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Resting state fMRI has been employed to identify alterations in functional connectivity within or between brain regions following acute and chronic exposure to Δ9-tetrahydrocannabinol (THC), the psychoactive component in cannabis. Most studies focused a priori on a limited number of local brain areas or circuits, without considering the impact of cannabis on whole-brain network organization. The present study attempted to identify changes in the whole-brain human functional connectome as assessed with ultra-high field (7T) resting state scans of cannabis users (N = 26) during placebo and following vaporization of cannabis. Two distinct data-driven methodologies, i.e. network-based statistics (NBS) and connICA, were used to identify changes in functional connectomes associated with acute cannabis intoxication and history of cannabis use. Both methodologies revealed a broad state of hyperconnectivity within the entire range of major brain networks in chronic cannabis users compared to occasional cannabis users, which might be reflective of an adaptive network reorganization following prolonged cannabis exposure. The connICA methodology also extracted a distinct spatial connectivity pattern of hypoconnectivity involving the dorsal attention, limbic, subcortical and cerebellum networks and of hyperconnectivity between the default mode and ventral attention network, that was associated with the feeling of subjective high during THC intoxication. Whole-brain network approaches identified spatial patterns in functional brain connectomes that distinguished acute from chronic cannabis use, and offer an important utility for probing the interplay between short and long-term alterations in functional brain dynamics when progressing from occasional to chronic use of cannabis.
Colorectal cancer (CRC) is one of the most common tumor entities worldwide and a common cause of cancer-associated death. Colorectal cancer liver metastases (CRLM) thereby constitute a severe life-limiting factor. The therapy of CRLM presents a major challenge and surgical resection as well as systemic chemotherapy remain the first-line treatment options. Over the years several locoregional, vascular- and image-based treatments offered by interventional radiologists have emerged when conventional therapies fail, or metastases recurrence occurs. Among such options is the conventional/traditional transarterial chemoembolization (cTACE) by local injection of a combination of chemotherapeutic- and embolic-agents. A similar treatment is the more recent irinotecan-loaded drug-eluting beads TACE (DEBIRI-TACE), which are administered using the same approach. Numerous studies have shown that these different types of chemoembolization can be applied in different clinical settings safely. Furthermore, such treatments can also be combined with other local or systemic therapies. Unfortunately, due to the incoherent patient populations of studies investigating TACE in CRLM, critics state that the definite evidence supporting positive patient outcomes is still lacking. In the following article we review studies on conventional and DEBIRI-TACE. Although highly dependent on the clinical setting, prior therapies and generally the study population, cTACE and DEBIRI-TACE show comparable results. We present the most representative studies on the different chemoembolization procedures and compare the results. Although there is compelling evidence for both approaches, further studies are necessary to determine which patients profit most from these therapies. In conclusion, we determine TACE to be a viable option in CRLM in different clinical settings. Nevertheless, a multidisciplinary approach is desired to offer patients the best possible care.
Low platelet count predicts reduced survival in potentially resectable hepatocellular carcinoma
(2022)
The prognostic role of platelet count in hepatocellular carcinoma (HCC) remains unclear, and in fact both thrombocytopenia and thrombocytosis are reported as predictors of unfavourable outcomes. This study aimed to clarify the prognostic value of preoperative platelet count in potentially resectable HCC. We retrospectively reviewed 128 patients who underwent hepatic resection for HCC at a tertiary academic centre (2007–2019). Patient data were modelled by regression analysis, and platelet count was treated as a continuous variable. 89 patients had BCLC 0/A tumours and 39 had BCLC B tumours. Platelet count was higher in patients with larger tumours and lower in patients with higher MELD scores, advanced fibrosis, and portal hypertension (p < 0.001 for all listed variables). After adjusting for BCLC stage and tumour diameter, low platelet count associated with reduced overall survival (hazard ratio 1.25 per 50/nL decrease in platelet count, 95% confidence interval (CI) 1.02–1.53, p = 0.034) and increased perioperative mortality (odds ratio 1.96 per 50/nL decrease in platelet count, 95% CI 1.19–3.53, p = 0.014). Overall, low platelet count correlates with increased liver disease severity, inferior survival, and excess perioperative mortality in resectable HCC. These insights might be applied in clinical practice to better select patients for resection.
Immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and psoriasis (Ps), represent autoinflammatory and autoimmune disorders, as well as conditions that have an overlap of both categories. Understanding the underlying pathogeneses, making diagnoses, and choosing individualized treatments remain challenging due to heterogeneous disease phenotypes and the lack of reliable biomarkers that drive the treatment choice. In this review, we provide an overview of the low-molecular-weight metabolites that might be employed as biomarkers for various applications, e.g., early diagnosis, disease activity monitoring, and treatment-response prediction, in RA, PsA, and Ps. The literature was evaluated, and putative biomarkers in different matrices were identified, categorized, and summarized. While some of these candidate biomarkers appeared to be disease-specific, others were shared across multiple IMIDs, indicating common underlying disease mechanisms. However, there is still a long way to go for their application in a routine clinical setting. We propose that studies integrating omics analyses of large patient cohorts from different IMIDs should be performed to further elucidate their pathomechanisms and treatment options. This could lead to the identification and validation of biomarkers that might be applied in the context of precision medicine to improve the clinical outcomes of these IMID patients.
Objective In rheumatoid arthritis (RA), chronic inflammation can enhance the development of sarcopenia with a depletion of muscle mass, strength and performance. Currently, a consensus definition for sarcopenia and solid results for the prevalence of sarcopenia in patients with RA are lacking.
