From Indirect Evidence to Head-to-Head Trials in Anticoagulation: Clinical Implications of the COBRRA Moment in DOAC Treatment.

Glycemic control and its benefits in preventing microvascular diabetic complications are convincingly proved by various prospective trials. Diabetes control and complications trial (DCCT) had reported variable glycated hemoglobin (HbA1C) as a cause of increased microvascular complications in conventional glycemic control group versus intensive one. However, in spite of several indirect evidences, its link with cardiovascular events or macrovascular complications is still not proved. Glycemic variability (GV) is one more tool to explain relation between hyperglycemia and increased cardiovascular risk in diabetic patients. In fact GV along with fasting blood sugar, postprandial blood sugar, HbA1C, and quality of life has been proposed to form glycemic pentad, which needs to be considered in diabetes management. Postprandial spikes in blood glucose as well as hypoglycemic events, both are blamed for increased cardiovascular events in Type 2 diabetics. GV includes both these events and hence minimizing GV can prevent future cardiovascular events. Modern diabetes management modalities including improved sulfonylureas, glucagon like peptide-1 (GLP-1)-based therapy, newer basal insulins, and modern insulin pumps address the issue of GV effectively. This article highlights mechanism, clinical implications, and measures to control GV in clinical practice.

Colorectal cancer, the most lethal long-term complication of chronic inflammatory bowel disease (IBD), is the culmination of a complex sequence of molecular and histologic derangements of the intestinal epithelium that are initiated and at least partially sustained by chronic inflammation. Dysplasia, the earliest histologic manifestation of this process, plays an important role in cancer prevention by providing the first clinical alert that this sequence is underway and serving as an endpoint in colonoscopic surveillance of patients at high risk for colorectal cancer. To review the histology, nomenclature, clinical implications, and molecular pathogenesis of dysplasia in IBD. Literature review and illustrations from case material. The diagnosis and grading of dysplasia in endoscopic surveillance biopsies play a decisive role in the management of patients with IBD. Although interpathologist variation, endoscopic sampling problems, and incomplete information regarding the natural history of dysplastic lesions are important limiting factors, indirect evidence that surveillance may be an effective means of reducing cancer-related mortality in the population with IBD has helped validate the histologic criteria, nomenclature, and clinical recommendations that are the basis of current practice among pathologists and clinicians. Emerging technologic advances in endoscopy may permit more effective surveillance, but ultimately the greatest promise for cancer prevention in IBD lies in expanding our thus far limited understanding of the molecular pathogenetic relationships between neoplasia and chronic inflammation.

Dental injuries, especially of the incisors, caused by punches in violent criminal attacks could be seen in daily forensic casework involving the identification of injuries to a living body. Sometimes, when there is neither circumstantial evidence nor information about the surrounding circumstances, it is difficult to discern the cause of these injuries and the manner in which they were inflicted. As an example of clinical forensic medicine, we present the case of a 58-year-old woman whose teeth were injured when fighting with her son-in-law over household affairs with no witnesses present. The two parties had conflicting stories about the cause of the woman's injury. The woman claimed that her teeth were lost while she was being beaten by her son-in-law, and the man argued that the damage to his mother-in-law's teeth was self-inflicted when she bit his fingers. The police attending the crime called for a forensic examination. Forensic practitioners analysed the mechanism of the tooth loss using multi-slice spiral computed tomography (MSCT) and imaging reconstruction technology. Local alveolar bone (medial alveolar) fracture and a small area of alveolar bone loss were found on MSCT. Thus, forensic medical experts speculated that the woman's lower central and lateral incisors were lost as a result of a violent attack and were not self-inflicted. Finally, forensic practitioners helped police in avoiding a miscarriage of justice and wrongful conviction.

