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The nine-member CLC gene family of Cl - chloride-transporting membrane proteins is divided into plasma membrane-localized Cl - channels and endo-/lysosomal Cl - /H + antiporters. Accessory proteins have been identified for ClC-K and ClC-2 channels and for the lysosomal ClC-7, but not the other CLCs. Here, we identified TMEM9 Domain Family Member B (TMEM9B), a single-span type I transmembrane protein of unknown function, to strongly interact with the neuronal endosomal ClC-3 and ClC-4 transporters. Co-expression of TMEM9B with ClC-3 or ClC-4 dramatically reduced transporter activity in Xenopus oocytes and transfected HEK cells. For ClC-3, TMEM9B also induced a slow component in the kinetics of the activation time course, suggesting direct interaction. Currents mediated by ClC-7 were hardly affected by TMEM9B, and ClC-1 currents were only slightly reduced, demonstrating specific interaction with ClC-3 and ClC-4. We obtained strong evidence for direct interaction by detecting significant Förster Resonance Energy Transfer (FRET), exploiting fluorescence lifetime microscopy-based (FLIM-FRET) techniques between TMEM9B and ClC-3 and ClC-4, but hardly any FRET with ClC-1 or ClC-7. The discovery of TMEM9B as a novel interaction partner of ClC-3 and ClC-4 might have important implications for the physiological role of these transporters in neuronal endosomal homeostasis and for a better understanding of the pathological mechanisms in CLCN3- and CLCN4 -related pathological conditions.

Purpose: In Familial Hypercholesterolemia (FH), female atherosclerotic cardiovascular disease occurs 20 years earlier than in women without FH. The aim of this study is to describe the differences in lipoprotein apheresis (LA), a last therapeutic option, in terms of efficacy, safety and clinical outcomes between the two sexes., Materials and Methods: Sex related differences were analysed in 31 subjects in on LA treatment with FH and not achieving LDL-cholesterol and/or Lp(a) target values on maximum lipid-lowering therapies. Moreover, sex related differences in time to major cardiovascular event (MACE) was investigated in 68 subjects, with at least one year of follow-up., Results: Among the 31 patients currently undergoing LA treatment who did not achieve LDL-cholesterol and/or Lp(a) target values, no differences in comorbidity were recorded despite a worse pre-LA treatment lipid profile (LDL-C 77 ± 60 mg/dl in males vs. 128 ± 105 mg/dl in females; p 0.025) and a longer mean inter-apheresis interval (17 ± 4 days in males vs. 19 ± 5 days in females; p 0.012) reported in females compared to males. Additionally, in comparison with men, it was found that the time between the first cardiovascular event and the beginning of LA, as well as the age at the beginning of LA, were significantly higher in females than in males (p 0.027 and 0.007, respectively)., Conclusions: Sex differences in FH subjects not only affect the diagnosis and treatment but also influence varied responses to the treatment itself., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: In heterozygous Familial Hypercholesterolemia (FH) woman atherosclerotic cardiovascular disease occurs 20-years earlier respect woman without FH while homozygous FH women may suffer from atherosclerotic cardiovascular disease even in childhood. Lipoprotein apheresis, a therapeutic "last chance saloon", is a well-tolerated procedure that markedly lowers LDL-cholesterol and Lp(a) levels in patients who do not achieve acceptable levels with maximal lifestyle and drug therapy., Methods and Results: The experience of LA treatment in 3 female homozygous FH patients was described. Moreover, an explore analysis on pre and post-LA hormonal levels was performed in 8 HeFH women showing a significant improvement in the atherogenic lipid profile (total cholesterol -56%, LDL cholesterol -71%, triglycerides -72%, Apo B lipoprotein -69%, Lp(a) -59%;) and a reduction of FSH and LH values (FSH - 28%, LH -31%)., Conclusions: Women with FH experience specific barriers to care, including underrepresentation in research, significant underestimation of risk, and discontinuation of therapy during pregnancy. Therefore, in this study, we investigated the possible effects of LA treatment on plasma FSH and LH levels., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: Conflict of interest: none declared.

