Tissue hypoxia is one of the main pathophysiologic mechanisms in sepsis and particularly in COVID-19. Microvascular dysfunction, endothelialitis and alterations in red blood cell hemorheology are all implicated in severe COVID-19 hypoxia and multiorgan dysfunction. Tissue hypoxia results in tissue injury and remodeling with re-emergence of fetal programming via hypoxia-inducible factor-1α (HIF-1a)-dependent and -independent pathways. In this context, thyroid hormone (TH), a critical regulator of organ maturation, may be of relevance in preventing fetal-like hypoxia-induced remodeling in COVID-19 sepsis. Acute triiodothyronine (T3) treatment can prevent cardiac remodeling and improve recovery of function in clinical settings of hypoxic injury as acute myocardial infarction and by-pass cardiac surgery. Furthermore, T3 administration prevents tissue hypoxia in experimental sepsis. On the basis of this evidence, the use of T3 treatment was proposed for ICU (Intensive Care Unit) COVID-19 patients . The rationale for T3 therapy in severe COVID-19 and preliminary experimental and clinical evidence are discussed in this review. It is well-recognized that changes in Thyroid Hormone (TH) metabolism occur in response to acute illness, known as non-thyroidal illness syndrome (NTIS). In this syndrome, an initial drop of circulating triiodothyronine (T3) levels is observed, and at later stages a decrease in both circulating L-thyroxine (T4) and T3 levels occurs. Numerous studies have reported that NTIS in acute illness is associated with poor outcomes and high mortality . SimilarTissue hypoxia due to disturbed microcirculation seems to be a unifying pathophysiologic mechanism in a spectrum of clinical conditions such as myocardial infarction, sepsis and trauma . In thisOn the basis of this evidence, the potential of T3 therapy in severe COVID-19 has been proposed and a clinical trial was initiated ,9. In thImpairment of microcirculation remains one of the main causes of tissue hypoxia and organ dysfunction in acute critical illness. Despite hemodynamic restoration and oxygen availability, there is a lack of improvement in organ perfusion both in sepsis and ischemia–reperfusion, such as myocardial infarction and by-pass surgery, due to the impaired microcirculation ,11. PersEndothelial injury and altered blood cell hemorheology are considered important pathogenetic mechanisms which may lead to impaired microcirculation . EndotheErythrocyte abnormalities are common in sepsis as well as in ischemia–reperfusion injury and have an impact on microcirculation. Erythrocyte aggregation initially occurs in areas of slow flow and impairs microcirculation. Impaired vascular flow enhances erythrocyte aggregation (a vicious circle), and this in turn causes sludging of blood and thrombosis . MoreoveTissue hypoxia can lead to tissue injury and remodeling, ultimately followed by organ failure. Interestingly, local lung hypoxia determines epithelial fate decisions during alveolar regeneration . In COVIAlthough hypoxia-induced apoptosis and remodeling remain the main pathophysiologic mechanisms of serious clinical conditions, effective therapies are not currently available. However, the recognition that hypoxia can induce pathologic remodeling in injured tissues via activation of fetal reprogramming has revived the interest in cell-based therapies and hormones, such as TH, which play a key role in organ maturation during development. In this context, the role of TH and its potential therapeutic use has been excessively studied in myocardial ischemia . At thisThe use of TH therapy in clinical practice has been limited due to the long-standing belief that TH can aggravate myocardial ischemia by increasing the metabolic rate and oxygen demand. However, over the past years, landmark experimental studies have challenged this long-standing belief, showing that the effects of TH are different in normal and diseased states (recently reviewed in ). In an Similar observations have been reported for other organs, such as the kidney and liver, in different experimental settings. TH treatment appears to induce protection against ischemic injury in the kidney ,46. T3 tTH regulates the microvascular function both directly and indirectly. T3, acting through thyroid hormone receptor α (TRα), induces endothelium-dependent vasodilation via endothelial nitric oxide synthase . The incThe therapeutic effect of TH on cardiac tissue hypoxia has been tested in experimental models and recently in clinical trials. TH pre-treatment can protect against myocardial ischemia–reperfusion injury in a pattern similar to ischemic pre-conditioning . High-doPost-ischemic cardiac remodeling appears to be associated with distinct temporal changes in TRs , and an Along this line, T3 therapy has favorable effects on cardiac dysfunction due to excessive inflammation driven by TNFα overexpression . TNFα ovThere is accumulating evidence showing that alterations in TH metabolism frequently occur in COVID-19 patients. In spite of the relatively high heterogeneity between studies, low TH levels on admission were associated with COVID-19 disease severity and mortality. Furthermore, the probability of finding low Free T3 (FT3) and low Thyroid-Stimulating Hormone (TSH) levels was related to disease severity in patients without known thyroid disease. It should be noted that blood samples, in most of the studies reported in the literature, were collected on patients’ admission or during the first three days of hospitalization either in the ward or in ICU.A retrospective study of 46 patients evaluated the thyroid function in two different groups of consecutive patients affected by COVID-19, one with pneumonia and the other with acute respiratory syndrome (ARDS) requiring ICU admission in comparison with euthyroid patients. COVID-19 patients showed a statistically significant reduction in FT3 and TSH levels measured one day after admission, and as far as ICU patients were concerned, a further statistically significant reduction in FT3 and TSH was found. These findings probably indicate a negative association between FT3 and TSH levels with disease severity at initial presentation .Another cohort study by Lui et al. , after aIn a cohort observational study of 196 patients, an NTIS pattern  was observed in 60% of ICU and 36% of ward patients. TSH, FT4 and T3 levels were measured within 24 h of admission and related to the severity of the disease, while the incidence of NTIS between SARS-CoV-2-positive and -negative patients was not different . FurtherIn a retrospective study including 236 patients, low FT3 on admission independently correlated with the severity of COVID-19 . SimilarIn a prospective study of 250 hospitalized COVID-19 patients, both FT3 and FT4 levels on admission were found to be lower in critically ill ICU patients compared to ward patients . Chen etIn the study by Campi et al., almost half of the 144 COVID-19 patients had normal TH both on admission and during the 3–7-day follow-up . In 39% Along this line, a retrospective observational study of 127 COVID-19 patients showed that serum FT3 levels on admission were lower in non-survivors compared to survivors among moderate-to-critical patients, and the low FT3 state on admission was associated with an increased risk of all-cause in-hospital mortality in these patients . FurtherThe potential mechanisms implicated in TH abnormalities in COVID-19 are not fully understood. It is likely that changes in the Hypothalamic–Pituitary–Thyroid (HPT) axis and iodothyronine deiodinase activity due to abnormal systemic inflammatory response may occur. Furthermore, SARS-CoV-2, via its direct action, can result in destruction of the thyroid gland . ThyroidConcomitant medications used in COVID-19 patients may also affect thyroid function. Systemic corticosteroids, mainly dexamethasone, are recommended for patients with severe and critical COVID-19 based on the guidelines of the World Health Organization (WHO) to control the exacerbated inflammatory response , though On the basis of the above evidence, a pilot randomized clinical trial (RCT) was designed to test the effects of early, high-dose LT3 in COVID-19 patients admitted to the ICU (ThySupport study). The detailed protocol of this study has been previously described . Co-morbDuring patient screening, 18 critically ill COVID-19 patients were not included in the study according to trial protocol requirements . All these patients were intubated and admitted to the ICU, a complete medical history was recorded, and laboratory tests including total T3, total T4 and TSH were performed during admission to the ICU, as depicted in The Thy-Support study is the first study which was designed to test the potential effects of LT3 administration after intubation in patients with severe COVID-19. Despite the limited number of patients included in the first interim analysis, important novel findings were observed, which warrant further investigation in future clinical trials. In this clinical setting, LT3 was used in a similar therapeutic regimen as in patients with myocardial infarction , and basPreliminary data from the Thy-Support study showed that LT3 treatment of ICU COVID-19 patients resulted in an acute drop in the ESR within 48 h of its administration along with a trend of a decrease in troponin levels . Furtherp = 0.3. Furthermore, a strong inverse correlation was found between the ESR and TAPSE/PASP ratio at 48 h ; see p = 0.31).Here, from the same patients included in Thy-Support, we provide additional findings probably indicating a novel effect of LT3 treatment on functional indices of the right ventricle (RV) in ICU COVID-19 patients. RV dysfunction is detected in nearly 39% of COVID-19 patients and is associated with a worse prognosis . RV dysfCollectively, these data probably indicate that LT3 in severe COVID-19 can improve RV–pulmonary artery circulation coupling, and this, at least in a part, may be mediated via changes in the erythrocyte aggregation and hemorheology. Historically, the link between hyperviscosity and right ventricular dysfunction was recognized by Sir William Osler, who treated the RV dilatation with phlebotomy .The Thy-Support study has been prematurely discontinued due to continuously changing therapeutic protocols for management of COVID-19 patients. These modifications in therapeutic protocols negatively affected patients’ recruitment. The Thy-Support study was designed to investigate the effects of T3 administered in COVID-19 patients with early mechanical respiratory support before the development of multiorgan failure and hemodynamic deterioration requiring high-dose vasoactive agents. However, after the use of novel therapies  patients’ mechanical respiratory support was delayed  and a grRecent research has revived the interest in the use of TH for combating hypoxia- induced injury and tissue remodeling. TH, once considered to be detrimental in hypoxia, is now realized to have reparative actions after hypoxic injury via evolutionary conserved mechanisms. In this context, experimental and clinical evidence signals for further investigation of the potential use of TH in sepsis and particularly COVID-19. Favorable effects of acute LT3 treatment have recently been reported in patients with myocardial infarction (Thy-Repair) without major adverse effects .The following patents are relevant to the work in this manuscript.PCT/EP2019/087056. L-triiodothyronine (T3) for use in limiting microvascular obstruction.PCT/4972/2021. A pharmaceutical composition comprising L-triiodothyronine (T3) for use in the treatment of tissue hypoxia and sepsis.


