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Investigating the complex interactions between microbiota and immunity is crucial for a fruitful understanding progress of human health and disease. This review assesses animal models, next-generation in vitro models, and in silico approaches that are used to decipher the microbiome-immunity axis, evaluating their strengths and limitations. While animal models provide a comprehensive biological context, they also raise ethical and practical concerns. Conversely, modern in vitro models reduce animal involvement but require specific costs and materials. When considering the environmental impact of these models, in silico approaches emerge as promising for resource reduction, but they require robust experimental validation and ongoing refinement. Their potential is significant, paving the way for a more sustainable and ethical future in microbiome-immunity research.

Methicillin-resistant Staphylococcus Aureus (MRSA) bacteremia is a complex and lethal condition. We reported the clinical case of a 58-year-old woman who developed MRSA bacteremia after a 3-month hospitalization for trauma and sepsis. Delay in diagnosis of aortic and mitral endocarditis in the setting of new-onset regurgitations, as the application of suboptimal therapy with linezolid and vancomycin, led to widespread disease with embolic dissemination and development of septic infarctions. Clinicians must be aware of the necessity to consider as high risk of endocarditis new onset valvular regurgitations and of the evidence about the need for daptomycin in treating high-risk MRSA bacteremia.

Bedside echocardiography stands as a cornerstone diagnostic tool in internal medicine, offering rapid, real-time evaluation of cardiac structure and function across a wide spectrum of acute and chronic conditions. Its application, particularly when combined with lung and inferior vena cava (IVC) ultrasound, significantly enhances diagnostic accuracy for fluid balance assessment, dyspnea, and hypotensive states, guiding timely therapeutic decisions. Focused cardiac ultrasound (FoCUS) enables internists to assess left ventricular function, right atrial pressure, valvular abnormalities, and pericardial effusion, facilitating differentiation between cardiac and non-cardiac causes of symptoms such as dyspnea, chest pain, and hemodynamic instability. While operator-dependent, echocardiography can be effectively integrated into internal medicine practice through structured training programs that combine theoretical knowledge with supervised hands-on experience. This integration enhances clinical decision-making, optimizes patient management, and reduces the need for immediate specialist consultation. Widespread adoption of focused ultrasound techniques in internal medicine wards promises not only improved patient outcomes but also more efficient utilization of healthcare resources. Continued education and institutional support are fundamental to embedding echocardiography into routine care, ensuring internists are equipped to leverage this powerful bedside modality. This narrative review aims to underscore the transformative impact of bedside echocardiography in internal medicine, demonstrating its capacity, when combined with lung and IVC ultrasound, to optimize diagnostic pathways and treatment decisions across diverse acute and chronic settings.

ObjectivesIn systemic sclerosis (SSc), gastrointestinal involvement is one of the earliest events. We compared the gut microbiota (GM), its short-chain fatty acids (SCFAs) and host-derived free fatty acids (FFAs) in patients with very early diagnosis of SSc (VEDOSS) and definite SSc.MethodsStool samples of 26 patients with SSc, 18 patients with VEDOSS and 20 healthy controls (HC) were collected. The GM was assessed through 16S rRNA sequencing, while SCFAs and FFAs were assessed by gas chromatography-mass spectrometry.ResultsIn patients with VEDOSS, an increase in Bacteroidales and Oscillospirales orders and a decrease in Bacilli class, Blautia, Romboutsia, Streptococcus and Turicibacter genera was detected in comparison with HC. In patients with SSc, an elevated number of Acidaminococcaceae and Sutterellaceae families, along with a decrease of the Peptostreptococcaceae family and Anaerostipes, Blautia, Romboutsia and Turicibacter genera was found in comparison with HC. Patients with SSc and VEDOSS had a significantly lower butyrate and higher acetate with respect to HC. In VEDOSS, an increase in Oscillospiraceae family and Anaerostipes genus, and a decrease in Alphaproteobacteria class, and Lactobacillales order was identified with respect to SSc. Moreover, patients with VEDOSS exhibited higher acetate and lower valerate compared with definite SSc.ConclusionA GM dysbiosis with depletion of beneficial anti-inflammatory bacteria (especially butyrate-producing) and a significant decrease in faecal butyrate was identified in patients with VEDOSS. This early GM imbalance may foster the growth of inflammatory microbes, worsening intestinal dysbiosis and inflammation in early SSc stages. The potential butyrate administration in early disease phases might be considered as a novel therapeutic approach to mitigate gastrointestinal discomfort and progression preserving patient’s quality of life.

