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Promises and Challenges of Target-Based Drug Discovery

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Promises and Challenges of Target-Based Drug Discovery

With rapid advances in molecular biology, recombinant technology and genomics, target-based drug discovery (TBDD) has become the leading approach adopted by the pharmaceutical industry for the past three decades. While advantageous in throughput and costs, TBDD has not led to a concomitant increase in the number of new molecular entities and biological product discoveries, despite increasing investment by pharmaceutical companies. In this article, we will compare the two key drug discovery approaches, the challenges and opportunities of each and the future of TBDD.

Target-based versus phenotypic drug discovery


TBDD starts with a defined molecular target such as a gene, gene product or molecular mechanism that has been identified through genetic GFN or biological studies. Genetic and molecular biology methods are typically used to identify genes involved in diseases and with cheaper and faster sequencing, results from large-scale projects such as the Human Genome Project are also being exploited to expand the number of potential molecular targets. Following this, recombinant technology is used to express genes in simpler organisms like yeast, which allows for screening against large compound libraries in a high-throughput fashion to identify “hits” – small molecules and / or biologics that interact with the target of interest.

The typical process includes target identification, target validation, assay development, hit identification, lead optimization, followed by preclinical and clinical development. A good example demonstrating the utility of TBDD is the discovery of 5HT2a receptor as a key molecular target involved in psychosis. Following this discovery, the drug pimavanserin was identified as an inverse agonist and approved by the US Food and Drug Administration (FDA) to treat Parkinson’s disease psychosis in 2016. Technological advances in the field of computer science have given rise to machine learning models that can improve the outcomes of TBDD through virtual drug screening and de novo drug design. One example is the application of machine learning strategies to quantitative structure-activity relationship (SAR) modeling, to better identify relationships between the chemical structure of a drug and its activity. This approach has been used to optimize lead compounds by structural modifications to enhance activity or decrease or eliminate adverse side effects.

Phenotypic versus Target-based Screening for Drug Discovery

The other common strategy for drug discovery is phenotypic or target-agnostic screening where drugs are identified without prior knowledge of a specific molecular target. Instead, drugs are tested for their pharmacological actions, typically in animal models, to achieve a desired physiological response or to restore a particular phenotype. Antibiotics are a good example of medicines that are discovered in this way, as they have largely been identified through their ability to inhibit bacterial growth or kill bacteria, without knowledge of its biological mechanism. Dr. John Moffat and co-workers opined that phenotypic drug discovery projects against infectious diseases often have strong chain of translatability which means that a simple assay readout like inhibition of bacterial, viral or parasitic replication can strongly correspond to anti-infective activity in preclinical animal models and patients.

Promising examples of target-based drug discovery


A main advantage of target-based drug discovery is its ease of execution compared to the phenotypic approach. It is also generally faster and less costly. Furthermore, once a molecular target is identified, drug discovery researchers can make use of advanced tools like crystallography, computational modeling, genomics and mutational GFN to better understand how a drug interacts with its target to optimize its structural-activity relationship, or to enhance its
biodistribution.

Recently,
Dr. Lanyon-Hogg, a principal investigator at the University of Oxford, and colleagues developed a photochemical probe to elucidate how a small molecule inhibitor can bind to human Hedgehog acyltransferase (HHAT) which is part of the mammalian membrane-bound O-acyltransferase (MBOAT) superfamily implicated in diseases such as cancer and obesity. The Lanyon-Hogg Group exploits synthetic chemistry and biochemistry approaches to develop biologically active small molecules.

“Information on the binding site and molecular mechanisms of small-molecule inhibitors HHAT remain elusive. In this paper, we used medicinal chemistry and a novel assay for HHAT lipid transferase activity (Acyl-cLIP) to analyze the SAR for HHAT inhibition and identify a single-enantiomer inhibitor, IMP-1575, which is the most potent HHAT inhibitor reported to -date, ”said Lanyon-Hogg.

“The identification of a small molecule binding site in HHAT, along with very recent solving of the cryo-EM structures of HHAT, now opens the possibility of using structure-guided approaches to accelerate inhibitor development. There may be substantial follow-up work in medicinal chemistry studies of HHAT inhibitors as these compounds are optimized further. Structure-guided medicinal chemistry may be an important stepping-stone in validating HHAT as a drug target in cancer, by aiding the development of tool molecules for target validation in in vivo models. ”

Lately, Francis Crick Institute’s
Dr. Cassandra Kennedy and co-workers designed a novel photoaffinity alkyne-tagged probe that binds to MCC950, a potent small molecule inhibitor of the NLR-family inflammasome pyrin domain-containing 3 (NLRP3) protein that has been shown to inhibit inflammation in animal models. This study found that MCC950 could associate with targets other than those for which the drug was meant to bind which had not been identified until now. These off-target interactions can lead to toxicity if unrelated biological pathways are unintentionally interrupted.