Aim: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulator of low-density-lipoprotein cholesterol (LDL-C), a major risk factor for cardiovascular (CV) disease. Since the hormone leptin has been suggested as having a role in CV risk regulation, possibly by modulating LDL receptor expression through the PCSK9 pathway, nutritional status may represent a potential regulator. Thus, evaluation of PCSK9 levels in human eating disorders appears to be of interest. In this report, we evaluate the lipoprotein profile, PCSK9, and leptin levels in subjects affected by anorexia nervosa (AN) to improve our understanding of the metabolic alterations in this disease., Methods and Results: We designed a case-control observational study, enrolling 20 anorexic adolescent females and 20 adolescent females without AN as the control group, age- and sex-matched. Subjects affected by AN showed lower BMI, total cholesterol, and LDL-C in comparison to the control group, with lipoprotein levels in the normal range. Furthermore, adolescent girls with AN show significantly higher PCSK9 (+24%, p < 0.005) and lower leptin levels (-43%, p < 0.01), compared to the control group., Conclusions: The findings of increased levels of PCSK9 and reduced leptin levels among AN subjects warrant further research in order to unravel the role of the liver and adipose tissue in the management of PCSK9/LDL metabolism in adolescents affected by AN., (© 2023. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

Background: Despite advance in pharmacotherapy of lipid disorders, lipoprotein apheresis (LA) plays a leading role in the management of severe hypercholesterolemia and in atherosclerosis prevention., Methods: Aim of this study was to retrospectively evaluate Charlson Comorbidity Index (CCI), presence of major comorbidity, and/or concomitant polypharmacy (definite as 5+ drugs daily) in patients with inherited dyslipidemias on chronic LA., Results: Since 1994, we performed more than 500 LA treatment/year and followed a total of 83 patients (age 56 [47-65] years, male 75%). In subjects with more than 5 years of LA treatment (38 patients, age 54 [45-62] years, male 66%), at the end of the observation time (9 [7-16] years), patients had higher CCI, polypharmacy, anemia, heart failure, peptic ulcer disease, and benign prostatic hyperplasia., Discussion: Even in the era of new lipid-lowering therapies, the LA treatment established itself as a safe and lifesaving intervention. Patients on chronic LA require a multidisciplinary approach to address their comorbidity and the apheresis unit's medical staff (doctors and nurses) play a pivotal role creating a bridge toward the general practitioner and other specialists for overcoming clinical issues., (© 2023 Wiley Periodicals LLC.)

