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text:
Clinical equipoise, also known as the principle of equipoise, provides the ethical basis for medical research that involves assigning patients to different treatment arms of a clinical trial. The term was first used by Benjamin Freedman in 1987, although references to its use go back to 1795 by Dr. Edward Jenner. In short, clinical equipoise means that there is genuine uncertainty in the expert medical community over whether a treatment will be beneficial. This applies also for off-label treatments performed before or during their required clinical trials.

An ethical dilemma arises in a clinical trial when the investigator(s) begin to believe that the treatment or intervention administered in one arm of the trial is significantly outperforming the other arms. A trial should begin with a null hypothesis, and there should exist no decisive evidence that the intervention or drug being tested will be superior to existing treatments, or that it will be completely ineffective. As the trial progresses, the findings may provide sufficient evidence to convince the investigator of the intervention or drug's efficacy. Once a certain threshold of evidence is passed, there is no longer genuine uncertainty about the most beneficial treatment, so there is an ethical imperative for the investigator to provide the superior intervention to all participants. Ethicists contest the location of this evidentiary threshold, with some suggesting that investigators should only continue the study until they are convinced that one of the treatments is better, and with others arguing that the study should continue until the evidence convinces the entire expert medical community.

The extent to which major research ethics policies endorse clinical equipoise varies. For instance, the Canadian Tri-Council Policy Statement endorses it, whereas the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) does not. With regard to clinical equipoise in practice, there is evidence that industry-funded studies disproportionately favor the industry product, suggesting unfavorable conditions for clinical equipoise. In contrast, a series of studies of national cancer institute funded trials suggests an outcome pattern consistent with clinical equipoise.

History
Shaw and Chalmers argued early on that "If the clinician knows, or has good reason to believe, that a new therapy (A) is better than another therapy (B), he cannot participate in a comparative trial of Therapy A versus Therapy B. Ethically, the clinician is obligated to give Therapy A to each new patient with a need for one of these therapies."  Researchers would thus face an ethical dilemma if they wanted to continue the study and collect more evidence, but had compelling evidence that one of the tested therapies was superior. They further stated that any results should be withheld from the researchers during the trial until completion to avoid this ethical dilemma and ensure the study's completion.

This method proved to be difficult in modern research, where many clinical trials have to be performed and analyzed by experts in that field.  Freedman proposed a different approach to this ethical dilemma called clinical equipoise.  Clinical equipoise occurs "if there is genuine uncertainty within the expert medical community — not necessarily on the part of the individual investigator — about the preferred treatment." Clinical equipoise is distinguished from theoretical equipoise, which requires evidence on behalf of the alternative treatments to be exactly balanced and thus yields a very fragile epistemic threshold for favoring one treatment over the other. Theoretical equipoise could be disturbed, for example, by something as simple as anecdotal evidence or a hunch on the part of the investigator. Clinical equipoise allows investigators to continue a trial until they have enough statistical evidence to convince other experts of the validity of their results, without a loss of ethical integrity on the part of the investigators.

Equipoise is also an important consideration in the design of a trial from a patient's perspective. This is especially true in randomized controlled trials (RCTs) for surgical interventions, where both trial and control arms are likely to have their own associated risks and hopes for benefits. The condition of the patient is also a factor in these risks. Ensuring that trials meet the standards of clinical equipoise is an important part of patient recruitment in this regard; it is likely that past trials that did not meet conditions of clinical equipoise suffered from poor recruitment.

Criticism
Miller and Brody argue that the notion of clinical equipoise is fundamentally misguided. The ethics of therapy and the ethics of research are two distinct enterprises that are governed by different norms. They state, "The doctrine of clinical equipoise is intended to act as a bridge between therapy and research, allegedly making it possible to conduct RCTs without sacrificing the therapeutic obligation of physicians to provide treatment according to a scientifically validated standard of care. This constitutes therapeutic misconception concerning the ethics of clinical trials, analogous to the tendency of patient volunteers to confuse treatment in the context of RCTs with routine medical care." Equipoise, they argue, only makes sense as a normative assumption for clinical trials if one assumes that researchers have therapeutic obligations to their research participants.
Further criticisms of clinical equipoise have been leveled by Robert Veatch and by Peter Ubel and Robert Silbergleit.

See also
 Bracketing (phenomenology)
 Cartesian doubt
 Suspension of judgment

References

External links
 Bioethics: An Anthology, pg. 429
  For and against, BMJ 2000;321:756–758
 The Tri-Council Policy Statement (Canada)

Ethical principles
Clinical trials
Medical ethics

redpajama_set_name: RedPajamaWikipedia


text:
Growing In Marriage
Religion Christianity Kids and Family Bigrich Coaching Counselor Growinginmarriage Husband Marriagecoach Talk Wife Big Rich & DeAnna Big Rich Deanna Counseling Marriage Lifestyle Relationship Society
By Big Rich & DeAnna and Big Rich. Discovered by Player FM and our community — copyright is owned by the publisher, not Player FM, and audio is streamed directly from their servers. Hit the Subscribe button to track updates in Player FM, or paste the feed URL into other podcast apps.
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140. Advice for Newlyweds
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On this week's episode of the Growing In Marriage podcast, Big Rich and DeAnna are giving advice to newlyweds.
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The latest, scaled-down, designs have been submitted to City of Lincoln Council.
Final plans have been submitted to City of Lincoln Council for a long-talked-about pedestrian footbridge over the Brayford Wharf East level crossing, without lifts.
The new, scaled down application follows original approval of a bridge with elevator towers. Changes have been made due to what Network Rail describes as financial restraints.
The crossing, which is used by around 16,000 pedestrians and 7,000 vehicles a day, has a current barrier downtime of up to 20 minutes every hour – a statistic that is expected to increase.
The Brayford level crossing is currently ranked the second highest risk level crossing on the East Midlands Route.
New designs also appear to show an extension to the path beside the bridge, requiring significant roadworks, where just this autumn Lincolnshire County Council invested in a new one-way road system with islands and new traffic lights.
As reported previously, proposals for the bridge have been through a number of incarnations and the project was shelved for around a year due to cost.
The footbridge has undergone a number of delays and redesigns since its initial proposal.
Plans have been submitted by Network Rail to City of Lincoln Council planners.
Representations in response to the proposals must be made by January 6, 2017 and plans will be considered by the council at a date to be determined.
This summer, Network Rail completed its new level crossing footbridge on Lincoln High Street.


