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Abstract Background Group A streptococci (Strep A) orStreptococcus pyogenes is a major human pathogen causing an estimated 500,000 deaths worldwide each year. Disease can range from mild pharyngitis to more severe infections, such as necrotizing fasciitis, septicemia, and toxic shock syndrome. Untreated, Strep A infection can lead to the serious post streptococcal pathologies of rheumatic fever/rheumatic heart disease and post-streptococcal glomerulonephritis. An effective vaccine against Strep A would have great benefits worldwide. Here, we test two products, J8 and p*17—both peptide derivatives of a highly conserved region in the M protein, in combination with the protein subunit K4S2 of SpyCEP, an IL-8 protease associated with neutrophil chemoattraction. Each peptide is individually conjugated to cross reacting material (CRM197), and the conjugated peptide vaccines are abbreviated as J8-K4S2 or p*17-K4S2. Methods This single-site phase I, two-stage clinical trial in Edmonton, Alberta, Canada, aims to recruit a total of 30 healthy volunteers, aged 18–45 years, without any evidence of pre-existing valvular heart disease. The trial is divided into the initial unblinded safety test dose stage (stage 1) and the randomized, double-blinded, controlled trial stage (stage 2). Stage 1 will recruit 10 volunteers—5 each to receive either J8-K4S2 or p*17-K4S2 in an unblinded, staggered fashion, whereby volunteers are dosed with intentional spacing of at least 2 days in between doses to monitor for any immediate side effects before dosing the next. Once all 5 volunteers have received 3 doses of the first test vaccine, a similar process will follow for the second test vaccine. Once safety is established in stage 1, we will proceed to stage 2, which will recruit 20 volunteers to our 3-arm randomized controlled trial (RCT), receiving either of the trial vaccines, J8-K4S2 or p*17-K4S2, or comparator (rabies) vaccine. All product dosing will be at 0, 3, and 6 weeks. The primary outcome is vaccine safety; the secondary outcome is immunogenicity and comparative analyses of the different vaccine regimens. Discussion This Strep A vaccine clinical trial aims to investigate safety and immunogenicity of two novel conjugated peptide-based vaccines, J8-KS42 and p*17-K4S2. If one or both vaccine products demonstrate favorable primary and secondary outcomes, the product(s) will move into phase II and III studies. Trial registration ClinicalTrials.gov Identifier: NCT04882514. Registered on 2021–05-12, https://clinicaltrials.gov/study/NCT04882514 .

BackgroundThe digitalization of health care organizations is an integral part of a clinician’s daily life, making it vital for health care professionals (HCPs) to understand and effectively use digital tools in hospital settings. However, clinicians often express a lack of preparedness for their digital work environments. Particularly, new clinical end users, encompassing medical and nursing students, seasoned professionals transitioning to new health care environments, and experienced practitioners encountering new health care technologies, face critically intense learning periods, often with a lack of adequate time for learning digital tools, resulting in difficulties in integrating and adopting these digital tools into clinical practice. ObjectiveThis study aims to comprehensively collect advice from experienced HCPs in Switzerland to guide new clinical end users on how to initiate their engagement with health ITs within hospital settings. MethodsWe conducted qualitative interviews with 52 HCPs across Switzerland, representing 24 medical specialties from 14 hospitals. The interviews were transcribed verbatim and analyzed through inductive thematic analysis. Codes were developed iteratively, and themes and aggregated dimensions were refined through collaborative discussions. ResultsTen themes emerged from the interview data, namely (1) digital tool understanding, (2) peer-based learning strategies, (3) experimental learning approaches, (4) knowledge exchange and support, (5) training approaches, (6) proactive innovation, (7) an adaptive technology mindset, (8) critical thinking approaches, (9) dealing with emotions, and (10) empathy and human factors. Consequently, we devised 10 recommendations with specific advice to new clinical end users on how to approach new health care technologies, encompassing the following: take time to get to know and understand the tools you are working with; proactively ask experienced colleagues; simply try it out and practice; know where to get help and information; take sufficient training; embrace curiosity and pursue innovation; maintain an open and adaptable mindset; keep thinking critically and use your knowledge base; overcome your fears, and never lose the human and patient focus. ConclusionsOur study emphasized the importance of comprehensive training and learning approaches for health care technologies based on the advice and recommendations of experienced HCPs based in Swiss hospitals. Moreover, these recommendations have implications for medical educators and clinical instructors, providing advice on effective methods to instruct and support new end users, enabling them to use novel technologies proficiently. Therefore, we advocate for new clinical end users, health care institutions and clinical instructors, academic institutions and medical educators, and regulatory bodies to prioritize effective training and cultivating technological readiness to optimize IT use in health care.

In order to characterize a novel restorative material, knowledge about the toxicological effect on human cells and the physical behavior of a glass ionomer cement (GIC) containing flavonoids was established. The flavonoids apigenin, naringenin, quercetin, and liquiritigenin were manually incorporated into a GIC. In the control group, no incorporation was performed. Two cell culture assays evaluated the toxicity of GICs: SRB and MTT. For both assays, the keratinocyte cell line (HaCaT) was exposed to GIC (n = 3/group) for 24 h. The physical properties of the GICs were evaluated by compressive strength (n = 10), surface roughness (n = 10), and hardness (n = 10) tests. Cell viability by SRB ranged from 103% to 97%. The control revealed a significant decrease in the metabolism of cells (61%) by MTT, while the GIC+apigenin slightly increased the succinic dehydrogenase activity (105%; p > 0.05), also confirmed microscopically. The compressive strength and roughness values were similar among groups, but the hardness increased after the incorporation of naringenin and quercetin into GIC (p < 0.05). The incorporation of flavonoids positively altered the biological and physical properties of the GICs.

Silk sericin, the glue protein binding fibroin fibers together, is present in the Bombyx mori silkworms’ cocoons. In recent years, sericin has gained attention for its wide range of properties and possible opportunities for various applications, as evidenced by the meta-analysis conducted in this review. Sericin extraction methods have evolved over the years to become more efficient and environmentally friendly, preserving its structure. Due to its biocompatibility, biodegradability, anti-inflammatory, antibacterial, antioxidant, UV-protective, anti-tyrosinase, anti-aging, and anti-cancer properties, sericin is increasingly used in biomedical fields like drug delivery, tissue engineering, and serum-free cell culture media. Beyond healthcare, sericin shows promise in industries such as textiles, cosmetics, and food packaging. This review aims to highlight recent advancements in sericin extraction, research, and applications, while also summarizing key findings from earlier studies.