"The lower, the better" is the recommended approach in the management of high LDL cholesterol. Unfortunately, this does not always achieve as in the case of a 69-year-old woman referred to our Institute for her lipid profile (LDL cholesterol 412mg/dl), bilateral xanthelasma and cutaneous xanthomas. With a maximized and personalized lipid-lowering therapies (rosuvastatin, ezetimibe, PCSK9i and lipoprotein apheresis), after only six months, the patient showed an impressive regression in her cutaneous xanthomas., (Copyright © 2023 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Primary hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM) represent the liver's two most common malignant neoplasms. Liver-directed therapies such as ablation have become part of multidisciplinary therapies despite a paucity of data. Therefore, an expert panel was convened to develop evidence-based recommendations regarding the use of microwave ablation (MWA) and radiofrequency ablation (RFA) for HCC or CRLM less than 5 cm in diameter in patients ineligible for other therapies., Methods: A systematic review was conducted for six key questions (KQ) regarding MWA or RFA for solitary liver tumors in patients deemed poor candidates for first-line therapy. Subject experts used the GRADE methodology to formulate evidence-based recommendations and future research recommendations., Results: The panel addressed six KQs pertaining to MWA vs. RFA outcomes and laparoscopic vs. percutaneous MWA. The available evidence was poor quality and individual studies included both HCC and CRLM. Therefore, the six KQs were condensed into two, recognizing that these were two disparate tumor groups and this grouping was somewhat arbitrary. With this significant limitation, the panel suggested that in appropriately selected patients, either MWA or RFA can be safe and feasible. However, this recommendation must be implemented cautiously when simultaneously considering patients with two disparate tumor biologies. The limited data suggested that laparoscopic MWA of anatomically more difficult tumors has a compensatory higher morbidity profile compared to percutaneous MWA, while achieving similar overall 1-year survival. Thus, either approach can be appropriate depending on patient-specific factors (very low certainty of evidence)., Conclusion: Given the weak evidence, these guidelines provide modest guidance regarding liver ablative therapies for HCC and CRLM. Liver ablation is just one component of a multimodal approach and its use is currently limited to a highly selected population. The quality of the existing data is very low and therefore limits the strength of the guidelines., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Many studies highlighted the importance of the IK channel for the proliferation and the migration of different types of cancer cells, showing how IK blockers could slow down cancer growth. Based on these data, we wanted to characterize the effects of IK blockers on melanoma metastatic cells and to understand if such effects were exclusively IK-dependent. For this purpose, we employed two different blockers, namely clotrimazole and senicapoc, and two cell lines: metastatic melanoma WM266-4 and pancreatic cancer Panc-1, which is reported to have little or no IK expression. Clotrimazole and senicapoc induced a decrease in viability and the migration of both WM266-4 and Panc-1 cells irrespective of IK expression levels. Patch-clamp experiments on WM266-4 cells revealed Ca 2+ -dependent, IK-like, clotrimazole- and senicapoc-sensitive currents, which could not be detected in Panc-1 cells. Neither clotrimazole nor senicapoc altered the intracellular Ca 2+ concentration. These results suggest that the effects of IK blockers on cancer cells are not strictly dependent on a robust presence of the channel in the plasma membrane, but they might be due to off-target effects on other cellular targets or to the blockade of IK channels localized in intracellular organelles.

Background: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) represent a breakthrough in the treatment of hypercholesterolemia. The aim of this study was to perform a multicentre prospective analysis on the effects of PCSK9i since their distribution in Italy., Methods: During the study period (July 2017 to February 2022) 246 patients (mean age 61 ± 11 years, male 73%) who were evolocumab (142/246) or alirocumab (104/246) new users were enrolled in the CERTI (Costo Efficacia Regione Toscana Inibitori PCSK9) study. Lipid value, adverse events (AEs), major cardiovascular events (MACEs) and intima-media thickness were analysed., Results: PCSK9i therapy allowed a significant improvement in patients' lipid profile [total cholesterol -35%, P < 0.001; triglycerides -9%, P < 0.05; low-density lipoprotein (LDL) cholesterol -51%, P < 0.001; Lp(a) levels -4%, P < 0.05], maintained during the follow-up. No significant variations in intima-media thickness were observed. In the subgroup of patients with more than 1 year of PCSK9i therapy (165/246 patients) we highlighted: a 66% reduction in MACEs compared with the year before recruitment; a progressive increase in MACEs during the follow-up (MACEs event/rate at first year 0.08 vs. MACEs event/rate at year 5: 0.47); a patients cluster with late MACEs older, with higher prevalence of hypertension, smoking habit and peripheral vascular disease. During the follow-up, we recorded AEs in 31% of patients, which mainly resulted in reduction/discontinuation of lipid-lowering therapy for 50 patients or in discontinuation/shift of PCSK9i (respectively 8 and 6 cases)., Conclusion: Our data agree with the large evidence on the effectiveness/tolerability of PCSK9i therapy; however, although PCSK9i represents a good cholesterol-lowering therapeutic option, our study shows a progressive increase in MACEs during the late follow-up that deserve further research., (Copyright © 2023 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Real-life outcomes data for elderly patients with infections caused by Klebsiella pneumoniae producing New Delhi metallo-beta-lactamase (NDM-Kp) are lacking. We conducted a retrospective cohort study enrolling 33 consecutive adult patients (mean age 77.4 years; 48.5% males; mean Charlson Comorbidity Index-CCI 5.9) hospitalized for NDM-Kp infections during a 24-month period in an Italian highly endemic area. 78.8% were admitted to Internal Medicine ward. 45.4% of patients had bloodstream infections (BSI), 39.4% urinary tract infections (UTI) without BSI, 9.1% respiratory tract infections and 6.1% intra-abdominal infections. 93.9% had rectal colonization.Adequate definitive antibiotic therapy (mainly represented by aztreonam plus ceftazidime/avibactam) was provided to 36.4% of cases. Mean age and CCI of patients adequately treated were significantly lower than those inadequately treated (71.2 vs 80.9 years, p = 0.041, and 4.6 vs 6.7, p = 0.040, respectively). Patients adequately treated had a mean hospitalization length significantly higher (28 vs 15 days, p = 0.016). The overall 30-day survival rate of patients adequately and inadequately treated was 83.3% and 57.1%, respectively: this difference was not statistically significant. Mean age and CCI of 22 patients who survived at 30 days were lower than those of 11 patients who died (73.7 vs 84.8 years, p = 0.003, and 5.3 vs 7.2, p = 0.049, respectively). Twelve survivors received an inadequate therapy: 8/12 had UTI. Six of nine patients inadequately treated who died within 30 days, died before microbiological diagnosis. Our study provides real-life data on outcomes of elderly and multimorbid patients hospitalized for infections caused by NDM-Kp. Further studies with larger sample size are warranted., (© 2023. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

