Search

Psychiatric conditions can affect the experience of pain. Several reports indicate that Major Depressive Disorder (MDD) is associated with an increased pain threshold, while Anxiety Disorders (ADs) may amplify the perception of pain. However, available data on the nociceptive threshold in these psychiatric conditions are controversial. This meta-analysis examines: 1) the nociceptive threshold among people diagnosed with MDD or ADs compared to healthy controls, and 2) the available evidence that pharmacological treatments affect these relationships. Electronic searches were conducted in PubMed and PsycINFO between June 2022 and December 2024. A total of 25 studies were included. "Pain threshold" measurement was considered as a direct comparison between subjects affected by MDD or ADs (both medicated and unmedicated) and healthy control subjects. For each study, the effect size (ES) was calculated, with a positive ES indicating a lower pain threshold. The heterogeneity of the specific set of effect sizes and the effects of selected moderators were tested using the I² index and the Q statistic. Results indicated that patients with Major Depressive Disorder (MDD) had a higher pain threshold (ES: -0.60), while those with Anxiety Disorders (ADs) had a lower pain threshold (ES: -0.34) compared to healthy controls. These findings were confirmed when analyses were limited to studies of unmedicated patients. Exploratory analyses restricted to studies containing medicated MDD patients were inconclusive, and for medicated ADs patients, analyses were not possible due to insufficient data. These meta-analytic data support higher pain threshold associated with MDD, and lower pain threshold associated with ADs., Competing Interests: Declaration of Competing Interest None, (Copyright © 2025 Elsevier Ltd. All rights reserved.)

The most recurrent familial cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the presence of an abnormal number of intronic GGGGCC (G 4 C 2 ) repetitions in the C9orf72 gene, which has been proposed to drive ALS/FTD pathogenesis. Recently, it has been shown that such G 4 C 2 repetitions can fold into G-quadruplex (G4) secondary structures. These G4s have been selectively stabilized by small-molecule binders, furnishing proof-of-principle that targeting these non-canonical nucleic acid sequences represents a novel and effective therapeutic strategy to tackle neurodegenerative disorders. However, precise information on the mechanism of action of these compounds is still lacking. Here, by performing in silico investigations, we unraveled the molecular basis for the selectivity of a series of known structurally related C9orf72 G4-binders. Moreover, we investigated the binding properties of a strong and selective metal-based G4 stabilizer, the Au I bis-N-heterocyclic carbene (NHC) complex - Au(TMX) 2 - showing that it moderately stabilizes G 4 C 2 G4 RNA by Förster resonance energy transfer (FRET) DNA melting assays. Using metadynamics (metaD) simulations, the Au(TMX) 2 binding mode and the associated free-energy landscape were also evaluated. This information paves the way for developing improved compounds to tackle ALS/FTD neurodegenerative disorders., (© 2025 The Author(s). ChemBioChem published by Wiley-VCH GmbH.)

We report the use of a new multiplex Real-Time PCR platform to simultaneously identify 24 pathogens and 3 antimicrobial-resistance genes directly from respiratory samples of COVID-19 patients. Results were compared to culture-based diagnosis. Secondary infections were detected in 60% of COVID-19 patients by molecular analysis and 73% by microbiological assays, with no significant differences in accuracy, indicating Gram-negative bacteria as the predominant species. Among fungal superinfections, Aspergillus spp. were detected by both methods in more than 7% of COVID-19 patients. Oxacillin-resistant S. aureus and carbapenem-resistant K. pneumoniae were highlighted by both methods. Secondary microbial infections in SARS-CoV-2 patients are associated with poor outcomes and an increased risk of death. Since PCR-based tests significantly reduce the turnaround time to 4 hours and 30 minutes (compared to 48 hours for microbial culture), we strongly support the routine use of molecular techniques, in conjunction with microbiological analysis, to identify co/secondary infections., 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 © 2024 Elsevier Inc. All rights reserved.)

Background: Italy has been the first European Country dealing with SARS-CoV-2, whose diffusion on the territory has not been homogeneous. Among Italian regions, Sardinia represented one of the lowest incidence areas, likely due to its insular nature. Despite this, the impact of insularity on SARS-CoV-2 genetic diversity has not been comprehensively described., Methods: In the present study, we performed the high throughput sequencing of 888 SARS-CoV-2 genomes collected in Sardinia during the first 23 months of pandemics. In addition, 1439 high-coverage SARS-CoV-2 genomes circulating in Sardinia along three years (December 2019 - January 2023) were downloaded from GISAID, for a total of 2327 viral sequences that were characterized in terms of phylogeny and genomic diversity., Results: Overall, COVID-19 pandemic in Sardinia showed substantial differences with respect to the national panorama, with additional peaks of infections and uncommon lineages that reflects the national and regional policies of re-opening and the subsequent touristic arrivals. Sardinia has been interested by the circulation of at least 87 SARS-CoV-2 lineages, including some that were poorly represented at national and European level, likely linked to multiple importation events. The relative frequency of Sardinian SARS-CoV-2 lineages has been compared to other Mediterranean Islands, revealing a unique composition., Conclusions: The genomic diversity of SARS-CoV-2 in Sardinia has been shaped by a complex interplay of insular geography, low population density, and touristic arrivals, leading on the one side to the importation of lineages remaining rare at the national level, and resulting on the other side in the delayed entry of otherwise common variants., 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 © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Malaria-causing protozoa of the genus Plasmodium have exerted one of the strongest selective pressures on the human genome, and resistance alleles provide biomolecular footprints that outline the historical reach of these species 1 . Nevertheless, debate persists over when and how malaria parasites emerged as human pathogens and spread around the globe 1,2 . To address these questions, we generated high-coverage ancient mitochondrial and nuclear genome-wide data from P. falciparum, P. vivax and P. malariae from 16 countries spanning around 5,500 years of human history. We identified P. vivax and P. falciparum across geographically disparate regions of Eurasia from as early as the fourth and first millennia BCE, respectively; for P. vivax, this evidence pre-dates textual references by several millennia 3 . Genomic analysis supports distinct disease histories for P. falciparum and P. vivax in the Americas: similarities between now-eliminated European and peri-contact South American strains indicate that European colonizers were the source of American P. vivax, whereas the trans-Atlantic slave trade probably introduced P. falciparum into the Americas. Our data underscore the role of cross-cultural contacts in the dissemination of malaria, laying the biomolecular foundation for future palaeo-epidemiological research into the impact of Plasmodium parasites on human history. Finally, our unexpected discovery of P. falciparum in the high-altitude Himalayas provides a rare case study in which individual mobility can be inferred from infection status, adding to our knowledge of cross-cultural connectivity in the region nearly three millennia ago., (© 2024. The Author(s).)

Introduction: The ESCPM group (Enterobacter species including Klebsiella aerogenes - formerly Enterobacter aerogenes, Serratia species, Citrobacter freundii complex, Providencia species and Morganella morganii) has not yet been incorporated into systematic surveillance programs., Methods: We conducted a multicentre retrospective observational study analysing all ESCPM strains isolated from blood cultures in 27 European hospitals over a 3-year period (2020-2022). Diagnostic approach, epidemiology, and antimicrobial susceptibility were investigated., Results: Our study comprised 6,774 ESCPM isolates. MALDI-TOF coupled to mass spectrometry was the predominant technique for bacterial identification. Susceptibility to new β-lactam/β-lactamase inhibitor combinations and confirmation of AmpC overproduction were routinely tested in 33.3% and 29.6% of the centres, respectively. The most prevalent species were E. cloacae complex (44.8%) and S. marcescens (22.7%). Overall, third-generation cephalosporins (3GC), combined third- and fourth-generation cephalosporins (3GC + 4GC) and carbapenems resistance phenotypes were observed in 15.7%, 4.6%, and 9.5% of the isolates, respectively. AmpC overproduction was the most prevalent resistance mechanism detected (15.8%). Among carbapenemase-producers, carbapenemase type was provided in 44.4% of the isolates, VIM- (22.9%) and OXA-48-enzyme (16%) being the most frequently detected. E. cloacae complex, K. aerogenes and Providencia species exhibited the most notable cumulative antimicrobial resistance profiles, with the former displaying 3GC, combined 3GC + 4GC and carbapenems resistance phenotypes in 15.2%, 7.4%, and 12.8% of the isolates, respectively. K. aerogenes showed the highest rate of both 3GC resistant phenotype (29.8%) and AmpC overproduction (32.1%), while Providencia species those of both carbapenems resistance phenotype (42.7%) and carbapenemase production (29.4%). ESCPM isolates exhibiting both 3GC and combined 3GC + 4GC resistance phenotypes displayed high susceptibility to ceftazidime/avibactam (98.2% and 95.7%, respectively) and colistin (90.3% and 90.7%, respectively). Colistin emerged as the most active drug against ESCPM species (except those intrinsically resistant) displaying both carbapenems resistance phenotype (85.8%) and carbapenemase production (97.8%)., Conclusions: This study presented a current analysis of ESCPM species epidemiology in Europe, providing insights to inform current antibiotic treatments and guide strategies for antimicrobial stewardship and diagnostics., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