Background and Objectives: The Albumin-to-Alkaline Phosphatase ratio (AAPR) is an easily applicable and cost-effective marker investigated as an outcome predictor in solid cancers. Preliminary evidence in breast cancer suggests that a low AAPR correlates with a poor response to neoadjuvant chemotherapy (NAC) in primary tumors. However, data regarding the axillary response are lacking. This study aims to evaluate whether the AAPR can predict the axillary response in initially nodal-positive (cN+) breast cancer patients undergoing NAC. Materials and Methods: Clinical and biochemical variables of cN+ breast cancer patients undergoing NAC were collected. Pre-NAC albumin and alkaline phosphatase serum values were utilized in the AAPR calculation. Fisher’s exact test was performed to identify differences between the two groups of patients (high and low AAPR according to the cut-off reported in the literature). The primary outcome was the nodal pathologic complete response (pCR) rate in the two groups of patients. Results: Nodal pCR was achieved in 20/45 (44.4%) patients. A total of 36/45 (80%) patients had an AAPR > 0.583. Among patient and tumor characteristics, the only statistically significant difference between the two groups was the axillary pCR between the low and high AAPR groups (p-value = 0.03, OR = 0.129, 95% CI = 0.00–0.835). Conclusions: This pilot study suggests that the pre-treatment AAPR might be an early predictor of axillary response in cN+ breast cancer patients undergoing NAC. This result justifies further investigation in larger prospective trials to validate this finding.

The increased proportion of women in the workplace and the labor force aging have been demanding investigations of the link between menopause and occupational health issues, especially in healthcare settings. Evidence on the association between menopause and occupational burnout in healthcare settings is still inconclusive. Therefore, we aimed to evaluate the association between menopause and burnout among clinical and non-clinical workers in different occupational health environments. A multi-center, cross-sectional study, applying the Oldenburg Burnout Inventory (OBI) was conducted from September 2021 to March 2023 in University Medical Center (UMC) hospitals in Astana, Kazakhstan. The study involved 125 physicians and nurses and 82 non-clinical administrative and service staff. We found that 63.9% of respondents had disengagement and 61.7% had exhaustion. The affiliated clinical setting was associated with disengagement (p = 0.034), with the highest prevalence among employees in surgical departments (76.9%), while a higher prevalence of exhaustion was found in individuals with different work experience (p = 0.023) and among those who were dissatisfied with their work environment (74.3%). While burnout was identified in almost two-thirds of respondents, the self-reported menopause status of participants was not significantly related to either disengagement (p = 0.34) or exhaustion (p = 0.73), even though a higher prevalence of both was revealed among the postmenopausal group. We propose that healthcare management should understand the importance of burnout among postmenopausal healthcare workers and facilitate open communication and a supportive work environment.

Abstract Background Integration of symptom and palliative care for people with advanced cancer is established in many tumour types, but its role in people with hepatocellular carcinoma (HCC) has not been clearly defined. This study aims to evaluate the clinical and cost effectiveness of an intervention involving a suite of strategies designed to assess and treat palliative care symptoms and needs in adult outpatients with HCC attending four New South Wales (NSW) metropolitan tertiary hospitals. Methods This trial will use a pragmatic cluster-based randomised-controlled design, with ambulatory HCC services as the clusters. HCC patients will be recruited if they have Barcelona Clinical Liver Cancer (BCLC) stage A disease with active tumour or a current or prior diagnosis of BCLC stage B or C disease regardless of tumour activity. Patients with BCLC stage D disease will be excluded as palliative care is the standard of care (SOC) in this group. Cluster sites will be randomised to the study intervention or control where patients are managed according to SOC. All participants will complete the liver-specific Edmonton Symptom Assessment Scale (ESAS) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire at regular ambulatory clinic appointments. At intervention sites, patients scoring ≥ 5 on any liver-specific ESAS symptom will be referred to palliative care physicians for consultation. The primary clinical outcome will be improvement in all symptoms scored ≥ 5 on the liver-specific ESAS by 50% within 3 months and the primary implementation outcome will recording the liver-specific ESAS in ≥ 80% of all participants attending clinic appointments. Caregivers of patients enrolled in the trial will be invited to perform Carer Support Needs Assessment Tool at each appointment. Discussion This trial will inform if earlier palliative care involvement significantly reduces the symptom burden associated with HCC. If found to be effective, earlier implementation of palliative care consultation should be included in HCC treatment guidelines. Trial registration ACTRN12623000010695. Registered on September 1, 2023.

Background: Despite the high frequency of tinnitus and its impact on wellbeing, little is known about its economic burden, and, to our knowledge, no data are available on out-of-pocket (OOP) expenses. Methods: In 2022, a survey was conducted on OOP costs of tinnitus. We enrolled 679 participants with slight, moderate, and severe tinnitus in Italy, United Kingdom, Netherlands, Germany, and Spain. We estimated annual OOP expenses for tinnitus-related healthcare visits, treatments, medications, and alternative medicine practices. Prevalence of tinnitus in the general population, obtained from a representative survey we conducted in Europe in 2017–2018, was used to generalize costs for people with any tinnitus at the national level. Results: OOP expenses were 368€ (95% confidence intervals [CI], 78€–690€), 728€ (95% CI, 316€–1,288€), and 1,492€ (95% CI, 760€–2,688€) for slight, moderate, and severe tinnitus, respectively, with annual expenditure of 565€ for people with any tinnitus: 209€ for healthcare visits; 93€ for treatments; 16€ for drugs; 64€ for hearing supporting systems; and 183€ for acupuncture, homeopathy, and osteopathy. Individuals with slight, moderate, and severe tinnitus expressed a willingness to invest 1.6, 4.3, and 7.0 times their monthly income, respectively, to achieve complete relief from tinnitus. Conclusion: This study offers for the first time insights into the OOP expenses incurred by individuals with tinnitus. OOP expenses exhibited substantial variations based on severity status, accounting for more than 17 billion € in the countries considered. In terms of financial burden, these findings align tinnitus to the recognized leading disabilities, including back pain and migraine.

Abstract Loss-of-function mutations in MECP2 are associated to Rett syndrome (RTT), a severe neurodevelopmental disease. Mainly working as a transcriptional regulator, MeCP2 absence leads to gene expression perturbations resulting in deficits of synaptic function and neuronal activity. In addition, RTT patients and mouse models suffer from a complex metabolic syndrome, suggesting that related cellular pathways might contribute to neuropathogenesis. Along this line, autophagy is critical in sustaining developing neuron homeostasis by breaking down dysfunctional proteins, lipids, and organelles. Here, we investigated the autophagic pathway in RTT and found reduced content of autophagic vacuoles in Mecp2 knock-out neurons. This correlates with defective lipidation of LC3B, probably caused by a deficiency of the autophagic membrane lipid phosphatidylethanolamine. The administration of the autophagy inducer trehalose recovers LC3B lipidation, autophagosomes content in knock-out neurons, and ameliorates their morphology, neuronal activity and synaptic ultrastructure. Moreover, we provide evidence for attenuation of motor and exploratory impairment in Mecp2 knock-out mice upon trehalose administration. Overall, our findings open new perspectives for neurodevelopmental disorders therapies based on the concept of autophagy modulation.