The use of alternative solutions for pest management to replace pesticides in agriculture is of great interest. Proteinaceous complexes deriving from edible oyster mushrooms were recently proposed as environmentally friendly bioinsecticides. Such complexes, composed of ostreolysin A6 (OlyA6) and pleurotolysin B (PlyB), target invertebrate-specific membrane sphingolipids in insect's midgut, causing death through the formation of transmembrane pores. In this work, the potential impact of OlyA6/PlyB complexes was tested in the Mediterranean sea urchin Paracentrotus lividus, as an indicator of environmental quality. The ability of the fluorescently tagged OlyA6 to bind sea urchin gametes (sperm, eggs), the lipidome of sea urchin gametes, and the potential toxic effects and developmental anomalies caused by OlyA6/PlyB complexes on P. lividus early development (embryo, larvae) were investigated. The binding of the fluorescently tagged OlyA6 could be observed only in sea urchin eggs, which harbor OlyA6 sphingolipid membrane receptors, conversely to sperm. High protein concentrations affected sea urchin fertilization (>750 µg/L) and early development (> 375 µg/L in embryos; >100 µg/L in larvae), by causing toxicity and morphological anomalies in embryos and larvae. The main anomalies consisted in delayed embryos and incorrect migration of the primary mesenchyme cells that caused larval skeletal anomalies. The classification of these anomalies indicated a slight environmental impact of OlyA6/PlyB complexes at concentrations higher than 750 µg/L. Such impact should not persist in the marine environment, due to the reversible anomalies observed in sea urchin embryos and larvae that may promote defense strategies. However, before promoting the use of OlyA6/PlyB complexes as bio-pesticides at low concentrations, further studies on other marine coastal species are needed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This study analyzed hospital admissions for invasive meningococcal disease (IMD) in epidemiological and economic terms in Italy from 2015 to 2019. The volume of acute admissions for meningococcal diagnosis was analyzed in the period from 2015 to 2019. IMD admissions were identified by ICD-9-CM diagnoses. Costs were assessed using current DRG tariffs. In 2019, a total of 237 admissions for meningococcal disease were recorded in Italy. The mean age of patients was 36.1 years. Lumbar puncture was reported in only 14% of hospital discharge forms. From 2015 to 2019, there was a mean annual reduction of - 1.2% nationally for IMD hospitalizations. For 2019, the total costs for acute inpatient admissions were €2,001,093. Considering annual incidence due to IMD, a significant decrease was noted in the age group from 0 to 1 year (p = 0.010) during 2015-2019. For all years, mortality associated with meningeal syndrome was lower compared to septic shock with or without meningitis. From 2015 to 2019, hospitalizations for IMD appear to be decreasing slightly in Italy, even if mortality remains high. Favorable trends in hospitalizations for IMD were seen in the 0-1-year age group, which may be attributable to increased vaccination. Costs of hospitalizations for IMD remain high., (© 2023. The Author(s).)

