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This paper presents the case of a male dialysis patient, with generalised epilepsy, who experienced complications after starting medium cut-off (MCO) dialysis. While receiving haemodiafiltration, the patient’s epilepsy had been relatively well controlled using two antiseizure medications (brivaracetam and sodium valproate). However, the patient’s seizure frequency increased when he was changed to MCO dialysis. MCO is a new dialysis method that has been developed to allow for better clearance of uraemic toxins through its larger pore size. We hypothesise that using the highly permeable MCO membrane changed the seizure threshold by an unknown mechanism. This is the first reported case to observe increased seizure frequency in a patient receiving MCO dialysis. The case highlights the need for caution when prescribing dialysis methods to patients with epilepsy.

Wound repair is a systematic biological program characterized by four overlapping phases: hemostasis, inflammation, proliferation, and remodeling. Notwithstanding differences between species and distinct anatomical sites, the fundamental phases in the wound healing process are conserved among mammalian species. Oral wound healing is defined as an ideal wound healing model because it resolves rapidly and without scar formation. Understanding the regulation and contribution of the different molecular events that drive rapid wound healing in oral mucosa compared with those of the skin will help us define how these lesions heal more efficiently and may provide new therapeutic strategies that can be translated to the clinical settings for patients with chronic nonhealing wounds. Although all epithelial tissues have remarkable ability for tissue repair, the efficiency of such repair differs between epithelia (oral mucosa vs. cutaneous). This prompts the long-standing, fundamental biological and clinically relevant questions as to why and how does the oral mucosa achieve its enhanced wound healing capacity. In this review, we focus on (1) distinct innate wound healing capabilities of the oral mucosa, (2) lessons learned from comparative transcriptomic studies of oral mucosa versus skin, and (3) translation of findings to therapeutics for enhanced wound healing.

Iron deficiency and the more severe sequela, iron deficiency anemia, are public health problems associated with morbidity and mortality, particularly among pregnant women and younger children. The 1998 Centers for Disease Control and Prevention recommendations for prevention and control of iron deficiency in the United States is old and does not reflect recent evidence but is a foundational reference for many federal, clinical, and program guidelines.Surveillance data for iron deficiency are sparse at all levels, with critical gaps for pregnant women and younger children. Anemia, iron deficiency, and iron deficiency anemia are often conflated but should not be. Clinical guidelines for anemia, iron deficiency, and iron deficiency anemia give inconsistent recommendations, causing nonsystematic assessment of iron deficiency. Screening for iron deficiency typically relies on identifying anemia, despite anemia’s low sensitivity for iron deficiency. In the National Health and Nutrition Examination Survey, more than 70% of iron deficiency is missed among pregnant women and children by relying on hemoglobin for iron deficiency screening.To improve assessment and diagnosis and strengthen surveillance, better and more complete data and updated foundational guidance on iron deficiency and anemia are needed that consider new evidence for measuring and interpreting laboratory results. (Am J Public Health. 2022;112(S8):S826–S835. https://doi.org/10.2105/AJPH.2022.306998 )

Introdução: O Projeto Terapêutico Singular é um trabalho realizado pela equipe interdisciplinar de saúde com vistas ao acompanhamento de um caso específico que envolve um sujeito ou uma comunidade. Objetivo: Relatar a experiência acadêmico assistencial de estudantes de Enfermagem durante a elaboração conjunta de um projeto terapêutico singular (PTS) na Unidade de saúde da Família Guaxuma em visita domiciliar de usuária com doença crônica agudizada. Método: Trata-se de uma pesquisa qualitativa, do tipo relato de Experiência, que aborda a vivência das enfermeirandas, no estágio curricular obrigatório em uma Unidade de Saúde da Família, na construção de um PTS. Resultados: foram realizados visitas domiciliar e encontros semanais com a equipe multiprofissional em saúde para discussão dos casos, visando alinhar os objetivos terapêuticos a curto, médio e longo prazo, resultando na construção do plano de intervenções baseado nas necessidades de saúde, sociais e político-programáticas do sujeito singular. Considerações finais: A proposta do PTS permitiu problematização por parte da equipe multiprofissional das necessidades específicas do individuo, contemplando a integralidade da atenção em uma perspectiva humanizada do atendimento, socialização dos saberes, incorporação da multidimensionalidade nas abordagens e o aprimoramento das práticas assistenciais.

Background and aim: Metabolic dysfunctions, particularly hyperlipidemia, are a common finding in Primary Biliary Cholangitis (PBC). In presence of metabolic components of fatty-liver-disease (MAFLD), the liver fibrosis progression risk is higher. The aim of this study was to evaluate lifestyle of PBC patients compared to controls. Methods: In a prospective, multicenter study 107 PBC patients were enrolled; among these, 54 subjects were age-and sex-matched with 54 controls with a propensity-score-matching-analysis. Eating habits and physical activity were evaluated, respectively, with a food-frequency-questionnaire and with a short pre-validated-questionnaire. The adherence to Mediterranean diet was assessed with the alternate Mediterranean diet score. Results: The total fat intake was higher in controls than in PBC (p=0.004), unless above the national recommendations in both groups. Moreover, in PBC monounsaturated-fat and polyunsaturated-fatty-acid intakes and the adherence to Mediterranean diet were significantly lower than in controls (p

A single-crystal diamond sample grown by highpressure high temperature (HPHT) technique was used for the fabrication of a metal-semiconductor-metal photoconductor. The sample quality was evaluated by means of spectral photocurrent measurements highlighting the presence of a significant density of defect states within the diamond bandgap, responsible for trapmediated conduction mechanisms. The photoconductor was fully characterized under 6 MeV pulsed X-rays, sourced by a medical linear accelerator, in the 0.05 – 10 Gy and 1 – 6 Gy/min dose and dose-rate ranges, respectively. Photocurrent measurements performed with a conventional precision electrometer showed that the detector performance is strongly affected by charge-trapping phenomena, resulting in a sub-linear dependence with the doserate (power-law dependence with an exponent of 0.86). Measurements were repeated in the same experimental conditions by coupling the detector to a specifically developed gatedintegrator, allowing for a synchronous integration of photocurrent pulses (limited to 40 μs) centered on each impinging X-ray pulse. In this case, the detector photoresponse showed an excellent linearity with both the dose and the dose-rate (power-law dependence with 1.0009 ± 0.0004 and 1.009 ± 0.005 exponents, respectively). Significantly, the proposed synchronous integration technique is then able to mitigate the detrimental effect that defects have on detector performance. The proposed method paves therefore the way to the exploitation of HPHT-diamond as a lowcost alternative to single-crystal CVD-diamond for the fabrication of accurate and linear X-ray dosimeters.

