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This study aims at the synthesis and initial biological evaluation of novel rhenium–tricarbonyl complexes of 3,3′,4′,5,7-pentahydroxyflavone (quercetin), 3,7,4΄-trihydroxyflavone (resokaempferol), 5,7-dihydroxyflavone (chrysin) and 4΄,5,7-trihydroxyflavonone (naringenin) as neuroprotective and anti-PrP agents. Resokaempferol was synthesized from 2,2΄,4-trihydroxychalcone by H2O2/NaOH. The rhenium–tricarbonyl complexes of the type fac-[Re(CO)3(Fl)(sol)] were synthesized by reacting the precursor fac-[Re(CO)3(sol)3]+ with an equimolar amount of the flavonoids (Fl) quercetin, resokaempferol, chrysin and naringenin and the solvent (sol) was methanol or water. The respective Re–flavonoid complexes were purified by semi-preparative HPLC and characterized by spectroscopic methods. Furthermore, the structure of Re–chrysin was elucidated by X-ray crystallography. Initial screening of the neuroprotective properties of these compounds included the in vitro assessment of the antioxidant properties by the DPPH assay as well as the anti-lipid peroxidation of linoleic acid in the presence of AAPH and their ability to inhibit soybean lipoxygenase. From the above studies, it was concluded that the complexes’ properties are mainly correlated with the structural characteristics and the presence of the flavonoids. The flavonoids and their respective Re-complexes were also tested in vitro for their ability to inhibit the formation and aggregation of the amyloid-like abnormal prion protein, PrPSc, by employing the real-time quaking-induced conversion assay with recombinant PrP seeded with cerebrospinal fluid from patients with Creutzfeldt–Jakob disease. All the compounds blocked de novo abnormal PrP formation and aggregation. Graphical abstract

Sunscreen use has increased in recent years, as sunscreen products minimize the damaging effects of solar radiation. Active ingredients called ultraviolet (UV) filters or UV agents, either organic or inorganic, responsible for defending skin tissue against harmful UV rays, are incorporated in sunscreen formulations. UV agents have a serious impact on many members of bio communities, and they are transferred to the environment either directly or indirectly. Many organic UV filters are found to be accumulated in marine environments because of high values of the octanol/water partition coefficient. However, due to the fact that UV agents are not stable in water, unwanted by-products may be formed. Experimental studies or field observations have shown that organic UV filters tend to bioaccumulate in various aquatic animals, such as corals, algae, arthropods, mollusks, echinoderms, marine vertebrates. This review was conducted in order to understand the effects of UV agents on both the environment and marine biota. In vivo and in vitro studies of UV filters show a wide range of adverse effects on the environment and exposed organisms. Coral bleaching receives considerable attention, but the scientific data identify potential toxicities of endocrine, neurologic, neoplastic and developmental pathways. However, more controlled environmental studies and long-term human use data are limited. Several jurisdictions have prohibited specific UV filters, but this does not adequately address the dichotomy of the benefits of photoprotection vs lack of eco-friendly, safe, and approved alternatives.

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347, BACKGROUND: The COVID-19 pandemic presented major challenges for critical care facilities worldwide. Infections which develop alongside or subsequent to viral pneumonitis are a challenge under sporadic and pandemic conditions; however, data have suggested that patterns of these differ between COVID-19 and other viral pneumonitides. This secondary analysis aimed to explore patterns of co-infection and intensive care unit-acquired infections (ICU-AI) and the relationship to use of corticosteroids in a large, international cohort of critically ill COVID-19 patients. METHODS: This is a multicenter, international, observational study, including adult patients with PCR-confirmed COVID-19 diagnosis admitted to ICUs at the peak of wave one of COVID-19 (February 15th to May 15th, 2020). Data collected included investigator-assessed co-infection at ICU admission, infection acquired in ICU, infection with multi-drug resistant organisms (MDRO) and antibiotic use. Frequencies were compared by Pearson's Chi-squared and continuous variables by Mann-Whitney U test. Propensity score matching for variables associated with ICU-acquired infection was undertaken using R library MatchIT using the "full" matching method. RESULTS: Data were available from 4994 patients. Bacterial co-infection at admission was detected in 716 patients (14%), whilst 85% of patients received antibiotics at that stage. ICU-AI developed in 2715 (54%). The most common ICU-AI was bacterial pneumonia (44% of infections), whilst 9% of patients developed fungal pneumonia; 25% of infections involved MDRO. Patients developing infections in ICU had greater antimicrobial exposure than those without such infections. Incident density (ICU-AI per 1000 ICU days) was in considerable excess of reports from pre-pandemic surveillance. Corticosteroid use was heterogenous between ICUs. In univariate analysis, 58% of patients receiving corticosteroids and 43% of those not receiving steroids developed ICU-AI. Adjusting for potential confounders in the propensity-matched cohort, 71% of patients receiving corticosteroids developed ICU-AI vs 52% of those not receiving corticosteroids. Duration of corticosteroid therapy was also associated with development of ICU-AI and infection with an MDRO. CONCLUSIONS: In patients with severe COVID-19 in the first wave, co-infection at admission to ICU was relatively rare but antibiotic use was in substantial excess to that indication. ICU-AI were common and were significantly associated with use of corticosteroids. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)., European Society of Intensive Care Medicine ACM is supported by a Clinician Scientist Fellowship from the Medical Research Council (MR/V006118/1)

