The use of medicinal products derived from cannabis and its synthetic analogues has grown in recent years for various health conditions, which led to an increase in systematic reviews (SR) on the topic. The objective of this overview was to identify, synthesize, and critically appraise the evidence from SR on the benefits and harms of cannabis derivatives when used for therapeutic purposes in different health conditions. A comprehensive search was conducted to identify all relevant SR in Embase, Epistemonikos, MEDLINE, and Cochrane Database of Systematic Reviews. The inclusion criteria was SR assessing the effects of cannabis and its derivatives for any clinical condition that included only randomized controlled trials. A structured selection and extraction process was performed by two independent researchers. The methodological quality of the included SR was assessed using AMSTAR-2. This overview included 102 SR, 68.6% of which were of critically low quality and 17.6% were of high quality. There is low to moderate certainty of evidence of benefits from these interventions for ulcerative colitis, chronic non-cancer pain, Crohn's disease, multiple sclerosis, and post-chemotherapy nausea and vomiting. The results point to a lack of benefits for sleep disorders, chronic cancer pain refractory to opioids, pain related to radiotherapy, and pain in people receiving palliative care. For other conditions, the certainty of the evidence was very low or not assessed. This overview opens a broad and complex field for the development of primary studies to evaluate the effects of cannabinoids as primary or adjunctive therapy for different health conditions and reinforces the importance of safety assessment. Decision-makers and guideline developers can be guided by the results summarized in this overview. However, when making formal recommendations, it is essential to consider the quality of the SR and the certainty of the evidence identified for each outcome.
Robotic surgery has progressively expanded within hepato-pancreato-biliary (HPB) practice, aiming to overcome the technical limitations of conventional laparoscopy in complex resections and reconstructions. Over the past 2 decades, its role has evolved from feasibility reports to comparative analyses, consensus statements, and randomized controlled trials. However, evidence remains heterogeneous across liver, pancreas, and biliary domains, and the clinical impact of robotic surgery appears to be procedure-specific rather than universal. This study aimed to provide an evidence-based narrative review of the evolution of robotic HPB surgery, with emphasis on perioperative outcomes, oncologic safety, technical indications, and current limitations. A narrative literature review was conducted using PubMed, Embase, and Scopus databases, including studies published between January 2000 and February 2026. Search terms included combinations of "robotic surgery", "hepatectomy", "liver resection", "pancreatic surgery", "pancreatoduodenectomy", "distal pancreatectomy", "biliary surgery", "cholangiocarcinoma", and "hepaticojejunostomy". Original studies, systematic reviews, meta-analyses, randomized trials, and consensus guidelines were included. Data were synthesized qualitatively, incorporating quantitative outcomes when available, including operative time, estimated blood loss, conversion rates, complications, oncologic outcomes, and learning-curve metrics. Robotic liver surgery has demonstrated comparable perioperative and oncologic outcomes to laparoscopic and open approaches, with lower conversion rates, reduced blood loss, and shorter operative time in selected high-difficulty resections. Robotic pancreatic surgery has expanded with increasing standardization. Robotic distal pancreatectomy shows consistent advantages compared to laparoscopic distal pancreatectomy with comparable overall morbidity and shorter postoperative hospital stay. Robotic pancreatoduodenectomy has reached randomized evaluation with comparable overall morbidity and shorter postoperative recovery when performed in high-volume centers by experienced surgeons. Robotic biliary surgery remains less standardized and is concentrated in specialized centers; however, recent comparative studies suggest feasibility in bile duct reconstruction and potential advantages in lymphadenectomy. Across all domains, outcomes are strongly influenced by institutional expertise, structured training, and case selection. Robotic HPB surgery has emerged as a key advancement in minimally invasive surgery, with its greatest value in complexity-dependent, technically demanding procedures. Although current evidence supports its safety and oncologic adequacy in selected patients, outcomes remain highly contingent on case selection, surgical expertise, and structured implementation. Future progress will depend on defining optimal indications rather than feasibility, supported by standardized reporting, cost-effectiveness analyses, and robust long-term oncologic data.