Nasopharyngeal and otitis media tuberculosis are rare extrapulmonary manifestations of Mycobacterium tuberculosis infection. We present a case of a middle-aged woman with manifestations of both conditions along with a description of the anatomical and temporal evolution of the disease. This case also highlights the difficulty of diagnosis and management of this condition, requiring a multidisciplinary approach. Extrapulmonary tuberculosis must be considered in the differential diagnosis of multiple head and neck conditions, including refractory chronic rhinosinusitis and otitis.

The 21st century is known as the age of knowledge and informational data. This revolution in the way of managing knowledge required organizations to reinvent themselves in the search for competitive advantages. New models or strategic management tools have come to confer advantages for organizations. In this context, knowledge management (KM) is presented as a set of processes to govern the creation, storage, dissemination, and use of knowledge, aiming to improve organizational performance. This differential requires companies to carry out a previous diagnosis in order to know their strengths and weaknesses. Assessing the degree of maturity in KM supports the elaboration of a management plan, as well as improving the level of development and indicating points of improvement, evolution, and progress of organizations. This work uses information technology to diagnose the level of maturity in KM in a public pharmaceutical industry. Results showed a reasonable degree of maturity and that it is necessary to improve the implementation of equitable KM at all levels of the organization.

Pharmaceutical companies are seen as slow in adopting principles of operation excellence and advanced technologies. This article aims to explore the reasons why an industry, recognized as profitable and intensive in capital and science, is reluctant to implement emerging technologies and management tools capable of improving its operational performance. Operational excellence incorporates the fundamentals of Lean Six Sigma (LSS) methodology to the organizational culture and strategic management of companies. LSS is also known as the most used approach in continuous improvement programs in the industrial segment. Despite being a methodology used for many years, LSS continues to evolve, incorporating new trends such as data science technologies, which significantly maximize LSS results. Applying LSS integrated with I4.0 can generate essential information for the organization's decision makers through data identification, extraction, and analysis. In this sense, information technology is a strong ally of operational performance management in the pharmaceutical industry.

The purpose of this study was to explore the different sub-skills of students’ written arguments (i.e., writing an argument, choosing a convincing argument) that might exist, and the content dependency of arguments. This paper presents two written argumentation tools that were designed for 11-14 year-old students, and the main outcomes from applying the tools to evaluate the written arguments of 246 students. The analysis of the data implies that choosing a convincing argument is a different kind of skill than any of the other three aspects of argumentation that were evaluated in these tests; that argumentation is content specific, and that argument construction is easier when the students’ have knowledge of the topic, regardless of whether this is a scientific or an everyday life topic. A main contribution in this study is that we have identified the degree of complexity for all four sub-skills that were included in the test. By identifying that writing an argument is a more difficult skill to acquire, or that students are not acquainted with it, it can help educators to design better scaffolding structures to support students when writing counterarguments. Research implications arising from the findings include exploring in detail how students choose to agree or disagree with given claims in different situations – for example exploring the difference in agreeing with media claims on socioscientific issues as opposed to scientific claims in the science classroom. Implications for teaching include using different teaching approaches for scientific and everyday argumentation.

Introduction: Left ventricular (LV) hypertrophy is the main feature of cardiac involvement in Anderson-Fabry disease (FD), but the right ventricle (RV) is also frequently affected. Previous studies failed to demonstrate an independent association between conventional parameters of RV performance and outcomes in FD. Nevertheless, if RV free wall strain (RV-FWS), assessed by 2D speckle tracking analysis, may provide a better prognostication is currently unknown. Methods: We retrospectively evaluated the association between RV-FWS and the occurrence of cardiovascular events in a cohort of 56 patients with FD. The study endpoint comprises cardiovascular mortality, severe heart failure symptoms, new-onset atrial fibrillation and major arrhythmias requiring device implantation. Results: Reduced RV-FWS, defined by values lower than 23%, was found in 25 (45%) patients. During a median follow-up of 47 months, 16 (29%) patients met the study endpoint. A ROC-curve analysis confirmed the threshold of reduced RV-FWS (

23 p.-2 tab., Stem borers (Lepidoptera) are common cereal pests. In many parts of the world, the species Ostrinia nubilalis and Sesamia nonagrioides stand out as important insect pests of economically important crops such as maize. Their management relied mainly on transgenic host plant resistance over the last 25 years. Technologies based on the insecticidal properties of Bacillus thuringiensis-derived proteins allowed widespread pest population suppression, especially for O. nubilalis. However, the recent discovery of Bt resistance, which has revitalized interest in both pests’ biology and management, may jeopardize the effectiveness of such transgenic technologies. Historical information on O. nubilalis bionomy may need to be reassessed in light of changing climate conditions and changing agricultural practices, as well as increased production of alternate host crops across its distribution range. The current paper examines the bioecology and historical research that has been conducted to manage these two important maize-boring pests.

