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Viral community-acquired pneumonia (CAP) is a potentially serious illness, particularly in adult patients with underlying chronic conditions. In addition to the most recent SARS-CoV-2, influenza, and respiratory syncytial virus (RSV) are considered the most relevant causes of viral CAP.To describe the clinical features of hospitalised adults admitted for influenza-A/B and RSV pneumonia and analyse, according to aetiology, factors associated with non-invasive ventilation (NIV) failure and in-hospital death (IHD).This was a retrospective and multi-centre study of all adults who were admitted for laboratory-confirmed influenza-A/B or RSV pneumonia, during two consecutive winter seasons (October-April 2017-2018 and 2018-2019) in three tertiary hospitals in Portugal, Italy and Cyprus.A total of 356 adults were included in the study. Influenza-A, influenza-B and RSV were deemed to cause pneumonia in 197 (55.3%), 85 (23.9%) and 74 (20.8%) patients, respectively. Patients with both obstructive sleep apnoea or obesity hypoventilation syndrome and influenza-A virus pneumonia showed a higher risk for NIV failure (odds ratio (OR) 4.66; 95% confidence interval (CI) 1.42-15.30). Patients submitted to NIV showed a higher risk for IHD, regardless of comorbidities (influenza-A OR 3.00; 95% CI 1.35-6.65, influenza-B OR 4.52; 95% CI 1.13-18.01, RSV OR 5.61; 95% CI 1.26-24.93).The increased knowledge of influenza-A/B and RSV pneumonia burden may contribute to a better management of patients with viral CAP.

The coronavirus disease 2019 (COVID-19) pandemic has changed many aspects of our everyday lives and medical practice, including oncology treatment; thyroid cancer surgery is not an exception. The reported number of fine-needle aspirations performed during the first semester of 2020 was significantly reduced. Poorly differentiated, medullary and anaplastic thyroid tumors are considered important indications for immediate surgical intervention. By contrast, most well-differentiated carcinomas present slow growth, and thus surgery can be deferred for a short period of time during which patients are under active surveillance. Thyroid surgeries have decreased during the COVID-19 pandemic. Furthermore, prior to any intervention, negative COVID-19 status – with the use of a nasopharyngeal swab and reverse transcription PCR assay as the gold standard and chest CT scan as a complementary modality in some cases – must be confirmed to achieve a COVID-free pathway. Thorough preoperative assessment regarding both oncological and anatomical aspects should be performed to identify optimal timing for safe management.

Purpose The role of adipokines in causing inflammation and insulin resistance in normal weight and obese patients is generally well studied. However, there are often conflicting results regarding their levels in type 1 diabetes mellitus (T1DM) patients and their relationship to micro- and macrovascular disease. We therefore investigated which serum adipokine levels are independently associated with markers of early atherosclerosis and microvascular complications in patients with T1DM. Methods A cross-sectional study was performed in the Diabetes Outpatient Clinic of Hippokrateion General Hospital, Thessaloniki, Greece. Sixty T1DM patients (30 females, mean age 38.8 ± 10.6 years, mean diabetes duration 17.4 ± 9.9 years) were included. Plasma adiponectin, leptin, and resistin, carotid artery intima media thickness (cIMT), and arterial stiffness (pulse wave velocity, PWV/SpygmoCor CP System and Mobil-O-Graph 24 h PWA) were assessed. Results Leptin and resistin levels were significantly higher in overweight and obese patients (p = 0.002 and p = 0.039, respectively). Adiponectin was the only adipokine negatively correlated with BMI (rs = - 0.41, p = 0.001). We report a bivariate association between serum adiponectin levels and retinopathy (p = 0.007). Resistin was the only adipokine that showed significant correlation with systolic (rs = 0.42, p = 0.001) and diastolic (rs = 0.29, p = 0.024) hypertension and PWV (p = 0.035). Conclusions Serum adipokine levels demonstrate similar bivariate associations with anthropometric variables in patients with T1DM to those in normal weight subjects. Although microvascular complications are associated with serum adipokine levels by bivariate analysis, only resistin, an inflammatory marker, is independently associated with arterial stiffness in patients with T1DM.

Aim To assess the efficacy and safety of sotagliflozin in patients with type 2 diabetes mellitus. Methods We searched Medline, Embase, the Cochrane Library, and grey literature sources up to August 2021 for randomized controlled trials (RCTs) that compared sotagliflozin with placebo or other antidiabetic agents in patients with type 2 diabetes. Our primary outcome was change in HbA1c from baseline. We additionally assessed 3 secondary efficacy and 15 safety outcomes. We synthesized data using weighted mean differences (WMDs) and odds ratios (ORs), along with 95% confidence intervals (CIs). Findings We included 11 RCTs comprising 16411 subjects in the meta-analysis. Compared with placebo, sotagliflozin reduced HbA1c (WMD -0.42 %, 95% CI -0.56 to -0.29), body weight (WMD -1.33 kg, 95% CI -1.57 to -1.09) and systolic blood pressure (WMD -2.44 mmHg, 95% CI -2.81 to -2.07). No difference was evident against other active comparators. Sotagliflozin reduced myocardial infarction (OR 0.72, 95% CI 0.54 to 0.97) and heart failure (OR 0.68, 95% CI 0.58 to 0.79) compared with placebo, and had a neutral effect on all-cause mortality, cardiovascular mortality, and stroke. Treatment with sotagliflozin was safe regarding incidence of serious adverse events, hypoglycaemia, and diabetic ketoacidosis. Nevertheless, it was associated with increased incidence of diarrhoea, genital infections, and volume depletion events. Conclusions Sotagliflozin reduces blood glucose, body weight and systolic blood pressure, and demonstrates a beneficial effect on heart failure and myocardial infarction. Its overall safety profile is comparable to other SGLT-2 inhibitors. This article is protected by copyright. All rights reserved.

Summary Background Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab in patients with moderately to severely active ulcerative colitis who had been previously treated with anti-tumour necrosis factor (TNF) agents. Methods HICKORY was a multicentre, phase 3, double-blind, placebo-controlled study in adult (18–80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6–12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) previously treated with TNF inhibitors. Patients were recruited from 184 treatment centres across 24 countries in North America, South America, Europe, Asia, Oceania, and the Middle East. Patients needed to have an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In cohort 1, patients received open-label etrolizumab 105 mg every 4 weeks for a 14-week induction period. In cohort 2, patients were randomly assigned (4:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks for the 14-week induction phase. Patients in either cohort achieving clinical response to etrolizumab induction were eligible for the maintenance phase, in which they were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks through to week 66. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants (induction randomisation only), baseline disease activity, week 14 MCS remission status (maintenance randomisation only), and induction cohort (maintenance randomisation only). All patients and study site personnel were masked to treatment assignment. Primary endpoints were remission (Mayo Clinic total score [MCS] ≤2, with individual subscores of ≤1 and a rectal bleeding subscore of 0) at week 14, and remission at week 66 among patients with a clinical response (MCS with ≥3-point decrease and ≥30% reduction from baseline, plus ≥1 point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) at week 14. Efficacy was analysed using a modified intent-to-treat population. Safety analyses included all patients who received at least one dose of study drug during the induction phase. This study is registered at ClinicalTrials.gov , NCT02100696 . Findings HICKORY was conducted from May 21, 2014, to April 16, 2020, during which time 1081 patients were screened, and 609 deemed eligible for inclusion. 130 patients were included in cohort 1. In cohort 2,479 patients were randomly assigned to the induction phase (etrolizumab n=384, placebo n=95). 232 patients were randomly assigned to the maintenance phase (etrolizumab to etrolizumab n=117, etrolizumab to placebo n=115). At week 14, 71 (18·5%) of 384 patients in the etrolizumab group and six (6·3%) of 95 patients in the placebo group achieved the primary induction endpoint of remission (p=0·0033). No significant difference between etrolizumab and placebo was observed for the primary maintenance endpoint of remission at week 66 among patients with a clinical response at week 14 (27 [24·1%] of 112 vs 23 [20·2%] of 114; p=0·50). Four patients in the etrolizumab group reported treatment-related adverse events leading to treatment discontinuation. The proportion of patients reporting at least adverse event was similar between treatment groups for induction (etrolizumab 253 [66%] of 384; placebo 63 [66%] of 95) and maintenance (etrolizumab to etrolizumab 98 [88%] of 112; etrolizumab to placebo 97 [85%] of 114). The most common adverse event in both groups was ulcerative colitis flare. Most adverse events were mild or moderate. During induction, the most common serious adverse event was ulcerative colitis flare (etrolizumab ten [3%] of 384; placebo: two [2%] of 95). During maintenance, the most common serious adverse event in the etrolizumab to etrolizumab group was appendicitis (two [2%] of 112) and the most common serious adverse events in the etrolizumab to placebo group were ulcerative colitis flare (two [2%] of 114) and anaemia (two [2%] of 114). Interpretation HICKORY demonstrated that a significantly higher proportion of patients with moderately to severely active ulcerative colitis who had been previously treated with anti-TNF agent were able to achieve remission at week 14 when treated with etrolizumab compared with placebo; however, there was no significant difference between groups in remission at week 66 among patients with a clinical response at week 14. Funding F Hoffmann-La Roche.