Background: Severe COVID-19 patients are characterized by a dysregulated host response to an infection, with uncontrolled pro- and anti- inflammatory pathway activation. Consistent proportion of patients require admission in intensive care units and are at risk of progression to severe forms of disease. These patients are generally admitted during later stages of the disease, when effective antiviral and monoclonal antibody are not indicated. We aimed to assess the potential role of IgM-enriched intra venous immunoglobulins (IGAM) preparations in this setting., Methods: This retrospective, observational case-controlled study was conducted at a single-center University Hospital of Udine in the Friuli Venezia Giulia Region of Italy. Patients referring to the center between March 2020 and April 2021 was included. During the study period, patient who received Pentaglobin ® IGAM treatment (N.=56), administered as compassionate use, was compared with a control group (N.=169) to assess, by propensity score analysis, clinical outcome., Results: Untreated controls required, respect to patient treated with IGAM therapy, longer time to hospitalization with no significant differences in death and orotracheal intubation requirement. Significant differences in the two cohort were in: SOFA was higher in treated, while D-dimer and P/F ratio was better in the treatment cohort. Multivariate logistic regression analysis performed on the "matched sample," obtained by a weighting propensity score approach, identify, as significant protective factor for death outcome, the Pentaglobin ® treatment (0.820 [0.698-0.963], P=0.016) and low C-reactive protein (1.001 [1.000-1.002], P=0.031) value while the delay of onset hospitalization is associate with a worst outcome (0.983 [0.967-0.999], P=0.041)., Conclusions: The present study offers a significant insight concerning the use of IgM-enriched immunoglobulin preparations in patients with SARS-CoV-2 severe infection and also could identifying the specific immunological and biochemical profile of the patient who can more benefit from this therapeutic option.

Aims: In view of the consolidating evidence on the causal role of Lp(a) in cardiovascular disease, the Italian Society for the Study of Atherosclerosis (SISA) has assembled a consensus on Lp(a) genetics and epidemiology, together with recommendations for its measurement and current and emerging therapeutic approaches to reduce its plasma levels. Data on the Italian population are also provided., Data Synthesis: Lp(a) is constituted by one apo(a) molecule and a lipoprotein closely resembling to a low-density lipoprotein (LDL). Its similarity with an LDL, together with its ability to carry oxidized phospholipids are considered the two main features making Lp(a) harmful for cardiovascular health. Plasma Lp(a) concentrations vary over about 1000 folds in humans and are genetically determined, thus they are quite stable in any individual. Mendelian Randomization studies have suggested a causal role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis and observational studies indicate a linear direct correlation between cardiovascular disease and Lp(a) plasma levels. Lp(a) measurement is strongly recommended once in a patient's lifetime, particularly in FH subjects, but also as part of the initial lipid screening to assess cardiovascular risk. The apo(a) size polymorphism represents a challenge for Lp(a) measurement in plasma, but new strategies are overcoming these difficulties. A reduction of Lp(a) levels can be currently attained only by plasma apheresis and, moderately, with PCSK9 inhibitor treatment., Conclusions: Awaiting the approval of selective Lp(a)-lowering drugs, an intensive management of the other risk factors for individuals with elevated Lp(a) levels is strongly recommended., Competing Interests: Declaration of competing interest APM received personal fees from AstraZeneca, Bayer, Novartis for the participation in study committees, outside the present work. M Arca has received research grant support and lecturing fees from Alfasigma, Amarin, Amgen, Amryt, IONIS/Akcea Therapeutics, Daiichi Sankyo, Novartis, Pfizer, Regeneron and Sanofi, SOBI. ALC in the last three years has received honoraria, lecture fees or research grants from Aegerion, Akcea Therapeutics, Amarin, Amgen, Amryt Pharma, AstraZeneca, Daiichi Sankyo, Esperion, Ionis Pharmaceutical, Medscape Education, Menarini, Merck, Mylan, Novartis, PeerVoice, Pfizer, Recordati, Regeneron, Sanofi, The Corpus, Viatris. GC, MGZ, AB, CMB, CB, FC, DN, MP, AAR, TS, FS, M Averna declare no competing interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