21 pages, 8 figures, 1 table, supporting information https://doi.org/10.1111/mec.16840.-- Data Availability Statement: Raw reads have been deposited to European Nucleotide Archive (ENA) under the accession id PRJEB45992. A VCF file with all filtered and unlinked SNPs used in the analyses of this study is provided as an additional file., By evaluating genetic variation across the entire genome, one can address existing questions in a novel way while raising new ones. The latter includes how different local environments influence adaptive and neutral genomic variation within and among populations, providing insights into local adaptation of natural populations and their responses to global change. Here, under a seascape genomic approach, ddRAD data of 4609 single nucleotide polymorphisms (SNPs) from 398 sardines (Sardina pilchardus) collected in 11 Mediterranean and one Atlantic site were generated. These were used along with oceanographic and ecological information to detect signals of adaptive divergence with gene flow across environmental gradients. The studied sardines constitute two clusters (FST = 0.07), a pattern attributed to outlier loci, highlighting putative local adaptation. The trend in the number of days with sea surface temperature above 19°C, a critical threshold for successful sardine spawning, was crucial at all levels of population structuring with implications on the species' key biological processes. Outliers link candidate SNPs to the region's environmental heterogeneity. Our findings provide evidence for a dynamic equilibrium in which population structure is maintained by physical and ecological factors under the opposing influences of migration and selection. This dynamic in a natural system warrants continuous monitoring under a seascape genomic approach that might benefit from a temporal and more detailed spatial dimension. Our results may contribute to complementary studies aimed at providing deeper insights into the mechanistic processes underlying population structuring. Those are key to understanding and predicting future changes and responses of this highly exploited species in the face of climate change, This study was carried out within the European Research Contract SPELMED (EASME/EMFF/2016/032) funded by the Executive Agency for Small- and Medium-sized Enterprises (EASME) of the European Commission (DGMARE). [...]. MC would like to acknowledge partial funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 869300 (FutureMARES). MC and FR acknowledge the institutional support of the “Severo Ochoa Centre of Excellence” accreditation (CEX2019-000928-S). FR was supported by the Ramón y Cajal programme (Spanish Ministerio de Ciencia e Innovación, RYC2020-030078-I). This research was supported in part through computational resources provided by IMBBC (Institute of Marine Biology, Biotechnology and Aquaculture) of the HCMR (Hellenic Centre for Marine Research). Funding for establishing the IMBBC HPC has been received from the MARBIGEN (EU Regpot) project, LifeWatchGreece RI and the CMBR (Centre for the study and sustainable exploitation of Marine Biological Resources) RI, implemented under the Action “Reinforcement of the Research and Innovation Infrastructure,” funded by the Operational Programme “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014-2020) and cofinanced by Greece and the European Union (European Regional Development Fund)

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by a multistep evolutionary pathway, with an initial phase called monoclonal gammopathy of undetermined significance (MGUS), potentially evolving into the symptomatic disease, often preceded by an intermediate phase called “smoldering” MM (sMM). From a biological point of view, genomic alterations (translocations/deletions/mutations) are already present at the MGUS phase, thus rendering their role in disease evolution questionable. On the other hand, we currently know that changes in the bone marrow microenvironment (TME) could play a key role in MM evolution through a progressive shift towards a pro-inflammatory and immunosuppressive shape, which may drive cancer progression as well as clonal plasma cells migration, proliferation, survival, and drug resistance. Along this line, the major advancement in MM patients’ survival has been achieved by the introduction of microenvironment-oriented drugs (including immunomodulatory drugs and monoclonal antibodies). In this review, we summarized the role of the different components of the TME in MM evolution from MGUS as well as potential novel therapeutic targets/opportunities.

The Aeolian cultural heritage preserves hundreds of testimonies of the past that have passed through six millennia of history. Among these, the Archeological Park of the Aeolian Islands with the Museum Luigi Bernab`o Brea (Italy) preserves a valuable set of artworks, which are related to a little-known ‘popular’ figurative heritage. It is an assemblage of small glass foils decorated using the technique of reverse painting, datable to between the end of the 17th century and the end of the 18th century, and actually under investigation by historians. Here, an X-ray fluorescence (XRF) spectroscopy study (performed with portable equipment) is combined with a multivariate approach that allows us to define the best way to process the data to detect compositional differences and similarities among the glass supports. The Principal Component Analysis (PCA) and Hierarchical Cluster Analysis (HCA) were applied both on normalized spectra and on normalized peak areas in order to establish the chemometric approach with the highest grouping ability. Results showed that the analysis of the normalized area provides the most reliable grouping based on the different elemental compositions, without problems coming from the background or peak-shape distortions. The obtained results can be used by researchers involved in the analysis of XRF data as a guideline to perform chemometrics. Furthermore, regarding the reverse glass, they can be divided into different typologies based on composition differences, providing a further discrimination criterion for historians involved in the study of the collection to determine the provenance and dating of the items.

Purpose: Uncertainties remain about the safety and efficacy of therapies for managing intracranial hypertension in acute brain injured (ABI) patients. This study aims to describe the therapeutical approaches used in ABI, with/without intracranial pressure (ICP) monitoring, among different pathologies and across different countries, and their association with sixmonths mortality and neurological outcome. Methods: A preplanned subanalysis of the SYNAPSE-ICU study, a multicentre, prospective, international, observational cohort study, describing the ICP treatment, graded according to Therapy Intensity Level (TIL) scale, in patients with ABI during the first week of intensive care unit (ICU) admission. Results: 2320 patients were included in the analysis. The median age was 55 (I-III quartiles = 39-69) years, and 800 (34.5%) were female. During the first week from ICU admission, no-basic TIL was used in 382 (16.5%) patients, mild-moderate in 1643 (70.8%), and extreme in 295 cases (eTIL, 12.7%). Patients who received eTIL were younger (median age 49 (I-III quartiles = 35-62) vs 56 (40-69) years, p

In the first textbook on Roman law published in Polish language, The Principles of Roman Common Law [i.e. Civil Law] based on the Institutions of Justinian, containing also a brief excursus on the historical development of Roman legislation, Franciszek Maciejowski quoted several provisions of the Law of the Twelve Tables, without however providing their translation. Not all the provisions quoted by him came from Gothofredus’ Palingenesis, as declared by the author, but some of them originated from an earlier work constituting an attempt to systematise the work of Decemvirs, i.e. Oldendorp’s work, which passed unnoticed by Maciejowski. W pierwszym napisanym w języku polskim podręczniku prawa rzymskiego Zasady prawa rzymskiego pospolitego [tzn. cywilnego] podług Instytucji Justyniańskich wraz z krótkim wywodem dziejowego rozwoju prawodawstwa rzymskiego Franciszek Maciejowski zacytował kilka przepisów Ustawy XII Tablic, ale ich nie przetłumaczył. Nie wszystkie przytoczone przez niego przepisy pochodzą z palingenezji Gothofredusa, jak podaje autor, ale z wcześniejszej próby usystematyzowania tego źródła, czyli z pracy Oldendorpa, czego autor nie zauważa.

