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Drug-induced liver injury is a leading cause of compound attrition during both preclinical and clinical drug development, and early strategies are in place to tackle this recurring problem. Human-relevant in vitro models that are more predictive of hepatotoxicity hazard identification, and that could be employed earlier in the drug discovery process, would improve the quality of drug candidate selection and help reduce attrition. We present an evaluation of four human hepatocyte in vitro models of increasing culture complexity (i.e., two-dimensional (2D) HepG2 monolayers, hepatocyte sandwich cultures, three-dimensional (3D) hepatocyte spheroids, and precision-cut liver slices), using the same tool compounds, viability end points, and culture time points. Having established the improved prediction potential of the 3D hepatocyte spheroid model, we describe implementing this model into an industrial screening setting, where the challenge was matching the complexity of the culture system with the scale and throughput required. Following further qualification and miniaturization into a 384-well, high-throughput screening format, data was generated on 199 compounds. This clearly demonstrated the ability to capture a greater number of severe hepatotoxins versus the current routine 2D HepG2 monolayer assay while continuing to flag no false-positive compounds. The industrialization and miniaturization of the 3D hepatocyte spheroid complex in vitro model demonstrates a significant step toward reducing drug attrition and improving the quality and safety of drugs, while retaining the flexibility for future improvements, and has replaced the routine use of the 2D HepG2 monolayer assay at GlaxoSmithKline.

Aims The current study evaluated the association of echocardiography, cardiac magnetic resonance (CMR), and ferritin data with 10-year survival in thalassemia patients. Methods Demographics, ferritin, echocardiography, and CMR parameters of stable consecutive thalassemia patients were prospectively collected. Results In total, 75 patients (mean age 37 ± 11 years, 45% male) with thalassemia were included and dichotomized based on their survival status after a median follow-up period of 10.3 [9.6-10.9] years. Older age (HR: 1.071, p = 0.001), ferritin ≥2000 ng/ml (HR: 4.682, p = 0.007) and ≥1700 ng/ml (HR: 7.817, p = 0.002), elevated LV end-diastolic pressure (HR: 1.019, p = 0.044), TR Vmax >2.8 m/s (HR: 6.845, p = 0.005), and CMR T2∗ ≤20 msec (HR: 3.602, p = 0.043) and ≤34 msec (HR: 5.854, p = 0.026) were associated with increased all-cause mortality (primary endpoint). A baseline model including age was created and became more predictive of worse survival by adding TR Vmax >2.8 m/s instead of elevated LV end-diastolic pressure (C index 0.767 vs. 0.760, respectively), ferritin ≥1700 ng/ml instead of ≥2000 ng/ml (C index 0.890 vs. 0.807, respectively), or CMR T2∗≤34 msec instead of ≤20 msec (C index 0.845 vs. 0.839, respectively). Parameters associated with the combined endpoint of cardiac mortality/cardiac hospitalization (secondary endpoint) after adjusting for age were ferritin ≥1700 ng/ml (HR 3.770, p = 0.014), ratio E/A wave >2 (HR 3.565, p = 0.04), TR Vmax >2.8 m/s (HR 4.541, p = 0.049), CMR T2∗ ≤20 ms (HR 9.462, p = 0.001), and CMR T2∗ ≤34 ms (HR 11.735, p = 0.002). The model including age and T2∗ ≤34 ms instead of T2∗ ≤20 ms was more predictive of the secondary endpoint (C-index 0.844 vs 0.838, respectively). Conclusions In thalassemia patients, TR Vmax >2.8 m/s, ferritin ≥2000 ng/ml, and CMR T2∗ ≤20 ms were associated with worse long-term survival. In the current era of advanced chelation therapy, aiming for ferritin ≤1700 ng/ml and CMR T2∗ ≥34 ms may improve their prognosis.

Chemotherapy-associated steatosis is poorly understood in the context of colorectal cancer. In this study, Stage II–III colorectal cancer patients were retrospectively selected to evaluate the frequency of chemotherapy-associated steatosis and to determine whether patients on statins throughout adjuvant chemotherapy develop chemotherapy-associated steatosis at a lower frequency. Baseline and incident steatosis for up to one year from chemotherapy start date was assessed based on radiology. Of 269 patients, 76 (28.3%) had steatosis at baseline. Of the remaining 193 cases, patients receiving adjuvant chemotherapy (n = 135) had 1.57 (95% confidence interval [CI], 0.89 to 2.79) times the adjusted risk of developing steatosis compared to patients not receiving chemotherapy (n = 58). Among patients who underwent chemotherapy, those using statins for pre-existing hyperlipidemia (n = 37) had 0.71 (95% CI, 0.10 to 2.75) times the risk of developing steatosis compared to patients who were not prevalent users of statins (n = 98). Chemotherapeutic treatment of Stage II–III colorectal cancer appears to be consistent with a moderately increased risk of steatosis, although larger studies are necessary to assess the significance of this observation. Prospective trials should be considered to further explore the potential for protective use of statins in this curative patient population.

Primary aldosteronism (PA) is the most common endocrine cause of arterial hypertension. Despite the increasing incidence of hypertension worldwide, the true prevalence of PA in hypertension was only recently recognized. The objective of the work was to estimate the prevalence of PA in patients at different stages of hypertension based on a newly developed screening-diagnostic overnight test. This is a prospective study with hypertensive patients (n=265) at stage I (n=100), II (n=88), and III (n=77) of hypertension. A group of 103 patients with essential hypertension without PA was used as controls. PA diagnosis was based on a combined screening-diagnostic overnight test, the Dexamethasone-Captopril-Valsartan Test (DCVT) that evaluates aldosterone secretion after pharmaceutical blockade of angiotensin-II and adrenocorticotropic hormone. DCVT was performed in all participants independently of the basal aldosterone to renin ratio (ARR). The calculated upper normal limits for post-DCVT aldosterone levels [3 ng/dl (85 pmol/l)] and post-DCVT ARR [0.32 ng/dl/μU/ml (9 pmol/IU)] from controls, were applied together to establish PA diagnosis. Using these criteria PA was confirmed in 80 of 265 (30%) hypertensives. The prevalence of PA was: 21% (21/100) in stage I, 33% (29/88) in stage II, and 39% (30/77) in stage III. Serum K+ levels were negatively correlated and urinary K+ was positively correlated in PA patients with post-DCVT ARR (r=–0.349, p

Background and Objective: Cancer and diabetes are two highly prevalent diseases worldwide and greatly influence quality of life of those suffering from it. The study aimed to compare quality of life in patients diagnosed with cancer and diabetes with those without diabetes both undergoing chemotherapy and to investigate the factors responsible for the difference between the two groups. Methods: A convenience sample of 101 participants who had cancer and type 2 diabetes and 99 who had cancer without diabetes were used. Results: Patients with comorbid diabetes were divided based on their diabetes duration and whether they had glycaemic control or not. Diabetic cancer patients without glycaemic control had lower scores in global health status and in physical and emotional functioning compared to diabetic cancer patients with glycaemic control and patients without diabetes (p < .05). After adjusting for demographic characteristics, the differences between the group with diabetes and without glycaemic control and the other two groups regarding global health status were statistically significant (p < .05). Patients with more than a 7-year history of diabetes had a significantly lower emotional functioning than the no diabetes group and lower global health status score than both of the other groups (p < .05). After adjusting for clinical and demographic characteristics, only the difference between the ≥ 7 years diabetes duration group and the no diabetes groups remained significant. Conclusion: The presence of diabetes in cancer patients who underwent chemotherapy seems to negatively influence certain domains of quality of life and this may be affected by the duration of diabetes and whether glycaemic control has been achieved or not.