In monkeypox virus (MPXV) transmission caused by contaminated material, we have to consider that recently the outbreak of several MPXV cases was linked to tattoo parlors in Cadiz, Spain. These tattoo parlors did not cause a single outbreak, but instead are an established transmission route for MPXV, underscoring the need for increased awareness. We recommend increasing awareness among tattooists and piercers not only to protect their own safety and health, but also to prevent spreading the virus to their customers. Personal protective equipment such as gloves should be utilized and vaccination can be considered for those at risk of occupational exposure.

Background and Purpose: Stroke has been described as a COVID-19 complication. However, its occurrence rate, risk factors, and causal relationships are still not well established., Methods: We describe the characteristics of confirmed COVID-19-related strokes among all cases of COVID-19 hospitalized in our health network, from November 1, 2020 to April 30, 2021. Risk factor analysis has been conducted for ischemic stroke (IS), which represents 92% of all confirmed cases of Covid-19-related strokes, and a "causal attribution to infection" classification is provided., Results: In all, 62/4105 hospitalized COVID-19 patients had an acute stroke (1.51%). Severe COVID-19 (OR 2.27-CI 1.06-4.77; p  = 0.032), atrial fibrillation (OR 3.65-CI 1.63-7.98; p  = 0.001), and ischemic heart disease (OR 4.590-CI 1.714-12.137; p  = 0.002) proved to be independent risk factors for IS, while obesity was a protective factor (OR 0.90-CI 0.82-0.97; p  = 0.012). COVID-19 had a causal role in 32.1% of IS cases, was a relevant cofactor in 28.6% of cases of IS, and was a possible trigger in 39.3% of events., Conclusion: Our stroke occurrence rate is consistent with other population-based reports (range 0.34-2.7%). Prespecified peculiar clinical and radiological features allow the distinction between "IS caused by COVID-19" and "IS triggered by COVID-19." Clinical history of vascular diseases and risk factors is crucial in determining the risk of IS in patients with COVID-19. However, the protective effect of a BMI > 30 kg/m 2 seems to suggest an obesity paradox., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Janes, Sozio, Gigli, Ripoli, Sbrana, Kuris, Nesi, Semenzin, Bertolino, Deana, Bagatto, Ciardi, Fabris, Merlino, Bax, Nilo, Pez, Valente and Tascini.)

The aim of this study is to investigate for the first time the uptake and ecotoxicological effects of nanoplastics (NPs) in a marine cnidarian. Ephyrae of the moon jellyfish Aurelia sp. of different ages (0 and 7 days old) were exposed to negatively charged polystyrene NPs for 24 h; then, the uptake was assessed through traditional and novel techniques, namely microscopy and three-dimensional (3D) holotomography. Immobility and behavioral responses (frequency of pulsations) of ephyrae were also investigated to clarify if NP toxicity differed along the first life stages. NP uptake was observed in ephyrae thanks to the 3D technique. Such internalization did not affect survival, but it temporarily impaired the pulsation mode only in 0 day old ephyrae. This may be ascribed to the negative charged NPs, contributing to jellyfish behavioral alteration. These findings promote 3D holotomography as a suitable tool to detect NPs in marine organisms. Moreover, this study recommends the use of cnidarians of different ages to better assess NP ecotoxicological effects in these organisms, key components of the marine food web., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We aimed to assess the potential role of Asymmetric dimethylarginine (ADMA) in conditioning respiratory function and pulmonary vasoregulation during Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) infection. Within 72 h from admission, samples from 90 COVID-19 patients were assessed for ADMA, SDMA, L-arginine concentrations. In addition to classical statistics, patients were also clustered by a machine learning approach according to similar features. Multivariable analysis showed that C-reactive protein (OR 1.012), serum ADMA (OR 4.652), white blood cells (OR = 1.118) and SOFA (OR = 1.495) were significantly associated with negative outcomes. Machine learning-based clustering showed three distinct clusters: (1) patients with low severity not requiring invasive mechanical ventilation (IMV), (2) patients with moderate severity and respiratory failure whilst not requiring IMV, and (3) patients with highest severity requiring IMV. Serum ADMA concentration was significantly associated with disease severity and need for IMV although less pulmonary vasodilation was observed by CT scan. High serum levels of ADMA are indicative of high disease severity and requirement of mechanical ventilation. Serum ADMA at the time of hospital admission may therefore help to identify COVID-19 patients at high risk of deterioration and negative outcome., (© 2023. The Author(s).)