Die Langerhans-Zell-Histiozytose (LCH) ist eine sehr seltene Ursache einer sekundar sklerosierenden Cholangitis. Wir berichten von einem 42-jahrigen Patienten mit sklerosierender Cholangitis und histologischem Nachweis einer LCH aus der Gallengangsbiopsie. Bei raschem Krankheitsprogress und Ausschopfung konservativer Therapieversuche erfolgte eine Lebertransplantation. Knapp zwei Jahre nach Transplantation besteht eine gute Transplantatfunktion ohne Hinweis auf Reaktivierung der Grunderkrankung.

Global warming affects the aquatic ecosystems, accelerating pathogenic microorganisms' and toxic microalgae's growth and spread in marine habitats, and in bivalve molluscs. New parasite invasions are directly linked to oceanic warming. Consumption of pathogen-infected molluscs impacts human health at different rates, depending, inter alia, on the bacteria taxa. It is therefore necessary to monitor microbiological and chemical contamination of food. Many global cases of poisoning from bivalve consumption can be traced back to Mediterranean regions. This article aims to examine the marine bivalve's infestation rate within the scope of climate change, as well as to evaluate the risk posed by climate change to bivalve welfare and public health. Biological and climatic data literature review was performed from international scientific sources, Greek authorities and State organizations. Focusing on Greek aquaculture and bivalve fisheries, high-risk index pathogenic parasites and microalgae were observed during summer months, particularly in Thermaikos Gulf. Considering the climate models that predict further temperature increases, it seems that marine organisms will be subjected in the long term to higher temperatures. Due to the positive linkage between temperature and microbial load, the marine areas most affected by this phenomenon are characterized as 'high risk' for consumer health.

The therapeutic range of cyclic nucleotide phosphodiesterase 5 inhibitors (PDE5) inhibitors is getting wider in the last years. This review study focuses on the potential employment of PDE5 inhibitors as an adjunct tool for the therapeutic management of male infertility. The literature tends to suggest a beneficial effect of PDE5 inhibitors on Leydig and Sertoli cells secretory function. It also appears that PDE5 inhibitors play a role in the regulation of the contractility of the testicular tunica albuginea and the epididymis. Moreover, scientific data suggest that PDE5 inhibitors enhance the prostatic secretory function leading to an improvement in sperm motility. Other studies additionally demonstrate the role of PDE5 inhibitors in the regulation of the sperm capacitation process. Placebo-controlled, randomized, blind studies are necessary to unambiguously incorporate PDE5 inhibitors as an adjunct tool for the pharmaceutical treatment of semen disorders and male infertility.

Coronavirus disease-2019 (COVID-19) represents a global public health nightmare. The “cytokine storm,” the most prominent underlying pathophysiologic mechanism of this disease, can theoretically be targeted at several stages. Janus kinase (JAK) inhibitors constitute a drug class that could ameliorate the inflammatory response and enhance antibody production. Herein, we aimed to evaluate the efficacy of JAK inhibitors in patients with COVID-19, performing the most updated relevant meta-analysis. We searched two major databases for randomized controlled trials (RCTs) enrolling adult patients with documented COVID-19 in the in-hospital setting, assigned either to JAK inhibitor treatment plus standard of care or standard of care alone. We set as primary efficacy outcome the endpoint of COVID-19 death on day 28 and as secondary efficacy composite outcome that of mechanical ventilation or initiation of extracorporeal membrane oxygenation (ECMO). We finally pooled data of interest from 4 RCTs in a total of 1338 subjects with documented COVID-19 infection, utilizing the following JAK inhibitors: baricitinib, ruxolitinib, tofacitinib, and nezulcitinib. Treatment with JAK inhibitor compared to control resulted in a significant reduction in the risk for COVID-19 death by 43%, while it also led to a significant decrease in the risk for mechanical ventilation or ECMO initiation by 36%. Herein, we demonstrate a clear benefit with JAK inhibitors added to standard of care in patients with COVID-19 in terms of risk reduction concerning major outcomes. Larger RCTs will elucidate their place in treatment armamentarium against COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s10067-021-05884-4.

Microvascular dysfunction is the key element in the pathogenesis of systemic sclerosis (SSc), whereas the contribution of large and medium size vessel abnormalities is yet to be established. The aim of the present study is to assess the association between micro- and macrovascular function by utilizing a broad spectrum of assessments of vascular performance.We included consecutive, consenting SSc patients who underwent nailfold video capillaroscopy (NVC) for microcirculation evaluation. Peripheral and central systolic and diastolic blood pressure, carotid intima-media thickness (cIMT), aortic augmentation index (AIx) corrected for a heart rate of 75 beats per minute (AIx-75), and carotid-femoral pulse wave velocity (PWV) were also performed to assess macrovascular function. Cardiovascular risk disease (CVD) algorithms were also calculated and included in the analysis.A total of 81 patients (6 males) were studied with mean age 55.44 ± 13.40 years. Reduced capillary density was inversely correlated with arterial stiffness (Alx-75) and augmentation pressure (r = - 0.262, p = 0.018, and r = - 0.249, p = 0.025 respectively). Alx was significantly lower in the early compared to late pattern (28.24 ± 11.75 vs 35.63 ± 10.47, p = 0.036). A significant trend was found among NVC patterns with Alx-75 values being higher with the progression of microangiopathy towards the "late" group (26.36 ± 10.90 vs 30.81 ± 11.59 vs 35.21 ± 7.90, p = 0.027 for trend). Similarly, Framingham risk score and Atherosclerotic Cardiovascular Disease score were progressively higher across the worsening NVC patterns (4.10 ± 4.13 vs 2.99 ± 2.72 vs 6.36 ± 5.65, p = 0.023, and 6.99 ± 7.18 vs 5.63 ± 4.41 vs 12.09 ± 9.90, p = 0.019, respectively, for trends). Finally, QRISK3 (10-year cardiovascular disease risk) and ASCVD (Atherosclerotic Cardiovascular Disease) scores were inversely correlated with the number of capillaries (r = - 0.231, p = 0.048, and r = - 0.260, p = 0.038 respectively).These data suggest that CVD risk scores and macrovascular parameters are strongly correlated with microvasculopathy in patients with SSc. Key Points • Microangiopathy is the hallmark of SSc, but the relationship between subclinical atherosclerosis and small vessel disease remains unknown. • Arterial stiffening and CVD risk scores are positively associated with the degree of progression of peripheral microvasculopathy assessed with NVC. • The results of the study suggest an association between NVC abnormalities and higher CVD risk in SSc patients.

Introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce blood glucose and glycosylated haemoglobin (HbA1c), the risk of hospitalization for heart failure (HF) and the incidence of serious adverse kidney function events (chronic kidney disease, CKD) in patients with type 2 diabetes mellitus (T2DM). Ertugliflozin is the last SGLT2i approved by Food and Drug Administration (FDA) in the USA and European Medical Agency (EMA) in Europe for the treatment of T2DM alone or in combination with other drugs.Areas covered: The authors critically discuss in this drug evaluation the safety and efficacy of the ertugliflozin + metformin combination in patients with T2DM without complications, those with CKD, or those with heart failure (HF). Furthermore, the authors discuss the results of the VERTIS CV trial (MK-8835-004), the trials NCT01986881 and NCT01986855 and other smaller studies.Expert opinion: The ertugliflozin + metformin combination is safe and effective in patients with T2DM with renal impairment, HF of any kind, or those without diabetic complications. These have practical implications that will help diabetologists, cardiologists, internists, nephrologists and general practitioners in selecting the proper combination of SGLT2i on top of metformin, if needed.