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.

Objective: Postictal generalized electroencephalography (EEG) suppression (PGES) is a surrogate marker of sudden unexpected death in epilepsy (SUDEP). It is still unclear which ictal phenomena lead to prolonged PGES and increased risk of SUDEP. Semiology features of generalized convulsive seizure (GCS type 1) have been reported as a predictor of prolonged PGES. Progressive slowing of clonic phase (PSCP) has been observed in GCSs, with gradually increasing inhibitory periods interrupting the tonic contractions. We hypothesized that PSCP is associated with prolonged PGES. Methods: We analyzed 90 bilateral convulsive seizures in 50 consecutive patients (21 female; age: 11–62 years, median: 31 years) recruited to video-EEG monitoring. Five raters, blinded to all other data, independently assessed the presence of PSCP. PGES and seizure semiology were evaluated independently. We determined inter-rater agreement (IRA) for the presence of PSCP, and we evaluated its association, as well as that of other ictal features, with the occurrence of PGES, prolonged PGES (≥20 s) and very prolonged PGES (≥50 s) using multivariate logistic regression analysis. Results: We found substantial IRA for the presence of PSCP (percent agreement: 80%; beyond-chance agreement coefficient:.655). PSCP was an independent predictor of the occurrence of PGES and prolonged PGES (p

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.

E1 and E2 (E1E2), the fusion proteins of Hepatitis C Virus (HCV), are unlike that of any other virus yet described, and the detailed molecular mechanisms of HCV entry/fusion remain unknown. Hypervariable region-1 (HVR-1) of E2 is a putative intrinsically disordered protein tail. Here, we demonstrate that HVR-1 has an autoinhibitory function that suppresses the activity of E1E2 on free virions; this is dependent on its conformational entropy. Thus, HVR-1 is akin to a safety catch that prevents premature triggering of E1E2 activity. Crucially, this mechanism is turned off by host receptor interactions at the cell surface to allow entry. Mutations that reduce conformational entropy in HVR-1, or genetic deletion of HVR-1, turn off the safety catch to generate hyper-reactive HCV that exhibits enhanced virus entry but is thermally unstable and acutely sensitive to neutralising antibodies. Therefore, the HVR-1 safety catch controls the efficiency of virus entry and maintains resistance to neutralising antibodies. This discovery provides an explanation for the ability of HCV to persist in the face of continual immune assault and represents a novel regulatory mechanism that is likely to be found in other viral fusion machinery.

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.