Abstract Background Patient and Public Involvement (PPI) is increasingly recognized as an essential aspect of clinical research, particularly for ensuring relevancy and impact of research to those most affected. This study addresses the gap in involving older patients, particularly nursing home residents, in the research process by exploring motivations, expectations, and experiences of nursing home residents in Bremen, Germany, involved in PPI for developing a clinical trial on polypharmacy. Methods Two Patient Advisory Boards (PABs) were established in nursing homes as part of the INVOLVE-Clin project. A Patient Advocate (PA) facilitated communication between nursing home residents and researchers. A qualitative case study approach was employed, involving semi-structured interviews and group discussions with nursing home residents and researchers. Data was analyzed using structured qualitative content analysis. Results The study found varied motivations and expectations between nursing home residents and researchers. Nursing home residents valued the social interaction and the opportunity to voice their health concerns, while researchers aimed to incorporate patients’ perspectives into study design. The PA was considered crucial in facilitating communication between nursing home residents and researchers. Challenges included the complexity of the study topic and the need for methodological adjustments to suit nursing home residents´ cognitive abilities. Generally, PAB participation was experienced to provide mental stimulation and increased confidence among nursing home residents in discussing their medication management. The PAB’s influence led to the decision not to conduct a polypharmacy study. Discussion The findings underscore the importance of flexible approaches to PPI, particularly when involving older nursing home residents. Methodological adjustments, such as tailoring content and structure of PABs, and the inclusion of additional boards for diverse perspectives, are vital for effective involvement. The study also highlights the need for ongoing innovation in PPI methods to ensure meaningful engagement of older patients in clinical research. Conclusion This study contributes essential insights into the practical implementation of PPI with nursing home residents, highlighting the need for patient-centric approaches that recognize their unique challenges and contributions. These findings are critical for shaping scientifically robust but also socially relevant and impactful research, especially in an aging society.

Background: Chronic obstructive pulmonary disease (COPD) is linked to altered nutritional status due to increased catabolism, leading to muscle mass loss. This study aims to identify and map available evidence regarding multidisciplinary interventions focused on prevention, diagnosis and nutrition education, as well as the role of diet, to prevent and manage malnutrition in patients with COPD. Methods: A scoping review was conducted using the Cochrane, PubMed/Medline, CINAHL, Embase, Scopus, and Web of Science databases. This study adhered to the Arksey and O’Malley framework and JBI methodology. Results: Of the 1761 records identified, 15 were included. Evidence suggests that the Malnutrition Universal Screening Tool and Mini Nutritional Assessment are the most suitable screening scale. Guidelines have highlighted that personalized nutritional counseling is a very common intervention as it allows for a consideration of all physical, psychological, and social aspects of the patient. Conclusions: The role of healthcare professionals is crucial in the early identification of nutrition-related issues and in educating patients about the prevention and management of malnutrition, both in hospital and community settings. Key aspects include early malnutrition detection, personalized counseling and patient education, and a multidisciplinary approach. These findings provide a foundation for developing of targeted patient educational initiatives to improve the nutritional management of COPD patients.

AbstractSocial prescribing (SP) embodies a comprehensive approach to addressing the social determinants of health. Access to Resources in the Community (ARC) is an innovative SP program offering bilingual services that involves a single point of entry for health and social needs and introduces practice changes to assist primary care providers in engaging patients, along with a nonclinical lay navigator who supports patients in accessing relevant community resources. The ARC team has created a SP toolkit offering practical guidance for setting up, implementing, monitoring the progress of and evaluating SP programs. The four ARC guides can be easily customized for application in diverse practice and research settings.

RésuméLa prescription sociale est une approche globale qui agit sur les déterminants sociaux de la santé. « Accès aux ressources communautaires » (ARC) est un programme de prescription sociale novateur aux services bilingues qui offre un point d’entrée unique pour les besoins en matière de santé et de services sociaux et qui permet d’apporter des changements dans les lieux de pratique dans le but d’aider les fournisseurs de soins primaires à mobiliser leurs patients, grâce à un intervenant-pivot non clinicien qui aide les patients à accéder aux ressources communautaires pertinentes. L’équipe du programme ARC a créé une trousse d’outils de prescription sociale qui contient des conseils pratiques sur l’établissement, la mise en oeuvre et l’évaluation de programmes de prescription sociale ainsi que sur le suivi des progrès. Les quatre guides du programme ARC sont facilement adaptables à divers milieux de pratique et de recherche.

Despite the advent of robotics and the decreasing rate of complications after radical cystectomy, several factors are renowned to impair the early outcomes of this procedure. The aim of this paper is to provide a multivariate analysis (MVA) of patient and surgical procedure-related variables likely to affect postoperative course and 30-day complication rate. Fifty-five robotic-assisted radical cystectomies (RARCs) performed at a single center from July 2021 to March 2023 were enrolled. Baseline demographics, comorbidities, and intraoperative and postoperative data were collected. Uni- and multivariate analyses were performed to evaluate the relationship with Clavien ≥ II complications arising within 30 days of surgery. A postoperative Clavien ≥ II complication was evident in 15 patients (28%), whereas Clavien ≥ III occurred only in 5 (9%). At MVA, the only independent predictor of Clavien ≥ II complications was a prior neoadjuvant chemotherapy (OR 5.6; 95% CI 1.22–25.3, p = 0.026). Recognized the small sample size, patients who received a prior NAC should deserve special care within the postoperative course.

The aim of this study is to perform a bibliometric and demographic analysis of the 10 most productive researchers over the past 7 years in relation to the selection of key topics in andrology. We conducted a bibliometric analysis in December 2023, using Scopus Researcher Discovery. Seven major andrological topics were identified: erectile dysfunction (T1), premature ejaculation (T2), male infertility (T3), Peyronie’s disease (T4), male hypogonadism (T5), priapism (T6), and low sexual desire (T7). A total of 10 researchers per topic were identified (51 unique authors). Most were urologists (65%) or endocrinologists (23%). Most authors belonged to centers in the USA (35.7%) and Italy (32.9%). The majority of authors were male (77.1%) and over 40 years old (83.3% of authors of known age). The mean (standard deviation (SD)) H-index of the 10 top researchers was 42.6 (24.6), ranging from 6 to 119. Male infertility was the topic with the most articles (1110) written by the top 10 researchers and the most cited (20,585). Erectile dysfunction was the second topic for articles (678) and third for citations after male hypogonadism (6046 vs. 11,384). The mean (SD) impact factor of the journals in which the andrological articles were published varied from 3.5 (0.53) for premature ejaculation to 5.33 (1.85) for hypogonadism.

