Background
Routine colonoscopy was traditionally recommended after acute diverticulitis to exclude coexistent malignancy. Improved CT imaging may make routine colonoscopy less required over time but ...most guidelines still recommend it. The aim of this review was to assess the role of colonoscopy in patients with CT‐proven acute diverticulitis.
Methods
PubMed and Embase were searched for studies reporting the prevalence of advanced colorectal neoplasia (ACN) or colorectal carcinoma in patients who underwent colonoscopy within 1 year after CT‐proven left‐sided acute diverticulitis. The prevalence was pooled using a random‐effects model and, if possible, compared with that among asymptomatic controls.
Results
Seventeen studies with 3296 patients were included. The pooled prevalence of ACN was 6·9 (95 per cent c.i. 5·0 to 9·4) per cent and that of colorectal carcinoma was 2·1 (1·5 to 3·1) per cent. Only two studies reported a comparison with asymptomatic controls, showing comparable risks (risk ratio 1·80, 95 per cent c.i. 0·66 to 4·96). In subgroup analysis of patients with uncomplicated acute diverticulitis, the prevalence of colorectal carcinoma was only 0·5 (0·2 to 1·2) per cent.
Conclusion
Routine colonoscopy may be omitted in patients with uncomplicated diverticulitis if CT imaging is otherwise clear. Patients with complicated disease or ongoing symptoms should undergo colonoscopy.
This systematic review demonstrates that the prevalence of colorectal cancer in all patients with diverticulitis is slightly higher than in controls, whereas patients with uncomplicated diverticulitis have a colorectal cancer prevalence comparable to that of asymptomatic controls from the literature. Therefore, routine colonoscopy should be omitted in those with uncomplicated diverticulitis and these patients may be referred back to the colorectal cancer screening programme. However, routine colonoscopy should remain the protocol for differential diagnosis after non‐surgical treatment of complicated diverticulitis.
Not needed routinely
Chemotherapy treatment of metastatic colon cancer ultimately fails due to development of drug resistance. Identification of chemotherapy-induced changes in tumor biology may provide insight into drug ...resistance mechanisms.
We studied gene expression differences between groups of liver metastases that were exposed to preoperative chemotherapy or not. Multiple patient-derived colonosphere cultures were used to assess how chemotherapy alters energy metabolism by measuring mitochondrial biomass, oxygen consumption, and lactate production. Genetically manipulated colonosphere-initiated tumors were used to assess how altered energy metabolism affects chemotherapy efficacy.
Gene ontology and pathway enrichment analysis revealed significant upregulation of genes involved in oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis in metastases that were exposed to chemotherapy. This suggested chemotherapy induces a shift in tumor metabolism from glycolysis towards OXPHOS. Indeed, chemotreatment of patient-derived colonosphere cultures resulted in an increase of mitochondrial biomass, increased expression of respiratory chain enzymes, and higher rates of oxygen consumption. This was mediated by the histone deacetylase sirtuin-1 (SIRT1) and its substrate, the transcriptional coactivator PGC1α. Knockdown of SIRT1 or PGC1α prevented chemotherapy-induced OXPHOS and significantly sensitized patient-derived colonospheres as well as tumor xenografts to chemotherapy.
Chemotherapy of colorectal tumors induces a SIRT1/PGC1α-dependent increase in OXPHOS that promotes tumor survival during treatment. This phenomenon is also observed in chemotherapy-exposed resected liver metastases, strongly suggesting that chemotherapy induces long-lasting changes in tumor metabolism that potentially interfere with drug efficacy. In conclusion, we propose a novel mechanism of chemotherapy resistance that may be clinically relevant and therapeutically exploitable.
We present the stellar atmospheric parameters (effective temperature, surface gravity, overall metallicity), radial velocities, individual abundances, and distances determined for 425,561 stars, ...which constitute the fourth public data release of the RAdial Velocity Experiment (RAVE). The stellar atmospheric parameters are computed using a new pipeline, based on the algorithms of MATISSE and DEGAS. The spectral degeneracies and the Two Micron All Sky Survey photometric information are now better taken into consideration, improving the parameter determination compared to the previous RAVE data releases. The individual abundances for six elements (magnesium, aluminum, silicon, titanium, iron, and nickel) are also given, based on a special-purpose pipeline that is also improved compared to that available for the RAVE DR3 and Chemical DR1 data releases. Together with photometric information and proper motions, these data can be retrieved from the RAVE collaboration Web site and the Vizier database.