Infections of bacterial, viral, or fungal origin pose a major threat to patients with acute leukemia. Empiric antibiotic and antifungal treatment is a commonly used approach in leukemia patients with febrile neutropenia. To investigate the utility of flexible bronchoscopy (FB) with bronchoalveolar lavage (BAL) in acute leukemia (AL) patients with pneumonia who were already treated with broad-spectrum antibiotics and antifungal agents, we investigated bronchoalveolar samples of 88 patients. Our results indicate that despite broad-spectrum anti-infective treatment, in approximately half of all patients, pathogens could still be isolated in bronchoalveolar samples. Nevertheless, the detection of pathogens does not lead to frequent changes in anti-infective treatments, with most changes performed in patients with herpes simplex and influenza virus detection, and these pathogens might also be detected in less invasive examinations. The need for FB with BAL in patients with AL who are already receiving broad-spectrum empiric anti-infective treatment should therefore be weighed carefully.Aspergillus fumigatus detected most frequently. BAL-guided anti-infective therapy changes were performed in 15%. The detection of herpes simplex and influenza viruses were the main reasons for treatment changes. Despite broad-spectrum anti-infective treatment, in approximately half of all patients, pathogens could still be isolated in BAL samples. However, consecutive changes in anti-infective treatment were considerably less frequent, with most changes performed in patients with Herpes simplex virus and Influenza A detection. The need for FB with BAL in patients with AL receiving broad-spectrum empiric anti-infective treatment should therefore be weighed carefully.Despite therapeutic advances in the prevention and treatment of febrile neutropenia, acute leukemia (AL) patients still have considerable febrile neutropenia-related mortality. However, the diagnostic yield of flexible bronchoscopy (FB) and bronchoalveolar lavage (BAL) in acute leukemia patients is unclear. In this retrospective single-center study, we analyzed 88 BAL samples of patients with acute leukemia and pulmonary infiltrates in spite of treatment with broad-spectrum anti-infective agents. The aim was to investigate the impact of FB with BAL on detecting causative organisms, which would result in a change in treatment regimens. The median age was 59 years, and 86% had acute myeloid leukemia. In 47%, pathogens were detectable in BAL fluid , with  Infections of bacterial, viral, or fungal origin pose a major threat to patients with acute leukemia (AL), both at the initial diagnosis of AL and particularly during intensive chemotherapy due to prolonged, profound neutropenia . TherefoIn general, there are different approaches to treat leukemia patients with FN or signs of pulmonary infection: (a) Empiric (treatment without clear focus or detection of a pathogen), (b) pre-emptive (treatment with clear focus or detection of a pathogen), or (c) targeted (treatment after resistance testing of pathogens) approaches are used . An advaBy adding LDCT in cases of ongoing FN despite empiric anti-infective treatment, pneumonia can be detected in 50% to 95% of FN-patients in whom no infection focus was previously detectable ,11. AccoHere, we report on a single-center retrospective analysis with the aim to investigate the utility of FB and BAL and possible clinical implications in patients with AL and pulmonary infiltrates who are already empirically treated with broad-spectrum anti-infective agents.Aged ≥ 18 years.Diagnosed with either AML or acute lymphoblastic leukemia (ALL).Pneumocystis jirovecii  v5.0 grading . High-riClinical data regarding treatment and disease characterization were collected from the patient’s electronic medical records. Laboratory investigations, LDCT, and FB with BAL were obtained during the clinical routine.Retrospective data collection was performed in accordance with local legal requirements and was reviewed and approved by the Ethics Committee of the Medical Council of Hamburg (vote number PV7335). Informed consent was waived by the ethics committee since only pseudonymous data were analyzed and published.FB with BAL was performed in a standardized manner by an experienced pulmonologist. In the preparation of all procedures, an LDCT was reviewed to assess the characteristics and location of lung parenchymal changes. Coagulation studies and platelet counts were obtained to assess the risk of bleeding. In the case platelet count was below 20,000 per µL, a platelet transfusion was administered prior to bronchoscopy. Intravenous sedation for the procedure was provided according to patient preference. It was achieved using a bolus application of 2 mg of midazolam and repetitive bolus applications of 10 to 20 mg of propofol every two to three minutes. Topical anesthesia was applied to the laryngeal, tracheal, and bronchial mucosa using 5 mL of lidocaine 0.8% applied through the working channel of the bronchoscope in aliquots of 1 mL. A flexible video bronchoscope  passed through the mouth was used for the procedures. After inspection of the tracheobronchial tree, the bronchoscope was advanced into the appropriate airway. BAL was then performed using normal saline at room temperature, being instilled in aliquots of 20 mL and then aspirated. After completion of the procedure, BAL fluid was immediately sent to the laboratory for microbiological testing.Pneumocystis jirovecii PCR, Cytomegalovirus PCR, and Herpes simplex virus (HSV) PCR. Furthermore, multiplex PCR for common respiratory viruses was performed including adenoviruses, bocaviruses, coronaviruses , enteroviruses, human metapneumovirus, Influenza A and B, Parainfluenza 1-4, Respiratory syncytial virus, and Rhinovirus. Multiplex PCR for Mucor mucoralis was additionally performed in selected cases if deemed clinically appropriate, but not on a regular basis, and was therefore not analyzed in this study. All detected viruses were assigned to be pathologic, and for the detection of HSV, the relevant viral load was defined as >50,000 copies per mL. Bacteria that are part of the normal oral and pharyngeal flora and those that could be detected in such a small number that a more precise specification was not possible were defined as non-pathogenic. Regarding the detection of fungi, yeasts and not otherwise specified Penicillium species were defined as non-pathogenic  and GraphPad Prism, version 9 for macOS . Continuous values are presented as the median with interquartile range (IQR). Categorial variables are expressed as a number with percentages (%).The primary objective of this study was to determine the rate of pathogenic microorganisms detected in BAL fluid that led to a change in the anti-infective treatment approach in AL patients who are already under broad-spectrum antibiotic and antifungal therapy.In total, 88 patients met the inclusion criteria. Fifty-nine patients (67%) were male, and the median age at FB was 59 years (IQR: 48–68). The underlying disease was AML in 76 patients (86%) and ALL in 12 patients  with newly diagnosed AL prior to the start of chemotherapy, in 51 patients (58%) during induction chemotherapy, in 7 patients (8%) during consolidation chemotherapy, in 21 patients (24%) during salvage-chemotherapy, and in 8 patients (9%) during non-intensive chemotherapy. At the time of BAL, profound neutropenia was present in 83 patients (94%) and high-risk neutropenia (defined as neutrophile count <500/µL over 7 days) in 38 (43%). The median duration of neutropenia was 15 days (IQR: 10–25) before FB. The median value of the C-reactive protein (CrP) on the day of BAL was 162 mg/L (IQR: 105–217). Fever was observed in 28 patients (32%), and 10 patients (11%) had subfebrile body temperature. In 25 patients (28%), LDCT revealed typical infiltrates of lobar pneumonia. Atypical infiltrates were found in 63 cases (72%). Invasive mechanical ventilation due to pneumonia was required in 17 patients (19%), and a total of 12 patients (14%) died from respiratory insufficiency within 30 days after the onset of pneumonia. None of the patients had bronchoscopy-associated complications. In particular, no bleeding events occurred during FB.Stenotrophomonas maltophilia ; for viruses, Herpes simplex virus 1 ; and for fungi, Aspergillus fumigatus . None of the detected bacterial strains were identified as a strain with extended or multi-resistance against anti-infective compounds.At least one pathogen was identified that most likely caused the infection episode in 41 cases 47%, . PathogeClostridium difficile intestine infection. For antifungal treatment, in the majority, sixty-eight patients (77%), amphotericin B was administered, whereas nine patients (10%) were treated with caspofungin, seven patients (8%) were treated with voriconazole, three patients (3%) with posaconazole, and one patient (1%) with anidulafungin. Different therapeutic approaches were used due to potential interactions with agents to treat AML or ALL, other contraindications, or patients’ intolerance.All patients were treated with broad-spectrum antibiotic and antifungal agents according to hospital-based standard operation procedures for patients with FN . SeventyP. jirovecii was administered irrespective of the occurrence of FN. Two patients (2%) received additional therapy with oseltamivir due to previously laboratory-confirmed influenza virus infection  by changing aciclovir dosage. In five patients (5%), Influenza A or B virus was detected and led to therapeutic consequences, with the administration of oseltamivir in three patients, whereas the remaining two patients were already under oseltamivir treatment due to positive nasopharyngeal swabs prior to BAL. Regarding the detection of fungi, a therapeutic consequence was observed in one patient (1%) in whom Pneumocystis spp. Were detected in BAL. This patient received cotrimoxazole in the therapeutic dosage  were covered by calculated antimicrobial therapies already administered in this patient cohort. None of the detected bacterial strains had multi-drug resistance. Negative microbiological