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Abstract Carbapenem-resistant Acinetobacter baumannii (CRAB) is a major human pathogen and a research priority for developing new antimicrobial agents. CRAB is a causative agent of a variety of infections in different body sites. One of the manifestations is catheter-associated urinary tract infection, which exposes the bacteria to the host’s urine, creating a particular environment. Exposure of two CRAB clinical isolates, AB5075 and AMA40, to human urine (HU) resulted in the differential expression levels of 264 and 455 genes, respectively, of which 112 were common to both strains. Genes within this group play roles in metabolic pathways such as phenylacetic acid (PAA) catabolism, the Hut system, the tricarboxylic acid (TCA) cycle, and other processes like quorum sensing and biofilm formation. These results indicate that the presence of HU induces numerous adaptive changes in gene expression of the infecting bacteria. These changes presumably help bacteria establish and thrive in the hostile conditions in the urinary tract. These analyses advance our understanding of CRAB’s metabolic adaptations to human fluids, as well as expand knowledge on bacterial responses to distinct human fluids containing different concentrations of human serum albumin (HSA).

Maintaining healthy cognitive functioning and delaying cognitive decline in cognitively intact and cognitively impaired adults are major research initiatives for addressing dementia disease burden. Music interventions are promising, non-pharmaceutical treatment options for preserving cognitive function and psychological health in older adults with varying levels of cognitive function. While passive, music interventions have attracted considerable attention in the abnormal cognitive aging literature, active, music interventions such as music creativity are less well-studied. Among 58 older adults with different levels of cognitive function (cognitively healthy to mild cognitive impairment), we examined the feasibility and acceptability of "Project CHROMA", a Stage 1 clinical trial developed to assess the effects of a novel, music creativity curriculum on various health outcomes. Music intervention participation (93%), overall study retention (78%), and intervention satisfaction (100%) rates were comparable to other similarly designed clinical trials. Exploratory analyses using mixed-level modeling tested the efficacy of the intervention on cognitive and psychological outcomes. Compared to those in the control condition, participants in the music condition showed some improvements in cognitive functioning and socioemotional well-being. Findings suggest that a 6-week music creativity clinical trial with several multi-modal health assessments can be feasibly implemented within a sample of varying cognitive ability.

Abstract Background Brain inflammation contributes significantly to the pathophysiology of Alzheimer’s disease, and it is manifested by glial cell activation, increased production of cytokines/chemokines, and a shift in lipid mediators from a pro-homeostatic to a pro-inflammatory profile. However, whether the production of bioactive lipid mediators is affected at earlier stages, prior to the deposition of Aβ plaques and tau hyperphosphorylation, is unknown. The differential contribution of an evolving amyloid and tau pathology on the composition and abundance of membrane phospholipids and bioactive lipid mediators also remains unresolved. Methods In this study, we examined the cortical levels of DHA- and AA-derived bioactive lipid mediators and of membrane phospholipids by liquid chromatography with tandem mass spectrometry in transgenic rat models of the Alzheimer’s-like amyloid and tau pathologies at early and advanced pathological stages. Results Our findings revealed a complex balance between pro-inflammatory and pro-resolving processes in which tau pathology has a more pronounced effect compared to amyloid pathology. At stages preceding tau misfolding and aggregation, there was an increase in pro-resolving lipid mediators (RVD6 and NPD1), DHA-containing phospholipids and IFN-γ levels. However, in advanced tau pathology displaying NFT-like inclusions, neuronal death, glial activation and cognitive deficits, there was an increase in cytokine and PGD2, PGE2, and PGF2α generation accompanied by a drop in IFN-γ levels. This pathology also resulted in a marked increase in AA-containing phospholipids. In comparison, pre-plaque amyloid pathology already presented high levels of cytokines and AA-containing phospholipids together with elevated RVD6 and NPD1 levels. Finally, Aβ plaque deposition was accompanied by a modest increase in prostaglandins, increased AA-containing phospholipids and reduced DHA-containing phospholipids. Conclusions Our findings suggest a dynamic trajectory of inflammatory and lipid mediators in the evolving amyloid and tau pathologies and support their differing roles on membrane properties and, consequentially, on signal transduction.