Mitochondrial dysfunction is involved in many complex diseases. Efficient and accurate evaluation of mitochondrial functionality is crucial for understanding pathology as well as facilitating novel ...therapeutic developments. As a popular platform, Seahorse extracellular flux (XF) analyzer is widely used for measuring mitochondrial oxygen consumption rate (OCR) in living cells. A hidden feature of Seahorse XF OCR data is that it has a complex data structure, caused by nesting and crossing between measurement cycles, wells and plates. Surprisingly, statistical analysis of Seahorse XF data has not received sufficient attention, and current methods completely ignore the complex data structure, impairing the robustness of statistical inference.
To rigorously incorporate the complex structure into data analysis, here we developed a Bayesian hierarchical modeling framework, OCRbayes, and demonstrated its applicability based on analysis of published data sets.
We showed that OCRbayes can analyze Seahorse XF OCR experimental data derived from either single or multiple plates. Moreover, OCRbayes has potential to be used for diagnosing patients with mitochondrial diseases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Our aim was to gain insight into the effect of COVID-19 measures on SARS-CoV-2 incidence in secondary schools and the association with classroom CO
concentration and airborne contamination.
Between ...October 2020-June 2021, 18 schools weekly reported SARS-CoV-2 incidence and completed surveys on school-initiated COVID-19 measures (e.g. improving hygiene or minimizing contacts). CO
was measured in occupied classrooms twice, and SARS-CoV-2 air contamination longitudinally using electrostatic dust collectors (EDC) and analyzed using RT-qPCR. National COVID-19 policy measures varied during pre-lockdown, lockdown and post-lockdown periods. During the entire study, schools were recommended to improve ventilation. SARS-CoV-2 incidence rate ratios (IRR) were estimated by Generalized Estimating Equation (GEE) models.
During 18 weeks follow-up (range: 10-22) SARS-CoV-2 school-incidence decreased during national lockdown (adjusted IRR: 0.41, 95%CI: 0.21-0.80) and post-lockdown (IRR: 0.60, 0.39-0.93) compared to pre-lockdown. School-initiated COVID-19 measures had no additional effect. Pre-lockdown, IRRs per 10% increase in time CO
exceeded 400, 550 and 800 ppm above outdoor level respectively, were 1.08 (1.00-1.16), 1.10 (1.02-1.19), and 1.08 (0.95-1.22). Post-lockdown, CO
concentrations were considerably lower and not associated with SARS-CoV-2 incidence. No SARS-CoV-2 RNA was detected in any of the EDC samples.
During a period with low SARS-CoV-2 population immunity and increased attention to ventilation, with CO
levels most of the time below acceptable thresholds, only the national policy during and post-lockdown of reduced class-occupancy, stringent quarantine, and contact testing reduced SARS-CoV-2 incidence in Dutch secondary schools. Widespread SARS-CoV-2 air contamination could not be demonstrated in schools under the prevailing conditions during the study.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
The recovery of muscle oxygen consumption (m
V
˙
O
2
) after exercise provides a measure of skeletal muscle mitochondrial capacity, as more and better-functioning mitochondria will be able to ...restore m
V
˙
O
2
faster to the pre-exercise state. The aim was to measure muscle mitochondrial capacity using near-infrared spectroscopy (NIRS) within a healthy, normally active population and relate this to parameters of aerobic fitness, investigating the applicability and relevance of using NIRS to assess muscle mitochondrial capacity non-invasively.
Methods
Mitochondrial capacity was analysed in the gastrocnemius and flexor digitorum superficialis (FDS) muscles of eight relatively high-aerobic fitness (
V
˙
O
2
peak ≥ 57 mL/kg/min) and eight relatively low-aerobic fitness male subjects (
V
˙
O
2
peak ≤ 47 mL/kg/min). Recovery of whole body
V
˙
O
2
, i.e. excess post-exercise oxygen consumption (EPOC) was analysed after a cycling protocol.
Results
Mitochondrial capacity, as analysed using NIRS, was significantly higher in high-fitness individuals compared to low-fitness individuals in the gastrocnemius, but not in the FDS (
p
= 0.0036 and
p
= 0.20, respectively). Mitochondrial capacity in the gastrocnemius was significantly correlated with
V
˙
O
2
peak (
R
2
= 0.57,
p
= 0.0019). Whole body
V
˙
O
2
recovery was significantly faster in the high-fitness individuals (
p
= 0.0048), and correlated significantly with mitochondrial capacity in the gastrocnemius (
R
2
= 0.34,
p
= 0.028).