A small proportion of patients suffering from chronic active gastritis are diagnosed with gastric Helicobacter species other than Helicobacter pylori. Circumstantial evidence has suggested that these bacteria, also referred to as "Helicobacter heilmannii"-like organisms (HHLO), may be transmitted through animals. The isolation of a Helicobacter bizzozeronii strain from a human patient confirmed this hypothesis. It was the aim of the present study to assess the presence of animal Helicobacter species and H. pylori in humans infected with HHLO, as diagnosed by histology. Paraffin-embedded gastric biopsy specimens of 108 HHLO-infected patients (42 women and 66 men) from three clinical centers were screened for the presence of animal gastric Helicobacter species by polymerase chain reaction (PCR), using assays targeting the 16S rDNA region of the three known canine and feline helicobacters (H. bizzozeronii, H. salomonis and H. felis), "Candidatus H. suis", and "Candidatus H. bovis". In addition, the presence of H. pylori was evaluated by multiplex PCR analysis. In 63.4% of the stomachs (64/101) classification of the Helicobacter infection into the above mentioned groups was achieved. Non-pylori Helicobacter species commonly colonizing the stomachs of cats and dogs were found in 48.5% (49/101) of the patients. Fourteen (13.9%) samples tested positive for "Candidatus H. suis", and "Candidatus H. bovis" was demonstrated in 1 (0.9%) patient. The presence of H. pylori was established in 13 patients (12.9%). Eleven stomachs (10.9%) were infected with at least two different Helicobacter species. This study identifies animal Helicobacter species in the stomach of a large series of HHLO-infected patients, which may have clinical implications in a subset of patients with gastric disease.

Angiogenesis is defined as a neoformation of blood vessels of capillary origin. Hematopoiesis is closely linked with angiogenesis, for they share a common ancestor, the hemangioblast. Although it is well established that growth in solid tumors is dependent on angiogenesis, its role in hematologic malignancies has not yet been clarified. In this review, the direct evidence, ie, increased microvessel density, and the indirect evidence, ie, elevated level of angiogenic factors or overexpression of messenger RNA or protein of angiogenic factors, for and against the role of angiogenesis in the development and progression of hematologic malignancies are presented.

Aims: The aim of this chapter is to critically review the potential impact of congenital uterine anomalies (CUA) on the fertility potential of the woman. Evidence is based on: (1) the analysis of their prevalence in the general and infertile population, (2) the achievement of pregnancy in patients having CUA and, (3) treatment results. Brief description of the reviewed data: The presence of CUA might be associated with a detrimental effect on patient’s fertility; the probability of conception, assisted or spontaneous, is decreased by ~15 % (Recommendation Class IIb). It is not still clear what is the impact of the different types of CUA on woman’s fecundity. Based mainly on indirect evidence, it could be supported that the more severe the malformation of the uterine cavity is, the more the possibility to play a role for the achievement and evolution of pregnancy; septate uterus and more severe forms of uterine anomalies could adversely affect the reproductive potential of the woman whereas this does not seem to be the case for arcuate uterus. Clinical implications: In view of this evidence, infertile patients should be investigated for the presence of CUA with high accuracy non-invasive diagnostic methods. This, also, support the notion that surgical treatment is indicated in infertile patients. Open issues for further research: There is a need of prospective well-designed studies to improve the level of the existing evidence and to draw definite conclusions. The accumulation of further relevant epidemiological data might elucidate the exact role of each type of uterine anomaly on reproductive potential of the woman, and enhance our understanding of the pathophysiology. The new ESHRE/ESGE classification system should be the working basis for the design of those studies offering the crucial additional advantages of accurate diagnostic criteria and precise categorization of the anomaly type.