Abstract Background This case describes the youngest patient documented in the literature who presented with a giant hydatidiform mole, effectively addressed through conservative treatment. Case presentation Our department received a 20-year-old Caucasian patient who was admitted due to significant metrorrhagia in an undisclosed pregnancy. During examination, we identified a massive, highly vascularized hydatidiform mole measuring 22 cm (cm). We performed a surgical dilatation and curettage. The anatomopathological findings confirmed the presence of a complete hydatidiform mole (CHM). Following the established guidelines, we conducted weekly monitoring of human chorionic gonadotropin (hCG). Unfortunately, the patient discontinued the follow-up and became pregnant again before achieving hCG negativation. Conclusion This case suggests that conservative treatment is a viable option regardless of the size of gestational trophoblastic disease (GTD), especially when the preservation of fertility is a crucial consideration, as effectively demonstrated in our case.

Abstract Motivation Long non-coding RNAs (lncRNAs) are a class of molecules involved in important biological processes. Extensive efforts have been provided to get deeper understanding of disease mechanisms at the lncRNA level, guiding towards the detection of biomarkers for disease diagnosis, treatment, prognosis and prevention. Unfortunately, due to costs and time complexity, the number of possible disease-related lncRNAs verified by traditional biological experiments is very limited. Computational approaches for the prediction of disease-lncRNA associations allow to identify the most promising candidates to be verified in laboratory, reducing costs and time consuming. Results We propose novel approaches for the prediction of lncRNA-disease associations, all sharing the idea of exploring associations among lncRNAs, other intermediate molecules (e.g., miRNAs) and diseases, suitably represented by tripartite graphs. Indeed, while only a few lncRNA-disease associations are still known, plenty of interactions between lncRNAs and other molecules, as well as associations of the latters with diseases, are available. A first approach presented here, NGH, relies on neighborhood analysis performed on a tripartite graph, built upon lncRNAs, miRNAs and diseases. A second approach (CF) relies on collaborative filtering; a third approach (NGH-CF) is obtained boosting NGH by collaborative filtering. The proposed approaches have been validated on both synthetic and real data, and compared against other methods from the literature. It results that neighborhood analysis allows to outperform competitors, and when it is combined with collaborative filtering the prediction accuracy further improves, scoring a value of AUC equal to 0966. Availability Source code and sample datasets are available at: https://github.com/marybonomo/LDAsPredictionApproaches.git

ABSTRACT Cefiderocol, a siderophore-cephalosporine conjugate antibiotic, shows promise as a therapeutic option for carbapenem-resistant (CR) Acinetobacter infections. While resistance has already been reported in A. baumannii, combination therapies with avibactam or sulbactam reduce MICs of cefiderocol, extending its efficacy. However, careful consideration is necessary when using these combinations. In our experiments, exposure of A. baumannii and A. lwoffii to cefiderocol and sulbactam or avibactam led to the selection of cefiderocol-resistant strains. Three of those were subjected to whole genome sequencing and transcriptomic analysis. The strains all possessed synonymous and non-synonymous substitutions and short deletions. The most significant mutations affected efflux pumps, transcriptional regulators, and iron homeostasis genes. Transcriptomics showed significant alterations in expression levels of outer membrane proteins, iron homeostasis, and β-lactamases, suggesting adaptive responses to selective pressure. This study underscores the importance of carefully assessing drug synergies, as they may inadvertently foster the selection of resistant variants and complicate the management of CR Acinetobacter infections.IMPORTANCEThe emergence of carbapenem-resistant Acinetobacter strains as a serious global health threat underscores the urgent need for effective treatment options. Although few drugs show promise against CR Acinetobacter infections, resistance to both drugs has been reported. In this study, the molecular characterization of spontaneous cefiderocol-resistant variants, a CR A. baumannii strain with antagonism to sulbactam, and an A. lwoffii strain with antagonism to avibactam, provides valuable insights into the mechanisms of resistance to cefiderocol. Some mechanisms observed are associated with mutations affecting efflux pumps, regulators, and iron homeostasis genes. These findings highlight the importance of understanding resistance mechanisms to optimize treatment options. They also emphasize the importance of early evaluation of drug synergies to address the challenges of antimicrobial resistance in Acinetobacter infections.