“We used photo-affinity labeling (PAL) and thermal protein profiling (TPP) with proteomics to identify protein targets of MCC950, a potent NLRP3 inhibitor. We identified and validated carbonic anhydrase 2 (CA2) as an off-target protein for MCC950 at biologically relevant concentrations. This work highlights the powerful scope of chemical biology tools and proteomics in on- and off-target identification and validation, ”he said. Kennedy.

Newly developed tools, such as the probes mentioned above, provide an effective means to confirm drug – target interactions. By understanding this interaction, it is possible to optimize the compound further using medicinal chemistry approaches, to improve selectivity and affinity to the target. In contrast, without a prior understanding of a drug – target interaction, it can be challenging to further optimize the drug’s characteristics, which can be a limitation of the phenotypic screening approach. In other words, target-based drug discovery allows researchers to isolate a problem and address it efficiently by enhancing drug design.

TBDD is also particularly useful when there is a proven, strong link between a gene and disease, and this applies not only to monogenic diseases but common illnesses as well. For instance, it was found that a gain of function mutation in the
PCSK9 gene elevated levels of low-density lipoproteins (LDLs), sometimes referred to as “bad cholesterol”, in human blood. This discovery eventually led to the approval of drugs alirocumab and evolucumab by the FDA in 2015. Both drugs work by blocking PCSK9, lowering LDL cholesterol and consequently reducing the risk of heart disease.

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Challenges of target-based drug discovery


Nevertheless, TBDD has limitations, one of which being overly simplified assays. Assays using synthetic recombinant cells do not always reflect the complexities found within the physiological environment of intact organisms. In fact, with huge progress in phenotypic screening tools such as induced pluripotent stem cells,
organoids, organ-on-a-chip systems, high-content imaging methods and gene editing techniques such as CRISPR-Cas, there has been a resurgence of phenotypic drug discovery in the pharmaceutical industry.

Another challenge of TBDD is that drugs may act on more than one target, and the observed therapeutic efficacy might not always be attributed to the identified molecular mechanism. For instance, selective serotonin re-uptake inhibitors
may also treat depression by regulating inflammation. Another well-known example is sildenafil (more commonly known as Viagra) which was designed to treat cardiovascular disease but had an unexpected pharmacology to alleviate erectile dysfunction. Furthermore, common diseases that have huge socioeconomic consequences like depression and obesity, are often multifactorial and it will be challenging to identify a single molecular target. In cases where there could be adverse side effects, the therapeutic benefit of lowering just one out of many risk factors may not outweigh the negative impact.

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The best of both worlds


An ideal strategy to successfully develop a drug is to integrate the best attributes from both target-based and phenotypic drug discovery approaches. In reality, the majority of successful drug discovery projects combine knowledge of a molecular target with physiologically relevant cellular assays to identify the molecular mechanism of action. This is useful because as technologies for these drug discovery approaches improve, there is a greater chance of successfully identifying a drug using an integrated strategy.

Another important reason why an integrated approach is advantageous is that there is still insufficient understanding of basic human disease biology (and hence, molecular targets) and current disease models do not fully recapitulate human diseases (hence, insufficiency of the phenotypic drug discovery approach). For instance, while the molecular drivers for Alzheimer’s disease may be similar in humans and mouse models, the resulting pathogenic mechanisms differ. Additionally, most preclinical animal models are unable to faithfully capture details of a complex tissue microenvironment such as that seen in late-stage solid tumors where there is considerable patient heterogeneity in cell composition and mutations. The lack of highly predictive animal models and a quantifiable assay end point that mechanically corresponds to a causal disease biomarker makes the case for an integrated approach stronger.

Conclusions


On average, drug development takes 12 years from the time of development to the approval and launch of a product. While not perfect, TBDD has been shown to be a powerful way to exploit knowledge of specific molecular mechanisms to identify and validate a drug target. Continual developments in molecular biology and genomics will enable better mechanistic understanding of human disease biology while machine learning can further enhance methods like high-content imaging and computational modeling to improve lead optimization. While often discussed as opposing methods, target-based and phenotypic drug discovery approaches can in fact be complementary and integrating them may enhance the chances of successfully developing a drug.

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Column | Troubled ‘turbantor’ Harbhajan and his aggressive instincts

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The retirement of Harbhajan Singh from all forms of competitive cricket in December 2021 brought to close the career of a gifted cricketer who courted controversy at every turn of his career. During the first years of the 21st century, he was arguably the best spin bowler in the world and though his wicket-taking abilities hit a plateau after that, he sustained himself by the versatility that saw him play all formats of the game at the highest level with reasonable success. He was a regular in the national side and part of the team that won the International Cricket Council (ICC) T20 World Cup in 2007 and the ICC World Cup in 2011. Though he lost his place in the national squad in 2015, he continued playing in Indian Premier League (IPL) till he chose to hang up his playing boots last month.