BAL fluid did not result in de-escalation or withdrawal of any empiric anti-infective treatment in accordance with our local standard operating procedures regarding FN in patients with hematological malignancies.In 74 patients (84%), FB with BAL assessment did not lead to any therapeutic consequences because no pathogen was detected that was not covered by empiric anti-infective treatment. Regarding viral infections, treatment change could be observed in nine (10%) patients diagnosed with c dosage . Of noteDespite all the advances that have been made in the prevention and treatment of FN, AL patients still display the highest FN-related in-hospital mortality among all cancer patients, mainly due to a prolonged period of profound neutropenia ,2,3,4,5.Aspergillus fumigatus was the most detected pathogen albeit the empiric anti-fungal treatment in every patient, indicating the high risk of invasive aspergillosis in patients with AL underlying previous reported data [Of note, despite the extensive empiric anti-infective treatment in our study population, in nearly every second BAL fluid (47%), relevant pathogens could be isolated. ted data ,22,25. Rted data . Marchested data . Moreoveted data .BAL findings resulted in subsequent anti-infective treatment changes in 15% of patients, which is in line with one of the very few studies investigating the impact of BAL in patients with AL under extensive anti-infective therapies, showing a low rate of 9.3% of BAL-guided treatment changes . In all Herpes simplex virus 1 or Influenza A/B virus, nasopharyngeal swabs, throat rinses, and/or sputum might be a reasonable method prior to BAL to detect herpes and influenza viruses. By excluding these cases in which pathogens might be detected non-invasively, only in 2 out of 88 patients (2%) were BAL-guided therapy changes observed. Even if a primary impact on the anti-infective treatment approach in these patients is seen in a minority in our cohort, there are some aspects that should be discussed when considering the necessity of FB with BAL: Leukemia patients undergo several therapy cycles, and the majority of patients are allocated to allogeneic stem cell transplantation for consolidation therapy. The isolation of pathogens from BAL or detection of fungal pneumonia in LDCT during infection periods in previous cycles of chemotherapy might lead to different prophylactic approaches when a patient undergoes, for example, the second induction chemotherapy or an allogeneic stem cell transplantation.Since most treatment changes in our patient cohort were required due to the detection of Although there are already several publications on the utility of BAL in hematological patients with and without FN, we herein investigated one of the few diagnostic yields of BAL in a large, homogeneous collective consisting only of patients with AL and subsequent prolonged and profound neutropenia. In addition, all patients included in this study were treated with broad-spectrum empiric anti-infective therapies and consistent anti-infective prophylaxis leading to a minimization of a study population selection bias. Furthermore, patients who previously underwent allogeneic stem cell transplantation were excluded. Moreover, in all patients, FB with BAL was based on the most recent LDCT findings to increase the possible utility of BAL. Nevertheless, the question remains unanswered as to why, in 53% of patients with radiological infiltrates, no pathogens could be detected in LDCT-finding conducted BAL. Compared to other studies in non-hematological patients, where BAL is used for the confirmation of diagnosis , the rate of negative BAL results is high in our cohort . This miMucor mucoralis. Further large prospective studies are necessary for this patient cohort, comparing BAL-guided anti-infective treatment versus empiric anti-infective treatment, to establish predicting factors for BAL-guided treatment changes.Due to the retrospective study design, there is a risk of potential selection bias and residual confounding factors in this analysis, particularly due to a missing control group. Moreover, even though we did not observe any multi-resistant bacteria, our observations cannot thoroughly be transferred to other European or non-European countries based on different local resistances. Furthermore, microbiological testing was limited to frequent opportunistic fungi and viruses and did not regularly include testing for Our results indicate that despite broad-spectrum anti-infective treatment approaches, in approximately half of all patients with AL and FN and/or increased CrP levels and radiologically confirmed diagnosis of pneumonia, pathogens could still be isolated in BAL samples. Nevertheless, the detection of pathogens did not lead to frequent changes in anti-infective treatments, with most changes performed in patients with herpes simplex and influenza virus detection. Although no FB-related complications occurred in our study population, these pathogens might also be detected in less invasive examinations. In conclusion, the need for FB with BAL in patients with AL who are already receiving broad-spectrum empiric anti-infective treatment should be weighed carefully.


The present study aims to explore risk factors related to in-stent restenosis (ISR) in elderly patients with coronary heart disease and type 2 diabetes within 2 years after the first drug-eluting stent (DES) implantation.This case-control study retrospectively analyzed the clinical data of patients with coronary heart disease and diabetes undergoing percutaneous coronary intervention (PCI) in Shenzhen Sun Yat-sen Cardiovascular Hospital between January 2010 and March 2020. Univariate and multivariate models were used to assess independent factors for DES-ISR. Categorical principal component analysis of clinical variables was performed to determine important components for DES-ISR. Nomogram was constructed to quantitatively predict the probability of DES-ISR development. The diagnostic potential of clinical variables was determined by receiver operating characteristic curve.2, fasting blood glucose ≥6.5 mmol/L, multivessel coronary artery disease, coronary artery diffuse disease, PCI operation time (≥60 min), emergency PCI were associated with ISR. High Nomogram score was associated with the increased risk of ISR. Further analysis of the validation cohort showed that higher levels of HbA1c-coefficient of variation (CV) were significantly associated with the increased risk of ISR. HbA1c-CV exhibited good predictive ability for ISR in the validation cohort.In the derivation cohort, 1,741 cases were included in this study, and a total of 227 pairs of cases and controls were generated by propensity score matching. In the validation cohort, 102 cases were included with 19 cases (18.6%) with DES-ISR. Glomerular filtration rate <60 ml/min/1.73 mIn conclusion, the fasting blood glucose level during the perioperative period of emergency PCI and the long-term variation of HbA1c during the follow-up period are related to the incidence of DES-ISR and the degree of stenosis. Reducing blood glucose fluctuations may decrease the risk of DES-ISR. Cardiovascular disease is the first major causes of deaths among all urban and rural residents in China according to China Cardiovascular Disease Report 2019, and coronary heart disease affects around 11 million people in China . CoronarIn-stent restenosis (ISR) is an important cause of stent failure and repeated revascularization, and is the main limiting factor for PCI treatment . AlthougThis study included 1,843 patients (≥65 years old) with coronary heart disease and diabetes undergoing PCI in Shenzhen Sun Yat-sen Cardiovascular Hospital between January 2010 and March 2020. All patients provided written and informed consent. The institutional review boards at Shenzhen Sun Yat-sen Cardiovascular Hospital approved the present study.The inclusion criteria were as follow: (1) PCI was conducted according to the Chinese Guidelines for Percutaneous Coronary Intervention (2016). (2) Diabetes was diagnosed according to the National guidelines for the prevention and control of diabetes in primary care (2018). (3) Patients received DES implantation. (4) Patients received PCI for the first time in Shenzhen Sun Yat-sen Cardiovascular Hospital. (5) The duration of follow-up ≥24 months. (6) During follow-up, ISR was diagnosed by coronary angiography (CAG) and requiring target lesions revascularization (TLR). The exclusion criteria were as follow: (1) Patients received PCI in other hospitals. (2) Patients received BMS implantation. (3) Patients received CABG or stent grafting during the follow-up period. (4) Patients received revascularization treatment due to stent fracture.All clinical data were collected from the follow-up database of patients in Shenzhen Sun Yat-sen Cardiovascular Hospital. The clinical data including the basic characteristics of the patient, past medical history, medication history, CAG characteristics, and first PCI characteristics. All patients were treated with a standardized PCI strategy. Oral aspirin (600 mg) combined with clopidogrel (300 mg) were administered before emergency PCI. Oral aspirin (100 mg/day) combined with clopidogrel (75 mg/day), or ticagrelor (90 mg twice daily) after emergency PCI and elective PCI were given to patient for >1 year. The target lesion revascularization is defined as the stent placement or balloon expansion at the site of the stent due to angina pectoris. ISR is defined as the stenosis of the stent segment vessel lumen ≥50% as confirmed by CAG , 16. AllIn the derivation cohort, 1,741 patients with coronary heart disease and diabetes undergoing PCI in Shenzhen Sun Yat-sen Cardiovascular Hospital between January 2010 and January 2016 were included. In this cohort, 233 DES-ISR patients and 1,508 non-DES-ISR patients were included in the study. Propensity score matching  was performed to control for potential bias. Propensity scores were calculated using a logistic regression model with access route as the dependent variable. Independent variables included age and gender. In order to prevent poor matches, the caliper was