Background Stratifying risk of postoperative pulmonary complications after major abdominal surgery allows clinicians to modify risk through targeted interventions and enhanced monitoring. In this study, we aimed to identify and validate prognostic models against a new consensus definition of postoperative pulmonary complications. Methods We did a systematic review and international external validation cohort study. The systematic review was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched MEDLINE and Embase on March 1, 2020, for articles published in English that reported on risk prediction models for postoperative pulmonary complications following abdominal surgery. External validation of existing models was done within a prospective international cohort study of adult patients (≥18 years) undergoing major abdominal surgery. Data were collected between Jan 1, 2019, and April 30, 2019, in the UK, Ireland, and Australia. Discriminative ability and prognostic accuracy summary statistics were compared between models for the 30-day postoperative pulmonary complication rate as defined by the Standardised Endpoints in Perioperative Medicine Core Outcome Measures in Perioperative and Anaesthetic Care (StEP-COMPAC). Model performance was compared using the area under the receiver operating characteristic curve (AUROCC). Findings In total, we identified 2903 records from our literature search; of which, 2514 (86·6%) unique records were screened, 121 (4·8%) of 2514 full texts were assessed for eligibility, and 29 unique prognostic models were identified. Nine (31·0%) of 29 models had score development reported only, 19 (65·5%) had undergone internal validation, and only four (13·8%) had been externally validated. Data to validate six eligible models were collected in the international external validation cohort study. Data from 11 591 patients were available, with an overall postoperative pulmonary complication rate of 7·8% (n=903). None of the six models showed good discrimination (defined as AUROCC ≥0·70) for identifying postoperative pulmonary complications, with the Assess Respiratory Risk in Surgical Patients in Catalonia score showing the best discrimination (AUROCC 0·700 [95% CI 0·683–0·717]). Interpretation In the pre-COVID-19 pandemic data, variability in the risk of pulmonary complications (StEP-COMPAC definition) following major abdominal surgery was poorly described by existing prognostication tools. To improve surgical safety during the COVID-19 pandemic recovery and beyond, novel risk stratification tools are required. Funding British Journal of Surgery Society.

This educational topical review and Task Force report aims to address learning objectives of the International League Against Epilepsy (ILAE) curriculum. We sought to extract detailed features involving semiology from video recordings and interpret semiological signs and symptoms that reflect the likely localization for focal seizures in patients with epilepsy. This glossary was developed by a working group of the ILAE Commission on Diagnostic Methods incorporating the EEG Task Force. This paper identifies commonly used terms to describe seizure semiology, provides definitions, signs and symptoms, and summarizes their clinical value in localizing and lateralizing focal seizures based on consensus in the published literature. Video-EEG examples are included to illustrate important features of semiology in patients with epilepsy.

Purpose To accommodate the unprecedented number of critically ill patients with pneumonia caused by coronavirus disease 2019 (COVID-19) expansion of the capacity of intensive care unit (ICU) to clinical areas not previously used for critical care was necessary. We describe the global burden of COVID-19 admissions and the clinical and organizational characteristics associated with outcomes in critically ill COVID-19 patients. Methods Multicenter, international, point prevalence study, including adult patients with SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) and a diagnosis of COVID-19 admitted to ICU between February 15th and May 15th, 2020. Results 4994 patients from 280 ICUs in 46 countries were included. Included ICUs increased their total capacity from 4931 to 7630 beds, deploying personnel from other areas. Overall, 1986 (39.8%) patients were admitted to surge capacity beds. Invasive ventilation at admission was present in 2325 (46.5%) patients and was required during ICU stay in 85.8% of patients. 60-day mortality was 33.9% (IQR across units: 20%-50%) and ICU mortality 32.7%. Older age, invasive mechanical ventilation, and acute kidney injury (AKI) were associated with increased mortality. These associations were also confirmed specifically in mechanically ventilated patients. Admission to surge capacity beds was not associated with mortality, even after controlling for other factors. Conclusions ICUs responded to the increase in COVID-19 patients by increasing bed availability and staff, admitting up to 40% of patients in surge capacity beds. Although mortality in this population was high, admission to a surge capacity bed was not associated with increased mortality. Older age, invasive mechanical ventilation, and AKI were identified as the strongest predictors of mortality. Correction in: Intensive Care Medicine, vol. 48, issue 8, pages 1130-1131.DOI: 10.1007/s00134-022-06801-2

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.

Purpose To examine student nurses' attitudes and experiences of door policies and restrictive measures in acute psychiatric care. Methods A mixed-method study with 274 third-year students. Results Participants' attitudes towards door locking and other containment measures appeared to be more a matter of custom, practice and tradition at particular units. The therapeutic benefits of open doors was the central organizing element in open units experiences while locked doors appeared to be "invisible" when the locked unit was perceived as a caring environment. Practical implications Exploring student nurses' attitudes towards crucial and debatable aspects of mental health practice contributes in cultivating a critical and analytical attitude towards the service they provide necessary for supporting a recovery mental health model and building a strong professional identity.