The high mortality associated with tuberculosis (TB), alongside the lack of efficient therapeutics against emerging multidrug-resistant Mycobacterium tuberculosis (Mtb) strains, emphasizes the need for novel antitubercular targets. Mycobacterial peptidoglycan (PG), displaying characteristic modifications comprising the amidation of D-iso-glutamate (D-iGlu) and the N-glycolylation of muramic acid, is therefore a promising therapeutic target. The genes encoding the enzymes mediating these modifications (murT/gatD and namH) were silenced in Mtb using CRISPR interference (CRISPRi) to investigate their impact on β-lactam susceptibility and host immune responses. First, qRT-PCR confirmed successful target mRNA knockdown and phenotyping assays corroborated the essentiality of D-iGlu amidation for mycobacterial growth, in contrast to muramic acid N-glycolylation. The susceptibility assays demonstrated that both PG modifications promote β-lactam resistance. Indeed, we observed reductions in the minimum fractional inhibitory concentration index (FICImin) value for AMX/MEM + CLA and EMB combinations following the depletion of both PG modifications. Furthermore, D-iGlu amidation was found to promote Mtb fitness within THP-1-derived macrophages 6 days post-infection. Infection with MurT/GatD-depleted Mtb was associated with increased IL-1β and decreased IL-10, whereas NamH depletion was linked to increased IL-1β and IL-10 levels. Altogether, our findings unveiled the potential of targeting these PG modifications for the development of innovative therapeutic regimens against TB.
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Aortic dimensions vary according to age, sex, and population characteristics. This study aimed to establish computed tomography (CT)-based reference diameters for the abdominal aorta in a Portuguese hospital population, providing reference data that may support the assessment of aortic dilatation and future population-specific studies of aneurysm diagnosis and surveillance. A single-centre cross-sectional study was conducted using CT examinations performed at a tertiary referral hospital in Portugal during 2018. CT scans were randomly selected using a stratified sampling strategy according to month and time of day. Patients with known aortic disease or CT examinations requested in the context of vascular or cardiac surgery consultations were excluded. Aortic diameters were measured on multiplanar reconstructions using outer-to-outer wall measurements at standardised anatomical locations. Analyses were performed overall and stratified by sex and age group (<50, 50-75, and >75 years). Comparisons were performed using Student's t test and linear regression models, including age-adjusted analyses for sex comparisons. A total of 479 patients were included, of whom 266 (55.5%) were male. Mean age was 64.5 years (SD 17.3). Mean abdominal aortic diameters were 23.71 mm (SD 4.32) at the coeliac level, 22.07 mm (SD 4.08) at the superior mesenteric artery level, and 20.95 mm (SD 4.14) at the renal level. Infrarenal diameters ranged from 18.95 mm (SD 4.05) proximally to 17.72 mm (SD 3.89) distally. Men had significantly larger diameters than women at all anatomical locations (all p < 0.001). Aortic diameter increased significantly with age across all segments (all p < 0.001), with consistent and additive effects of age and sex. This study provides CT-based reference values for abdominal aortic diameters in a Portuguese population. Aortic size is strongly influenced by age and sex, supporting the need for population-specific and demographically stratified reference values.
To synthesize and quantify the effects of exercise interventions on physical function and patient-reported outcomes in adults with multiple myeloma (MM). A systematic review and meta-analysis was conducted in accordance with PRISMA guidelines and prospectively registered in PROSPERO (CRD420251271216). PubMed, EBSCO, Cochrane Library, Scopus, and Web of Science were searched from inception to April 2026. Randomized and nonrandomized studies evaluating structured exercise interventions in adults with MM were considered eligible. Methodological quality was assessed using the PEDro scale, and risk of bias was evaluated with the RoB 2 tool. Random-effects meta-analyses were performed using standardized mean differences. The search identified 10,907 records, of which 20 studies met the eligibility criteria for qualitative synthesis (n = 1,032) and 9 for quantitative synthesis (n = 576). Exercise interventions lasted a mean of 14.4 weeks, were performed 3.3 times per week, and were most commonly based on combined aerobic and resistance training. Quantitative synthesis was conducted for aerobic capacity, quality of life, fatigue, upper-limb strength, lower-limb strength, and pain. Across outcomes, pooled effects were generally small and did not reach statistical significance. Heterogeneity was low to moderate for most outcomes, although substantial inconsistency was observed for aerobic capacity and lower-limb strength. Methodological quality ranged from fair to good, and 55.6% of the randomized studies were rated as having a high risk of bias, mainly due to missing outcome data. Mean study-level attrition rates were observed in both exercise and control groups, supporting the feasibility of exercise interventions in this population. Exercise interventions in patients with MM appear feasible, but current evidence shows small and non-significant effects on aerobic capacity, muscle strength, fatigue, quality of life, and pain. Given the limited number of studies, small sample sizes, and methodological heterogeneity, the true magnitude of exercise-related benefits remains uncertain. Larger, well-designed randomized controlled trials with standardized exercise protocols are needed to clarify the efficacy and optimal prescription of exercise in this population. This study indicates that structured exercise programs are feasible and well-tolerated by individuals with MM. Although current evidence shows limited immediate effects on physical function and quality of life, patients can safely engage in combined aerobic and resistance training. Survivors should discuss personalized, well-monitored exercise options with their healthcare team to maintain activity levels while more definitive guidelines are established.