set as 0.03.t-test or Mann-Whitney U-test when group distributions were skewed. Categorical variables were presented as percentages and relative frequencies; comparisons were conducted using chi-square statistics or Fisher exact test as appropriate. Multivariable Cox proportional hazards regression models with adjustments for confounding factors were used to assess the associations of clinical parameters with MACEs. Correlation analysis was evaluated by Pearson Correlation analysis. Correlations between clinical variables were detected by non-linear categorical principal component analysis (CatPCA). The CatPCA benefits from optimal data scaling and is suitable for data recorded with uncertain units , and the Nomogram was constructed using R software version 4.0.2. Continuous variables were presented as mean ± standard deviation; comparisons were conducted by Student's in units . Origina2, dyslipidemia, multi-vessel coronary heart disease (CHD), diffuse CHD and emergency PCI, number and total length of implanted stent, operation duration for PCI were significantly higher, the rate of single-vessel CHD and minimum diameter of implanted stent was significantly lower in the DES-ISR group than that in the non-DES-ISR group , PCI operation duration and type of PCI were significantly associated with the occurrence of DES-ISR in the PSM cohort  exhibited no significant effect on the risk of DES-ISR . High FPHbA1c-CV was significantly associated with the risk of developing DES-ISR, and the higher levels of HbA1c-CV was correlated with higher rate of DES-ISR . In the The diagnostic potential of CRP level was further assessed with ROC analysis. In the validation cohort, the CRP level was significantly higher in DES-ISR group than that in the non-DES-ISR group . The ROCCategorical principal component analysis of clinical variables was performed to determine important components for DES-ISR in the validation cohort. Based on CATPCA analysis, PC1, PC2, and PC3 explained 20.90, 16.14, and 10.43% of the total variation of the data of the validation cohort . The mos2, fasting blood glucose ≥6.5 mmol/L, multivessel coronary artery disease, coronary artery diffuse disease, percutaneous coronary intervention (PCI) operation time (≥60 min), and emergency PCI were associated with ISR. High Nomogram score was associated with the increased risk of ISR. Further analysis of the validation cohort showed that higher levels of HbA1c-coefficient of variation (CV) were significantly associated with the increased risk of ISR. HbA1c-CV exhibited good predictive ability for ISR in the validation cohort.This case-control study retrospectively analyzed the clinical data of patients with coronary heart disease and diabetes. Our results showed that glomerular filtration rate <60 ml/min/1.73 mCompared with BMS, DES minimizes new intimal hyperplasia, and the coating on DES can cause delay in intimal hyperplasia. This intimal hyperplasia can last for many years. Therefore, the time when DES-ISR appears has been largely extended for several years after stent implantation . For DESStudies have identified many factors that are associated with DES-ISR. Our analysis exhibited inconsistency with previous studies, which indicates that there are more accurate prediction methods for elderly diabetic patients, and the prediction model for non-specific populations is likely to miss important predictors for elderly diabetic patients. Age (<60 years) and diabetes have been confirmed to be important predictors of ISR . Our res2 , Shenzhen Fundamental Research Program (No. JCYJ20180302173849459), the Fund of “Sanming” Project of Medicine in Shenzhen (No. SZSM201811096) and the Shenzhen Strategic Emerging Industry Development Special Fund (No. ZDYBH201900000007).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Older individuals with subjective cognitive decline (SCD) perceive that their cognition has declined but do not show objective impairment on neuropsychological tests. Individuals with SCD are at elevated risk of objective cognitive decline and incident dementia. Non-pharmacological interventions  are a potential strategy to maintain or improve cognition in SCD, which may ultimately reduce dementia risk.MAge = 72.7 years; 64% female) were recruited from memory clinics in four European countries and randomized to one of two group-based, 8-week interventions: a Caring Mindfulness-based Approach for Seniors (CMBAS) or a health self-management program (HSMP). Participants were assessed at baseline, post-intervention (week 8), and at 6-month follow-up (week 24) using a range of cognitive tests. From these tests, three composites were derived—an “abridged” Preclinical Alzheimer’s Cognitive Composite 5 (PACC5Abridged), an attention composite, and an executive function composite. Both per-protocol and intention-to-treat analyses were performed. Linear mixed models evaluated the change in outcomes between and within arms and adjusted for covariates and cognitive retest effects. Sensitivity models repeated the per-protocol analyses for participants who attended ≥ 4 intervention sessions.This study utilized data from the SCD-Well randomized controlled trial. One hundred forty-seven older adults with SCD . There was weaker evidence of an improvement in attention but no effects on executive function.Across all cognitive composites, there were no significant time-by-trial arm interactions and no measurable cognitive retest effects; sensitivity analyses supported these results. Improvements, however, were observed within both trial arms on the PACC5Two non-pharmacological interventions conferred small, non-differing improvements to a global cognitive composite sensitive to amyloid-beta-related decline. There was weaker evidence of an effect on attention, and no evidence of an effect on executive function. Importantly, observed improvements were maintained beyond the end of the interventions. Improving cognition is an important step toward dementia prevention, and future research is needed to delineate the mechanisms of action of these interventions and to utilize clinical endpoints .ClinicalTrials.gov, NCT03005652.The online version contains supplementary material available at 10.1186/s13195-022-01057-w. Individuals with subjective cognitive decline (SCD) perceive that their cognition has worsened but do not show impairment on standardized cognitive tests used to detect mild cognitive impairment (MCI) and dementia . It is iIn response to this accumulating evidence, an increasing number of randomized controlled trials (RCTs) have targeted cognitive and affective outcomes in people with SCD, with the ultimate aim of attenuating dementia risk. However, two systematic reviews concluded that existing RCTs in SCD were of variable quality and that the evidence of efficacy across targeted outcomes was limited , 10. BotFrom a theoretical perspective, mindfulness-based interventions (MBIs) appear a promising approach for ameliorating the cognitive and affective features of SCD. The core components of MBIs are three taught practices , conceptualized as means of promoting attentional and emotional self-regulation . By virtHere, we report the results of a multinational RCT of a novel MBI versus an HSMP in individuals with SCD, focusing on objective cognitive function outcomes. Given that limited existing work has been conducted in this area, our hypotheses were based on prior meta-analyses which evaluated MBIs in a range of populations, including healthy older adults and individuals with MCI , 20. WhiSCD-Well was a European multicenter, observer-blind RCT with two intervention arms: an MBI named the Caring Mindfulness-based Approach for Seniors (CMBAS) and an HSMP. The study was conducted across four sites . The trial was registered on ClinicalTrials.gov (NCT03005652). SCD-Well was sponsored by the French National Institute of Health and Medical Research (INSERM), and ethical approval and regulatory authorizations were obtained at each site. Written informed consent was obtained from all participants (please see the “Declarations” section for further details). Further details pertaining to the study’s eligibility criteria, interventions, and assessments are available in the trial protocol , as wellDue to the group-based nature of the interventions, participants were recruited in two waves at each site. Briefly, participants fulfilling the eligibility criteria were invited to the baseline visit (week 0) for cognitive and behavioral assessments. They were then randomized with a 1:1 allocation, using permuted block sizes of 4 and 6, stratified by site and centralized via a secure electronic case report form. Participants were invited to meet their intervention facilitator at a pre-class meeting, during which their trial allocation was revealed. The assessments were repeated at both post-intervention (week 8) and 6-month (week 24) follow-up visits. The size of each intervention group ranged from 7 to 13 participants.Recruitment took place from March 2017 through January 2018. For study inclusion, participants were required to fulfill the research criteria for SCD .The CMBAS followed the general format of a mindfulness-based stress reduction program, consisting of a pre-class interview, eight weekly group-based sessions of 2 h, and a half-day of meditation practice in the sixth week of the program to help consolidate learning. In addition to standard MBI practices , CMBAS pThe HSMP followed the same format and structure as CMBAS and was matched in administration, dosage, and duration . The intervention was based on a manual for living with chronic health conditions ; the manEach site had two clinically trained facilitators experienced in leading group-based programs, one for each intervention. Facilitators received their respective intervention manual, instructions, and intervention-specific training prior to the start of the study. After each class, facilitators completed a self-report checklist  to indicWe calculated three composite measures of cognition from the broad battery of tests that were administered  in SCD-Well, as only one episodic memory measure was available. The tests constituting