The apparent molecular mass of human milk bile salt-stimulated lipase (BSSL) varies between mothers. The molecular basis for this is unknown, but indirect evidence has suggested the differences to reside in a region of repeats located in the C-terminal part of the protein. We here report that a polymorphism within exon 11 of the BSSL gene is the explanation for the molecular variants of BSSL found in milk. By Southern blot hybridization we analyzed the BSSL gene from mothers known to have BSSL of different molecular masses in their milk. A polymorphism was found within exon 11, previously shown to consist of 16 near identical repeats of 33 bp each. We detected deletions or, in one case, an insertion corresponding to the variation in molecular mass of the BSSL protein found in milk from the respective woman. Furthermore, we found that 56%, out of 295 individuals studied, carry deletions or insertions within exon 11 in one or both alleles of the BSSL gene. Hence, this is a hypervariable region and the current understanding that exon 11 in the human BSSL gene encodes 16 repeats is an oversimplification and needs to be revisited. Natural variation in the molecular mass of BSSL may have clinical implications.

BackgroundMild cognitive impairment (MCI) is set to become a major health problem with the exponential ageing of the world's population. The association between MCI and autonomic dysfunction, supported by indirect evidence and rich with clinical implications in terms of progression to dementia and increased risk of mortality and falls, has never been specifically demonstrated.AimTo conduct a comprehensive assessment of autonomic function in subjects with MCI by means of power spectral analysis (PSA) of heart rate variability (HRV) at rest and during provocative manoeuvres.MethodsThis cross-sectional study involved 80 older outpatients (aged ≥65) consecutively referred to a geriatric unit and diagnosed with MCI or normal cognition (controls) based on neuropsychological testing. PSA was performed on 5-minute electrocardiographic recordings under three conditions—supine rest with free breathing (baseline), supine rest with paced breathing at 12 breaths/minute (parasympathetic stimulation), and active standing (orthosympathetic stimulation)—with particular focus on the changes from baseline to stimulation of indices of sympathovagal balance: normalized low frequency (LFn) and high frequency (HFn) powers and the LF/HF ratio. Blood pressure (BP) was measured at baseline and during standing. Given its exploratory nature in a clinical population the study included subjects on medications with a potential to affect HRV.ResultsThere were no significant differences in HRV indices between the two groups at baseline. MCI subjects exhibited smaller physiological changes in all three HRV indices during active standing, consistently with a dysfunction of the orthosympathetic system. Systolic BP after 10 minutes of standing was lower in MCI subjects, suggesting dysautonomia-related orthostatic BP dysregulation.ConclusionsOur study is novel in providing evidence of autonomic dysfunction in MCI. This is associated with orthostatic BP dysregulation and the ongoing follow-up of the study population will determine its prognostic relevance as a predictor of adverse health outcomes.

Intraoperative Echocardiography in Valvular Heart Disease: An Evidence-Based Appraisal

Thrombolytic agents are widely used for the treatment of acute thromboembolic diseases, especially acute myocardial infarction (AMI). These compounds include streptokinase, anistreplase, alteplase, urokinase and, although not commercially available yet, saruplase (prourokinase). The therapeutic window of these compounds is relatively small and subtherapeutic or toxic plasma concentrations may have serious clinical implications (insufficient thrombolysis, reocclusion and bleeding). Among the factors that affect the pharmacokinetics and pharmacodynamics of thrombolytic agents, comedication is especially relevant since these drug interactions are partly predictable and sometimes preventable. Based on knowledge of the pharmacology of thrombolytic agents and general mechanisms by which pharmacokinetic drug interactions occur, interactions with alteplase and saruplase are expected. The clearance of alteplase is dependent on hepatic blood flow (HBF), and scientific evidence is emerging that saruplase is also a high-clearance compound. Each pharmacological agent that alters HBF and is given concurrently with one of these agents can change the plasma concentrations of those thrombolytics. Although there are no published data confirming drug-induced changes in the metabolism of alteplase or saruplase by this mechanism in humans, indirect supportive evidence (clinical observations and animal experiments) is available. An overview is presented of the anticipated effects of compounds that are frequently coadministered with thrombolytic agents on the pharmacokinetics of the thrombolytics with high-clearance properties. Since the clearance of these thrombolytics may be strongly affected by hypoperfusion of the liver as a result of cardiogenic haemodynamic failure, the role of circulatory changes in potential drug-drug interactions is also discussed. Pharmacodynamic drug interactions are highly relevant in the treatment of acute thrombotic lesions and are still being evaluated to further optimise treatment strategies. As most of these treatments exist as combinations of thrombolytic, antithrombin and antiplatelet compounds, beneficial effects are partly offset by bleeding complications. Changes in the pharmacokinetics and/or pharmacodynamics of thrombolytic agents may have serious consequences. It becomes imperative for the practising physician to be aware of benefits and risks of interactions with thrombolytic agents and especially of the fact that the principal way by which the pharmacokinetics of alteplase and, presumably, saruplase can be affected is by drug- and/or haemodynamic failure-induced changes of HBF.