En este trabajo se presentan los resultados de los análisis antracológicos efectuados en el sitio arqueológico Cerro de las Pajas Blancas 1 (CDLPB1). CDLPB1 es un sitio clásico dentro de la literatura del NEA tradicionalmente caracterizado como un asentamiento Guaraní, pero que recientes excavaciones muestran una clara ocupación asociada a la entidad arqueológica Goya-Malabrigo. En el marco de estos últimos trabajos, se efectuaron estudios antracológicos sobre la totalidad de maderas carbonizadas recuperadas en el sitio. Para la identificación, se elaboró la primera clave identificatoria del área, y la interpretación incluyó aproximaciones cuantitativas y cualitativas. Se identificaron 22 taxones. Los resultados indican una importante frecuencia de algarrobo (Neltuma sp.) y espinillo (Vachellia sp.) que podrían haber sido utilizados como combustible para la cocción de alfarería y/o de alimentos y para obtener luz y calor. Otras maderas blandas con frecuencias menores (Salix sp. -sauce, Enterolobium sp. -timbó-, Nectandra sp. -laurel, Myrsine sp. -canelón, Erythrina sp. -seibo-) podrían haber sido recolectadas para la fabricación de artefactos y como avivadoras o iniciadoras de fuegos. A su vez, la presencia de especímenes no-locales como Schinopsis sp. (quebracho) refuerza la idea de una circulación e intercambio de objetos con poblaciones humanas del Centro-Norte argentino en tiempos prehispánicos.

A doença hepática gordurosa não alcoólica (DHGNA) afeta indivíduos em todo o mundo e é caracterizada por esteatose, estresse oxidativo, lipotoxicidade e inflamação. Nesse contexto, os antioxidantes dietéticos são importantes para a defesa eficiente contra os danos oxidativos. Nossa hipótese é que a amêndoa de baru (Dipteryx Alata Vog.) pode ser um agente terapêutico promissor para o tratamento da DHGNA. Assim, o objetivo do presente estudo foi avaliar o efeito da farinha de amêndoa de baru (BAF) no perfil lipídico e nas defesas antioxidantes em ratos alimentados com dieta hiperlipídica. Quarenta ratos Fisher foram divididos no grupo controle (C) (dieta AIN-93M); controle de baru (CB) (AIN-93M com 2% de BAF); alto teor de gordura (H) (AIN-93M com 2% de colesterol e 25% de óleo de soja); e baru com alto teor de gordura (HB) (dieta hiperlipídica com 2% de BAF) por 12 semanas. A dieta hiperlipídica reduziu o HDL-colesterol, aumentou os níveis séricos da fração não-HDL, colesterol total. Além disso, induziu esteatose hepática, dano hepático e estresse oxidativo, como demonstrado pela presença de ALT elevadas e níveis de GSSG. A amêndoa de baru demonstrou alto teor de compostos fenólicos e atividade antioxidante. O tratamento com BAF atenuou os níveis séricos de colesterol. Além disso, BAF melhorou o sistema de glutationa hepática, aumentando o conteúdo de glutationa. Esses resultados mostram que o BAF é uma fonte promissora de antioxidantes alimentares naturais e tem efeitos benéficos no estado redox in vivo. Mais estudos para elucidar suas propriedades funcionais e mecanismos subjacentes são, portanto, necessários. Palavras-chave: Dipteryx Alata Vog. Dieta hiperlipídica. Antioxidante. Fígado.

Objectives The use of cannabis-based medicine (CBM) as a therapeutic has surged in Australia over the past 5 years. Historically, the United Nations Single Convention on Narcotic Drugs (1961) prohibited cannabis use in Europe, the USA, the UK and Australia, leading to legislative resistance and limited preclinical data on CBM. Existing safety monitoring systems for CBM are poorly structured and do not integrate well into the workflows of busy health professionals. As a result, postmarketing surveillance is inconsistent. This review aims to evaluate international systems for monitoring CBM side effects and adverse events.Design To undertake a scoping review with a systematic approach, we used the Population, Intervention, Comparison, Outcome (PICO) framework to develop keyword elements, and two search queries to maximise search sensitivity and specificity.Data sources Search queries were entered into Embase and Scopus for peer-reviewed literature, and additional searches for grey literature were conducted on 23 June 2023.Eligibility criteria We included 54 full-text articles in the review: 39 from peer-reviewed searches, 8 from grey literature and 7 from citations of relevant texts.Data extraction and synthesis Our search yielded two main forms of monitoring systems: databases and registries. Out of the 24 monitoring systems identified, there were 10 databases and 14 registries, with databases often created by regulatory authorities. Systems differed in methods of causality assessment, level of detail collected, terminology and affiliations.Results Within the monitoring systems with enough published data for analysis, all except one remain active at the time of this review. VigiBase is the largest centralised monitoring system, receiving international case reports, however data heterogeneity persists.Conclusions Our study emphasises the need for a centralised, consistent and accessible system for the postmarketing surveillance of side effects and adverse events associated with medicinal cannabis use.