Air embolism (a result of direct communication with the vasculature and an external pressure gradient from the gastrointestinal or the biliary tract), although rare, is a potentially devastating adverse event seen in endoscopic retrograde cholangiopancreatography (ERCP) procedures. Whether venous, arterial, or paradoxical, the clinical presentation ranges from asymptomatic patients to cardiorespiratory arrest. This is of particular importance because it makes the diagnosis of air embolism even more difficult in an already sedated patient. Since early recognition increases the chances of patients’ survival, endoscopists should be highly motivated and trained to recognize this complication as early as possible. With only 60 cases of air embolism reported (and even fewer related to paradoxical air embolism), we aimed to report a case of paradoxical cerebral air embolism in a patient undergoing ERCP due to a common bile duct stricture and to provide a mini-review of this clinical entity that can serve as a bedside quick reference guide for endoscopists worldwide.

A substantial number of pregnant women at some point experience cardiac arrhythmia, which is mostly treated by antiarrhythmic medication. In some instances, arrhythmias can be drug-resistant and pose a relevant risk to both mother and unborn child as they can result in hemodynamic compromise. In recent years, invasive electrophysiology procedures have been carried out with ever reducing exposure to ionising radiation, and multiple techniques have been established to achieve ZERO exposure. Of course, these techniques should all be applied when contemplating an invasive mapping and ablation procedure during pregnancy. The role of the cardio-obstetrics team in planning and performing such procedures is paramount. Careful assessment of the pregnant mother and her unborn child is mandatory. Only with good preparation is a complete understanding of both cardiac anatomy and physiology achievable, which is a pre-requisite of a successful ablation outcome. Various aspects of the ablation procedure itself are discussed and evaluated from the perspective of all team members involved, including the obstetrician, the anaesthetist and the electrophysiologist. This review aims to inform the reader about the techniques available and reports on the published outcomes for ablations during pregnancy in the last decade.

Aim: to describe diabetes nurses' perspectives on the impact of the COVID-19 pandemic on people with diabetes and diabetes services across Europe. Methods: an online survey developed using a rapid Delphi method. The survey was translated into 17 different languages and disseminated electronically in 27 countries via national diabetes nurse networks. Results: survey responses from 1829 diabetes nurses were included in the analysis. The responses indicated that 28% (n = 504) and 48% (n = 873) of diabetes nurses felt the COVID-19 pandemic had impacted 'a lot' on the physical and psychological risks of people with diabetes, respectively. The following clinical problems were identified as having increased 'a lot': anxiety 82% (n = 1486); diabetes distress 65% (n = 1189); depression 49% (n = 893); acute hyperglycaemia 39% (n = 710) and foot complications 18% (n = 323). Forty-seven percent (n = 771) of respondents identified that the level of care provided to people with diabetes had declined either extremely or quite severely. Self-management support, diabetes education and psychological support were rated by diabetes nurse respondents as having declined extremely or quite severely during the COVID-19 pandemic by 31% (n = 499), 63% (n = 1,027) and 34% (n = 551), respectively. Conclusion: the findings show that diabetes nurses across Europe have seen significant increases in both physical and psychological problems in their patient populations during COVID-19. The data also show that clinical diabetes services have been significantly disrupted. As the COVID-19 situation continues, we need to adapt care systems with some urgency to minimise the impact of the pandemic on the diabetes population., Foundation of European Nurses in Diabetes

Background: Diabetic Nephropathy is a frequent complication of diabetes mellitus due to functional and structural modifications in multiple kidney compartments. Probiotics have risen lately as a forthcoming therapeutic intervention but they have not been systematically evaluated in diabetic nephropathy so far. The aim of this systematic review was to evaluate randomized controlled trials and experimental studies assessing the effect of probiotic supplements on diabetic nephropathy. Methods: An extensive literature search was conducted through electronic databases (PubMed, Scopus, Cinahl and Medline) with the Medical Subject Headings and entry terms of “diabetic nephropathy”, “diabetic renal disease” and “probiotics”. The search yielded 116 results, 9 of which met the inclusion criteria for this systematic review. Results: Most of the microorganisms used in the studies belonged to the Lactobacillus and Bifidobacterium genus. The dosage ranged from 2×107 to 6×1010 CFU/ g. The form of the probiotics varied across the studies (capsules, sachets, soy milk, kefir and honey). The majority of the studies demonstrated the benefits of probiotic supplementation on the reduction of inflammation, oxidative stress and on the amelioration of renal function biomarkers in subjects with diabetic nephropathy. No major gastrointestinal adverse events were observed during the intervention time with probiotics. Conclusion: : Findings of this systematic review demonstrate the positive impact of probiotics on Diabetic Nephropathy without any major adverse events. Moreover, future larger randomized controlled trials with bigger samples and longer follow-up time are deemed necessary for further valid results on the effectiveness of probiotic supplementation on Diabetic Nephropathy.

Thalassemia Major (TM) is a hereditary disease caused by defective globin synthesis. Because of the significant increase in life expectancy, these patients suffer from various health conditions, including endocrinopathies and low bone mineral density.Aim:The aim of the present study was to evaluate the fracture incidence regarding the markers of bone metabolism, bone mineral density and treatment of osteoporosis as well as treatment of comorbidities.Methods:Sixty-four patients with TM (32 men and 32 women) participated in a cross-sectional study design. The patients were recruited from “Aghia Sofia” Children’s Hospital and evaluated using dual-energy X-ray absorptiometry (DXA) of the lumbar spine and femoral neck and with markers of bone remodeling including receptor activator of nuclear factor kappa-Β ligand (RANKL), osteoprotegerin (OPG), C-terminal telopeptide (CTX), and sclerostin.Results:The statistical analysis of markers of bone metabolism in relation to fractures revealed no statistical significance. However, statistical analysis of bone mineral density and markers of bone metabolism in relation to fractures was also not significant.Conclusions:In TM patients, fractures are not related to bone mineral density. Maybe some other conditions are the cause, haemosidirosis, drugs, comorbid conditions.

Objectives To determine predictive values of isolated and combined ultrasound signs in the diagnosis of adnexal torsion. Methods This work was a retrospective study of 129 adult female patients who underwent an ultrasound examination followed by a definitive surgical procedure within a 24-hour period to determine whether adnexal torsion was present. Results The positive predictive value (PPV) of the ultrasound diagnosis of adnexal torsion was 82.2%. The statistically significant ultrasound signs in multivariate logistic regression with single-predictor analyses were relative enlargement of the ovary, an abnormal adnexal position, a twisted vascular pedicle, and the follicular edema "ring sign." Possible combinations of these ultrasound criteria showed high specificities (74%-100%), high PPVs (93%-100%), and lower sensitivities (29%-71%) and negative predictive values (24%-35%). Any combination that included a twisted vascular pedicle or the follicular ring sign as one of the signs had high odds ratios and positive likelihood ratios. Conclusions Ultrasound has a high PPV as a first-choice imaging modality in the diagnosis of adnexal torsion. The combinations of the following 4 statistically significant ultrasound signs, consisting of an abnormal position, relative enlargement of the index ovary, a twisted vascular pedicle, and the follicular edema ring sign, substantially narrow the imaging differential diagnosis in such cases. The presence of vascular pedicle twisting and the follicular ring sign was highly associated with a positive ovarian torsion diagnosis, with 100% specificity.