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.

The malaria parasite replicates asexually in the red blood cells of its vertebrate host employing epigenetic mechanisms to regulate gene expression in response to changes in its environment. We used chromatin immunoprecipitation followed by sequencing in conjunction with RNA sequencing to create an epigenomic and transcriptomic map of the developmental transition from asexual blood stages to male and female gametocytes and to ookinetes in the rodent malaria parasite Plasmodium berghei. Across the developmental stages examined, heterochromatin protein 1 associates with variantly expressed gene families localised at subtelomeric regions and variant gene expression based on heterochromatic silencing is observed only in some genes. Conversely, the euchromatin mark histone 3 lysine 9 acetylation (H3K9ac) is abundant in non-heterochromatic regions across all developmental stages. H3K9ac presents a distinct pattern of enrichment around the start codon of ribosomal protein genes in all stages but male gametocytes. Additionally, H3K9ac occupancy positively correlates with transcript abundance in all stages but female gametocytes suggesting that transcription in this stage is independent of H3K9ac levels. This finding together with known mRNA repression in female gametocytes suggests a multilayered mechanism operating in female gametocytes in preparation for fertilization and zygote development, coinciding with parasite transition from host to vector.

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.

© 2020 Occupational Therapy Australia Introduction: Driving is an important occupation, which enables other recovery goals for adult mental health consumers. Multidisciplinary clinicians can support consumers to engage in safe driving practices, which may include referral to a specialist occupational therapy driver assessor. There is presently limited evidence to inform us about the role of occupational therapy driver assessors in mental health and the impact of such services for consumers. Therefore, this study aimed to describe the reasons for referral and the recommendations resulting from driver assessments with adult consumers in a mental health setting and understand the experiences of driver assessors providing these services. Methods: A mixed-methods sequential design was employed in this study. Thirty driver assessments (n = 27 consumers) were analysed to identify consumer demographics, assessment recommendations, impact on licence status and rehabilitation outcomes. Focus groups were then conducted with five occupational therapy driver assessors. Quantitative data were analysed descriptively using frequencies and means, while qualitative data were subjected to content analysis. Results: The majority of consumers were diagnosed with psychotic disorders and presented with complex needs. The three primary reasons for referral were (a) cognitive or mental health concerns, (b) consumers directed by licencing authority to undertake driver assessment and (c) consumers wanting to resume driving after not driving for a significant time. Overall, 21 consumers (70%) were recommended to hold a driver licence after completion of an occupational therapy driver assessment. Qualitative themes about the experience of occupational therapy driver assessors included the reality of driver assessments; that outcomes are usually positive, and further support is needed for driver assessments. Conclusion: Driver assessments enable most consumers to return to driving. Occupational therapy driver assessors require greater support to perform this role, including dedicated time and peer support, to facilitate multidisciplinary clinicians and consumers to collaboratively achieve driving outcomes.

Goals The aim of this study was to investigate the implementation of a 14-day quadruple nonbismuth concomitant regimen, as proposed by recent Guidelines and Consensus Statements. Background In Greece, a region with >20% clarithromycin resistance where bismuth is unavailable, the 10-day quadruple concomitant scheme has already been adopted as the accepted first-line Helicobacter pylori eradication treatment. Study Our prospective randomized study included 364 patients with newly diagnosed H. pylori infection, randomized to receive a 10-day or a 14-day nonbismuth quadruple concomitant scheme. Treatment outcome was assessed by C-urea breath test and/or histology at least 4 weeks after therapy. Intention to treat and per protocol analyses of the eradication rates were performed. Secondary endpoints included patient adherence, safety, and the impact of prior antibiotic exposure in treatment efficacy. Results The overall eradication rates of the 2 treatments were 87.9% versus 87.4% in the intention to treat analysis, P=1.000, and 93% versus 94.1%, P=0.859, in the per protocol analysis for the 10-day and the 14-day treatment group, respectively. Both groups displayed excellent compliance rates (99.5% for the 10-day vs. 96.2% for the 14-day treatment duration, P=0.067). As regards treatment safety, serious adverse events that led to the discontinuation of both regimens were few, with no statistical difference between the 2 groups (0.5% in the 10-day group and 2.2% in the 14-day group, P>0.05). Previous antibiotic exposure was not significant with regard to treatment efficacy. Conclusion In Greece, the 10-day concomitant nonbismuth quadruple regimen for first-line treatment remains the most efficient strategy for H. pylori eradication.