the PACC5Abridged were the Rey Auditory Verbal Learning Test , the WAIS-IV Coding subtest (raw score), category fluency for animals , and the Mattis Dementia Rating Scale-2 . The primary cognitive functions assessed by these measures are episodic memory, attention, semantic fluency, and global neuropsychological status, respectively. To create the global composite, each constituent score was first standardized, by subtracting the baseline pooled sample mean from each individual’s score at each available time point, and the result was divided by the baseline pooled standard deviation. We then took the average of these four scores, yielding the PACC5Abridged.Donohue and colleagues  devised We also calculated an attention cognitive composite (“attention composite”). To calculate this measure, we first standardized scores from the Trail-Making Test Part A , a “naming” condition from the Stroop requiring participants to name the color of rectangular stimuli arranged in a grid (completion time in seconds), and WAIS-IV Coding (raw score). TMT-A and Stroop scores were multiplied by minus one, so that higher scores reflected better performance. We took the average of these three standardized scores, yielding the attention composite.Lastly, we calculated an executive function cognitive composite (“executive composite”). To calculate this measure, we first standardized scores from the TMT-B (completion time in seconds), letter fluency for “P” , and a Stroop “interference” score (time in seconds). The Stroop interference score was calculated by subtracting the completion time of the Stroop naming condition (see the previous paragraph) from the completion time of a Stroop “incongruent” condition requiring participants to name the ink color of color words, where the ink color was incongruent with the word itself. TMT-B and Stroop interference scores were multiplied by minus one, so that higher scores reflected better performance. We took the average of these three standardized scores, yielding the executive composite.Depressive symptoms were assessed using the 15-item Geriatric Depression Scale ; higher scores reflect greater depressive symptoms . Anxietyn = 147). For the present analyses, we calculated the statistical power for the PACC5Abridged only, as this was considered the main outcome. For an effect size of 0.25 on the PACC5Abridged, the power achieved by the study was 33%; for an effect size of 0.50, the power was 87%  from pre- to post-intervention between intervention arms. This resulted in a minimum total number of 128 (64 per group) , which tAnalyses were conducted according to both per-protocol (PP) and intention-to-treat (ITT). In the “Results” section we report PP analyses and note where these differ from ITT. The PP analyses included all available  cognitive test data; the main reasons for missingness were participants not attending the post-intervention and/or follow-up visits due to dropping out or being lost to follow-up  were multiply-imputed using chained equations  for each arm/outcome/time point, as well as change (Δ) in composite scores within and across groups, were produced using emmeans v.1.7.0. Multivariate imputation by chained equations was performed using mice v.3.14.0. For all analyses, uncorrected p-values are reported and were deemed statistically significant at < 0.05.Analyses were conducted in Individuals undergoing repeated cognitive testing on the same measures are likely to learn task characteristics, which may result in improved performance over time. This study did not include an inactive comparator condition, and thus, cognitive retest effects could not be quantified empirically; we thus adjusted for these in statistical analyses. Cognitive retest effects were modeled based on recommendations . Among tData collection was completed on September 18, 2018. A total of 147 participants with SCD  were randomized. See Table In the CMBAS condition, checklists indicated that 87.5% of sessions included all planned elements, with facilitators missing no more than one element in a session. All missed elements were minor in nature . In the HSMP condition, checklists indicated that facilitators covered all planned elements without exception.No significant differences were observed between the trial arms for mean (SD) CEQ-credibility  or CEQ-expectancy . Similarly, there were no significant between-arm differences for the mean number of intervention sessions attended , the proportion of participants who attended ≥ 4 intervention sessions , or the proportion of participants who reported continued engagement with CMBAS/HSMP activities between the post-intervention (week 8) and follow-up (week 24) visits . Furthermore, one hundred six (72%) participants completed home practice on at least four occasions .Abridged were equivalent; the following results describe the PP analyses . The interaction between time and trial arm was non-significant, indicating that trajectories did not differ between arms . The LMM using a factorial time metric  revealed that, while PACC5Abridged performance did not significantly change between baseline and post-intervention (week 8), scores significantly increased from baseline to follow-up . The visit-by-arm interaction was not significant at post-intervention nor follow-up. The improvement in PACC5Abridged at follow-up was thus comparable in both arms . These findings were substantively unchanged in sensitivity analyses. Table Abridged and other composites; these data are presented visually in Fig. Findings from the PP and ITT models for the PACC5= 0.31 0.1, 0.41).= 0.31 0.1, 0.41).The linear time LMM did not show an effect of time on attention composite scores in either the PP or ITT analyses, neither was there a significant interaction between time and trial arm. The factorial time LMM did not show a significant change for this outcome between baseline and post-intervention (week 8) in PP analyses, but the ITT model showed a significant improvement over this interval. Moreover, both PP and ITT analyses showed that attention scores increased overall from baseline to follow-up visit . The visit-by-arm interaction was not significant at post-intervention nor follow-up in either analysis. Considered separately, the within-group change in attention composite scores from baseline to follow-up was not significant for either arm . These findings were substantively unchanged in sensitivity analyses.The PP and ITT analyses yielded equivalent findings for the executive composite. The linear time LMM did not show an effect of time on executive composite scores, neither was there a significant interaction between time and trial arm. The results from the factorial time LMM supported these findings; scores on the executive composite did not increase from baseline to post-intervention (week 8), nor from baseline to follow-up (week 24). There were no significant interactions with the trial arm. These findings were substantively unchanged in sensitivity analyses.Abridged, in the CMBAS arm only, female  sex predicted significantly greater PACC5Abridged gains; higher CEQ-credibility ratings were also associated with greater increases in global cognition in CMBAS participants. For the attention composite, lower baseline scores in the CMBAS arm were associated with greater gains on this measure. HSMP participants at the Lyon (versus Barcelona) site also showed greater attentional improvement. For the executive composite, lower baseline scores in both arms were associated with greater gains. Lower GDS-15 scores in the CMBAS arm were also associated with greater executive composite gains. See Additional file Analyses (according to PP) were conducted using linear regression to determine the strength of association between participant baseline characteristics and change on each composite during the study (for each arm separately). The candidate predictors were age, sex, education, site, GDS-15, STAI-A, CEQ-credibility, CEQ-expectancy, and the baseline composite score. Considering the PACC5Abridged), attention, and executive functioning. Scores on the PACC5Abridged, a measure previously shown to be sensitive to early Aβ-related cognitive decline [Abridged scores corresponded to a small effect size . These results were unchanged for the subset of participants who attended four or more intervention sessions. Therefore CMBAS, like other MBIs [SCD-Well was a large, multicenter RCT that randomized individuals with SCD to one of two 8-week non-pharmacological interventions. Here, we report outcome data for three composites, measuring global cognition  and follow-up (both PP and ITT) in the factorial time models. A possible explanation for this discrepancy is that the adjustment for cognitive retest effects  attenuated effects in the linear time model. While some of the analyses using factorial time showed an increase in attention scores overall, none indicated improvement for either arm individually . For example, the baseline to follow-up analyses showed significant attentional improvement overall, but not for either arm separately. This suggests that the within-group analyses may have been underpowered. In summary, on the basis of the mixed findings reported above, we conclude that there was weak evidence of an effect of both interventions on attention. Neither linear nor factorial time models identified an effect of either intervention on the executive composite.Abridged, given the various cognitive functions assessed by its constituents. Contrary to our prediction, PACC5Abridged scores improved to a similar degree in both trial arms. Returning to the prior meta-analysis, half of the comparators included in the quantitative synthesis were inactive, and subgroup analyses suggested that the overall effect was driven by results from inactively controlled trials [To support the interpretation of our findings, we considered the results from recent meta-analyses which pooled cognitive data from MBI RCTs. While a number of quantitative syntheses exist, some excluded older adults , did nod trials . IntegraTheoretical frameworks , we were unable to quantify cognitive retest effects empirically. When we controlled