Harbhajan Singh

Chennai Super Kings bowler Harbhajan Singh bowls during the 2019 Indian Premier League (IPL) match. Photo by Sajjad Hussain/AFP


Harbhajan kickstarted his career during the 1997-98 season when he found himself playing for the national side in March 1998 within four months after making his debut for Punjab in Ranji Trophy. His performances at the junior level and the absence of top quality off-spin bowlers were factors that prompted the selectors to try out this rookie bowler, then still in his teens. He did not set Kaveri on fire on his Test debut, which took place against Australia at Bangalore. Within one month, he made his bow in One Day Internationals (ODIs) as well but a string of below-par performances saw him lose his place in the side soon thereafter.

Harbhajan Singh

Indian off-spinner Harbhajan Singh appeals to the umpire at Buffalo Park in East London 19 October 2001. Photo: Tirsa Ellis/AFP


After going through a period of near oblivion when he was also thrown out of a training programme in National Cricket Academy on charges of indiscipline, Harbhajan staged a comeback to the national side in the winter of 2000-2001 with a performance that will be remembered by followers of the game in India for all times. Australia, led by Steve Waugh, had landed in India to conquer the “final frontier”. The visitors were on a high, having won the previous 15 matches on the trot and looked forward to creating a new world record with 17 consecutive triumphs in Tests, while also winning the series. And when they won the first Test at Mumbai by a margin of 10 wickets, everyone thought that they were on their way to attaining both their goals.

Harbhajan Singh

Indian players incluing Sourav Ganguly (R), Harbhajan Singh (3rd L), Shiv Sundar Singh (fourth from L, with helmet), VVS Laxman (2nd from R) run to celebrate India’s victory over Australia. Photo: Arko Datta/AFP


The Kolkata Test against Australia in February 2001 is known as “Laxman’s Test”, for his knock of 281 runs in the second innings which helped India to script a magnificent turnaround and win this game, after trailing in the first innings by 274 runs. Harbhajan also had a crucial role to play in this victory as he took 13 wickets (7 for 123 in first innings and 6 for 73 in the second), including a hat-trick on the first day. In the last Test at Chennai, Harbhajan again played a stellar role, bagging 15 wickets for 217 runs (7 for 133 in first and 8 for 84 in second innings) to finish the series with a tally of 32 wickets. Aussie batsmen did not have any answer for his wiles and even such accomplished performers as Rickey Ponting and Adam Gilchrist appeared shell-shocked while facing him. Australian media nicknamed him as “Turbanator”- a tribute to his destructive capacity with the ball.

Harbhajan Singh

Indian spinners Anil Kumble (L) and Harbhajan Singh at the Ferozeshah Kotla ground in New Delhi. Photo: Ravi Raveendran/AFP


Harbhajan’s career did not ever attain the stratospheric heights that this performance promised. The surfeit of limited overs’ cricket made him focus more on restricting runs than on “buying” wickets. This resulted in bowling a flatter line without “giving the ball air”; the classic loop which is the hallmark of a top-class off-spinner also disappeared. This made him a less destructive bowler except on helpful surfaces and the returns also started growing thinner. When Anil Kumble returned to the side after recovering from an injury, Harbhajan moved into the slot of support spin bowler.

Harbhajan Singh

Injured spinner Harbhajan Singh watches the action on the first day of the third Test Match being played at the MCG in Melbourne 26 December 2003. Photo: William West/AFP


A finger injury caused Harbhajan to return home during the tour to Australia in 2003-04. He returned to the side the next season and was amongst wickets with most of the games being played at home. However, the arrival of Greg Chappell as coach and the exit of Sourav Ganguly as captain of the national side in 2005 caused hiccups in Harbhajan’s career. He was the first Indian cricketer to publicly criticise Chappell and his methods and said that the coach was “instilling fear and insecurity” in the side. Though his explanation was called for, Harbhajan managed to escape action and issued a statement lauding Chappell soon thereafter!

Harbhajan Singh

Gerg Chappell (L), talks with Harbhajan Singh (R), during a net practice session at The Punjab Cricket Association (PCA) stadium in Mohali. Photo: Raveendran/AFP


Harbhajan found himself in the midst of one of the biggest controversies in cricket when India toured Australia in 2007-08. In the second Test at Adelaide, Australia lodged a formal complaint that he indulged in racial abuse against Andrew Symonds. The relations between the two sides were at a low ebb and this incident even threatened to disrupt the conduct of the remaining part of the tour. Harbhajan vehemently denied the charges and the Indian team management supported him. But Mike Proctor, the match referee, found him guilty and slapped a punishment. India promptly appealed against this verdict and got a stay, which allowed the tour to go on. Eventually, the ICC appeals Commissioner Justice John Hansen overturned the verdict of the match referee and absolved Harbhajan.