Though microscopy is most often intended as a technique for providing qualitative assessment of cellular and subcellular properties, when coupled with other instruments such as wavelength selectors, lasers, photoelectric devices and computers, it can perform a wide variety of quantitative measurements, which are demanding in establishing relationships between the properties and structures of biological material in all their spatial and temporal complexities. These combinations of instruments are a powerful approach to improve non-destructive investigations of cellular and subcellular properties (both physical and chemical) at a macromolecular scale resolution. Since many subcellular compartments in living cells are characterized by structurally organized molecules, this review deals with three advanced microscopy techniques well-suited for these kind of investigations, i.e., microspectrophotometry (MSP), super-resolution localization microscopy (SRLM) and holotomographic microscopy (HTM). These techniques can achieve an insight view into the role intracellular molecular organizations such as photoreceptive and photosynthetic structures and lipid bodies play in many cellular processes as well as their biophysical properties. Microspectrophotometry uses a set-up based on the combination of a wide-field microscope and a polychromator, which allows the measurement of spectroscopic features such as absorption spectra. Super resolution localization microscopy combines dedicated optics and sophisticated software algorithms to overcome the diffraction limit of light and allow the visualization of subcellular structures and dynamics in greater detail with respect to conventional optical microscopy. Holotomographic microscopy combines holography and tomography techniques into a single microscopy set-up, and allows 3D reconstruction by means of the phase separation of biomolecule condensates. This review is organized in sections, which for each technique describe some general aspects, a peculiar theoretical aspect, a specific experimental configuration and examples of applications (fish and algae photoreceptors, single labeled proteins and endocellular aggregates of lipids).

(1) Background: Infections are among the most frequent and life-threatening complications of cardiovascular implantable electronic device (CIED) implantation. The aim of this study is to compare the outcome and safety of a single-procedure device extraction and contralateral implantation versus the standard-of-care (SoC) two-stage replacement for infected CIEDs. (2) Methods: We retrospectively included 66 patients with CIED infections who were treated at two Italian hospitals. Of the 66 patients enrolled in the study, 27 underwent a single procedure, whereas 39 received SoC treatment. All patients were followed up for 12 months after the procedure. (3) Results: Considering those lost to follow-up, there were no differences in the mortality rates between the two cohorts, with survival rates of 81.5% in the single-procedure group and 84.6% in the SoC group ( p = 0.075). (4) Conclusions: Single-procedure reimplantation associated with an active antibiofilm therapy may be a feasible and effective therapeutic option in CIED-dependent and frail patients. Further studies are warranted to define the best treatment regimen and strategies to select patients suitable for the single-procedure reimplantation.