for these statistically we continued to observe increases in PACC5 effects , whereasAbridged. The first relates to the interventional elements common to both the CMBAS and HSMP; these include increased social contact, gentle exercise, behavioral activation, and input from caring professionals [Abridged gains to specific interventional elements. Nevertheless, considering the topics taught in the HSMP [Abridged gains include improved sleep [Two types of mechanism, shared and specific, may account for the intervention-related improvements in PACC5ssionals , 43. Parssionals . The secssionals , 40. Thethe HSMP , possibled sleep , increased sleep , and/or ed sleep . In the The present research has a number of strengths. SCD-Well remains one of a limited number of RCTs which recruited individuals with SCD, achieved a larger sample size than comparable studies, used blinded outcome raters, and included an active comparator which matched the MBI on a number of key characteristics. Moreover, the study measured the outcomes at both post-intervention (week 8) and follow-up week 24), administered a comprehensive battery of cognitive measures across a range of domains, and is one of the first reported RCTs to include a version of the PACC as an outcome. The study thus addressed a number of limitations noted in previous reviews of the MBI  and SCD , adminisThe study also has limitations. Firstly, the data reported here were secondary outcomes of the SCD-Well RCT, and we did not correct statistical models for multiple comparisons. Given the increasing interest in MBIs as a novel strategy to reduce cognitive decline in older persons , 40, it Abridged, a composite sensitive to Aβ-related decline; gains were maintained for at least 4 months post-intervention. In contrast, there was weaker evidence for salutary effects across both arms on an attention composite, and no effect on executive function. Integrating both the current and previous research findings, cognitive retest effects may have contributed to the observed gains, but could not account for these entirely. These results are encouraging and add to the recognized benefits of MBIs on psycho-affective outcomes in older adults [In conclusion, we studied the effects of two non-pharmacological interventions, based on mindfulness and health self-management respectively, on a range of cognitive outcomes in older adults with SCD. Both interventions conferred small, non-differing, and significant improvements to the PACC5r adults . Future r adults , seek toAdditional file 1. Supplementary Methods. Supplementary Results. Table S1. Collinearity diagnostics for alternate specifications of the cognitive retest effect variable. Table S2. Unadjusted (observed) and model-adjusted means for each trial arm at each timepoint . Table S3. Linear mixed models fitted using a linear and factorial time specification, respectively  to follow-up (week 24) change scores on composite outcomes, broken down by trial arm. Table S5. Pooled linear mixed models derived from analyses of multiply-imputed SCD-Well trial data (m = 5). Figure S1. Missing data pattern for the ‘wide’ format dataset. Figure S2. Estimated change in individual cognitive tests for each trial arm (linear-time specification). Figure S3. Estimated change in individual cognitive tests for each trial arm (linear-time specification).


Staphylococcus aureus bacteraemia (SAB).To determine clinical practice variation and identify knowledge gaps in antibiotic treatment of A web-based survey with questions addressing antibiotic treatment of SAB was distributed through the ESGAP network among infectious disease specialists, clinical microbiologists and internists in Croatia, France, Greece, the Netherlands and the UK between July 2021 and November 2021.18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG-PET/CT) to guide antibiotic treatment duration. Persistent bacteraemia was the only risk factor for complicated SAB that would prompt a majority to extend treatment from 2 to 4–6 weeks.A total number of 1687 respondents opened the survey link, of whom 677 (40%) answered at least one question. For MSSA and MRSA bacteraemia, 98% and 94% preferred initial monotherapy, respectively. In patients with SAB and non-removable infected prosthetic material, between 80% and 90% would use rifampicin as part of the treatment. For bone and joint infections, 65%–77% of respondents would consider oral step-down therapy, but for endovascular infections only 12%–32% would. Respondents recommended widely varying treatment durations for SAB with different foci of infection. Overall, 48% stated they used This survey in five European countries shows considerable clinical practice variation between and within countries in the antibiotic management of SAB, in particular regarding oral step-down therapy, choice of oral antibiotic agents, treatment duration and use of 18F-FDG-PET/CT. Physicians use varying criteria for treatment decisions, as evidence from clinical trials is often lacking. These areas of practice variation could be used to prioritize future studies for further improvement of SAB care. Staphylococcus aureus bacteraemia (SAB) is an exceptionally heterogeneous disease and its clinical course can range from mild to life-threatening.1 This clinical heterogeneity is the result of complex interplay between pathogen and host factors, and is reflected by varying distributions of clinical phenotypes and mortality rates between observational cohort studies.23–5 Conversely, appropriate antibiotic treatment, one of the key components of SAB management, is still guided by evidence of poor quality.1 This is reflected in current guidelines on SAB, which vary widely in their recommendations regarding choice of antibiotic agents, treatment duration and optimal administration route.6–9In recent decades, evidence-based interventions including infectious disease (ID) consultation, follow-up blood cultures, echocardiography and source control interventions have improved clinical outcomes in SAB patients.It is likely that the paucity of high-level evidence results in clinical practice variation in antibiotic treatment of SAB. In order to substantiate the clinical practice variation, a web-based survey was designed and distributed among ID specialists, clinical microbiologists and internists in five European countries. Areas of variation in management may indicate knowledge gaps, and identifying them may therefore guide future research efforts.JAC Online). The final version included 17 questions addressing the following topics: choice of antibiotic agents; use of rifampicin; oral antibiotic step-down therapy; and treatment duration. We also included two scenarios describing patients with SAB, with questions on recommended antibiotic treatment duration to illustrate clinical practice.We designed a web-based survey in two subsequent steps. First, we organized an online discussion with ID specialists and clinical microbiologists involved in SAB management to identify topics for inclusion in the survey. We developed a first draft of the survey with questions based on these topics. Second, this draft was tested in an independent group of ID specialists and clinical microbiologists. Their comments were used to adjust the survey and develop a final version  to participate in the survey: the Netherlands, France, the UK, Greece and Croatia. These countries were chosen based on their geographical spread in Europe. We did not perform a formal sample size calculation, but aimed for at least 50 respondents per country. Distribution of the survey was initiated on 6 July 2021 and data collection was stopped on 30 November 2021. There were no financial or other incentives provided to the target respondents.In all countries, the survey was shared by a web link and respondents were invited to forward the survey link to their colleagues. In the Netherlands, the survey was distributed through the Dutch Working Party on Antibiotic Policy, the Dutch Society for Infectious Disease specialists and the Dutch Society for Medical Microbiology. In France, the survey was shared via the French Society for Infectious Diseases, the French National Society for Internal Medicine, the French Young Infectious Diseases Network and the Young Internal Medicine Specialists Network. The survey was distributed in Croatia through the Croatian Society of Infectious Disease and the Croatian Society of Clinical Microbiology. In Greece, the survey was distributed through a network of ID specialists within the Greek Society for Infectious Diseases. In the UK, the survey was shared through the British Infection Association.A descriptive analysis of all survey questions was performed. Both complete and partially completed surveys were included in the data analysis. Continuous and categorical variables were presented as median (IQR) and absolute number (percentage), respectively. A sensitivity analysis was performed, excluding consultants in training. All analyses were performed using R version 4.0.3.The survey link was opened 1687 times. A total of 677 (40%) respondents answered at least one question concerning antibiotic treatment of SAB. Table For initial treatment of monobacterial MSSA bacteraemia, 98% (664/677) favoured antibiotic monotherapy and 2% (13/677) combination therapy. Of those who preferred antibiotic monotherapy, 81% (536/664) indicated an anti-staphylococcal penicillin as their first-choice antibiotic agent and 16% (108/664) a first-generation cephalosporin Figure . When trWhen treating a patient with confirmed monobacterial MRSA bacteraemia, 94% (635/677) would prefer initial antibiotic monotherapy. Of these respondents, 71% (452/635) preferred a glycopeptide (e.g. vancomycin) as initial antibiotic therapy and 23% (148/635) a lipopeptide (e.g. daptomycin) Figure . RespondIn patients with SAB and non-removable infected prosthetic material, between 80% (448/560) and 90% (503/560) of respondents would use rifampicin as part of the treatment, provided the isolates were susceptible Figure . For SABFigure 18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG-PET/CT) without signs of endocarditis or metastatic