Time synchronization for an Ethernet-based real-time token network

We present a distributed clock synchronization algorithm. It performs clock synchronization on an Ethernet-based real-time token local area network, without the use of an external clock source. It is used to enable the token schedulers in each node to agree upon a common time. Its intended use is in resource-lean systems, where heavyweight protocols like NTP cannot be used. We present a short overview of the working of the protocol, as well as experimental results

Intrahepatic cholangiocarcinoma in a non-cirrhotic liver in a patient with homozygous ZZ alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin (AAT) deficiency, which is an under-recognised metabolic genetic disorder, is known to cause severe lung disease and liver cirrhosis in about 10%-15% of cases. Patients with AAT deficiency are at a higher risk for developing hepatocellular carcinoma, both in cirrhotic and in non-cirrhotic livers. In this case report, a 48-year-old woman with homozygous ZZ AAT deficiency presented with abdominal pain, and by imaging, an abnormal area in the liver was found. The initial differential diagnosis consisted of benign abnormalities but a malignancy could not be ruled out. Finally, this abnormality turned out to be an intrahepatic cholangiocarcinoma (iCCA) in a non-cirrhotic liver. Since this type of tumour has been very infrequently described to be associated with AAT deficiency, the question remains whether alpha-1 trypsin accumulation in the hepatocytes was responsible for the development of iCCA. However, other associated factors for developing an iCCA were ruled out

Surgery for Ampullary Cancer in a Patient with Pancreatic Lipomatosis Caused by Cystic Fibrosis

A patient with cystic fibrosis (CF) with pancreatic insufficiency presented with jaundice due to an ampullary tumour. CF is known for a higher incidence of gastrointestinal malignancies. The patient suffered from pancreatic insufficiency. At computed tomography (CT), pancreatic lipomatosis with absence of the pancreatic duct was seen. This is uncommon, also in patients with CF. During surgery, a total pancreatectomy was performed, because there was no possibility to construct a duct to mucosa anastomosis due to the absence of the pancreatic duct and more importantly the pancreas was already afunctional. The presence of lipomatosis increases the risk of leakage at the pancreaticojejunal anastomosis. Therefore, it is important to take this phenomenon, in this case already visible on the preoperative CT scan, into account during the workup for surgery

Same-day discharge after appendectomy for acute appendicitis: a systematic review and meta-analysis

Purpose: Patients presenting with acute appendicitis are usually hospitalized for a few days for appendectomy and postoperative recovery. Shortening length of stay may reduce costs and improve patient satisfaction. The purpose of this study was to assess the safety of same-day discharge after appendectomy for acute appendicitis. Methods: A systematic review was performed according to PRISMA guidelines. A literature search of EMBASE, Ovid MEDLINE, Web of Science, Cochrane Central, and Google Scholar was conducted from inception to April 14, 2020. Two reviewers independently screened the literature and selected studies that addressed discharge on the same calendar day as the appendectomy. Risk of bias was assessed with the ROBINS-I tool. Main outcomes were hospital readmission, complications, and unplanned hospital visits in the postoperative course. A random effects model was used to pool risk ratios for the main outcomes. Results: Of the 1912 articles screened, 17 comparative studies and 8 non-comparative studies met the inclusion criteria. Most only included laparoscopic procedure for uncomplicated appendicitis. Most studies were considered at moderate or serious risk of bias. In meta-analysis, same-day discharge (vs. overnight hospitalization) was not associated with increased rates of readmission, complication, and unplanned hospital visits. Non-comparative studies demonstrated low rates of readmission, complications, and unplanned hospital visits after same-day discharge. Conclusion: This study suggests that same-day discharge after laparoscopic appendectomy for uncomplicated appendicitis is safe without an increased risk of readmission, complications, or unplanned hospital visits. Hence, same-day discharge may be further encouraged in selected patients. Trial registration: PROSPERO registration no. CRD4201811594

The USP7-TRIM27 axis mediates non-canonical PRC1.1 function and is a druggable target in leukemia