Rheumatoid arthritis and osteoarthritis both affect the articular cartilage, and are characterized by signs and symptoms that can affect the functions of the human body. This cross-sectional observational study evaluated electromyographic activity in the masseter and temporalis muscles, molar bite force, and mandibular mobility in adult women with rheumatoid arthritis or osteoarthritis. A total of 42 women were distributed into 3 groups: rheumatoid arthritis group (ARG, n=14); osteoarthritis group (OAG, n=14); and a healthy control group (CG, n=14). Electromyography was used to evaluate mandibular tasks at rest, right and left laterality, protrusion, and dental clenching during maximum voluntary contraction, with and without parafilm, and a dynamometer was used to analyse the right and left molar bite forces. A digital caliper was used to measure the range of mandibular movement for maximum mouth opening, right and left laterality, and protrusion. Statistical analyses were performed, including analysis of variance and Tukey’s test (P

Abstract Background For more than a decade, the Patient-Centered Medical Home model has been a guiding vision for the modernization of primary care systems. In Canada, Ontario’s Family Health Teams (FHTs) were designed in the mid-2000s with the medical home model in mind. These primary care clinics aim to provide accessible, comprehensive, and person-centered primary care services to communities across Ontario. Their services typically include mental health care for people experiencing common mental disorders, such as depression and anxiety disorders. It remains unclear, however, whether the mental health care delivered within FHTs is consistent with person-centered care approaches. In the current study, we aimed to explore the perspectives of FHT providers on the care delivered to people with common mental disorders to determine whether, and to what extent, they believed this care was person-centered. Methods We conducted a qualitative grounded theory study involving interviews with 65 health professionals and administrators from 18 FHTs across Ontario. Transcripts were coded using a three-step process of initial, focused, and axial coding that mixed inductive and deductive approaches informed by sensitizing concepts on person-centeredness. Results Practices and challenges associated with the delivery of mental health care in a person-centered way were captured by several themes regrouped into five domains: (1) patient as unique person, (2) patient-provider relationship, (3) sharing power and responsibility, (4) connecting to family and community, and (5) creating person-centered care environments. FHT providers perceived that they delivered person-centered care by delivering mental health care that was responsive, flexible, and consistent with biopsychosocial approaches. They emphasized the importance of creating long-lasting relationships with patients grounded in empathy and trust. Their challenges included being able to ensure continuity of care, adequately prioritizing patients’ mental health issues, and meaningfully engaging patients and families as partners in care. Conclusions Our findings suggest that FHT providers have adopted a range of person-centered practices for people with common mental disorders. However, greater attention to practices such as shared decision making, supporting self-management, and involving families in care would strengthen person-centeredness and bring teams closer to the Patient-Centered Medical Home vision.

Abstract Extracellularly released molecular inflammasome assemblies -ASC specks- cross-seed Aβ amyloid in Alzheimer’s disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using super-resolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Recombinant ASC specks accelerated SAA fibril formation and mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain (PYD). In a murine model of inflammatory AA amyloidosis, splenic amyloid load was conspicuously decreased in Pycard −/− mice which lack ASC. Treatment with anti-ASCPYD antibodies decreased amyloid loads in wild-type mice suffering from AA amyloidosis. The prevalence of natural anti-ASC IgG (−logEC50 ≥ 2) in 19,334 hospital patients was

Pulmonary sclerosing pneumocytoma (PSP) is a quite rare tumor outside Eastern countries. This rarity, together with a wide histological appearance, makes its correct identification a diagnostic challenge for pathologists under the microscope. Historically, PSP was considered a vascular-derived neoplasm (sclerosing hemangioma), but its immunohistochemical profile clearly supports its epithelial origin. No specific molecular fingerprint has been detected so far. This short narrative revisits the clinical, histological, immunohistochemical, and molecular aspects of this tumor, paying special attention to some controversial points still not well clarified, i.e., clinical aggressiveness and metastatic spread, multifocality, the supposed development of sarcomatoid change in a subset of cases, and tumor associations with lung adenocarcinoma and/or well-differentiated neuroendocrine hyperplasia/tumors. The specific diagnostic difficulties on fine-needle aspiration cytology/biopsy and perioperative frozen sections are also highlighted. Finally, a teaching case of tumor concurrence of lung adenocarcinoma, neuroendocrine lesions, and PSP, paradigmatic of tumor association in this context, is also presented.

Background: In this study, we hypothesized that safety footwear (SF) impacts gait patterns, potentially contributing to the podiatric symptoms reported by workers. The purpose of this work was to compare the gait analyses of workers wearing SF and sneakers using inertial sensors while also examining the occurrence of foot problems. Methods: A consecutive cohort of workers from different occupational sectors who wore SF during their work shifts were prospectively assessed through a gait analysis. The gait analysis was conducted under two conditions: first, while wearing SF, and second, while wearing sneakers. In both conditions, inertial sensors were used (Wiva® MOB). Participants also underwent a podiatric physical examination to evaluate foot problems. Results: This study shows that SF resulted in a worsening gait pattern compared to sneakers in both genders. The impact was particularly pronounced in female participants, resulting in a significant decline in walking speed and cadence. Discomfort was reported by 83.3% of participants, with a higher prevalence in females (46.6% vs. 36.6%). The SF group exhibited an elevated prevalence of foot problems, with no significant gender variations. It seems that foot problems are more likely to occur when a foot deformity, such as flat or cavus foot or hallux valgus, is present. Conclusions: This study suggests that SF may contribute to the reported podiatric symptoms among workers. Certain footwear characteristics, including weight, mis-fit, and inadequate design, may be factors associated with footwear discomfort and adverse gait patterns, potentially leading to increased foot problems among workers.

Abstract Background In recent years, significant efforts have been directed towards the research and development of disease-modifying therapies for dementia. These drugs focus on prodromal (mild cognitive impairment, MCI) and/or early stages of Alzheimer’s disease (AD). Literature evidence indicates that a considerable proportion of individuals with MCI do not progress to dementia. Identifying individuals at higher risk of developing dementia is essential for appropriate management, including the prescription of new disease-modifying therapies expected to become available in clinical practice in the near future. Methods The ongoing INTERCEPTOR study is a multicenter, longitudinal, interventional, non-therapeutic cohort study designed to enroll 500 individuals with MCI aged 50–85 years. The primary aim is to identify a biomarker or a set of biomarkers able to accurately predict the conversion from MCI to AD dementia within 3 years of follow-up. The biomarkers investigated in this study are neuropsychological tests (mini-mental state examination (MMSE) and delayed free recall), brain glucose metabolism ([18F]FDG-PET), MRI volumetry of the hippocampus, EEG brain connectivity, cerebrospinal fluid (CSF) markers (p-tau, t-tau, Aβ1-42, Aβ1-42/1–40 ratio, Aβ1-42/p-Tau ratio) and APOE genotype. The baseline visit includes a full cognitive and neuropsychological evaluation, as well as the collection of clinical and socio-demographic information. Prognostic models will be developed using Cox regression, incorporating individual characteristics and biomarkers through stepwise selection. Model performance will be evaluated in terms of discrimination and calibration and subjected to internal validation using the bootstrapping procedure. The final model will be visually represented as a nomogram. Discussion This paper contains a detailed description of the statistical analysis plan to ensure the reproducibility and transparency of the analysis. The prognostic model developed in this study aims to identify the population with MCI at higher risk of developing AD dementia, potentially eligible for drug prescriptions. The nomogram could provide a valuable tool for clinicians for risk stratification and early treatment decisions. Trial registration ClinicalTrials.gov NCT03834402. Registered on February 8, 2019