Until today lipoprotein apheresis (LA) is considered the most effective treatment for patients with high-Lp(a) and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are often combined with LA to dampen the rebound in lipoprotein concentrations. The aim of the present work is to evaluate the effect of dose-adjustment strategy for alirocumab in a small cohort of high-Lp(a) subjects with ischemic heart disease and in chronic LA treatment. Chronic LA effect on Lp(a) levels is a significant reduction in pre-LA Lp(a) concentrations compared to native Lp(a) value (118 [116-119] mg/dl vs 150 [137-155] mg/dl; p < 0.001). Furthermore, the administration of Arilocumab 75 mg after 7 days from LA shows a significant pre-LA reduction in the Lp(a) concentrations respect to those obtained with administration immediately after the LA treatment. In high-Lp(a) patients treated with chronic LA the deferred addition of alirocumab, resulted in lower LDL-cholesterol and Lp(a) values., Competing Interests: COI None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Lactococcus species are micro-aerophilic Gram positive bacteria characterized by low virulence features and other biotechnological properties of industrial interest. They are thus widely employed in food fermentation processes. Despite its low pathogenic potential and food grade safety, L. lactis may, however, rarely cause infections, especially among immunocompromised hosts. Moreover, the growing complexity of patients implies increased detections of such infections. This said, there is a paucity of data concerning L. lactis infections from infusion of blood transfusion products. To our knowledge, this is the first case of L. lactis infection from transfusion of blood products, as observed in an 82-year-old Caucasian male undergoing weekly platelet and blood transfusion due to sustained severe thrombocytopenia. Albeit minimally pathogenic, L. lactis should be considered for thorough testing, especially in the case of human-derived infusion products such as platelets due to their storage requirements for extended times at room temperature and their use in immunocompromised and critically ill subjects.

Although progress has led to a drop in infections, meningitis still represents a threat worldwide, affecting some areas more than others. As a medical emergency, it requires prompt recognition and treatment. Moreover, diagnosis relies on invasive methods, while representing a tug-of-war with timely therapeutic interventions, since delays are burdened by mortality and life-long sequalae. While counterbalancing the overuse of antimicrobials, it is imperative to assess correct interventions in order to optimize treatments and reduce negative outcomes. Because the drop in mortality and consequences has been consistent, although not as impactful as with other vaccine-preventable diseases, the WHO has traced a roadmap detailing actions to reduce the meningitis burden by 2030. There are currently no updated guidelines, whereas novel diagnostic methods as well as pharmacological interventions are increasing, along with the shifting epidemiology. In light of the above, this paper wishes to summarize existing data and evidences and suggest potential novel solutions to a complex problem.

Cefditoren is an oral third-generation cephalosporin with a large spectrum activity against Gram-negative and Gram-positive bacteria which are reported to be responsible for respiratory tract and skin and skin structure infections. In this work we reviewed the pharmacodynamics, pharmacokinetics, and the main clinical indications of cefditoren. Similarly to other beta-lactams, cefditoren is a time-dependent antibiotic, and its "best" PK/PD target is probably 40% dosing interval time > 4- 5-fold MIC and 40-70% dosing interval time > 4- 5-fold MIC for bacteriostatic and bactericidal effect, respectively. In fasting patients oral bioavailability is low and increases when the drug is taken with food. This cephalosporin has significant bactericidal activity against S. pneumoniae (both penicillin-susceptible and penicillin-resistant strains), S. pyogenes, H. Influenzae and M. catarrhalis, as well as methicillin-susceptible S. aureus (MSSA). Regarding Enterobacterales, cefditoren has very low MICs90 against K. pneumoniae andE. coli but is not active against AmpC-, ESBL- and carbapenemase-producer' strains. Licensed indications are treatment of exacerbations of chronic bronchitis,acute rhinosinusitis, otitis media, upper respiratory tract infections (pharyngitis/tonsillitis), lower community-acquired respiratory tract infections (LRTIs), and skin and skin-structure infections (SSTI). Cefditoren might have a role in switching from parenteral to oral therapy in acute pyelonephritis and LRTIs. with a reduction of adverse effects and hospital costs. Eventually, due to its supposed binding to enterococcal penicillin binding proteins (PBPs) cefditoren, in combination with other beta-lactams, might have a role in partial oral enterococcal endocarditis treatment..