Claude AI Makes Insane Uptober Price Predictions For XRP, ASTER, and ADA – Best Crypto to Buy?  99Bitcoins
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Jakarta, Pintu News – Pi Network now presents two new features on their Testnet, namely decentralized exchange (DEX) and automated market maker . With these updates, users can exchange tokens, build liquidity pools, and experiment with various DeFi concepts in a secure test environment.
This is an important development that further strengthens Pi Coin’s usefulness in the future.
According to an official Pi Network post, developers can now create test tokens directly on the Pi Testnet blockchain. The tokens can be used in liquidity pools to simulate trading without risking real assets.
Read also: As Retail Investors Panic, Whales & Smart Money Scoop Up These Altcoins During the Market Dip
Decentralized exchange (DEX) and automated market maker (AMM) functionalities are available on the Testnet, allowing developers and Pioneers to experiment directly with token swaps, liquidity pools, and other decentralized finance tools. Developers can also now create test tokens… pic.twitter.com/Vf3wsNru2C
Meanwhile, on the main network, new token creation remains restricted so that any new functionality can be thoroughly tested.
Both developers and Pioneers can supply test tokens to mimic real trading activity. This provides important insights into how Pi Coin could function in future markets.
Recently, the Pi Network also managed to acquire a large listing, further driving Pi Coin adoption. These achievements strengthen the design of the Pi ecosystem while preparing the way for future Mainnet adoption.
With the arrival of DEX and AMM, Pi Network provides developers with essential tools to launch new projects. Automated market makers (AMMs) themselves are a core element of most blockchain-based exchanges as they enable token exchanges without the need for a centralized order book.
The addition of this feature signifies Pi’s commitment to conform to global DeFi regulations while opening up more opportunities for Pi Coin utilization.
The presence of various DeFi tools on Testnet confirms that Pi Network is no longer just a mobile mining application, but is starting to develop into a fully functional Web3 application.
Read also: Altcoin Season to Start in October 2025? Analysts Reveal Key Indicators!
By providing core tools for developers, the network gives Pioneers the opportunity to experiment with token markets. Slowly, Pi Network is building a real utility for Pi Coin that can be used in everyday needs.
The activation of DEX and AMM functions on Testnet is an important step towards wider adoption. One expert even mentioned that the SIGN Pi Network meeting could be the trigger for Pi Coin’s inclusion on the Binance list, potentially expanding its market reach significantly.
Question Asked: What’s the big fuss about the meeting between Pi Network and Sign?

My Answer: YZi Labs, the rebranded venture capital arm of Binance (formerly Binance Labs), recently made a $16 million investment in Sign, a company specializing in on-chain token distribution… pic.twitter.com/xrxxhCMozh
These updates not only strengthen the ecosystem, but also bring Pi Coin one step closer to becoming a fully functional digital asset with ever-expanding usability. The implementation of Protocol v23 on Testnet marks such important progress.
The Pi Core Team explained that the restriction of these features on Testnet is aimed at maintaining security, while still providing access to innovation. This phased approach allows developers to safely test features while utilizing DeFi tools in a restricted environment.
That’s the latest information about crypto. Follow us on Google News to get the latest crypto news about crypto projects and blockchain technology. Also, learn crypto from scratch with complete discussion through Pintu Academy and stay up-to-date with the latest crypto market such as bitcoin price today, xrp coin price today, dogecoin and other crypto asset prices through Pintu Market.
Enjoy an easy and secure crypto trading experience by downloading Pintu crypto app via Google Play Store or App Store now. Also, get a web trading experience with various advanced trading tools such as pro charting, various types of order types, and portfolio tracker only at Pintu Pro.
*Disclaimer
This content aims to enrich readers’ information. Pintu collects this information from various relevant sources and is not influenced by outside parties. Note that an asset’s past performance does not determine its projected future performance. Crypto trading activities have high risk and volatility, always do your own research and use cold cash before investing. All activities of buying and selling bitcoin and other crypto asset investments are the responsibility of the reader.
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Home> Community
Daisy Phillipson
Today we're looking at the incredible story of the retired couple who used math to crack the lottery code and win $26 million.
Now, we should point out that most of the time, you've got a better chance of getting struck by lightning than you do of winning the lottery.
Statistics show that the odds of winning the Powerball jackpot by matching all numbers with the white and red balls are one in 292 million.
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But Jerry and Marge Selbee from Evart, Michigan, discovered a smart way to beat these odds using what they described as 'simple arithmetic'.
Let it be known that they were only able to benefit from a specific game called the Cash Winfall, which has since been suspended after authorities realised people were exploiting it for easy cash.
So don't go quitting your jobs just yet.
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For the Selbees, however, they managed to cash in on the loophole, earning multiple and legitimate wins that made them $26 million in total.
It's quite the star story given that they had initially retired in their early 60s with no plan other than to put their feet up and 'enjoy life', as they explained in an episode of CBS News' 60 Minutes Overtime.
In Cash Winfall, if the jackpot reached $5 million and no one matched all six numbers, the money would 'roll down' to the lower-tier prize winners.
And since Jerry has always possessed what he calls a 'head for math', with a bachelor's degree in the subject, it only took a few minutes before he realised that this was a unique game.
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Though he explained his exact tactic in detail, you're going to need some serious math literacy to understand what he's saying.
See what you think: "If I played $1100, mathematically I'd have one four-number winner – that's 1000 bucks.
"I divided 1100 by six instead of 57, because I did a mental quick dirty, and I come up with 18. So I knew I'd have either 18 or 19 three-number winners, and that's 50 bucks each.
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"At 18, I got $1000 for a four-number winner, and I got 18 three-number winners worth $50 each, so that's 900 bucks.
"So I got $1100 invested and I've got a $1900 return."
Phew. Even if you didn't understand all of that, it's easy to see that a $800 return on a $1100 investment is pretty damn good.
The first time Jerry trialled the plan, he went all in buying $3600 worth of Winfall tickets – and his trick worked, earning the couple $6,300.
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The next time he bought $8,000 worth of tickets and nearly doubled the investment. This cycle continued, and before long they began playing with hundreds of thousands of dollars.
They even got their kids and close friends involved, only for the Winfall game to close down in Michigan.
But they just continued to cash in by playing it in Massachusetts where it was still being offered.
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"It is actually just basic arithmetic," added Jerry. "It gave you the satisfaction of being successful at something that was worthwhile to not only us personally but to our friends and our family."
Eventually their plan was foiled after the Boston Globe got a tip that the lottery game was being scammed, and it was shut down by the Massachusetts Lottery.
But it was 2011 at this point, and the Selbees and their loved ones had already made their fortune.
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Although authorities launched an investigation into the matter, they soon realised the couple hadn't committed any crimes whatsoever – they had simply discovered a loophole.
Their story is so larger than life, it became the subject of a feature film named Jerry & Marge Go Large, which was released last year and stars Bryan Cranston.
If you'd like to see the unlikely plot unfold on the big screen, the movie is available to watch on Paramount Plus.
Topics: US News, Life, Money, Film and TV
Daisy graduated from Kingston University with a degree in Magazine Journalism, writing a thesis on the move from print to digital publishing. Continuing this theme, she has written for a range of online publications including Digital Spy and Little White Lies, with a particular passion for TV and film. Contact her on [email protected]
@DaisyWebb77
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The Virginia Lottery offers multiple draw games for those aiming to win big. Here’s a look at Oct. 1, 2025, results for each game:
Powerball drawings are held Monday, Wednesday and Saturday at 11 p.m.
08-17-22-28-55, Powerball: 14, Power Play: 3
Check Powerball payouts and previous drawings here.
Saturday, October 04, 2025
DAY drawing at 1:59 p.m. NIGHT drawing at 11 p.m. each day.