Abstract Background Skeletal Stem Cells (SSCs) are required for skeletal development, homeostasis, and repair. The perspective of their wide application in regenerative medicine approaches has supported research in this field, even though so far results in the clinic have not reached expectations, possibly due also to partial knowledge of intrinsic, potentially actionable SSC regulatory factors. Among them, the pleiotropic cytokine RANKL, with essential roles also in bone biology, is a candidate deserving deep investigation. Methods To dissect the role of the RANKL cytokine in SSC biology, we performed ex vivo characterization of SSCs and downstream progenitors (SSPCs) in mice lacking Rankl (Rankl −/− ) by means of cytofluorimetric sorting and analysis of SSC populations from different skeletal compartments, gene expression analysis, and in vitro osteogenic differentiation. In addition, we assessed the effect of the pharmacological treatment with the anti-RANKL blocking antibody Denosumab (approved for therapy in patients with pathological bone loss) on the osteogenic potential of bone marrow-derived stromal cells from human healthy subjects (hBMSCs). Results We found that, regardless of the ossification type of bone, osteochondral SSCs had a higher frequency and impaired differentiation along the osteochondrogenic lineage in Rankl −/− mice as compared to wild-type. Rankl −/− mice also had increased frequency of committed osteochondrogenic and adipogenic progenitor cells deriving from perivascular SSCs. These changes were not due to the peculiar bone phenotype of increased density caused by lack of osteoclast resorption (defined osteopetrosis); indeed, they were not found in another osteopetrotic mouse model, i.e., the oc/oc mouse, and were therefore not due to osteopetrosis per se. In addition, Rankl −/− SSCs and primary osteoblasts showed reduced mineralization capacity. Of note, hBMSCs treated in vitro with Denosumab had reduced osteogenic capacity compared to control cultures. Conclusions We provide for the first time the characterization of SSPCs from mouse models of severe recessive osteopetrosis. We demonstrate that Rankl genetic deficiency in murine SSCs and functional blockade in hBMSCs reduce their osteogenic potential. Therefore, we propose that RANKL is an important regulatory factor of SSC features with translational relevance.

The occurrence of carbapenemases encoding genes in Providencia rettgeri is a critical public health concern since this species has intrinsic resistance to several antimicrobials, including polymyxins. The identification of this multidrug-resistant (MDR) pathogen outside the hospital setting has become increasingly frequent, and raises an alert for the global health agencies, as they indicate a possible spread of such pathogens. Herein, we described three MDR P. rettgeri isolates carrying a diversity of antimicrobial resistance genes (ARGs) isolated from stool samples of swine and bovine in Brazil. Molecular analysis revealed that all isolates belonged to the same clone. The whole genome sequencing (WGS) of a representative isolate (PVR-188) was performed by MiSeq Illumina® platform, while the assembling and annotation was achieved using SPAdes and Prooka, respectively. The WGS analyses indicated the presence of ARGs that confer resistance to β-lactams (blaNDM-1, blaCTX-M-2), quinolones (qnrD1), aminoglycosides (aadA2, aadA1, aph(3′)-Via), phenicol (catB2), sulfonamides (sul1, sul2), and trimethoprim (dfrA12, dfrA1). The presence of three plasmid replicons (Col3M, IncQ1, and IncT) was detected, but no phage sequences were found. The phylogenetic analyses confirmed the genomic relationship of the PVR-188 with P. rettgeri isolates recovered from animals and humans in the USA and Malaysia. In conclusion, we report the occurrence of MDR P. rettgeri clone colonizing the gut microbiota of food-producing animals in Brazil, revealing the spread of this pathogen beyond hospital boundaries.

ObjectivesThis study aims to describe the impact of COVID-19 on Orthopedic and Trauma surgical activity in a single level-I trauma center in Northern Italy during the lockdown period. We proposed comparing surgical procedures performed during the outbreak and in the same period the previous year.MethodsIn this single-center retrospective epidemiological cohort study, the “lockdown cohort” of patients who were treated from March 1st to May 24th, 2020, was compared to the “control cohort” who received treatment during the same period in 2019. The primary outcome was to evaluate the differences between the lockdown and control cohorts regarding surgical volumes. The secondary outcome was to evaluate any differences in the type of surgical procedures performed in the two cohorts in the elective and emergency setting.ResultsOrthopedic surgical activity has suffered a global reduction of 72.4% during the lockdown period (from 36 ± 6.1 to 10.7 ± 8.4 per week; p

BackgroundGenetic and genomic literacy of health professionals is of utmost importance to realize the full potential of personalized medicine. As part of a European Union project, we piloted an e-learning course on oncogenomics, primarily targeted to physicians, and we assessed both its effectiveness and users’ satisfaction.MethodsThe course materials were developed in English according to the Problem-Based Learning method. Learning objectives, covering the basic principles of genetics and the OMICS technologies applied to oncology, were defined based on previously identified core competencies. We used a pre-test vs. post-test study design to assess knowledge improvements. Performance results by demographic and professional characteristics of participants were analyzed using univariate or multivariate statistical methods.ResultsOverall, 346 Italian professionals (61% physicians, 39% biologists) successfully completed the course. Their average post-test score was almost 19% higher than the pre-test (71.6% vs. 52.9%), with no significant differences by sex. Older age (>50 years) and southern area of residence were both correlated with higher gains. The average proportion of correct answers in the final certification test after three attempts was 85% (69% at first attempt), with some differences across professional categories. Methodology, quality of content and usability of the e-learning platform were all highly rated via satisfaction questionnaire (average scores between 4 and 5, scale 1 to 5).ConclusionThe pilot phase confirmed the suitability of the e-learning as a cost-effective method to improve oncogenomic literacy of health professionals. Translation into natural languages and accreditation by European or country-specific Continuing Medical Education systems will be the main incentives for wider dissemination.

Editorial

Background: Sensitivity to ionizing radiation differs between individuals, but there is a limited understanding of the biological mechanisms that account for these variations. One example of such mechanisms are the mutations in the ATM (mutated ataxia telangiectasia) gene, that cause the rare recessively inherited disease Ataxia telangiectasia (AT). Hallmark features include chromosomal instability and increased sensitivity to ionizing radiation (IR). Objectives: To deepen the molecular understanding of radiosensitivity and to identify potential new markers to predict it, human ATM-mutated and proficient cells were compared on a proteomic level. Design: In this study, we analyzed 3 cell lines from AT patients, with varying radiosensitivity, and 2 cell lines from healthy volunteers, 24 hours and 72 hours post-10 Gy irradiation Methods: We used label-free mass spectrometry to identify differences in signaling pathways after irradiation in normal and radiosensitive individuals. Cell viability was initially determined by water soluble tetrazolium (WST) assay and DNA damage response was analyzed with 53BP1 repair foci formation along with KRAB-associated protein 1 (KAP1) phosphorylation. Results: Proteomic analysis identified 4028 proteins, which were used in subsequent in silico pathway enrichment analysis to predict affected biological pathways post-IR. In AT cells, networks were heterogeneous at both time points with no common pathway identified. Mitotic cell cycle progress was the most prominent pathway altered after IR in cells from healthy donors. In particular, components of the chromosome passenger complex (INCENP and CDCA8) were significantly downregulated after 72 hours. This could also be verified at the mRNA level. Conclusion: Altogether, the most striking result was that proteins forming the chromosome passenger complex were downregulated after radiation exposure in healthy normosensitive control cells, but not in radiosensitive ATM-deficient cells. Thus, mitosis-associated proteins form an interesting compound to gain insights into the development and prediction of radiosensitivity.