Harbhajan Singh

(L to R) Australian players Ricky Ponting, Michael Clarke, Andrew Symonds and Matthew Hayden are seen along side Indian player Harbhajan Singh and assistant Indian team manager M.V. Sridhar prior to the start of the appeal hearing against a three-match ban imposed on Indian cricketer Harbhajan Singh by the ICC at the Adelaide Federal Court, 29 January 2008. Photo: Robert Cianflone/Pool/AFP


Controversy continued to dog Harbhajan even after the closure of this episode. During the Indian Premier League (IPL) matches in 2008, he slapped fellow India teammate S Sreesanth after the game between Kings XI Punjab and Mumbai Indians, which the latter side, led by Harbhajan, lost. The slapping of a national player in full view of television cameras drew widespread criticism and Board of Control for Cricket in India (BCCI) moved fast and initiated action against Harbhajan.

Harbhajan Singh

Indian cricketers Harbhajan Singh (L) and S Sreesanth. Photo: AFP


Incidentally, this was not the first time that Harbhajan had got physical with Sreesanth. During the Champions Cup trophy match in 2007, he had shoulder charged the fast bowler when he was walking to the top of his bowling mark. BCCI had chosen to ignore this incident despite it being witnessed across the country. But the “slapgate” was too serious to be brushed under the carpet and Harbhajan was barred from playing the remaining matches of that season of IPL, besides a five-match suspension from ODI’s.

Harbhajan’s international career took a severe reverse when he was injured during the tour to England in 2011. He was not selected for the tour to Australia in 2011-12 and his appearances in international matches became sporadic after that. He played his last Test in August 2015 and his final appearance in an ODI took place two months later, though he continued to play domestic first-class cricket till 2017. Since then, his appearances on the cricket field were limited to playing in IPL, where he picked up 150 wickets in 13 editions.

Harbhajan Singh

Harbhajan Singh hold his Man of the Series trophy after India defeated Australia by two wickets in the the third test, hence winning the series in Madras 22 March 2001. Photo: Ravi Raveendran/AFP


A tally of 417 wickets in Tests and 269 scalps in ODI’s makes Harbhajan the second most successful off-spinner to play for India, after Ravichandran Ashwin. He could also wield the willow effectively as evident from a total of 2,224 runs in Tests with 2 centuries and 9 fifties. He was also the first spin bowler from India to adjust to the demands of all versions of cricket effectively. But his tendency to create controversies and lack of amenability to discipline cast a cloud over his career which could have reached much greater heights given the prodigious talent he was blessed with.

Sreesanth

S Sreesanth with teammate Harbhajan Singh. Photo: Alexander Joe/AFP


Followers of the game from Kerala could be forgiven for not harbouring a soft spot towards this highly competitive cricketer as he is considered to be the bugbear of Sreesanth and the source of all troubles that the Kochi born pacer found himself in. News reports indicate that the two cricketers subsequently spoke to each other and resolved their differences. But it would be difficult for the fans to forgive so easily as the bad taste created by those incidents does not vanish quickly. The same is the case with cricketers and cricket-loving public of Australia, as could be understood from the observations in the autobiography of Gilchrist, despite Harbhajan and Symonds sharing the same dugout in IPL.

In retrospect, one is forced to conclude that it would have been better for Indian cricket if the aggressive instincts of Harbhajan Singh were channelled properly on the cricket field and outside.

(The author is a former international umpire and a senior bureaucrat)

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Sports Betting’s Next Big Election Battles Are in California

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Sports Betting’s Next Big Election Battles Are in California

TEMECULA, Calif. — Legal sports betting in the United States accelerated in 2021 as a flurry of states either overcame legislative logjams, as Ohio did just before Christmas, or signed off on online wagering, as New York did just after Election Day.

But those efforts are likely to pale in comparison to the all-out lobbying, campaigning and legal jousting in 2022 involving what a DraftKings executive recently called “one of the holy grails” in sports betting: California.

By November, Californians may be asked to vote on as many as four sports betting initiatives. That’s why deep-pocketed interests, including national sports books and Native American casinos, have been gearing up to spend $200 million to persuade voters in California to support their particular proposal — or to reject the others.

One measure that has already qualified for the state ballot, sponsored by powerful tribes in California, would add sports wagering, but only in person, at tribal casinos or horse racing tracks. Online betting initiatives, now gathering signatures, dangle the prospect of making bets anywhere through the internet. Others offer a middle ground.

