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Abstract Aims Fluoropyrimidine chemotherapy is important for treatment of many solid tumours but is associated with cardiotoxicity. The relationship of fluoropyrimidine‐associated cardiotoxicity (FAC) with conventional cardiovascular (CV) risk factors is poorly understood, and standard cardiovascular risk scores are not validated in this context. Methods and results Single‐centre retrospective study of patients treated with fluoropyrimidine chemotherapy using electronic health records for cardiovascular risk factors (and calculation of QRISK3 score), cancer treatment, and clinical outcomes. FAC was defined by cardiovascular events during or within 3 months of fluoropyrimidine treatment, and Cox regression was used to assess associations of CV risk and cancer treatment with FAC. One thousand eight hundred ninety‐eight patients were included (45% male; median age 64 years), with median follow up 24.5 (11.5–48.3 months); 52.7% of patients were at moderate or high baseline CV risk (QRISK3 score >10%) Cardiovascular events occurred in 3.1% (59/1898)—most commonly angina (64.4%, 38/59) and atrial fibrillation (13.6%, 8/59), with 39% events during cycle one of treatment. In univariable analysis, QRISK3 score >20% was significantly associated with incident FAC (HR 2.25, 95% CI 1.11–4.93, P = 0.03). On multivariable analysis, beta‐blocker use (HR 1.04, 95% CI 1.00–1.08, P = 0.04) and higher BMI (HR 2.33, 95% CI 1.04–5.19, P = 0.04) were independently associated with incident CV events. Thirty‐two of the 59 patients with FAC were subsequently rechallenged with fluoropyrimidine chemotherapy, with repeat CV events in 6% (2/32). Incident FAC did not affect overall survival (P = 0.50). Conclusions High BMI and use of beta‐blockers are associated with risk of CV events during fluoropyrimidine chemotherapy. QRISK3 score may also play a role in identifying patients at high risk of CV events during fluoropyrimidine chemotherapy. Re‐challenge with further fluoropyrimidine chemotherapy can be considered in patients following CV events during prior treatment.

Background Primary care plays a key role in addressing domestic violence and abuse (DVA) globally. However, DVA remains underdiagnosed and inadequately addressed in primary care, necessitating a deeper understanding of patients’ perspectives in the UK.Objectives To explore patients’ perceptions of their awareness of DVA signs and their attitudes towards using the Woman Abuse Screening Tool (WAST)-short during routine primary care encounters.Methods An anonymous 29-item e-Survey, available in 18 languages and including information about DVA support services, was administered via the Qualtrics XM Platform™ from March to October 2022. Eligible UK National Health Service patients aged 18+ were identified by GP practices in Northwest London and invited via SMS to participate.Results Data were collected from 6,967 NHS patients. The majority (78.0%) claimed awareness of the signs of DVA in adults and children, while about 22% were unaware or unsure of the signs of DVA. Nearly 85% reported insufficient public awareness about DVA. Around 70% recommended implementing the WAST-short screening tool during primary care encounters to raise awareness and support survivors. Over 50% viewed general practice as the optimal setting for identifying and referring survivors.Conclusion Improved public education on DVA is needed, as a significant proportion of patients remain unaware or unsure of its signs, with the majority deeming public knowledge insufficient. Patients’ strong support for using standardised screening tools like the WAST-short reflects their trust in healthcare providers to conduct sensitive assessments. Integrating these tools into routine practice could enhance DVA interventions.

Introduction: Conjunctival cysts are usually asymptomatic but they can cause foreign body sensation and contribute to dry eye disease. The purpose of this case report is to describe the presentation and treatment of an infected inclusion cyst of a conjunctival nevus in a healthy 36-year-old patient. Case Presentation: A healthy 36-year-old man presented to the emergency department for redness and pain in his left eye for 1 day. Slit-lamp examination revealed a conjunctival hyperemia and a conjunctival nevus with 4 inclusion cysts, one of which was filled with purulent material. Fluorescein staining of the conjunctival epithelium was negative. Α mini-incision of the white cyst was performed using a 30 G needle, followed by bimanual drainage and topical treatment with tobramycin and moxifloxacin drops every 3 h for a week. A swab of the purulent drainage was positive for gram-positive flora. One week after the drainage of the cyst, the patient was asymptomatic and on slit-lamp examination, the 4 inclusion cysts were filled with a transparent liquid, there was not any vessel dilation and fluorescein staining was negative. Conclusion: Conjunctival inclusion cysts, although considered benign, can become infected and form a conjunctival abscess. A mini-incision on the slit lamp combined with bimanual drainage and followed by topical antibiotic drops seems to be a safe and effective treatment.

Summary: We investigated the effects of 35 inflammatory cytokines on respiratory outcomes, including COVID-19, asthma (atopic and non-atopic), chronic obstructive pulmonary disease (COPD), and pulmonary function indices, using Mendelian randomization and colocalization analyses. The emerging associations were further explored using observational analyses in the UK Biobank. We found an inverse association between genetically predicted macrophage colony stimulating factor (MCSF), soluble intercellular adhesion molecule-1 (sICAM), and soluble vascular cell adhesion molecule-1 with risk of COVID-19 outcomes. sICAM was positively associated with atopic asthma risk, whereas tumor necrosis factor-alfa showed an inverse association. A positive association was shown between interleukin-18 and COPD risk (replicated in observational analysis), whereas an inverse association was shown for interleukin-1 receptor antagonist (IL-1ra). IL-1ra and monocyte chemotactic protein-3 were positively associated with lung function indices, whereas inverse associations were shown for MCSF and interleukin-18 (replicated in observational analysis). Our results point to these cytokines as potential pharmacological targets for respiratory traits.