Summary: Background: Mucositis is a common and highly impactful side effect of conventional and emerging cancer therapy and thus the subject of intense investigation. Although common practice, mucositis assessment is heterogeneously adopted and poorly guided, impacting evidence synthesis and translation. The Multinational Association of Supportive Care in Cancer (MASCC) Mucositis Study Group (MSG) therefore aimed to establish expert recommendations for how existing mucositis assessment tools should be used, in clinical care and trials contexts, to improve the consistency of mucositis assessment. Methods: This study was conducted over two stages (January 2022–July 2023). The first phase involved a survey to MASCC-MSG members (January 2022–May 2022), capturing current practices, challenges and preferences. These then informed the second phase, in which a set of initial recommendations were prepared and refined using the Delphi method (February 2023–May 2023). Consensus was defined as agreement on a parameter by >80% of respondents. Findings: Seventy-two MASCC-MSG members completed the first phase of the study (37 females, 34 males, mainly oral care specialists). High variability was noted in the use of mucositis assessment tools, with a high reliance on clinician assessment compared to patient reported outcome measures (PROMs, 47% vs 3%, 37% used a combination). The World Health Organization (WHO) and Common Terminology Criteria for Adverse Events (CTCAE) scales were most commonly used to assess mucositis across multiple settings. Initial recommendations were reviewed by experienced MSG members and following two rounds of Delphi survey consensus was achieved in 91 of 100 recommendations. For example, in patients receiving chemotherapy, the recommended tool for clinician assessment in clinical practice is WHO for oral mucositis (89.5% consensus), and WHO or CTCAE for gastrointestinal mucositis (85.7% consensus). The recommended PROM in clinical trials is OMD/WQ for oral mucositis (93.3% consensus), and PRO-CTCAE for gastrointestinal mucositis (83.3% consensus). Interpretation: These new recommendations provide much needed guidance on mucositis assessment and may be applied in both clinical practice and research to streamline comparison and synthesis of global data sets, thus accelerating translation of new knowledge into clinical practice. Funding: No funding was received.

ABSTRACT Mycobacterium abscessus (Mab) affects patients with immunosuppression or underlying structural lung diseases such as cystic fibrosis (CF). Additionally, Mab poses clinical challenges due to its resistance to multiple antibiotics. Herein, we investigated the synergistic effect of dual β-lactams [sulopenem and cefuroxime (CXM)] or the combination of sulopenem and CXM with β-lactamase inhibitors [BLIs—avibactam (AVI) or durlobactam (DUR)]. The sulopenem-CXM combination yielded low minimum inhibitory concentration (MIC) values for 54 clinical Mab isolates and ATCC19977 (MIC50 and MIC90 ≤0.25 µg/mL). Similar synergistic effects were observed in time-kill studies conducted at concentrations achievable in clinical settings. Sulopenem-CXM outperformed monotherapy, yielding ~1.5 Log10 CFU/mL reduction during 10 days. Addition of BLIs enhanced this antibacterial effect, resulting in an additional reduction of CFUs (~3 Log10 for sulopenem-CXM and AVI and ~4 Log10 for sulopenem-DUR). Exploration of the potential mechanisms of the synergy focused on their interactions with L,D-transpeptidases (Ldts; LdtMab1–LdtMab4), penicillin-binding-protein B (PBP B), and D,D-carboxypeptidase (DDC). Acyl complexes, identified via mass spectrometry analysis, demonstrated the binding of sulopenem with LdtMab2–LdtMab4, DDC, and PBP B and CXM with LdtMab2 and PBP B. Molecular docking and mass spectrometry data suggest the formation of a covalent adduct between sulopenem and LdtMab2 after the nucleophilic attack of the cysteine residue at the β-lactam carbonyl carbon, leading to the cleavage of the β-lactam ring and the establishment of a thioester bond linking the LdtMab2 with sulopenem. In conclusion, we demonstrated the biochemical basis of the synergy of sulopenem-CXM with or without BLIs. These findings potentially broaden the selection of oral therapeutic agents to combat Mab.IMPORTANCETreating infections from Mycobacterium abscessus (Mab), particularly those resistant to common antibiotics like macrolides, is notoriously difficult, akin to a never-ending struggle for healthcare providers. The rate of treatment failure is even higher than that seen with multidrug-resistant tuberculosis. The role of combination β-lactams in inhibiting L,D-transpeptidation, the major peptidoglycan crosslink reaction in Mab, is an area of intense investigation, and clinicians have utilized this approach in the treatment of macrolide-resistant Mab, with reports showing clinical success. In our study, we found that cefuroxime and sulopenem, when used together, display a significant synergistic effect. If this promising result seen in lab settings, translates well into real-world clinical effectiveness, it could revolutionize current treatment methods. This combination could either replace the need for more complex intravenous medications or serve as a “step down” to an oral medication regimen. Such a shift would be much easier for patients to manage, enhancing their comfort and likelihood of sticking to the treatment plan, which could lead to better outcomes in tackling these tough infections. Our research delved into how these drugs inhibit cell wall synthesis, examined time-kill data and binding studies, and provided a scientific basis for the observed synergy in cell-based assays.