We aimed to evaluate the diagnostic agreement between radiofrequency (RF) intravascular ultrasound (IVUS) and optical coherence tomography (OCT) for thin-cap fibroatheroma (TCFA) in non-infarct-related coronary arteries (non-IRA) in patients with ST-segment elevation myocardial infarction (STEMI). In the Integrated Biomarker Imaging Study (IBIS-4), 103 STEMI patients underwent OCT and RF-IVUS imaging of non-IRA after successful primary percutaneous coronary intervention and at 13-month follow-up. A coronary lesion was defined as a segment with ≥ 3 consecutive frames (≈1.2 mm) with plaque burden ≥ 40% as assessed by grayscale IVUS. RF-IVUS-derived TCFA was defined as a lesion with > 10% confluent necrotic core abutting to the lumen in > 10% of the circumference. OCT-TCFA was defined by a minimum cap thickness

We performed a systematic review and meta-analysis of randomized controlled trials to assess the efficacy and safety of the novel, ultra-rapid acting insulins aspart and lispro in adults with type 1 or type 2 diabetes. Our primary outcome was change in HbA1c from baseline. We additionally assessed eight efficacy and six safety endpoints. We calculated weighted mean differences (WMD) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes, alongside 95% confidence intervals (CIs). We additionally assessed statistical heterogeneity among studies with the I2 statistic, considering values greater than 60% indicative of substantial heterogeneity. Nine studies comprising 5931 patients were included in the systematic review; eight active-controlled studies could be synthesized in terms of a meta-analysis. Treatment with ultra-rapid acting insulins had a similar effect on change in HbA1c, compared with rapid-acting insulins (WMD -0.02 %, 95% CI -0.08 to 0.05, I2 =61% for patients with type 1 diabetes and -0.02 %, 95% CI -0.09 to 0.04, I2 =19% for patients with type 2 diabetes). Similarly, no difference was evident in terms of change in fasting plasma glucose, self-measured plasma glucose, body weight, basal or bolus insulin dose, incidence of serious adverse events and hypoglycaemia. Compared with rapid-acting insulins, ultra-rapid insulins reduced 1-hour and 2-hour postprandial glucose (PPG) increment based on a liquid meal test, both in patients with type 1 and type 2 diabetes (WMD -0.94 mmol/L, 95% CI -1.17 to -0.72, I2 =0% and -0.56 mmol/L, 95% CI -0.79 to -0.32, I2 =0%, respectively for change in 1-hour PPG increment). In conclusion, ultra-rapid acting insulins were as efficacious and safe as rapid-acting insulins, demonstrating a favourable effect solely on PPG control. This article is protected by copyright. All rights reserved.

Introduction: Statins are powerful lipid-lowering agents which reduce cardiovascular (CV)–related morbidity and mortality. However, a large proportion of patients cannot attain the target low-densi...

Aim To compare the effects of glucose-lowering drugs on body weight and blood pressure in adults with type 2 diabetes. Methods We searched Medline, Embase, the Cochrane Library, and grey literature sources until 29 September 2020 for randomized controlled trials of at least 24 weeks' duration assessing the effects of glucose-lowering drugs on body weight and blood pressure in adults with type 2 diabetes. We performed frequentist network meta-analyses and calculated weighted mean differences and 95% confidence intervals combining trial arms of different approved doses of a given intervention into a single group. We evaluated the confidence in pooled estimates using the CINeMA (Confidence In Network Meta-Analysis) framework. Results In total, 424 trials (276 336 patients) assessing 21 antidiabetic medications from nine drug classes were included. Subcutaneous semaglutide was the most efficacious in reducing body weight followed by oral semaglutide, exenatide twice-daily, liraglutide, and the sodium-glucose co-transporter-2 (SGLT-2) inhibitors empagliflozin, canagliflozin, dapagliflozin and ertugliflozin. The same agents also conferred the greatest reductions in systolic blood pressure. Metformin had a modest effect in reducing body weight and systolic blood pressure. Diastolic blood pressure was reduced with the SGLT-2 inhibitors pioglitazone, exenatide twice-daily and semaglutide. In subgroup analyses of trials with over 52 weeks' duration, semaglutide and SGLT-2 inhibitors reduced both body weight and systolic blood pressure. Conclusions Semaglutide and SGLT-2 inhibitors conferred reductions both in body weight and blood pressure that were sustainable for over 1 year of treatment. These agents may be preferable treatment options for patients with type 2 diabetes who are overweight/obese and/or hypertensive.

Purpose Pulmonary rehabilitation (PR) including exercise training improves muscle strength, exercise capacity, and health-related quality of life in patients with chronic obstructive pulmonary disease (COPD). However, the evidence of the effect of upper limb exercise training (ULET) on activities of daily living (ADL) is sparse. This study investigated the effect of two different types of ULET on ADL in addition to standard PR. Methods Patients were randomly assigned to a strength or a combined ULET group. Both groups exercised 2 d/wk for 12 wk. Outcome measures were handgrip strength and muscle strength of biceps and triceps muscles. Moreover, health-related quality of life was assessed through the COPD assessment test (CAT) and Saint George Respiratory Questionnaire. Ability to perform ADL was evaluated through an ADL simulation test. Dyspnea was evaluated by a modified Medical Research Council scale, whereas dyspnea and fatigue perception during strength and ADL tests were measured through a modified Borg scale. Results Thirty-six patients with COPD (67.4 ± 5.3 yr) participated in the study. Significant improvements in upper limb strength and CAT were found within both groups. At the end of the study period, patients in the combined group improved time of the ADL test (P = .02) with reduced perception of fatigue (P = .03) compared with patients in the strength group. Conclusions In addition to standard PR of patients with COPD, the combined endurance and resistance ULET program improved ADL and muscle strength, whereas resistance training only increased strength.

Background Prognostic stratification of breast cancers remains a challenge to improve clinical decision making. We employ machine learning on breast cancer transcriptomics from multiple studies to link the expression of specific genes to histological grade and classify tumours into a more or less aggressive prognostic type. Materials and methods Microarray data of 5031 untreated breast tumours spanning 33 published datasets and corresponding clinical data were integrated. A machine learning model based on gradient boosted trees was trained on histological grade-1 and grade-3 samples. The resulting predictive model (Cancer Grade Model, CGM) was applied on samples of grade-2 and unknown-grade (3029) for prognostic risk classification. Results A 70-gene signature for assessing clinical risk was identified and was shown to be 90% accurate when tested on known histological-grade samples. The predictive framework was validated through survival analysis and showed robust prognostic performance. CGM was cross-referenced with existing genomic tests and demonstrated the competitive predictive power of tumour risk. Conclusions CGM is able to classify tumours into better-defined prognostic categories without employing information on tumour size, stage, or subgroups. The model offers means to improve prognosis and support the clinical decision and precision treatments, thereby potentially contributing to preventing underdiagnosis of high-risk tumours and minimising over-treatment of low-risk disease.

Introduction: Fluoroscopy-guided endourology procedures require proper radiation protection to minimize radiation risk. This multicenter study aimed at investigating radiation protection practice and related radiation exposure of operating team members. Materials and Methods: Six endourology centers from the South-Eastern European Group for Urolithiasis Research answered questionnaires and collected data of 315 procedures performed within a 3-months period, with simultaneous measurement of dose to staff and dose area product (DAP) to patient. A pair of calibrated personal dosimeters, one for body and one for eye-lens dose, was worn by all key staff members. Dosimeters were centrally calibrated, measured, and analyzed. Results: The annual workload ranged from 173 to 865 procedures per center. Practice of personal dose monitoring and use of radiation protection shielding was found to be inconsistent. Lead aprons and thyroid collars were used by all, whereas protective eyewear was used in only half of centers. Due to the regular use of protective aprons, the whole-body dose of all 44 monitored staff members was safely below the regulatory dose limits. Eye-lens dose of 17 (14 urologists and 3 assisting staff) was above the dosimeter detection level, and dose per procedure varied from

Background Although both neural mobilization (NM) and cervical traction (CT) are widely used interventions in cervical radiculopathy (CR), there is limited clinical data to support their use. Objective To evaluate the effects of CT, with or without the addition of NM, on pain, function, and disability in patients with CR. Design A randomized, double-blinded, placebo-controlled clinical trial. Methods 66 patients with CR were randomly allocated to: a group (n = 22) received CT combined with NM (CT + NM), a group (n = 22) received CT combined with sham NM (CT + shamNM) and a wait-list control (WLC) group (n = 22). The Neck Disability Index (NDI), the Patient-Specific Functional Scale, the Numeric Pain Rating Scale (NPRS), grip strength and cervical spine mobility were used as outcome measures. A two-way analysis of variance was used to evaluate differences between the three groups at baseline and at 4-week follow-up. Results Statistically and clinically significant between-group differences at 4-week follow-up were found between CT + NM and WLC groups in favor of CT + NM group in NDI scores (d = 1.30), NRPS (d = 1.94), and active cervical rotation towards the opposite arm (d = 1.18) and between CT + NM and CT + shamNM groups in favor of CT + NM group in NRPS (d = 1.21). No significant differences were observed between CT + shamNM and WLC groups in all outcome measures. Clinically significant within-group improvements were found only for the CT + NM group. Conclusion At 4-week follow-up, CT in combination with NM resulted in improved outcomes in pain, function and disability in patients with CR.