Conclusion
NIRS measurements can be used to assess differences in mitochondrial muscle oxygen consumption within a relatively normal, healthy population. Furthermore, mitochondrial capacity correlated with parameters of aerobic fitness (
V
˙
O
2
peak and EPOC), emphasising the physiological relevance of the NIRS measurements.
Abstract
Background
Currently thioguanine is solely used as treatment for inflammatory bowel disease after azathioprine and/or mercaptopurine failure. This study aimed to determine the safety, ...effectiveness, and 12-month drug survival of thioguanine in thiopurine-naïve patients with inflammatory bowel disease.
Methods
A retrospective cohort study was performed in thiopurine-naïve patients with inflammatory bowel disease treated with thioguanine as first thiopurine derivate. Clinical effectiveness was defined as the continuation of thioguanine without the (re)initiation of concurrent biological therapy, systemic corticosteroids, or a surgical intervention. All adverse events were categorized by the Common Terminology Criteria for Adverse Events.
Results
A total of 114 patients (male 39%, Crohn’s disease 53%) were included with a median treatment duration of 25 months and a median thioguanine dosage of 20 mg/d. Clinical effectiveness at 12 months was observed in 53% of patients, and 78% of these responding patients remained responsive until the end of follow-up. During the entire follow-up period, 26 patients were primary nonresponders, 8 had a secondary loss of response, and 11 patients were unable to cease therapy with systemic corticosteroids within 6 months and were therefore classified as nonresponders. After 12 months, thioguanine was still used by 86% of patients. Fifty (44%) patients developed adverse events (grade 1 or 2) and 9 (8%) patients ceased therapy due to the occurrence of adverse events. An infection was documented in 3 patients, none of them requiring hospitalization and pancytopenia occurred in 2 other patients. No signs of nodular regenerative hyperplasia or portal hypertension were observed.
Conclusions
At 12 months, first-line thioguanine therapy was clinically effective in 53% of thiopurine-naïve inflammatory bowel disease patients with an acceptable safety profile.
Summary Background & aims Oxidative stress and low antioxidant levels are implicated in the aetiology of sarcoidosis, an inflammatory disease. Quercetin is a potent dietary antioxidant that also ...displays anti-inflammatory activities. Consequently, the aim is to examine the effect of quercetin supplementation on markers of oxidative stress and inflammation in sarcoidosis. Methods A double-blind intervention study has been conducted with two groups of non-smoking, un-treated sarcoidosis patients, matched for age and gender. One group was given 4x500 mg quercetin ( n = 12) orally within 24 h, the other one placebo ( n = 6). Plasma malondialdehyde levels were used as marker of oxidative damage, plasma ratios of TNFα/IL-10 and IL-8/IL-10 as pro-inflammatory markers. Results Quercetin supplementation improved the antioxidant defence, indicated by the increased total plasma antioxidant capacity. Moreover, quercetin supplementation also reduced markers of oxidative stress and inflammation in the blood of sarcoidosis patients. The effects of quercetin supplementation appeared to be more pronounced when the levels of the oxidative stress and inflammation markers were higher at baseline. Conclusions Sarcoidosis patients might benefit from the use of antioxidants, such as quercetin, to reduce the occurring oxidative stress as well as inflammation. The effects of long-term use of antioxidant supplementation in sarcoidosis, using e.g. quercetin, on improvement of lung function remain to be investigated. ( www.clinicaltrials.gov ; NCT-00402623).
Intronic single‐nucleotide polymorphisms (SNPs) in FOXO3A are associated with human longevity. Currently, it is unclear how these SNPs alter FOXO3A functionality and human physiology, thereby ...influencing lifespan. Here, we identify a primate‐specific FOXO3A transcriptional isoform, FOXO3A‐Short (FOXO3A‐S), encoding a major longevity‐associated SNP, rs9400239 (C or T), within its 5′ untranslated region. The FOXO3A‐S mRNA is highly expressed in the skeletal muscle and has very limited expression in other tissues. We find that the rs9400239 variant influences the stability and functionality of the primarily nuclear protein(s) encoded by the FOXO3A‐S mRNA. Assessment of the relationship between the FOXO3A‐S polymorphism and peripheral glucose clearance during insulin infusion (Rd clamp) in a cohort of Danish twins revealed that longevity T‐allele carriers have markedly faster peripheral glucose clearance rates than normal lifespan C‐allele carriers. In vitro experiments in human myotube cultures utilizing overexpression of each allele showed that the C‐allele represses glycolysis independently of PI3K signaling, while overexpression of the T‐allele represses glycolysis only in a PI3K‐inactive background. Supporting this finding inducible knockdown of the FOXO3A‐S C‐allele in cultured myotubes increases the glycolytic rate. We conclude that the rs9400239 polymorphism acts as a molecular switch which changes the identity of the FOXO3A‐S‐derived protein(s), which in turn alters the relationship between FOXO3A‐S and insulin/PI3K signaling and glycolytic flux in the skeletal muscle. This critical difference endows carriers of the FOXO3A‐S T‐allele with consistently higher insulin‐stimulated peripheral glucose clearance rates, which may contribute to their longer and healthier lifespans.
