breakdown of anti-hypertensive and other treatments is provided in The unadjusted odds ratio (OR) of the association between hypertension and severe COVID-19 was 2.33 ; . AdjustiIn hypertensive individuals receiving antihypertensive medications, there was a J-shaped relationship between the level of BP and risk of severe COVID-19, using a SBP level of 120–129 mmHg as a reference . A SBP oThere did not appear to be any difference in the risk of severe COVID-19 between individuals taking ACEi and those taking ARBs, or other antihypertensive medications . This waThe above analyses were repeated on a dataset of COVID-19 positive individuals, which additionally included any individual whose most recent BP measurement ≥ SBP 140mmHg or DBP 90mmHg, irrespective of their ICD10 coding status. Under this broader classification, 54.7%  individuals had hypertension, of whom 53.8%  were treated. Hypertension was present in 70.9%  of individuals with severe COVID-19 versus 50.1%  of individuals without severe COVID-19 and having hypertension was associated with a 38% higher risk of severe COVID-19 (OR): 1.38 ) , as was a SBP<120mmHg. However, the type of antihypertensive medication did not appear to influence the risk of severe COVID-19.The majority of the effect of hypertension on development of severe COVID-19 was direct. However, a modest proportion of the effect was mediated via CV comorbidities such as PVD, MI, CHD, arrhythmias and stroke. Broadening our classification of hypertension to additionally include those individuals with SBP ≥140mmHg or DBP ≥90mmHg showed that hypertension had a slightly higher association with severe COVID-19, compared with the association based on our original hypertension classification. Interestingly, very little of this effect was mediated via CV comorbidities, whereas age, smoking, being male, having a lower SES, higher BMI, being diabetic, as well as having hypertension were all associated with a higher risk of severe COVID-19.per se. Indeed, J-Shaped associations between SBP and CV event rates and mortality have been demonstrated previously [Our study also suggests that there are further effects influencing the severity of COVID-19 beyond a dichotomous diagnosis of hypertension. Individuals with a higher than target SBP, may be less healthy, less active, suffering more severe hypertension or have developed drug resistant hypertension, all suggesting that the effects of hypertension have already had detrimental physiological effects on the CV system, which in turn may offer some explanation for the higher risk of severe COVID-19 with uncontrolled SBP. Our analyses also showed that the association between SBP and severe COVID-19 was J-shaped, with a SBP<120mmHg associated with a 36% higher risk of severe COVID-19 in treated hypertensive individuals. This may be due to reverse causality, where low SBP levels may indicate poorer health, such that the occurrence of severe COVID-19 may be related to underlying disease rather than the level of SBP eviously . NeverthA key rationale for undertaking our study was the premise that alterations in circulating levels of ACE2, which the SARS-COV2 virus binds to for cell entry, may alter susceptibility to severe COVID-19. Indeed, upregulation of ACE2 occurs in hypertensive individuals treated with ACEi or ARBs and expression of ACE2 is increased in diabetics treated with ACEi or ARBs (2), hence concerns over prescribing these drugs during the coronavirus pandemic. It should be noted, however, that the evidence concerning upregulation of ACE2 with ARBs, in particular, is inconsistent, and varies by organ and receptor blocker 27). We found no association between use of ACEi or ARBs and severe COVID-19, in concordance with published data showing little association between RAAS drugs and the risk of severe COVID-19 compared with other BP lowering medications or no medications , 25–27. . We founper se. Many of the previous studies assessing the effects of RAAS drugs and COVID-19 have compared groups taking RAAS drugs with those taking no medications. However, we compared the effects of RAAS drugs with other BP lowering medications, more accurately reflecting the hypertensive population.The strengths of this study include the large cohort with detailed demographic variables, as well as large numbers of primary health care records available to be linked to the database providing recent covariate, prescription and diagnostic data. To our knowledge, this is the first study to focus on the effects of SBP, in addition to the effects of hypertension, We believe that censoring these data in early 2021 helped to reduce confounding from mutations that have increased transmissibility but reduced severity of disease, as well as effects of widespread vaccination and outpatient treatments. There are however, several limitations to the study and the data used for these analyses. The UK Biobank population is generally ‘healthier’ than the general UK population and has relatively few participants from ethnic minority groups, so generalisations to the wider UK population need to be undertaken with caution. Moreover, it was shown early on in the pandemic that the incidence of severe COVID-19 was 27% lower in the UK Biobank population compared with the wider population in England . HoweverThere are vast variations in testing frequency across the UK, so analysing the subset of those individuals who tested positive for COVID-19 would not eliminate all bias. Testing frequency and the incidence of COVID-19 also changed during the year of follow-up. However, we did not find any interaction with hypertension and testing season and our time-to-event analyses gave comparable results. Moreover, the findings of a previous study did not change substantially when severe COVID-19 patients were stratified by date of diagnosis . FinallyDue to the nature of the SARS-Cov2 virus affecting individuals in vastly differing ways, with many asymptomatic infected individuals, we focused on individuals who were hospitalised with COVID-19 and are likely to have suffered from severe symptoms from COVID-19. There are, however, additional limitations to the interpretations of these results. There may be individuals who tested positive for COVID-19, not as an in-patient, but who later were admitted to hospital, or who tested negative but later tested positive and admitted to hospital. Additionally, all inpatients were tested for COVID-19, so in some cases the primary reason for being admitted to an inpatient unit may not have been COVID-19.Even though the mortality rate due to COVID-19 has been hugely reduced over the last year due to mutation, vaccination and effective treatments, this study highlights the importance of hypertension as a risk factor for COVID-19, potentially increasing susceptibility to SARS-Cov2 via the RAAS. In particular, our data suggest that further research is needed into the mechanisms driving hypertension as a risk factor for COVID-19 in case of novel, more severe strains or other viruses in the future.Hypertension is a risk factor for COVID-19, the association between hypertension and COVID-19 was amplified if the individuals were treated and their BP remained uncontrolled. The odds of severe COVID-19 was not affected by medication type.S1 Checklist(DOCX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.