Objective: Bladder cancer (BC) is considered one of the malignancies with moderate-high incidence, high rate of recurrence and costly management. Diagnosis and staging are thus important for therapeutic purposes. Considering the risk of residual tumour and understaging, in specific cases, international guidelines recommend performing a second transurethral resection of the bladder (reTURB). Our study aimed to evaluate the impact of hexaminolevulinate Photodynamic Diagnostics (PDD) at first TURB on the rate of residual tumour. Materials and Methods: We retrospectively analysed patients undergoing TURB in our centre between 2012 and 2020. Eightytwo patients had a re-TURB after a first complete TURB with a delay < 3 months. Patients who had an incomplete first resection were excluded. We compared patients who underwent standard white light cystoscopy/TURB and then hexaminolevulinate PDDguided reTURB (group A, n = 49) and patients with PDD-cystoscopy/ TURB at the first procedure then white light cystoscopy/reTURB (group B, n = 33). The residual tumour rate at reTURB as well as median recurrence-free survival (RFS) were compared between the two groups. Results: Residual tumour at reTURB was detected in 48.8% of cases in our cohort, with a significant difference between the two groups (71.4% in group A versus 12.5% in group B, p < 0.001). After a median follow-up of 22 months, the median RFS was 15 months in Group A and 32 months in Group B, but this difference was not significant (p = 0.7). Conclusions: Using PDD at the time of the initial TURB had a statistically significant impact on the rate of residual tumour at the reTURB. Nevertheless, the percentage of residual tumour even with the use of PDD does not allow for safely omitting second resection. Performing a reTURB with PDD for patients who did not have it initially, provides the same benefit in terms of recurrence-free survival.

Summary Background Cutaneous immune-related adverse events (irAEs) represent the most frequent toxicities induced by immune checkpoint inhibitors (ICIs). Objectives To investigate clinical associations of cutaneous toxicities induced by different ICI therapies. Methods This was a multicentre retrospective international cohort study of patients with cancer who developed cutaneous irAEs under ICI therapy. Analysis was performed of the rates and basic characteristics of all cutaneous toxicities, and identification of any associations was performed using univariate and multivariate models. Results In total, 762 patients were included, who developed 993 cutaneous toxicities. Forty different types of skin toxicities were identified. Psoriasis (175 patients, 23·0%) and pruritus (171 patients, 22·4%) were the most common toxicities, followed by macular rash (161 patients, 21·1%) and eczematous-type reactions (150 patients, 19·7%). Multivariate analysis showed that among patients with macular rash, vitiligo or multiple toxicities, patients received ICIs more frequently for melanoma than for NSCLC. Moreover, anti-CTLA4 was less frequent than anti-programmed death 1 treatment in patients with macular rash [odds ratio (OR) 0·11, 95% confidence interval (CI) 0·01–0·76] and vitiligo (OR 0·07, 95% CI 0·006–0·78). A significant association was also seen in patients treated with a combination of ICI and chemotherapy vs. ICI monotherapy. They less frequently developed psoriasis (OR 0·08, 95% CI 0·02–0·31), lichenoid reactions (OR 0·15, 95% CI 0·03–0·77) and eczematous reactions (OR 0·24, 95% CI 0·07–0·78), all compared with pruritic rash. Conclusions Our study showed that skin-oriented toxicities do not share a single pattern and are related to several factors, including the specific agent administered and the underlying malignancy treated. Follow-up plans should be individualized in order to minimize the risk for severe reactions that could compromise optimum therapeutic outcome. What is already known about this topic? Patients with cancer treated with different immune checkpoint inhibitors (ICIs) carry an increased risk of developing various types of skin toxicities. What are the clinical implications of this work? In this multicentre cohort study we showed that ICI-related skin toxicities do not share a single pattern and may depend on several factors, including the specific agent administered and the underlying malignancy.Among patients with macular rash, vitiligo or multiple skin toxicities, patients received ICIs more frequently for melanoma than for non-small cell lung cancer.The combination of ICI and chemotherapy compared with ICI monotherapy occurred to a lesser extent in patients with psoriatic rash lichenoid and eczematous reactions, compared with patients with pruritus.Clinical awareness and specialized dermatological consultation should be advocated.

Background and objectives The C9orf72 expansion is the most common genetic cause of frontotemporal dementia (FTD) and/or motor neuron disease (MND). Corticospinal degeneration has been described in post-mortem neuropathological studies in these patients, especially in those with MND. We used MRI to analyze white matter (WM) volumes in presymptomatic and symptomatic C9orf72 expansion carriers and investigated whether its measure may be helpful in predicting the onset of symptoms. Methods We studied 102 presymptomatic C9orf72 mutation carriers, 52 symptomatic carriers: 42 suffering from FTD and 11 from MND, and 75 non-carriers from the Genetic Frontotemporal dementia Initiative (GENFI). All subjects underwent T1-MRI acquisition. We used FreeSurfer to estimate the volume proportion of WM in the brainstem regions (midbrain, pons, and medulla oblongata). We calculated group differences with ANOVA tests and performed linear and non-linear regressions to assess group-by-age interactions. Results A reduced WM ratio was found in all brainstem subregions in symptomatic carriers compared to both noncarriers and pre-symptomatic carriers. Within symptomatic carriers, MND patients presented a lower ratio in pons and medulla oblongata compared with FTD patients. No differences were found between presymptomatic carriers and non-carriers. Clinical severity was negatively associated with the WM ratio. C9orf72 carriers presented greater age-related WM loss than non-carriers, with MND patients showing significantly more atrophy in pons and medulla oblongata. Discussion We find consistent brainstem WM loss in C9orf72 symptomatic carriers with differences related to the clinical phenotype supporting the use of brainstem measures as neuroimaging biomarkers for disease tracking.

Lysine-specific demethylase 5C (KDM5C) has been identified as an important chromatin remodeling gene, contributing to X-linked neurodevelopmental disorders (NDDs). The KDM5C gene, located in the Xp22 chromosomal region, encodes the H3K4me3-me2 eraser involved in neuronal plasticity and dendritic growth. Here we report 30 individuals carrying 13 novel and one previously identified KDM5C variants. Our cohort includes the first reported case of somatic mosaicism in a male carrying a KDM5C nucleotide substitution, and a dual molecular finding in a female carrying a homozygous truncating FUCA1 alteration together with a de novo KDM5C variant. With the use of next generation sequencing strategies, we detected 1 frameshift, 1 stop codon, 2 splice-site and 10 missense variants, which pathogenic role was carefully investigated by a thorough bioinformatic analysis. The pattern of X-chromosome inactivation was found to have an impact on KDM5C phenotypic expression in females of our cohort. The affected individuals of our case series manifested a neurodevelopmental condition characterized by psychomotor delay, intellectual disability with speech disorders, and behavioral features with particular disturbed sleep pattern; other observed clinical manifestations were short stature, obesity and hypertrichosis. Collectively, these findings expand the current knowledge about the pathogenic mechanisms leading to dysfunction of this important chromatin remodeling gene and contribute to a refinement of the KDM5C phenotypic spectrum.