A rapid and deep haematologic response is fundamental in order to improve outcomes of patients with AL amyloidosis. We evaluated the impact of timing and depth of haematologic response at early time points (at 1 and 3 months from the start of therapy) in 227 consecutive previously untreated AL patients, who received bortezomib-based primary therapy. After 1 month of therapy, 30.5% had ≥VGPR, 28% PR and 36% no response (NR), with 11% having iFLC

Sarcomas are a rare group of neoplasms with a mesenchymal origin that are mainly characterized by the abnormal growth of connective tissue cells. The standard treatment for local control of sarcomas includes surgery and radiation, while for adjuvant and palliative therapy, chemotherapy has been strongly recommended. Despite the availability of multimodal therapies, the survival rate for patients with sarcoma is still not satisfactory. In recent decades, there has been a considerable effort to overcome chemotherapy resistance in sarcoma cells. This has led to the investigation of more cellular compounds implicated in gene expression and transcription processes. Furthermore, it has been discovered that histone acetylation/deacetylation equilibrium is affected in carcinogenesis, leading to a modified chromatin structure and therefore changes in gene expression. In addition, histone deacetylase inhibition is found to play a key role in limiting the tumor burden in sarcomas, as histone deacetylase inhibitors act on well-described oncogenic signaling pathways. Histone deacetylase inhibitors disrupt the increased cell motility and invasiveness of sarcoma cells, undermining their metastatic potential. Moreover, their activity on evoking cell arrest has been extensively described, with histone deacetylase inhibitors regulating the reactivation of tumor suppressor genes and induction of apoptosis. Promoting autophagy and increasing cellular reactive oxygen species are also included in the antitumor activity of histone deacetylase inhibitors. It should be noted that many studies revealed the synergy between histone deacetylase inhibitors and other drugs, leading to the enhancement of an antitumor effect in sarcomas. Therefore, there is an urgent need for therapeutic interventions modulated according to the distinct clinical and molecular characteristics of each sarcoma subtype. It is concluded that a better understanding of histone deacetylase and histone deacetylase inhibitors could provide patients with sarcoma with more targeted and efficient therapies, which may contribute to significant improvement of their survival potential.

Highlights • Peritoneal carcinomatosis with concurrent liver metastases should not be treated as end stage disease. • IPAA anastomosis can be applied simultaneously with HIPEC, improving quality of life especially for Familial Adenomatosis Polyposis patients. • HIPEC as a prognostic factor of anastomotic healing; ileorectal anastomosis. • Liver metastasectomy with cytoreductive surgery and HIPEC may prolong survival., Introduction Cytoreductive surgery (CRS) with hyperthermal intraperitoneal chemotherapy (HIPEC) are established treatments for peritoneal carcinomatosis that prolong survival in carefully selected patients. At the time of diagnosis, 4–7% of patients with colorectal cancer (CRC) have metastasis to the peritoneum. There is a lack of evidence in the literature if J-pouch can be applied simultaneously with HIPEC to improve quality of life in patients with familial adenomatous polyposis syndrome (FAP) and peritoneal carcinomatosis. Case presentation We describe a case of a 41-year-old Caucasian male with Familial Adenomatous Polyposis which was diagnosed as metastatic colorectal cancer in the liver and peritoneum. He was treated with systemic chemotherapy followed by total proctocolectomy with a J-shaped IPAA, liver metastasectomy, right hemidiaphragm resection, CRS and HIPEC. Discussion CRS and HIPEC have been implicated with high morbidity and mortality rates. A major independent risk factor correlated with high morbidity is anastomotic failure. J-Pouch formation although considered a technique with high complication rates, improves the quality of life of patients after total proctocolectomy and is related to high patient satisfaction. There are inconclusive data on whether anastomotic failure rates are higher when performing J-Pouch and HIPEC together. Conclusions J-Pouch after CRS and HIPEC can be offered as a treatment as long as the patient is carefully selected, in high volume centers with experienced surgeons.

Significance Malaria is transmitted among humans through mosquito bites. Here, we characterize a protein found on the surface of mosquito stages of malaria parasites and reveal that it serves to evade the mosquito immune system and ensure disease transmission. Neutralization of PIMMS43 (Plasmodium Infection of the Mosquito Midgut Screen 43), either by eliminating it from the parasite genome or by preincubating parasites with antibodies that bind to the PIMMS43 protein, inhibits mosquito infection with malaria parasites. Differences in PIMMS43 detected between African malaria parasite populations suggest that these populations have adapted for transmission by different mosquito vectors that are also differentially distributed across the continent. We conclude that targeting PIMMS43 can block malaria parasites inside mosquitoes before they can infect humans., After being ingested by a female Anopheles mosquito during a bloodmeal on an infected host, and before they can reach the mosquito salivary glands to be transmitted to a new host, Plasmodium parasites must establish an infection of the mosquito midgut in the form of oocysts. To achieve this, they must first survive a series of robust innate immune responses that take place prior to, during, and immediately after ookinete traversal of the midgut epithelium. Understanding how parasites may evade these responses could highlight new ways to block malaria transmission. We show that an ookinete and sporozoite surface protein designated as PIMMS43 (Plasmodium Infection of the Mosquito Midgut Screen 43) is required for parasite evasion of the Anopheles coluzzii complement-like response. Disruption of PIMMS43 in the rodent malaria parasite Plasmodium berghei triggers robust complement activation and ookinete elimination upon mosquito midgut traversal. Silencing components of the complement-like system through RNAi largely restores ookinete-to-oocyst transition but oocysts remain small in size and produce a very small number of sporozoites that additionally are not infectious, indicating that PIMMS43 is also essential for sporogonic development in the oocyst. Antibodies that bind PIMMS43 interfere with parasite immune evasion when ingested with the infectious blood meal and significantly reduce the prevalence and intensity of infection. PIMMS43 genetic structure across African Plasmodium falciparum populations indicates allelic adaptation to sympatric vector populations. These data add to our understanding of mosquito–parasite interactions and identify PIMMS43 as a target of malaria transmission blocking.

Purpose The purpose of this paper is to describe the development of a scale for the evaluation of the perceived quality of services provided to students with disabilities by Special Vocational Education (SVE) institutions in Greece. Design/methodology/approach SVE service quality was approached on the basis of the performance-only model. The participatory research paradigm was followed, engaging students with disability and specifically with intellectual disability in several stages of the instrument development. The methodological design included two phases for the establishment and testing of the reliability and validity of the scale. Findings The findings of the study support a multifactorial construct of SVE service quality consisting of five factors: responsiveness, surroundings, personalization, training and facilities adequacy. Research limitations/implications Generalization of results should be attempted with concern. The type and severity of disability should be considered in future use of the scale. The construct of training for students with disability needs to be further investigated. Practical implications SVE-Service-Quality Scale may be used in SVE settings highlighting areas of improvement or as an instrument for the assessment of implemented interventions. Social implications Participatory research may serve as an empowerment opportunity for students with disability, whose active engagement in the research design allows for a small-scale yet valuable social impact, promoting emancipation for people with disability. Originality/value The study draws attention on the field of SVE service quality where research is scarce, introducing SVE in the discussion about educational service quality assessment.