The effects of ultraviolet (UV) radiation trigger human skin reaction, which can result in erythema, photoaging, and/or skin cancer. Sunscreens play an important role against the negative effects of UV radiation on the human skin. However, they should satisfy certain criteria, with the main one being photostability, to avoid the formation of health-threatening reactive intermediates. It has to be kept in mind, however, that photo-stable UV filters have the undesirable propensity to transfer energy to molecular oxygen and generate the very reactive singlet oxygen. They should also be well tolerated, while at the same time, they should not permeate into the skin and cause toxic effects. Thus, there is an ongoing need to develop effective and safe non-penetrating sunscreen formulations. The search for innovative active substances, efficacious combinations, and the design of vehicles or carriers has led to the implementation of advanced delivery systems. This study intended to review the commonly used UV radiation thwarting agents (organic and inorganic UV filters), compile the relevant toxicity studies, evaluate their margin of safety, and assess the current situation on innovative sunscreen formulations.

Immunocompromised individuals including patients with hematological malignancies constitute a population at high risk of developing severe disease upon SARS-CoV-2 infection. Protection afforded by vaccination is frequently low and the biology leading to altered vaccine efficacy is not fully understood. A patient cohort who had received bone marrow transplantation or CAR-T cells was studied following a 2-dose BNT162b2 mRNA vaccination and compared to healthy vaccine recipients. Anti-Spike antibody and systemic innate responses were compared in the two vaccine cohorts. The patients had significantly lower SARS-CoV-2 Spike antibodies to the Wuhan strain, with proportional lower cross-recognition of Beta, Delta, and Omicron Spike-RBD proteins. Both cohorts neutralized the wildtype WA1 and Delta but not Omicron. Vaccination elicited an innate cytokine signature featuring IFN-γ, IL-15 and IP-10/CXCL10, but most patients showed a diminished systemic cytokine response. In patients who failed to develop antibodies, the innate systemic response was dominated by IL-8 and MIP-1α with significant attenuation in the IFN-γ, IL-15 and IP-10/CXCL10 signature response. Changes in IFN-γ and IP-10/CXCL10 at priming vaccination and IFN-γ, IL-15, IL-7 and IL-10 upon booster vaccination correlated with the Spike antibody magnitude and were predictive of successful antibody development. Overall, the patients showed heterogeneous adaptive and innate responses with lower humoral and reduced innate cytokine responses to vaccination compared to naïve vaccine recipients. The pattern of responses described offer novel prognostic approaches for potentiating the effectiveness of COVID-19 vaccination in transplant patients with hematological malignancies.

At the beginning of the pandemic, there have been considerable concerns regarding coronavirus disease 2019 (COVID-19) severity and outcomes in patients with severe asthma treated with biologics.To prospectively observe a cohort of severe asthmatics treated with biologics for the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and disease severity during the COVID-19 pandemic.Physicians from centers treating patients with severe asthma all over Greece provided demographic and medical data regarding their patients treated with biologics. Physicians were also asked to follow up patients during the pandemic and to perform a polymerase chain reaction test in case of a suspected SARS-Cov-2 infection.Among the 591 severe asthmatics (63.5% female) included in the study, 219 (37.1%) were treated with omalizumab, 358 (60.6%) with mepolizumab, and 14 (2.4%) with benralizumab. In total, 26 patients (4.4%) had a confirmed SARS-CoV-2 infection, 9 (34.6%) of whom were admitted to the hospital because of severe COVID-19, and 1 required mechanical ventilation and died 19 days after admission. Of the 26 infected patients, 5 (19.2%) experienced asthma control deterioration, characterized as exacerbation that required treatment with systemic corticosteroids. The scheduled administration of the biological therapy was performed timely in all patients with the exception of 2, in whom it was postponed for 1 week according to their doctors' suggestion.Our study confirms that despite the initial concerns, SARS-CoV-2 infection is not more common in asthmatics treated with biologics compared with the general population, whereas the use of biologic treatments for severe asthma during the COVID-19 pandemic does not seem to be related to adverse outcomes from severe COVID-19.