While platinum(II)-based drugs continue to be employed in cancer treatments, the escalating occurrence of severe side effects has spurred researchers to explore novel sources for potential therapeutic agents. Notably, cobalt(III) has emerged as a subject of considerable interest due to its ubiquitous role in human physiology. Several studies investigating the anticancer effects of Salphen complexes derived from cobalt(III) have unveiled intriguing antiproliferative properties. In a bid to enhance our understanding of this class of compounds, we synthesized and characterized two novel half Salphen cobalt(III) complexes. Both compounds exhibited notable stability, even in the presence of physiologically relevant concentrations of glutathione. The application of spectroscopic and computational methodologies unravelled their interactions with duplex and G4-DNAs, suggesting an external binding affinity for these structures, with preliminary indications of selectivity trends. Importantly, antiproliferative assays conducted on 3D cultured SW-1353 cancer cells unveiled a compelling anticancer activity at low micromolar concentrations, underscoring the potential therapeutic efficacy of this novel class of cobalt(III) complexes.

Introduction: A COVID-19 outbreak occurred at the end of October 2021 among pilgrims returning from Medjugorje (Bosnia and Herzegovina)., Methodology: Whole genome sequencing (WGS) of SARS-CoV-2, epidemiological data, and phylogenetic analysis were used to reconstruct outbreak dynamics., Results: The results suggest that only in one case, associated with the SARS-CoV-2 sub-lineage AY.9.2, it is possible to trace back the place of contagion to Medjugorje, while the other cases were likely to be acquired in the country of origin., Conclusions: The combined use of phylogenetic data derived from WGS, and epidemiological data allowed us to study epidemic dynamics and to formulate a possible hypothesis on the place of exposure to SARS-CoV-2. The identification of different sub-lineages of the SARS-CoV-2 Delta variant also suggested that different chains of transmission contributed to the outbreak., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Alessandra Lo Presti, Salvatore Rubino, Gabriele Ibba, Luigina Ambrosio, Angela Di Martino, Federica Ferraro, Alessia Rapiti, Francesco Maraglino, Emanuela Maria Frisicale, Giovanni Rezza, Flavia Angioj, Sergio Uzzau, Maria Luciana Contini, Stefania Manca, Ferdinando Coghe, Germano Orrù, Anna Teresa Palamara, Paola Stefanelli, the AOUSS COVID team.)

Aims: In this study, five essential oils (EOs) from different species of Lavandula hybrida abrialis , for Lavandula hybrida R.C., Lavandula hybrida 'super A', Lavandula hybrida 'super Z' and Lavandula vera and its hybrids Lavender were evaluated against 26 dust-isolated fungal strains from North Africa., Methods and Results: The composition of the different EOs was determined from volume to dry weight. The photochemical analyses were performed via gas chromatography (GC). The cytotoxic effect of five lavender EOs on human epithelial colorectal adenocarcinoma cells (Caco-2) cell line was done. A total of 26 strains of filamentous fungi including Aspergillus spp. , Botrytis cinerea , Ceriporia spp. , Fusarium spp. and Penicillium glabrum were isolated from sand dust samples via molecular diagnostic tool of PCR. Fungal strains with the lowest minimal lethal concentration (MLC) were Penicillium glabrum, Ceriporia spp. and a strain of Aspergillus spp., Conclusions: More studies are needed to verify the activity of this EO against more different fungal species, and determine the active ingredients. Significance and impact of study: MIC of the antifungal efficacy relating to EOs was evaluated. The EOs tests showed no cytotoxic effect at very low concentrations, ranging from 0.03% (IC 50 0.9132 mg/mL) ( L. hybrid Abrialis) to 0.001% (IC 50 1.631 mg/mL) ( L. hybrid R.C.).

Purpose: There is a growing body of literature documenting glioma heterogeneity in terms of radiographic, histologic, molecular, and genetic characteristics. Incomplete spatial specification of intraoperative tumor samples may contribute to variability in the results of pathological and biological investigations. We have developed a system, termed geo-tagging, for routine intraoperative linkage of each tumor sample to its location via neuronavigation., Methods: This is a single-institution, IRB approved, prospective database of undergoing clinically indicated surgery. We evaluated relevant factors affecting data collection by this registry, including tumor and surgical factors (e.g. tumor volume, location, grade and surgeon)., Results: Over a 2-year period, 487 patients underwent craniotomy for an intra-axial tumor. Of those, 214 underwent surgery for a newly diagnosed or recurrent glioma. There was significant variation in the average number of samples collected per registered case, with a range of samples from 2.53 to 4.75 per tumor type. Histology and grade impacted on sampling with a range of 2.0 samples per tumor in Grade four, IDH-WT gliomas to 4.5 samples in grade four, IDH-mutant gliomas. The range of cases with sampling per surgeon was 6 to 99 with a mean of 47.6 cases and there was a statistically significant differences between surgeons. Tumor grade did not have a statistically significant impact on number of samples per case. No significant correlation was found between the number of samples collected and enhancing tumor volume, EOR, or volume of tumor resected., Conclusion: We are using the results of this analysis to develop a prospective sample collection protocol., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The goal of this study was to monitor the microbial biodiversity in beach sand that is heavily visited by tourists during the summer, and to determinate whether the high presence of bathers (around 5000 per day) can modify sand microbial composition., Methods: Between 2016 and 2020, 150 sand samples were collected from nine different points at La Pelosa beach in Sardinia, Italy. Non-culturing methods were used; DNA extraction and meta-barcode sequencing were performed. All samples were analyzed with sequencing methods for 16S and ITS sequences., Results: Fungal genera differ on the three beaches and in the winter/summer zones. The ITS sequence showed the most common presence of Candida during summer and Paradendryphiella in the winter. The greatest diversity was found in the dune during winter, while in other parts of the beach, there are differences between bacteria and fungi, particularly in the wash zone during the winter, with high diversity for 16S sequences but low diversity for ITS sequences., Conclusions: It appears reasonable that the sands, even on non-urban beaches, should be included in health monitoring programs in addition to the waters, and that access to them should be regulated by limiting the number of bathers with the aim of reducing the presence of pathogenic fungal species.

The chemical shift (CS) values obtained by 1 H NMR spectroscopy for the hydrogen atoms of a tetradentate N 2 O 2 -substituted Salphen ligand (H 2 L1 ) are differently shifted in its complexes of nickel(II), palladium(II), platinum(II), and zinc(II), all bearing the same charge on the metal ions. To rationalize the observed trends, DFT calculations have been performed in the implicit d 6 -DMSO solvent in terms of the electronic effects induced by the metal ion and of the nature and strength of the metal-N and metal-O bonds. Overall, the results obtained point out that, in the complexes involving group 10 elements, the CS values show the greater shift when considering the two hydrogen atoms at a shorter distance from the coordinated metal center and follow the decreasing metal charge in the order Ni > Pd > Pt. This trend suggests a more covalent character of the ligand-metal bonds with the increase of the metal atomic number. Furthermore, a slightly poorer agreement between experimental and calculated data is observed in the presence of the nickel(II) ion. Such discrepancy is explained by the formation of stacked oligomers, aimed at minimizing the repulsive interactions with the polar DMSO solvent.