OBJECTIVE: To characterize in detail the electroclinical features of typical absence seizures and elucidate whether EEG or semiology features, alone or in combination, can predict long-term therapeutic outcome. METHODS: We analysed video-EEG recordings from 213 typical absence seizures from 61 patients with idiopathic generalized epilepsy. We extracted semiological features, in addition to hallmark manifestations (motor/behavioural arrest, non-responsiveness), their location, timing and frequency. We evaluated the duration and frequency of generalized spike-wave discharges and the presence of polyspikes. We used a supervised machine-learning approach (random forest) to search for classifier features for long-term therapeutic outcome (>one year). RESULTS: Besides the hallmark manifestations, additional semiological features were identified in 87% of patients (75% of seizures). The most common additional semiological features were automatisms and eye blinking (observed in 45% and 41.5% of seizures, respectively). Automatisms were associated with longer seizure duration, and oral automatisms occurred earlier compared to limb automatisms (4.03 vs. 6.19 seconds; p=0.005). The mean duration of the ictal spike-wave discharges was nine seconds, and the median frequency was 3 Hz. Polyspikes occurred in 46 seizures (21.6%), in 19 patients (31%). Median follow-up was five years, and 73% of the patients were seizure-free at the end of the follow-up. None of the semiological features, alone or in combination, were predictors of therapeutic outcome. The only significant classifier was the presence of polyspikes, predicting a non-seizure-free outcome with an accuracy of 73% (95% CI: 70-77%), positive predictive value of 92% (95% CI: 84-98%) and negative predictive value of 60% (95% CI: 39-81%). SIGNIFICANCE: Semiological features, in addition to behavioural arrest and non-responsiveness, are common in typical absence seizures, but they do not predict long-term therapeutic outcome. The presence of polyspikes has a high positive predictive value for unfavourable therapeutic outcome, and their presence should therefore be included when reporting EEGs in patients with typical absence seizures.

BACKGROUND Recently one randomized trial and several phase II studies underscored that patients with metastatic colorectal cancer who progressed after an initial clinical benefit from anti-epidermal growth factor receptor (EGFR) treatment may further benefit from rechallenge with anti-EGFR therapy. Testing circulating tumor DNA (ctDNA) RAS status prior to anti-EGFR rechallenge seems a promising non-invasive method to predict and monitor response to anti-EGFR readministration. AIM To assess the capability of liquid biopsy ctDNA in exploring RAS status and in predicting outcome of metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibody rechallenge. MATERIALS AND METHODS Systematic review of literature and meta-analysis of the available evidence. RESULTS Data from four studies involving 117 patients were available. All patients harbored RAS wild type tumors and derived benefit from first line anti-EGFR therapy. Of these, 65 underwent plasma ctDNA before anti-EGFR treatment rechallenge and were eligible for analyses: 35 patients had RAS wild type ctDNA, and 30 RAS mutated, indicating that 46% of patients underwent RAS status conversion after primary anti-EGFR therapy. Anti-EGFR rechallenge among patients with plasma ctDNA RAS wild type status was associated with a consistent benefit in progression free survival (hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.22-0.70; p = 0.001; I2 = 0) and overall survival (HR 0.37, 95% CI 0.16-0.85; p = 0.02; I2 = 74%) when compared to its use among patients with plasma ctDNA RAS mutation. Patients with plasma ctDNA RAS wild type profile also performed statistically better in term of disease control rate, risk for disease progression at 3 and 6 months, and risk for death at 6 and 12 months. CONCLUSION RAS status assessment continues to be useful in predicting benefit for anti-EGFR treatment.

Summary Bleeding and thrombosis are major complications in patients supported with extracorporeal membrane oxygenation (ECMO). In this multicentre observational study of 152 consecutive patients (≥18 years) with severe COVID‐19 supported by veno‐venous (VV) ECMO in four UK commissioned centres during the first wave of the COVID‐19 pandemic (1 March to 31 May 2020), we assessed the incidence of major bleeding and thrombosis and their association with 180‐day mortality. Median age (range) was 47 years (23–65) and 75% were male. Overall, the 180‐day survival was 70·4% (107/152). The rate of major bleeding was 30·9% (47/152), of which intracranial bleeding (ICH) was 34% (16/47). There were 96 thrombotic events (63·1%) consisting of venous 44·7% [68/152 of which 66·2% were pulmonary embolism (PE)], arterial 18·6% (13/152) and ECMO circuit thrombosis 9·9% (15/152). In multivariate analysis, only raised lactate dehydrogenase (LDH) at the initiation of VV ECMO was associated with an increased risk of thrombosis [hazard ratio (HR) 1·92, 95% CI 1·21‐3·03]. Major bleeding and ICH were associated with 3·87‐fold (95% CI 2·10–7·23) and 5·97‐fold [95% confidence interval (CI) 2·36–15·04] increased risk of mortality and PE with a 2·00‐fold (95% CI1·09–3·56) risk of mortality. This highlights the difficult balancing act often encountered when managing coagulopathy in COVID‐19 patients supported with ECMO.

Background:The spectrum of neurological and psychiatric complications associated with paediatric SARS-CoV-2 infection is poorly understood. We aimed to analyse the range and prevalence of these complications in hospitalised children and adolescents. Methods:We did a prospective national cohort study in the UK using an online network of secure rapid-response notification portals established by the CoroNerve study group. Paediatric neurologists were invited to notify any children and adolescents (age Findings:Between April 2, 2020, and Feb 1, 2021, 52 cases were identified; in England, there were 51 cases among 1334 children and adolescents hospitalised with COVID-19, giving an estimated prevalence of 3·8 (95% CI 2·9–5·0) cases per 100 paediatric patients. 22 (42%) patients were female and 30 (58%) were male; the median age was 9 years (range 1–17). 36 (69%) patients were Black or Asian, 16 (31%) were White. 27 (52%) of 52 patients were classified into the COVID-19 neurology group and 25 (48%) were classified into the PIMS-TS neurology group. In the COVID-19 neurology group, diagnoses included status epilepticus (n=7), encephalitis (n=5), Guillain-Barré syndrome (n=5), acute demyelinating syndrome (n=3), chorea (n=2), psychosis (n=2), isolated encephalopathy (n=2), and transient ischaemic attack (n=1). The PIMS-TS neurology group more often had multiple features, which included encephalopathy (n=22 [88%]), peripheral nervous system involvement (n=10 [40%]), behavioural change (n=9 [36%]), and hallucinations at presentation (n=6 [24%]). Recognised neuroimmune disorders were more common in the COVID-19 neurology group than in the PIMS-TS neurology group (13 [48%] of 27 patientsvs1 [vssix [22%] of 27 patients, p=0·0001) and received immunomodulatory treatment (22 [88%] patientsvs12 [44%] patients, p=0·045). 17 (33%) patients (10 [37%] in the COVID-19 neurology group and 7 [28%] in the PIMS-TS neurology group) were discharged with disability; one (2%) died (who had stroke, in the PIMS-TS neurology group). Interpretation:This study identified key differences between those with a primary neurological disorder versus those with PIMS-TS. Compared with patients with a primary neurological disorder, more patients with PIMS-TS needed intensive care, but outcomes were similar overall. Further studies should investigate underlying mechanisms for neurological involvement in COVID-19 and the longer-term outcomes.