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Bush needs 'mojo back'
May 2, 2006 — 12.44am
The new chief of staff at the White House says it is time for the Bush administration to get its "mojo back".
Josh Bolten made no promises about pulling up President George W Bush's all-time low approval ratings.
But he said he and Bush would "put the president out more in ways that the American people can see what he's really like".
However, he said that tactical change did not mean a policy overhaul.
"What the change does provide is an opportunity for the White House to step back, refresh, re-energise at a time when we're five and half years into an administration - normally a slow point, a low point, in many administrations - and a chance for us to get our mojo back," he said on Fox News.


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Georgia's new voting system actually decreases election security, say experts
Georgia is one of many states that is adopting or considering voting technology that some experts say decreases security and election integrity.
Image: Reuters/Leah Mills
Timothy Pratt
Earlier this year, Georgia's Secure, Accessible, and Fair Elections Commission held a public meeting at the state capitol to answer a pressing question: What should Georgia do to replace its aging, touchscreen voting machines, as well as other parts of its election system? In the preceding years, security vulnerabilities in the state's election system had been repeatedly exposed: by Russian operatives, friendly hackers, and even a Georgia voter who, just days ahead of the 2018 midterms, revealed that anyone could go online and gain access to the state's voter registration database.
Computer scientists and elections experts from around the country had weighed in during the seven months of the commission's deliberations on the issue. They submitted letters and provided testimony, sharing the latest research and clarifying technical concepts tied to holding safe, reliable elections. Their contributions were underscored by commission member Wenke Lee, co-director of Georgia Tech's Institute for Information Security and Privacy, and the group's only computer scientist.
Despite this, the commission ultimately did not recommend measures backed by Lee and his colleagues at places like Stanford, Yale, Princeton, MIT, and Google—including the recommendation that the state return to a system of paper ballots filled out by hand, combined with what scientists call risk-limiting audits. Instead, the commission recommended buying a system that included another, more expensive touchscreen voting machine that prints a paper ballot. Months later, Lee was at a loss to explain: "I don't understand why they still don't understand," he said.
With its decision, Georgia's counties remain among the 33% of counties nationwide that use either machines with no paper trail or machines that print paper ballots, which are then scanned on separate machines. The vast majority of the rest of the counties use paper ballots filled out by hand, which are then scanned or counted by hand. With the passing of the Help America Vote Act (HAVA) in 2002, all polling places nationwide must also include at least one electronic voting machine for voters with disabilities.
But with Texas, Ohio, Pennsylvania, Delaware, and New Jersey among the many states also overhauling their election systems before the 2020 presidential election, Georgia's decision has computer scientists and election experts worried that lessons learned over nearly two decades of computerized voting are being woefully ignored. Indeed, hundreds of millions of dollars have been or will soon be spent in these and other states on technology that experts say decreases election security and erodes election integrity. And this, they say, will only contribute to the sizeable portion of the American public who already worry that their votes are vulnerable to hacking and other threats.
The sentiments of many computer scientists were crystallized by Richard DeMillo, a colleague of Lee's at Georgia Tech who recommends casting paper ballots filled out by hand for all voters, except those with disabilities who would benefit from using machines. "You simply can't construct a trusted paper trail," DeMillo said, "if you let a machine make a ballot for you."
Computer science's scrutiny of voting systems goes back several decades. The Federal Election Commission issued its first standards for computer-based voting as far back as 1990, but it wasn't until the 2000 presidential election between George W. Bush and Al Gore, which hinged on the shortcomings of punch-card voting, that states across the nation began to digitize their election systems to varying degrees. Just three years later, one of the first independent computer security analyses of electronic voting systems was already raising flags.
With the global spread of computer technology and the increasingly sophisticated tactics of nefarious actors, concerns have only multiplied since then—not least because many state voting systems have not been redesigned since shortly after the Bush-Gore election. Those systems are "vulnerable to nation-states now," said John Sebes, the chief technology officer at OSET Institute, a nonprofit organization that researches and develops election technology, "and operated by county officials with no IT experience."
That was among the concerns raised in a 160-page report published last year by the National Academies of Sciences, Engineering, and Medicine. In that report, some of the nation's leading experts on computer science and elections concluded that there is no "technical mechanism currently available that can ensure that a computer application—such as one used to record or count votes—will produce accurate results." One reason, the authors noted: "[Malicious software] can be introduced at any point in the electronic path of a vote—from the software behind the vote-casting interface to the software tabulating votes—to prevent a voter's vote from being recorded as intended."
Voting systems across the US.
Image: Pew Research Center/Verified Voting Foundation
It was with such realities in mind that Wenke Lee tried to explain to the Georgia committee, early in its deliberative process, just what it would take to build a more secure electronic voting system. He drew on a concept that had been kicking around computer science for more than a decade called "software independence." The idea, introduced in a 2008 paper, refers to the ability to verify computerized election results without depending on the software used in that system. Examples provided by the authors included paper ballots filled out by hand and scanned, and touchscreen machines that print out paper ballots.
That might seem like a straightforward solution, but a series of studies since 2008 have tested the notion that voters using a touchscreen or other electronic machine will or can verify their votes on a printed ballot. The answer is mostly, "no." Last year, DeMillo collaborated on a study of voter interaction with one such system used during the 2018 Tennessee primary elections. The analysis came to two troubling conclusions: Most voters don't bother to verify paper ballot summary cards, and a significant percentage can't recall the selections they had made on the computer touchscreen anyway—even when they had cast their votes just moments before.
Andrew Appel, a computer science professor at Princeton University and one of the authors of the National Academies report, said DeMillo's research "has strong implications about how we assess voting technology." If voters don't and can't verify ballots printed by machines, he said, then "the average voter can't notice if the machine is cheating."
Lee had DeMillo's results in mind when he tried, near the end of the Georgia commission's last meeting, to alert his fellow members to questions he had asked the voting machine vendors who had submitted proposals to the state. "Have you done [a] study to show that the voters can actually clearly verify the contents?" he recalled asking the companies. Their answer, according to Lee: "We don't deal with that."
Katina Granger, spokeswoman for Elections Systems & Software, the nation's largest election technology company, according to the National Academies report, confirmed that her company doesn't do such research. Instead, she said, the research "should be conducted by a third-party, across jurisdictions and over time, and the research should be peer reviewed."
As it happens, the Tennessee system DeMillo studied uses the same technology Georgia is now preparing to buy for $150 million. Georgia will then have one of the nation's most expensive election systems.
The decisions Georgia and other states are making on updating their election systems are not regulated by the federal government. Instead, since the Help America Vote Act passed in 2002, the Election Assistance Commission and the National Institute for Standards and Technology work together to develop voluntary guidelines for election systems. Most states use these guidelines in some way, but DeMillo and other computer scientists have criticized the guidelines for being vague and unenforceable.
Georgia and other states are not only changing their voting machines. They are also looking at how to ensure the validity of election results through audits. And if experts insisted to Georgia policymakers that ballots marked by hand are the only way to produce reliable paper trails for any audit, the National Academies report was clear about what kind of audit should be used: "States should mandate risk-limiting audits" before certifying election results, the authors wrote.
For decades, many states performed audits by hand-counting ballots in a fixed percentage of precincts. But a fixed percentage "may not provide adequate assurance with regard to the outcome of a close election," the National Academies report authors wrote. Risk-limiting audits, on the other hand, examine "randomly selected paper ballots until sufficient statistical assurance is obtained." The so-called "risk limit" refers to the largest possible chance that the audit will not correct an inaccurate result. For example, a 10% risk limit means there is 90% chance of an audit identifying the correct result of an election.
Philip B. Stark, a statistics professor at UC Berkeley, developed the idea of risk-limiting audits more than a decade ago. He says that pilots of the technique have been conducted in a handful of states. But he cautions that risk-limiting audits should not be conducted with machine-printed ballots. "If the paper trail is not reliable, all you're doing is confirming what the papers show."
Georgia state Senator William T. Ligon Jr. doesn't agree that touchscreens are a less reliable method for casting votes. He was a sponsor of the bill, now signed into law, overhauling Georgia's election system. (State Representative Barry Fleming, the bill's lead sponsor, as well as co-chair of the SAFE Commission, did not respond to multiple requests for comment.) Ligon said he wasn't familiar with Lee and his advice to the commission. Instead, Ligon cited the testimony of former Georgia Secretary of State Cathy Cox as one of the reasons he chose to back a system based on touchscreen voting machines that print out a paper ballot.
Cox told the legislature about "under votes, over votes, and stray votes. They all come with hand-marked paper ballots," Ligon said. It was clear to him that printed ballots bring more certainty. When asked about research demonstrating that voters don't or can't verify their ballots when printed, Ligon said, "voters have to take some responsibility for verifying their ballots."
"In my opinion, we've built in as many systems to protect the vote as possible—and that's the goal," Ligon concluded.
Meanwhile, in Europe, countries such as the United Kingdom, Germany, and the Netherlands all use paper ballots marked by hand. The Netherlands has recently taken computers out of vote tallying as well.
Until such standards are reached in the US, Lee said, he will not be dissuaded from speaking up on the issue of election security and integrity, and he hopes other scientists will do the same. "I would urge all scientists and engineers, when they have the opportunity… to educate about what technologies should be used, and not stay in our ivory towers."
Timothy Pratt is a journalist based in the Atlanta area. He has written for The New York Times, The Economist, and The Guardian, among many other publications.
This article was originally published on Undark. Read the original article.