Introduction A proportion of people develop Long Covid after acute COVID-19, but with most studies concentrated in high-income countries (HICs), the global burden is largely unknown. Our study aims to characterise long-term COVID-19 sequelae in populations globally and compare the prevalence of reported symptoms in HICs and low-income and middle-income countries (LMICs).Methods A prospective, observational study in 17 countries in Africa, Asia, Europe and South America, including adults with confirmed COVID-19 assessed at 2 to

Abstract Lentiviral vectors (LV) are efficient vehicles for in vivo gene delivery to the liver. LV integration into the chromatin of target cells ensures their transmission upon proliferation, thus allowing potentially life-long gene therapy following a single administration, even to young individuals. The glycoprotein of the vesicular stomatitis virus (VSV.G) is widely used to pseudotype LV, as it confers broad tropism and high stability. The baculovirus-derived GP64 envelope protein has been proposed as an alternative for in vivo liver-directed gene therapy. Here, we perform a detailed comparison of VSV.G- and GP64-pseudotyped LV in vitro and in vivo. We report that VSV.G-LV transduced hepatocytes better than GP64-LV, however the latter showed improved transduction of liver sinusoidal endothelial cells (LSEC). Combining GP64-pseudotyping with the high surface content of the phagocytosis inhibitor CD47 further enhanced LSEC transduction. Coagulation factor VIII (FVIII), the gene mutated in hemophilia A, is naturally expressed by LSEC, thus we exploited GP64-LV to deliver a FVIII transgene under the control of the endogenous FVIII promoter and achieved therapeutic amounts of FVIII and correction of hemophilia A mice.

This preclinical proof-of-concept study aimed to evaluate the effectiveness of secretome therapy in diabetic mice with pressure ulcers. We utilized a custom-made hyaluronic acid (HA)-based porous sponge, which was rehydrated either with normal culture medium or secretome derived from human mesenchymal stromal cells (MSCs) to achieve a hydrogel consistency. Following application onto skin ulcers, both the hydrogel-only and the hydrogel + secretome combination accelerated wound closure compared to the vehicle group. Notably, the presence of secretome significantly enhanced the healing effect of the hydrogel, as evidenced by a thicker epidermis and increased revascularization of the healed area compared to the vehicle group. Notably, molecular analysis of healed skin revealed significant downregulation of genes involved in delayed wound healing and abnormal inflammatory response in ulcers treated with the hydrogel + secretome combination, compared to those treated with the hydrogel only. Additionally, we found no significant differences in therapeutic outcomes when comparing the use of secretome from fetal dermal MSCs to that from umbilical cord MSCs. This observation is supported by the proteomic profile of the two secretomes, which suggests a shared molecular signature responsible of the observed therapeutic effects.

This cross-sectional study examined the lower limb balance, ankle dorsiflexion, orofacial tissue pressure, and occlusal strength of rugby players. Twenty-six participants were divided into groups: rugby players (n ​= ​13) and healthy sedentary adults (n ​= ​13). Participants underwent an analysis of lower limb balance using a composite score (Y-Balance Test). Ankle dorsiflexion was measured using the Lunge Test. The Iowa Oral Performance Instrument was employed to measure orofacial tissue pressure. Bite force was measured with a dynamometer, and T-Scan assessed occlusal contact distribution. Data were analyzed using the t-test (p ​

Background: Sleep is a complex phenomenon that affects several aspects of life, including cognitive functioning, emotional regulation, and overall well-being. Sleep disturbances, especially during adolescence, can negatively impact emotional regulation, making it a critical factor in targeting psychopathology. Methods: This study explores the interplay between emotional dysregulation (ED) and sleep patterns in a sample of 90 adolescent patients by means of self- and parent-rated clinical measures. Results: Our findings reveal a bidirectional relationship between ED and sleep problems. Adolescents with higher affective instability experience poorer sleep quality, while those with worse sleep quality exhibit higher internalizing problems. Additionally, emotional reactivity is associated with disrupted circadian rhythms. Conclusions: These results emphasize the significance of addressing sleep problems in the context of psychopathology treatment, potentially leading to improved outcomes. Further research is needed to determine the most effective treatment strategies, including nonpharmacological and pharmacological interventions. Understanding the intricate relationship between sleep problems and emotion regulation offers insights for more targeted and effective treatment approaches for youths struggling with ED.

Abstract Background Persistent pain is a common yet debilitating complication after breast cancer surgery. Given the pervasive effects of this pain disorder on the patient and healthcare system, post-mastectomy pain syndrome (PMPS) is becoming a larger population health problem, especially as the prognosis and survivorship of breast cancer increases. Interventions that prevent persistent pain after breast surgery are needed to improve the quality of life of breast cancer survivors. An intraoperative intravenous lidocaine infusion has emerged as a potential intervention to decrease the incidence of PMPS. We aim to determine the definitive effects of this intervention in patients undergoing breast cancer surgery. Methods PLAN will be a multicenter, parallel-group, blinded, 1:1 randomized, placebo-controlled trial of 1,602 patients undergoing breast cancer surgery. Adult patients scheduled for a lumpectomy or mastectomy will be randomized to receive an intravenous 2% lidocaine bolus of 1.5 mg/kg with induction of anesthesia, followed by a 2.0 mg/kg/h infusion until the end of surgery, or placebo solution (normal saline) at the same volume. The primary outcome will be the incidence of persistent pain at 3 months. Secondary outcomes include the incidence of pain and opioid consumption at 1 h, 1–3 days, and 12 months after surgery, as well as emotional, physical, and functional parameters, and cost-effectiveness. Discussion This trial aims to provide definitive evidence on an intervention that could potentially prevent persistent pain after breast cancer surgery. If this trial is successful, lidocaine infusion would be integrated as standard of care in breast cancer management. This inexpensive, widely available, and easily administered intervention has the potential to reduce pain and suffering in an already afflicted patient population, decrease the substantial costs of chronic pain management, potentially decrease opioid use, and improve the quality of life in patients. Trial registration This trial has been registered on clinicaltrials.gov (NCT04874038, Dr. James Khan. Date of registration: May 5, 2021).