Production scheduling is a critical task in the management of manufacturing systems. It is difficult to derive an optimal schedule due to the problem complexity. Computationally expensive and time-consuming solutions have created major issues for companies trying to respect their customers’ demands. Simple dispatching rules have typically been applied in manufacturing practice and serve as a good scheduling option, especially for small and midsize enterprises (SMEs). However, in recent years, the progress in smart systems enabled by artificial intelligence (AI) and machine learning (ML) solutions has revolutionized the scheduling approach. Under different production circumstances, one dispatch rule may perform better than others, and expert knowledge is required to determine which rule to choose. The objective of this work is to design and implement a framework for the modeling and deployment of a deep reinforcement learning (DRL) agent to support short-term production scheduling. The DRL agent selects a dispatching rule to assign jobs to manufacturing resources. The model is trained, tested and evaluated using a discrete event simulation (DES) model that simulates a pilot case from the bicycle production industry. The DRL agent can learn the best dispatching policy, resulting in schedules with the best possible production makespan.

Summary: Background: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations. Methods: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously. Findings: The 3-DF joint test revealed two significant loci with p-value

Frailty describes a health state related to ageing where people become less resilient to health challenges and more likely to have adverse outcomes if they become unwell. People experiencing homelessness (PEH) are known to have poor health, with research suggesting that many become frail at a younger age than the general population. Previous research using small-scale primary data collection suggests that the prevalence of frailty in homeless populations varies widely (16–55%), with variations in sample sizes and settings partially accounting for differences in current estimates. The prevalence, risks, and outcomes of frailty in PEH are poorly understood. We propose to carry out a secondary analysis of existing health survey data collected from 2,792 PEH. This will involve creating a Frailty Index (FI) to identify frail people within the dataset. Regression analyses will be used to identify associations between potential risk factors and outcomes of frailty in this population. This protocol will: 1) Outline the creation of a FI to assess the frailty prevalence within a dataset of health information collected from a cohort of PEH and 2) Describe proposed methods of regression analysis for identification of associations between frailty and risks factors/outcomes of frailty in the cohort of PEH within the dataset. The processes described in this paper can inform future development of FIs in other datasets. It is expected that the FI created will be an appropriate and robust method for identifying frailty in a cohort of PEH and results of the secondary data analysis will provide a more robust estimate of the associations between frailty and risk factors/outcomes.

Abstract Background Persistent infection by oncogenic human papillomavirus (HPV) is necessary although not sufficient for development of cervical cancer. Behavioural, environmental, or comorbid exposures may promote or protect against malignant transformation. Randomised evidence is limited and the validity of observational studies describing these associations remains unclear. Methods In this umbrella review, we searched electronic databases to identify meta-analyses of observational studies that evaluated risk or protective factors and the incidence of HPV infection, cervical intra-epithelial neoplasia (CIN), cervical cancer incidence and mortality. Following re-analysis, evidence was classified and graded based on a pre-defined set of statistical criteria. Quality was assessed with AMSTAR-2. For all associations graded as weak evidence or above, with available genetic instruments, we also performed Mendelian randomisation to examine the potential causal effect of modifiable exposures with risk of cervical cancer. The protocol for this study was registered on PROSPERO (CRD42020189995). Results We included 171 meta-analyses of different exposure contrasts from 50 studies. Systemic immunosuppression including HIV infection (RR = 2.20 (95% CI = 1.89–2.54)) and immunosuppressive medications for inflammatory bowel disease (RR = 1.33 (95% CI = 1.27–1.39)), as well as an altered vaginal microbiome (RR = 1.59 (95% CI = 1.40–1.81)), were supported by strong and highly suggestive evidence for an association with HPV persistence, CIN or cervical cancer. Smoking, number of sexual partners and young age at first pregnancy were supported by highly suggestive evidence and confirmed by Mendelian randomisation. Conclusions Our main analysis supported the association of systemic (HIV infection, immunosuppressive medications) and local immunosuppression (altered vaginal microbiota) with increased risk for worse HPV and cervical disease outcomes. Mendelian randomisation confirmed the link for genetically predicted lifetime smoking index, and young age at first pregnancy with cervical cancer, highlighting also that observational evidence can hide different inherent biases. This evidence strengthens the need for more frequent HPV screening in people with immunosuppression, further investigation of the vaginal microbiome and access to sexual health services.

The emerging digitalization in today’s industrial environments allows manufacturers to store online knowledge about production and use it to make better informed management decisions. This paper proposes a multi-agent framework enhanced with digital twin (DT) for production scheduling and optimization. Decentralized scheduling agents interact to efficiently manage the work allocation in different segments of production. A DT is used to evaluate the performance of different scheduling decisions and to avoid potential risks and bottlenecks. Production managers can supervise the system’s decision-making processes and manually regulate them online. The multi-agent system (MAS) uses asset administration shells (AASs) for data modelling and communication, enabling interoperability and scalability. The framework was deployed and tested in an industrial pilot coming from the bicycle production industry, optimizing and controlling the short-term production schedule of the different departments. The evaluation resulted in a higher production rate, thus achieving higher production volume in a shorter time span. Managers were also able to coordinate schedules from different departments in a dynamic way and achieve early bottleneck detection.

Hepatitis E virus (HEV) poses significant health concerns worldwide, particularly among people living with HIV (PLWHIV), due to an increased risk of chronic infection and progression to cirrhosis in individuals with low CD4 cell counts. This study aimed to investigate the prevalence, chronicity potential, and risk factors of HEV infection among PLWHIV in Greece, where data are currently absent. A synchronic multicentric study encompassing five major Greek university hospitals was executed over 24 months, recruiting 696 PLWHIV participants. The prevalence of HEV IgG antibodies was 16.5%, with 8.6% showing evidence of acute HEV infection (HEV IgM). Active viral replication (HEV RNA) was present in 2.3% of the study population. Longitudinal analysis revealed that of the 25 initially anti-HEV IgM-positive individuals, only 3 seroconverted to IgG positivity, and among those with prior HEV RNA positivity (16), none showed evidence of active replication in subsequent tests. Comparative subgroup analysis highlighted the lack of significant differences in HIV-related parameters between HEV seropositive and seronegative individuals. Laboratory evaluations generally showed no significant disparities across most parameters; however, a higher seropositivity for Hepatitis A was observed in the HEV-positive subgroup. Our findings highlight a considerable prevalence of HEV among PLWHIV in Greece, with no observed cases of chronicity.