Thalassemia major (TM) is a hereditary disease caused by defective globin synthesis. Because of the significant increase in life expectancy, these patients are suffering from various health conditions, including endocrinopathies and low bone mineral density. The aim of the present study was to investigate the correlation between clinical and biochemical parameters as well as to identify possible relations in a genotype to phenotype pattern. 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. Clinical and biochemical parameters were evaluated as well as specific mutations were identified. We have found significant correlations between biochemical parameters and iron chelation, hormone replacement treatment as well as TM genotype and hematocrit and T-score. To conclude, the current study showed that clinical parameters of TM patients correlate significantly with both biochemical factors and genotypical patient parameters. Our present study showed that there is a connection between genotype and phenotype as, for example, the identified relation between hematocrit and T-scores and TM-specific mutations. This connection indicates that there is still much more to learn about the role of mutations not only in the disease itself but also in the underlying comorbidities.

The present article describes the cultural adaptation and validation of the Greek version of the Acceptability of Locking the Door Questionnaire and aims to determine students' preference regarding mental health nursing as a possible career choice. The linguistic adaptation of the original instrument was performed according to the most recent guidelines and it was then administered to 274 third-year nursing students. Results support the validity and reliability of the instrument, which can be used to assess effectively the attitudes of the intended population. Sixty per cent of students considered mental health nursing as a possible career choice. Research on students' attitudes appeared to be a strategy of creating the space for lively discussions among them and capturing their interest in mental health education and practice. Theoretical preparation and clinical placements of mental health nursing students should incorporate strategies to improve their perceptions of working in mental health settings.

To assess whether trainees can learn and implement the operational definition of interictal epileptiform discharges (IEDs) of the International Federation of Clinical Neurophysiology (IFCN), based on six morphological criteria, and whether its implementation improves their diagnostic performance and inter-rater agreement (IRA). Seven trainees evaluated a balanced dataset of 70 EEG samples containing sharp transients (35 from patients with epilepsy and 35 from patients with non-epileptic paroxysmal events). The gold standard was derived from video-EEG recordings of the habitual clinical episodes. The trainees individually reviewed the EEGs, blinded to all other data, in two successive training sessions, three months apart. The second session was preceded by a teaching module about the IFCN criteria, and the trainees implemented them during the second reading session. By implementing the IFCN criteria, trainees significantly improved their specificity (94.29% vs. 77.14%; p=0.01) and overall accuracy (81.43% vs. 64.29%; p=0.01) for identifying IEDs. Sensitivity also improved but did not reach the level of statistical significance (77.14% vs. 60%; p=0.07). IRA improved significantly from fair (k=0.31; 95% CI: 0.22-0.40) to high-moderate (k=0.56; 95% CI:0.46-0.67) beyond-chance agreement. Implementing the IFCN criteria significantly improves the diagnostic performance and IRA of trainees in identifying IEDs. Teaching the IFCN criteria for IEDs will increase specificity in clinical EEG and avoid over-reading, the most common cause of misdiagnosing epilepsy.

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.

Cognitive Behavioral Therapy (CBT) has long been recognized as a type of psychotherapy for the management of glycemic control and comorbid psychological disorders and symptoms in adults with diabetes, and has been previously reported with varying outcomes. The aim of this scoping review is to evaluate the randomized controlled trials (RCTs) in order to determine the effects of CBT on Type 2 diabetes mellitus (T2DM) patients regarding depressive and anxiety symptoms, diabetes distress, and quality of life. An extensive literature search was conducted of the Pubmed, Scopus, Cinahl and Medline electronic databases. The search yielded 349 studies, of which 12 eventually met the entry requirements for RCTs. The majority of the studies included in the current scoping review demonstrated the benefits of CBT intervention in the amelioration of depressive symptoms, diabetes-related distress and quality of life in patients with T2DM. However, some studies reported limited evidence to support the use of CBT as an adjuvant therapy. The considerable levels of heterogeneity associated with most RCTs included warrant caution when interpreting results. The findings of this scoping review demonstrate the positive impact of CBT on depressive symptoms and other psychological aspects of everyday life in patients with T2DM.