The efficacy of orthobiologic therapies, such as platelet-rich plasma (PRP) and concentrated bone marrow aspirate (cBMA), is influenced by not only the biologic product but also the patient's systemic biological milieu. Emerging preclinical and clinical evidence suggests that modifiable metabolic factors, including obesity, insulin resistance, chronic low-grade inflammation, inflammaging, sarcopenia, dysbiosis, poor sleep, and lifestyle behaviors such as smoking and alcohol use, can impair tissue regeneration and reduce the effectiveness of orthobiologics. A structured approach guided article selection. Searches in PubMed, Embase, and Scopus through July 2025 were supplemented by reference checking. Terms included "metabolic optimization," "obesity," "insulin resistance," "inflammation," "sarcopenia," "dysbiosis," "sleep," "orthobiologics," "PRP," and "bone marrow aspirate." Preclinical and clinical studies, mechanistic reviews, and meta-analyses assessing the impact of metabolic factors on musculoskeletal regeneration and orthobiologic outcomes were included. Only English-language articles relevant to mechanisms, clinical implications, or patient optimization were considered. Narrative review. Level 5. Evidence-based strategies to optimize metabolic health include targeted exercise, nutritional optimization, pharmacologic interventions, sleep regulation, microbiome support, and behavioral counseling for tobacco and alcohol cessation. While clinical evidence remains limited and of low methodological rigor, preclinical and available clinical studies support the plausibility, safety, and potential efficacy of these interventions. Optimizing metabolic factors can enhance tissue responsiveness, reduce interpatient variability, and improve orthobiologic therapy outcomes. Optimizing metabolic health before orthobiologic therapy improves the biological environment and regenerative outcomes. Screening and managing factors such as insulin resistance, chronic inflammation, and poor sleep are essential. Further randomized controlled trials and biomarker-guided studies are needed to validate strategies and personalize interventions.Strength-of-Recommendation Taxonomy (SORT):C: Supported mostly by preclinical and indirect clinical evidence.

Autoimmunity and COPD: Clinical Implications

The diagnosis of Barrett's esophagus: goblets, goblets, goblets

Hydroxy-methylglutaryl coenzyme A reductase-inhibitors (HMG-CoA [statins]) are currently the most effective method to pharmacologically decrease total plasma cholesterol levels. A number of multicenter studies have demonstrated, that statins administered for several years lead to a significant reduction of cardiovascular events and mortality compared with placebo. Apart from the well known LDL- and cholesterol lowering effect, statins have been postulated to exert beneficial effects on mortality due to so called 'non-lipid effects'. There is circumstantial evidence from a number of experimental studies that statins can improve endothelial function, exert anti-inflammatory and anti-oxidative effects, stabilize arteriosclerotic plaque and inhibit proliferation and activation of smooth muscle cells. However, the clinical implications of these beneficial 'non-lipid effects' are unclear, but appear to exert only a minor role in comparison to the lowering effect of statins on total plasma cholesterol levels.

Painful Dry Eye Symptoms: A Nerve Problem or a Tear Problem?