This study assesses the prevalence of hepatitis D virus (HDV) in people living with HIV (PLWHIV) in Greece. Given the compounding effects of HDV and hepatitis B (HBV) on liver disease progression, as well as the emergence of new therapeutic options such as bulevirtide, understanding regional disparities and the epidemiological impact of such co-infections is vital. A cross-sectional analysis was conducted utilizing 696 serum samples from PLWHIV attending five major university hospitals. The methodology included HDV antibody detection by ELISA and HDV RNA confirmation. Of the 30 HBsAg-positive samples analyzed, the study population was primarily male (93%), with a median age of 54 years. Participants had been on antiretroviral therapy for a median of 10 years, and the median CD4 count was 738 (539–1006) copies/mL. Additional serological findings revealed a 7% prevalence of hepatitis C virus (HCV) IgG antibodies and a 55% prevalence of hepatitis A virus (HAV) IgG antibodies. Seroreactivity for syphilis (RPR/VDRL/TPHA positive) was identified in 33% of the participants. The results indicated a low HDV prevalence, with only one individual (3%) testing positive for anti-HDV IgG antibodies and none for HDV RNA. This indicates a lower prevalence of HDV among PLWHIV with chronic HBV in Greece compared to global data.

Summary: Background: Tumour-promoting inflammation is a “hallmark” of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. Findings: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10–1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20–1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53–0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88–0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48–4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. Interpretation: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. Funding: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).

3,5-Diphenyl-4H-1,2,6-thiadiazin-4-one treated with meta-chloroperoxybenzoic acid undergoes an oxidative ring contraction to give 2-benzoyl-4-phenyl-1,2,5-thiadiazol-3(2H)-one 1,1-dioxide in a 29% yield, the structure of which is supported by single-crystal X-ray diffraction analysis and the available spectroscopic data.

ABSTRACTZinc cluster transcription factors (Zcfs) encoding zcf genes are exclusive for fungi and required for multiple cellular processes including metabolism and development. Genome-wide screening of 228 zinc cluster transcription factor encoding genes by overexpression in Aspergillus fumigatus revealed 11 genes which provided increased tolerance to the broadly applied azole voriconazole or to the polyene amphotericin B or to both. These include four oxidative stress and drug resistance genes (odrA-D) genes encoding factors, which provide broad cellular stress protection. Thereby, the corresponding fungal OdrA/Mdu2- and AtrR/OdrD-dependent genetic networks are interconnected. OdrA/Mdu2 activates atrR/odrD transcription by direct binding to the promoter, whereas AtrR/OdrD functions as repressor of odrA/mdu2 expression. odrA/mdu2 overexpression provides combined resistance to amphotericin B, voriconazole, itraconazole, and reactive oxygen species generated by menadione. OdrA/Mdu2-mediated itraconazole resistance is evoked by direct regulation of the transporter encoding gene mdr1. Oxidative stress-inducing substances like amphotericin B and menadione promote OdrA/Mdu2 accumulation in the nucleus to regulate stress response genes like mdr1 and the putative glutathione-S-transferase encoding gene gstD. The expression levels and external stress conditions fostering nuclear accumulation of OdrA/Mdu2 determine the regulation of the target genes. Hence, OdrA/Mdu2 provides a combined adaptation strategy for survival in nature or within a potential host, where this fungus represents the most common agent for human mold pneumonia worldwide. The OdrA/Mdu2 controlled genetic network highlights the tight connection between oxidative stress response and antifungal drug adaption to secure A. fumigatus survival in various hostile environments.IMPORTANCEAn overexpression screen of 228 zinc cluster transcription factor encoding genes of A. fumigatus revealed 11 genes conferring increased tolerance to antifungal drugs. Out of these, four oxidative stress and drug tolerance transcription factor encoding odr genes increased tolerance to oxidative stress and antifungal drugs when overexpressed. This supports a correlation between oxidative stress response and antifungal drug tolerance in A. fumigatus. OdrA/Mdu2 is required for the cross-tolerance between azoles, polyenes, and oxidative stress and activates genes for detoxification. Under oxidative stress conditions or when overexpressed, OdrA/Mdu2 accumulates in the nucleus and activates detoxifying genes by direct binding at their promoters, as we describe with the mdr1 gene encoding an itraconazole specific efflux pump. Finally, this work gives new insights about drug and stress resistance in the opportunistic pathogenic fungus A. fumigatus.

Recent advances in automatic piano transcription have enabled large scale analysis of piano music in the symbolic domain. However, the research has largely focused on classical piano music. We present PiJAMA (Piano Jazz with Automatic MIDI Annotations): a dataset of over 200 hours of solo jazz piano performances with automatically transcribed MIDI. In total there are 2,777 unique performances by 120 different pianists across 244 recorded albums. The dataset contains a mixture of studio recordings and live performances. We use automatic audio tagging to identify applause, spoken introductions, and other non-piano audio to facilitate downstream music information retrieval tasks. We explore descriptive statistics of the MIDI data, including pitch histograms and chromaticism. We then demonstrate two experimental benchmarks on the data: performer identification and generative modeling. The dataset, including a link to the associated source code is available at https://almostimplemented.github.io/PiJAMA/.

A primary aortoenteric fistula (PAEF) is a rare condition, and its associated mortality has remained high. We have presented two challenging cases of PAEF related to a small abdominal aortic aneurysm and an abdominal penetrating aortic ulcer. In both cases, a definite diagnosis was established intraoperatively, and the PAEF was repaired with in situ aortic reconstruction. Despite the successful outcome for the first patient, the postoperative complications were fatal for the second patient. The diagnosis of PAEF requires high suspicion and should be a part of the differential diagnosis in every case of gastrointestinal bleeding, especially when a history of, or risk factors for, aortic pathology are present.