Posteromedial ankle approaches are commonly used for posterior malleolar fractures, but inconsistent terminology limits comparison across studies. To systematically review published descriptions of posteromedial ankle approaches and summarize their anatomical corridors, patient positioning, and distal tibial exposure. Functional outcomes and complications were assessed secondarily. A PRISMA-guided systematic review of Medline, Web Science, and Scopus was performed from database inception through December 2024. Two reviewers independently screened studies, extracted data, and assessed risk of bias. Twenty studies met inclusion criteria. Four reproducible anatomical corridors were identified, although terminology and patient positioning varied considerably. Cadaveric studies suggested differences in posterior distal tibial exposure between corridors. Clinical outcome and complication data were limited, heterogeneous, and strongly confounded by fracture pattern, soft-tissue condition, and treatment-related factors. No consensus exists on posteromedial ankle approach nomenclature. A corridor-based framework may improve standardization, but current evidence does not support robust comparative conclusions.
Post-tuberculosis lung disease (PTLD) is a frequent and underrecognized cause of chronic respiratory morbidity, characterized by heterogeneous structural and functional sequelae following microbiological cure of tuberculosis. Although most patients are managed with medical therapy, rehabilitation, and bronchoscopic interventions, a selected subset develops irreversible disease requiring surgical treatment. This article focuses on PTLD, emphasizing the role of surgical management within multidisciplinary care, and discusses the underlying pathophysiology, clinical phenotypes, diagnostic approach, and surgical indications, including bronchiectasis, hemoptysis, destroyed lung, aspergillosis, and airway stenosis.
Real-world data on dupilumab for eosinophilic esophagitis (EoE), particularly regarding flexible dosing and fibrostenotic phenotypes, are scarce. To evaluate the effectiveness and safety of dupilumab in clinical practice using the EoE CONNECT registry. This cross-sectional analysis included all patients prospectively recruited in the largest European multicenter EoE registry. Baseline characteristics, dosing regimens (300 mg weekly vs. semi-weekly), clinico-histological response (CHR), dose adjustments, and treatment tolerability were assessed. We analyzed 161 patients (145 adults; 16 adolescents). At baseline, 69.1% of patients displayed endoscopic fibrotic features (rings/strictures). After a median of 6.5 months, peak eosinophil count decreased from 57±45 to 8±19 eos/hpf, EREFS score declined from 3.0±1.6 to 1.3±1.3, and DSS improved from 5.8±3.7 to 2.5±2.8 (all p<0.001). CHR was achieved by 86.0% of patients on 300 mg weekly and 81.2% on semi-weekly dosing (p=0.57). Multivariate analysis identified severe atopy as the reason for starting dupilumab as the strongest predictor for semi-weekly regimen choice (OR: 26.9; p<0.001), with conjunctivitis, asthma, and having two or more food allergies being significant. Both regimens were equally effective in reducing peak eos/hpf, symptomatology and EREFS. Dose tapering from weekly to semi-weekly/monthly was successful in all evaluable cases (8/8), while dose escalation from semi-weekly to weekly rescued 80% (4/5) of non-responders. Discontinuation occurred only in 8 patients (5%), primarily due to adverse events. Dupilumab is effective and safe in real-world EoE management, with no significant differences between weekly and semi-weekly induction. Efficacy was generally regained after escalation or maintained after dose tapering.