Globally, antibiotic-resistant Klebsiella spp. cause healthcare-associated infections with high mortality rates, and the rise of hypervirulent Klebsiella pneumoniae (hv Kp ) poses a significant threat to human health linked to community-acquired infections and increasing non-susceptibility. We investigated the phenotypic and genetic features of 36 Klebsiella isolates recovered from invasive infections at Hospital Central of Maputo in Mozambique during one year. The majority of the isolates displayed multidrug resistance (MDR) (29/36) to cephalosporins, gentamicin, ciprofloxacin, and trimethoprim-sulfamethoxazole but retained susceptibility to amikacin, carbapenems, and colistin. Most isolates were ESBLs-producing (28/36), predominantly carrying the bla CTX-M-15 and other beta-lactamase genes ( bla SHV , bla TEM-1 , and bla OXA-1 ). Among the 16 genomes sequenced, multiple resistance genes from different antibiotic classes were identified, with bla CTX-M-15 , mostly in the IS Ecp1 - bla CTX-M-15 - orf477 genetic environment, co-existing with bla TEM-1 and aac(3)-IIa in five isolates. Our results highlight the presence of polyclonal MDR ESBL-producing K. pneumoniae from eight sequence types (ST), mostly harbouring distinct yersiniabactin within the conjugative integrative element (ICE). Further, we identified susceptible hv Kp ST23, O1-K1-type isolates carrying yersiniabactin ( ybt1 /ICEKp10), colibactin, salmochelin, aerobactin, and hypermucoid locus ( rmpADC ), associated with severe infections in humans. These findings are worrying and underline the importance of implementing surveillance strategies to avoid the risk of the emergence of the most threatening MDR hv Kp .

Objective: This study seeks to assess rheumatology fellows' (RFs') and program directors' (PDs') interests in different educational tools and methods and to facilitate curriculum development for reproductive health related to rheumatic disease., Methods: Constructs were conceptualized in four dimensions: 1) RF and PD confidence in their current curriculum relating to the American College of Rheumatology (ACR) Reproductive Health Guidelines (RHGs), 2) personal interest in this topic, 3) opinions of the importance of this topic, and 4) interest in a range of learning materials and educational experiences. The final survey was distributed to 753 RFs and 179 PDs in the United States using the ACR Committee on Training and Workforce email list., Results: Response rates were 13% (n = 98) for RFs and 25% (n = 44) for PDs. Both groups indicated more interest in the topic than confidence in their curriculum and rated summary sheets, question banks, didactics, and online modules higher than nine other educational tools or methods. Despite interest in the topic, 38% of RF respondents and 24% of PD respondents were unaware of the recently published ACR RHGs., Conclusion: RFs and PDs consider reproductive health very important and report high personal interest in this topic. In contrast, both groups indicated lower confidence in current curricula, and substantial proportions of both groups were unaware of recently published guidelines. RFs' and PDs' interests in specific educational modalities are aligned. Curriculum development efforts should prioritize summary sheets, question banks, didactics, and online modules. Efforts are needed to address the educational needs of practicing rheumatologists and other professionals caring for patients with rheumatic disease., (© 2023 American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

The occupational risk of operators using display screen equipment (DSE) is usually evaluated according to the extent of time spent in active operator-DSE interactions. Risk assessment is based on activity data collected through questionnaires. We evaluated an original and innovative system that can objectively assess active operator-DSE interactions by collecting electrical impulses generated by the activation of mouse, keyboard and a camera that collects attentive eye-screen fixation. The main aim of this study was to evaluate the system's performance on an employee sample involved in the task of active reading and copying at a DSE workstation connected to the system. In the context of mandatory health surveillance at work, we enrolled 38 DSE operators with normal neuropsychological and eye assessments who were required to complete two predefined reading and writing tasks. The obtained results show that the system is able to collect activity data derived from operator-DSE interactions through screen fixation, keyboard tapping and mouse handling. In the copying task, the session duration as recorded by the system was highly related to the screen fixation time. In the copying task, mouse and keyboard activities were more strongly related to session duration than screen fixation. For the copying task, it was also possible to obtain individual profiles of operator-DSE interactions while performing the same standardized tasks. Collected data can allow an objective evaluation of active time spent by DSE operators at their workstations, thus allowing a more accurate occupational health risk assessment and management. Prospective analysis of individual operator-DSE interaction profiles can favor the setup of targeted preventive and organizational interventions from an of even wider worker wellbeing perspective.

DNA G-rich sequences can organize in four-stranded structures called G-quadruplexes (G4s). These motifs are enriched in significant sites within the human genomes, including telomeres and promoters of cancer related genes. For instance, KIT proto-oncogene promoter, associated with diverse cancers, contains three adjacent G4 units, namely Kit2, SP, and Kit1. Aiming at finding new and selective G-quadruplex binders, we have synthesized and characterized five non-charged metal complexes of Pt(II), Pd(II), Ni(II), Cu(II) and Zn(II) of a chlorine substituted Salphen ligand. The crystal structure of the Pt(II) and Pd(II) complexes was determined by XRPD. FRET measurements indicated that Pt(II) and Pd(II) compounds stabilize Kit1 and Kit2 G4s but not SP, telomeric and double stranded DNA. Spectroscopic investigations (UV-Vis, circular dichroism and fluorescence) suggested the Cu(II) complex as the most G4-selective compound. Interestingly, docking simulations indicate that the synthesized compounds fit groove binding pockets of both Kit1 and Kit2 G4s. Moreover, they exhibited dose-dependent cytotoxic activity in MCF-7, HepG2 and HeLa cancer cells.

Rare information is available on clinical Enterococcus faecium encountered in Sardinia, Italy. This study investigated the antimicrobial susceptibility profiles and genotypic characteristics of E. faecium isolated at the University Hospital of Sassari, Italy, using the Vitek2 system and PCR, MLST, or WGS. Vitek2 revealed two VanB-type vancomycin-resistant Enterococcus faecium (VREfm) isolates (MICs mg/L = 8 and ≥32) but failed to detect vancomycin resistance in one isolate (MIC mg/L ≤ 1) despite positive genotypic confirmation of vanB gene, which proved to be vancomycin resistant by additional phenotypic methods (MICs mg/L = 8). This vanB isolate was able to increase its vancomycin MIC after exposure to vancomycin, unlike the "classic" occult vanB -carrying E. faecium , becoming detectable by Vitek 2 (MICs mg/L ≥ 32). All three E. faecium had highly mutated vanB 2 operons, as part of a chromosomally integrated Tn 1549 transposon, with common missense mutations in VanH and VanB 2 resistance proteins and specific missense mutations in the VanW accessory protein. There were additional missense mutations in VanS, VanH, and VanB proteins in the vanB 2 -carrying VREfm isolates compared to Vitek2. The molecular typing revealed a polyclonal hospital-associated E. faecium population from Clade A1, and that vanB 2 -VREfm, and nearly half of vancomycin-susceptible E. faecium (VSEfm) analyzed, belonged to ST117. Based on core genome-MLST, ST117 strains had different clonal types (CT), excluding nosocomial transmission of specific CT. Detecting vanB 2 -carrying VREfm isolates by Vitek2 may be problematic, and alternative methods are needed to prevent therapeutic failure and spread.

Samples of the carbonaceous asteroid Ryugu were brought to Earth by the Hayabusa2 spacecraft. We analyzed 17 Ryugu samples measuring 1 to 8 millimeters. Carbon dioxide-bearing water inclusions are present within a pyrrhotite crystal, indicating that Ryugu's parent asteroid formed in the outer Solar System. The samples contain low abundances of materials that formed at high temperatures, such as chondrules and calcium- and aluminum-rich inclusions. The samples are rich in phyllosilicates and carbonates, which formed through aqueous alteration reactions at low temperature, high pH, and water/rock ratios of <1 (by mass). Less altered fragments contain olivine, pyroxene, amorphous silicates, calcite, and phosphide. Numerical simulations, based on the mineralogical and physical properties of the samples, indicate that Ryugu's parent body formed ~2 million years after the beginning of Solar System formation.