Melatonin (MLT) is involved in many functions of the human body, mainly in sleeping-related disorders. It also has anti-oxidant potential and has been proven very effective in the treatment of seasonal affective disorders (SAD), which afflict some people during short winter days. Melatonin has been implicated in a range of other conditions, including Parkinson’s disease, Alzheimer’s and other neurological conditions, and in certain cancers. Its poor solubility in water leads to an insufficient absorption that led scientists to investigate MLT inclusion in cyclodextrins (CDs), as inclusion of drugs in CDs is a way of increasing the solubility of many lipophilic moieties with poor water solubility. The aim of this review is to gather all the key findings on MLT/CD complexes. The literature appraisal concluded that MLT inclusion leads to a 1:1 complex with the majority of CDs and increases the solubility of the hormone. The interactions of MLT with CDs can be studied by a variety of techniques, such as NMR, FT-IR, XRD and DCS. More importantly, the in vivo experiments showed an increase in the uptake of MLT when included in a CD.

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.

Glucose-6 phosphate dehydrogenase (G6PD) deficiency has an estimated prevalence of 5 -7.5% of the global population. Administration of some drugs in G6PD deficient patients may result in clinical conditions of varying severity, including potentially fatal sequels. For these reasons, in case of G6PD deficiency, the use of high dose toxic chemotherapy regimens in potentially curable malignancies with associated risk of tumor lysis syndrome, such as in advanced germ cell tumors, raises both physicians' preoccupations and issues for safeguard patients' health. Nonetheless no systematic information is actually available for safety in premedication to be administered, chemotherapy regimens adopted, and supportive care drugs needed to be provided in some particular situations.We present a case of a patient with metastatic testicular cancer and known g6pd deficiency, admitted in our department. We also performed a literature review in tree medical libraries searching for articles addressing the overmentioned security issues.Available literature is particularly scant. nonetheless, there is no evidence contradicting the administration of cytotoxic chemotherapy to G6PD deficient individuals. Our patient was able to complete the preplaned chemotherapy cycles, without any complications.Given the absence of data supporting the limitation of chemotherapy to G6PD deficient patients, the latter should not be deprived of the indicated antineoplastic treatment. However, certain premedication agents must be avoided. Continuous patient monitoring during treatment may alleviate physicians' and patients' anxiety and preoccupations.

The aim of the present prospective study was to evaluate the retention and effectiveness of two types of sealants (clear vs. opaque) on early pit and fissure occlusal non-cavitated ICDAS II #1-3, caries lesions of permanent posterior teeth of children.Study Design: 6986 pit and fissure occlusal surfaces were randomly sealed with clear or opaque sealants out of which, 5828 sealants were placed on sound and 1158 on questionable surfaces, while 3508 were clear and 3478 opaque sealants. The mean age of the sample at initial sealant placement was 9.5 (±2.9) years and the follow-up time was 12-48 months. The median (IQR, range) follow-up time was 17.9 (8.7-28.6) months. Study inclusion and exclusion criteria applied to the combined database in order to select the study sample. Teethmate™ F-1 natural and opaque sealants (Kuraray, Hattersheim am Main, Germany) were applied following the standard procedure of preparation with moisture control kept by cotton rolls handled Dri-Angles" and a 30 seconds acid-etch with 37% ortho-phosphoric acid gel was used followed by 10 sec air-water spraying washing and polymerization for 20x2 sec. Sealants were applied on sound tooth surfaces (ICDAS #0) with no visible defects or on surfaces with early caries lesions (ICDAS #1-3), randomly and interchangeably on the upper or lower Jaw. Total retention was considered when all pits and fissures were completely sealed, while partial or complete loss was scored as one code, although was registered separately.Separate analyses were performed for each type of failure (loss of sealant or restoration). Cumulative probabilities of failure over time after sealant placement, overall or by specific characteristics, were calculated using the Kaplan-Meier method. Association between these characteristics and the hazard of failure were investigated using appropriate Cox proportional hazard models.Sealed surfaces with ICDAS II # 1-3, showed 100% higher probability of having a restoration and 60% higher probability of sealant loss, with both differences being statistically significant (aHR=2.03, p=0.046), adjusted for age, sex, type of sealant and location of surface. Opaque sealants presented statistically significant (p 0.009) higher re-application rate, while fissures had 70% statistically significant (p0.001) higher probability for resealing with time compared to pits, with gender not affecting sealant retention while the earlier a sealant was placed on children's teeth, the more probable it was to need resealing or restoration (p0.012).The therapeutic use of sealants on occlusal surfaces of posterior permanent molars with early carious lesions (ICDAS II 1-3) is inferior compared to sound surfaces, showing higher sealant failures and restorations.