If one of the measures passes, nearly two-thirds of Americans will live in states that allow or regulate sports betting. And with California and New York on board, sports wagering would essentially be national in scope, fueling a market that Goldman Sachs recently estimated could grow to $40 billion in revenues in a decade from $900 million now.

Yet gambling expansion in California has often fallen short or been torpedoed by competing interests. Indeed, California’s card rooms, which primarily operate around larger cities and offer a more limited range of games, just filed a lawsuit to invalidate the qualified tribal measure.

“We’re never going to get sports betting figured out at any level unless California comes on board,” Jason Giles, executive director of the National Indian Gaming Association, said at a recent sports betting conference at the Pechanga Resort and Casino in Temecula. “That will be the game changer for the United States.”

Since the Supreme Court’s decision in 2018 to strike down a federal law banning commercial sports betting in states other than Nevada, more than 30 states have authorized sports wagering, including about a dozen in the last year. More than 20 states have gone live.

New York just started mobile sports betting after awarding licenses for it to two coalitions featuring marquee names, Caesars Sportsbook and Bally’s Interactive. Gov. Mike DeWine of Ohio signed a bill legalizing sports betting in late December. And legislators in Wyoming and Arizona, among others, quickly approved sports betting.

“Look at this massive expansion across the country and where we are — it’s becoming very mainstream,” said Brandt Iden, a former state representative in Michigan who pushed to legalize sports betting in his home state. Iden is now head of government affairs for Sportradar, which collects and analyzes data for sports books. “I talk to legislators who say, you know what, I don’t support gambling, but everybody is doing it.”

Of the holdouts, Texas considered several bills in 2021, and some lawmakers expect momentum when the legislature reconvenes in 2023. Florida, meanwhile, is a mess: A federal judge recently blocked the Seminole Tribe’s new sports betting app, and DraftKings and FanDuel are racing to gather enough signatures to get a referendum on the 2022 ballot.

In California, gambling — mostly on slot machines and blackjack — has been legal for two decades on tribal lands under compacts negotiated with the state. The state also permits gambling at horse racing tracks, which was legalized in 1933, and card rooms, which trace their lineage to poker-playing miners during the Gold Rush.

Any changes would require constitutional amendments through a voter referendum, or legislation backed by the voters.

Previous attempts have bogged down; online poker, for instance, failed in part because the tribes themselves were split. But now there appears to be less resistance on moral and philosophical grounds.

“If we think about progressive legislation, or legislation to protect consumer welfare, California lies at the forefront, whether we want to talk about minimum wage or privacy protection,” said Marc Edelman, a law professor at Baruch College who has written extensively on sports gambling. “If California legalizes sports gambling it becomes very unlikely that another state would arise as the consumer-oriented opposer of sports gambling.”

This time, the push to expand gambling began before the pandemic, from a coalition of 18 tribes that have dominated casino gambling in the state.

Across the United States, tribal gambling generated $27.8 billion in revenue in its fiscal year from Oct. 1, 2019, to Sept. 30, 2020, despite the pandemic. California is the biggest state, with 66 tribal casinos on federally recognized lands, mostly far from the coast, yielding about $8 billion, with much of that coming from slot machines.

Under the tribes’ initiative, which is backed by a political action committee that has raised more than $13 million, sports wagering would be permitted at tribal casinos and horse tracks. Roulette and games played with dice, such as craps, would also be allowed under the proposal, which qualified for the ballot in May 2021 after collecting more than one million valid signatures.

One thing that is not included is online betting, because the initiative is intended to be “a very measured, incremental step,” said Mark Macarro, tribal chairman of the Pechanga Band of Luiseño Indians in Riverside County.

“We think this is the right thing to do for tribes and tribal sovereignty,” he said at the conference here. “There’s enough skittishness out there about what could happen to brick-and-mortar facilities.”

The initiative would also create a new civil enforcement tool allowing anyone suspicious of any illegal gambling operations to file lawsuits. It is this provision that has fueled two separate but related efforts by California’s card rooms to defeat the tribes, and to get their own sports betting measure passed.

California has more than 80 card rooms ranging from pub-like places with a few poker tables to sleek behemoths with 270 tables accompanied by restaurants and plentiful A.T.M.s. Collectively, they employ 23,000 people in urban areas, many of them Asian, Black and Hispanic, and pump in $300 million in federal, state and local tax revenues each year, according to the California Gaming Association, a trade group.