infections  as a requirement for using oral step-down therapy.Most respondents considered clearance of bacteraemia 48–72 h after initiation of adequate antibiotic treatment  and absence of CNS infection  as requirements for oral step-down therapy, provided the patient is able to take oral medication Figure . TransoeWhen treating a patient with MSSA bacteraemia with oral step-down therapy, 65% (319/489) preferred monotherapy and 35% (170/489) combination therapy, assuming there is no implanted prosthetic material and the isolate is susceptible to the drug. Preferred agents for oral step-down were anti-staphylococcal penicillins and clindamycin (both 32%). Eleven percent (36/319) of respondents most commonly prescribed a fluoroquinolone and 10% (33/319) trimethoprim/sulfamethoxazole Figure . For oraTable Approximately half of respondents  stated they used 18F-FDG-PET/CT to guide antibiotic treatment duration in SAB. Respondents from Greece reported the lowest use of 18F-FDG-PET/CT  and respondents from the Netherlands the highest  Table . RespondRespondents were asked to provide a recommendation on duration of antibiotic treatment in two scenarios describing patients with SAB. A full description of both scenarios is provided in Figure No substantial differences were observed between the results of all respondents and those of registered consultants only, excluding those in training (data not shown).This survey in five European countries showed considerable clinical practice variation between and within countries in the antibiotic management of SAB. Areas of consensus were choice of IV antibiotic agents, use of combination therapy and use of rifampicin-based treatment in prosthetic material infection. Main areas of controversy were eligibility for oral step-down therapy, choice of oral antibiotic agents, treatment duration and use of 18F-FDG-PET/CT.10 This difference might be explained by the recent publication of observational studies indicating comparable effectiveness of both agents and less antibiotic discontinuation due to adverse events in patients using cefazolin.12 Randomized clinical trials might provide stronger evidence about the equivalence of first-generation cephalosporins compared with anti-staphylococcal penicillins in SAB treatment.14A large majority of respondents preferred monotherapy for treatment of microbiologically confirmed MSSA and MRSA bacteraemia. Most respondents would use an anti-staphylococcal penicillin for MSSA bacteraemia. On the other hand, three-quarters of respondents considered first-generation cephalosporins to have equivalent clinical effectiveness to anti-staphylococcal penicillins in MSSA bacteraemia without CNS infection. This is considerably higher than in a previous study among ID specialists in the USA and Canada, of whom only 32% considered nafcillin and cefazolin equivalent in the treatment of left-sided MSSA endocarditis without CNS involvement.15 The underlying evidence to support these recommendations is, however, limited since previous studies were either small or potentially suffered from confounding by indication.16–18 In the ARREST trial, adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in SAB.19 However, only 14 (2%) patients in this study had infected prosthetic material, limiting the generalizability of the results to this subgroup. The consensus regarding use of rifampicin, despite a lack of high-quality studies, illustrates that agreement between respondents is not always a reflection of a solid evidence base. Since rifampicin-based therapies carry a high risk of adverse drug events and drug interactions, future studies demonstrating a robust effect of rifampicin on patient outcomes are needed to justify their ubiquitous use in clinical practice.There was substantial agreement between respondents concerning the use of rifampicin for different types of prosthetic material infection. International guidelines recommend rifampicin as part of combination therapy for SAB and associated infected prosthetic material, including prosthetic valve endocarditis and prosthetic joint infections.20 Previous studies were performed in heterogeneous patient populations, included only small numbers of patients with SAB, or resulted in conflicting conclusions.21–24 For example, the POET trial on partial oral treatment of endocarditis included only 47 participants with S. aureus endocarditis who received oral treatment.24 We did not assess in our survey after how many days of IV therapy respondents would consider oral step-down, which might contribute to variation in respondents’ answers. Currently, several studies examine the efficacy and safety of oral switch therapy in SAB, including the SABATO trial and the SNAP trial , and the results are eagerly awaited to inform clinical practice.25A large majority indicated they would consider oral step-down antibiotic therapy in SAB. There was relative consensus that endovascular infections, including infective endocarditis and central venous catheter infection, should not be treated with oral antibiotics. On the other hand, a majority would consider oral step-down for non-endovascular infections including arthritis, osteomyelitis and skin-and-soft-tissue infection without abscess. This survey also highlights the fact that clinicians apply different criteria to selected patients who can be treated with oral antibiotics. Absence of CNS infection and absence of persistent bacteraemia were consistent requirements for oral step-down therapy, but there was substantial disagreement on other criteria. This may originate from the fact that there is limited evidence to support the use of oral antibiotics in SAB.26 A previous survey in the USA observed similar responses regarding the factors influencing extension of therapy.10 This lack of consensus may be caused by scarcity of high-quality studies, and is in line with a previous survey among ID physicians in Australia and New Zealand, which identified optimal duration of therapy as the number one research priority in SAB.27 Currently, randomized controlled trials are investigating whether antibiotic therapy can be safely shortened from 6 to 4 weeks in selected patients with complicated SAB  and from 14 to 7 days in patients with uncomplicated SAB.28Respondents recommended widely varying treatment durations for SAB with different foci of infection. A patient with septic arthritis and accompanying SAB would receive 4 weeks of treatment from approximately half of the respondents, 2 weeks from a fifth of respondents and 6 weeks from a third of respondents. The lack of consensus is also illustrated by respondents’ answers on the factors that influence their decision to extend antibiotic therapy from 2 to 4–6 weeks. Only persistent bacteraemia would prompt a majority to extend treatment. Even factors that previous studies identified as conferring a high risk for complications, such as persistent fever and delay in start of adequate antibiotic treatment, were mentioned by only a minority of respondents.30 Half of respondents in the survey indicated they used 18F-FDG-PET/CT in SAB management, with substantial differences between countries. These local differences might be explained by differences in availability of scanners and associated costs.32 Previous surveys in the USA and Australia and New Zealand did not include questions on use of 18F-FDG-PET/CT in SAB.27 Moreover, this survey provides insight into the way clinicians incorporate 18F-FDG-PET/CT results in decision-making in SAB management. Interestingly, we observed no major differences between respondents who used 18F-FDG-PET/CT and the group that did not, with the assumption of a negative 18F-FDG-PET/CT. These findings suggest that absence of metastatic infections on an 18F-FDG-PET/CT has at present very limited influence on the decision whether or not to extend treatment.Recent studies suggest that performing 18F-FDG-PET/CT might be beneficial by detecting metastatic infections, with subsequent treatment modifications.Strengths of this study are that we tested the survey format in an independent group of clinicians in the development phase, and obtained data from a large number of respondents from different geographical regions in Europe. We acknowledge that this study has limitations. First, since participation was voluntary, selection bias may limit generalizability. Second, clinical practices were self-reported and might not adequately reflect everyday real-life practice. Furthermore, we did not assess whether respondents were primarily involved in SAB care for adults, children or both. Since clinical practice might vary per patient age group, this might have biased the results. Last, almost half of the respondents practised in France and therefore the results might disproportionally reflect clinical practice in this country. To adjust for this, we performed exploratory analyses stratified per country Tables .25 Nevertheless, such studies are much needed for guidance of clinical decision-making. The final step is to implement existing and future evidence into clinical practice, as practice variation is not only determined by lack of evidence. This survey indicates the main areas of practice variation, which could be used to direct and prioritize future studies for further improvement of SAB care (Figure This survey shows that considerable practice variation is present in Europe in antibiotic treatment of SAB. Clinicians have the difficult task of identifying patients who are eligible for certain targeted interventions, such as shorter, extended or oral step-down therapy. Physicians use varying criteria, as evidence from the literature is often lacking and virtually no guideline recommendations on SAB exist, which leads to clinical practice variation. This calls for methodologically sound and preferably randomized studies investigating interventions in well-defined subgroups of SAB patients. The difficulty of performing these studies is illustrated by the SABATO trial, for which enrolment started in 2013 and which was only completed in 2020 after decreasing the target sample size.dkac237_Supplementary_DataClick here for additional data file.