Background Increased understanding of whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection is an urgent requirement. We aimed to investigate whether antibodies against SARS-CoV-2 were associated with a decreased risk of symptomatic and asymptomatic reinfection. Methods A large, multicentre, prospective cohort study was done, with participants recruited from publicly funded hospitals in all regions of England. All health-care workers, support staff, and administrative staff working at hospitals who could remain engaged in follow-up for 12 months were eligible to join The SARS-CoV-2 Immunity and Reinfection Evaluation study. Participants were excluded if they had no PCR tests after enrolment, enrolled after Dec 31, 2020, or had insufficient PCR and antibody data for cohort assignment. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2–4 weeks) and completed questionnaires every 2 weeks on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive, or previous positive PCR or antibody test) or negative cohort (antibody negative, no previous positive PCR or antibody test). The primary outcome was a reinfection in the positive cohort or a primary infection in the negative cohort, determined by PCR tests. Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, or possible) and symptom-status, depending on the hierarchy of evidence. Primary infections in the negative cohort were defined as a first positive PCR test and seroconversions were excluded when not associated with a positive PCR test. A proportional hazards frailty model using a Poisson distribution was used to estimate incidence rate ratios (IRR) to compare infection rates in the two cohorts. Findings From June 18, 2020, to Dec 31, 2020, 30 625 participants were enrolled into the study. 51 participants withdrew from the study, 4913 were excluded, and 25 661 participants (with linked data on antibody and PCR testing) were included in the analysis. Data were extracted from all sources on Feb 5, 2021, and include data up to and including Jan 11, 2021. 155 infections were detected in the baseline positive cohort of 8278 participants, collectively contributing 2 047 113 person-days of follow-up. This compares with 1704 new PCR positive infections in the negative cohort of 17 383 participants, contributing 2 971 436 person-days of follow-up. The incidence density was 7·6 reinfections per 100 000 person-days in the positive cohort, compared with 57·3 primary infections per 100 000 person-days in the negative cohort, between June, 2020, and January, 2021. The adjusted IRR was 0·159 for all reinfections (95% CI 0·13–0·19) compared with PCR-confirmed primary infections. The median interval between primary infection and reinfection was more than 200 days. Interpretation A previous history of SARS-CoV-2 infection was associated with an 84% lower risk of infection, with median protective effect observed 7 months following primary infection. This time period is the minimum probable effect because seroconversions were not included. This study shows that previous infection with SARS-CoV-2 induces effective immunity to future infections in most individuals. Funding Department of Health and Social Care of the UK Government, Public Health England, The National Institute for Health Research, with contributions from the Scottish, Welsh and Northern Irish governments.

Summary Background BNT162b2 mRNA and ChAdOx1 nCOV-19 adenoviral vector vaccines have been rapidly rolled out in the UK from December, 2020. We aimed to determine the factors associated with vaccine coverage for both vaccines and documented the vaccine effectiveness of the BNT162b2 mRNA vaccine in a cohort of health-care workers undergoing regular asymptomatic testing. Methods The SIREN study is a prospective cohort study among staff (aged ≥18 years) working in publicly-funded hospitals in the UK. Participants were assigned into either the positive cohort (antibody positive or history of infection [indicated by previous positivity of antibody or PCR tests]) or the negative cohort (antibody negative with no previous positive test) at the beginning of the follow-up period. Baseline risk factors were collected at enrolment, symptom status was collected every 2 weeks, and vaccination status was collected through linkage to the National Immunisations Management System and questionnaires. Participants had fortnightly asymptomatic SARS-CoV-2 PCR testing and monthly antibody testing, and all tests (including symptomatic testing) outside SIREN were captured. Data cutoff for this analysis was Feb 5, 2021. The follow-up period was Dec 7, 2020, to Feb 5, 2021. The primary outcomes were vaccinated participants (binary ever vacinated variable; indicated by at least one vaccine dose recorded by at least one of the two vaccination data sources) for the vaccine coverage analysis and SARS-CoV-2 infection confirmed by a PCR test for the vaccine effectiveness analysis. We did a mixed-effect logistic regression analysis to identify factors associated with vaccine coverage. We used a piecewise exponential hazard mixed-effects model (shared frailty-type model) using a Poisson distribution to calculate hazard ratios to compare time-to-infection in unvaccinated and vaccinated participants and estimate the impact of the BNT162b2 vaccine on all PCR-positive infections (asymptomatic and symptomatic). This study is registered with ISRCTN, number ISRCTN11041050, and is ongoing. Findings 23 324 participants from 104 sites (all in England) met the inclusion criteria for this analysis and were enrolled. Included participants had a median age of 46·1 years (IQR 36·0–54·1) and 19 692 (84%) were female; 8203 (35%) were assigned to the positive cohort at the start of the analysis period, and 15 121 (65%) assigned to the negative cohort. Total follow-up time was 2 calendar months and 1 106 905 person-days (396 318 vaccinated and 710 587 unvaccinated). Vaccine coverage was 89% on Feb 5, 2021, 94% of whom had BNT162b2 vaccine. Significantly lower coverage was associated with previous infection, gender, age, ethnicity, job role, and Index of Multiple Deprivation score. During follow-up, there were 977 new infections in the unvaccinated cohort, an incidence density of 14 infections per 10 000 person-days; the vaccinated cohort had 71 new infections 21 days or more after their first dose (incidence density of eight infections per 10 000 person-days) and nine infections 7 days after the second dose (incidence density four infections per 10 000 person-days). In the unvaccinated cohort, 543 (56%) participants had typical COVID-19 symptoms and 140 (14%) were asymptomatic on or 14 days before their PCR positive test date, compared with 29 (36%) with typical COVID-19 symptoms and 15 (19%) asymptomatic in the vaccinated cohort. A single dose of BNT162b2 vaccine showed vaccine effectiveness of 70% (95% CI 55–85) 21 days after first dose and 85% (74–96) 7 days after two doses in the study population. Interpretation Our findings show that the BNT162b2 vaccine can prevent both symptomatic and asymptomatic infection in working-age adults. This cohort was vaccinated when the dominant variant in circulation was B1.1.7 and shows effectiveness against this variant. Funding Public Health England, UK Department of Health and Social Care, and the National Institute for Health Research.

BACKGROUND Coronavirus disease 2019 (COVID-19) is a highly contagious infection caused by the severe acute respiratory syndrome coronavirus 2 virus and has a unique underlying pathogenesis. Hemodialysis (HD) patients experience high risk of contamination with COVID-19 and are considered to have higher mortality rates than the general population by most but not all clinical series. We aim to highlight the peculiarities in the immune state of HD patients, who seem to have both immune-activation and immune-depression affecting their outcome in COVID-19 infection. CASE SUMMARY We report the opposite clinical outcomes (nearly asymptomatic course vs death) of two diabetic elderly patients infected simultaneously by COVID-19, one being on chronic HD and the other with normal renal function. They were both admitted in our hospital with COVID-19 symptoms and received the same treatment by protocol. The non-HD sibling deteriorated rapidly and was intubated and transferred to the Intensive Care Unit, where he died despite all supportive care. The HD sibling, although considered more “high-risk” for adverse outcome, followed a benign course and left the hospital alive and well. CONCLUSION These cases may shed light on aspects of the immune responses to COVID-19 between HD and non-HD patients and stimulate further research in pathophysiology and treatment of this dreadful disease.