Many municipal budgets rely heavily on the card rooms to finance vital services and bolster juvenile justice and other programs, said Mayor Tasha Cerda of Gardena, which has two card rooms. She has backed an initiative that would permit sports betting at the card rooms, tribal casinos and racetracks, as well as allow for internet sports betting. That initiative has raised $450,000 to date. Meanwhile, some of the bigger card rooms have poured more than $24 million into a “No” campaign against the tribes’ initiative.

During a recent tour of Hollywood Park Casino in Inglewood, adjacent to SoFi Stadium, the host of the Super Bowl next month and the College Football Playoff national championship in 2023, Deven Kumar, the casino’s general manager, estimated sports betting could increase revenues — already hurt by the coronavirus pandemic — by 20 percent to 25 percent. He and James T. Butts Jr., Inglewood’s mayor, warned that the tribes’ civil enforcement provision could drain their existing business by up to 75 percent, compounded by the inevitable legal costs.

“They are attempting to make gambling a monopoly at the expense of others,” Butts said. “They are not the disenfranchised group they once were. The minority majority cities deserve the opportunity for equity as well.”

In the city of Hawaiian Gardens, where the Gardens Casino supplied 68 percent of the tax revenues in the 2019-20 municipal budget, Keith A. Sharp, the casino’s general counsel, said sports betting could transform Sundays at the casino — now mostly empty — into bustling periods where customers could wager on N.F.L. games while also playing baccarat or other games.

If the card rooms were hobbled, however, Nary Chin, a longtime card dealer and single mother of four, said she feared for her future.

“I learned English in the card room, not school,” said an emotional Chin, who immigrated from Cambodia in 1984. “I am very grateful. This is my home. If I didn’t have this job, I don’t know what I’d do.”

The third initiative comes from online sports books, including DraftKings and FanDuel, that want to enter California for the first time and offer online betting.

The measure requires those companies to partner with tribes, and its supporters say voters can pass both their initiative and the tribes’ in-person one. Most of the state’s profits would be dedicated to homelessness measures, and to the tribes themselves. It would also allow betting on nonathletic events, like award shows and video game contests, but not youth sports or elections, according to the nonpartisan Legislative Analyst’s Office.

“We view brick-and-mortar as very complementary to mobile,” Jonathan Edson, FanDuel’s senior vice president for business development, said at the sports betting conference.

“California is one of the holy grails in sports,” added Jeremy Elbaum, senior vice president for business development at DraftKings.

The supporters, buffeted by an initial $100 million from seven sports books, have lined up mayors in Long Beach, Oakland, Fresno and Sacramento, plus advocates working to combat a homeless crisis. They are confident they will collect enough signatures to be certified by the June ballot deadline.

“We are focused on ongoing stable revenue to fund the key programs that we know we need,” said Tommy Newman, vice president for engagement and activation at the United Way of Greater Los Angeles. “If we’re honest, this is regulating and capturing value from something that is happening, for people in communities that absolutely need the investment.”

In November, a fourth initiative arrived supporting both online and in-person betting, backed by a different group of tribes, including the Rincon Band of Luiseño Indians and the San Manuel Band of Mission Indians.

“Out-of-state and international gaming operators want to rewrite the balanced system California has created so that the future belongs to them, paying a pittance to serious local and statewide social problems, and trying to divide the Tribes by offering temporary riches to a few while taking future growth opportunities away from the rest,” the tribes wrote in their application to the California attorney general.

A lawyer for the tribes, Scott Crowell, did not respond to messages seeking comment.

Some gambling analysts believe that a plethora of initiatives may confuse voters, who may just say no to everything. Another wild card is a lawsuit filed in December by two card rooms claiming that the qualified tribal initiative violates the state constitution, which says initiatives can focus only on one subject, because the tribes are trying to add retail sports betting as well as add more table games.

Still, no matter the outcome of the lawsuit or the ballot measures, many sports and technology companies are building audiences through free-to-play games, contests, fantasy sports and national marketing campaigns, even in states where sports betting has not yet been cleared, said Rob Phythian, founder and chief executive of SharpLink Gaming, a technology company.

Teams like the Minnesota Vikings have hired companies like SharpLink to build fantasy games. That could be consequential in California, where there are 19 teams in the N.F.L., M.L.B., N.B.A., N.H.L. and W.N.B.A. — by far the most of any state.

“We’re just a bridge to betting,” Phythian said. “It’s sort of like training the muscle.”

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Addressing maternal health inequities | AAMC

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Addressing maternal health inequities | AAMC

Kysha Shaw lives with a lot of uncertainty. Among other things, the 42-year-old single mother of three worries about COVID-19, schools closing, and drug use and crime in her West Baltimore neighborhood.

“I love this community, but it can be really sad,” she says. “You see people begging for shoes and clothes. You might see someone slumped over with a needle in their arm. People sell drugs in front of the convenience stores.”