In an attempt to unravel functionality of the non-canonical PRC1.1 Polycomb complex in human leukemogenesis, we show that USP7 and TRIM27 are integral components of PRC1.1. USP7 interactome analyses show that PRC1.1 is the predominant Polycomb complex co-precipitating with USP7. USP7 inhibition results in PRC1.1 disassembly and loss of chromatin binding, coinciding with reduced H2AK119ub and H3K27ac levels and diminished gene transcription of active PRC1.1-controlled loci, whereas H2AK119ub marks are also lost at PRC1 loci. TRIM27 and USP7 are reciprocally required for incorporation into PRC1.1, and TRIM27 knockdown partially rescues USP7 inhibitor sensitivity. USP7 inhibitors effectively impair proliferation in AML cells in vitro, also independent of the USP7-MDM2-TP53 axis, and MLL-AF9-induced leukemia is delayed in vivo in human leukemia xenografts. We propose a model where USP7 counteracts TRIM27 E3 ligase activity, thereby maintaining PRC1.1 integrity and function. Moreover, USP7 inhibition may be a promising new strategy to treat AML patients

2 days versus 5 days of postoperative antibiotics for complex appendicitis:a pragmatic, open-label, multicentre, non-inferiority randomised trial

Background: The appropriate duration of postoperative antibiotics for complex appendicitis is unclear. The increasing global threat of antimicrobial resistance warrants restrictive antibiotic use, which could also reduce side-effects, length of hospital stay, and costs. Methods: In this pragmatic, open-label, non-inferiority trial in 15 hospitals in the Netherlands, patients with complex appendicitis (aged ≥8 years) were randomly assigned (1:1) to receive 2 days or 5 days of intravenous antibiotics after appendicectomy. Randomisation was stratified by centre, and treating physicians and patients were not masked to treatment allocation. The primary endpoint was a composite endpoint of infectious complications and mortality within 90 days. The main outcome was the absolute risk difference (95% CI) in the primary endpoint, adjusted for age and severity of appendicitis, with a non-inferiority margin of 7·5%. Outcome assessment was based on electronic patient records and a telephone consultation 90 days after appendicectomy. Efficacy was analysed in the intention-to-treat and per-protocol populations. Safety outcomes were analysed in the intention-to-treat population. This trial was registered with the Netherlands Trial Register, NL5946. Findings: Between April 12, 2017, and June 3, 2021, 13 267 patients were screened and 1066 were randomly assigned, 533 to each group. 31 were excluded from intention-to-treat analysis of the 2-day group and 30 from the 5-day group owing to errors in recruitment or consent. Appendicectomy was done laparoscopically in 955 (95%) of 1005 patients. The telephone follow-up was completed in 664 (66%) of 1005 patients. The primary endpoint occurred in 51 (10%) of 502 patients analysed in the 2-day group and 41 (8%) of 503 patients analysed in the 5-day group (adjusted absolute risk difference 2·0%, 95% CI −1·6 to 5·6). Rates of complications and re-interventions were similar between trial groups. Fewer patients had adverse effects of antibiotics in the 2-day group (45 [9%] of 502 patients) than in the 5-day group (112 [22%] of 503 patients; odds ratio [OR] 0·344, 95% CI 0·237 to 0·498). Re-admission to hospital was more frequent in the 2-day group (58 [12%] of 502 patients) than in the 5-day group (29 [6%] of 503 patients; OR 2·135, 1·342 to 3·396). There were no treatment-related deaths. Interpretation: 2 days of postoperative intravenous antibiotics for complex appendicitis is non-inferior to 5 days in terms of infectious complications and mortality within 90 days, based on a non-inferiority margin of 7·5%. These findings apply to laparoscopic appendicectomy conducted in a well resourced health-care setting. Adopting this strategy will reduce adverse effects of antibiotics and length of hospital stay. Funding: The Netherlands Organization for Health Research and Development.</p

Two versus five days of antibiotics after appendectomy for complex acute appendicitis (APPIC): Study protocol for a randomized controlled trial