Testicular metastases from ureteral carcinoma are rare and they are generally mimic orchiepididymitis. For this reason, these are associated to misleading diagnoses and cancer treatment delay. We believe that both timing and knowledge of genital blood and lymph reverse flow routes may represent two important parameters for avoiding misleading diagnoses and speed proper anticancer treatment. We describe a case and discuss pathophysiological data and relevant literature.

Tumors of the median nerve are difficult to diagnose and median nerve schwannomas are rare. During a ten-year period, we treated eleven median nerve schwannomas found on the hand (nine) and wrist (two). All the tumors were treated by enucleation under loupe magnification and tourniquet application. All had a favorable result at a mean follow up of five years. We present three of our most typical cases, with schwannomas found on the wrist, palm and thumb. We also review the literature offering a wider view on the pathology, diagnosis and treatment of schwannomas in general.

To gain insights into the characteristics of clinical resistance to lenalidomide, we evaluated the outcomes of 147 consecutive patients with multiple myeloma (MM) homogeneously treated with immunomodulatory imide drugs (IMiDs) pomalidomide and dexamethasone (Pd) for relapsed and/or refractory MM (median, 3 prior lines of treatment). We focused our analysis on the effect of the lenalidomide dose at which resistance was developed, the duration of lenalidomide exposure, and lenalidomide-free interval. On intent to treat, 33% of patients achieved ≥partial remission (PR) with Pd. When Pd was given immediately after lenalidomide, ≥PR was 32% (vs 37% after bortezomib). The response rates were similar for patients that received 5 to 15 mg vs 25 mg of lenalidomide (38.5% vs 30.5%, P = .329). Response rates were higher for patients that had received at least 12 months of lenalidomide (44% vs 27%) and for those with ≥18 months from last lenalidomide dose to pomalidomide dose (65% vs 23%). Median progression-free survival (PFS) and overall survival (OS) were 5 and 12.1 months, respectively, which was similar for patients who received lenalidomide, bortezomib or other regimens just before Pd and similar for patients who were receiving different doses of lenalidomide. IMiD-free interval ≥18 months was associated with longer PFS (10.3 vs 3.9 months, P = .003) and OS (27.1 vs 9.3, P = .008) as well as duration of last lenalidomide therapy ≥12 months (PFS: 7.8 vs 3.2, P = .023; OS: 16.5 vs 7.9, P = .005) even after adjustment for the number of prior therapies, duration of disease, and last lenalidomide dose.

Background/aim Osteopetrosis is an inherited disease characterized by increased bone density. Its genetic variability results in various phenotype expressions, whereas clinically are classified in three types: malignant infantile, intermediate and adult. The various oral manifestations of the disease give a crucial role to the pediatric dentists in diagnosis. Case presentation A 7-year-old girl with persistent swelling on right cheek visited a pedodontic clinic. After extra- and intra-oral examination/findings, the patient was referred for further investigation concerning a possible general pathological background. An extraction, included in the initial dental treatment plan, led to the diagnosis of osteopetrosis. Various medical examinations co-led to the diagnosis of osteopetrosis but without genetic identification. Extractions of carious teeth, under general anesthesia, and full cover or sealants, on chair, of unaffected teeth were conducted respectively to minimize the microbial load and to prevent from osteomyelitis relapse and new caries. Two more general anesthesia sessions took place due to relapse of lower jaw osteomyelitis. Follow-up was conducted every 3 months for 2 years. Conclusion Osteopetrosis' diagnosis can be triggered by its oral manifestations (rampant caries, osteonecrosis, enamel defects, malformed roots/crowns, missing teeth), for which the pediatric dentist could be the first observer. Management of these patients needs multidisciplinary approach and follow-up appointments should be very frequent.

Background Smoking has been consistently associated with increased cardiovascular risk in adults. Although exposure to tobacco products often starts in early life, evidence for the possible adverse effects on the cardiovascular system of the young is scarce. We sought to derive pooled estimates of smoking effects on indices of early vascular damage in children and adolescents. Design and methods We performed a systematic review and meta-analysis of clinical studies involving young individuals up to 21 years old that provided data on smoking exposure (active or passive) and flow-mediated dilatation, carotid to femoral pulse wave velocity and maximum carotid intima-media thickness. We employed three distinct methodologies of random-effects data synthesis, including the Sidik-Jonkman estimator, the Hartung and Knapp correction and a Bayesian method with a well-informed prior on the level of between-study variance. Results In 12 studies and 5279 individuals in total, smoking exposure was related to deterioration in all three outcomes (mean adjusted flow-mediated dilatation decrease: −0.77%, 95% confidence interval −1.38–−0.15, mean adjusted pulse wave velocity increase: 0.1 m/s, 95% confidence interval 0.02–0.17 and mean adjusted carotid intima-media thickness increase: 0.35 mm, 95% confidence interval 0.16–0.55, for the Sidik-Jonkman estimator). No difference was established between active and passive smoking on associations with arterial damage. Conclusions Exposure to tobacco products is associated with subclinical vascular damage early in life, even from childhood. Public health initiatives should target these very young age groups to prevent early smoking exposure and associated arterial damage and its sequelae.

OBJECTIVE. The purpose of this study was to identify the sensitivity of contrast-enhanced CT in detecting high-grade prostate adenocarcinoma. MATERIALS AND METHODS. A retrospective analysis included 100 patients with prostate cancer proven by biopsy between January 2010 and December 2017 who underwent staging CT of the abdomen and pelvis within 3 months of diagnosis. The control subjects were 100 randomly selected aged-matched male outpatients with no known history of malignancy who underwent contrast-enhanced CT of the abdomen and pelvis in the same time period as the patients with cancer. Two readers, blinded to both groups, independently assessed the likelihood of prostate cancer on the basis of the CT finding of focal abnormally increased peripheral enhancement in the prostate. Binary classification of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) was used to assess the diagnostic utility of CT versus the reference standard of transrectal ultrasound-guided biopsy. RESULTS. Eighty-three of 100 patients with biopsy-proven prostate cancer and 92 of 100 control subjects were correctly identified (sensitivity, 0.83; specificity, 0.92; PPV, 0.91; NPV, 0.84). There was no significant difference in diagnostic accuracy among subjects with different Gleason scores. Interrater agreement on both the cancer and control patients was 0.76 as assessed by Cohen kappa statistic. CONCLUSION. Incidental detection of a focal area of increased enhancement in the periphery of the prostate at contrast-enhanced CT may represent a clinically significant cancer and deserves further workup with prostate-specific antigen measurement and correlation with clinical risk factors for prostate cancer.