Objective To leverage large scale genetic association data to investigate the interplay between circulating cytokines and cardiometabolic traits, and thus identifying potential therapeutic targets.Design Bi-directional Mendelian randomisation study.Setting Genome-wide association studies from three Finnish cohorts (Northern Finland Birth Cohort 1966, Young Finns Study, or FINRISK study), and genetic association summary statistics pooled from observational studies for expression quantitative trait loci and cardiometabolic traits.Participants Data for 47 circulating cytokines in 13 365 individuals from genome-wide association studies, summary statistic data for up to 21 735 individuals on circulating cytokines, summary statistic gene expression data across 49 tissues in 838 individuals, and summary statistic data for up to 1 320 016 individuals on cardiometabolic traits.Interventions Relations between circulating cytokines and cardiovascular, anthropometric, lipid, or glycaemic traits (coronary artery disease, stroke, type 2 diabetes mellitus, body mass index, waist circumference, waist to hip ratio, systolic blood pressure, glycated haemoglobin, high density lipoprotein cholesterol, low density lipoprotein cholesterol, total cholesterol, triglycerides, C reactive protein, glucose, fasting insulin, and lifetime smoking).Main outcome methods Genetic instrumental variables that are biologically plausible for the circulating cytokines were generated. The effects of cardiometabolic risk factors on concentrations of circulating cytokines, circulating cytokines on other circulating cytokines, and circulating cytokines on cardiometabolic outcomes were investigated.Results Genetic evidence (mendelian randomisation P0.5) suggested that coronary artery disease risk is increased by higher concentrations of circulating tumour necrosis factor related apoptosis-inducing ligand (TRAIL), interleukin-1 receptor antagonist (IL1RA), and macrophage colony-stimulating factor (MCSF).Conclusion This study offers insight into inflammatory mediators of cardiometabolic risk factors, cytokine signalling cascades, and effects of circulating cytokines on different cardiometabolic outcomes.

The sea urchin Diadema setosum is an ecological key species across its range, particularly on coral reefs. In 2006 D. setosum was first observed in the Mediterranean Sea, and since, it has proliferated to occupy the entire Levantine Basin. Here we report the mass mortality of the invasive D. setosum in the Mediterranean Sea. This is the first report of D. setosum mass mortality. The mortality spans over 1000 km along the Levantine coast of Greece and Turkey. The current mortality shows similar pathologies to previously reported Diadema mass mortality events, suggesting pathogenic infection as the cause of mortalities. Maritime transport, local currents, and fish predation of infected individuals may distribute pathogens at varying geographical scales. Due to the proximity of the Levantine Basin to the Red Sea, the risk of pathogen transport to the native Red Sea D. setosum population is imminent—with potentially catastrophic consequences.

Background: Intravascular imaging with either intravascular ultrasound (IVUS) or optical coherence tomography (OCT) during percutaneous coronary intervention (PCI) is associated with improved outcomes, but these techniques have previously been underutilized in the real world. We aimed to examine the change in utilization of intravascular imaging-guided PCI over the past decade in the United States and assess the association between intravascular imaging and clinical outcomes following PCI for myocardial infarction (MI). Methods: We surveyed the National Inpatient Sample from 2008 to 2019 to calculate the number of PCIs for MI guided by IVUS or OCT. Temporal trends were analyzed using Cochran-Armitage trend test or simple linear regression for categorical or continuous outcomes, respectively. Multivariable logistic regression was used to compare outcomes following PCI with and without intravascular imaging. Results: A total of 2,881,746 PCIs were performed for MI. The number of IVUS-guided PCIs increased by 309.9 % from 6,180 in 2008 to 25,330 in 2019 (P-trend

Abstract Background Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomisation (MR) analysis. Methods Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian, and prostate), and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12,906 for endometrial to 133,384 for breast cancer). Results There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95% CI 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85) and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses. Conclusions Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer aetiology. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for cancer prevention.

A computational and experimental method is introduced for the mathematical description of stress–strain curves for high-speed steels dependent on strain-rate and temperature. The developed method is based on an FEM-supported evaluation of imprints created on the surface of HSS (high-speed steel) specimens subjected to repetitive impacts by a cemented carbide ball indenter. The experiments were performed at various impact times and temperatures. The quasi-static HSS material properties were determined using an FEM based evaluation of nanoindentation results carried out at various temperatures on the HSS specimens. In the conducted FEM calculations, the stress, strain, and stain-rate data for the cemented carbide ball indenter were taken from a recent publication. By simulating the impact test with a finite element model, the quasi-static HSS stress–strain data were proportionally adjusted by the stress augmentation ratio (SAR) until the calculated imprint depths converged with the measured ones at various temperatures and impact times. Hence, equations were developed describing SAR depending on the strain rate and temperature. Characteristic implementation examples of these equations to describe HSS stress, strain properties dependent on strain-rate and temperature are presented.

Moxonidine is a centrally acting, anti-hypertensive medication that exerts additional metabolic properties. It is unknown whether its effects are mediated by neurotransmitters or sympathetic tone regulators, including Neuropeptide Y (NPY). In this study, we evaluated the effects of moxonidine administration on serum NPY in humans. Methods: Ninety individuals with mild or moderate arterial hypertension that required monotherapy were categorized in three age and gender-matched groups according to their Body Mass Index (BMI) as normal weight (n = 30), overweight (n = 30), and obese (n = 30). Moxonidine was administered in therapeutic doses of up to 0.6 mg daily for 12 weeks, and clinical, biochemical and hormonal parameters were recorded. Results: In all three groups, a decrease in systolic and diastolic blood pressure and heart rate was shown. After treatment, BMI, 24 h urine catecholamines and catecholamines’ metabolites, and serum total cholesterol were also reduced. Most importantly, we found a decrease in serum NPY levels in all study groups, with the largest mean decrease in the group of obese and overweight participants compared to normal weight. Conclusions: Moxonidine administration results in improvement in cardio-metabolic parameters, as well as a decrease in serum NPY levels, which therefore represents it being a potent agent against obesity-associated hypertension. Its involvement in energy balance regulation warrants further investigation.