But Shaw is determined to keep herself and her children healthy, which she’s done thanks in part to an innovative effort called B’more for Healthy Babies Upton/Druid Heights (BHB U/DH). Founded in 2011, the program is part of a citywide initiative and is a partnership between the local community, the University of Maryland Medical Center, and the University of Maryland, Baltimore.

BHB-U/DH supports mothers and babies in West Baltimore, where 92% of residents are Black and 66% of children live below the federal poverty level. It provides prenatal education, support groups, smoking cessation, some rental assistance, and connection to a range of social services. Among other achievements, the effort has reduced infant mortality by 75%.

Experts believe that programs like BHB U/DH are essential if the United States hopes to address the inequities in maternal health found in so many crowded cities and remote rural towns.

The statistics are striking: Black and American Indian/Alaskan Native women are two to three times more likely to die from pregnancy-related causes than White women. Black women are twice as likely to experience serious perinatal complications. And early indicators suggest that COVID-19 is only exacerbating such inequities.

What’s more, advanced degrees and full bank accounts don’t close the gap. In fact, a college-educated Black woman faces a 60% greater risk of maternal death than a White woman with no high school diploma. Why is that? Experts point to the effects of subtle and explicit racism as well as weathering, the biological fallout of ongoing stress that can cause premature aging and related health problems.

Faced with this worrisome reality, researchers and providers are working to improve the health of vulnerable pregnant people before, during, and after childbirth.

“It’s incredible, some of the things I’ve heard our moms go through when they’re seeking care. It’s heartbreaking.”

Kamilah Dixon-Shambley, MD
Medical director of Moms2B

“Inequities are so pervasive and persistent that they require multisector efforts,” says AAMC Health Equity Research Analyst Funmi Makinde, MPH. “We need to address transportation, employment, and housing as well as physician shortages, and we need more diverse providers. We need high-quality data that are shared publicly to ensure accountability. The list goes on.”

Throughout all this work, it’s crucial to include the perspectives of patients who are often overlooked, experts say. In one recent survey, 20% of Black, biracial, and Latinx people felt their medical requests were refused or ignored, compared with 11% of White people.

“It’s incredible, some of the things I’ve heard our moms go through when they’re seeking care. It’s heartbreaking,” says Kamilah Dixon-Shambley, MD, medical director of Moms2B, an Ohio State University Wexner Medical Center program that provides yearlong supports and health education to low-income new and expectant mothers. “It’s crucial that patients and the community can trust their providers.”

Below, AAMCNews profiles multifaceted efforts to address maternal health inequities across the country.

Data that save lives

In 2006, California officials noted a worrisome trend: Maternal mortality was on the rise, even as the state recorded the most births nationwide.

Hoping to reverse the disturbing death rate, they turned to Stanford University School of Medicine to co-found the multistakeholder group that became the California Maternal Quality Care Collaborative (CMQCC).

Serious number-crunching has fueled much of the CMQCC’s work. For one, it collects and analyzes hospitals’ raw data to quickly identify areas ripe for improvement, including racial and ethnic disparities.

“We send hospitals back reports, and they are flabbergasted when data are broken down by race and ethnicity. They may see that their Black patients have 6 percentage points higher C-section rates than Whites,” says CMQCC Medical Director Elliott Main, MD. “That really spurs them on to look at addressing racism in labor and delivery.”

CMQCC experts also use data to identify the need for and then create step-by-step provider toolkits on key causes of birth-related complications. One on postpartum hemorrhage, which covers such crucial moves as measuring and effectively treating blood loss, reduced disparities between Black and White patients by nearly 80%.

“The standardized protocols in toolkits take away a lot of provider subjectivity,” Main says. “Subjectivity is the entrée for biases that impact patient care.”

And hospitals in the collaborative — there are more than 200 of them — can receive training on implementing the toolkits. “A toolkit that sits on the shelf does nothing,” he adds.

“We send hospitals back reports, and they are flabbergasted when data are broken down by race and ethnicity. … That really spurs them on to look at addressing racism in labor and delivery.”

Elliott Main, MD
Medical director of the California Maternal Quality Care Collaborative

All of these efforts have borne fruit: Since the launch of the collaborative, California’s maternal deaths have dropped by 65%.

Now, the CMQCC is crafting additional equity-related recommendations, such as handing expectant patients a staff-signed commitment promising to treat every patient with dignity and engage them in all birth-related decisions.

Also high on the CMQCC agenda is assessing the approaches of maternal mortality review committees, the bodies that study every pregnancy-related death.

“Often a problem is that review materials are medical-centric, and obviously the patient can’t tell her own story,” says Main. “We’re now exploring interviewing family members who lost a relative for their perspective. I think that’s going to be the future of committee reviews.”