ABSTRACT Resistance to ceftazidime-avibactam (CZA) due to Klebsiella pneumoniae carbapenemase (KPC) variants is increasing worldwide. We characterized two CZA-resistant clinical Klebsiella pneumoniae strains by antimicrobial susceptibility test, conjugation assays, and WGS. Isolates belonged to ST258 and ST45, and produced a KPC-31 and a novel variant KPC-197, respectively. The novel KPC variant presents a deletion of two amino acids on the Ω-loop (del_168–169_EL) and an insertion of two amino acids in position 274 (Ins_274_DS). Continued surveillance of KPC variants conferring CZA resistance in Colombia is warranted.IMPORTANCELatin America and the Caribbean is an endemic region for carbapenemases. Increasingly high rates of Klebsiella pneumoniae carbapenemase (KPC) have established ceftazidime-avibactam (CZA) as an essential antimicrobial for the treatment of infections due to MDR Gram-negative pathogens. Although other countries in the region have reported the emergence of CZA-resistant KPC variants, this is the first description of such enzymes in Colombia. This finding warrants active surveillance, as dissemination of these variants could have devastating public health consequences.

Key Clinical Message This case suggests using dual orexin receptor antagonists to treat alcohol use disorder and comorbid sleep disorders may be effective, commencing treatment in withdrawal and continuing it to prevent relapse. Abstract Effective medications for the treatment of alcohol use disorder are limited. This is partially due to the heterogenous nature of the symptomatology associated with alcohol use disorder and the abundance of presenting comorbidities. One common, and often overlooked, symptom that occurs during withdrawal of alcohol use is sleep disruption. Here, we report a case study of a participant with comorbid alcohol use disorder and insomnia. This participant was treated with a dual orexin receptor antagonist, suvorexant (Belsomra®), currently approved to treat insomnia. We demonstrate improvements in alcohol cravings, physical and psychological health, and sleep outcomes with treatment. These data support abundant preclinical and emerging clinical data in this space. The findings from this case report highlight the potential for suvorexant to treat comorbid alcohol use disorder and insomnia with fully powered, randomized controlled trials moving forward.

IntroductionOver the past years, there has been a growing interest in the role of immunotherapy in locally advanced (LA) and recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). High-quality data from prospective trials are lacking for the elderly subpopulation. This systematic review and meta-analysis aims to review the efficacy and safety of immunotherapy in older patients.MethodsA systematic literature search was conducted. Randomized clinical trials providing outcome data on a subgroup of elderly (>65 years old) were available for meta-analysis. Primary outcomes of interest were OS and PFS for efficacy analysis.ResultsSeven studies were included in the systematic review and four in the efficacy analysis. The pooled analysis of OS and PFS showed a consistent benefit (HR 0.78 and 0.91, respectively).ConclusionsImmunotherapy may be an effective and well-tolerated treatment option in the elderly population, but more prospective and randomized data are needed.Systematic Review RegistrationPROSPERO (CRD42022333891).