Objective: Non-alcoholic fatty liver disease (NAFLD) negatively impacts on renal function with the contribution of the I148M variant in the patatin like phospholipase containing domain 3 (PNPLA3) gene. We hypothesized that children with prediabetes present with lower estimated glomerular filtration rate (eGFR) than those with normal glucose tolerance (NGT) and that the 148M PNPLA3 allele could play a worsening role. We aimed evaluating the influence of the I148M PNPLA3 polymorphism on the relationship between eGFR and prediabetes in children with obesity. Methods: One thousand thirty-six children underwent to complete assessment and were genotyped for the I148M PNPLA3 polymorphism. Results: Patients with prediabetes showed lower eGFR levels (171.03±40.32 vs. 190.80±41.71ml/min/1.73 m2; p=0.001) and higher prevalence of NAFLD (80% vs. 59%; p=0.003) than those with NGT. Children with prediabetes showed lower eGFR levels than those with NGT (150.97±14.56 vs 192.88±40.09; p

RationaleIn 2016, a new interferon-gamma release assay (IGRA) was introduced, QuantiFERON-TB Gold Plus (QFT-Plus), claimed to have improved sensitivity in active tuberculosis (TB).ObjectivesThis study aimed to determine the performance of QFT-Plus, compared with previous generation IGRAs and the tuberculin skin test (TST), in children with TB in Europe.MethodsMulticentre, ambispective cohort study within the Paediatric Tuberculosis Network European Trials Group (ptbnet), a dedicated paediatric TB research network comprising >300 members, capturing TB cases Measurements and main results1001 TB cases from 16 countries were included (mean age (IQR) 5.6 (2.4–12.1) years). QFT-Plus was performed in 358, QFT Gold in-Tube (QFT-GIT) in 600, T-SPOT.TBin 58 and TST in 636 cases. The overall test sensitivities were: QFT-Plus 83.8% (95% CI 80.2% to 87.8%), QFT-GIT 85.5% (95% CI 82.7% to 88.3%), T-SPOT.TB77.6% (95% CI 66.9% to 88.3%) and TST (cut-off ≥10 mm) 83.3% (95% CI 83.3% to 86.2%). There was a trend for tests to have lower sensitivity in patients with miliary and/or central nervous system (CNS) TB (73.1%, 70.9%, 63.6% and 43.5%, respectively), and in immunocompromised patients (75.0%, 59.6%, 45.5% and 59.1%, respectively).ConclusionsThe results indicate that the latest generation IGRA assay, QFT-Plus, does not perform better than previous generation IGRAs or the TST in children with TB disease. Overall, tests performed worse in CNS and miliary TB, and in immunocompromised children. None of the tests evaluated had sufficiently high sensitivity to be used as a rule-out test in children with suspected TB.

Background: Emerging evidence suggests that elevated circulating levels of HDL-C (high-density lipoprotein cholesterol) could be linked to an increased mortality risk. However, to the best of our knowledge, the relationship between HDL-C and specific cardiovascular events has never been investigated in patients with hypertension. Methods: To fill this knowledge gap, we analyzed the relationship between HDL-C levels and cardiovascular events in hypertensive patients within the Campania Salute Network in Southern Italy. Results: We studied 11 987 patients with hypertension, who were followed for 25 534 person-years. Our population was divided in 3 groups according to the HDL-C plasma levels: HDL-C80 mg/dL (high HDL-C). At the follow-up analysis, adjusting for potential confounders, we observed a total of 245 cardiovascular events with a significantly increased risk of cardiovascular events in the low HDL-C group and in the high HDL-C arm compared with the medium HDL-C group. The spline analysis revealed a nonlinear U-shaped association between HDL-C levels and cardiovascular outcomes. Interestingly, the increased cardiovascular risk associated with high HDL-C was not confirmed in female patients. Conclusions: Our data demonstrate that there is a U-shaped association between HDL-C and the risk of cardiovascular events in male patients with hypertension.

Hypothesis: The possibility to use hexamethylenediamine (HMDA) to impart film forming ability to natural polymers including eumelanins and plant polyphenols endowed with biological activity and functional properties has been recently explored with the aim to broaden the potential of polydopamine (PDA)-based films overcoming their inherent limitations. 5,6-dihydroxyindole-2-carboxylic acid, its methyl ester (MeDHICA) and eumelanins thereof were shown to exhibit potent reducing activity. Experiments: MeDHICA and HMDA were reacted in aqueous buffer, pH 9.0 in the presence of different substrates to assess the film forming ability. The effect of different reaction parameters (pH, diamine chain length) on film formation was investigated. Voltammetric and AFM /SEM methods were applied for analysis of the film redox activity and morphology. HPLC, MALDI-MS and 1HNMR were used for chemical characterization. The film reducing activity was evaluated in comparison with PDA by chemical assays and using UV stressed human immortalized keratinocytes (HaCat) cells model. Findings: Regular and homogeneous yellowish films were obtained with moderately hydrophobic properties. Film deposition was optimal at pH 9, and specifically induced by HMDA. The film consisted of HMDA and monomeric MeDHICA accompanied by dimers/small oligomers, but no detectable MeDHICA/HMDA covalent conjugation products. Spontaneous assembly of self-organized networks held together mainly by electrostatic interactions of MeDHICA in the anion form and HMDA as the dication is proposed as film deposition mechanism. The film displayed potent reducing properties and exerted significant protective effects from oxidative stress on HaCaT