Night: 3-9-8, FB: 6
Day: 3-1-3, FB: 9
Check Pick 3 payouts and previous drawings here.
DAY drawing at 1:59 p.m. NIGHT drawing at 11 p.m. each day.
Night: 8-2-3-2, FB: 4
Day: 2-9-7-9, FB: 9
Check Pick 4 payouts and previous drawings here.
DAY drawing at 1:59 p.m. NIGHT drawing at 11 p.m. each day.
Night: 8-2-0-7-2, FB: 3
Day: 8-2-3-2-9, FB: 1
Check Pick 5 payouts and previous drawings here.
Drawing everyday at 9 p.m.
04-19-23-36-44, Cash Ball: 04
Check Cash4Life payouts and previous drawings here.
Drawing times: Coffee Break 9 a.m.; Lunch Break 12 p.m.; Rush Hour 5 p.m.; Prime Time 9 p.m.; After Hours 11:59 p.m.
Coffee Break: 15
After Hours: 05
Prime Time: 14
Rush Hour: 12
Lunch Break: 05
Check Cash Pop payouts and previous drawings here.
Drawing every day at 11 p.m.
04-11-18-21-42
Check Cash 5 payouts and previous drawings here.
Bank a Million draws are held every Wednesday and Saturday at 11 p.m.
02-21-25-26-27-37, Bonus: 08
Check Bank a Million payouts and previous drawings here.
Feeling lucky? Explore the latest lottery news & results
This results page was generated automatically using information from TinBu and a template written and reviewed by a Center for Community Journalism (CCJ) editor. You can send feedback using this form.

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Trials volume 26, Article number: 385 (2025) Cite this article
Portal hypertension is a major complication in patients with liver cirrhosis, leading to severe outcomes such as variceal bleeding and ascites. Transjugular intrahepatic portosystemic shunt (TIPS) has emerged as an effective interventional treatment of recurrent ascites and variceal bleeding. However, up to 30% of patients with recurrent ascites show TIPS refractory ascites, and prior data have shown that the frequency of paracenteses before TIPS implantation predicts ascites clearance indicating that TIPS implantation may be too late in some patients. Especially, patients with grade 2 ascites and a MELD score ≥ 15, or grade 3 ascites irrespective of MELD score at first decompensation with ascites face a high risk of further decompensation and mortality. Therefore, these patients may benefit from early TIPS implantation in order to improve post-TIPS mortality. We hypothesise that early TIPS implantation in these selected patients at the time of the first decompensation may improve transplantation-free survival compared to standard medical treatment (SMT).
The eTIPS study is a prospective, randomised, open, multicenter interventional, superiority trial. Patients will be randomised 1:1 in the intervention group with TIPS implantation and in the SMT group. The primary endpoint is transplantation-free survival. Secondary endpoints include the time to ascites with need for paracentesis and quality of life assessed six and 12 months after randomisation.
Expanding the concept of early TIPS implantation to ascites management may offer significant survival benefits and may significantly change the treatment algorithm of patients with ascites.
German Registry for Clinical Studies DRKS00034545. Registered on 20/02/2025.
Clinical trials NCT06576934. Registered on 04/12/2024.
Peer Review reports
Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).
Title {1}
Early implantation of a transjugular intrahepatic portosystemic shunt (TIPS) in patients with liver cirrhosis and ascites: a multicentre, randomised controlled trial
Trial registration {2a and 2b}
NCT06576934
DRKS00034545
Protocol version {3}
version 1.3., 03.07.2025
Funding {4}
This clinical study is funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG).
GZ: BE 7734/2–1
Project number: 529465923
Author details {5a}
Prof. Dr. Dominik Bettinger
Department of Medicine II, Medical Center—University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany
dominik.bettinger@uniklinik-freiburg.de
Dr. Marco Janoschke
Medical Center – University of Freiburg, Clinical Trials Unit, Elsässer Str. 2, 79,110 Freiburg, Germany
marco.janoschke@uniklinik-freiburg.de
Dr. Carolin Jenkner
Medical Center – University of Freiburg, Clinical Trials Unit, Elsässer Str. 2, 79,110 Freiburg, Germany
carolin.jenkner@uniklinik-freiburg.de
Dr. Margit Kaufmann
Medical Center – University of Freiburg, Clinical Trials Unit, Elsässer Str. 2, 79,110 Freiburg, Germany
margit.kaufmann@uniklinik-freiburg.de
Julia van Gessel
Medical Center – University of Freiburg, Clinical Trials Unit, Elsässer Str. 2, 79,110 Freiburg, Germany
julia.vangesssel@uniklinik-freiburg.de
Hans-Heinrich Otter
Medical Center – University of Freiburg, Clinical Trials Unit, Elsässer Str. 2, 79,110 Freiburg, Germany
hans-heinrich.otter@uniklinik-freiburg.de
PD Dr. Michael Schultheiss
Department of Medicine II, Medical Center—University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany
michael.schultheiss@uniklinik-freiburg.de
Prof. Dr. Robert Thimme
Department of Medicine II, Medical Center—University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany
robert.thimme@uniklinik-freiburg.de
Name and contact information for the trial sponsor {5b}
Medical Center—University of Freiburg represented by the Chief Medical Officer (CMO, Leitende Ärztliche Direktion) and the Chief Financial Officer (CFO, Kaufmännische Direktion), Breisacher Str. 153, 79,110 Freiburg, Germany
Role of sponsor {5c}
The Medical Center- University of Freiburg is the study sponsor. The sponsor does not have a role in study design, collection, management and analysis of data, interpretation of data and writing of the report or the decision regading publication.
Portal hypertension is a hallmark of liver cirrhosis leading to oesophageal and gastric varices, variceal bleeding and ascites [1,2,3]. These complications may trigger further complications such as hepatorenal syndrome and spontaneous bacterial peritonitis, and they are associated with significant morbidity and mortality [2, 4]. Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) is a safe and effective interventional treatment for portal hypertension, and TIPS implantation has emerged as a major component within the treatment algorithm for portal hypertension [5, 6]. The most common indications for TIPS implantation are secondary prophylaxis of variceal bleeding and recurrent or treatment refractory ascites [5]. According to recent evidence, early TIPS (i.e. pre-emptive TIPS) within the first 72 h following the bleeding event in patients with acute variceal bleeding and a high risk of re-bleeding (CHILD–Pugh C < 14 or CHILD–Pugh B > 7 with active bleeding in index endoscopy) is associated with improved survival [7]. Even patients with acute-on-chronic liver failure (ACLF) after variceal bleeding show a survival benefit after pre-emptive TIPS implantation [8]. Therefore, the concept of early TIPS implantation after variceal bleeding is recommended by current guidelines [1, 7].
In contrast, patients with ascites are allocated to TIPS implantation at later stages of disease (treatment refractory or recurrent ascites) when diuretic treatment and large-volume paracenteses (LVP) do not lead to sufficient ascites control [1]. The clinical benefit of TIPS implantation has been confirmed in several randomised controlled trials, although these studies showed very heterogeneous results with respect to improvement of survival [1, 9,10,11]. In the majority of these studies, uncovered stents were used, but today, the use of covered stents is exclusively recommended due to their superior patency. Only in the study by Bureau et al. covered stents were used, and thus this study may be considered representative for everyday clinical practice [12]. A clear survival benefit for patients allocated to TIPS implantation was shown, and the prevalence of post-TIPS hepatic encephalopathy (HE) was not increased in these patients. Patients who received TIPS implantation due to recurrent or refractory ascites show ascites clearance without the need for further paracenteses in only 51% to 68% [1, 11]. In contrast, the study by Bureau et al. reported a significantly improved treatment response, and treatment failure occurred in only 29% of patients treated with TIPS implantation [12]. Improved response to treatment and increased survival may be explained by meticulous patient selection, as only patients with recurrent ascites were included in this study. These patients had no more than six paracenteses within the last three months, and patients were allocated to TIPS implantation after a mean of 4.5 paracenteses indicating that these patients did not fulfil the definition of refractory ascites [12]. These facts highlight the rationale for early allocation to TIPS implantation.