Background: Acute appendicitis is one of the most common indications for emergency surgery. In patients with a complex appendicitis, prolonged antibiotic prophylaxis is recommended after appendectomy. There is no consensus regarding the optimum duration of antibiotics. Guidelines propose 3 to 7 days of treatment, but shorter courses may be as effective in the prevention of infectious complications. At the same time, the global issue of increasing antimicrobial resistance urges for optimization of antibiotic strategies. The aim of this study is to determine whether a short course (48 h) of postoperative antibiotics is non-inferior to current standard practice of 5 days. Methods: Patients of 8 years and older undergoing appendectomy for acute complex appendicitis - defined as a gangrenous and/or perforated appendicitis or appendicitis in presence of an abscess - are eligible for inclusion. Immunocompromised or pregnant patients are excluded, as well as patients with a contraindication to the study antibiotics. In total, 1066 patients will be randomly allocated in a 1:1 ratio to the experimental treatment arm (48 h of postoperative intravenously administered (IV) antibiotics) or the control arm (5 days of postoperative IV antibiotics). After discharge from the hospital, patients participate in a productivity-cost-questionnaire at 4 weeks and a standardized telephone follow-up at 90 days after appendectomy. The primary outcome is a composite endpoint of infectious complications, including intra-abdominal abscess (IAA) and surgical site infection (SSI), and mortality within 90 days after appendectomy. Secondary outcomes include IAA, SSI, restart of antibiotics, length of hospital stay (LOS), reoperation, percutaneous drainage, readmission rate, and cost-effectiveness. The non-inferiority margin for the difference in the primary endpoint rate is set at 7.5% (one-sided test at α 0.025). Both per-protocol and intention-to-treat analyses will be performed. Discussion: This trial will provide evidence on whether 48 h of postoperative antibiotics is non-inferior to a standard course of 5 days of antibiotics. If non-inferiority is established, longer intravenous administration following appendectomy for complex appendicitis can be abandoned, and guidelines need to be adjusted accordingly

Early intervention with inhaled corticosteroids in subjects with rapid decline in lung function and signs of bronchial hyperresponsiveness: results from the DIMCA programme.

Contains fulltext : 51862.pdf (publisher's version ) (Open Access)BACKGROUND: Asthma is generally accepted as an inflammatory disease that needs steroid treatment. However, when to start with inhaled steroids remains unclear. A study was undertaken to determine when inhaled corticosteroids should be introduced as the first treatment step. OBJECTIVE: To investigate the effectiveness of early introduction of inhaled steroids on decline in lung function in steroid-naive subjects with a rapid decline in lung function in general practice. SUBJECTS: Patients with signs/symptoms suspect of asthma (i.e., persistent and/or recurrent respiratory symptoms) and a decline in forced expiratory volume in 1 s (FEV(1)) during 1-year monitoring of 0.080 l or more and reversible obstruction (> or =10% predicted) or bronchial hyperresponsiveness (PC(20)< or =8 mg/ml) were studied. They had been identified in a population screening aiming to detect subjects at risk for chronic obstructive pulmonary disease (COPD) or asthma. DESIGN: A placebo-controlled, randomized, double-blind study. METHODS: 75 subjects out of a random population of 1155 were found eligible, and 45 were willingly to participate. Subjects were randomly treated with placebo or fluticasone propionate 250 microg b.i.d., and FEV(1) and PC(20) were monitored over a 2-year period. OUTCOME VARIABLES: The primary outcome measure was decline in FEV(1); the secondary outcome measure was bronchial hyperresponsiveness (PC(20)). RESULTS: 22 subjects were randomly allocated to the active group with inhaled corticosteroids and 23 to placebo. Change of FEV(1) in the active treated group was +43 ml in post-bronchodilator FEV(1) (p =0.341) and +62 ml/year (p =0.237) in pre-bronchodilator FEV(1) after 1 year, and -22 ml (p =0.304) for post-bronchodilator FEV(1) and -9.4 ml (p =0.691) for pre-bronchodilator FEV(1) after 2 years, compared to placebo. The effect on PC(20) was almost one dose-step (p =0.627) after 1 year and one dose-step (p =0.989) after 2 years. CONCLUSION: In this study, the early introduction of inhaled corticosteroids in newly diagnosed asthmatic subjects with rapid decline in lung function did not prove to be either clinically relevant or statistically significant in reversing the decline in FEV(1). For PC(20), no significant changes were detected