Background: Current literature highlights that chronic kidney disease (CKD) is a public health problem and that metabolic syndrome (MS) is a potential risk factor, especially among the elderly population, since aging seems to create metabolic disorders such as hypertension, hypertriglyceridemia, and glycemic decompensation. Despite this, some mechanisms/events of the relationship between kidney damage and MS remain controversial. Objective: The objective of this study is to investigate the association of compromised glomerular filtration rate with metabolic syndrome and its components in a population of Brazilian elderly. Methods: This is a cross-sectional study carried out in Northeast Brazil with 273 elderly men and women aged between 60 and 93 years. Clinical, sociodemographic, anthropometric, and lifestyle data, as well as biochemical, blood pressure, and glomerular filtration rate variables, were evaluated. Data were analyzed using Stata® (Statacorp, College Station, Texas, USA), version 14, adopting a significance level of p Results: There was a significant difference between impaired renal function and adequate values of WC (p = 0.044), triglycerides (p = 0.018), LDL-c (p = 0.015), and the presence of more than three components of MS (p = 0.036). High values of triglycerides (PR 1.48; p = 0.025) and LDLc (PR 1.44; p = 0.017) and presence of more than three components of MS (PR 1.45; p = 0.023) increase the chance of kidney damage. Conclusion: The presence of individual and combined components of MS (high triglycerides, cholesterol and LDL-c, and low HDL-c) promotes the impairment of renal function among the elderly studied. It is noteworthy that MS does not represent a significant independent factor to generate losses to GFR.

10 Pág., The most commonly used technique to vitrify pig embryos is the super open pulled straw (SOPS), where a maximum of 6 embryos can be vitrified simultaneously per device without compromising the minimum volume necessary for optimal preservation. Since optimal embryo transfer (ET) demands a transfer of 20-40 embryos per recipient, the customary use of SOPS complicates embryo warming and ET in field conditions. Such complications could be avoided when using the Cryotop® (OC) system, which has been proven to be an effective option for vitrifying at least 20 porcine embryos simultaneously. This study aimed to investigate the changes in the transcriptome of blastocysts caused by vitrification using both systems. In vivo-derived blastocysts were OC- (n = 60; 20 embryos/device) and SOPS- (n = 60; 4-6 embryos/device) vitrified and cultured for 24 h after warming. Nonvitrified blastocysts (n = 60) cultured for 24 h postcollection acted as controls. At the end of culture, 48 viable embryos from each group (6 pools of 8 embryos) were selected for microarray (GeneChip® Porcine Genome Array, P/N 900624, Affymetrix) analysis of differentially expressed genes (DEGs). The survival rate of embryos vitrified with the OC and SOPS systems (>97%) was similar to that of the control embryos (100%). Microarray analysis of each vitrification system compared to the control group showed 245 DEGs (89 downregulated and 156 upregulated) for the OC system and 210 (44 downregulated and 166 upregulated) for the SOPS system. Two pathways were enriched for the DEGs specifically altered in each vitrification system compared to the control (glycolysis/gluconeogenesis and carbon metabolism pathways for the OC system and amino sugar and nucleotide sugar metabolism and lysosome pathways in the SOPS group). The OC group showed 31 downregulated and 24 upregulated genes and two enriched pathways (mineral absorption and amino sugar and nucleotide sugar metabolism pathways) when compared to the SOPS group. In summary, vitrification with the OC system altered fewer genes related to apoptosis and activated genes related to cell proliferation. We conclude that vitrification with either the OC or SOPS system has a moderate to low effect on the transcriptome of in vivo-derived porcine blastocysts. Further investigation is needed to elucidate how the differences in the transcriptome of embryos vitrified with these systems affect their subsequent developmental ability after ET., The authors would like to acknowledge the financial support from the Spanish Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033) and from ERDF “A way of making Europe” (RTI2018-093525-B-I00), Madrid, Spain; Fundacion Seneca (19892/GERM/15), Murcia, Spain and the Research Council FORMAS (project 2019-00288), Stockholm, Sweden. We are also grateful to the Spanish Ministry of Science and Innovation for the grant-based support to A Gonzalez-Plaza (PRE2019-090508). We would also like to thank the staff of the Agropor piggery (Murcia, Spain) for their excellent care of the animals.

Introduction: Despite numerous scientific advances, cancer continues to be one of the main causes of death in the world. This situation has driven the search for promising molecules. Lichen substances have been widely described for their pharmacological potential. Objective: The present study evaluated the antitumour potential of a depsidone isolated from Parmotrema concurrens– salazinic acid (SAL) – through in vitro, in vivo and in silico studies. Methods: The molecule was isolated from the acetonic extract of the lichen and recrystallized in acetone. The macrophage J774, sarcoma-180 and MDA-MB-231 cell lines were used for the MTT cytotoxicity assay. The antitumor assay used a murine model (Swiss albino mice) with sarcoma-180. The animals were treated for seven consecutive days with doses of SAL (25 and 50 mg/kg) and 5-fluorouracil (20 mg/kg). Results: Its purity was determined using high-performance liquid chromatography (94%), and its structure was confirmed by H1 and C13 nuclear magnetic resonance. SAL was not considered toxic to cancer cell lines, showing cell viability rates of 79.49 ± 4.15% and 86.88 ± 1.02% for sarcoma-180 and MDA-MB-231, respectively. The tumour inhibition rate was greater than 80% in the animals treated with SAL and 65% for those that received 5-fluorouracil. Simulations of molecular dynamics to estimate the flexibility of the interactions between human thymidylate synthase and derivatives of SAL and 5-fluorouracil revealed that SAL exhibited greater enzymatic interaction capacity, with highly favourable energy, compared to 5-fluorouracil. Conclusion: The present results demonstrate the potential of salazinic acid as a tumour inhibition agent.

Introduction: Alzheimer’s disease is a multifactorial syndrome, which is not yet fully understood, causing memory loss, dementia, and, ultimately, death. Acetylcholinesterase inhibitors are the mainstay drugs that are used in disease-symptomatic treatment. In this work, we report a new synthetic route yielding sugar amides as low to moderate acetylcholinesterase inhibitors. Methods: Commercially available diacetone glucose was converted into perbenzyl D-glucono-1,4- lactone, which reacted with aromatic or aliphatic amines to afford the corresponding new amides in a high isolated yield. Docking studies of the most promising hydroxybutylamide and benzylamide were performed to assign binding interactions with acetylcholinesterase and determine the key features for bioactivity. Results: The inhibitors are accommodated in enzyme gorge, blocking the access to Ser203 mainly due to π-π stacking interactions of sugar benzyl groups with the aromatic gorge residues, Tyr337 and Tyr341 for both inhibitors and Trp439 only for the hydroxybutylamide. Conclusion: Bonding is also significant through sugar interaction with the residues Tyr124 and Ser125-OH in both inhibitors. Flexibility of these open-chain structures seems to be quite relevant for the observed binding to acetylcholinesterase.