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FDA approves first ever non-surgical treatment for rare neuroendocrine cancers
The U.S. Food and Drug Administration (FDA) has approved the first ever non-surgical treatment for the rare neuroendocrine cancers pheochromocytoma and paraganglioma. The approval was based on a multi-center trial led by researchers in the Abramson Cancer Center of the University of Pennsylvania and was granted to Progenics Pharmaceuticals for AZEDRA (iobenguane I131).
"This is a true breakthrough. Until today, there were no anti-tumor therapies available for patients with these tumors who were not candidates for surgery," said the trial's principal investigator Daniel A. Pryma, MD, an associate professor of Radiology and Radiation Oncology, chief of Nuclear Medicine and Clinical Molecular Imaging at Penn's Perelman School of Medicine, and a member of Penn's Abramson Cancer Center.
AZEDRA is a targeted, high-specific-activity radiotherapeutic, indicated for the treatment of adult and pediatric patients (12 years and older) with a positive iobenguane scan, and unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy. AZEDRA is the first and only approved therapy for this indication.
Pheochromocytoma and paraganglioma are neuroendocrine tumors that form from the same type of tissue. Pheochromocytoma forms in the adrenal gland, while paraganglioma forms outside of the gland. There are an estimated 650 to 2,600 new cases in the United States each year, with between 10 and 35 percent of cases metastatic or locally invasive at diagnosis. In addition, when the disease returns, it may not be resectable surgically. The five-year survival rate of unresectable cases can be as low as 12 percent.
AZEDRA is a radiotherapy drug that attacks these tumors with a high, specifically-targeted dose. The FDA gave it an Orphan Drug designation, Fast Track status, and Breakthrough Therapy designation in the U.S.
Researchers discover unexpected role for the clock gene in prostate cancer progression
Study: Oral sex can increase risk of HPV-related oropharyngeal cancer
IU research findings could prevent common complication of blood stem cell transplantation in leukemia
In the Penn-led trial, 68 patients received at least one therapeutic dose of AZEDRA. Twenty-five percent of patients who received at least one dose met the trial clinical benefit endpoint, and the number jumped to 32 percent in patients who received two doses. That clinical benefit was measured by a 50 percent or greater reduction in the amount of hypertensive medications these patients took for at least 6 months, as high blood pressure and associated cardiovascular side effects are a major cause of harm from these cancers. Additionally, 92 percent of evaluable patients who received at least one dose achieved a partial response or stable disease.
"This therapy not only controls the tumor, but also the debilitating symptoms caused by their excess hormone production, meaning it provides a dual benefit to patients," Pryma said.
Pryma noted that Penn is one of the few academic medical centers in the country that has a dedicated tumor board for these rare cancers, making it an ideal institution to lead the multi-center trial. In fact, this is the second FDA approval in which the center has played a role this year. In January, the FDA approved Lutathera (lutetium Lu 177 dotatate) for the treatment of gastroenteropancreatic neuroendocrine tumors which originate in the pancreas or gastrointestinal tract.
"Penn's multidisciplinary approach draws on our physicians' extensive experience in dealing with rare tumors and brings multiple experts from varying backgrounds together to offer cutting-edge treatments," said David C. Metz, MD, the co-director, with Debbie Cohen, MD, of the Neuroendocrine Tumor Center at Penn.
"This is a very exciting step in bringing a much needed treatment to patients with metastatic pheochromocytomas and paragangliomas where limited treatment options exist," Cohen said.
https://www.med.upenn.edu/
Posted in: Medical Procedure News | Medical Condition News | Pharmaceutical News
Tags: Adrenal Gland, Blood, Blood Pressure, Cancer, Education, Gastrointestinal Tract, Healthcare, High Blood Pressure, Hormone, Hospice, Hospital, Imaging, Medical School, Medicine, Molecular Imaging, Nuclear Medicine, Oncology, Pancreas, Pharmaceuticals, Pheochromocytoma, Radiology, Radiotherapy, Research, Surgery, Tumor
Cancer cells hibernate to survive harsh environment created by chemotherapy
Scientists identify bacteria-based approach against cancer
Study reveals connection between oral sex and oropharyngeal cancer
Researchers investigate protein phosphatase to identify new treatments for cancer, other diseases
Master Regulator proteins control cancer transcriptional identity
Researchers discover a new approach to inhibit intrahepatic cholangiocarcinoma
Mediterranean diet has the potential to effect progression of prostate cancer
UTSW study uncovers a gene linked to growth of breast cancer