Extended-spectrum β-lactamase (ESBL)-producing extraintestinal pathogenic Escherichia coli (ExPEC), particularly high-risk lineages, are responsible for severe infections and increased mortality and hospital costs worldwide, with a major burden in low-income countries. Here we determined the antimicrobial susceptibility and performed whole-genome sequencing of E. coli isolates from extraintestinal infections of patients during 2017-2018 at Maputo Central Hospital (Mozambique). Multidrug resistance was displayed by 71% of isolates (17/24). All isolates resistant to cefotaxime and ceftazidime were positive for ESBL genes (16/24; 67%) and were co-resistant to amoxicillin/clavulanate (14/16; 88%), piperacillin/tazobactam (8/16; 50%), gentamicin (12/16; 75%), trimethoprim/sulfamethoxazole (15/16; 94%) and ciprofloxacin (11/16; 69%). Several major high-risk ExPEC lineages were identified, such as H30Rx-ST131, fimH41-ST131, H24Rx-ST410, ST617, ST361 and ST69 harbouring bla CTX-M-15 , and H30R-ST131, ST38 and ST457 carrying bla CTX-M-27 . Dissemination of CTX-M transposition units (ISEcp1-bla CTX-M-15 -orf477 and ISEcp1-bla CTX-M-27 -IS903B) among different sequence types could be occurring through the mobility of IncF plasmids. Additionally, all H24Rx-ST410 isolates carried ISEcp1-mediated bla CMY-2 AmpC and specific mutations in PBP3/OmpC proteins, potentially contributing to carbapenem resistance even in the absence of carbapenemase genes. Genome analysis highlighted a high assortment of ExPEC/UPEC virulence-associated genes mainly involved in adhesion, invasion, iron uptake and secretory systems among isolates, and an ExPEC/EAEC hybrid pathotype (fimH27-ST131&#95;O18-ac:H4) showing the highest virulence gene content. cgMLST showed clonality and closely related isolates, particularly among ST131 and ST410, suggesting hospital-acquired infections and long-term ward persistence. Our study provides new insights into ExPEC clones, urging measures to prevent and contain their diffusion in this hospital and Mozambique., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In this work, we observed an increased presence of antibodies (Abs) against type I interferon (IFN-I) in coronavirus disease 2019 (COVID-19) patients admitted to the intensive care unit (ICU) compared to non-ICU COVID-19 patients and healthy control (HC) subjects. Human endogenous retrovirus W (HERV-W) can reactivate after viral infection; therefore, we also investigated the presence of antibodies against HERV-W envelope (HERV-W-env)-derived epitopes. A total of 113 subjects (41 female and 72 male subjects) were analyzed. A significant difference in autoantibodies against IFN-α, IFN-ω, and HERV-W was observed between HCs and ICU patients; indeed, the latter have higher levels of autoantibodies against IFN-α, IFN-ω, and HERV-W than subjects with mild COVID-19 and HCs. Neutralizing anti-IFN-I autoantibodies may affect the ability of IFN-I to bind to the type I interferon receptor (IFNAR), blocking the activation of the antiviral response. IMPORTANCE In this work, we report the increased presence of IFN autoantibodies in correlation with HERV-W-env autoantibodies in ICU COVID-19 patients. The novelty of the results is in the association of these IFN autoantibodies with autoantibodies against HERV-W-env, a protein recently discovered to be overexpressed in lymphocytes of COVID-19 patients and correlated with severe disease and pneumonia. Type I IFNs are part of a complex cross-regulatory network; however, in a small percentage of cases, the increase in autoantibodies against these proteins may lead to damage to the host instead of protection against infectious diseases.

Eumycetoma is a chronic debilitating fungal disease endemic to tropical and subtropical regions, with Sudan featuring the highest eumycetoma incidence. Among the 50 species of fungi most commonly associated with eumycetoma Madurella mycetomatis (M. mycetomatis) is often referenced as the most common pathogen. However, there is an enormous knowledge gap related to this neglected disease and its pathogenesis, epidemiological features, and host-specific factors that could contribute to either the host susceptibility and resistance. In this study, we were able to utilize a metagenomic approach and samples collected from clinical black grains (BG) and familiar household environments aimed to assay both the habitat of eumycetoma-associated fungi and its possible connection with eumycetoma patients living in two different eumycetoma endemic villages within the White Nile State of Sudan. DNA sequencing targeting the fungal ITS2 domain was performed on soil, animal dung, housing walls and roofs, and Acacia-species thorn samples and compared with culture-dependent methods of fungal isolation. Additionally, we compared the soil samples obtained in the endemic zone with that from non-endemic zones, including Wagga village in Kassala State and Port Sudan suburb in Port Sudan State. Overall, a total of 392 Amplicon Sequence Variants (ASVs) were detected by ITS2 metagenomics Eumycetoma causative organisms accounted for 10% of total ASVs which included 11 genera: Exserohilum (2%), Aspergillus (1.7%), Curvularia (1%), Alternaria (0.9%), Madurella (0.5%), Fusarium (0.4%), Cladosporium (0.2%) Exophiala (0.15%), and, in a lesser extent, Microascus (0.05%) Bipolaris and Acremonium (0.01%) for each. Only five genera were identified by culture method, which included Fusarium (29%), Aspergillus (28%), Alternaria (2.5%), Bipolaris (1.6%), and Chaetomium (0.8%). M. mycetomatis was detected within all the studied patients' houses, accounting for 0.7% of total sequences. It was the first common eumycetoma-associated agent detected in soil samples and the third common in the dung and wall samples. In contrast, it was not detected in the roof or thorn samples nor in the soils from non-endemic regions. Exserohilum rostratum, Aspergillus spp and Cladosporium spp were detected in all samples. M. mycetomatis and other eumycetoma-associated fungal identified in the patients' black grains (BG) samples by metagenomics were identified in the environmental samples. Only Acremonium alternatum and Falciformispora senegalensis, responsible for eumycetoma in two patients were not detected, suggesting the infections in these patients happened outside these endemic areas. The soil, animal dung, and houses built from the same soil and dung are the main risk factors for M. mycetomatis infection in these endemic villages. Furthermore, the poor hygienic and environmental conditions, walking barefooted, and the presence of animals within the houses increase the risk of M. mycetomatis and other fungi causing eumycetoma., Competing Interests: The authors have declared that no competing interests exist.

Meningiomas are the most common intracranial primary tumor in adults. Surgery is the predominant therapeutic modality for symptomatic meningiomas. Although the majority of meningiomas are benign, there exists a subset of meningiomas that are clinically aggressive. Recent advances in genetics and epigenetics have uncovered molecular alterations that drive tumor meningioma biology with prognostic and therapeutic implications. In this review, we will discuss the advances on molecular determinants of therapeutic response in meningiomas to date and discuss findings of targeted therapies in meningiomas., 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 © 2022 Lynes, Flores-Milan, Rubino, Arrington, Macaulay, Liu, Beer-Furlan, Tran, Vogelbaum and Etame.)

Mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome continue to threaten the global landscape of the coronavirus disease 2019 (COVID-19) pandemic. The Omicron variant (B.1.1.529) rapidly displaced previous 'variants of concern' (VoC) in 2021 due to its high rate of transmissibility and multitude of mutations. This global influx of infections saturated healthcare systems, overwhelmed testing capacity and case reporting, and increased the COVID-19 death toll. Global health leaders are now being faced with the most transmissible COVID-19 variants yet, the Omicron sublineages BA.4 and BA.5, which contain additional spike protein (S) mutations from previous Omicron and VoC serotypes. With universally observed antibody waning, increasing vaccine-variant mismatch, and resuming international travel, the stage is set for unprecedented levels of breakthrough infections and superspreading events. In this paper, we raise awareness to these novel variants and provide context for the high likelihood of an upcoming wave of infection capable of inflicting significant disease burden on a global scale., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2022 Benjamin Hewins, Christopher Richardson, Salvatore Rubino, Alyson Kelvin, Ali Toloue Ostadgavahi, David J Kelvin.)

Competing Interests: 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.