Verticillium transcription activator of adhesion 3 (Vta3) is required for plant root colonization and pathogenicity of the soil-borne vascular fungus Verticillium dahliae. RNA sequencing identified Vta3-dependent genetic networks required for growth in tomato xylem sap. Vta3 affects the expression of more than 1,000 transcripts, including candidates with predicted functions in virulence and morphogenesis such as Egh16-like virulence factor 1 (Elv1) and Master transcription factor 1 (Mtf1). The genes encoding Elv1 and Mtf1 were deleted and their functions in V. dahliae growth and virulence on tomato (Solanum lycopersicum) plants were investigated using genetics, plant infection experiments, gene expression studies and phytohormone analyses. Vta3 contributes to virulence by promoting ELV1 expression, which is dispensable for vegetative growth and conidiation. Vta3 decreases disease symptoms mediated by Mtf1 in advanced stages of tomato plant colonization, while Mtf1 induces the expression of fungal effector genes and tomato pathogenesis-related protein genes. The levels of pipecolic and salicylic acids functioning in tomato defense signaling against (hemi-) biotrophic pathogens depend on the presence of MTF1, which promotes the formation of resting structures at the end of the infection cycle. In summary, the presence of VTA3 alters gene expression of virulence factors and tames the Mtf1 genetic subnetwork for late stages of plant disease progression and subsequent survival of the fungus in the soil.

Introduction Clinical disadvantages of initiating ART at low CD4 counts have been clearly demonstrated but whether any excess risk remains even after reaching relatively high/safe CD4 levels remains unclear. We explore whether individuals starting ART with Methods Data were derived from a multicenter cohort (AMACS). Adults, starting PI, NNRTI or INSTI based ART, in or after 2000 were eligible, provided they started ART with ≥500 (“High CD4”) or started with CD4 Results The study included 694 persons in the “High CD4” and 3,306 in the “Low CD4” group. Median (IQR) follow-up was 66 (36, 106) months. In total, 257 events (40 AIDS related, 217 SNAEs) were observed. Rates of progression did not differ significantly between the two groups but the subgroup of those initiating ART with Conclusions Individuals starting ART with

Febrile neutropenia (FN) is a common but serious complication encountered in patients with cancer and is associated with significant morbidity and mortality. In this prospective study, 63 patients with solid tumors under chemotherapy or immunotherapy were admitted to the hospital due to febrile neutropenia, confirmed through clinical or microbiological documentation. The aim of this study was to provide a comprehensive overview of the epidemiological and microbiological characteristics of hospitalized neutropenic patients with solid tumors undergoing treatment. Additionally, we aimed to assess the duration of neutropenia and identify factors influencing patient outcomes. The median age of patients was 71 ± 10.2 years, most of which were males (66.7%), and the primitive tumor location was the lung (38.1%), with most patients (82.5%) being at disease stage IV. The median duration of neutropenia was three days (range 1–10), and, notably, mucositis was significantly associated with neutropenia lasting ≥3 days (p = 0.012). Patients with lung cancer (38.1%) and patients with stage IV disease (82.5%) presented a higher risk of FN, although these differences did not reach statistical significance. The site of infection was identifiable in 55.6% of patients, with positive cultures detected in 34.9% and positive blood cultures (BC) drawn in 17.5% of cases. Gram-positive bacteria were the predominant causative agents in BC (63.6%), with Staphylococci being the most prevalent among them (66.7%). The median duration of hospitalization was nine days (range, 3–43 days), and most patients showed improvement or cure of infection (16.9% and 74.6%, respectively). Among recorded risk factors, the Eastern Cooperative Oncology Group (ECOG) performance status (PS) appears to be statistically significant. Patients with an impaired PS score (2–4) experienced worse outcomes and higher likelihood of mortality (p = 0.004). Regarding the outcome, a longer duration of neutropenia was also statistically significant (p = 0.050). Of the patients, 12.7% ultimately succumbed to their conditions, with 37.5% attributed to infections. FN is a common yet serious complication in solid tumor patients. Adequate knowledge of the predictors of mortality and the microbiological causes are of utmost importance to allow accurate diagnosis and prompt treatment as they significantly influence patient outcomes.

Understanding driving behavior – even in the rapid emergence of automation - remains in the spotlight, for decomposing complex driving dynamics, enabling the development of user-friendly and acceptable autonomous vehicles and ensuring the safe co-existence of autonomous and conventional vehicles on the road. Mobile crowdsensing has emerged as a means to understand and model driving behavior. Although the advantages of collecting data through smartphones are many (speed, accuracy, low cost etc.), the challenges including, but do not limited to, the preparation rate, the processing needs, as well as the methodological, legislative and security issues, are significant. The present paper aims to review the research dedicated to analyzing driving behavior based on smartphone sensors’ data streams. We first establish an inclusive stepwise framework to describe the path from data collection to informed decision making. Next, the existing literature is thoroughly analyzed and challenges in relation to data collection and data mining practices are critically discussed placing particular emphasis on the limitations and concerns regarding the use of mobile phones for driving data collection, as well as using crowd sensed data for feature extraction. Subsequently, modeling driving behavior practices and end-to-end solutions for driver assistance and recommendation systems are also reviewed. The paper ends with a discussion on the most critical challenges arising from the literature and future research steps.

The aim of this review is to investigate the association between metabolic syndrome (MetS) and cognitive decline in distinct cognitive domains, and to perform a complementary study description through the bibliometric analysis. PubMed and Scopus databases were searched from inception to 15 December 2021 to identify longitudinal studies that examined the association of MetS with incident decline, in order to prevent reverse causality. The Preferred Reporting Items for Systematic Review and Meta-Analysis checklist was used to conduct the present systematic review. Thirty studies were included and results were analyzed across the cognitive domains of global cognition, memory, executive functions, attention, visuoconstructive abilities, and language. The majority of the studies reviewed did not report statistically significant results for most cognitive domains investigated, and decline in specific cognitive domains was not consistently associated with the presence of MetS. Meta-analyses were not conducted due to the high degree of between-study heterogeneity regarding the MetS definitions, the cognitive domains examined, the specific tests used for each cognitive domain and the different measures of association used. Bibliometric analysis revealed that most studies are conducted by research teams from USA and China, and that cognitive tasks that reflect real-life abilities are rarely examined. Future studies should employ larger sample sizes, longer follow-up periods, a global consensus for MetS definition and standardized tests of the above mentioned cognitive domains as well as problem-solving tasks with high sensitivity and specificity to clarify the impact of MetS on cognition and its underlying mechanisms.