The present study examined whether and how attitudes toward the COVID-19 vaccine , mental health statuses , and interpersonal factors  would predict COVID-19 vaccine hesitancy.N = 194). Well- validated measures were used, including the Perceived Stress Scale, the Center for Epidemiologic Studies Depression Scale, the Online Social Support Questionnaire, and the Perceived Social Support Scale. Perceived safety, efficacy, price of COVID-19 vaccine, vaccine hesitancy, and actual intake were also measured.The two-wave longitudinal surveys were conducted in December 2019 and 2020 in Chinese medical college students (p < 0.05) and depression  were risk factors for positive attitudes toward the COVID-19 vaccine; online social support  and positive attitudes toward the COVID-19 vaccine  were protective factors of intention to get vaccinated in future.Only 2.1% of participants had been vaccinated against COVID-19 in the early stages of the pandemic; 13.4% intended to get vaccinated in the next 3 months, and 66% intended to have it in the next 12 months upon follow-up. Multiple regression analyses revealed that perceived stress (βm = −0.15, Findings suggest that intervention efforts should be made to reduce negative attitudes toward the COVID-19 vaccine among people with poor mental health and enhance online social support to promote COVID-19 vaccination. The emergence of severe acute respiratory syndrome coronavirus 2, which causes the disease COVID-19, has had a destructive influence on global health and economy . As of 2Attitude refers to an individual’s overall feeling that the behavior is favorable or unfavorable . The TheN = 1,041) and in the United Kingdom   . Another= 2,025) . Studies= 2,025) . A pre-C= 2,025) .Few studies have investigated whether interpersonal factors, such as social support, affect COVID-19 vaccination attitudes and intention. It has been revealed that social support can foster feelings of self-efficacy for particular health behaviors advocated by that social group . This phLinking with social networks, such as one’s neighborhood, closely, also allows access to risk and prevention information , enablinTo the best of our knowledge, few studies have investigated how mental health and interpersonal status affect COVID-19 vaccination intention. Furthermore, it is essential to carry out a longitudinal study to monitor mental health and interpersonal status at different stages of the ongoing COVID-19 pandemic. However, no such studies have used a longitudinal design to identify their causal relationships. The current two-wave longitudinal study investigated the intention to get a COVID-19 vaccination and the potential influencing factors, including attitudes toward the COVID-19 vaccine , mental health statuses , and interpersonal factors , in a sample of Chinese college students. We hypothesized that negative attitudes toward the COVID-19 vaccine, a poor mental health status, and a poor interpersonal status predict a weak intention to get the COVID-19 vaccination.This longitudinal study was originally designed to investigate medical college students’ stress and mental/behavioral health over time during their college life. Participants were recruited at Wenzhou Medical University in Wenzhou City, Zhejiang Province, China. The university has about 19,100 students. A total of 219 undergraduate students majoring in Anesthesia, Forensic, Oral medicine, and Traditional Chinese Medicine were invited to participate in the survey in December 2019 and 2020, respectively. Therefore, the baseline was a pre-COVID-19 survey, while the follow-up was conducted when the epidemic had been under control in China and the government started to promote COVID-19 vaccination. The inclusion criteria of this study were as follows: (1) being a college student; and (2) willing to participate in the baseline and follow-up studies. The exclusion criteria were as follows: (1) non-Chinese speaker; and (2) having a cognitive impairment that impeded the ability to understand the survey questions. Of the 219 participants who completed the baseline, 198 completed the follow-up. In addition, we found that four respondents had taken the vaccine; we excluded their data in the analyses because the number of this subgroup was too small for data analyses. As a result, data from the 194 participants was reported in this study.The surveys were conducted in classroom settings. A research assistant with 2-year experience in data collection assisted with data collection. The respondents were assured that the participation was voluntary, and refusals would have no negative consequences. Participants were fully informed that their responses would be kept confidential and only the researchers could access the data. Data was matched by Student ID. Researchers were not able to access students’ identifying information . All respondents were briefed about the purpose and background of the study and provided their informed consent to participate in this anonymous survey. The study procedures were carried out in accordance with the Declaration of Helsinki. Ethical approval was obtained from the affiliated university of the corresponding author.At follow-up, attitudes toward the COVID-19 vaccine were measured using three questions, as follows: “To what extent do you agree that the COVID-19 vaccine is effective?”, “To what extent do you agree that the COVID-19 vaccine is safe ?”, and “To what extent do you agree that the price of the COVID-19 vaccine is reasonable?”. Participants responded to these questions using a Likert-type scale ranging from 1 (strongly disagree) to 5 (strongly agree). Higher sum scores indicated more positive attitudes toward the COVID-19 vaccine. The scale had good reliability in the current sample .To measure COVID-19 vaccine hesitancy/acceptance, participants were asked two questions: “Imagine that a vaccine against COVID-19 was available for anyone who wanted it at follow-up. Whether you would be likely to take the vaccine in (1) the next 3 months and (2) in the next 12 months?” . ResponsAt both baseline and follow-up, the 14-item Chinese version of the Perceived Stress Scale  was usedDepression was assessed using the Chinese version of the 20-item Center for Epidemiologic Studies Depression Scale . ParticiAt both baseline and follow-up, the 23-item Online Social Support Questionnaire  was usedThe 12-item Perceived Social Support Scale  was usedp < 0.05.The proportions of endorsement of the items of attitudes toward the COVID-19 vaccine (“agree” or “strongly agree”) and COVID-19 vaccine hesitancy/acceptance (“yes”) at follow-up were reported. Linear regression analyses were performed to identify the background variables, mental health status, and interpersonal factors at baseline that were significantly associated with attitudes toward the COVID-19 vaccine  at follow-up; the significant background variables of the outcomes (if any), mental health status, and interpersonal factors at follow-up were adjusted for in the linear regression analyses. Similarly, logistic regression analyses were performed to identify whether these factors and attitudes toward the COVID-19 vaccine were significantly associated with vaccine acceptance  at follow-up, respectively; Standardized coefficients (β)/Odds ratio (OR) and 95% confidence interval (95%CI) were reported. All the analyses were performed using SPSS 21.0. The level of statistical significance was set at 2 was 0.145. A post hoc power analysis using G-Power (version 3.1) indicated that a sample of 194 students would provide 99% power to detect an effect size f2 = 0.145 .Our primary aim was to investigate the predictors of COVID-19 vaccine acceptance. In the current multiple linear regression analyses, the R square explained by the five predictors was 0.127; the effect size fOf the participants (mean of age = 19.4), 59.8% were female; 52.1% were from urban areas; 47.9% lived in a one-child family; and 43.8% majored in traditional Chinese medicine .As shown in p > 0.05). Therefore, no background variable was adjusted for in the following regression analyses.Background variables were not significantly associated with positive attitudes toward the COVID-19 vaccine or vaccine hesitancy/acceptance in simple regression analyses (p < 0.05) and depression  were negatively associated with positive attitudes toward the COVID-19 vaccine. Online social support  and positive attitudes toward the COVID-19 vaccine  were positively associated with vaccine acceptance.As shown in p < 0.05) and depression  were negatively associated with positive attitudes toward the COVID-19 vaccine (p < 0.01) and attitudes toward the COVID-19 vaccine  were positively associated with vaccine acceptance  and vaccine acceptance. These findings corroborate those of recent studies performed in various populations and cultures that suggested perceived efficacy and safety of the vaccine were positively associated with the likelihood of vaccination . Such peIn addition, a reasonable price may also encourage people to get vaccinated. At the time when this survey was conducted, there were debates about the market price of getting vaccinated and the local government had not officially announced the price. From 09 January 2021, vaccination is free of charge for Chinese citizens, which may have reduced vaccine hesitancy for some citizens. However, according to a report conducted in Beijing, the capital of China, 167.3 million doses of the vaccine were administered across the country; this is still far from the goal of vaccinating 560 million people (about 40% of the population), by the end of June 2021 . AnotherOne of the most key contributions of the current study is that we found mental health status and interpersonal variables predicted attitudes toward the COVID-19 vaccine and vaccine hesitancy/acceptance. People with poor mental health statuses (more severe perceived stress and depressive symptoms) were more likely to have pessimistic attitudes and responses toward the COVID-19 vaccine. The results are consistent with previous studies, which showed that people with poor mental health reported reduced intentions to engage in health-related behaviors  . AccordiOur findings may highlight the need to pay more attention to those with poor mental/emotional status when promoting COVID-19 vaccination and other preventive behaviors in the general population. Prevention programs should make an effort to reduce negative feelings in the generation population. However, our result is inconsistent with those of recent COVID-19 studies that have reported non-significant relationships between mental health history and vaccine acceptance  and negavia the Internet may enhance vaccine acceptance among college students. This result also supports the theoretical model of social media-enabled healthcare for chronic disease, which asserts that different functions of social media are able to foster social support, where user creation affordance allows informational support. Social learning facilitates experiential support and user interaction facilitates emotional support. Such support is linked to self-care, health-related self-management, and psychological health , reducing stress and depressive symptoms, and enhancing online social support in health behavior promotion among young people. The findings may facilitate vaccine promotion in a future pandemic.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of the Wenzhou Medical University. The patients/participants provided their written informed consent to participate in this study.XY and ZW conceptualized the aims and hypotheses for the study. XY and XW were responsible for drafting the results and the manuscript. ZW and SZ assisted with manuscript editing. ND, GZ, CZ, HX, XL, and XT assisted with data collection. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.