This is a review for AnxiClear to help you make a decision regarding the purchase of this product. This is one of the best anxiety treatment products I have ever been able to review. The manufacturer claims that this product is able to help you feel calm and peaceful both night and day and supports a positive outlook on life. They also claim this product helps you to feel more confident and secure. Keep reading for more information about this product.
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There are five different package options for AnxiClear. The starter bottle costs $49.95. If you would like to purchase in bulk, the mild program costs $69.90 and provides you with two bottles. The advanced program gives you four bottles of AnxiClear for only $99.80. If you would like four bottles of just the original AnxiClear, this also costs $99.80. The most popular package is the prevention program which is buy three get three free for $135.70. There are a number of reviews that state that this is a high quality system and gets rid of anxiety and helps significantly with depression and sleeplessness.
The manufacturer offers a 60 day money back guarantee for all of their products. If you return your products within 60 days and receive a refund without the shipping charges. You can return both opened and unopened bottles and receive a refund with no questions asked. There are a number of customer reviews that state this product is effective in keeping your anxiety and depression under control.
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You will find Majvor Franzén's biography HERE.
Nice pages! Thanks for posting this. Good resource for all fans of the engraved stamp!
It's a pleasure, Stephan, thanks for reading my blog!
Hi Tom, that would be the 'Wall Hanging' definitive of 1979, a 4k value. It is a detail from a woven fabric from Skåne, printed in chalky blue and red, SG993, Facit1073.


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Fighter Legend : Brigadier General Steve Ritchie
by Ewen Menzies Oct 8, 2015
The Vietnam War saw only five "aces" during the course of the war. Of those, only two were pilots; the other three were weapons system officers. One of those remarkable pilots was a young USAF Captain named Richard S. "Steve" Ritchie.
Hailing from North Carolina, the star high school football quarterback graduated first in his class from the Air Force Academy in 1964. A complex character, he has been described by his peers as brilliant, cocky, egotistical and lacking in self-discipline. In August 1965, the now-Lieutenant Ritchie was finally awarded his wings at Laredo AFB in Texas and was billeted to Eglin AFB in Florida as an F-104 Starfighter pilot with Flight Test Operations.
Two years later, Ritchie was combat qualified on the McDonnell Douglas F-4 Phantom II and preparing for his first tour in war-torn South East Asia. He soon found himself at Da Nang Air Base as part of 480th Tactical Fighter Squadron, flying Fast FAC missions. For the most part, the low-powered Cessna O-1 Bird Dog and O-2 Skymaster Forward Air Controller (FAC) aircraft were more than adequate for the job.
However, in certain areas where large calibre guns and surface-to-air missiles were in use, Fast FAC aircraft were utilized due to their ability to get in and out of the area of operations quickly. They would head out on four hour sorties with a full load of smoke rockets and 20 mm cannon rounds and would rarely return with much left of either. In this role, Lieutenant Ritchie completed a grand total of 195 missions.
Following his return to the U.S. he was selected to attend the Fighter Weapons Instructor Course at Nellis AFB in Nevada and was subsequently invited to become one of its instructors. He accepted, and became the Fighter Weapons School's youngest instructor, teaching air-to-air combat between 1970 and 1972.
Photo Courtesy of the Collings Foundation.
In January 1972, Ritchie volunteered for his second combat tour of Vietnam. He was assigned to the 432nd Tactical Reconnaissance Wing, where he joined the 555th Tactical Fighter Squadron. Whilst with 555th TFS, he would be flying the F-4D Phantom II, which came equipped with some top secret avionics known as Combat Tree. This advanced electronic warfare suite had the ability to detect the transponder signals emitted by Vietnamese MiGs as they identified themselves to ground radar.
It was as leader of an element of F-4s on 10 May 1972 that Captain Ritchie would score the first of 5 kills that would make him the only Air Force Ace pilot of the Vietnam war. Whilst on patrol, the flight was vectored to a formation of 4 MiG-21s. They managed to take out three aircraft, but were ambushed by a flight of MiG-19s loitering nearby. At this point Captain Ritchie and his Weapons Systems Officer (WSO) Captain Charles "Chuck" DeBellvue rolled in behind the last MiG-21. They obtained radar lock and launched two AIM-7 Sparrow missiles. The second one hit and they had joined the ranks of the USAF MiG killers.
Captain Ritchie's second kill came on 31 May 1972 whilst on patrol over North Vietnam with WSO Capt. Lawrence Pettit. The USS Chicago, using the callsign of Red Crown, provided early warning of a flight of MiG-21s 40 miles southwest of Ritchie's position. Waiting until they were within 15 miles, he commenced a descending turn until he was behind and below the tail end MiG. Finally achieving lock-on, he let loose all 4 of his Sparrow missiles, with the last one finding its target.
Kills three and four came on 8 July 1972 with DeBellvue in the back seat. This time they were flying lead in a four-ship formation under the callsign of Paula and consisted of F-4E Phantoms–equipped with the 20mm M61A1 Vulcan cannon. Another flight of F-4s had been jumped by MiGs and one had to break formation and make a run for home, leaking fuel and hydraulics. Ritchie's flight headed over to provide assistance and received warning of additional MiG activity.
Seeing a MiG-21 at his 10 o'clock, he dropped his external tanks, engaged afterburners and turned to meet it head-on. They passed close enough to see the enemy pilot in the cockpit but, knowing there was another MiG, Captain Ritchie decided not to turn in behind it. After the second MiG passed head-on, he immediately commenced a tight turn to the left which ended with him below and at the MiG's 5 o'clock. Flying right at the edge of the AIM-7's effective operating parameters, Ritchie let two fly. The first hit the MiG in the centre of the fuselage and the second disappeared into the resulting fireball.
But there was no time to celebrate. The first MiG had taken off in pursuit of the rest of Ritchie's formation and was positioning behind the last F-4. Captain Ritchie turned hard to get in behind the MiG and ended up on its 5 o'clock – in his own words:
"I put him in the gunsight, Chuck (his WSO) told me that he had a lock; that's all I needed to know. The missile (an AIM-7 Sparrow) came off the airplane. It looked like a Sidewinder, it began to snake and did not appear to guide, and I was telling it: 'the target is over here!'. Suddenly, the missile appeared to do a 90 degree right turn and it hit the MiG in the fuselage. The missile was pulling about 25g and had accelerated to about 1200 miles per hour when it hit, so you can imagine the explosion!"
Scratch 4.
His fifth and final kill occurred on 28th August 1972, whilst flying in support of a strike north of Hanoi. Ironically, flying the very same aircraft in which he scored his first kill, his flight was vectored to a formation of MiG-21s approximately 30 miles southwest of Hanoi. Approaching the reported area at 15,000 feet, DeBellevue picked up the MiGs on his radar. Concerned about the proximity of the MiGs to another flight in the area, Ritchie ordered his flight to increase their speed and climb. DeBellvue established the MiG's altitude at 25,00 feet.
Read Next: Watch: Last F-4 Phantom Flight: The Air Force Says Goodbye
As he climbed, Ritchie spotted the MiGs above him and headed in the opposite direction. He then began a climbing turn to intercept, all the time receiving continuous range call-outs from DeBellvue. His first two Sparrow missiles missed their mark but by following its contrail, he managed to track one MiG and fire his last two missiles. As it pulled into an evasive maneuver, the MiG -21 closed the distance to the missiles and was hit by the second.
After 339 combat sorties and over 800 flying hours in Vietnam, Ritchie left active service and joined the Colorado Air National Guard in April 1974. Transferring to the Air Force Reserve in 1984, he retired with the rank of Brigadier General on 9th February 1999.
Brigadier General Steve Ritchie was decorated many times throughout his career, including the Silver Star with three oak leaf clusters, the Distinguished Flying Cross with nine oak leaf clusters and the prestigious Air Force Cross.
"Through his extraordinary heroism, superb airmanship and aggressiveness in the face of the enemy, Captain Ritchie reflected the highest credit upon himself and the United States Air Force." – Extract from the Air Force Cross Citation.
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With the presidential elections this year, the exciting primaries including characters like Trump and Sanders, and now the dead or judge Scalia, possibly allowing Obama to nominate another Supreme Court judge, American politics could change along a number of interesting paths. Yet, the most pressing issue is often forgotten amongst partisan rhetorics – the tedious political struggle accompanied by bipartisan governments. Continue reading Who is partisan now?
Posted on 22. February 2016 22. February 2016 Author SkalgCategories PolitikTags 2009, 2016, Data, Democrats, elections, GOP, OBAMA, Republicans, States, USALeave a comment on Who is partisan now?