In this study the effect of a surface combat swimming (sCS) training program on performance in freestyle swimming and sCS was examined. Forty-five officer cadets were divided into three equivalent groups: a control group (CG), a group that was trained only with a swimsuit and fins (SF), and a group that was trained with combat uniform and equipment (UE). Groups SF and UE followed a 60-min training program with sCS for 4 weeks, 4 times per week. Before and after the training program all groups performed 4×50 and 400-m freestyle swimming, 250-m sCS with a uniform and equipment, 350-m with a swimsuit and fins, and 300-m with a swimsuit. The UE group showed improved performance in 4×50-m (mean±SD 14±9 s) and in 250-m sCS (24±14 s) (In this study the effect of a surface combat swimming (sCS) training program on performance in freestyle swimming and sCS was examined. Forty-five officer cadets were divided into three equivalent groups: a control group (CG), a group that was trained only with a swimsuit and fins (SF), and a group that was trained with combat uniform and equipment (UE). Groups SF and UE followed a 60-min training program with sCS for 4 weeks, 4 times per week. Before and after the training program all groups performed 4×50 and 400-m freestyle swimming, 250-m sCS with a uniform and equipment, 350-m with a swimsuit and fins, and 300-m with a swimsuit. The UE group showed improved performance in 4×50-m (mean±SD 14±9 s) and in 250-m sCS (24±14 s) (

Resumen Introduccion y objetivos Evaluar la capacidad del endourologo para evaluar la composicion del calculo mediante la observacion de imagenes endoscopicas. Materiales y metodos Una serie de 20 videoclips de tratamientos endoscopicos de calculos urinarios que tambien estaba disponible el resultado de la espectroscopia infrarroja se cargo en un sitio de YouTube accesible solo a miembros del South Eastern Group for Urolithiasis Research (SEGUR) a quienes se les pregunto para identificar la composicion de los calculos. Resultados Un total de 32 endourologos de 9 paises diferentes participaron en el estudio. El numero promedio de detecciones correctas de participantes fue de 7.81 ± 2.68 (1–12). La precision general fue del 39% (250 de 640 predicciones). Calculos de dihidrato de oxalato de calcio se han detectado correctamente en el 69.8%, monohidrato de oxalato de calcio en el 41.8%, acido urico en el 33.3%, oxalato de calcio / acido urico en el 34.3% y cistina en el 78.1%. Las tasas de precision para estruvita (15.6%), fosfato de calcio (0%) y oxalato de calcio / fosfato de calcio (9.3%) fueron bastante bajas. Conclusiones La observacion del calculo durante el procedimiento endoscopico no fue confiable para identificar la composicion de la mayoria de los calculos, aunque los calculos de oxalato de calcio dihidrato y cistina pueden identificarse con buena precision. Sin embargo, se debe alentar la presentacion de fotos o videos de calculo intacto y su estructura interna para implementar los resultados del analisis de calculo despues de la cirugia. Los endourologos deben mejorar su capacidad de identificacion visual de los diferentes tipos de calculos.

Low-density lipoprotein cholesterol (LDL-C) is a proven causative factor for developing atherosclerotic cardiovascular disease. Individuals with genetic conditions associated with lifelong very low LDL-C levels can be healthy. We now possess the pharmacological armamentarium (statins, ezetimibe, PCSK9 inhibitors) to reduce LDL-C to an unprecedented extent. Increasing numbers of patients are expected to achieve very low (

Aim To assess the efficacy and safety of glucose-lowering drugs used as adjunct to insulin therapy in adults with type 1 diabetes. Methods We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials up to January 24, 2020 for randomised controlled trials. Our primary outcome was change in HbA1c . We additionally assessed 8 efficacy and 6 safety secondary endpoints. We performed random-effects frequentist network meta-analysis to estimate mean differences (MDs) and odds ratios (ORs), alongside 95% confidence intervals (CIs). We assessed risk of bias and evaluated confidence in the evidence for the primary outcome. Results We included 58 trials comprising 13 216 participants. Overall, sodium-glucose co-transporter (SGLT) inhibitors, liraglutide, glibenclamide, acarbose and metformin reduced HbA1c compared with placebo (MDs ranging from -0.46% [95% CI -0.64 to -0.29] for empagliflozin to -0.20% [-0.35 to -0.06] for metformin). SGLT inhibitors, exenatide daily, liraglutide, and metformin reduced body weight and total daily insulin dose, while liraglutide and SGLT inhibitors reduced blood pressure. Diabetic ketoacidosis and genital infections were more frequent with SGLT inhibitors, while exenatide, liraglutide, pramlintide and metformin increased odds of nausea. No drug increased odds of severe hypoglycaemia. Confidence in evidence was mainly moderate to very low. Conclusions Specific drugs may improve glycaemic control and reduce body weight, blood pressure and total daily insulin dose in patients with type 1 diabetes. However low quality of evidence and increased risk of diabetic ketoacidosis, genital infections or gastrointestinal adverse events should be taken into consideration by healthcare providers and patients. Future long-term trials are needed to clarify their benefit-to-risk profile and elucidate their role in clinical practice. This article is protected by copyright. All rights reserved.

Introduction: During the first COVID-19 wave, a considerable decline in hospital admissions was observed worldwide. Aim: This retrospective cohort study aimed to assess if there were any changes in the number of patients hospitalized for respiratory diseases in Greece during the first CO­VID-19 wave. Methods: In the present study, we evaluated respiratory disease hospitalization rates across 9 tertiary hospitals in Greece during the study period (March–April 2020) and the corresponding period of the 2 previous years (2018–2019) that served as the control periods. Demographic data and discharge diagnosis were documented for every patient. Results: Of the 1,307 patients who were hospitalized during the study period, 444 (35.5%) were males with a mean (±SD) age of 66.1 ± 16.6 years. There was a 47 and 46% reduction in all-cause respiratory morbidity compared to the corresponding periods of 2018 and 2019, respectively. The mean incidence rate for respiratory diseases during the study period was 21.4 admissions per day, and this rate was significantly lower than the rate during the same period in 2018 (40.8 admissions per day; incidence rate ratio [IRR], 0.525; 95% confidence interval [CI], 0.491–0.562; p < 0.001) or the rate during 2019 (39.9 admissions per day; IRR, 0.537; 95% CI, 0.502–0.574; p < 0.001). The greatest reductions (%) in the number of daily admissions in 2020 were observed for sleep apnoea (87% vs. 2018 and 84% vs. 2019) followed by admissions for asthma (76% vs. 2018 and 79% vs. 2019) and chronic obstructive pulmonary disease (60% vs. 2018 and 51% vs. 2019), while the lowest reductions were detected in hospitalizations for pulmonary embolism (6% vs. 2018 and 23% vs. 2019) followed by tuberculosis (25% vs. both 2018 and 2019). Discussion/Conclusion: The significant reduction in respiratory admissions in 2020 raises the reasonable question of whether some patients may have avoided seeking medical attention during the COVID-19 pandemic and suggests an urgent need for transformation of healthcare systems during the pandemic to offer appropriate management of respiratory diseases other than COVID-19.

This paper introduces a method for training operators using digital technologies. More specifically the training is focused on the teleoperation and remote control of resources and sensors using a simulated environment with virtual elements, before entering the real one. The objective is to improve the training of the operators and bring them closer to Industry 4.0 technologies where robotic and other automation solutions are tackled to support production activities. In this training activity the benefits of using a simulated environment as well as VR technology are presented. More specifically, a simulation application has been created and can be executed on a PC showing a virtual environment where a mobile platform can navigate freely around, calculating its path, and use its camera for obstacle or part detection purposes. On the other side, the VR application can be executed on a smartphone device with Android OS and can be used to see the field of view of the camera attached on the robot. The aforementioned applications can be connected through TCP/IP connection and enable the operator in real time to see and navigate in the virtual world using either the VR or simulation application. Furthermore, a specific scenario has been created and elaborated in the paper, where the robot needs to navigate inside a virtual infrastructure and perform inspection activities using its camera. Lastly, the benefits of each application are further detailed in the paper, focusing mainly on the validation of the inspection automated solution and its remote control in an intuitive and immersive way.