Abstract Background Action on the social determinants of health is important to strengthen primary health care and promote access among underserved populations. We report on findings from stakeholder consultations undertaken at one of the Canadian sites of the Innovative Models Promoting Access-to-Care Transformation (IMPACT) program, as part of the development of a best practice intervention to improve access to primary health care. The overarching objective of this qualitative study was to understand the processes, barriers, and facilitators to connect patients to health enabling community resources (HERs) to inform a patient navigation model situated in primary care. Methods Focus groups and interviews were conducted with primary care physicians, and community health and social service providers to understand their experiences in supporting patients in reaching HERs. Current gaps in access to primary health care and the potential of patient navigation were also explored. We applied Levesque et al., (2013) access framework to code the data and four themes emerged: (1) Approachability and Ability to Perceive, (2) Acceptability and Ability to Seek, (3) Availability and Accommodation, and Ability to Reach, and (4) Appropriateness. Results Determinants of access included patient and provider awareness of HERs, the nature of the patient-provider relationship, funding of HERs, integration of primary and community care services, and continuity of information. Participants’ perspectives about the potential scope and role of a patient navigator provided valuable insight for the development of the Access to Resources in the Community (ARC) navigation model and how it could be embedded in a primary care setting. Conclusion Additional consultation with key stakeholders in the health region is needed to gain a broader understanding of the challenges in caring for primary care patients with social barriers and how to support them in accessing community-based primary health care to inform the design of the ARC intervention.

Abstract Background Dyspepsia is a commonly encountered clinical condition in Dutch general practice, which is often treated through the prescription of acid-reducing medication (ARM). However, recent studies indicate that the majority of chronic ARM users lack an indication for their use and that their long-term use is associated with adverse outcomes. We developed a patient-focussed educational intervention aiming to reduce low-value (chronic) use of ARM. Methods We conducted a randomized controlled study, and evaluated its effect on the low-value chronic prescription of ARM using data from a subset (n = 26) of practices from the Nivel Primary Care Database. The intervention involved distributing an educational waiting room posters and flyers informing both patients and general practitioners (GPs) regarding the appropriate indications for prescription of an ARM for dyspepsia, which also referred to an online decision aid. The interventions’ effect was evaluated through calculation of the odds ratio of a patient receiving a low-value chronic ARM prescription over the second half of 2021 and 2022 (i.e. pre-intervention vs. post-intervention). Results In both the control and intervention groups, the proportion of patients receiving chronic low-value ARM prescriptions slightly increased. In the control group, it decreased from 50.3% in 2021 to 49.7% in 2022, and in the intervention group it increased from 51.3% in 2021 to 53.1% in 2022. Subsequent statistical analysis revealed no significant difference in low-value chronic prescriptions between the control and intervention groups (Odds ratio: 1.11 [0.84–1.47], p > 0.05). Conclusion Our educational intervention did not result in a change in the low-value chronic prescription of ARM; approximately half of the patients of the intervention and control still received low-value chronic ARM prescriptions. The absence of effect might be explained by selection bias of participating practices, awareness on the topic of chronic AMR prescriptions and the relative low proportion of low-value chronic ARM prescribing in the intervention as well as the control group compared to an assessment conducted two years prior. Trial registration 10/31/2023 NCT06108817.

Fiberoptic bronchoscopy (FBO) has diagnostic or therapeutic purposes but can cause respiratory deterioration, particularly in patients with pre-existing acute respiratory failure (ARF). Non-invasive ventilation (NIV) and high-flow nasal cannula oxygen therapy (HFNC) are used as respiratory support for ARF as well as to prevent significant oxygen deterioration during FBO. The combined use of NIV and early therapeutic FBO to clear retained abundant infected secretions from the airways may be an alternative to intubation and invasive mechanical ventilation (IMV), but no data exist on the combined use of FBO and HFNC. A 78-year-old male patient with ARF secondary to chronic obstructive pulmonary disease (COPD) exacerbation and pneumonia was admitted to our non-intensive geriatric ward. After an initial improvement, his respiratory conditions worsened. While continuing HFNC, he underwent a series of eight FBOs over 9 days, each performed in response to significant decreases in peripheral oxygen saturation (SpO2). The goal was to remove copious and occlusive infected secretions from the airways, with each procedure resulting in good SpO2 recovery. After etiological targeted antibiotic therapy based on bronchial aspirate, the patient improved and was discharged. Next, six consecutive similar ARF patients were treated using the same strategy of combining HFNC with repeated toilet FBO performed within the ward to clear secretions. All patients showed improvement and were discharged. The combination of HFNC and repeated toilet FBO could be a safe and effective intervention in non-intensive wards to prevent intubation and IMV in frail and elderly patients with ARF secondary to copious and occlusive infected secretions in the airways.

Summary: Background: Severe and prolonged mpox courses have been described during the 2022–2023 outbreak. Identifying predictors of severe evolution is crucial for improving management and therapeutic strategies. We explored the predictors of mpox severity and tested the association between mpox severity and viral load in biological fluids. We also analysed the predictors of disease duration and kinetics of inflammatory markers and described the viral presence and duration of shedding in biological fluids. Methods: This multicentre historical cohort study included adults diagnosed with laboratory-confirmed mpox diagnosis between May 2022 and September 2023 at 15 Italian centres. Patients were followed up from the day of diagnosis until clinical recovery. Biological fluids (blood, urine, saliva, and oropharyngeal and rectal swabs) were collected from each subgroup during the course of the disease and after healing. The primary outcomes were disease severity (presence of mucosal involvement, extended rash, or need for hospitalisation) and its association with the cycle threshold value (Ct-value, surrogate of viral load) in biological fluids, using standard linear and linear mixed-effect logistic regression models. Among the secondary outcomes, predictors of disease duration were assessed using a linear regression model. Findings: A total of 541 patients were enrolled, including four (0.74%) women, with a median age of 38 years (IQR 33–44). Among the 235 people living with HIV (PLWH) (43.44%), 22 (4.07%) had a CD4 count lower than 350 cells/μL. Severe mpox was reported in 215 patients (39.74%). No patient died. Multivariable analysis showed that, severe mpox was more likely among Caucasians (OR 1.82; 95% CI 1.14–2.90, p = 0.012) and patients who had an onset of fever (1.95; 1.27–2.99, p = 0.002), lymphadenopathy (2.30; 1.52–3.48, p

The integration of robotics and artificial intelligence into medical practice is radically revolutionising patient care. This fusion of advanced technologies with healthcare offers a number of significant benefits, including more precise diagnoses, personalised treatments and improved health data management. However, it is critical to address very carefully the medico-legal challenges associated with this progress. The responsibilities between the different players concerned in medical liability cases are not yet clearly defined, especially when artificial intelligence is involved in the decision-making process. Complexity increases when technology intervenes between a person’s action and the result, making it difficult for the patient to prove harm or negligence. In addition, there is the risk of an unfair distribution of blame between physicians and healthcare institutions. The analysis of European legislation highlights the critical issues related to the attribution of legal personality to autonomous robots and the recognition of strict liability for medical doctors and healthcare institutions. Although European legislation has helped to standardise the rules on this issue, some questions remain unresolved. We argue that specific laws are needed to address the issue of medical liability in cases where robotics and artificial intelligence are used in healthcare.