The benefit of timely TIPS implantation (i.e. following recurrent ascites instead of refractory ascites) was supported by the study from Piecha et al. [13]. In this study, a higher frequency of paracenteses as a surrogate marker for the duration of decompensation and a high serum creatinine were associated with a reduced clearance of ascites after TIPS implantation [13]. These data support to expand the concept of “early TIPS implantation” to patients with ascites. Balcar et al. analysed the clinical course of patients with ascites as the first decompensating event. They were able to show that patients with grade 2 ascites and a MELD score ≥ 15 as well as patients with grade 3 ascites irrespective of the MELD score had a high risk of further decompensation and increased risk for death [14]. We hypothesise that these patients may benefit from early TIPS implantation. This highly relevant clinical question has not yet been addressed in a prospective randomised controlled trial. Therefore, we aim to analyse the concept of “early TIPS implantation” in these selected patients with liver cirrhosis and ascites as the first single decompensating event.
The primary objective of this study is to assess a survival benefit in patients with early allocation to TIPS implantation in comparison to patients with SMT. The secondary objectives aim to assess the efficacy of TIPS implantation on the course of liver disease and quality of life (QOL).
The eTIPS study is a prospective, randomised, open, multicentre interventional, superiority trial. Patients will be randomised 1:1 in the intervention group with TIPS implantation and in the SMT group. Blinding is not possible because of the interventional character of TIPS implantation.
We hypothesise that early TIPS implantation in cirrhotic patients with first decompensation with ascites leads to improved transplantation-free survival compared to SMT. The trial design is shown in Fig. 1.
Trial design of the eTIPS study (created with biorender.com)
This is a multicentre trial that will be performed in approximately 10 tertiary academic centres in Germany that are highly experienced in the management of patients with advanced chronic liver disease, portal hypertension and TIPS implantation. List of participating sites can be obtained from continuously updated entries found in the registry on clinicaltrials.gov and in the German registry for Clinical Trials (DRKS). If necessary, additional qualified centres can be included during the study period. All participating centres must provide a multidisciplinary team including hepatologists, interventional radiologists (only in case TIPS implantations are performed by them), intensive care and general surgery with expertise in liver surgery and liver transplantation. The TIPS procedure should be done by an interventional radiologist or an interventional hepatologist who has experience in this procedure (performance of at least 5 TIPS intervention under supervision and at least 15 TIPS procedures without supervision). This qualification will be asked during the site selection visit by self-assessment. If there are personal changes during the study period, the sites are responsible for providing these data for the persons involved in TIPS implantation.
The eligibility criteria are summarised in Table 1. No gender ratio has been stipulated in this trial as the results of the preclinical and clinical studies did not indicate any gender effect of the trial treatment in terms of efficacy and safety.
Cirrhotic patients with ascites as the first single decompensating event with grade 2 ascites and MELD score ≥ 15 or grade 3 ascites will be screened for eligibility. If a patient appears to be eligible for the trial, the investigator will inform the patient about the trial and ask the patient for his/her written consent. It is imperative that written consent is obtained prior to any trial-specific procedures. Importantly, the screening examinations are performed during routine clinical management and are not exclusively related to the study participation so that they may be performed prior to written informed consent.
Blood and urine samples are collected during the study period at pre-defined timepoints. No additional biological specimens will be sampled.
Currently, TIPS implantation is recommended for patients with liver cirrhosis and refractory or recurrent ascites [1, 7]. However, response to treatment (ascites clearance) is often reduced in these patients with advanced liver disease and long-standing decompensation with ascites [13, 15]. Therefore, we hypothesise that early TIPS implantation in selected patients with ascites as the first decompensating event (grade 2 ascites and MELD ≥ 15 or grade 3 ascites) will lead to a higher rate of ascites clearance and improved transplantation-free survival. Therefore, patients with grade 2 ascites and MELD score ≥ 15 or grade 3 ascites as the first single decompensating event will be randomised in an early TIPS group in addition to standard of care and in a SMT group. Patients in the SMT group will be treated following current evidence-based treatment guidelines [1], and therefore, the SMT group reflects the current approach in treatment of patients with ascites. All patients (also including patients in the TIPS group) are advised to adhere to moderate restriction of sodium intake (80–120 mmol/day = 4.6–6.9 g of salt) according to the current EASL guidelines [1, 16]. Treatment of ascites will be performed according to current evidence-based treatment guidelines. Diuretic treatment (using an anti-mineralocorticoid drug and/or loop diuretics) will be used by clinical judgement under regular control of renal function, sodium and potassium values. The body weight loss should not exceed 0.5 kg/day in patients without peripheral oedema and 1 kg/day in the presence of peripheral oedema. The dose of diuretics can be increased after 72 h of treatment until the maximum dose (spironolactone, 400 mg/day; furosemide, 160 mg/day; torasemid, 40 mg/day) is reached or diuretic-induced complications occur [1, 16]. Diuretic-induced complications are defined as acute kidney injury (defined according the KDIGO criteria) and/or diuretic-induced hyponatraemia (decrease of serum sodium by > 10 mmol/l or to a serum sodium < 125 mmol/l) and/or diuretic-induced hypo-or hyperkalaemia (changes in serum potassium to < 3 mmol/l or > 6 mmol/l despite appropriate measures) and/or disabling muscle cramps.
In patients with grade > 2 ascites, LVP will be performed according to current recommendations. Plasma volume expansion with albumin infusion will be performed following completion of LVP (albumin 8 g/l of ascites drained). If less than 5 l of ascites was drained, no plasma expansion is necessary [1].
The current Baveno VII guidelines make a strong recommendation for the use of non-selective beta-blockers (NSBB; preferred carvedilol or propranolol) for the prevention of decompensating events and therefore, this will be a common co-medication in the SMT group. NSBB should be stopped in case of acute kidney injury (AKI) and persistently systolic blood pressure < 90 mmHg or mean arterial pressure < 65 mmHg. After blood pressure returns to normal and AKI is resolved, NSBB can be restarted [7].
In case of development of overt hepatic encephalopathy, treatment will be started incorporating lactulose (10 ml twice or more daily as necessary) and/or rifaximin 550 mg twice daily [17].
TIPS implantation has emerged as an important interventional treatment option in patients with decompensated liver cirrhosis. It leads to a significant decrease in portal vein pressure and effective control of portal hypertension related complications [5].
A high-resolution flat-panel X-ray C-arm with digital subtraction angiography is necessary. During TIPS implantation, vital signs including non-invasive blood pressure monitoring, heart rate, electrocardiogram and peripheral oxygen saturation are monitored.
TIPS implantation will be performed by experienced interventional hepatologists or radiologists (performance of at least 5 TIPS interventions under supervision and at least 15 TIPS procedures without supervision). Before TIPS implantation, LVP may be necessary to facilitate the TIPS procedure. This paracentesis will be documented on the TIPS implantation page in the eCRF and will not be considerd as a secondary endpoint.