Axillosubclavian artery injury is relatively uncommon; however, it is related to a high rate of morbidity and mortality. Although open repair as well as endovascular techniques have been proposed for the treatment of axillosubclavian artery injury, the ideal approach is still under investigation. We present a case of a 20-year-old patient who suffered from complete subclavian artery transection, following blunt thoracic trauma. Using percutaneous access, a balloon catheter was inflated under fluoroscopy, in the origin of his affected subclavian artery ceasing the haemorrhage, thus immediately afterwards he was submitted to arterial bypass. The combination of endovascular and open repair ensured his life and limb salvage while the complications of an otherwise extensive dissection were obviated.

Abstract Background To assess the level of knowledge and trust in the policy decisions taken regarding the coronavirus disease (COVID-19) pandemic among Epirus Health Study (EHS) participants. Methods The EHS is an ongoing and deeply-phenotyped prospective cohort study that has recruited 667 participants in northwest Greece until August 31st, 2020. Level of knowledge on coronavirus (SARS-CoV-2) transmission and COVID-19 severity was labeled as poor, moderate or good. Variables assessing knowledge and beliefs towards the pandemic were summarized overall and by sex, age group (25–39, 40–49, 50–59, ≥60 years) and period of report (before the lifting of lockdown measures in Greece: March 30th to May 3rd, and two post-lockdown time periods: May 4th to June 31st, July 1st to August 31st). A hypothesis generating exposure-wide association analysis was conducted to evaluate the associations between 153 agnostically-selected explanatory variables and participants’ knowledge. Correction for multiple comparisons was applied using a false discovery rate (FDR) threshold of 5%. Results A total of 563 participants (49 years mean age; 60% women) had available information on the standard EHS questionnaire, the clinical and biochemical measurements, and the COVID-19-related questionnaire. Percentages of poor, moderate and good knowledge status regarding COVID-19 were 4.5, 10.0 and 85.6%, respectively. The majority of participants showed absolute or moderate trust in the Greek health authorities for the management of the epidemic (90.1%), as well as in the Greek Government (84.7%) and the official national sources of information (87.4%). Trust in the authorities was weaker in younger participants and those who joined the study after the lifting of lockdown measures (p-value≤0.001). None of the factors examined was associated with participants’ level of knowledge after correction for multiple testing. Conclusions High level of knowledge about the COVID-19 pandemic and trust in the Greek authorities was observed, possibly due to the plethora of good quality publicly available information and the timely management of the pandemic at its early stages in Greece. Information campaigns for the COVID-19 pandemic should be encouraged even after the lifting of lockdown measures to increase public awareness.

Industry 4.0 (I4.0) aims at achieving the interconnectivity of multiple industrial assets from different hierarchical layers within a manufacturing environment. The Asset Administration Shell (AAS) is a pilar component of I4.0 for the digital representation of assets and can be applied in both physical and digital assets, such as enterprise software, artificial intelligence (AI) agents, and databases. Multi-agent systems (MASs), in particular, are useful in the decentralized optimization of complex problems and applicable in various planning or scheduling scenarios that require the system’s ability to adapt to any given problem by using different optimization methods. In order to achieve this, a universal model for the agent’s information, communication, and behaviors should be provided in a way that is interoperable with the rest of the I4.0 assets and agents. To address these challenges, this work proposes an AAS-based information model for the description of scheduling agents. It allows multiple AI methods for scheduling, such as heuristics, mathematical programming, and deep reinforcement learning, to be encapsulated within a single agent, making it adjustable to different production scenarios. The software implementation of the proposed architecture aims to provide granularity in the deployment of scheduling agents which utilize the underlying AAS metamodel. The agent was implemented using the SARL agent-oriented programming (AOP) language and deployed in an open-source MAS platform. The system evaluation in a real-life bicycle production scenario indicated the agent’s ability to adapt and provide fast and accurate scheduling results.

The COVID-19 pandemic led to unprecedented stress on healthcare systems worldwide, forming settings of concern for increasing antimicrobial resistance. We investigated the impact of SARS-CoV-2 preventive measures against healthcare-associated infections (HAIs) from antibiotic-resistant bacteria in two tertiary-care hospitals. We compared infection rates between March 2019 and February 2020 (pre-intervention period) and March 2020 and February 2021 (COVID-19 intervention period) from drug-resistant ESKAPEE bacteria (methicillin-resistant Staphylococcus aureus; vancomycin-resistant Enterococci; carbapenem-resistant Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species and Escherichia coli). Over 24 months, 586 drug-resistant ESKAPEE HAIs occurred in 439 patients (0.3% of 179,629 inpatients) with a mean age of 63 years, with 43% being treated in intensive care units (ICUs), and having a 45% inpatient mortality rate. Interrupted time series analysis revealed increasing infection rates before the intervention that were sharply interrupted by abrupt drops for most pathogens and henceforth remained stable in the ICUs but progressively increased in ordinary wards. In the ICUs, the pooled infection rate was 44% lower over the intervention period compared to the pre-intervention period (incidence rate ratio (IRR) 0.56, 95%CI 0.41–0.75, p < 0.001). Pooled infection rates in the wards were slightly higher over the COVID-19 period (IRR 1.12, 95%CI 0.87–1.45, p = 0.368). The findings confirmed the ancillary beneficial impact of the enhanced bundle of transmission-based precautions adopted against SARS-CoV-2 in rapidly constraining antimicrobial-resistant HAIs in two Greek hospitals.

The article deals with the basic criteria involved in the selection of situations to be investigated and cases to be prosecuted before the International Criminal Court. These are examined in light of the goals of international criminal justice and the structural and evidentiary difficulties encountered by judicial mechanisms of international mission and composition. The analysis focuses on the limits of prosecutorial discretion at the level of international criminal justice. The Mavi Marmaraship incident is used hereto as a key point of reference.

BackgroundCoronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which since 2019 has caused over 5 million deaths to date. The pathogenicity of the virus is highly variable ranging from asymptomatic to fatal. Evidence from experimental and observational studies suggests that circulating micronutrients may affect COVID-19 outcomes.ObjectivesTo complement and inform observational studies, we investigated the associations of genetically predicted concentrations of 12 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, vitamin D, and zinc) with SARS-CoV-2 infection risk and COVID-19 severity using Mendelian randomization (MR).MethodsTwo-sample MR was conducted using 87,870 individuals of European descent with a COVID-19 diagnosis and 2,210,804 controls from the COVID-19 host genetics initiative. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.ResultsCompared to the general population, nominally significant associations were noted for higher genetically predicted vitamin B-6 (Odds ratio per standard deviation [ORSD]: 1.06; 95% confidence interval [CI]: 1.00, 1.13; p-value = 0.036) and lower magnesium concentrations (ORSD: 0.33; 95%CI: 0.11, 0.96; P = 0.042) with COVID-19 infection risk. However, the association for magnesium was not consistent in some sensitivity analyses, and sensitivity analyses could not be performed for vitamin B-6 as only two genetic instruments were available. Genetically predicted levels of calcium, folate, β-carotene, copper, iron, vitamin B-12, vitamin D, selenium, phosphorus, or zinc were not associated with the outcomes from COVID-19 disease.ConclusionThese results, though based only on genetically predicated circulating micronutrient concentrations, provide scant evidence for possible associations of micronutrients with COVID-19 outcomes.

Objective Assess the suitability of clinical vignettes in benchmarking the performance of online symptom checkers (OSCs).Design Observational study using a publicly available free OSC.Participants Healthily OSC, which provided consultations in English, was used to record consultation outcomes from two lay and four expert inputters using 139 standardised patient vignettes. Each vignette included three diagnostic solutions and a triage recommendation in one of three categories of triage urgency. A panel of three independent general practitioners interpreted the vignettes to arrive at an alternative set of diagnostic and triage solutions. Both sets of diagnostic and triage solutions were consolidated to arrive at a final consolidated version for benchmarking.Main outcome measures Six inputters simulated 834 standardised patient evaluations using Healthily OSC and recorded outputs (triage solution, signposting, and whether the correct diagnostic solution appeared first or within the first three differentials). We estimated Cohen’s kappa to assess how interpretations by different inputters could lead to divergent OSC output even when using the same vignette or when compared with a separate panel of physicians.Results There was moderate agreement on triage recommendation (kappa=0.48), and substantial agreement on consultation outcomes between all inputters (kappa=0.73). OSC performance improved significantly from baseline when compared against the final consolidated diagnostic and triage solution (p

Background: Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker. Methods: We conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (nine single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs), and GrimAge (4 SNPs) on multiple cancers (i.e. breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N = 34,710), and for cancer from the UK Biobank (N cases = 2671–13,879; N controls = 173,493–372,016), FinnGen (N cases = 719–8401; N controls = 74,685–174,006) and several international cancer genetic consortia (N cases = 11,348–122,977; N controls = 15,861–105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach. Results: Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR = 1.12 per year increase in GrimAge acceleration, 95% CI 1.04–1.20, p = 0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR = 1.15, 95% CI 1.09–1.21, p = 0.006), than rectal cancer (IVW OR = 1.05, 95% CI 0.97–1.13, p = 0.24). Results were less consistent for associations between other epigenetic clocks and cancers. Conclusions: GrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results. Funding: FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic’s Operational Programme ‘Competitiveness, Entrepreneurship & Innovation’ (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5, respectively) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer’s Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor’s Research Fellow at the University of Bristol.

Objectives: Despite the proven efficacy of several smoking cessation medications that have been shown to improve long-term abstinence rates, approximately two-thirds of smokers report not having used medication in their most recent quit attempt. A main barrier could be delayed access to pharmacological interventions. This study investigated the utility of a primary care linked online portal to streamline timely access to pharmacological support to patients who want to quit smoking by making an asynchronous request for treatment to their general practitioner. Study design: Prospective cohort study. Methods: An online portal with added functionality was developed, which allowed patients with a unique link to make an asynchronous request for treatment. Two GP practices identified a total of 4337 eligible patients who received an SMS or email invite to engage with an online portal including an electronic survey to capture information about smoking behaviours and to request treatment. Portal informatics and patient level data were analysed to measure the efficacy of the online system in reducing the time between making a formal request to treatment and access to pharmacological support. The primary outcome measure was the time between making a formal request for treatment and access to pharmacological support from a designated community pharmacy. Results: 323 patients (7.4%) initiated the survey, but only 56 patients completed the survey and made a formal request for treatment. 94% of participants did not return to use the portal to make a second or follow-up request for treatment. Only 3 participants completed the 12-week pathway. A total of 75 medication items were prescribed and collected by 56 patients. The time difference between the formal request to treatment and GP review ranged between 20 h and 1 week. The time difference between approval of prescription by the GP and access to medication was 5 days ± 2.1 days (range = 1.9–7.0 days). Conclusion: The widespread adoption and diffusion of an IT enabled and asynchronous primary care led remote consultation pathway can streamline timely access to smoking cessation support without the need for the patient to see a GP or an independent prescriber in the first instance.

Abstract Background While arthroscopic complete repair of massive rotator cuff tears (MRCT) back to their anatomic footprint is preferential, there are cases where this type of repair is not applicable due to the contraction of the torn tendons. In such cases, a non-anatomic incomplete or partial repair can be performed. A number of clinical studies have investigated the clinical and functional outcomes of arthroscopic partial repair for irreparable MRCT. To our knowledge, no systematic review has been published yet to synthetically evaluate these results. Methods Two reviewers independently conducted the search in a PRISMA-compliant systematic way using the MEDLINE/PubMed database and the Cochrane Database of Systematic Reviews. These databases were queried with the terms “arthroscopy”[MeSH Terms] OR arthroscopic surgical procedure [Text Word (tw)] AND massive rotator cuff tears [tw] AND arthroscopic partial repair [tw]. Results From the 55 initial studies, we finally chose 11 clinical studies which were eligible to our inclusion-exclusion criteria. The mean modified methodology Coleman score was 58/100, whereas it ranged from 41/100 to 78/100. In total, 643 patients were included in this review. All postoperative mean clinical and functional subjective scores, as well as muscle strength of patients treated with arthroscopic partial repair, were found significantly improved, when compared with the respective mean preoperative values. The rate of structural failure of the partial repair, as it was estimated by postoperative imaging modalities, was 48.9%. The overall reoperations’ rate was 2.9% regarding the patients who were treated with partial repair. Conclusions Arthroscopic partial repair might be a safe and effective alternative treatment for irreparable contracted MRCT, where a complete repair cannot be performed. The methodological quality of the relevant, available literature is low to moderate; therefore, further studies of higher quality are required to confirm these results.