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Home Entry Topic Review Current: Bile Salt Hydrolases
Bile Salt Hydrolases
This entry is adapted from 10.3390/microorganisms9061122
Bile salt hydrolase (BSH; EC 3.5.1.24) is an enzyme produced by the intestinal microbiota that catalyzes the hydrolysis of amide bonds in conjugated BAs, resulting in the release of free amino acids. These enzymes belong to the N-terminal nucleophilic (Ntn) hydrolase superfamily and share a similar αββα-core structure to an N-terminal catalytic cysteine residue. This residue is critical to the catalysis mechanism and acts both as a nucleophile and a proton donor. The N-terminal amino group serves as the proton acceptor and activates the nucleophilic thiol group of the cysteine side chain. Besides the cysteine residue, other amino acids conserved in most BSHs are also relevant to the catalytic reaction, including Arg18, Asp21, Asn82, Asn175, and Arg228.
bile salt hydrolases bile acids gut microbiota
Subjects: Biochemistry & Molecular Biology
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The gastrointestinal tract hosts a large and complex community of microorganisms, collectively known as the gut microbiota. This community consists of around 1014 microorganisms and is dominated by the presence of about 500–1000 different bacterial species [1][2]. The gut microbiota lives in a close relationship with the host and is crucial for many physiological processes [3][4]. Several mechanisms have been proposed to mediate the effects of these microorganisms on metabolic health. One important function carried out by the human gut microbiota is the deconjugation of primary bile acids (BAs) by BSH enzymes and their impact on host health [5][6]. The presence of active BSHs has long been recognized as a selection criterion for defining potential probiotics. BAs are amphipathic molecules that are initially produced by the host and subsequently transformed by the gut microbiota. Host primary BAs (CA, cholic acid; CDCA, chenodeoxycholic acid) are synthesized from cholesterol and conjugated with glycine or taurine in the liver (GCA and GCDCA, glycocholic acid and glycochenodeoxycholic acid; TCA and TCDCA, taurocholic acid and taurochenodeoxycholic acid). Conjugation improves the solubility of such hydrophobic BAs and reduces the potential damage of the cell membranes. Conjugated BAs are then excreted into the duodenum from the biliary duct, where they contribute to the solubilization of dietary lipids and their absorption through the small intestine and colon [7][8]. Around 95% of BAs are reabsorbed in the distal ileum. They are further effluxed into portal circulation, redirected, and stored in the liver through the enterohepatic cycle (EHC). The remaining primary BAs that escape EHC undergo further microbial biotransformations, including deconjugation, oxidation, epimerization, 7-dehydroxylation, esterification, and desulfatation by the gut microbiota [9]. The prominent secondary BAs are comprised of deoxycholic acid (DCA) and lithocholic acid (LCA), which result from the dehydroxylation of CA and CDCA, respectively [10][11]. Both primary and secondary BAs serve as signaling molecules that influence several processes, including lipid, glucose, and energy metabolism as well as inflammation [12][13].
Recently, increasing attention has been paid to better explore (i) the variety of enzymes catalyzing BA biotransformation, (ii) their distribution, and (iii) their relevance to the host's health and to disease [14][15][16][17][18][19].
2. Distribution of BSH-Active Bacteria in the Gut Microbiota
Many reports described that most studied BSHs are encoded by lactic acid bacteria and are used as probiotics to prevent mainly metabolic disorders in humans [20][21][22]. Recently, it was demonstrated that the human gut microbiota plays key a role in contributing to host health [23]. Among these microbial functions, the deconjugation of BAs by BSH enzymes comprises an imperative gateway reaction in the metabolism of BAs [6]. Considering the importance of BAs as biomolecules, gaps in our knowledge of these enzymes need to be filled. To uncover BSH gene abundance and their activity distribution in the gut microbiota, different approaches such as biochemical assays and metagenomic analysis are currently used; however, both approaches have inherent limitations. Indeed, standard biochemical assays that measure substrate consumption or product generation are unsuitable for defining and characterizing BSH enzymatic activities from complex biological samples. Through functional and comparative metagenomic analysis, Jones et al. highlighted the presence of BSH activity in all major bacterial divisions and the enrichment of BSHs in the human gut metagenomes of healthy subjects. Indeed, most metagenomic BSH-active clones were found to belong to Firmicutes, Bacteroidetes, and Actinobacteria [24]. Recently, taxonomic analyses among 11 different worldwide healthy populations have revealed 591 BSH enzymes, which are distributed over 117 genera and 447 bacterial strains [25]. The majority of the identified BSHs in the study belong to five genera, namely Bacteroides, Blautia, Eubacterium, Clostridium, and Roseburia. Around 27% of BSH-encoding bacteria behave as paralogs and are mainly assigned to Bacteroides. Given that the presence of paralogs introduces significant BSH sequence dissimilarity, Song et al. proposed an eight phylotype classification based on a phylogenetic tree as a more rational alternative than the classification by genera. A multivariable regression analysis showed that the relative abundance of BSHs does not significantly correlate with gender, age, and body mass index (BMI), while BSH distribution varies among populations from different geographical regions. At the biochemical level, enzyme activity assays highlighted different deconjugation selectivity between the phylotypes, in agreement with previous reports [25][26]. For example, while the T0 (Clostridium, Intestinibacter, Lactobacillus, Enterococcus), T1 (Eubacterium, Blautia, Clostridium, Roseburia, Ruminococcus), T3 (Lactobacillus), T4 (Bifidobacterium and Collinsella), and T7 (mainly Blautia) groups have significant specific activity for most bile salts, the T5 and T6 groups (assigned to Bacteroides) exhibit lower specificity towards GCA and both GCA/TCA, respectively. In contrast, the T1, T3, and T4 groups display the highest specific activities with GCA. When GCDCA and TCDCA are used as substrates, the highest specific activity is observed for group T2. Using a chemoproteomic approach to target BSH activities in the gut, Parasar et al. (2019) showed that this activity increases during intestinal inflammation, which results in higher deconjugated BAs [27]. Further studies are required to understand the relevance of gut BSH activities in host diseases.