Spontaneous spinal subdural hematomas (SSH) are rare occurrences that can occur most commonly secondary to vascular malformations or coagulopathies. Only a small fraction of spontaneous SSHs are caused by acquired coagulation disorders such as leukemia, hemophilia, and thrombocytopenia. This case report describes a patient with a history of Guillain-Barré syndrome (GBS), hemophilia A, and mantle cell lymphoma, on zanubrutinib therapy, a Bruton tyrosine kinase inhibitor associated with a risk of spontaneous hemorrhage. This patient developed a spontaneous spinal subdural hematoma, most likely due to the zanubrutinib therapy and exacerbated due to hemophilia. Treatment was delayed due to the patient's history of GBS that confounded the clinical diagnosis. This case is the first report of a spontaneous SSH in a patient on zanubrutinib, highlighting the need for a high index of suspicion for CNS hemorrhage in patients on Bruton's tyrosine kinase (BTK) inhibitor therapy., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

In December 2019, a novel coronavirus emerged in Wuhan, China, rapidly spreading into a global pandemic. Italy was the first European country to experience SARS-CoV-2 epidemic, and one of the most severely affected during the first wave of diffusion. In contrast to the general restriction of people movements in Europe, the number of migrants arriving at Italian borders via the Mediterranean Sea route in the summer of 2020 had increased dramatically, representing a possible, uncontrolled source for the introduction of novel SARS-CoV-2 variants. Importantly, most of the migrants came from African countries showing limited SARS-CoV-2 epidemiological surveillance. In this study, we characterized the SARS-CoV-2 genome isolated from an asymptomatic migrant arrived in Sardinia via the Mediterranean route in September 2020, in comparison with SARS-CoV-2 isolates arrived in Sicily through the Libyan migration route; with SARS-CoV-2 isolates circulating in Sardinia during 2020; and with viral genomes reported in African countries during the same summer. Results showed that our sequence is not phylogenetically related to isolates from migrants arriving in Sicily, nor to isolates circulating in Sardinia territory, having greater similarity to SARS-CoV-2 genomes reported in countries known for being sites of migrant embarkation to Italy. This is in line with the hypothesis that most SARS-CoV-2 infections among migrants have been acquired prior to embarking to Italy, possibly during the travel to or the stay in crowded Libyan immigrant camps. Overall, these observations underline the importance of dedicated SARS-CoV-2 surveillance of migrants arriving in Italy and in Europe through the Mediterranean routes., 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 © 2022 Grandi, Paglietti, Cusano, Ibba, Lai, Piu, Angioj, Serra, Kelvin, Tramontano and Rubino.)

Brain metastases are the most common form of brain cancer. Increasing knowledge of primary tumor biology, actionable molecular targets and continued improvements in systemic and radiotherapy regimens have helped improve survival but necessitate multidisciplinary collaboration between neurosurgical, medical and radiation oncologists. In this review, we will discuss the advances of targeted therapies to date and discuss findings of studies investigating the synergy between these therapies and stereotactic radiosurgery for non-small cell lung cancer, breast cancer, melanoma, and renal cell carcinoma brain metastases., 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 © 2022 Rubino, Oliver, Tran, Vogelbaum, Forsyth, Yu, Ahmed and Etame.)

Purpose: The purpose of this study is to review the neonatal and early childhood course of children who were treated with intravitreal bevacizumab for APROP and identify any long term limitations these children face years after treatment., Methods: This retrospective consecutive case series reviewed both ophthalmologic and pediatric medical records to determine ocular and neurologic function following treatment with a single injection of intravitreal bevacizumab (IVB) for APROP. Patient records were reviewed to identify the gestational age, average birth weight, gender, post-menstrual age (PMA) at the time of injection, regression status, rescue therapy events, final visual acuity, final refraction, ophthalmologic diagnoses and complications, neurologic diagnoses, and duration of follow up., Results: The study included 43 eyes from 13 male and 9 female children. The average gestational age was 24 weeks and average birth weight was 625.2 grams. The average follow-up was 4.08 years (range: 1.85-7.36 years). The average PMA at time of bevacizumab injection was 35.59 weeks. Thirty-five eyes eventually received laser photocoagulation at an average PMA of 53.17 weeks. All eyes in this study demonstrated regression without progression to retinal detachment. At last follow up, 67% (29/43) of eyes were able to discern letters or shapes, with an average visual acuity of 20/37. 16 (72%) children were diagnosed with perinatal neurological disorders. 59% ( n = 13) developed chronic neurological impairment, 77% ( n = 10) of whom developed neurodevelopmental delay. Several infants were diagnosed with endocrine disease or genetic syndromes., Conclusions: Extreme prematurity is associated with significant morbidity. Nearly all infants (92%) who developed chronic neurologic disease were diagnosed with neurologic disease during the perinatal period. Intravitreal bevacizumab, often with adjuvant photocoagulation, led to regression without detachment in 100% of eyes, with most verbal children retaining functional vision., 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 © 2022 Naravane, Belin, Rubino and Quiram.)

Background: Gangliogliomas are well-differentiated, slow-growing glioneuronal neoplasms frequently reported to harbor upregulating alterations in the mitogen-activated protein kinase pathway, particularly serine-threonine protein kinase B-RAF alterations. Fusions involving neurotrophin tyrosine receptor kinase (NTRK) genes have rarely been reported in ganglioglioma. Similarly, echinoderm microtubule-associated protein-like (EML) 4 gene fusion has been described in lung cancer, but none has been reported in ganglioglioma., Observations: This report discusses the care of a 72-year-old man presenting with medication-refractory, left-sided focal seizures who was found to have a nongadolinium-enhancing, T2-hyperintense, right frontoparietal lesion. The patient received resection, and histological analysis found a World Health Organization grade I ganglioglioma, with genetic analysis demonstrating an EML4-NTRK3 gene fusion protein., Lessons: To our knowledge, this is the first report of an NTRK3 fusion, EML4-NTRK3, in an adult ganglioglioma, which is otherwise mostly associated with BRAF alterations and activation of the mitogen-activated protein kinase signaling pathway. Further studies are needed to elucidate the function of the resultant fusion protein and determine whether it may serve as a future therapeutic target.

Introduction: SARS-CoV-2 is fundamentally a respiratory pathogen with a wide spectrum of symptoms. The COVID-19 related pancreatitis is less considered than other clinical features. The purpose is to describe two cases of pancreatitis associated with COVID-19., Methodology: Patients' demographics, clinical features, laboratory, and instrumental findings were collected., Results: Two patients admitted to the hospital were diagnosed with COVID-19 and severe acute pancreatitis, according to the Atlanta criteria. Other causes of acute pancreatitis were excluded. Treatment included broad-spectrum antibiotics, proton pump inhibitors, and low molecular weight heparin. Steroids, oxygen, antifungal treatment, and pain killers were administered when appropriate. Both patients were asymptomatic, with normal vital parameters and blood exams, and were discharged in a good condition., Conclusion: It is recommendable to include lipase and amylase on laboratory routine tests in order to evaluate the need for the abdominal CT-scan and specific therapy before hospital admission of the patients with COVID-19 related life-threatening acute pancreatitis., 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 © 2022 Fiore, Beretta, De Vito, Barac, Maida, Joeseph Kelvin, Piu, Lai, Madeddu, Rubino, Stevanovic, Korica and Babudieri.)

Introduction: The novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), etiological agent of coronavirus disease 2019 (COVID-19) was first reported in China in December 2019 and spread worldwide. As of March 6th, 2021, there have been 116,670,105 million confirmed cases globally including 2,592,085 deaths. COVID-19 cases have been reported in 219 countries and territories, creating global panic. Mozambique has witnessed the evolution of COVID-19 epidemic associated with the weakness of health system, mostly in terms of laboratory diagnosis capacity, concerns on compliance to effective public health measures including physical distancing, use of masks in crowded indoor areas, hand hygiene, isolation and quarantine of people., Methodology: The data included in this study were collected from published articles regarding COVID-19 imported cases and severity in Africa, especially in Mozambique. Additionally, official documents of COVID-19 epidemiology from Minister of Health and National Institute of Health of Mozambique from 22nd of March 2020 to 1st of August 2020 were included., Results: The SARS-CoV-2 strains imported mainly from South Africa and European countries might have been playing an important role on COVID-19 epidemic evolution in Mozambique., Conclusions: These circulating strains in the country, might be similar enough to the strains found in other countries, yet the genomic characterization is needed particularly during the phase of borders reopening through understanding the source of infections and guiding the implementation of containment and mitigation measures in the country., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2021 José Sumbana, Alfeu Passanduca, Salvatore Rubino.)