Genetic studies of humans have identified the gene FOXO3A to be associated with longevity. Here, we describe how a primate‐specific form of FOXO3A which is regulated by a FOXO3A locus longevity variant functions to control insulin sensitivity in the skeletal muscle. This discovery demonstrates a potentially causative relationship between increased glucose clearance and longer life in humans and provides a molecular tool for further discovery of genes regulating human longevity.
CASSIOPEIA part 1 showed superior depth of response and significantly improved progression-free survival with daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, ...thalidomide, and dexamethasone (VTd) as induction and consolidation in patients with autologous stem-cell transplant (ASCT)-eligible newly diagnosed multiple myeloma. In part 2, we compared daratumumab maintenance versus observation only.
CASSIOPEIA is a two-part, open-label, randomised, phase 3 trial of patients aged 18–65 years with newly diagnosed multiple myeloma and Eastern Cooperative Oncology Group performance status 0–2, done in 111 European academic and community practice centres. In part 1, patients were randomly assigned (1:1) to induction and consolidation with D-VTd or VTd. Patients still on study who had a partial response or better were randomly assigned (1:1) by an interactive web-response system to daratumumab 16 mg/kg intravenously every 8 weeks (a reduced frequency compared with standard daratumumab long-term dosing) or observation only for up to 2 years. Stratification factors were induction treatment and depth of response in part 1. The part 2 primary endpoint was progression-free survival from second randomisation. This preplanned interim analysis of progression-free survival was done after 281 events and shall be considered the primary analysis of progression-free survival. Sponsor personnel and designees who were involved in the analysis were masked to treatment group until the independent data monitoring committee recommended that the preplanned interim analysis be considered the main analysis of progression-free survival in part 2. Otherwise, treatment assignments were unmasked. The interaction between induction and consolidation and maintenance was tested at a two-sided significance level of 0·05 by a stratified Cox regression model that included the interaction term between maintenance treatment and induction and consolidation treatment. Efficacy analyses were done in the maintenance-specific intention-to-treat population, which comprised all patients who underwent second randomisation. Safety was analysed in all patients in the daratumumab group who received at least one dose and all patients randomly assigned to observation only. This trial is registered with ClinicalTrials.gov, NCT02541383. Long-term follow-up is ongoing and the trial is closed to new participants.
Between May 30, 2016, and June 18, 2018, 886 patients (458 84% of 543 in the D-VTd group and 428 79% of 542 in the VTd group) were randomly assigned to daratumumab maintenance (n=442) or observation only (n=444). At a median follow-up of 35·4 months (IQR 30·2–39·9) from second randomisation, median progression-free survival was not reached (95% CI not evaluable NE–NE) with daratumumab versus 46·7 months (40·0–NE) with observation only (hazard ratio 0·53, 95% CI 0·42–0·68, p<0·0001). A prespecified analysis of progression-free survival results showed a significant interaction between maintenance and induction and consolidation therapy (p<0·0001). The most common grade 3 or 4 adverse events were lymphopenia (16 4% of 440 patients in the daratumumab group vs eight 2% of 444 patients in the observation-only group), hypertension (13 3% vs seven 2%), and neutropenia (nine 2% vs ten 2%). Serious adverse events occurred in 100 (23%) patients in the daratumumab group and 84 (19%) patients in the observation-only group. In the daratumumab group, two adverse events led to death (septic shock and natural killer-cell lymphoblastic lymphoma); both were related to treatment.
Daratumumab maintenance every 8 weeks for 2 years significantly reduced the risk of disease progression or death compared with observation only. Longer follow-up and other ongoing studies will shed further light on the optimal daratumumab-containing post-ASCT maintenance treatment strategy.
Janssen Research & Development, the Intergroupe Francophone du Myélome, and the Dutch-Belgian Cooperative Trial Group for Hematology Oncology.
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