Background: Achieving low-density lipoprotein cholesterol (LDL-C) target levels after an acute coronary syndrome (ACS) is of paramount importance, and is often burdened by undertreatment and medication or lifestyle non-adherence issues. Objective: We examined the effect of a patient-centered, physician-led motivational intervention following ACS on relevant secondary prevention aspects. Methods-design: The IDEAL-LDL is a single-center, randomized controlled clinical trial, conducted among patients hospitalized due to an ACS. Following discharge, all patients undergo a baseline assessment of lipid profile. Patients in the intervention group receive an in-person educational session and an informative leaflet, and also undergo two phone-based, motivational interviewing sessions at 1 and 6 months. These interventions emphasize on LDL-C goals, adherence to lipid-lowering medication, and healthy dietary-lifestyle habits, and are not provided to patients in the control group, who receive usual care. At 12 months after each patient's discharge, an in-person interview and lipid profile reassessment are performed. The primary outcomes are the assessment of LDL-C goal achievement (50% reduction from baseline levels) from baseline to 1 year and changes in medication adherence. Secondary outcomes relate to the incidence of the composite outcome of cardiovascular death, nonfatal myocardial infarction/stroke, need for myocardial revascularization, and recurrent hospitalization during the follow-up period. Discussion: This paper describes the protocol, design, and rationale for key methodology for an ongoing clinical trial featuring a simple and feasible intervention. Similar adherence efficacy trials have not led to sufficient improvements, and there remains a gap regarding how adherence interventions should be implemented into clinical care. Keywords: Acute coronary syndrome, Dyslipidemia, Statin therapy, Medication adherence, Lifestyle modification

Background: Considering the increasing burden of cardiovascular risk factors and recent advances on the management of acute coronary syndromes (ACS), we studied the epidemiological characteristics ...

To determine the diagnostic accuracy of focused appendiceal CT as a feasible alternative to the standard CT of the abdomen and pelvis (CT-AP) in patients with suspected acute appendicitis. Retrospective review of 200 adults with suspected acute appendicitis between January and October 2016 were included in this study. Each patient underwent CT-AP with oral and intravenous (IV) contrast. A subset of axial images starting at the top of L4 vertebral body to the roof of the acetabula were obtained from each study which served as the focused appendiceal CT. After review of the focused CTs, the non-focused CT-AP scans were reviewed, each patient acting as their own control. Images were assessed for ability to identify the appendix, assess for appendicitis, or identify alternative diagnoses that could account for the presenting symptoms. Of 200 cases, the appendix was visualized in the focused CT in 191 patients. In nine studies, the appendix was not visualized in focused or standard CT-AP. Using focused CT, 42 cases were positive for acute appendicitis. This result was identical when reviewing standard CT-AP. Alternative diagnoses were present in 38 patients. Using focused CT, 14 of these were not fully covered but the readers were able to make the diagnoses confidently on the focused CTs. Only one patient had acute non-appendiceal pathology mostly outside of the field of view. Focused appendiceal CT with IV and oral contrast in the setting of clinically suspected appendicitis is a suitable alternative to conventional CT-AP.

Background: Recent coronary stent implantation requires Dual Antiplatelet Therapy (DAPT) for at least 6 months. Serious issues are raised when non-cardiac surgery is required during this period, because of the balance between ischemic and haemorrhagic complications. Case Reports: We report 2 high ischemic risk cases requiring intermediate bleeding risk non-cardiac surgery, during the first month of DAPT initiation. Perioperative management with discontinuation of the P2Y12 inhibitor and bridging with tirofiban, while aspirin was uninterrupted, was uneventful. Conclusion: Bridging with intravenous glycoprotein IIb/IIIa receptor inhibitors may be a safe and effective alternative to P2Y12 inhibitor discontinuation in non-deferrable non-cardiac surgery.

Epilepsy is a neurological disorder mainly characterised by recurrent seizures that affect the entire population diagnosed with the condition. Currently, there is no cure for the disease and a significant proportion of patients have been deemed to have treatment-resistant epilepsy (TRE). A patient is deemed to have TRE if two or more antiepileptic drugs (AEDs) fail to bring about seizure remission. This inefficacy of traditional AEDs, coupled with their undesirable side effect profile, has led to researchers considering alternative forms of treatment. Phytocannabinoids have long served as therapeutics with delta-9-THC (Δ9-THC) receiving extensive focus to determine its therapeutic potential. This focus on Δ9-THC has been to the detriment of analysing the plethora of other phytocannabinoids found in the cannabis plant. The overall aim of this review is to explore other novel phytocannabinoids and their place in epilepsy treatment. The current review intends to achieve this aim via an exploration of the molecular targets underlying the anticonvulsant capabilities of cannabidiol (CBD), cannabidavarin (CBDV), delta-9-tetrahydrocannabivarin (Δ9-THCV) and cannabigerol (CBG). Further, this review will provide an exploration of current pre-clinical and clinical data as it relates to the aforementioned phytocannabinoids and the treatment of epilepsy symptoms. With specific reference to epilepsy in young adult and adolescent populations, the exploration of CBD, CBDV, Δ9-THCV and CBG in both preclinical and clinical environments can guide future research and aid in the further understanding of the role of phytocannabinoids in epilepsy treatment. Currently, much more research is warranted in this area to be conclusive.

The aim of the study was to investigate the relation between subjective quality of life and quality of vocational education services from the view of students with intellectual disability who participate in public special vocational education schools in Greece. The level of quality of life and quality of special vocational education services was explored. The article presents a functional description of service quality in special vocational education and operationalizes quality of life for students with disability. Instruments were developed and adapted in line with the participatory research paradigm. Convenience sampling was used. Data was gathered from 131 students with intellectual disability. All measures showed good evidence of internal consistency and construct validity. The findings suggest relationship between quality of life and quality of special vocational education services received by students with intellectual disability. Low levels of self-determination are highlighted. Practical implications concerning the application of the instruments in special education settings as measures for the quality assessment and the evaluation of educational interventions are discussed.

Plasmodium falciparum malaria remains a major cause of global morbidity and mortality, mainly in sub-Saharan Africa. The numbers of new malaria cases and deaths have been stable in the last years despite intense efforts for disease elimination, highlighting the need for new approaches to stop disease transmission. Further understanding of the parasite transmission biology could provide a framework for the development of such approaches. We phenotypically and functionally characterized three novel genes, PIMMS01, PIMMS57, and PIMMS22, using targeted disruption of their orthologs in the rodent parasite Plasmodium berghei. PIMMS01 and PIMMS57 are specifically and highly expressed in ookinetes, while PIMMS22 transcription starts already in gametocytes and peaks in sporozoites. All three genes show strong phenotypes associated with the ookinete to oocyst transition, as their disruption leads to very low numbers of oocysts and complete abolishment of transmission. PIMMS22 has a secondary essential function in the oocyst. Our results enrich the molecular understanding of the parasite-vector interactions and identify PIMMS01, PIMMS57, and PIMMS22 as new targets of transmission blocking interventions.