The development of carbapenem resistance in extraintestinal pathogenic Escherichia coli (ExPEC) has significant clinical implications, particularly in countries where second-line antimicrobials are not readily available, rendering treatments ineffective, and ExPEC infections untreatable. Thus, early detection of high-risk ExPEC lineages and raising awareness of the specific mechanisms underlying carbapenem resistance are mandatory for the selection of appropriate treatment options and the prevention of E. coli spread. This study aims to investigate the phenotypic and genotypic features of the first NDM-5 carbapenemase-producing ExPEC strain isolated from the blood of a patient admitted to the Maputo Central Hospital (MCH), in Mozambique. E. coli SSM100 isolate was identified by MALDI-TOF, it displayed high-level resistance to third generation cephalosporins, carbapenems, fluoroquinolones, and aminoglycosides, performing antimicrobial susceptibilities testing by VITEK 2 system. E. coli SSM100 isolate was classified through whole-genome sequencing as ST405-D-O102: H6, a globally distributed lineage associated with antimicrobial resistance, carrying the bla NDM-5 gene located on an F1:A1:B49 plasmid, coharboring bla CTX-M-15, bla TEM-1, aadA2 , sul1 , and dfrA12 genes. In addition, mutations in gyrA (S83L and D87N), parC (S80I and E84V), and parE (I529L) conferring fluoroquinolone resistance were also found. Moreover, SSM100 isolate carried 88 virulence genes, of which 28 are reported to be associated with UPEC. The emergence of NDM-5 carbapenemase in a pandemic ST405-D-O102:H6 clone in Mozambique is of great concern. Locations of extended-spectrum β-lactamase determinants and NDM-5 carbapenemase gene on Inc F -plasmid can increase their spread reinforcing the need for antimicrobial surveillance and the urgent introduction of carbapenemase detection tests in diagnostic laboratories of the country.

Introduction: To analyze the virus spread among Sassari Hospital staff in the first Covid-19 wave and the impact of the Swab Team, a multidisciplinary task force entitled of nasopharyngeal swab collection and testing., Methodology: Nasopharyngeal swabs from HCWs between March 6 and May 28 2020 are evaluated., Results: 4919 SARS-CoV-2 tests were performed on 3521 operators. Nurses and doctors are the categories at highest risk. After the Swab Team institution, the average number of swabs raised from 47/day to 86/day (p = 0.007). Positive samples decreased from 18.6% to 1.7% (p < 0.0001)., Conclusions: The Swab Team is effective in increasing the cases tested and in reducing the reporting time. Procedure standardization reduces the risk for all the subjects involved (no transmission among swab team members, nor during the sample collection)., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2021 Francesco Bussu, Davide Rizzo, Laura Saderi, Antonio Piras, Laura Maria De Luca, Giacomo De Riu, Luigi Angelo Vaira, Antonello Serra, Paola Altrudo, Domenico Delogu, Ignazio Dettori, Francesco Giuseppe Riu, Flavia Angioj, Laura Firino, Rosalba Govoni, Gabriele Ibba, Vincenzo Lai, Erica Mura, Bianca Paglietti, Claudia Piu, Anna Puggioni, Elena Rimini, Giulia Rocca, Caterina Serra, Sergio Uzzau, Salvatore Rubino, Giovanni Sotgiu.)

Severe acute respiratory syndrome coronavirus 2 infection might induce a significant and sustained lymphopenia, increasing the risk of developing opportunistic infections. Mucormycosis is a rare but severe invasive fungal infection, mainly described in immunocompromised patients. The first case of a patient diagnosed with coronavirus disease (COVID-19) who developed a pulmonary mucormycosis with extensive cavitary lesions is here reported. This case highlights how this new coronavirus might impair the immune response, exposing patients to higher risk of developing opportunistic infections and leading to worse outcomes., (© 2020. The Author(s).)

Ingestion of caustic substances, whether accidental or for the purpose of suicide, can cause severe lesions of the lips, oral cavity, pharynx, upper gastrointestinal system, and upper airways. In particular, caustic agents could be responsible for severe esophageal injuries resulting in short- and long-term complications. Because of these important clinical implications, timely diagnosis and appropriate management are crucial. In the evaluation of esophageal injuries, thoraco-abdominal computed tomography (CT) is preferable to endoscopy as it avoids the risk of esophageal perforation and allows the evaluation of esophageal injuries as well as of the surrounding tissue. In this review, we report CT findings of esophageal injuries and possible related thoracic complications caused by caustic ingestion., (© 2021. American Society of Emergency Radiology.)

Recent evidence suggests that, in some foci, elimination of onchocerciasis from Africa may be feasible with mass drug administration (MDA) of ivermectin. To achieve continental elimination of transmission, mapping surveys will need to be conducted across all implementation units (IUs) for which endemicity status is currently unknown. Using boosted regression tree models with optimised hyperparameter selection, we estimated environmental suitability for onchocerciasis at the 5 × 5-km resolution across Africa. In order to classify IUs that include locations that are environmentally suitable, we used receiver operating characteristic (ROC) analysis to identify an optimal threshold for suitability concordant with locations where onchocerciasis has been previously detected. This threshold value was then used to classify IUs (more suitable or less suitable) based on the location within the IU with the largest mean prediction. Mean estimates of environmental suitability suggest large areas across West and Central Africa, as well as focal areas of East Africa, are suitable for onchocerciasis transmission, consistent with the presence of current control and elimination of transmission efforts. The ROC analysis identified a mean environmental suitability index of 0·71 as a threshold to classify based on the location with the largest mean prediction within the IU. Of the IUs considered for mapping surveys, 50·2% exceed this threshold for suitability in at least one 5 × 5-km location. The formidable scale of data collection required to map onchocerciasis endemicity across the African continent presents an opportunity to use spatial data to identify areas likely to be suitable for onchocerciasis transmission. National onchocerciasis elimination programmes may wish to consider prioritising these IUs for mapping surveys as human resources, laboratory capacity, and programmatic schedules may constrain survey implementation, and possibly delaying MDA initiation in areas that would ultimately qualify., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: WM is Program Analyst in Population and Development at the United Nations Population Fund-UNFPA Country Office in Peru, institution which not necessarily endorses this study. JAS reports personal fees from Crealta/Horizon, Medisys, Fidia, UBM LLC, Trio health, Medscape, WebMD, Clinical Care options, Clearview healthcare partners, Putnam associates, Focus forward, Navigant consulting, Spherix, Practice Point communications, the National Institutes of Health, the American College of Rheumatology, Simply Speaking. JAS reports other contributions from Amarin, Viking, Moderana and Vaxart pharmaceuticals. JAS reports non-financial support from the FDA Arthritis Advisory Committee, the Steering committee of OMERACT, an international organization that develops measures for clinical trials and receives arms length funding from 12 pharmaceutical companies, the Veterans Affairs Rheumatology Field Advisory Committee, and the Editor and the Director of the UAB Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis.