A central vascular access for TIPS implantation is obtained by introducing a sheath (10F) in the right internal jugular vein. If the right jugular vein cannot be assessed due to thrombosis or other vascular abnormalities, the left internal jugular vein should be used. Under fluoroscopic and sonographic guidance, the TIPS needle is inserted in the hepatic vein (normally right or middle hepatic vein) and the needle is introduced through the liver parenchyma towards the (right) portal vein branch. It is recommended to use ultrasound guidance for the transhepatic puncture of the portal vein. After the portal vein has been assessed, a guidewire is introduced in the splenic vein or in the superior mesenteric vein. Portography is performed and the portosystemic gradient (PSG) is measured [7, 18, 19]. PSG is calculated as the difference between the inferior vena cava (IVC) and the pressure in the main portal vein. In addition, the pressure in the right atrium is measured. After a PSG > 10 mmHg has confirmed portal hypertension, the parenchymal tract is dilated with a 6-mm dilation balloon. An 8–10 mm controlled-expansion polytetrafluoroethylene (ePTFE)-covered stent is introduced and the stent graft is implanted. It is important that the stent is placed sufficiently within the liver vein (close to the IVC). In patients who are suitable for liver transplantation, the location of the stent is important. A too proximal stent position (stent direct to the right atrium) and too distal stent position (close to the confluence) must be avoided.
Only covered stents with controlled expansion must be used in this trial. The stent will first be dilated to 6 mm and the PSG is measured. If PSG will not show reduction to levels lower than 12 mmHg or no pressure reduction of more than 50% has been reached, the stent will be dilated to a diameter of 8, 9 or 10 mm until the reduction of PSG reaches the target pressure range (PSG < 12 mmHg or PSG reduction > 50%).
Between each dilation, PSG must be measured and documented. In addition, systemic haemodynamic parameters (blood pressure and heart rate) at the time of PSG measurements must be added to the documentation.
If portosystemic collaterals are detected during portography, these varices or major collaterals can be embolised using metallic coils or glue according to the interventionalist’s choice, especially if these collaterals lead to a steal phenomenon with reduced inflow into the TIPS stent. TIPS implantation will normally be performed in deep sedation using centre specific sedation regimes [20]. According to local standard, general anaesthesia is permitted within the trial. Importantly, sedation has a significant impact on pressure values and therefore, a second measurement of the portal vein pressure and the pressure in the IVC and right atrium should be performed 24–72 h after TIPS implantation. If necessary, however not recommended, mild sedation with low-dose midazolam (0.02 mg/kg body weight) is permitted [7].
TIPS implantation is performed with X-ray fluoroscopy. Approximately 20 min of X-ray fluoroscopy is necessary for TIPS implantation. The second pressure measurement requires a maximum of 5 min X-ray fluoroscopy. It is within the responsibility of the interventionalist to take measures to reduce X-ray exposure (reducing the X-ray field and rate of fluoroscopy). Contrast medium is used for visualisation of vessels, and it should be reduced to a minimum. If locally available, CO₂ angiography can be used.
Patients in the SMT group may be allocated to TIPS implantation according to current Baveno VII guidelines and the EASL guideline for the management of decompensated cirrhosis [1, 5, 7, 21]. TIPS implantation is indicated in the following situations:
Massive variceal bleeding with implantation of a fully covered self-expanding metal stent (fcSEMS) for bleeding control (rescue TIPS implantation) [22].
Variceal bleeding (esophageal or gastric varices) in patients with Child–Pugh B > 7 points and active bleeding during index gastroscopy or patients with Child–Pugh C < 14 points (pre-emptive TIPS implantation) [7].
Recurrent esophageal bleeding in patients with Child–Pugh A or Child–Pugh B 7 points despite adequate secondary prophylaxis with beta-blockers and endoscopic band ligation (EBL) [7].
Recurrent ascites (as defined by requirement of ≥ 3 large-volume paracenteses [removal of > 5 L of ascites] within 1 year) in stable situations can be considered for TIPS implantation. Importantly, only paracenteses in stable conditions will be considered. Stable conditions are defined as a clinical situation without concomitant infections, without acute kidney injury and/or bleeding at the time of paracentesis [1, 7].
If TIPS implantation is planned in the SMT arm, the indication should be discussed with the coordinating investigator.
The strict adherence to inclusion and exclusion criteria should improve adherence to the intervention. Further, randomisation is performed as late as possible. At each scheduled visit, the study team will reinforce the importance of treatment adherence and may help in solving upcoming problems.
No medication is prohibited. Treatment with transfusions (red blood cells and platelets) and supportive care as well as intensive care treatment are permitted after the initiation of study treatment. Patients should receive treatment/medication appropriate to their clinical condition in an emergency. The patient must notify the investigational site of any new medication he/she starts taking after signature of informed consent. All concomitant medications and significant non-drug therapies (including physical therapy and blood transfusions) must be listed in the source documents and additionally documented in eCRF especially diuretic treatment, NSBB and medications for hepatic encephalopathy will be considered [23].
After the patient has completed follow-up in the study, the patient will return to routine clinical practice and will receive follow-up in the outpatient clinic every 3 to 6 months according to his/her clinical condition.
All patients included in the study will have insurance in accordance with the applicable law and regulations (Insurance: Newline Group, Policy-No.: NEV081957A).
Table 2 summarises the objectives and the corresponding endpoints of this trial. The following estimands are defined.
The primary estimand that corresponds to the primary trial objective to show superiority of early implantation of a TIPS in patients with liver cirrhosis and ascites compared to standard medical treatment based on the primary endpoint transplantation-free survival is specified by the following 5 attributes.
Population: [A] The population targeted by the primary estimand will be called full analysis set (FAS). This means that the patients will be analysed in the treatment arms to which they were randomised. All randomised patients will be included in the FAS.
Treatments: The randomised experimental arm (TIPS implantation) is compared to the randomised control arm (SMT) of ascites regardless of dosing modifications, treatment interruptions, treatment discontinuation and regardless of intake of additional medications.
Treatment groups are called early TIPS and standard medical treatment.
Variable (endpoint): The endpoint is transplantation-free survival defined as time from randomisation to liver transplantation or death.
Intercurrent events: ascites, TIPS implantation and TIPS revision will be ignored.
Population-level summary: The population-level summary is defined by the statistical analysis approach.
Estimand 2 that corresponds to the secondary trial objective to assess the efficacy of TIPS implantation on the course of liver disease is specified by the following 5 attributes. Population: [A], Treatments: [A].
Variable (endpoint): The endpoint is ascites with need for paracenteses defined as time from randomisation to date of paracentesis.
Intercurrent events: transplantation, death will be considered as competing events.
Population-level summary: The population-level summary is defined by the statistical analysis approach which is described below.
Estimand 3 that corresponds to the secondary trial objective quality of life is specified by the following 5 attributes.
Population [B,C]: 6, 12-month survival of FAS Treatments: [A].
Variable (endpoint): The endpoint is quality of life measured by SF-36 and CLDQ.
Intercurrent events: There are no intercurrent events not already addressed by the specification of population, treatments and variables.
Population-level summary: The population-level summary is defined by the statistical analysis approach which is described below.
Table 3 summarises the participant timeline including the assessments at each visit.
Sample size calculation is based on the primary endpoint transplantation-free survival (TFS), defined as time from randomisation to liver transplantation or death. It is assumed that the TFS probability of patients in the control group (SMT) is approximately 66% after one year. With an assumed TFS rate of approximately 82% in the TIPS group, this corresponds to a hazard ratio of 0.48 of the TIPS group compared to the control group (SMT group). The assumption is based on the study by Bureau et al. that analysed 62 patients. The one-year rate of TFS in the TIPS group was 93% (95%CI, 82%–100%) [12]. The TFS probability of the SMT group was assumed according to data from patients with first decompensation with ascites in the INCA trial (unpublished data [24] and, the data provided by Balcar et al. that report1-year TFS in patients with LVP [14]. The effect of TIPS implantation will be assessed by a test at two-sided significance level of 5% and by estimation of the hazard ratio with corresponding asymptotic two-sided 95% confidence interval. The null hypothesis is rejected if the confidence interval does not contain one. Under the above assumptions, the study is planned to detect a difference between the experimental intervention (TIPS group) and the control group (SMT group) with a power of 80%, which requires a total number of 57 events to be observed. The required number of patients to be randomised to observe this amount of events depends on the length of follow-up. With a recruitment period of three years, an additional follow-up period after the end of recruitment of two years, it can be safely assumed that a sufficient number of events will have been observed by the end of the trial if 116 patients are available for analysis (software used, e.g. n Query Advisor 8.3). Furthermore, the exponential drop-out rate is assumed to be 0.01. Therefore, 134 patients will be randomised. Before the end of the planned recruitment phase, a blinded assessment of the TFS rate (both treatments combined) will be performed. If the TFS rate appears to be higher than anticipated, the recruitment phase will be extended, and the required number of patients will be calculated anew under the amended assumptions. Irrespective of this sample size amendment, the analysis will be conducted after the observation of 57 events as planned, so no alpha adjustment is necessary.