This study reports an exceptional case of a 14-year-old girl with sickle cell disease that was diagnosed with agenesis of the vermiform appendix and ileal duplication. Both consist of extremely rare gastrointestinal malformations whose association has never been described. The preadolescent girl presented with abdominal pain and vomiting, and the ultrasound was suggestive of acute appendicitis. Surgical findings were agenesis of the vermiform appendix and a T-shaped ileal malformation with inflammatory changes. The patient underwent resection and ileal end-to-end anastomosis. Histopathological evaluation identified an ileal duplication, with small bowel and colonic mucosa, no communication to the adjacent ileum and ischaemic changes. At 8-month follow-up, the patient was asymptomatic.

Research Findings: During the COVID-19 pandemic, the education system faced unprecedented challenges, including global school closures, the cancellation of face-to-face teaching, and ultimately school step-wise or partial reopening. Childcare providers have faced additional significant stressors from the beginning of the outbreak. The present study aimed at investigating the effect of childcare providers’ regulatory emotional self-efficacy on their subjective well-being (i.e. positive and negative affect), including indirectly through a reduction in stress during the first COVID-19 lockdown in Italy. Three hundred and sixty-four childcare providers at daycares and preschools in Italy participated in the study by completing an online survey. A structural equation model revealed an indirect effect between self-efficacy beliefs in the management of negative emotions and negative affect, via stress. More specifically, childcare providers with high self-efficacy beliefs in the management of negative emotions experienced less negative affect, alongside lower levels of stress. Practice or Policy:​ ​The findings suggest the crucial role played by childcare providers’ regulatory emotional self-efficacy beliefs in protecting their subjective well-being during the COVID-19 outbreak. The practical implications of the study are discussed.

Purpose The relevance of the subfamily A members of ATP-binding cassette (ABCA) transporters as biomarkers of risk and response is emerging in different tumors, but their mechanisms of action have only been partially defined. In this work, we investigated their role in Ewing sarcoma (EWS), a pediatric cancer with unmet clinical issues. Methods The expression of ABC members was evaluated by RT-qPCR in patients with localized EWS. The correlation with clinical outcome was established in different datasets using univariate and multivariate statistical methods. Functional studies were conducted in cell lines from patient-derived xenografts (PDXs) using gain- or loss-of-function approaches. The impact of intracellular cholesterol levels and cholesterol lowering drugs on malignant parameters was considered. Results We found that ABCA6, which is usually poorly expressed in EWS, when upregulated became a prognostic factor of a favorable outcome in patients. Mechanistically, high expression of ABCA6 impaired cell migration and increased cell chemosensitivity by diminishing the intracellular levels of cholesterol and by constitutive IGF1R/AKT/mTOR expression/activation. Accordingly, while exposure of cells to exogenous cholesterol increased AKT/mTOR activation, the cholesterol lowering drug simvastatin inhibited IGF1R/AKT/mTOR signaling and prevented Ser166 phosphorylation of MDM2. This, in turn, favored p53 activation and enhanced pro-apoptotic effects of doxorubicin. Conclusions Our study reveals that ABCA6 acts as tumor suppressor in EWS cells via cholesterol-mediated inhibition of IGF1R/AKT/MDM2 signaling, which promotes the pro-apoptotic effects of doxorubicin and reduces cell migration. Our findings also support a role of ABCA6 as biomarker of EWS progression and sustains its assessment for a more rational use of statins as adjuvant drugs.

PURPOSE: To describe data on epidemiology, microbiology, clinical characteristics and outcome of adult patients admitted in the intensive care unit (ICU) with secondary peritonitis, with special emphasis on antimicrobial therapy and source control. METHODS: Post hoc analysis of a multicenter observational study (Abdominal Sepsis Study, AbSeS) including 2621 adult ICU patients with intra-abdominal infection in 306 ICUs from 42 countries. Time-till-source control intervention was calculated as from time of diagnosis and classified into 'emergency' (< 2 h), 'urgent' (2-6 h), and 'delayed' (> 6 h). Relationships were assessed by logistic regression analysis and reported as odds ratios (OR) and 95% confidence interval (CI). RESULTS: The cohort included 1077 cases of microbiologically confirmed secondary peritonitis. Mortality was 29.7%. The rate of appropriate empiric therapy showed no difference between survivors and non-survivors (66.4% vs. 61.3%, p = 0.1). A stepwise increase in mortality was observed with increasing Sequential Organ Failure Assessment (SOFA) scores (19.6% for a value ≤ 4-55.4% for a value > 12, p < 0.001). The highest odds of death were associated with septic shock (OR 3.08 [1.42-7.00]), late-onset hospital-acquired peritonitis (OR 1.71 [1.16-2.52]) and failed source control evidenced by persistent inflammation at day 7 (OR 5.71 [3.99-8.18]). Compared with 'emergency' source control intervention (< 2 h of diagnosis), 'urgent' source control was the only modifiable covariate associated with lower odds of mortality (OR 0.50 [0.34-0.73]). CONCLUSION: 'Urgent' and successful source control was associated with improved odds of survival. Appropriateness of empirical antimicrobial treatment did not significantly affect survival suggesting that source control is more determinative for outcome. TRIAL REGISTRATION: ClinicalTrials.gov NCT03270345.

Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, and the International Standard ISO 23162:2021. With these tools, we propose that authors should be instructed to follow these laboratory methods in order to publish studies in peer-reviewed journals, preferable by using a checklist as suggested in an Appendix to this article.