Background: The SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus 2) has led to more than 165 million COVID-19 cases and >3.4 million deaths worldwide. Epidemiological analysis has revealed that the risk of developing severe COVID-19 increases with age. Despite a disproportionate number of older individuals and long-term care facilities being affected by SARS-CoV-2 and COVID-19, very little is understood about the immune responses and development of humoral immunity in the extremely old person after SARS-CoV-2 infection. Here we conducted a serological study to investigate the development of humoral immunity in centenarians following a SARS-CoV-2 outbreak in a long-term care facility., Methods: Extreme aged individuals and centenarians who were residents in a long-term care facility and infected with or exposed to SARS-CoV-2 were investigated between April and June 2020 for the development of antibodies to SARS-CoV-2. Blood samples were collected from positive and bystander individuals 30 and 60 days after original diagnosis of SARS-CoV-2 infection. Plasma was used to quantify IgG, IgA, and IgM isotypes and subsequent subclasses of antibodies specific for SARS-CoV-2 spike protein. The function of anti-spike was then assessed by virus neutralization assays against the native SARS-CoV-2 virus., Findings: Fifteen long-term care residents were investigated for SARS-CoV-2 infection. All individuals had a Clinical Frailty scale score ≥5 and were of extreme older age or were centenarians. Six women with a median age of 98.8 years tested positive for SARS-CoV-2. Anti-spike IgG antibody titers were the highest titers observed in our cohort with all IgG positive individuals having virus neutralization ability. Additionally, 5 out of the 6 positive participants had a robust IgA anti-SARS-CoV-2 response. In all 5, antibodies were detected after 60 days from initial diagnosis., Competing Interests: Mary K. Foley – Ms. Foley has nothing to disclose. Samuel D. Searle - Dr. Searle received PhD and fellowship funding from the Canadian Frailty Network, Dalhousie Medical Research Foundation, Dalhousie University Internal Medicine Research Foundation and the QE II Innovation Fund. Ali Toloue – Toloue has nothing to disclose. Ryan Booth -Ryan Booth has nothing to disclose. Alec Falkenham – Dr. Falkenham has nothing to disclose. Darryl Falzarano – Dr. Falzarano has nothing to disclose. Salvatore Rubino – Dr. Rubino has nothing to disclose. Magen E. Francis – Ms. Francis has nothing to disclose. Mara McNeil – Ms. McNeil has nothing to disclose. Christopher Richardson – Dr. Richardson has nothing to disclose. Jason LeBlanc – Dr. LeBlanc has nothing to disclose. Sharon Oldford – Dr. Oldford has nothing to disclose. Volker Gerdts – Dr. Gerdts has nothing to disclose. Melissa K. Andrew – Dr. Andrew reports grants from Sanofi, grants from GSK, grants from Pfizer, grants from Canadian Frailty Network, grants from CIHR, grans from Public Health Agency of Canada, personal fees from Sanofi, from Pfizer, personal fees from Seqirus, outside the submitted work. Shelly A. McNeil – Dr. McNeil reports grants, personal fees and other from Pfizer, other from Medicago, personal fees and other from Sanofi, grants, personal fees and other from GlaxoSmithKline, grants personal fees and other from Merck, other from CanSino, other from IMV, other from Janssen, outside the submitted work. Barry Clarke – Dr. Clarke has nothing to disclose. Kenneth Rockwood – Dr. Rockwood reports personal fees from Clinical Cardio Day – Cape Breton University, personal fees from CRUIGM-Montreal, from Speaker at Jackson Lab, Bar Harbor MA, personal fees from Speaker at MouseAge Rome Italy, personal fees from Frontemporal Dementia Study Group, personal fees from SunLife Insurance Japan, outside the submitted work and Kenneth Rockwood is President and Co-founder of Ardea Outcomes, which in the last three years (as DGI Clinical) has contracts with pharma and device manufacturers (Shire, Hollister, Nutricia, Roche, Otsuka) on individualized outcome measurement. Otherwise any personal fees are for invited guest lectures and academic symposia, received directly from event organizers, chiefly for presentations on frailty. He is Associate Director of the Canadian Consortium on Neurodegeneration in Aging, which is funded by the Canadian Institutes of Health Research, and with additional funding from the Alzheimer Society of Canada and several other charities. He receives career support from the Dalhousie Medical Research Foundation as the Kathryn Allen Weldon Professor of Alzheimer Research, and research support from the Canadian Institutes of Health Research, The Canadian Frailty Network, the QEII Health Science centre Foundation, the Nova Scotia Health Research Fund and the Fountain Family Innovation Fund of the QEII Health Science centre Foundation. David J. Kelvin – Dr. Kelvin has nothing to disclose. Alyson A. Kelvin – Dr. A. Kelvin has nothing to disclose., (© 2021 The Authors.)

Objectives: Bruton's tyrosine kinase (BTK) plays a non-redundant signaling role downstream of the B-cell receptor (BCR) in B cells and the receptors for the Fc region of immunoglobulins (FcR) in myeloid cells. Here, we characterise BIIB091, a novel, potent, selective and reversible small-molecule inhibitor of BTK., Methods: BIIB091 was evaluated in vitro and in vivo in preclinical models and in phase 1 clinical trial., Results: In vitro, BIIB091 potently inhibited BTK-dependent proximal signaling and distal functional responses in both B cells and myeloid cells with IC 50 s ranging from 3 to 106 nm, including antigen presentation to T cells, a key mechanism of action thought to be underlying the efficacy of B cell-targeted therapeutics in multiple sclerosis. BIIB091 effectively sequestered tyrosine 551 in the kinase pocket by forming long-lived complexes with BTK with t 1/2 s of 87 and 106 nm observed with stimulated B cells and myeloid cells, respectively. 50 s of 87 and 106 nm observed with stimulated B cells and myeloid cells, respectively. In vivo , BIIB091 blocked B-cell activation, antibody production and germinal center differentiation. In phase 1 healthy volunteer trial, BIIB091 inhibited naïve and unswitched memory B-cell activation, with an in vivo IC 50 of 55 nm and without significant impact on lymphoid or myeloid cell survival after 14 days of dosing., Conclusion: Pharmacodynamic results obtained in preclinical and early clinical settings support the advancement of BIIB091 in phase 2 clinical trials., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

The neurosurgical management of spinal neoplasms has undergone immense development in parallel with advancements made in general spine surgery. Laminectomies were performed as the first surgical procedures used to treat spinal neoplasms. Since then, neurosurgical spinal oncology has started to incorporate techniques that have developed from recent advances in minimally invasive spine surgery. Neurosurgery has also integrated radiotherapy into the treatment of spine tumors. In this historical vignette, we present a vast timeline spanning from the Byzantine period to the current day and recount the major advancements in the management of spinal neoplasms., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Drug resistance in antifungal therapy, a problem unknown until a few years ago, is increasingly assuming importance especially in immunosuppressed patients and patients receiving chemotherapy and radiotherapy. In the past years, the use of essential oils as an approach to improve the effectiveness of antifungal agents and to reduce antifungal resistance levels has been proposed. Our research aimed to evaluate the antifungal activity of Colombian rue, Ruta graveolens , essential oil (REO) against clinical strains of Candida albicans , Candida parapsilopsis , Candida glabrata , and Candida tropicalis . Data obtained showed that C. tropicalis and C. albicans were the most sensitive strains showing minimum inhibitory concentrations (MIC) of 4.1 and 8.2 µg/mL of REO. Time-kill kinetics assay demonstrated that REO showed a fungicidal effect against C. tropicalis and a fungistatic effect against C. albicans . In addition, an amount of 40% of the biofilm formed by C. albicans was eradicated using 8.2 µg/mL of REO after 1 h of exposure. The synergistic effect of REO together with some antifungal compounds was also investigated. Fractional inhibitory concentration index (FICI) showed synergic effects of REO combined with amphotericin B. REO Lead a disruption in the cellular membrane integrity, consequently resulting in increased intracellular leakage of the macromolecules, thus confirming that the plasma membrane is a target of the mode of action of REO against C. albicans and C. tropicalis.

Purpose: There is an unmet need to develop prognostic biomarkers in post-neoadjuvant chemotherapy (NAC) muscle-invasive bladder cancer (MIBC) patients. We examine whether Ki-67 and PD-L1 expression can be used to guide adjuvant therapy., Methods: Tissue microarrays were constructed from 130 post-NAC radical cystectomy samples. Up to 5 cores per sample were included. Expressions of Ki-67 and PD-L1 were evaluated using immunohistochemistry (IHC)., Results: Using a Cox regression model, positive Ki-67 expression in post-NAC radical cystectomy samples was associated with poorer overall survival (OS) (HR = 2.412, 95% CI, 1.076-5.408), independent of the pathological lymph node/N-stage. Positive Ki-67 expression was also associated with lack of tumor downstaging in a multivariable logistic regression model analysis (OR = 0.081, 95% CI, 0.014-0.464). PD-L1 - and PD-L1 + expression was associated with a median OS of 49.8 months and 26.9 months, respectively, which did not reach statistical significance. Patients with Ki-67/PD-L1 double-negative tumors had a significantly longer median OS of 98.2 months versus 29.9 and 26.9 months in PD-L1 - /Ki-67 + and PD-L1 + /Ki-67 + tumors, respectively. Lack of tumor downstaging was significantly associated with positive Ki-67 and positive PD-L1 expression., Conclusion: Positive Ki-67 and PD-L1 expression in post-NAC radical cystectomy samples was associated with inferior OS and absence of tumor downstaging. IHC on Ki-67 and PD-L1 would help to select patients for adjuvant therapy in post-NAC muscle-invasive bladder cancer.