Background: Papillary thyroid carcinoma is the most common type of thyroid cancer; despite its generally indolent course, patients often develop local post-operative recurrences. Re-operation, however, holds a high complication rate, while at the same time, not all patients benefit from radioiodine ablation. This systematic review investigates the application of laser ablation therapy (LAT) for cervical lymph node metastases as an additional treatment modality.Methods: This systematic review was conducted in accordance with the PRISMA Statement. Medline electronic database and Cochrane Library were searched for eligible articles.Results: Five studies were included in the systematic review. All studies included patients with metastatic lymph nodes from papillary thyroid carcinoma, that were unsuitable for further radioiodine or surgical treatment. Patients were treated with two different LAT devices. Regardless of the utilized assessment modalities, all researchers reported significant outcomes on local disease control. No permanent complications were observed.Conclusions: LAT is relatively safe and effective for the treatment of cervical metastatic lymph nodes in patients with papillary thyroid carcinoma.

Introduction Cryptococcal meningoencephalitis is a life-threatening disease affecting mainly immunocompromised hosts. Case report We present a case of a 64-year-old immunocompetent patient, who initially developed a traumatic scalp skin infection due to Cryptococcus neoformans. The patient received oral fluconazole and subsequently liposomal amphotericin B due to the development of resistance with resolution of the infection. Two years later, during chemotherapy for newly diagnosed gastric and lung cancer, he developed fulminant cryptococcal meningoencephalitis, which did not respond to liposomal amphotericin B and flucytosine. Conclusions To our knowledge, this is the first case of fulminant cryptococcal meningoencephalitis following long latency after adequately treated primary cutaneous infection.

Background High‐dose (HD) methotrexate (MTX) is an essential component of treatment protocols in acute lymphoblastic leukemia, aggressive lymphoma, and osteosarcoma. However, delayed MTX clearance may lead to life‐threatening toxicities. Administration of supportive therapy for HD‐MTX is complex, and insufficient supportive care increases the risk of MTX toxicity. To improve patient safety, we investigated the implementation of a checklist and urine alkalinization protocol in addition to standard supportive care during HD‐MTX therapy. Materials and Methods The intervention included individualized patient checklists for control of adequate supportive care for every HD‐MTX treatment cycle and a urine alkalinization protocol for documentation and guidance during urine alkalinization therapy. The impact of these tools on the rate of adverse events (acute renal injury, delayed MTX clearance) was retrospectively assessed in patients treated from April 2017 to April 2019 (intervention group) and compared with patients treated from January 2015 to March 2017 who received standard supportive care for HD‐MTX according to a standard operating procedure (SOP). Results In total, 118 patients received 414 HD‐MTX cycles in the intervention group compared with 108 patients with 332 treatment cycles in the SOP group. Delayed MTX clearance was observed in 2.6% of treatment cycles in the intervention cohort opposed to 15.2% of cycles in the SOP group. The rate of acute kidney injury was also significantly reduced in the intervention group (6.2%. vs. 0.7%). The use of carboxypeptidase as rescue treatment for severe renal impairment and insufficient MTX clearance was necessary in five cases in the SOP group and in only two cycles within the intervention group. Conclusion The use of standardized documentation for supportive care during HD‐MTX therapy is recommended to minimize the risk of adverse events. Implications for Practice High‐dose methotrexate (HD‐MTX) is a commonly used treatment in several cancer types. Distinct supportive measures are necessary to minimize the risk of HD‐MTX side effects, which can be life‐threatening. Supportive care consists of certain examinations and interventions before starting HD‐MTX and permanent alkalinization of the urine, as this greatly increases the elimination of MTX and decreases the risk of kidney injury. After implementing a checklist for control of supportive care and a urine alkalinization protocol to optimize urine alkalinization, a significant decrease of side effects was observed in comparison to the standard of care; therefore, the use of a safety checklist and alkalinization protocol is recommended for all patients who receive HD‐MTX., Supportive measures are necessary to minimize the risk of side effects from high‐dose methotrexate (HD‐MTX) treatment. This article reports the findings of a study that investigated the implementation of a checklist for control of supportive care and a urine alkalinization protocol to optimize urine alkalinization.

Type 2 diabetes mellitus (DM) is a public health burden and its co-existence with hypertension is long established in the context of the metabolic syndrome. Both DM and hypertension are major risk factors, for end-stage renal disease, cardiovascular events and mortality. Strict blood pressure (BP) control in diabetics has been associated with a cardiovascular and renal risk decrease. Inhibitors of the sodium-glucose co-transporter 2 (SGLT-2) in the proximal tubule is a relatively novel class of agents for the treatment of type 2 DM. Inhibition of SGLT-2 co-transporter combines proximal tubule diuretic and osmotic diuretic action leading to glucose reabsorption reduction and mild natriuretic and diuretic effects. On this basis, several studies showed that treatment with SGLT-2 inhibitors can effectively decrease hyperglycemia but also increase BP control and reduce renal outcomes and cardiovascular mortality. Based on such evidence, the recent guidelines for the management of type 2 DM now suggest that SGLT-2 inhibitors should be preferred among oral agents in combination with metformin, in patients at increased cardiovascular risk, chronic kidney disease or heart failure. This review summarizes the existing data from studies evaluating the effect of SGLT-2 inhibitors on BP, and its potential value for cardio- and nephroprotection.

Increased arterial stiffness is independently associated with renal function decline in patients with diabetes mellitus (DM). Whether DM has additional deleterious effects on central hemodynamics and arterial stiffness in chronic kidney disease (CKD) patients is yet unknown. This study aimed to compare ambulatory central BP, arterial stiffness parameters, and trajectories between patients with diabetic and non‐diabetic CKD. This study examined 48 diabetic and 48 non‐diabetic adult patients (>18 years) with CKD (eGFR

The rapid emergence of the novel coronavirus [SARS-CoV2] and the coronavirus disease 2019 [COVID-19] has caused significant global morbidity and mortality. This is particularly concerning for vulnerable groups such as pregnant women with inflammatory bowel disease [IBD]. Care for pregnant IBD patients in itself is a complex issue because of the delicate balance between controlling maternal IBD as well as promoting the health of the unborn child. This often requires continued immunosuppressive maintenance medication or the introduction of new IBD medication during pregnancy. The current global COVID-19 pandemic creates an additional challenge in the management of pregnant IBD patients. In this paper we aimed to answer relevant questions that can be encountered in daily clinical practice when caring for pregnant women with IBD during the current COVID-19 pandemic. Podcast This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast

Background Several pharmacologic options for type 2 diabetes are available. Purpose To compare benefits and harms of glucose-lowering drugs in adults with type 2 diabetes. Data sources Several databases from inception through 18 December 2019 and ClinicalTrials.gov on 10 April 2020. Study selection English-language randomized trials that had at least 24 weeks of intervention and assessed the effects of glucose-lowering drugs on mortality, glycemic, and vascular outcomes. Data extraction Pairs of reviewers extracted data and appraised risk of bias. Data synthesis 453 trials assessing 21 antidiabetic interventions from 9 drug classes were included. Interventions included monotherapies (134 trials), add-on to metformin-based therapies (296 trials), and monotherapies versus add-on to metformin therapies (23 trials). There were no differences between treatments in drug-naive patients at low cardiovascular risk. Insulin regimens and specific glucagon-like peptide-1 receptor agonists (GLP-1 RAs) added to metformin-based background therapy produced the greatest reductions in hemoglobin A1c level. In patients at low cardiovascular risk receiving metformin-based background treatment (298 trials), there were no clinically meaningful differences between treatments for mortality and vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background treatment (21 trials), oral semaglutide, empagliflozin, liraglutide, extended-release exenatide, and dapagliflozin reduced all-cause mortality. Oral semaglutide, empagliflozin, and liraglutide also reduced cardiovascular death. Odds of stroke were lower with subcutaneous semaglutide and dulaglutide. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduced heart failure hospitalization and end-stage renal disease. Subcutaneous semaglutide and canagliflozin increased diabetic retinopathy and amputation, respectively. Limitation Inconsistent definitions of cardiovascular risk and low-level confidence in some estimates for patients at low cardiovascular risk. Conclusion In diabetic patients at low cardiovascular risk, no treatment differs from placebo for vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background therapy, specific GLP-1 RAs and SGLT-2 inhibitors have a favorable effect on certain cardiovascular outcomes. Primary funding source European Foundation for the Study of Diabetes, supported by an unrestricted educational grant from AstraZeneca. (PROSPERO: CRD42019122043).