PurposeConsistent with current literature, which highlights the role of narration as a key tool for exploring the processes by which people construct the meaning of their critical experiences the authors propose a theoretical and methodological model to analyse the narratives of illness and identify any innovative aspects. The generative model of mind presented refers to a semiotic, narrative and socio-constructivist perspective according to which narration constitutes one of the possible processes by which the affective and pre-verbal sense of experience is transformed into a meaning that can be symbolized and shared.Design/methodology/approachThe onset of an illness represents a critical event which interrupts a person's life narrative, shattering his/her biographical continuity and undermining any assumptions of him/herself and the world. In particular, the model proposes a method of analysis, currently absent in literature, of the narrative interview Narrative Function Coding System (NFC) in order to grasp the ways by which four main narrative functions, namely psychic functions, are classified: the search for meaning, the expression of emotions, the temporal organization and the orientation to action.FindingsNFC appears to be able to capture the complexity of the narrative process of construction of illness' sense-meaning making process, identifying both representative modalities of good functioning, which express a gradual process of connection with the variability of the experience, and modalities that express moments of disorganization and rigidity, which can persist throughout the time of treatment. The NFC represents not only a method for analysing illness narratives but also a method for tracking and monitoring the process of clinical intervention and change.Originality/valueThe sense-meaning making process perspective within the narrative socio-constructivist and semiotic framework of analysis proposed by NFC is currently absent in the literature. NFC can be a device for analysing the narrative process of sense-meaning making both for its use for clinical and preventive purposes. In addition we believe that this method, which focuses on the “form” and “way” of narratively constructing the subjective experience, rather than on the specific thematic content, can be used with all types of illness narratives, in particular the longitudinal one to explore the changes in sense-meaning making process.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved., A key factor to successful secondary prevention of cardiovascular disease (CVD) is optimal patient adherence to treatment. However, unsatisfactory rates of adherence to treatment for CVD risk factors and CVD have been observed consistently over the last few decades. Hence, achieving optimal adherence to lifestyle measures and guideline-directed medical therapy in secondary prevention and rehabilitation is a great challenge to many healthcare professionals. Therefore, in this European Association of Preventive Cardiology clinical consensus document, a modern reappraisal of the adherence to optimal treatment is provided, together with simple, practical, and feasible suggestions to achieve this goal in the clinical setting, focusing on evidence-based concepts.

PURPOSE: To describe the clinical phenotype of a cohort of patients with Wolfram syndrome (WS), focusing on the pattern of optic atrophy correlated with brain magnetic resonance imaging (MRI) measurements, as compared with patients with OPA1-related dominant optic atrophy (DOA).center dot DESIGN: Retrospective, comparative cohort study.center dot METHODS: We reviewed 25 patients with WS and 33 age-matched patients affected by OPA1-related DOA. Ophthalmologic, neurologic, endocrinologic, and MRI data from patients with WS were retrospectively retrieved. Ophthalmologic data were compared with data from patients with OPA1-related DOA and further analyzed for age dependency dividing patients in age quartiles. In a subgroup of patients with WS, we correlated the structural damage assessed by optical coherence tomography (OCT) with brain MRI morphologic measurements. Visual acuity (VA), visual field mean defect (MD), retinal nerve fiber layer (RNFL), and ganglion cell layer (GCL) thickness were assessed by OCT and MRI morphologic measurements of anterior and posterior visual pathways.center dot RESULTS: Optic atrophy was present in 100% of patients with WS. VA, MD, and RNFL thickness loss were worse in patients with WS with a faster decline since early age as compared with patients with DOA, who displayed a more stable visual function over the years. Conversely, GCL sectors were overall thinner in patients with DOA since early age compared to patients with WS, in which GCL thickness started to decline later in life. The neuroradiologic subanalysis on 11 patients with WS exhibited bilateral thinning of the anterior optic pathway, especially the prechiasmatic optic nerves and optic tracts. Optic tract thinning was significantly correlated with GCL thickness but not with RNFL parameters.center dot CONCLUSIONS: Our results showed a generally more severe and diffuse degeneration of both anterior and posterior visual pathways in patients with WS, with fast deterioration of visual function and structural OCT parameters since early age. The pattern observed with OCT suggests that retinal ganglion cell axonal degeneration (ie, RNFL) precedes cellular body atrophy (ie, GCL) by about a decade. This differs substantially from DOA, in which a more stable visual function is evident with predominant early loss of GCL, indirectly supporting the lack of a primary mitochondrial dysfunction in patients with WS. (Am J Ophthalmol 2022;241: 206-216. (c) 2022 Elsevier Inc. All rights reserved.)

In the present study, immunogenicity data in 61 vaccinated healthcare workers (HCWs) either infection naïve (naïve HCWs) or with infection of Delta and/or Omicron COVID-19 (experienced HCWs) were evaluated up to 270days after the second dose of BNT162b2 vaccine and up to 90days after a booster dose. A decrease in antibody levels at 270days following administration of the second dose (p=0.0335) was observed, although values did not fall below the positivity threshold (33.8 BAU/ml). After booster vaccination, antibody levels increased after 30days (p=0.0486), with much higher values than after first and second vaccination. Antibody levels then decreased at 60 and 90days after the booster dose. A comparison between mean antibody levels of naïve and experienced HCWs revealed higher values in experienced HCWs, resulting from both natural and vaccination-induced immunity. A total of 14.7% of HCWs contracted the Omicron virus variant after the vaccine booster, although none showed severe symptoms. These results support that a booster dose results in a marked increase in antibody response that subsequently decreases over time.

The in vivo role for RNase H1 in mammalian mitochondria has been much debated. Loss of RNase H1 is embryonic lethal and to further study its role in mtDNA expression we characterized a conditional knockout of Rnaseh1 in mouse heart. We report that RNase H1 is essential for processing of RNA primers to allow site-specific initiation of mtDNA replication. Without RNase H1, the RNA:DNA hybrids at the replication origins are not processed and mtDNA replication is initiated at non-canonical sites and becomes impaired. Importantly, RNase H1 is also needed for replication completion and in its absence linear deleted mtDNA molecules extending between the two origins of mtDNA replication are formed accompanied by mtDNA depletion. The steady-state levels of mitochondrial transcripts follow the levels of mtDNA, and RNA processing is not altered in the absence of RNase H1. Finally, we report the first patient with a homozygous pathogenic mutation in the hybrid-binding domain of RNase H1 causing impaired mtDNA replication. In contrast to catalytically inactive variants of RNase H1, this mutant version has enhanced enzyme activity but shows impaired primer formation. This finding shows that the RNase H1 activity must be strictly controlled to allow proper regulation of mtDNA replication.