3. BSH in Health and Disease
Several studies have investigated BSH-active bacteria for their clinical efficacy in lowering hypercholesterolemia [15][28][29]. These bacteria have been shown to increase BA deconjugation, which in turn decreases cholesterol absorption by enterocytes and enhances its fecal excretion [14]. Increased BSH activity was suggested to affect bile acid composition and to influence farnesoid X receptor (FXR) signaling. It has been demonstrated that reduced FXR activity promotes the downregulation of the small heterodimer partner (SHP) and increases the synthesis of BAs from cholesterol through the rate-limiting enzyme cholesterol 7α-hydroxylase (CYP7A1) [30] (Figure 1). The downregulation of the SHP elicits the activation of the liver X receptor (LXR), which in turn upregulates the adenosine triphosphate-binding cassette transporters G5 and G8 (ABCG5/G8) and promotes cholesterol transport into the bile [31][32] (Figure 1). The effect of BSH activity may be extended to weight gain through FXR signaling and the membrane receptor TGR-5. Previous studies demonstrated that the use of Tempol, an anti-oxidant, prevents obesity in mice through the reduction of BSH activity, resulting in FXR inhibition via the accumulation of tauro-β-muricholic acid. Furthermore, high-fat diet-fed FXR null mice showed reduced diet-induced obesity [12][33]. On the other hand, the activation of TGR-5 by BAs induced a significant weight reduction in mice on a high-fat diet. [34]. Obesity may also be associated with several liver-related diseases, including steatosis, hepatic cancer, and non-alcoholic fatty liver disease (NAFLD), which are linked to altered gut microbiota communities. NAFLD is a chronic liver disease with inflammation, hepatocyte injury, steatosis, and fibrosis as pathological features. Strategies for NAFLD treatment target the gut microbiota based on its ability to modulate insulin sensitivity and metabolism related to host energy, choline, and BAs. Of note, a clinical trial showed that VSL#3, a combination of eight probiotics, improves NAFLD through the increase in glucagon-like peptide-1 (GLP-1) [35]. Other probiotics, tested either in combination or isolated, also showed beneficial effects on NAFLD improvement [36][37]. Recently, Huang et al. demonstrated that Lactobacillus plantarum AR113 and L. casei pWQH0, which both display high BSH activity, decrease hepatic lipid accumulation in NAFLD cell models, which is potentially mediated by the BSH activity [38]. Besides cholesterol and lipid metabolism, BSH activity may be linked to inflammatory disorders. Gut metagenomic analysis revealed a reduced abundance in the BSH gene in patients suffering from inflammatory bowel diseases (IBD) and type 2 diabetes [39][40]. In the IBD context, the induced modification of the BA profile was suggested to alter the protective effect on the intestinal barrier mediated by FXR [40]. Repression of secondary BA metabolism via the modulation of BSH activity may represent a new therapeutic method for hepatic cancer treatment. In fact, primary BAs have been shown to stimulate the liver's accumulation of hepatic NKT cells and antitumor immunity, thus inhibiting tumorigenesis in a mice model [41]. Besides host–microbiome crosstalk, BSHs are suggested to protect commensal bacteria from BA toxicity and to contribute to bacterial survival and gut colonization [42][43][44]. They are also believed to confer a nutritional advantage since released amino acids might be used as sources of nitrogen, carbon, and energy [14]. Altogether, these data stress the importance of BSH activity and BA receptors as therapeutic targets in numerous diseases.
Figure 1. A schematic illustration of enterohepatic circulation and intestinal BA metabolism by BSH enzymes. The BAs are synthesized and conjugated with either taurine or glycine in the liver. They are further spilled over from the enterohepatic circulation and deconjugated by BSH-active gut bacteria. The hydrolysis of the conjugated BAs to deconjugated BAs and subsequent production of the secondary BAs can modulate several functions, including farnesoid X receptor (FXR), small heterodimer partner (SHP), cholesterol 7 alpha-hydroxylase (CYP7A1), liver X receptor (LXR), and ATP-binding cassette transporters G5/G8 heterodimer (ABCG5/8), which transports cholesterol into the bile canaliculi.
4. Therapeutic Relevance on BSH-Active Bacteria
This global overview leads us to focus on the analysis of the relevant roles of BSHs on human health and their potential as therapeutic alternatives to treat human diseases.
4.1. Metabolic Disorders
Hypercholesterolemia is reflected by high plasma levels of both the total and LDL-cholesterol (LDL-c), while the HDL-cholesterol (HDL-c) levels decrease. High cholesterol levels are a major risk factor in the development of atherosclerosis and cardiovascular disease (CVD), the leading cause of mortality in the world [45]. Nowadays, BSH-active bacteria represent the main candidate for the prevention of hypercholesterolemia [14][46][47][48]. Several studies aiming to characterize the BSH encoding members of the gut microbiota were reported [24][26][49]. Not surprisingly, numerous potential probiotics with high BSH activity significantly reduce circulating cholesterol levels. This includes specific Lactobacillus and bifidobacterial species such as B. longum, L. salivarius, L. plantarum, and L. reuteri [16][28][47][50]. Interestingly, Sridevi et al. (2009) demonstrated that the oral administration of immobilized BSH from Lactobacillus buchneri significantly reduced both triglycerides and serum cholesterol using a rodent model of hypercholesterolemia [51]. Using a placebo-controlled, randomized