It is intended to randomise 134 patients in approximately 10 centres within 36 months. There is no limit to the number of included patients at an individual study site. Patients with the first single decompensating event with ascites are also often seen in local hospitals and are allocated to a tertiary medical centre mostly only if ascites cannot be controlled after several LVPs and extensive diuretic treatment. In order to fulfil preliminary assumptions on recruitment rates, specific strategies (continuous medical education [CME] events to present the study to local family doctors, out-patient gastroenterologists and local hospitals, providing information material [flyer, presentation]) will be prepared.
If the informed consent is obtained, the qualified/authorised personnel will register the patient online in the eCRF (REDCap® system) by creation of a new patient record. The system will automatically assign the next consecutive number (e.g. 1, 2, 3). The unique patient identification number will then consist of a unique centre number assigned by REDCap® combined with the consecutive patient number. The registration date, the date on which the first patient data is entered in the eCRF, will be automatically collected.
The randomisation list will be provided by the biometrician and will be uploaded into REDCap®. The randomisation itself will be performed at the study site on the electronic randomisation form in REDCap®. The randomisation can only be performed if all requirements for randomisation are fulfilled (i.e. eligibility criteria of the patient for randomisation must be confirmed). The randomisation process is started by pushing the “randomise” button in the randomisation form. The randomisation result will be displayed in the form and is saved automatically. A notification of the randomisation result will be sent automatically via E-mail to the responsible data manager of the Clinical Trials Unit (CTU), and the principal investigator at the specific site.
Randomisation will be performed, stratified by site, in blocks of variable length in a ratio of 1:1. The block lengths will be documented separately and will not be disclosed to the sites. The randomisation code will be produced by validated programmes based on the Statistical Analysis System (SAS).
The randomisation is done via eCRF (REDCap® system) (see the Sequence generation {16a} section), which permits concealment of the randomisation sequence.
The randomisation code will be generated by the CTU to ensure that treatment assignment is unbiased and concealed from patients and investigator staff.
Blinding is not possible due to the interventional character of the study.
This is not applicable as the study is designed as an open-label trial.
Examinations and assessments will be performed at pre-defined timepoints as specified in Table 2. Data will be entered by the investigator/authorised personnel in the eCRF (REDCap® system). Questionnaires (SF-36 and CLDQ) are first filled out on paper and then transferred to the eCRF. At each visit, patient life status, liver transplantation and paracentesis performed are queried. Events related to TIPS implantation during and after the end of the procedure, categorised incidences for all patients and all other adverse events are collected in a patient safety form in the eCRF.
In the first year after randomisation, regular and timely visits support patient contact. After the first year, phone calls also promote long-term follow-up.
The setup of the eCRF and data management will be performed with the REDCap® system.
REDCap® uses built-in security features to prevent unauthorised access to patient data, including an encrypted transport protocol for data transmission from the participating sites to the study database. An audit trail provides a history of the data entered, changed, or deleted, indicating the processor and date.
Before any data entry is performed, the trial eCRF will be validated. Site data entry personnel will not be given access to the trial database until they have been trained.
Data will be checked during data entry by programmed warnings and so-called data rules. Furthermore, the Query Module of REDCap® will be used to assign queries manually and control data quality by executing data quality rules. Data corrections will be entered directly into REDCap® by the responsible personnel.
Furthermore, the data will be reviewed for completeness, consistency, plausibility and regarding protocol violations or distinctive medical problems using SAS® software. The resulting queries will be sent to the investigators for correction or verification of the documented data in the eCRF.
The investigator must ensure anonymity of the patients; patients must not be identified by names in any documents submitted to the sponsor. Signed informed consent forms and patient enrolment log must be kept strictly confidential to enable patient identification at the site. All study-related information will be stored securely at the study site. All participant information will be stored in locked file cabinets in areas with limited access. All laboratory specimens, reports, data collection, processes and administrative forms will be identified by a coded identification number only to maintain participant confidentiality.
Blood and urine samples will be collected at pre-defined timepoints as specified in Table 3. These data are collected in order to assess the safety and efficacy of the therapy in each group. Storage of biospecimens for further research is not planned. Embedded future substudies using data from the eTIPS study must have a specific protocol and must be confirmed by the coordinating investigator. Further, a specific approval from the ethics committee is obtained separately.
The following populations for analyses are defined: (I) The population targeted by the primary estimand will be called full analysis set (FAS). This means that the patients will be analysed in the treatment arms to which they were randomised. All randomised patients will be included in the FAS. (II) The safety set (SAF) includes all randomised patients who underwent TIPS procedure or received SMT, and patients are analysed according to the received treatment.
The estimand and competing events are described above and summarised in Table 4.
The effects of SMT and TIPS implantation with respect to the primary endpoint transplantation-free survival will be estimated and tested by Cox regression. The regression model will include treatment and study site as independent variables, as well as baseline bilirubin, creatinine and age. As an estimate of the effect size, the hazard ratio between the two treatment arms will be given with the corresponding asymptotic two-sided 95% confidence interval. The two-sided test on the difference between SMT and TIPS at significance level 5% will be based on the corresponding asymptotic two-sided 95% confidence interval from the Cox regression model.
The effects of SMT and TIPS implantation with respect to the secondary endpoint time to ascites with need for paracenteses will be estimated and tested by Cox regression. The probability of event over time will be estimated by cumulative incidence rates due to competing events, transplantation and death. The time to event will be compared between the treatment groups with Cox regression models for the event-specific hazard functions using two-sided Wald tests. The regression model will include treatment and study site as independent variables, as well as baseline bilirubin, creatinine and age. As an estimate of the effect size, the event-specific hazard ratio between the two treatment arms will be given with the corresponding asymptotic two-sided 95% confidence interval.
SF-36 and CLDQ will be compared between treatment arms at two different timepoints (months 6, 12). At both timepoints, a mixed linear model for repeated measures (MMRM) is used modelling the respective scale at this and the earlier timepoints, and including randomised treatment and the baseline value of the respective subscale and centre as covariates. Two-sided p values of the tests of the hypotheses that the treatment effect is zero at the respective timepoints will be calculated from these models. As estimates of the effect sizes, the differences of adjusted means (TIPS arm vs.SMT arm) will be calculated with two-sided 95% CI.
The total number of AEs, the minimum, maximum and mean number of adverse events (AEs) per patient, the total number of follow-up (FU) days (number of days in the observation period), the number of AEs per FU-day (total number of AEs divided by the total by the number of follow-up days), the number of patients who had at least one AE and the number of patients who stopped treatment due to AE will be given.