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Type IV collagen related nephropathy caused by heterozygous variants in the COL4A3 or COL4A4 genes shows a wide phenotypic variability, with asymptomatic individuals being relatively common. A cystic phenotype in these cases is uncommon and rarely presents with nephromegaly mimicking autosomal dominant polycystic kidney disease (ADPKD). We report a family with hereditary kidney disease showing an autosomal dominant inheritance pattern and marked phenotypic variability. Some family members were diagnosed with urate nephropathy, others met the Ravine-Pei criteria for ADPKD, and others were labeled as having chronic kidney disease of unknown etiology; five progressed to renal replacement therapy. The proband, who presented with bilateral renal cysts fulfilling ADPKD criteria, along with microhematuria and non-nephrotic proteinuria, tested negative for PKD1 and PKD2 variants after sequential genetic analysis. Meanwhile, another family member studied for persistent microhematuria and non-nephrotic proteinuria underwent a renal biopsy that revealed thinning of the glomerular basement membrane on electron microscopy, suggesting Alport syndrome. Genetic testing in both individuals identified the c.735+2T>C (p?) variant in the COL4A4 gene, classified as likely pathogenic due to its disruption of a splicing site. This case illustrates the phenotypic heterogeneity of heterozygous COL4A4-related Alport syndrome and highlights the importance of implementing genetic testing in the differential diagnosis of hereditary kidney disorders to prevent diagnostic delays with potential clinical consequences.
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To systematically review and investigate the dose-response (DR) relationship of aerobic exercise (AE), resistance exercise (RE) and combined (COMB) exercise programmes on cancer-related fatigue, lean mass, physical function and muscle strength in women with breast cancer during and following primary treatment. Systematic review with DR network meta-analysis (DR-NMA; CRD42023491118). CINAHL, Embase, LILACS, PubMed, SciELO, SPORTDiscus and Web of Science were searched from inception to 10 January 2024, with an updated search in April 2025. Randomised controlled trials evaluating COMB, RE or AE in women with breast cancer on the four specified outcomes. 64 trials (n=5156) were included. COMB was the most effective modality for improving fatigue and lean mass, and RE was the most effective for improving physical function and muscle strength. The smallest effective doses of COMB associated with significant changes in fatigue (standardised mean differences (SMD) 0.23 (95% CI 0.18 to 0.28)) and lean mass (SMD 0.30 (95% CI 0.22 to 0.38)) were 18 and 11 metabolic equivalents per week (METs.min/week), respectively. For RE, about 7-8 METs.min/week produced significant improvements in physical function (SMD 0.23 (95% CI 0.15 to 0.30)) and strength (SMD 0.24 (95% CI 0.20 to 0.29)). Fatigue benefits (SMD 0.58 (95% CI 0.46 to 0.69)) plateaued at ~1428 METs.min/week for COMB, whereas no plateau was observed for lean mass or strength across the evaluated dose range, with effects increasing throughout the available dose range. COMB and RE were the most effective interventions across outcomes in women with breast cancer. Benefits for the outcomes assessed in this systematic review with DR-NMA were achieved with exercise doses as low as 10-40 min/week. CRD42023491118.
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Rhabdomyolysis is the acute necrosis of striated skeletal muscle, with release of its constituents into the extracellular space and circulation. Acute muscle pain (myalgia), weakness, and edema are associated with serum levels of the muscle enzyme creatine kinase (CK) above 1,000 IU/L or 5 times the upper limit of the normal value. This narrative review provides an overview of the clinical and laboratory findings, etiology, treatment, and prevention of rhabdomyolysis in humans. Additionally, we highlighted the main syndromes and muscular disorders associated with rhabdomyolysis: 1. Clinical syndromes: neuroleptic malignant syndrome, serotoninergic syndrome, sympathomimetic syndrome, malignant hyperthermia, and anesthesia-induced rhabdomyolysis; and 2. Myopathies: toxic myopathies, idiopathic inflammatory myopathies, muscular dystrophies, ion channel diseases, glycogen storage diseases, fatty acid beta oxidation defects, and mitochondrial myopathies.
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A strategy for the selective C-H alkenylation of flavones is described. By using the carbonyl group of the flavone core as an intrinsic directing group, a series of 5-alkenylated derivatives were synthesized via coupling with alkenes, including acrylates, styrene, methyl vinyl ketone, and phenyl vinyl sulfone, affording the desired products in good to excellent yields (up to 92%). Notably, when a carbamate substituent was present at C7, the reaction proceeded with complete chemoselectivity, exclusively yielding C-5 alkenylated products. Although carbamate groups are widely recognized as efficient directing groups in alkenylation reactions, they proved to be ineffective within the flavone scaffold. Density functional theory (DFT) calculations were performed to rationalize the observed chemoselectivity and to provide mechanistic insight into the C-H activation process. The preference for C5 alkenylation arises from the lower energy profiles of the corresponding transition states and intermediates, whereas C8 functionalization is disfavored due to a greater tendency toward protodemetalation over migratory insertion.