Due to its nonspecific symptoms, in several cases, Acute Aortic Dissection (AAD) is a difficult-to-diagnose urgent condition. The torn intimal layer initiates a false lumen, which can potentially propagate and cause life-threatening ruptures or organ ischemia. Intramural hematoma can rarely develop inside the false lumen, resulting in compression of surrounding structures and worsening the patient’s prognosis. We report a case of AAD - Stanford Type A complicated by an intramural hematoma compressing the pulmonary artery, accompanied by a discussion of relevant literature. This patient presented to the emergency department with acute respiratory distress; clinical and initial diagnostic findings mimicked pulmonary embolism. However, a systematic differential evaluation supported by point-of-care ultrasound allowed a prompt diagnosis of AAD and avoided fixation errors.

Constituents of air pollution, the ultrafine particles (UFP) with a diameter of ≤0.1 μm, are considerably related to traffic emissions. Several studies link air pollution to Alzheimer's disease (AD), yet the exact relationship between the two remains poorly understood. Mitochondria are known targets of environmental toxicants, and their dysfunction is associated with neurodegenerative diseases. The olfactory mucosa (OM), located at the rooftop of the nasal cavity, is directly exposed to the environment and in contact with the brain. Mounting evidence suggests that the UFPs can impact the brain directly through the olfactory tract. By using primary human OM cultures established from nasal biopsies of cognitively healthy controls and individuals diagnosed with AD, we aimed to decipher the effects of traffic-related UFPs on mitochondria. The UFP samples were collected from the exhausts of a modern heavy-duty diesel engine (HDE) without aftertreatment systems, run with renewable diesel (A0) and petroleum diesel (A20), and from an engine of a 2019 model diesel passenger car (DI-E6d) equipped with state-of-the-art aftertreatment devices and run with renewable diesel (Euro6). OM cells were exposed to three different UFPs for 24-h and 72-h, after which cellular processes were assessed on the functional and transcriptomic levels. Our results show that UFPs impair mitochondrial functions in primary human OM cells by hampering oxidative phosphorylation (OXPHOS) and redox balance, and the responses of AD cells differ from cognitively healthy controls. RNA-Seq and IPA® revealed inhibition of OXPHOS and mitochondrial dysfunction in response to UFPs A0 and A20. Functional validation confirmed that A0 and A20 impair cellular respiration, decrease ATP levels, and disturb redox balance by altering NAD and glutathione metabolism, leading to increased ROS and oxidative stress. RNA-Seq and functional assessment revealed the presence of AD-related alterations in human OM cells and that different fuels and engine technologies elicit differential effects.

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells’ susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with – or caused by – ferroptosis.

Complete and precise knowledge of the neck anatomy and its eventual anomalies is crucial while performing a safe thyroid and parathyroid surgery. Embryo-genetic malformations of the IV branchial arch can lead to an uncommon anatomical alteration known as non-recurrent inferior laryngeal nerve. Its prevalence varies between 0.7% for the dextral branch and 0.04% for the sinistral. In these cases, the inferior laryngeal nerve branches originate directly from the cervical vagus nerve, entering the larynx without hooking, on the right side around the subclavian artery or on the left around the aortic arch. The presence of a non-recurrent laryngeal nerve is challenging, due to the increased risks of iatrogenic damage to the nerve, which results in hoarseness, dysphagia, glottal obstruction, vocal cords palsy, and serious airway impairment. We present the case of a 58-year-old woman. The patient was admitted to our department for a nodule classified as Bethesda IV in the right thyroid lobe. Through the use of intraoperative neuromonitoring (IONM), surgeons detected intraoperatively a non-recurrent laryngeal nerve. A subsequent computed tomography scan confirmed an anomalous right subclavian artery branching from the left aortic arch, the Lusoria Artery. Anatomical variants represent pitfalls in this case and an accurate knowledge of the neck region is imperative while performing thyroid surgery. Devices such as IONM are useful for detecting abnormalities that may lead to iatrogenic damages.

IntroductionHealthcare-associated infections are the main reported adverse event in healthcare, with significant economic costs that include those caused by medical malpractice claims. In Italy, there is a fault-based compensation system, but in this specific field, the burden of proof on the hospitals is particularly heavy. Hence, we aimed to verify the economic impact of the inclusion of experts in hospital infection surveillance into internal committees for claims assessment and to evaluate what would have been the economic impact of a mandatory no-fault system rather than the current system.Materials and methodsWe compared two 4-year periods (T1: 2015–2018 and T2: 2019–2022), investigating the medical malpractice claims related to healthcare-associated infections in a large tertiary public hospital in Florence, Italy. Decisions of the internal committee, evolutions of the claims after the decision, and conclusions of the claims were registered. No-fault system simulations were used to evaluate the cost-effectiveness of the model.ResultsWe observed a decrease in the number of claims after the implementation of infection prevention and control (IPC) experts into the committee (a 24% decrease in rejections and a 19% increase in admissions). We found a 6806.98 euros difference (not statistically significant) in compensations in T1 and T2. Moreover, our simulations found that a no-fault compensation system – if alternative to the traditional fault-based approach – could lead to gains or losses for the plaintiffs depending on the approach chosen. (We observed a 52% mean decrease in compensations with a 150000 euros maximal indemnity and a 134% mean increase with an indemnity tailored considering also life expectancy).DiscussionIntroducing experts in IPC into hospital committees for medico-legal claims management has proven to be cost-effective, offering a no-fault compensation system as an alternative to the traditional fault-based approach, supported by a properly evaluated maximal indemnity. Due to the limitations of our models, multicentric studies are recommended to verify our results.

Background Task-sharing of spinal anaesthesia care by non-specialist graduate physicians, termed medical officers (MOs), is commonly practised in rural Indian healthcare facilities to mitigate workforce constraints. We sought to assess whether spinal anaesthesia failure rates of MOs were non-inferior to those of consultant anaesthesiologists (CA) following a standardised educational curriculum.Methods We performed a randomised, non-inferiority trial in three rural hospitals in Tamil Nadu and Chhattisgarh, India. Patients aged over 18 years with low perioperative risk (ASA I & II) were randomised to receive MO or CA care. Prior to the trial, MOs underwent task-based anaesthesia training, inclusive of remotely accessed lectures, simulation-based training and directly observed anaesthetic procedures and intraoperative care. The primary outcome measure was spinal anaesthesia failure with a non-inferiority margin of 5%. Secondary outcome measures consisted of incidence of perioperative and postoperative complications.Findings Between 12 July 2019 and 8 June 2020, a total of 422 patients undergoing surgical procedures amenable to spinal anaesthesia care were randomised to receive either MO (231, 54.7%) or CA care (191, 45.2%). Spinal anaesthesia failure rate for MOs (7, 3.0%) was non-inferior to those of CA (5, 2.6%); difference in success rate of 0.4% (95% CI=0.36–0.43%; p=0.80). Additionally, there were no statistically significant differences observed between the two groups for intraoperative or postoperative complications, or patients’ experience of pain during the procedure.Interpretation This study demonstrates that failure rates of spinal anaesthesia care provided by trained MOs are non-inferior to care provided by CAs in low-risk surgical patients. This may support policy measures that use task-sharing as a means of expanding anaesthesia care capacity in rural Indian hospitals.Trial registration number NCT04438811.