Systemic autoimmune inflammatory disorders confer a higher risk of cardiovascular (CV) disease leading to increased morbidity and mortality and reduced life expectancy compared to the general population. CV risk in systemic sclerosis (SSc) has not been studied extensively but surrogate markers of atherosclerosis namely carotid intima media thickness (cIMT) and pulse wave velocity (PWV) are impaired in some but not all studies in SSc patients. The aim of this study was to investigate the prevalence of subclinical atherosclerosis assessed by cIMT and PWV between two well-characterized SSc and Rheumatoid Arthritis (RA) cohorts. Consecutive SSc patients attending the Scleroderma Clinic were compared with RA patients recruited in the Dudley Rheumatoid Arthritis Co-morbidity Cohort (DRACCO), a prospective study examining CV burden in RA. Augmentation Index (Aix75) and cIMT were measured in all participants. Propensity score matching was utilised to select patients from the two cohorts with similar demographic characteristics, CV risk factors and inflammatory load. Unpaired analysis was performed using unpaired t test for continuous variables and χ2 test for dichotomous variables. Statistical analysis was repeated using paired t test for continuous normal variables and McNemar’s test for dichotomous variables. Fifty five age- and sex-matched SSc and RA patients were included in the analysis. No difference was demonstrated between SSc and RA subjects regarding cIMT (0.66 mm vs 0.63 mm, respectively) and Aix75% measurements (33.4 vs 31.7, respectively) neither in paired (p = 0.623 for cIMT and p = 0.204 for Aix%) nor in unpaired t test analysis (p = 0.137 for cIMT and p = 0.397 for AIx%). The results of this comparative study show that subclinical atherosclerosis is comparable between SSc and RA, a systemic disease with well-defined high atherosclerotic burden. Such findings underscore the importance of CV risk management in SSc in parallel with other disease-related manifestations.

Background Sclerostin and Dickkopf-related protein-1 (Dkk-1) proteins are inhibitors of the canonical Wnt/β-catenin bone pathway. Sclerostin but not Dkk-1 is associated with increased arterial stiffness. This study examined the prognostic significance of sclerostin and Dkk-1 levels for cardiovascular outcomes and mortality in haemodialysis (HD) patients. Methods Serum sclerostin and Dkk-1 levels were measured with enzyme-linked immunosorbent assay in 80 HD patients that were followed-up for a median of 45 months. Factors that could interfere with the association of sclerostin and Dkk-1 with outcomes [including carotid–femoral pulse wave velocity (PWV), parathyroid hormone (PTH), calcium–phosphate product and others] were assessed at baseline. The primary endpoint was a combination of all-cause death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, hospitalization for decompensated heart failure and new-onset atrial fibrillation. Secondary endpoints included cardiovascular and all-cause mortality. Results Cumulative freedom from the primary endpoint was significantly lower for higher tertiles of sclerostin (77.8, 69.2 and 40.7%; Tertiles 1–3, respectively; log-rank P = 0.004). The risk for the primary outcome gradually increased for higher sclerostin tertiles [Tertile 3: hazard ratio (HR) = 3.847, 95% confidence interval (CI) 1.502–9.851]. No significant association was evident between sclerostin and all-cause mortality, whereas higher sclerostin levels presented a trend towards higher risk for cardiovascular mortality. Dkk-1 levels exhibited no association with the risk of the primary or secondary endpoints. In stepwise Cox regression modelled analysis, sclerostin levels were associated with the primary outcome, independently of PTH, calcium–phosphate product, serum albumin, C-reactive protein and PWV levels (HR = 2.921, 95% CI 1.401–6.090; P = 0.004). Conclusions High sclerostin levels are associated with lower cumulative freedom and higher risk for a composite endpoint of cardiovascular events and mortality. Dkk-1 exhibited no association with the future risk of adverse outcomes.

Highlights • Immunothrombosis is the basis of many syndromes at patients with COVID-19. • Administration of thrombolysis and immunosuppression could be a therapeutic option. • Concurrent rt-PA and Tocilizumab infusion significantly improved our patient. • Patient's skin ischemia, Cytokine Release Syndrome and ARDS resolved. • Such therapeutic combinations could prove beneficial for patients with COVID-19., In a proportion of patients Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes a multi-systematic syndrome characterized by hyperinflammation, Acute Respiratory Distress Syndrome (ARDS) and hypercoagulability. A 68-year-old man with Coronavirus Disease 2019 (COVID-19) presented in our Intensive Care Unit (ICU) with respiratory failure, Cytokine Release Syndrome (CRS) and skin ischemia – microthrombosis. Specific coagulation and inflammatory markers (D-dimer, ferritin and C-reactive protein) along with the clinical picture triggered the trial of recombinant tissue plasminogen activator (rt-PA) and Tocilizumab. This was followed by resolution of skin ischemia and CRS while respiratory parameters improved. No major complications associated with rt-PA or Tocilizumab occurred. Combination of rt-PA with targeted anti-inflammatory treatment could be a new therapeutic option for patients with COVID-19, ARDS, hyperinflammation and increased blood viscosity.

Aim To assess the efficacy and safety of combination therapy with a glucagon-like peptide-1 receptor agonist (GLP-1 RA) and a sodium-glucose co-transporter-2 inhibitor (SGLT2i) in patients with type 2 diabetes. Methods We searched Medline, Embase, the Cochrane Library and grey literature sources up to 2 December 2019 for randomized controlled trials in adults with type 2 diabetes assessing the combination of GLP-1RA and SGLT2i, either as co-initiation therapy or as add-on to each other, against placebo or an active comparator. The primary outcome was change in HbA1c . Secondary outcomes included change in body weight, blood pressure and estimated glomerular filtration rate, and incidence of severe hypoglycaemia, all-cause mortality, cardiovascular mortality, myocardial infarction, stroke and hospitalization for heart failure. We pooled data using random effects meta-analyses. Results Seven trials (1913 patients) were eligible. Compared with GLP-1RA, GLP-1RA/SGLT2i combination therapy was associated with a greater reduction in HbA1c (weighted mean difference -0.61%, 95% CI -1.09% to -0.14%, four studies), body weight (-2.59 kg, -3.68 to -1.51 kg, three studies) and systolic blood pressure (-4.13 mmHg, -7.28 to -0.99 mmHg, four studies). Compared with SGLT2i, GLP-1RA/SGLT2i combination therapy reduced HbA1c (-0.85%, -1.19% to -0.52%, six studies) and systolic blood pressure (-2.66 mmHg, -5.26 to -0.06 mmHg, six studies), but not body weight (-1.46 kg, -2.94 to 0.03 kg, five studies). After excluding data for one trial that had a considerably longer duration than the remaining studies, body weight was also reduced versus SGLT2i (-1.79 kg, -2.99 to -0.59 kg, five studies). Combination therapy did not increase the incidence of severe hypoglycaemia. Data for mortality and cardiovascular outcomes were scarce. Conclusions GLP-1RA/SGLT2i combination therapy seems to reduce HbA1c , body weight and systolic blood pressure without increasing the risk of severe hypoglycaemia compared with either GLP-1RA or SGLT2i. No conclusions can be made regarding long-term effectiveness or the effect on cardiovascular outcomes.

A typical meteorological year (TMY) is a set of meteorological and solar radiation parameters usually consisting of hourly values in a year for a given geographical location. Such TMYs have been derived in many countries for various applications. In Greece, TMYs have been generated mainly for Athens. The present work derives TMYs for 33 locations in Greece distributed all over the country and covering its 4 climatic zones defined for energy purposes. The TMYs are based on meteorological data collected from the Hellenic National Meteorological Service network in Greece in the period 1985–2014. The solar radiation needed in the generation of the TMYs is derived by using the meteorological radiation model. The TMY at every one of the 33 locations is provided in 5 versions to adapt to the applications of meteorology-climatology, bio-meteorology, agro-meteorology-hydrology, photovoltaics, and energy design of buildings. The 5 versions of the TMYs are generated following the modified Sandia National Laboratories method. After their generation, each version of the TMYs at any of the 33 locations is compared with the annual- and monthly-averaged values of the selected parameters of the initial 30-year database. The comparison shows that the errors (differences) do not usually exceed 5%, thus supporting the fact that the so-derived TMYs are representative of the sites selected. Also, the distribution of the errors follows the normal distribution curve.