Heme is a member of the porphyrins family of cyclic tetrapyrroles and influences various cell processes and signalling pathways. Enzyme deficiencies in the heme biosynthetic pathway provoke rare human inherited metabolic diseases called porphyrias. Protein levels and activity of enzymes involved in the heme biosynthetic pathway and especially 5′-Aminolevulinate Synthase 1 are featured by 24-h rhythmic oscillations driven by the biological clock. Heme biosynthesis and circadian pathways intermingle with mutual modulatory roles. Notably, heme is a ligand of important cogs of the molecular clockwork, which upon heme binding recruit co-repressors and inhibit the transcription of numerous genes enriching metabolic pathways and encoding functional proteins bringing on crucial cell processes. Herein, we assessed mRNA levels of circadian genes in patients suffering from porphyrias and found several modifications of core clock genes and clock-controlled genes expression, associated with metabolic and electrolytic changes. Overall, our results show an altered expression of circadian genes accompanying heme biosynthesis disorders and confirm the need to deepen the knowledge of the mechanisms through which the alteration of the circadian clock circuitry could take part in determining signs and symptoms of porphyria patients and then again could represent a target for innovative therapeutic strategies.

Acute Respiratory Distress Syndrome (ARDS) caused by COVID-19 is substantially different from ARDS caused by other diseases and its treatment is dissimilar and challenging. As many studies showed conflicting results regarding the use of Non-invasive ventilation in COVID-19-associated ARDS, no unquestionable indications by operational guidelines were reported. The aim of this study was to estimate the use and success rate of Helmet (h) Continuous Positive Airway Pressure (CPAP) in COVID-19-associated ARDS in medical regular wards patients and describe the predictive risk factors for its use and failure. In our monocentric retrospective observational study, we included patients admitted for COVID-19 in medical regular wards. hCPAP was delivered when supplemental conventional or high-flow nasal oxygen failed to achieve respiratory targets. The primary outcomes were hCPAP use and failure rate (including the need to use Bilevel (BL) PAP or oro-tracheal intubation (OTI) and death during ventilation). The secondary outcome was the rate of in-hospital death and OTI. We computed a score derived from the factors independently associated with hCPAP failure. Out of 701 patients admitted with COVID-19 symptoms, 295 were diagnosed with ARDS caused by COVID-19 and treated with hCPAP. Factors associated with the need for hCPAP use were the PaO2/FiO2 ratio < 270, IL-6 serum levels over 46 pg/mL, AST > 33 U/L, and LDH > 570 U/L; age > 78 years and neuropsychiatric conditions were associated with lower use of hCPAP. Failure of hCPAP occurred in 125 patients and was associated with male sex, polypharmacotherapy (at least three medications), platelet count < 180 × 109/L, and PaO2/FiO2 ratio < 240. The computed hCPAP-f Score, ranging from 0 to 11.5 points, had an AUC of 0.74 in predicting hCPAP failure (significantly superior to Call Score), and 0.73 for the secondary outcome (non-inferior to IL-6 serum levels). In conclusion, hCPAP was widely used in patients with COVID-19 symptoms admitted to medical regular wards and developing ARDS, with a low OTI rate. A score computed combining male sex, multi-pharmacotherapy, low platelet count, and low PaO2/FiO2 was able to predict hCPAP failure in hospitalized patients with ARDS caused by COVID-19.

Patients with von Hippel-Lindau (VHL) disease develop multiple distinct kidney cysts and clear cell renal cell carcinomas (ccRCCs) throughout their lifetime. Although cysts are typically considered precursors of ccRCC, no molecular evidence of cysts to tumor progression was provided to date, due to the lack of an accurate molecular characterization of these lesions. We performed a comprehensive molecular characterization of four kidney cysts and six ccRCCs obtained from the same VHL-disease patient, thus all sharing the same genetic germline and host environment. We combined whole genome sequencing (WGS) and RNA sequencing (RNA-seq) profiling with pathological examinations. Cysts and tumors exhibited distinct transcriptomic profiles. Tumors showed increased glycolysis and response to hypoxia, while cysts were associated with enrichment in extracellular matrix organization and inflammation and displayed elevated expression of nephron distal portion markers. Deconvolution analysis further revealed different stromal and immune microenvironments with cysts enriched in myofibroblasts and plasma cells signatures whereas tumors were associated with tumor-associated macrophages (TAMs) and tumor vasculature signatures. Genomically, most cysts and tumors were clonally independent, harboring distinct somatic single-nucleotide variants. Despite sharing some somatic mutational signatures, tumors and cysts exhibited divergent somatic copy number alterations. Only tumors displayed chromosome 3p loss, resulting in VHL loss of heterozygosity, without other driver mutations. VHL patients develop multiple kidney cysts and solid tumors throughout their lifetime and their clinical management is challenging. This study presents the first in-depth molecular analysis of kidney cysts and ccRCC in a single VHL patient. We observed distinct molecular profiles between cysts and tumors, suggesting independent origins. While preliminary, these findings challenge the assumption that cysts always serve as precursors of ccRCC in VHL disease and underscore the need for larger studies to improve surveillance and management of renal lesions in patients with VHL disease.