Background: Both healthcare-associated infections (HAIs) and antimicrobial resistance are associated with an increased length of stay and hospital costs, while they have also been linked to high morbidity and mortality rates. In 2016 and 2017, the latest point prevalence survey (PPS) of HAIs and antimicrobial use in European acute care hospitals highlighted an HAI prevalence of 6.5%, while Greece had a higher HAI prevalence of 10%. The aim of this PPS was to record the prevalence of HAIs and antimicrobial use in all eight public acute care hospitals in Crete, Greece during the COVID-19 pandemic in order to highlight the types of infections and antimicrobial practices that need to be prioritized for infection control initiatives. Methods: The PPS was conducted between 30 March and 15 April 2022, according to the ECDC standardized relevant protocol (version 5.3). Statistics were extracted using the ECDC Helics.Win.Net application (software version 4.1.0). Results: A total of 1188 patients were included. The overall point prevalence of patients with at least one HAI was 10.6%. The most frequent types of infections were pneumonia (34.3%), bloodstream infections (10.5%), systemic infections and urinary tract infections (10.5% and 9.1%, respectively). In 14 (12.4%) cases, the pathogen responsible for HAI was SARS-CoV-2 following onsite spread, accounting for almost 10% of all HAIs. Microorganisms were identified in 60.1% of HAIs. Antimicrobials were administered in 711 (59.8%) patients, with 1.59 antimicrobials used per patient. Conclusion: The prevalence of HAI and antimicrobial use among hospitalized patients in Crete, Greece was similar to the national HAI prevalence in 2016 despite the enormous pressure on public hospitals due to the COVID-19 pandemic. Nevertheless, both HAI prevalence and antimicrobial use remain high, underlining the need to implement adequate infection control and antimicrobial stewardship interventions.

Phytopathogenic Verticillia cause Verticillium wilt on numerous economically important crops. Plant infection begins at the roots, where the fungus is confronted with rhizosphere inhabiting bacteria. The effects of different fluorescent pseudomonads, including some known biocontrol agents of other plant pathogens, on fungal growth of the haploid Verticillium dahliae and/or the amphidiploid Verticillium longisporum were compared on pectin-rich medium, in microfluidic interaction channels, allowing visualization of single hyphae, or on Arabidopsis thaliana roots. We found that the potential for formation of bacterial lipopeptide syringomycin resulted in stronger growth reduction effects on saprophytic Aspergillus nidulans compared to Verticillium spp. A more detailed analyses on bacterial-fungal co-cultivation in narrow interaction channels of microfluidic devices revealed that the strongest inhibitory potential was found for Pseudomonas protegens CHA0, with its inhibitory potential depending on the presence of the GacS/GacA system controlling several bacterial metabolites. Hyphal tip polarity was altered when V. longisporum was confronted with pseudomonads in narrow interaction channels, resulting in a curly morphology instead of straight hyphal tip growth. These results support the hypothesis that the fungus attempts to evade the bacterial confrontation. Alterations due to co-cultivation with bacteria could not only be observed in fungal morphology but also in fungal transcriptome. P. protegens CHA0 alters transcriptional profiles of V. longisporum during 2 h liquid media co-cultivation in pectin-rich medium. Genes required for degradation of and growth on the carbon source pectin were down-regulated, whereas transcripts involved in redox processes were up-regulated. Thus, the secondary metabolite mediated effect of Pseudomonas isolates on Verticillium species results in a complex transcriptional response, leading to decreased growth with precautions for self-protection combined with the initiation of a change in fungal growth direction. This interplay of bacterial effects on the pathogen can be beneficial to protect plants from infection, as shown with A. thaliana root experiments. Treatment of the roots with bacteria prior to infection with V. dahliae resulted in a significant reduction of fungal root colonization. Taken together we demonstrate how pseudomonads interfere with the growth of Verticillium spp. and show that these bacteria could serve in plant protection.

Objective Investigate the impact of the COVID-19 lockdown on feelings of loneliness and social isolation in parents of school-age children.Design Cross-sectional online survey of parents of primary and secondary school-age children.Setting Community setting.Participants 1214 parents of school-age children in the UK.Methods An online survey explored the impact of lockdown on the mental health of parents with school-age children, and in particular about feelings of social isolation and loneliness. Associations between the UCLA Three-Item Loneliness Scale (UCLATILS), the Direct Measure of Loneliness (DMOL) and the characteristics of the study participants were assessed using ordinal logistic regression models.Main outcome measures Self-reported measures of social isolation and loneliness using UCLATILS and DMOL.Results Half of respondents felt they lacked companionship, 45% had feelings of being left out, 58% felt isolated and 46% felt lonely during the first 100 days of lockdown. The factors that were associated with higher levels of loneliness on UCLATILS were female gender, parenting a child with special needs, lack of a dedicated space for distance learning, disruption of sleep patterns and low levels of physical activity during the lockdown. Factors associated with a higher DMOL were female gender, single parenting, parenting a child with special needs, unemployment, low physical activity, lack of a dedicated study space and disruption of sleep patterns during the lockdown.Conclusions The COVID-19 lockdown has increased feelings of social isolation and loneliness among parents of school-age children. The sustained adoption of two modifiable health-seeking lifestyle behaviours (increased levels of physical activity and the maintenance of good sleep hygiene practices) wmay help reduce feelings of social isolation and loneliness during lockdown.