Methods In this cross-sectional study, 289 patients ≥18 years with RA were recruited. Dual X-ray absorptiometry was performed to measure appendicular lean mass. Assessment of muscle function included grip strength, gait speed and chair rise time. Prevalence of sarcopenia was defined using the updated European Working Group on Sarcopenia in Older People (EWGSOP2) and the Foundation for the National Institutes of Health (FNIH) definition. In addition, the RA study population was compared with existing data of healthy controls (n=280).
Results 4.5% of patients (59.4±11.3 years) and 0.4% of controls (62.9±11.9 years) were affected by sarcopenia according to the EWGSOP2 definition. Body weight (OR 0.92, 95% CI 0.86 to 0.97), body mass index (BMI) (OR 0.70, 95% CI 0.57 to 0.87), C reactive protein (CRP) (OR 1.05, 95% CI 1.01 to 1.10), disease duration (OR 1.08, 95% CI 1.02 to 1.36), current medication with glucocorticoids (OR 5.25, 95% CI 2.14 to 24.18), cumulative dose of prednisone equivalent (OR 1.04, 95% CI 1.02 to 1.05) and Health Assessment Questionnaire (HAQ) (OR 2.50, 95% CI 1.27 to 4.86) were associated with sarcopenia in patients with RA. In contrast, the prevalence was 2.8% in patients compared with 0.7% in controls when applying the FNIH definition, and body height (OR 0.75, 95% CI 0.64 to 0.88), BMI (OR 1.20, 95% CI 1.02 to 1.41), CRP (OR 1.06, 95% CI 1.01 to 1.11) and HAQ (OR 2.77, 95% CI 1.17 to 6.59) were associated with sarcopenia.
Conclusion Sarcopenia is significantly more common in patients with RA compared with controls using the EWGSOP2 criteria. The FNIH definition revealed sarcopenia in individuals with high BMI and fat mass, regardless of the presence of RA.
Trial registration number It was registered at the German Clinical Trials Registry (DRKS) as well as WHO Clinical Trials Registry (ICTRP) (DRKS00011873, registered on 16 March 2017).
We report a case of a 2-day-old neonate with bilious vomiting and abdominal distension. A small bowel obstruction with ileal perforation due to a misplaced clamping of the umbilical cord was apparent before laparotomy. This complication was a sequala after clamping the cord too close to the abdominal wall in a case where there was a hernia into the cord with intestinal content. A herniation of abdominal contents due to an omphalocele minor or a hernia must be taken into consideration during the inspection of the umbilical cord before clamping.
Patients with coronavirus disease 19 (COVID-19) commonly show abnormalities of liver tests (LTs) of undetermined cause. Considering drugs as tentative culprits, the current systematic review searched for published COVID-19 cases with suspected drug-induced liver injury (DILI) and established diagnosis using the diagnostic algorithm of RUCAM (Roussel Uclaf Causality Assessment Method). Data worldwide on DILI cases assessed by RUCAM in COVID-19 patients were sparse. A total of 6/200 reports with initially suspected 996 DILI cases in COVID-19 patients and using all RUCAM-based DILI cases allowed for a clear description of clinical features of RUCAM-based DILI cases among COVID-19 patients: (1) The updated RUCAM published in 2016 was equally often used as the original RUCAM of 1993, with both identifying DILI and other liver diseases as confounders; (2) RUCAM also worked well in patients treated with up to 18 drugs and provided for most DILI cases a probable or highly probable causality level for drugs; (3) DILI was preferentially caused by antiviral drugs given empirically due to their known therapeutic efficacy in other virus infections; (4) hepatocellular injury was more often reported than cholestatic or mixed injury; (5) maximum LT values were found for alanine aminotransferase (ALT) 1.541 U/L and aspartate aminotransferase (AST) 1.076 U/L; (6) the ALT/AST ratio was variable and ranged from 0.4 to 1.4; (7) the mean or median age of the COVID-19 patients with DILI ranged from 54.3 to 56 years; (8) the ratio of males to females was 1.8–3.4:1; (9) outcome was favorable for most patients, likely due to careful selection of the drugs and quick cessation of drug treatment with emerging DILI, but it was fatal in 19 patients; (10) countries reporting RUCAM-based DILI cases in COVID-19 patients included China, India, Japan, Montenegro, and Spain; (11) robust estimation of the percentage contribution of RUCAM-based DILI for the increased LTs in COVID-19 patients is outside of the current scope. In conclusion, RUCAM-based DILI with its clinical characteristics in COVID-19 patients and its classification as a confounding variable is now well defined, requiring a new correct description of COVID-19 features by removing DILI characteristics as confounders.
Complexome profiling (CP) is a powerful tool for systematic investigation of protein interactors that has been primarily applied to study the composition and dynamics of mitochondrial protein complexes. Here, we further optimised this method to extend its application to survey mitochondrial DNA- and RNA-interacting protein complexes. We established that high-resolution clear native gel electrophoresis (hrCNE) is a better alternative to preserve DNA- and RNA-protein interactions that are otherwise disrupted when samples are separated by the widely used blue native gel electrophoresis (BNE). In combination with enzymatic digestion of DNA, our CP approach improved the identification of a wide range of protein interactors of the mitochondrial gene expression system without compromising the detection of other multi-protein complexes. The utility of this approach was particularly demonstrated by analysing the complexome changes in human mitochondria with impaired gene expression after transient, chemically-induced mtDNA depletion. Effects of RNase on mitochondrial protein complexes were also evaluated and discussed. Overall, our adaptations significantly improved the identification of mitochondrial DNA- and RNA-protein interactions by CP, thereby unlocking the comprehensive analysis of a near-complete mitochondrial complexome in a single experiment.