study, Ooi et al. (2010) reported that the administration of a symbiotic capsule containing a BSH-active strain of L. gasseri with inulin resulted in significant reductions in total cholesterol and LDL-c compared to the placebo group [29]. Similar results were obtained with the L. reuteri strains. The effect of yogurts containing microencapsulated L. reuteri NCIMB 30242 was evaluated using a randomized, double-blinded study on hypercholesterolemic subjects. BSH-positive Lactobacillus reuteri NCIMB 30242 consumption over 6 and 9 weeks in [15][52], respectively, resulted in higher plasma deconjugated bile acid levels but lower total cholesterol, LDL-c, and non-HDL-c compared to the placebo group. Of note, Lactobacillus reuteri NCIMB30242 was the first strain of probiotics to be marketed (Cardioviva®) for cholesterol-reducing purposes based on BSH and the bile salt deconjugation mechanism. In another clinical trial, the consumption of yogurt containing L. reuteri CRL 1098 significantly decreased the total circulating cholesterol and LDL-c as well, while levels of HDL and triglycerides were unchanged [53]. Overall, these studies show that microbial BSH activity is able to impact lipid metabolism and reduce hypercholesterolemia. Most Lactobacillus species described as having a hypocholesterolemic effect in human trials have been patented [54][55][56][57]. The obtained hypocholesterolemic effects rely on the ability of BSH activity to deconjugate the primary intestinal BAs, thereby reducing cholesterol reabsorption [58].
In addition to cholesterol-lowering, accumulating research has been conducted to establish potential interplay between weight gain and/or obesity and gut microbiota-encoded BSHs through FXR signaling. Indeed, increasing evidence demonstrates that the microbiota, BAs, and FXR signaling are mandatory to induce obesity [12][59]. Additionally, the gut microbiota analysis of antibiotic-treated children revealed a correlation between body weight gain and prolonged reduction in overall BSH gene abundance [60]. In line with these findings, numerous BSH-expressing probiotics were shown to protect mice from weight gain and obesity as well as to influence the BA pool by modulating FXR signaling [61][62]. Advanced clinical studies showed that fecal microbiota transplantation in obese subjects did not reduce BMI but resulted in a BA profile similar to that of the donor [63][64]. Overall, these data support the hypothesis that targeted BSH enzymes can be delivered in order to control host lipidemia and to protect against weight gain. These effects may be particularly relevant seeing as some Lactobacillus and Bifidobacterium strains exhibiting BSH activity are regularly used in dairy products. In recognition of the importance of ensuring the host's safety, these strains are commonly subjected to extensive characterization [65]. Furthermore, new therapeutic directions are focused on semi-synthetic FXR agonists, derived from the CDCA molecule [66]. Owing to the emergence of new BSH active probiotics, these strains can be tested to generate deconjugated BAs as FXR agonists.
On the other hand, previous reports have suggested potential adverse effects of increased BSH activity in the intestine. High BSH activity is believed to generate significant amounts of unconjugated BAs, which may result in lipid malabsorption and trigger steatorrhea [67]. Increased BSH activity may also compromise lipid metabolism and colonic mucosal functions, thereby contributing to gallstone formation and colon cancer [68][69].
4.2. Infectious Diseases: Case of Giardia lamblia and Clostridium difficile
Giardia duodenalis (also named G. lamblia or G. intestinalis) is a protozoan parasite that infects humans and many animals through oro-fecal transmission [70][71][72]. G. duodenalis is widely distributed in the environment as a resistant cystic form; once ingested, these cysts differentiate into trophozoite (a flagelled replicative form) by excystation in the correct GI tract conditions [73]. The resulting enteropathogen can reach the colon and can cause giardiasis, one of the most common intestinal infectious diseases worldwide [74][75]. Considered a public health concern, several anti-infectious molecules have been developed to treat giardiasis [72]. However, the emergence of drug resistant strains limits the efficacy of the available treatments [72]. Recent reports established a strong interaction between G. duodenalis and the gut microbiota. In fact, it was highlighted that giardiasis susceptibility is highly influenced by the composition of the gut microbiota [76][77][78]. In turn, G. duodenalis colonization leads to gut microbiota composition changes [77]. Intriguingly, Riba et al. (2020) reported that Giardia infection alters the enteric microbiota composition in neonatal mice and modulates BAs and lipid metabolism, leading to reduced body weight gain and growth, as noted in infected infants [79]. Previous studies investigated the effect of probiotic bacteria (L. johnsonii La1, L. gasseri CNCM I-4884) in the field of giardiasis [80][81][82]. Both strains promote immune response, protect against Giardia-mediated tissue injury, and prevent trophozoite proliferation in murin models [80][82]. Of note, L. gasseri is more effective in vivo than L. jonshoni since L. gasseri reduces the cystic pool of the parasite [80]. Other lactobacillus strains, including L. casei MTCC 1423 and L. rhamnosus, have been tested in a murine model, showed similar protective effects, and reduced the severity/duration of giardiasis [83][84][85]. Interestingly, Shukla et al. (2020) reported an anti-giardia effect and enhanced mucosal immunity by the probiotic protein from L. rhamnosus as well as the heat-killed strain [86]. Although the underlying mechanism remains poorly understood [87][88][89], recent reports demonstrate a potential association between BSH activity and the protective effect against G. duodenalis infection [90][91]. As BSH activity allows for the conversion of primary BAs into deconjugated bile acids, it was suggested that the subsequent release of secondary BAs has a toxic effect and may alter parasite growth and survival. To address this hypothesis, the direct effects of conjugated and deconjugated BAs on the parasite were tested. Both tauro- and glyco-conjugated BAs were inert and did not inhibit parasite growth, while deconjugated BAs (DC and CDC) were toxic in a dose-dependent manner and exhibited a significant deleterious effect on the parasite [90]. Moreover, the simultaneous incubation of G. duodenalis with unconjugated BAs and BSH from C. perfringens allowed for the conversion of incubated BAs into their conjugated forms and consequently led to a killing effect on the parasite [90]. In addition, engineered E. coli to express BSH from L. johnsonii confirmed that BSH antagonized Giardia proliferation in vitro in a dose dependent manner as well as in vivo [91]. Altogether, these results support the promising prospect of using BSH active probiotics as a new therapeutic strategy to treat/prevent G. dudenalis infection.