Cardiac function impairment in the setting of hepatopulmonary syndrome (HPS) in patients with end stage liver disease remains an issue of debate. The current study evaluated possible correlations between HPS and biventricular systolic function in patients with decompensated cirrhosis. Consecutive liver transplantation candidates with stable decompensated cirrhosis were prospectively evaluated. HPS was defined as the presence of an elevated alveolar–arterial oxygen gradient and intrapulmonary vasodilatation, detected by contrast enhanced echocardiography. HPS severity was determined based on arterial blood oxygen pressure values, while shunt size was assessed with a semi-quantitative method. Demographic, clinical and laboratory parameters were also prospectively collected. In total, 130 patients (mean age 56.5, M/F: 94/36, MELD score 14.6 ± 5.6) were enrolled, of whom 45 (34.6%) fulfilled the criteria for HPS diagnosis (mild: 57.7%, moderate: 33.3%, severe 4.4% and very severe 4.4%). Significantly lower absolute left ventricular (LV) global longitudinal strain (GLS) values (− 21.6 ± 2.3 vs. − 22.6 ± 2.5%, p = 0.041) were measured in patients with HPS compared to cirrhotic patients without HPS, while there was no statistically significant difference regarding right ventricular GLS (− 22.1 ± 3.3 vs. − 23.2 ± 3.5%, p = 0.061) between the two groups. Lower LV ejection fraction values were also recorded in the HPS group (53.9 ± 3.5 vs. 56.3 ± 4.5%, p

Background and aims Achieving the low-density lipoprotein cholesterol (LDL-C) goal following an acute coronary syndrome (ACS) is a milestone often missed due to suboptimal adherence to secondary prevention treatments. Whether improved adherence could result in reduced LDL-C levels is unclear. We aimed to evaluate whether an educational-motivational intervention increases long-term lipid-lowering therapy (LLT) adherence and LDL-C goal attainment rate among post-ACS patients. Methods IDEAL-LDL was a parallel, two-arm, single-center, pragmatic, investigator-initiated randomized controlled trial. Hospitalized patients for ACS were randomized to a physician-led integrated intervention consisting of an educational session at baseline, followed by regular motivational interviewing phone sessions or usual care. Co-primary outcomes were the LLT adherence (measured by Proportion of Days Covered (PDC); good adherence defined as PDC>80%), and LDL-C goal ( Results In total, 360 patients (mean age 62 years, 81% male) were randomized. Overall, good adherence was positively associated with LDL-C goal achievement rate at one year. Median PDC was higher in the intervention group than the control group [0.92 (IQR, 0.82–1.00) vs. 0.86 (0.62–0.98); p = 0.03] while the intervention group had increased odds of good adherence (odds ratio: 1.76 (95% confidence interval 1.02 to 2.62; p = 0.04). However, neither the LDL-C goal achievement rate (49.6% in the intervention vs. 44.9% in the control group; p = 0.49) nor clinical outcomes differed significantly between the two groups. Conclusions Α multifaceted intervention improved LLT adherence in post-ACS patients without a significant difference in LDL-C goal attainment.

GABAB receptors are implicated in numerous central nervous system-based behaviours and mechanisms, including cognitive processing in preclinical animal models. Homeostatic changes in the expression and function of these receptors across brain structures have been found to affect cognitive processing. Numerous preclinical studies have focused on the role of GABAB receptors in learning, memory and cognition per se with some interesting, although sometimes contradictory, findings. The majority of the existing clinical literature focuses on alterations in GABAB receptor function in conditions and disorders whose main symptomatology includes deficits in cognitive processing. The aim of this chapter is to delineate the role of GABAB receptors in cognitive processes in health and disease of animal models and human clinical populations. More specifically, this review aims to present literature on the role of GABAB receptors in animal models with cognitive deficits, especially those of learning and memory. Further, it aims to capture the progress and advances of research studies on the effects of GABAB receptor compounds in neurodevelopmental and neurodegenerative conditions with cognitive dysfunctions. The neurodevelopmental conditions covered include autism spectrum disorders, fragile X syndrome and Down's syndrome and the neurodegenerative conditions discussed are Alzheimer's disease, epilepsy and autoimmune anti-GABAB encephalitis. Although some findings are contradictory, results indicate a possible therapeutic role of GABAB receptor compounds for the treatment of cognitive dysfunction and learning/memory impairments for some of these conditions, especially in neurodegeneration. Moreover, future research efforts should aim to develop selective GABAB receptor compounds with minimal, if any, side effects.

Chronic inflammation of the intestinal mucosa has been associated with the appearance of inflammatory polyps or pseudopolyps. Among the distinct categories of inflammatory polyps are inflammatory myoglandular polyps (IMGP) usually found in the colorectum. Only one case of IMGP in the terminal ileus has been described since their first description. We report the first case of an inflammatory polyp with both hyperplastic and myoglandular histological characteristics, in the terminal ileum of a patient with quiescent Crohn’s disease, causing recurrent intussusception.

The impact of small-bowel (SB) capsule endoscopy and device-assisted enteroscopy on clinical practice, since their introduction 2 decades ago, has been remarkable. These disruptive technologies have transformed the investigation and management of SB pathology and now have a firmly established place in guidelines and clinical algorithms. Furthermore, recent years have witnessed innovations, driven by the demand of new goals in the management of inflammatory bowel disease (IBD), such as mucosal healing and evolving strategies based on tight monitoring and accelerated escalation of care. These developments in SB endoscopy have also been paralleled by refinement in dedicated radiological SB imaging technologies. This updated review highlights the current state of the art and more recent innovations with a focus on their role in IBD.

COVID-19 is a prothrombotic condition and a major focus of attention has been to reduce thrombosis in order to improve outcomes. Extracorporeal membrane oxygenation (ECMO) triggers contact activation of coagulation, platelet dysfunction and systemic anticoagulation which may contribute to both thrombosis and bleeding complications. Methods: Multicentre observational study of mortality, thrombosis, and bleeding complications in 152 consecutive patients (≥18 years) supported with VV ECMO during the first wave of the COVID-19 pandemic (1st of March 2020 to 31st of May 2020) from four nationally commissioned UK ECMO centres. Findings: Of 152 patients, mortality during ECMO up to 120 days was 21.1% (32/152) whilst overall all cause in- hospital mortality up to 143 days from ECMO initiation was 25.7% (39/152). Median duration on ECMO was 17 days (interquartile range [IQR] 11-29.7). On multivariate analysis, mortality increased with age (Hazard ratio [HR] 1.09 [95% CI 1.03 - 1.14]), P=0.002. Rates of major bleeding and thrombosis during ECMO were 25.0% (38/152) and 17.1% (26/152). Presence of major bleeding prior to or at initiation of ECMO and intracranial haemorrhage during ECMO conferred 3.65 ([95% CI 1.16 - 11.48], P=0.027) and 6.92 ([95% CI 2.66 - 18.02]

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. GABA type B (GABAB) receptors (GABABRs) are the only metabotropic G protein-coupled receptors for GABA and can be found distributed not only in the central nervous system, but also in the periphery. This chapter introduces important, fundamental knowledge related to GABABR function and the various potential therapeutic applications of the development of novel GABABR-active compounds, as documented through extensive studies presented in subsequent chapters of this Current Topic in Behavioral Neurosciences volume on the role of the neurobiology of GABABR function. The compounds that have received increased attention in the last few years compared to GABABR agonists and antagonists - the positive allosteric modulators - exhibit better pharmacological profiles and fewer side effects. As we continue to unveil the mystery of GABABRs at the molecular and cellular levels, we further understand the significance of these receptors. Future directions should aim for developing highly selective GABABR compounds for treating neuropsychiatric disorders and their symptomatology.