Currently, IgG is the only class of antibodies employed for cancer therapy. However, harnessing the unique biological properties of a different class ( e.g., IgE) could engender potent effector cell activation, and unleash previously untapped immune mechanisms against cancer. IgE antibodies are best known for pathogenic roles in allergic diseases and for protective effector functions against parasitic infestation, often mediated by IgE Fc receptor-expressing macrophages. Notably, IgE possess a very high affinity for cognate Fc receptors expressed by tumor-associated macrophages (TAMs). This paper reviews pre-clinical studies, which indicate control of cancer growth by tumor antigen-specific IgE that recruit and re-educate TAMs towards activated profiles. The clinical development harnessing the antitumor potential of recombinant IgE antibodies in cancer patients is also discussed.

Arterial stiffness is a strong predictor of death and cardiovascular (CV) events in hemodialysis patients. Only few studies tested interventions aiming to improve arterial stiffness in this population. This study examines the effect of dry-weight reduction with a standardized lung-ultrasound-guided strategy on ambulatory aortic blood pressure (BP) and arterial stiffness parameters in hemodialysis. Seventy-one clinically euvolemic hemodialysis patients with hypertension, were included in this single-blind randomized clinical-trial. Patients were randomized in the active group (n = 35), following dry-weight reduction guided by the total number of US-B lines before a mid-week dialysis session and the control group (n = 36), following standard treatment. Patients underwent office evaluation of arterial stiffness and 48-h ABPM to capture ambulatory central systolic (cSBP) and diastolic BP (cDBP) and arterial stiffness indexes at baseline and after 8-weeks. US-B lines decreased in the active and slightly increased in the control group (p

Chronic opioid usage not only causes addiction behavior through the central nervous system, but also modulates the peripheral immune system. However, how opioid impacts the immune system is still barely characterized systematically. In order to understand the immune modulatory effect of opioids in an unbiased way, here we perform single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from opioid-dependent individuals and controls to show that chronic opioid usage evokes widespread suppression of antiviral gene program in naive monocytes, as well as in multiple immune cell types upon stimulation with the pathogen component lipopolysaccharide. Furthermore, scRNA-seq reveals the same phenomenon after a short in vitro morphine treatment. These findings indicate that both acute and chronic opioid exposure may be harmful to our immune system by suppressing the antiviral gene program. Our results suggest that further characterization of the immune modulatory effects of opioid is critical to ensure the safety of clinical opioids., Over 100 million of opioid prescriptions are issued yearly in the USA alone, but the impact of opioid use on the immune system is barely characterized. Here the authors report antiviral immune response is blunted in several types of blood cells from opioid-dependent individuals, and when healthy donor cells are exposed to morphine in a dish.

Introduction Sublingual immunotherapy (SLIT) with birch pollen extract has been shown to be an efficacious treatment of allergic rhinitis (AR). An as-yet unanswered question is whether and how clinical benefit translates into patient benefit, i.e. what benefit patients derive from this treatment. Methods This 1-year, open, prospective, multicenter, non-interventional study conducted in 75 German centers measured patient-relevant benefit of birch pollen SLIT (Staloral® Birch) using the questionnaire “Patient Benefit Index for Allergic Rhinitis (PBI-AR)”. At treatment onset, patients rated the importance of 25 treatment needs; after the first birch pollen season on treatment, goal achievement was evaluated. A preference-weighted benefit index was calculated and its association with gender, asthma, allergy status, and severity of AR symptoms was determined. Results Mean age of the 291 adult patients was 38.8 years; 58.4% were female. The most important treatment goals were to “be able to stay outdoors without symptoms” (87.3% quite or very important), “no longer have a runny or stuffed-up nose” (86.9%), and “be able to breathe through your nose more freely” (86.9%). The treatment goals with the highest benefit ratings (referring to those patients to whom the respective goal applied) were to “have confidence in the therapy” (60.5% has helped “quite” or “very much”), “have an easily applicable treatment” (55.6%), and “be able to breathe through my nose more freely” (51.7%). The average PBI-AR global score was 2.19 (SD 1.04) (0–4; with 4 indicating maximum benefit). No significant differences in PBI-AR global score or subscales were found between men and women, poly- and monoallergic patients, or patients with severe versus mild rhinoconjunctivitis. Patients with asthma reported relevant but lower benefit than patients without asthma. Conclusion After 1 year of birch pollen SLIT treatment, patients reported considerable benefit, mainly due to a reduction of physical symptoms and treatment burden.

This study sought to examine the utility of multimodality intravascular imaging and of the endothelial shear stress (ESS) distribution to predict atherosclerotic evolution.There is robust evidence that intravascular ultrasound (IVUS)-derived plaque characteristics and ESS distribution can predict, with however limited accuracy, atherosclerotic evolution; nevertheless, it is yet unclear whether multimodality imaging and ESS mapping enable more accurate prediction of coronary plaque progression.A total of 44 patients admitted with a myocardial infarction that had successful revascularization and 3-vessel IVUS and optical coherence tomography (OCT) imaging at baseline and 13-month follow-up were included in the study. The IVUS data acquired at baseline in the nonculprit vessels were fused with x-ray angiography to reconstruct coronary anatomy and in the obtained models blood flow simulation was performed and the ESS was estimated. The baseline plaque characteristics and ESS distribution were used to identify predictors of disease progression: defined as a lumen reduction and an increase in plaque burden at follow-up.Seventy-three vessels were included in the final analysis. Baseline ESS and the IVUS-derived but not the OCT-derived plaque characteristics were independently associated with a decrease in lumen area and an increase in plaque burden. Low ESS (odds ratio: 0.45; 95% confidence interval: 0.28 to 0.71; p 0.001) and plaque burden (odds ratio: 0.73; 95% confidence interval: 0.54 to 0.97; p = 0.030) were the only independent predictors of disease progression at follow-up. The accuracy of the IVUS-derived plaque characteristics in predicting disease progression did not improve when ESS (AUC: 0.824 vs. 0.847; p = 0.127) or when OCT variables and ESS (AUC: 0.842; p = 0.611) were added into the model.ESS and OCT-derived variables did not improve the efficacy of IVUS in predicting disease progression. Further research is required to investigate whether multimodality imaging combined with ESS mapping will allow more reliable vulnerable plaque detection. (Comparison of Biomatrix Versus Gazelle in ST-Elevation Myocardial Infarction [STEMI] [COMFORTABLE]; NCT00962416).

Background: The nature of humoral immunity in carcinogenesis remains poorly understood. In this systematic review and meta-analysis, we aimed to evaluate the association of serum immunoglobulin classes with solid cancer and test our hypothesis that the immune escape of tumors is accompanied by dysregulated systemic immunoglobulin class-switching. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched the Cochrane Library, Embase, and MEDLINE/PubMed databases for observational studies investigating the association between serum immunoglobulins (IgA, IgG, and IgM) and histologically confirmed diagnosis of solid cancer in adults. We selected case–control studies, including more than 20 cases, and those explicitly stating that no form of anticancer treatment was administered prior to immunoglobulin measurement. No eligible cohort studies were identified. The primary summary measure was the standardized mean difference (SMD) with 95% confidence intervals (CI) calculated using a random effects model. Results: Pooling 11 eligible studies comparing serum IgA levels in 1,351 patients and 560 control subjects revealed a statistically significant SMD (1.50; 95% CI, 0.96–2.04). Nonsignificant SMDs were observed for the 14 selected studies investigating serum IgG [SMD, −0.02 (95% CI, −0.22 to 0.18)] and for the 10 studies reporting serum IgM [SMD, 0.11 (95% CI, −0.10 to 0.32)]. Substantial heterogeneity between studies was observed despite sensitivity analysis by immunoglobulin measurement method, control matching, type of cancer, stage of disease, and sequential study exclusion. Conclusions: Serum immunoglobulin levels in patients diagnosed with solid cancer might be skewed toward class-switching to IgA, possibly reflecting Th2-polarized immunity. Impact: Further combinatorial analyses of serum immunoglobulin isotypes alongside other immune parameters in databases and observational studies are warranted.