The probability of AEs defined by preferred term (PT) according to MedDRA and of AEs defined by system organ class (SOC) according to MedDRA will be estimated by the Aalen-Johansen estimator. For this purpose, the time from randomisation to the first occurrence of the specific type of AE (defined by PT or defined by SOC) will be analysed. For patients not experiencing the specific type of AE, the time to the end of the documentation period or death, whatever occurs first, will enter the analysis and will be treated as a competing event. This will result in probability estimates (cumulative incidences) for the different AE types (defined by PT and by SOC) over time. The results will be displayed in summary tables by showing the cumulative incidences at the maximum observation time. Incidences of AEs will be calculated with 95% confidence intervals. Additionally, the number of non-serious AEs will be summarised by PT and by SOC.
No interim analysis is planned.
Demographic and other baseline data will be summarised descriptively by a randomised treatment arm. Numbers of complete and missing data (if any) will be shown. Relative frequencies will be shown as valid % (number of patients divided by the number of patients with non-missing values).
Unless otherwise stated in particular cases, missing values are not replaced and only observed cases are analysed.
The sponsor assures that the key design elements of this protocol will be posted in a publicly accessible clinical trials registry.
The coordinating centre consists of the principal coordinating investigator (DB, sponsor representative, University Medical Center Freiburg, Germany), the co-principal coordinating investigator (MS), the trial manager (MJ), the statistician (CJ), the data and safety management team (MK and the team from the Clinical Trials Unit Freiburg, Germany) and the monitoring team (HHO, Clinical Trials Unit Freiburg, Germany). The trial steering committee will be represented by the coordinating investigator (DB), co-principal coordinating investigator (MS), head of department of the coordinating centre (RT) and the Data Monitoring Committee (DMC).
An independent Data Monitoring Committee (DMC) is established. The DMC consists of two independent physicians (one interventional radiologist with experience in TIPS implantation and one hepatologists with longterm experience in treatment of patients with portal hypertension) and a statistician. The function of the DMC is to monitor the course of the trial and if necessary to give a recommendation to the coordinating investigator for continuation, modification or discontinuation of the trial. The underlying principles for the DMC are ethical and safety aspects for the patients. It is the task of the DMC to examine whether the conduct of the trial is still ethically justifiable, whether the safety of the patients is ensured, and whether the process of the trial is acceptable. For this, the DMC has to be informed about patient recruitment, adherence to the protocol and observed adverse events. A continuous safety survey of the study will be conducted as part of the annual DMC meetings. The DMC will evaluate mortality, frequency and type of SAEs taking into consideration discontinuation criteria.
An adverse event (AE) in this study is defined as any untoward medical occurrence/complication in a patient who underwent TIPS or received SMT and which does not necessarily have to have a causal relationship with the TIPS implantation or received therapy.
Table 5 summarises the parameter/adverse events that will be documented to monitor interventional and SMT safety.
Adverse events have to be documented in the eCRF starting from the date of ICF signature and until end of the study with the following information: characterisation of the event (listed complication, see above [diagnosis or symptoms, if diagnosis not yet available]), onset/end date, severity according to the current version of CTCAEv5, relationship to procedure (yes/no) or to the shunt (yes/no), serious/non-serious and outcome.
Monitoring is performed by the clinical research associates (CRAs) of the CTU, Medical Center—University of Freiburg. Risk-based monitoring will be conducted according to ICH-GCP E6 and standard operating procedures (SOPs) to verify that patients’ rights and well-being are protected, reported trial data are accurate, complete and verifiable from source documents and that the trial is conducted in compliance with the currently approved protocol/amendment, with ICH-GCP E6 and with the applicable regulatory requirements to ensure patient safety and integrity of clinical trial data.
The investigator will accept monitoring visits before, during and after the clinical trial. Prior to the trial, a site selection visit at each site is conducted to check the prerequisite of the team. Prior to patient recruitment, a site initiation visit at each site is conducted in order to train and introduce the investigators and their staff to the trial protocol, essential documents and related trial-specific procedures, ICH-GCP E6 and national/local regulatory requirements.
On the basis of a risk-based quality management process, the CRA will visit the site regularly depending on trial risk (in this case: low risk) and depending on the recruitment rate and quality of data. During these on-site visits, the CRA verifies that the trial is conducted according to the trial protocol, trial-specific procedures, ICH-GCP, international and national/local regulatory requirements, as applicable. The CRA also performs source data verification and source data review to ensure that the clinical trial data which are recorded in the source data and eCRFs are complete and accurate and to ensure the smooth flow of the processes which are agreed.
In addition to on-site visits, off-site visits can be carried out as long as the centre’s data quality permits (after consulting the project manager and coordinating investigator).
All trial-specific monitoring procedures, monitoring visit frequency and extent of source data verification will be predefined in a trial-specific monitoring plan. The investigator must maintain source documents for each patient in the trial, consisting of case and visit notes (hospital or clinic medical records) containing demographic and medical information, laboratory data, electrocardiograms and the results of any other tests or assessments. All information recorded on eCRFs must be traceable to source documents in the patient’s file. The investigator must also keep the original signed informed consent form (a signed copy is given to the patient).
The investigator must give the CRA direct access to all relevant source documents to confirm their consistency with the eCRF entries and document any protocol violation including corrective and preventive actions taken on a protocol deviation form as soon as possible.
The study may be audited at any time, with appropriate notification, by qualified personnel from the sponsor or an independent external party, to assess compliance with the protocol, good clinical practice (GCP) and regulatory requirements. The study may also be inspected by health authority inspectors, after appropriate notification. The investigator needs to inform the CTU immediately of an inspection requested by a regulatory authority. In the event of an audit or an inspection, the investigator should ensure that direct access to all study documentation/data, including source documents, will be granted to the auditors or inspectors.
Any change or addition to the protocol can only be made in a written protocol amendment that must be approved by the sponsor, competent authority where required, and the independent ethics committee (IEC). Only changes to the protocol that are required for patient safety may be implemented prior to IEC approval. Regardless of the need for approval of formal protocol amendments, the investigator is expected to take immediate action required for the safety of any patient included in this trial, even if this action represents a deviation from the protocol. In such cases, the sponsor has to be notified as soon as possible of this action; the IEC should be informed correspondingly. Information regarding important protocol modifications will be provided in due time to further relevant parties (e.g. investigators, trial participants, trial registries, journals).
Upon trial completion, the results of this trial will be submitted for publication and/or posted in a publicly accessible database of clinical trial results irrespective of the results of the trial. Reporting guidelines will be taken into account (see www.equator-network.org), e.g. the CONSORT will be adhered to in the preparation of papers on the results of randomised studies. Each publication of trial results will be in mutual agreement between the principal investigator, the other investigators involved and the CTU. All data collected in connection with the clinical trial will be treated in confidence by the coordinating investigator and all others involved in the trial until publication. Interim data and final results may only be published (orally or in writing) with the agreement of the coordinating investigator and the CTU. For authorship of the final clinical trial report and in publications of the trial protocol and results, the authorship criteria for manuscripts submitted for publication defined by the International Committee of Medical Journal Editors will be adhered to.
TIPS implantation has emerged as an important interventional treatment of complications of portal hypertension. Patients with liver cirrhosis and refractory ascites who are allocated to TIPS implantation are at risk for failure of ascites control [13]. One possible reason is that TIPS implantation is performed too late in these patients and that compensatory mechanisms may persist despite successful TIPS implantation [12, 13]. In the study by Bureau et al., patients were allocated to TIPS implantation after a mean of 4.5 paracenteses indicating that these patients did not fulfil the definition of refractory ascites. Interestingly, these patients showed excellent 1-year transplantation-free survival. Further, it has been shown that a lower paracentesis frequency before TIPS is associated with better ascites clearance after TIPS implantation [12]. Previously, a small retrospective study (n = 27) was published analysing the effect of anticipant TIPS implantation in patients with the first episode of ascites or variceal bleeding. Liver-related events were significantly reduced and overall survival was better in patients with anticipant TIPS implantation [26]. However, this study may harbour significant bias due to its retrospective design. One major issue is that patient selection for anticipant TIPS implantation was not predefined. Balcar et al. provide some evidence that patients with first decompensation of grade 2 ascites and a MELD score ≥ 15 as well as patients with grade 3 ascites irrespective of the MELD score may benefit from early TIPS implantation as these patients have a high risk of further decompensation and consecutively a higher risk for death [14]. As to date, there are no prospective data showing that TIPS implantation is associated with improved transplantation-free survival in these selected patients with first ascitic decompensation; our study aims to close an important gap in patients with ascites and may have the potential to change treatment algorithms.