Background: Eumycetoma is a chronic subcutaneous granulomatous disease that is endemic in Sudan and other countries. It can be caused by eight different fungal orders. The gold standard diagnostic test is culture, however, culture-independent methods such as imaging, histopathological and molecular techniques can support diagnosis, especially in cases of negative cultures., Methods: The amplicon-based internal transcribed spacer 2 metagenomic technique was used to study black grains isolated from 14 tissue biopsies from patients with mycetoma. Furthermore, mycological culture and surgical biopsy histopathological examinations of grains were performed., Results: Madurella mycetomatis (n=5) and Falciformispora spp. (n=4) organisms were identified by culture and confirmed by metagenomics. Metagenomics recognised, at the species level, Falciformispora as Falciformispora tompkinsii (n=3) and Falciformispora senegalensis (n=1), while in culture-negative cases (n=5), Madurella mycetomatis (n=3), Falciformispora senegalensis (n=1) and Fusarium spp. (n=1) were identified. Interestingly, the metagenomics results showed a 'consortium' of different fungi in each sample, mainly Ascomycota phylum, including various species associated with eumycetoma. The microbial co-occurrence in eumycetoma showed the co-presence of Madurella with Trichoderma, Chaetomium, Malasseziales and Sordariales spp., while Falciformispora co-presented with Inocybe and Alternaria and was in mutual exclusion with Subramaniula, Aspergillus and Trichothecium., Conclusion: Metagenomics provides new insights into the aetiology of eumycetoma in samples with negative culture and into the diversity and complexity of grains mycobiota, calling into question the accuracy of traditional culture for the identification of causative agents., (© The Author(s) 2021. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

The spread of new SARS-CoV-2 variants represents a serious threat worldwide, thus rapid and cost-effective methods are required for their identification. Since November 2020, the TaqPath COVID-19 assay (Thermo Fisher Scientific) has been used to identify viral strains of the new lineage B.1.1.7, since it fails to detect the S-gene with the ∆69/70 deletion. Here, we proposed S-gene mutations screening with the Allplex SARS-CoV-2 assay (Seegene), another widely used RT-PCR test that targets Sarbecovirus E, SARS-CoV-2 N, and RdRp/S genes. Accordingly, we evaluated the S gene amplification curve pattern compared to those of the other genes. Exploiting an Allplex assay-generated dataset, we screened 663 RT-PCR digital records, including all SARS-CoV-2 respiratory samples tested in our laboratory with the Allplex assay between January 1st and February 25th, 2021. This approach enabled us to detect 64 samples with peculiar non-sigmoidal amplification curves. Sequencing a selected group of 4 RNA viral genomes demonstrated that those curves were associated with B.1.1.7 variant strains. Our results strongly suggest that B.1.1.7 variant spread has begun in this area at least since January and imply the potential of these analytical methods to track and characterize the spread of B.1.1.7 strains in those areas where Allplex SARS-CoV-2 datasets have been previously recorded., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2021 Gabriele Ibba, Rosangela Sau, Flavia Angioj, Marcello Abbondio, Salvatore Rubino, Sergio Uzzau.)

Background: Surgery is the mainstay of treatment for gastric volvulus. Despite its rarity, early experience from recent publications suggests that laparoscopy is a safe and effective approach for the treatment of acute gastric volvulus. Yet, more data focusing on patients' postoperative quality of life (QoL) is needed. The aim of this study is to report our institutional experience with the management of acute gastric volvulus, assessing surgical outcomes and postoperative QoL. Materials and Methods: We performed a retrospective review of a prospectively maintained database, looking for patients with gastric volvulus, requiring emergency laparotomic or laparoscopic surgery, between 2016 and 2018. Follow-up included clinical evaluation, barium swallow X-ray, and two QoL questionnaires-Gastroesophageal Reflux Disease-Health-Related Quality of Life and Gastrointestinal Symptom Rating Scale. Results: Over a 3-year period, 9 patients underwent emergency surgery for acute gastric volvulus, 5 (55%) of which were performed laparoscopically. In this group, the only postoperative complication was found in 1 (20%) patient who presented mild delayed gastric empty. In the laparotomic group, 3 patients (75%) had immediate (30-day) postoperative complications-1 pneumonia, 1 bowel obstruction, and 1 sepsis with multiorgan failure. At a median follow-up of 25 (15-48) months, hiatal hernia recurred in 1 (20%) patient after laparoscopic repair. No recurrence occurred in the open group. With a 100% response rate, QoL questionnaires revealed that 80% of the subjects treated laparoscopically were fully satisfied of the surgical approach, reporting slightly better QoL scores than the open surgery group. Conclusions: Improved postoperative clinical outcomes and QoL after laparoscopic repair of acute gastric volvulus provide encouraging evidence in support of this minimally invasive approach as an alternative to laparotomy.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause serious illness in older adults and people with chronic underlying medical conditions; however, children and young people are often asymptomatic or with mild symptoms. We evaluated the presence of specific antibodies (Abs) response against Human coronavirus NL63 (HCoV-NL63) S protein epitopes (NL63-RBM1, NL63-RBM2&#95;1, NL63-RBM2&#95;2, NL63-RBM3, NL63-SPIKE 541-554 , and NL63-DISC-like) and SARS-CoV-2 epitopes (COV2-SPIKE 421-434 and COV2-SPIKE 742-759 ) in plasma samples of pre-pandemic, mid-pandemic, and COVID-19 cohorts by indirect ELISA. Moreover, a competitive assay was performed to check for cross reactivity response between COV2-SPIKE 421-434 and NL63-RBM3 among patients with a definitive diagnosis of SARS-CoV-2. Immune reaction against all SARS-CoV-2 and HCoV-NL63 epitopes showed a significantly higher response in pre-pandemic patients compared to mid-pandemic patients. The results indicate that probably antibodies against HCoV-NL63 may be able to cross react with SARS-CoV-2 epitopes and the higher incidence in pre-pandemic was probably due to the timing of collection when a high incidence of HCoV-NL63 is reported. In addition, the competitive assay showed cross-reactivity between antibodies directed against COV2-SPIKE 421-434 and NL63-RBM3 peptides. Pre-existing HCoV-NL63 antibody response cross reacting with SARS-CoV-2 has been detected in both pre- and mid-pandemic individual, suggesting that previous exposure to HCoV-NL63 epitopes may produce antibodies which could confer a protective immunity against SARS-CoV-2 and probably reduce the severity of the disease.

Frequency and duration of outpatient clinic follow-up for patients with shunted hydrocephalus varies among clinicians and assessment of follow-up regimens is lacking. The aim of this study is to investigate whether routine clinic visits alter care and whether they identify patients requiring shunt revision surgery, as well as, to better understand how patients utilize the outpatient clinic and present for shunt revision evaluation. This is a single-centered retrospective study of 154 patients requiring shunt revision surgery from 2009 to 2018 who had at least one prior clinic evaluation. The median age for shunt placement and revision were 3 months and 11 years old, respectively. Routine clinic visits led to a change in care for 16 patients (10.4%); including additional imaging, follow-up, or a combination of the two. With regards to revision surgery, days from prior shunt surgery, Chiari II/myelomeningocele pathology, and shunt type (p < 0.01) did affect time to presentation. Four patients (2.6%) requiring revision surgery were identified at routine clinic follow-up, while 92 (59.7%) and 47 (30.5%) presented to the emergency department and clinic sick visit, respectively. Presentation to clinic resulted in a statistically significant decrease in shunt revision surgery length-of-stay compared to presentation to the emergency department or inpatient admission for another condition. Even with increased emergency room utilization, increased clinic connectivity, and improved patient education, routine clinic visits remain an important component in the follow-up of patients with shunted hydrocephalus by helping to guide clinical care and identify patients requiring shunt revision surgery., 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 © 2020 Elsevier Ltd. All rights reserved.)

Introduction: The popularity of the ventriculoatrial shunt as a means for cerebrospinal fluid diversion was temporally limited, overcome by the success of the peritoneum as a site for distal drainage. Nevertheless, it remains an important tool for patients for whom ventriculoperitoneal shunting is not an option., Clinical Presentation: We present the case of a 9-year-old girl with a ventriculoatrial shunt, who had undergone multiple revisions. Ultimately, she suffered a wound dehiscence, resulting in infectious seeding of the bloodstream and formation of a thrombus, presumed granuloma, at the tip of the distal catheter in the right atrium. She underwent successful removal of the lesion via an open approach by our cardiothoracic colleagues., Discussion: Previous authors have noted a high number of mortalities as a result of these lesions. A collaborative approach resulted in a successful outcome for our patient. Although limited in utility today, the ventriculoatrial shunt remains a common procedure for neurosurgeons today., Conclusion: Recognizing the potential for atrial thrombus formation and using a team approach can help avoid a poor outcome., (Published by Elsevier Inc.)