Hands-on help

Pregnancy always brings some stress, but the tension is much higher for patients who struggle to understand English and the intricacies of the U.S. health care system.

That’s why Crista Johnson-Agbakwu, MD, founded Valleywise Health’s Refugee Women’s Health Clinic in Arizona in 2008.

Since then, the Phoenix-based center has served more than 16,000 patients, many from countries across Africa. Arizona, which ranks high on the list of states resettling refugees, is now integrating evacuees from Afghanistan, says Johnson-Agbakwu.

“These are people who have escaped war and gender-based violence and other human rights atrocities,” she notes. “It’s important to understand the communities’ needs and meet the priorities they identify.”

To help do that, the clinic hires cultural health navigators (CHNs) — lay health care workers steeped in the culture and language of those they serve. “CHNs deeply understand patients’ background, religion, and lived experience and can interpret their health care through those lenses.”

CHNs offer patients ongoing supports, from accompanying them to prenatal visits to facilitating a smooth hospital discharge. And they can chart all interactions in electronic health records so that physicians know what’s been done or discussed.

“These are people who have escaped war and gender-based violence and other human rights atrocities. It’s important to understand the communities’ needs.”

Crista Johnson-Agbakwu, MD
Founder of Valleywise Health’s Refugee Women’s Health Clinic

Like Baltimore’s BHB, Ohio’s Moms2B, and similar programs, the clinic’s supports are accompanied by classes on perinatal health. But its offerings include a tour of the hospital labor and delivery unit — a crucial support for participants unaccustomed to Western, medicalized births.

“Things like IV lines and beeping noises and blood pressure cuffs can be very scary for this population,” says Johnson-Agbakwu. “They’re used to being mobile in labor and can interpret what we do as tying them to the bed. The tour helps demystify a lot of this.”

In all its work, the clinic strives to honor patients’ perspectives. “We try to go beyond checking the boxes of ensuring medical care,” she says. “We are engaging in care that’s anchored in mutual respect. That’s a piece that can be missing in achieving maternal health equity.”

Reaching rural patients

Many of the patients treated by Vidant Health in eastern North Carolina face significant pregnancy-related risks. More than half are overweight or obese, and many have diabetes or hypertension. The poverty rate of this population is twice the national average, and nearly all live in remote rural areas.

Black people — who comprise roughly a third of Vidant’s birthing patients — often fare the worst. In one recent nine-year period, they represented nearly 70% of maternal deaths in the region.

And Vidant Medical Center, based in Greenville, is the only large hospital in an expanse covering 29 counties.

Since 2017, Vidant has been working to support providers throughout the region in efforts to ensure high-quality care during obstetrical emergencies.

One major focus is drills in birth-related crises. These simulations — hundreds have been held in 18 hospitals over the past three years — cover emergency cesarean sections, maternal resuscitation, and more.

The scenarios unfold realistically: A Vidant staff member assumes the role of a patient, and the local team races to save her — calling for emergency assistance, rushing to get instruments, and suggesting necessary maneuvers.

“In a small hospital, these emergencies happen maybe once every two or three years,” which makes it tough to keep skills fresh, says James deVente, MD, PhD, medical director of obstetrics at Vidant Medical Center. “We give them a chance to practice skills over and over so that when something actually happens, they’re ready.”

Traveling to provide training is not always the best option, though. So Vidant providers have also logged thousands of hours advising local providers on how to handle their toughest perinatal cases.

Now, in an effort launched in July 2020, Vidant experts also remotely treat high-risk patients, working in collaboration with 15 local obstetricians.

“Patients often need to drive 60 miles or more each way to be seen [at Vidant],” says Alan Sacks, MD, who heads the Maternal Outreach Through Telehealth for Rural Sites (MOTHeRS) Project. “Appointments can be a costly ordeal in wages lost for a day off from work, child care, and transportation. The project is patient-centered. We basically go to them.”

In addition to telehealth services like remote ultrasound, the effort screens all participants for food insecurity. Those in need immediately receive a food package and are connected to a local food bank. All patients with diabetes or obesity also receive ongoing nutrition counseling.

Sacks highlights another key component of the program: mental health care.

“Mental health disorders carry a 50% increase in severe maternal morbidity and mortality. Nearly 9% of maternal deaths are attributable to mental health disorders. All of these figures are higher in African American patients. The situation and statistics are tragic and can fuel a worrisome intergenerational cycle.”

Looking ahead, Sacks hopes to expand the MOTHeRS Project to additional remote locations. Meanwhile, Vidant’s efforts so far have made a difference. For example, the infant mortality rate in the region dropped by 24% in recent years.

“There’s more work to be done,” says deVente. “But we set out to make this region a better place to give birth and be born, and I think we’ve succeeded in doing that.”

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