We have collected one year of aerosol chemical speciation monitor (ACSM) data in Magadino, a village located in the south of the Swiss Alpine region, which is one of the most polluted areas in Switzerland. We analysed the mass spectra of organic aerosol (OA) by positive matrix factorization (PMF) using Source Finder Professional (SoFi Pro) to retrieve the origins of OA. Therein, we deployed the rolling algorithm to account for the temporal changes of the source profiles, which is closer to the real world. As the first ever application of rolling PMF analysis for a rural cite, we resolved two primary OA factors (traffic-related hydrocarbon-like OA (HOA) and biomass burning OA (BBOA)), one local OA (LOA) factor, a less oxidized oxygenated OA (LO-OOA) factor, and a more oxidized oxygenated OA (MO-OOA) factor. HOA showed stable contributions to the total OA through the whole year ranging from 8.1–10.1 %, while the contribution of BBOA showed a clear seasonal variation with a range of 8.3–27.4 % (highest during winter, lowest during summer) and a yearly average of 17.1 %. The OOA was represented by two factors (LO-OOA and MO-OOA) throughout the year. OOA contributed 71.6 % of the OA mass, varying from 62.5 % (in winter) to 78 % (in spring and summer). The uncertainties (σ) for the modelled OA factors (i.e., rotational uncertainty and statistical variability of the sources) varied from ±4 % (LOA) to a maximum of ±40 % (LO-OOA). Considering the fact that BBOA and LO-OOA (showing influences of biomass burning in winter) had significant contributions to the total OA mass, we suggest a reduction and control of the residential heating as a mitigation strategy for better air quality and lower PM levels in this region. In Appendix A, we conducted a head-to-head comparison between the conventional seasonal PMF analysis and the rolling mechanism. It showed similar or slightly improved results in terms of mass concentrations, correlations with external tracers and factor profiles of the constrained POA factors. The rolling results show smaller scaled residuals and enhanced correlations between OOA factors and corresponding inorganic salts than those of the seasonal solutions, was most likely because the rolling PMF analysis can capture the temporal variations of the oxidation processes for OOA sources. Specifically, the time dependent factor profiles of MO-OOA and LO-OOA can well explain the temporal viabilities of two main ions for OOA factors, m/z 44 (CO2+) and m/z 43 (mostly C2H3O+). This rolling PMF analysis therefore provides a more realistic source apportionment (SA) solution, with time-dependent OA sources. The rolling results show also good agreement with offline Aerodyne aerosol mass spectrometer (AMS) SA results from filter samples, except for winter. This is likely because the online measurement is capable of capturing the fast oxidation processes of biomass burning sources. This study demonstrates the strengths of the rolling mechanism and provides a comprehensive criterion list for ACSM users to obtain reproducible SA results and is a role model for similar analyses of such world-wide available data.

Introduction: In Greece, it is estimated that annually 600 new cases of cervical cancer are diagnosed, being the third most common form of cancer in women after breast cancer (22.9%) and colon cancer (9.4%).In addition to being life-threatening, such a diagnosis can also represent the psychological impact of gynecological cancers; there are negative emotional consequences of such a diagnosis for both patients and their families affecting the quality of life (QOL) of patients with gynecological cancer.Aim: To examine the quality of life (QOL) of women with recent diagnosis of gynecologic cancer (RDGC) in Greece during their illness and to identify the psychosocial problems and the symptoms faced by women in the early stages of the disease.Material and Method: A prospective study of 63 patients with RDGC before undergoing hysterectomy, who completed the EORTC QLQ-C30 questionnaire.Results: The patients were between 45 and 50 years old (19.6%). Impaired physical functioning of women with RDGC was associated with strenuous activity or a long walk. Emotionally, patients showed a lack of concentration, tension, anxiety, irritation and depression. Age was negatively correlated with depression (p-value = 0.05

Disordered coagulation, endothelial dysfunction, dehydration and immobility contribute to a substantially elevated risk of deep venous thrombosis, pulmonary embolism (PE) and systemic thrombosis in coronavirus disease 2019 (Covid-19). We evaluated the prevalence of pulmonary thrombosis and reported RV (right ventricular) dilatation/dysfunction associated with Covid-19 in a tertiary referral Covid-19 centre. Of 370 patients, positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 39 patients (mean age 62.3 ± 15 years, 56% male) underwent computed tomography pulmonary angiography (CTPA), due to increasing oxygen requirements or refractory hypoxia, not improving on oxygen, very elevated D-dimer or tachycardia disproportionate to clinical condition. Thrombosis in the pulmonary vasculature was found in 18 (46.2%) patients. However, pulmonary thrombosis did not predict survival (46.2% survivors vs 41.7% non-survivors, p = 0.796), but RV dilatation was less frequent among survivors (11.5% survivors vs 58.3% non-survivors, p = 0.002). Over the following month, we observed four Covid-19 patients, who were admitted with high and intermediate-high risk PE, and we treated them with UACTD (ultrasound-assisted catheter-directed thrombolysis), and four further patients, who were admitted with PE up to 4 weeks after recovery from Covid-19. Finally, we observed a case of RV dysfunction and pre-capillary pulmonary hypertension, associated with Covid-19 extensive lung disease. We demonstrated that pulmonary thrombosis is common in association with Covid-19. Also, the thrombotic risk in the pulmonary vasculature is present before and during hospital admission, and continues at least up to four weeks after discharge, and we present UACTD for high and intermediate-high risk PE management in Covid-19 patients.

Patients with beta-thalassemia major (β-ΤΜ) may develop cardiac arrhythmias through a multifactorial mechanism. The current study evaluated the association of cardiac structure and function on echocardiography with atrial ectopic burden on 24-hour tape recording in β-ΤΜ patients. This prospective study included consecutive β-ΤΜ patients. Demographic, laboratory, echocardiographic, cardiac magnetic resonance (CMR) T2* and 24-hour tape recording data were prospectively collected. The patients were classified according to the median value of premature atrial contractions (PACs) on 24-hour tape. In total, 50 β-TM patients (37.6 ± 9.1 years old, 50% male) were divided in 2 groups; PACs ≤ 24/day and > 24/day. Patients with PACs > 24/day were treated with blood transfusion for a longer period of time (39.0 ± 8.6 vs. 32.0 ± 8.9 years, p < 0.007), compared to their counterparts. Older age (OR: 1.121, 95% CI: 1.032–1.217, p = 0.007), longer duration of blood transfusion (OR:1.101, 95% CI:1.019–1.188, p = 0.014), larger LV end-diastolic diameter (OR: 4.522, 95% CI:1.009–20.280, p = 0.049), higher values of LA peak systolic strain (OR: 0.869, 95% CI: 0.783–0.964, p = 0.008), higher MV E/E′ average (OR: 1.407, 95% CI: 1.028–1.926, p = 0.033) and higher right ventricular systolic pressure (OR: 1.147, 95% CI: 1.039–1.266, p = 0.006) were univariably associated with PACs > 24/day. LA peak systolic strain remained significantly associated with PACs > 24/day after adjusting for the duration of blood transfusions or for CMR T2*. The multivariable model including blood transfusion duration and LA peak systolic strain was the most closely associated with PACs > 24/day. Receiver operating characteristic curve analysis identified a left atrial peak systolic strain of 31.5%, as the best cut-off value (83% sensitivity, 68% specificity) for prediction of PACs > 24/day. In β-TM patients, LA peak systolic strain was associated with the atrial arrhythmia burden independently to the duration of blood transfusions and CMR T2*.