The recruitment will start in March 2025, and the recruitment process is planned to be completed by March 2028. This is study protocol version 1.3, 03.07.2025.
The current version of the protocol is registered at ClinicalTrials.gov with the following ID: NCT06576934 and in the Deutsches Register Klinische Studien (DRKS): DRKS00034545. It is planned to publish the results of the trial in a peer-reviewed journal. Additionally, the final trial dataset will be provided upon request.
Acute-on-chronic liver failure
Adverse event
Acute kidney injury
Continuous medical education
Clinical Trials Unit
Data Monitoring Committee
European Association for the Study of the Liver
Electronic case report form
Expansion polytetrafluoroethylene
Full analysis set
Good clinical practice
Hepatitis B virus
Hepatitis C virus
Hepatic encephalopathy
Hepatic venous pressure gradient
Independent ethics committee
Large-volume paracenteses
Model of end-stage liver disease
Mixed linear model for repeated measures
Non-selective beta-blocker
New York Heart Association
Portosystemic gradient
Inferior vena cava
Preferred term
Portal vein thrombosis
Quality of life
Clinical research associate
Safety set
Statistical Analysis System
Spontaneous bacterial peritonitis
Standard medical treatment
System organ class
Standard operating procedure
Transplantation-free survival
Transjugular intrahepatic portosystemic shunt
Transthoracic echocardiogram
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eTIPS study group: to be linked with the following investigators
Lukas Sturm, lukas.sturm.med@uniklinik-freiburg.de; Marlene Reincke, marlene.reincke@uniklinik-freiburg.de; Michael Praktiknjo, michael.praktiknjo@ukmuenster.de; Jonel Trebicka, jonel.trebicka@ukmuenster.de; Frank Erhard Uschner, Frankerhard.Uschner@ukmuenster.de; Markus Kimmann, Markus.Kimmann@ukmuenster.de; Michael Koehler, Michael.Koehler@ukmuenster.de; C M; Johannes Chang, Johannes.Chang@ukbonn.de; Christian Jansen, Christian.Jansen@ukbonn.de; Carsten Meyer, Carsten.Meyer@ukbonn.de; Benjamin Maasoumy, Maasoumy.Benjamin@mh-hannover.de; Lisa Sandmann, Sandmann.Lisa@mh-hannover.de; Bernhard Meyer, meyer.bernhard@mh-hannover.de; Matti Joonas Peperhove, Peperhove.Matti@mh-hannover.de; Jens Marquardt, Jens.Marquardt@uksh.de; Sven Danneberg, Sven.Danneberg@uksh.de; Roman Kloeckner, Roman.Kloeckner@uksh.de; Alexander Zipprich, Alexander.Zipprich@med.uni-jena.de; Cristina Ripoll, Cristina.Ripoll@med.uni-jena.de; Rene Aschenbach, rene.aschenbach@med.uni-jena.de; Thomas Berg, thomas.berg@medizin.uni-leipzig.de; Jonas Schumacher, jonas.schumacher@medizin.uni-leipzig.de; Holger Goessmann, holger.goessmann@medizin.uni-leipzig.de; Christian M. Lange, Christian.lange@med.uni-muenchen.de; Christiana Graf, Christiana.Graf@med.uni-muenchen.de; Moritz Wildgruber, Moritz.Wildgruber@med.uni-muenchen.d; eTony Bruns, tbruns@ukaachen.de; Theresa Wirtz, thwirtz@ukaachen.de; Philipp Bruners, pbruners@ukaachen.de; Anselm Kunstein, Anselm.Kunstein@med.uni-duesseldorf.de; Johannes Bode, johannes.bode@uni-duesseldorf.de; Peter Minko, Peter.Minko@med.uni-duesseldorf.de
Open Access funding enabled and organized by Projekt DEAL. The trial is funded by the German Research Foundation (DFG). Project number: 529465923.
Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, University of Freiburg, Hugstetter Str. 55, Freiburg, 79106, Germany
Dominik Bettinger, Michael Schultheiss & Robert Thimme
Clinical Trials Unit, University Medical Center, University of Freiburg, Freiburg, Germany
Marco Janoschke, Carolin Jenkner, Margit Kaufmann, Julia van Gessel & Hans-Heinrich Otter
Faculty of Medicine, Berta-Ottenstein-Programme, University of Freiburg, Freiburg, Germany
Michael Schultheiss
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DB is the corresponding author of the study. DB, MS, RT, CJ, MK[LE1] and MJ designed the study and drafted the manuscript. MK and HHO are responsible for the data collection and monitoring. RT, MS and JVG revised the manuscript. All the authors have read and approved the final manuscript.
Correspondence to Dominik Bettinger.
Independent Ethics Committee of the University Medical Center Freiburg: reference number: 24-1525_1-S1. Written informed consent to participate will be obtained from all participants who can withdraw at any time without giving a particular reason.
There is a specific consent form for patient participation as well as a comprehensive patient information sheet. It is written in German. The German consent form is available on request.
DB: Lecture fees/consulting: W. L. Gore & Associates GmbH, Travel grant: Gilead Science.
MS: lecture fees/consulting: Falk Foundation e.V., W. L. Gore & Associates, Bentley InnoMed GmbH.
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FXStreet Team
FXStreet
Ripple (XRP) price climbs and trades at $2.98 at the time of writing on Thursday, up from $2.84 and observing a 4.86% increase in the last 24 hours. The daily trade volume increased by 32.72%, as nearly $6,740,590,058.35 in XRP was traded. Volume remains high, meaning strong interest from a large number of investors likely anticipating a gain in the token in the short term.
XRP gained 4.34% in the last 7 days, and the total market capitalization currently hits $178,368,725,408.33.

In the last 24 hours, Zcash, SPX6900 and DeXe emerge as top gainers, while MemeCore, Plasma and Pi are the top losers.
Token launches influence demand and adoption among market participants. Listings on crypto exchanges deepen the liquidity for an asset and add new participants to an asset’s network. This is typically bullish for a digital asset.
A hack is an event in which an attacker captures a large volume of the asset from a DeFi bridge or hot wallet of an exchange or any other crypto platform via exploits, bugs or other methods. The exploiter then transfers these tokens out of the exchange platforms to ultimately sell or swap the assets for other cryptocurrencies or stablecoins. Such events often involve an en masse panic triggering a sell-off in the affected assets.
Macroeconomic events like the US Federal Reserve’s decision on interest rates influence crypto assets mainly through the direct impact they have on the US Dollar. An increase in interest rate typically negatively influences Bitcoin and altcoin prices, and vice versa. If the US Dollar index declines, risk assets and associated leverage for trading gets cheaper, in turn driving crypto prices higher.
Halvings are typically considered bullish events as they slash the block reward in half for miners, constricting the supply of the asset. At consistent demand if the supply reduces, the asset’s price climbs.