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.

The endocannabinoid system plays a central role in the earliest stages of embryonic, postnatal and adolescent neurodevelopment. Aberrant activity of this system at key developmental phases has been shown to affect neural development. The aim of this review is to synthesise and analyse preclinical insights within rodent populations, focusing on the effects that perinatal (embryonic, gestational and early postnatal developmental stages) and adolescent (postnatal day 21–60) cannabinoid exposure impose across time on the subsequent activity of various drugs of abuse. Results in rodents show that exposure to cannabinoids during the perinatal and adolescent period can lead to multifaceted behavioural and molecular changes. In the perinatal period, significant effects of Δ9-THC exposure on subsequent opiate and amphetamine reward-related behaviours were observed primarily in male rodents. These effects were not extended to include cocaine or alcohol. In adolescence, various cannabinoid agonists were used experimentally. This array of cannabinoids demonstrated consistent effects on opioids across sex. In contrast, no significant effects were observed regarding the future activity of amphetamines and cocaine. However, these studies focused primarily on male rodents. In conclusion, numerous gaps and limitations are apparent in the current body of research. The sparsity of studies analysing the perinatal period must be addressed. Future research within both periods must also focus on delineating sex-specific effects, moving away from a male-centric focus. Studies should also aim to utilise more clinically relevant cannabinoid treatments.

GABA

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 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.

People with disabilities (PwDs) are under-represented in the workforce, especially during times of economic recession. Supported employment is recognized as an effective practice for promoting work inclusion of PwDs, including people with intellectual disabilities (IDs). This study aimed at exploring the experiences of workers with ID or mental health conditions who received supported employment services in Greece. Semi-structured interviews were conducted with nine workers with ID and five with mental health conditions. The thematic analysis revealed that emotional pressure was experienced by the participants with mental health conditions and those with ID during the job search and the adaptation period, respectively. On-the-job training was available for the participants with ID and assistance in finding suitable job opportunities was given to those with mental health conditions. All participants highlighted the importance of maintaining employment. The findings can inform efforts on developing employment services targeting social and work inclusion for PwDs.

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 ...

In Research Genetic Cancer Center (RGCC), we are in the process of synthesizing a novel ERK inhibitor. We have currently synthesized an intermediate molecule, RGCC169, that needed to be tested to confirm we are using the appropriate synthetic pathways. Because of the limited solubility the compound exhibits, a strategy had to be devised for the free entrance of the molecule into the cell. Extracellular vesicles (EVs) were isolated by polyethylene glycol precipitation and identified by western blot and scanning electron microscopy. Loading was determined by high-performance liquid chromatography, differential scanning calorimetry, and scanning electron microscopy. EV uptake was determined by fluorescent microscopy. The effect of EV-encapsulated RGCC169 was determined by MTT viability assay on MCF7 cells. RGCC169 was incorporated into EVs as shown by high-performance liquid chromatography (26.6%) and scanning electron microscopy. Differential scanning calorimetry peaks shifted from 100.84 to 108.79°C upon encapsulation. EVs were taken up by cells as evident from CD63 fluorescent signal inside the cell's cytoplasm. RGCC169 decreased MCF proliferation (93.5±2.2, P=0.02). EV-encapsulated RGCC169 decreased cell proliferation even further (93.5±2.2 vs. 81.6±2.8, P=0.0002). RGCC169 was successfully loaded into serum EVs possibly by incorporation into the lipid membrane. EVs were taken up by MCF7 cells possibly by endocytic pathways. Although RGCC169 significantly reduced MCF7 viability at 3 μmol/l, the same concentration of RGCC169 encapsulated into EVs decreased cells viability even further. Our findings validate the correctness of our methods and are very promising for the achievement of our final goal, that is, the synthesis of a novel cytotoxic agent.

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.