Another example of a gastrointestinal infectious disease includes Clostridioides difficile infection (CDI). C. difficile is a spore-forming pathogen that might colonize the gut of patients treated by broad-spectrum antibiotics [92][93]. CDI includes a broad range of disorders ranging from diarrhea to colitis and toxic megacolon [92]. Their incidence, severity, and costs are in continuous increase. In addition, they have evolved as a significant cause of mortality during the past decade [92][94][95]. Upon germination, vegetative cells are generated from spores, and the bacterium produces toxins that result in tissues damage, inflammation, and diarrhea [96][97]. In the GI tract, the germination process is mediated by a host-derived molecule including BA sensing through the bile acid germinant receptor [96][98][99][100]. In fact, TCA, CA, and DCA activate germination, while CDCA acts as a competitive inhibitor [101]. Other studies indicate that DCA is a potent inhibitor of this process, as reported with C. scindens. Upon administration, this strain enhances the resistance to infection in a DCA dependent fashion [102]. Recent reports revealed that severe and relapsing CDI patients display high levels of TCA, followed by a reduced abundance of BSH-producing species [103][104]. However, fecal transplantation is effective in treating these patients and increases their resistance to CDI [103][104][105]. Further analysis demonstrates that, following FMT, key bacterial genera responsible for BSH production are recovered, BSH activity and BSH gene copy numbers are balanced, and secondary BAs are restored [103][104]. Interestingly, unlike patients pre-FMT, the BA profiles, similar to that in patients post-FMT, were able to inhibit spores outgrowth into vegetative forms [106]. In addition, supernatants from either engineered E. coli expressing highly active BSH or naturally BSH-producing organisms (Bacteroides ovatus, Collinsella aerofaciens, Bacteroides vulgatus, and Blautia obeum) effectively reduced TCA-mediated C. difficile germination. These effects were also confirmed in a recurrent CDI mouse model, using the recombinant E. coli strain for BSH [103]. These distinctive features pave the way towards the potential use of BSH active probiotics to treat CDI. However, active research must be conducted in this field to unravel the molecular mechanism of how secondary BAs may inhibit C. difficile outgrowth, colonization, and the subsequent inhibition of infection.
4.3. Other Human Pathologies
Several reports highlighted the association of many human disorders to BA dysregulation. In this context, we recently demonstrated the impact of the gut microbiota, cholesterol, and BA metabolism in hypercholesterolemia and cardiovascular diseases [107]. Furthermore, IBD, including ulcerative colitis and Crohn's disease, are chronic immune-mediated inflammatory diseases that affect the gastrointestinal system. Targeted drugs are directed at the overactive immune response in these diseases [108]. Interestingly, several reports have suggested BA dysmetabolism as a contributing factor in IBD and irritable bowel syndrome (IBS) pathogenesis [109][110][111][112]. Among the potential mechanisms, the modification of the gut microbiota composition may lead to altered BA transformations in the gut and modulation of the circulating BAs. Direct enzyme activity assays in IBD patients revealed impaired deconjugation, dehydroxylation and, desulfation [113]. Otherwise, cholestasic diseases are also linked to changes in Bas, which are characterized by accumulated BAs levels in the biliary system. This dysfunction causes liver inflammation and injury [114].
Recently, the effect of ursodeoxycholic acid (UDCA) was studied in the context of the intrahepatic cholestasis of pregnancy (ICP) [115]. The reported results demonstrated that this BA counterbalances higher levels of BAs [115][116]. A recent study examined the clinical responses of the efficacy of the biotherapeutical agent UDCA in the case of the ICP cohort [115]. In this work, the authors were interested in the reaction mechanism associated with the effectiveness of UDCA, which counterbalances higher levels of BAs [115]. Such beneficial effects of UDCA were mediated by the gut microbiota through the enrichment of the BSH-expressing bacteria belonging to the Bacteroidetes phylum.
Modification of the BA metabolism is also linked to other human diseases such as liver disorders, including the primary sclerosing cholangitis (PSC). In this context, the gut microbiota and bile acid composition were analyzed in a mice model and demonstrated that the illness severity was increased in germ-free mice [117]. Moreover, Tabibian et al. (2016) described that PSC is reduced by the addition of UDCA, highlighting the protective potential of the gut microbiota and BA against PSC [117].
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Moez, R. Bile Salt Hydrolases. Encyclopedia. Available online: https://encyclopedia.pub/entry/10168 (accessed on 31 January 2023).
Moez R. Bile Salt Hydrolases. Encyclopedia. Available at: https://encyclopedia.pub/entry/10168. Accessed January 31, 2023.
Moez, Rhimi. "Bile Salt Hydrolases," Encyclopedia, https://encyclopedia.pub/entry/10168 (accessed January 31, 2023).
Moez, R. (2021, May 27). Bile Salt Hydrolases. In Encyclopedia. https://encyclopedia.pub/entry/10168
Moez, Rhimi. ''Bile Salt Hydrolases.'' Encyclopedia. Web. 27 May, 2021.
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