Von Hippel–Lindau (VHL) disease is a rare genetic syndrome caused by a germline pathogenic variant in one VHL allele. Any somatic event disrupting the other allele induces VHL protein (pVHL) loss of function, ultimately leading to patients developing multiple tumours in multiple organs at multiple timepoints, and reducing life expectancy. Treatment of this complex, rare disease is often fragmented, as patients visit specialist clinicians in isolation at different medical centres. Consequently, patients can receive sub-optimal treatment that results in decreased quality of life and a poor experience of health care systems. In 2021, we established a comprehensive clinical centre at San Raffaele Hospital, Milan, devoted to VHL disease. The centre provides a structured programme for the diagnosis, surveillance and treatment of patients alongside research into VHL disease and involves a multidisciplinary team of dedicated physicians. This programme demonstrates the benefits of care centralization, including concentration of knowledge and services, synergy and multidisciplinary management, improved networking and patient resources, reducing health care costs, and fostering research and innovation. VHL disease provides an ideal model to assess the advantages of centralizing care for rare disease and represents an unparalleled opportunity to broaden our understanding of cancer biology in general.In this Perspective, Larcher et al. describe a dedicated treatment programme for Von Hippel–Lindau disease established at San Raffaele Hospital, which encompasses diagnosis, surveillance, treatment, research and outreach. The authors then discuss the benefits of care centralization for Von Hippel–Lindau disease and other rare diseases.

Guideline-based patient educational materials (PEMs) empower patients and reduce misinformation, but require frequent updates and must be adapted to the readability level of patients. The aim is to assess whether generative artificial intelligence (GenAI) can provide readable, accurate, and up-to-date PEMs that can be subsequently translated into multiple languages for broad dissemination. The European Association of Urology (EAU) guidelines for prostate, bladder, kidney, and testicular cancer were used as the knowledge base for GPT-4 to generate PEMs. Additionally, the PEMs were translated into five commonly spoken languages within the European Union (EU). The study was conducted through a single-blinded, online randomized assessment survey. After an initial pilot assessment of the GenAI-generated PEMs, thirty-two members of the Young Academic Urologists (YAU) groups evaluated the accuracy, completeness, and clarity of the original versus GPT-generated PEMs. The translation assessment involved two native speakers from different YAU groups for each language: Dutch, French, German, Italian, and Spanish. The primary outcomes were readability, accuracy, completeness, faithfulness, and clarity. Readability was measured using Flesch Kincaid Reading Ease (FKRE), Flesch Kincaid Grade Level (FKGL), Gunning Fog (GFS) scores and Smog (SI), Coleman Liau (CLI), Automated Readability (ARI) indexes. Accuracy, completeness, faithfulness, and clarity were rated on a 5-item Likert scale. The mean time to create layperson PEMs based on the latest guideline by GPT-4 was 52.1 seconds. The readability scores for the 8 original PEMs were lower than for the 8 GPT-4-generated PEMs (Mean FKRE: 43.5 vs. 70.8; p < .001). The required reading education levels were higher for original PEMs compared to GPT-4 generated PEMs (Mean FKGL: 11.6 vs. 6.1; p < .001). For all urological localized cancers, the original PEMs were not significantly different from the GPT-4 generated PEMs in accuracy, completeness, and clarity. Similarly, no differences were observed for metastatic cancers. Translations of GPT-generated PEMs were rated as faithful in 77.5% of cases and clear in 67.5% of cases. GPT-4 generated PEMs have better readability levels compared to original PEMs while maintaining similar accuracy, completeness, and clarity. The use of GenAI's information extraction and language capabilities, integrated with human oversight, can significantly reduce the workload and ensure up-to-date and accurate PEMs. Some cancer facts made for patients can be hard to read or not in the right words for those with prostate, bladder, kidney, or testicular cancer. This study used AI to quickly make short and easy-to-read content from trusted facts. Doctors checked the AI content and found that they were just as accurate, complete, and clear as the original text made for patients. They also worked well in many languages. This AI tool can assist providers in making it easier for patients to understand their cancer and the best care they can get.