Information on these pages contains forward-looking statements that involve risks and uncertainties. Markets and instruments profiled on this page are for informational purposes only and should not in any way come across as a recommendation to buy or sell in these assets. You should do your own thorough research before making any investment decisions. FXStreet does not in any way guarantee that this information is free from mistakes, errors, or material misstatements. It also does not guarantee that this information is of a timely nature. Investing in Open Markets involves a great deal of risk, including the loss of all or a portion of your investment, as well as emotional distress. All risks, losses and costs associated with investing, including total loss of principal, are your responsibility. The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of FXStreet nor its advertisers. The author will not be held responsible for information that is found at the end of links posted on this page.
If not otherwise explicitly mentioned in the body of the article, at the time of writing, the author has no position in any stock mentioned in this article and no business relationship with any company mentioned. The author has not received compensation for writing this article, other than from FXStreet.
FXStreet and the author do not provide personalized recommendations. The author makes no representations as to the accuracy, completeness, or suitability of this information. FXStreet and the author will not be liable for any errors, omissions or any losses, injuries or damages arising from this information and its display or use. Errors and omissions excepted.
The author and FXStreet are not registered investment advisors and nothing in this article is intended to be investment advice.
Litecoin price continues to climb, trading above $118 on Thursday, extending gains of over 10% so far this week. The bullish momentum is further supported by rising Open Interest and trading volume in the LTC token.
Zcash (ZEC) rally outperforms the broader cryptocurrency market, driven by Grayscale's launch of a ZEC trust and a record-high Open Interest. DeXe (DEXE) and MYX Finance (MYX) follow as top performers with double-digit gains. 
Tether is exploring a partnership with Rumble to drive USAT adoption in the US market through the launch of a stablecoin wallet. Tether plans to leverage the video streaming platform Rumble to drive adoption of USAT, its US-focused stablecoin, CEO Paolo Ardoino said.
On-chain researcher ZachXBT reported a potential hack of Japanese mining pool SBI Crypto, involving the withdrawal of $21 million worth of Bitcoin (BTC), Ethereum (ETH), Litecoin (LTC), Dogecoin (DOGE) and Bitcoin Cash (BCH).
Bitcoin (BTC) price hovers around $109,000 at the time of writing on Friday after shedding nearly 5% so far this week. The broader cryptocurrency market experienced its largest single-day liquidation event of the year, wiping out mostly long positions.
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Colts.com Writer
The Colts on Wednesday placed cornerback Xavien Howard on the reserve/retired list and signed safety Trey Washington to the 53-man roster from the practice squad.
Howard joined the Colts as a free agent in August and started the first four games of the 2025 season. He totaled 11 tackles with one fumble recovery with the Colts. The 32-year-old Howard spent the previous eight years of his career (2015-2023) with the Miami Dolphins, where he was a four-time Pro Bowler and first-team AP All-Pro in 2020.
Washington initially joined the Colts as an undrafted free agent this spring.
The Colts made the roster moves on Tuesday.
The Colts made the roster moves on Saturday.
The cornerback spent 2021-2024 with the Cincinnati Bengals, playing under Lou Anarumo. 
The Colts made the roster moves on Tuesday.
The Colts made the roster move on Saturday. 
The Colts made the roster moves on Tuesday.
The Colts made the roster move on Monday. 
The Colts made the roster moves on Saturday.
The Colts made the roster move on Monday. 
The Colts made the roster move on Thursday.
The Colts made the roster move on Thursday.
2025 Schedule Is Here!
Explore the schedule and secure your seats today while you still can. Single game tickets are on sale now!
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Are you gearing up for the 2025 Joint Admissions and Matriculation Board (JAMB) Unified Tertiary Matriculation Examination (UTME)? Wondering what the schedule looks like or how to navigate the day successfully? What if you could grasp all the essential details before even stepping into the examination centre? Wouldn’t that give you a remarkable edge? Let’s explore what you need to know to tackle the UTME with confidence and ease. The Joint Admissions and Matriculation Board (JAMB) administers the Unified Tertiary Matriculation Examination (UTME), a pivotal assessment for students aspiring to enter higher education institutions in Nigeria. If you’re planning to sit the UTME in 2025, it’s crucial to understand the structure and requirements of the exam to enhance your preparation and performance.
See also: Prohibited Items for JAMB 2025 UTME.



The UTME is set to commence on April 25, 2025, with four distinct batches each day to accommodate all candidates efficiently:
Each batch is designed to ensure that the examination process is smooth and that all candidates have adequate time to complete their papers.
The examination comprises four subjects, selected according to the candidate’s chosen field of study:
A total of 180 questions must be answered in a consolidated time of two hours. Notably, 10 questions will be from the JAMB recommended reading text, highlighting the importance of thorough preparation.
Candidates are advised to use an average of 40 seconds per question, a strategy that will help in managing the limited time effectively during the examination.
Understanding the keyboard shortcuts provided by JAMB can significantly enhance your efficiency during the exam:
For subjects involving calculations, an on-screen calculator will be available. It’s vital to familiarize yourself with its functionality before the exam day.
Biometric verification is the primary mode of admission into the examination centres. This verification is mandatory and serves as the attendance register during the examinations. Candidates experiencing issues with biometric verification should be recaptured at the centre to ensure their eligibility to sit for the exam.
It is important to be aware that expo/runz—illegally obtaining exam questions and answers—is not possible with JAMB. Any claims of providing prior access to exam content should be regarded as fraudulent.
On the exam day, ensure you arrive at your designated centre early, bearing in mind the batch you are assigned to. Read all instructions carefully before starting the exam, and remember that your performance depends not only on your knowledge but also on how well you follow these instructions.
This comprehensive overview should serve as your foundational guide to preparing for the 2025 UTME. Remember, a well-prepared candidate is already on the path to success. Good luck!



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Boasting over a decade of expertise in the education sector, Olusegun offers current insights into educational trends, career opportunities, and the latest news.
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1. 1 flight attendant injured after Delta regional jets collide at LaGuardia Airport, airline says  ABC News – Breaking News, Latest News and Videos
2. 2 regional jets collide at LaGuardia airport with a wing slamming into a cockpit window  CNN
3. Two Delta regional jets collide on taxiway at LaGuardia Airport; 1 injured  Fox News
4. Plane taxiing at LaGuardia Airport is clipped by another jet on the ground  NBC News
5. Two Planes Collide on LaGuardia Airport Taxiway  The New York Times

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October 1, 2025 Gist Lovers Entertainment 0
The Oluwo of Iwo, Oba Abdulrasheed Akanbi, has stirred heated controversy after alleging that the Ooni of Ife, Oba Enitan Ogunwusi, had an affair with his ex-wife while they were still married.
In a video circulating on social media, shared via his official Instagram page, the outspoken monarch claimed his ex-wife was introduced to him from Canada as part of a conspiracy to destroy his reign and even assassinate him.
A post shared by Adewale Akanbi (@emperortelu1)
“My things are hidden. None of you can endure what these people have done to me. They packaged a woman for me. I didn’t know her from Canada. It was a setup. She was in my house for over three years, communicating with them and plotting my death.”
According to the Iwo monarch, the woman, who bore a child during their marriage, allegedly poisoned him twice and made several attempts on his life while secretly collaborating with the Ooni of Ife and his allies.
“They were setting me up with videos and many things in my own house. This supposedly ex-wife was asking me questions in the room, but it was death they sent into my home. She had a child, whom I don’t even know if he’s my child now. I have to confirm that through DNA.”
Oba Akanbi went on to claim that after he sent the woman away, the Ooni of Ife personally arranged accommodation for her and the child. He alleged that the monarch was also seen with her at a hotel.
Concluding his outburst, Oluwo declared that his conflict with the Ooni of Ife would “never end,” hinting at a deep-seated royal rivalry between the two influential traditional rulers.
The explosive allegations have left Nigerians divided online. While some have called for restraint and peaceful resolution, others insist the matter exposes a long-standing rift between Yoruba monarchs.

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