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Desert Hot Springs man comes forward as fifth person in remission … – Desert Sun

'I still have to remind myself that it's real'

Video: Paul Edmonds is fifth person in HIV remission

Paul Edmonds, a current Desert Hot Springs resident, is the fifth person living with HIV worldwide to go into full remission following a stem cell transplant.

Taya Gray, Palm Springs Desert Sun

For the past two years, Paul Edmonds has been part of an extremely exclusive club with a membership that has reached five people.

After navigating HIV for more than 30 years, along with a leukemia diagnosis that came in 2018, a life-saving stem cell transplant became available thanks to a donor who had a rare genetic mutation that makes the body resistant to most strains of HIV. In 2021, Edmonds stopped taking his HIV medication, what he was dependent on for almost half his life. Today the 67-year-old who lives in Desert Hot Springs is the fifth person in the world in remission of HIV.

Edmonds joins four others who have received similar news, including the late Palm Springs residentTimothy Ray Brown (who was known as the "Berlin Patient"), the first person cured of the virus, who died from a reoccurrence of cancerin 2020. Others who are in remission of HIV are "London Patient" Adam Castillejo, "Dsseldorf Patient" Marc Franke and the "New York Patient," the first woman to be considered cured who has not come forth publicly. Edmonds is the eldest among the group and had HIV the longest.

"I can remember the day and hearing about Timothy Ray Brown, that was huge," Edmonds told The Desert Sun in a recent interview. "That was the first time that I ever thought there could be a cure."

After two years of being anonymously known as the "City of Hope Patient," he decided to publicly come forward with his story. By sharing his journey, he wants to advocate for and offer hope to those living and aging with HIV that a cure could be possible one day.

Related: 'People with HIV are my family': London patient revealed as cured joins Palm Springs man, who was the first

Related: 'London Patient' Adam Castillejo, second person cured of HIV

Edmonds grew up in a small town in Georgia about 100 miles northeast of Atlanta. During his high school years, he struggled with his sexual identity and didn't have a support system because he kept it all to himself. His "lifesaver" at the time was his involvement in his school's band, which consisted of a close-knit group of people, some of whom he's still in contact with today.

By the end of his senior year, Edmonds felt he couldn't handle the pressure anymore. He decided to live with his cousins in Pensacola, Florida, where he would finish high school and begin college, until he moved back to Atlanta. He received therapy, found support and was able to "accept who I was and come out" as a gay man.

With a different outlook on life, Edmonds, 21 at the time, made the decision to move to San Francisco in 1976.

"Gay men were kind of flocking there from all over at that time," he said of the California city. "It was just an unbelievable experience. I'd never seen anything like it, and I no longer felt alone. It was just exciting and thrilling."

Everything was "just great" until the 1980s rolled around, and many of his peers started getting sick. "No one knew what was going on," Edmonds said about that time, although many would refer to it as a "gay cancer."

Human immunodeficiency virus, more commonly referred to as HIV, is a virus that attacks cells that help the body fight infections. If left untreated, it can lead to AIDS, or acquired immunodeficiency syndrome. On June 5, 1981, the Centers for Disease Control and Prevention reported on the first five cases of what would be known as AIDS.

Rare lung infections and anaggressive cancer calledKaposis sarcoma first began to show among men who have sex with men (MSM) in 1981, and by the end of the year, there were 270 reportedcases of severe immune deficiencyamong MSM. The following year,more cases appeared among MSM in Southern California, which suggested the illness wassexual,leading to the name "gay-related immune deficiency." Cases also surfaced among those who inject drugs, hemophiliacs and Haitians.

Today, it is widely understood that the virus can be spread to all people, though some are still at higher risk of infection. Approximately84.2 million people around the world have been infected by HIV since the start of the epidemicand40.1 million people have died from AIDS-related illnesses.

Related: For decades, queer men have had trouble donating blood. Change could be on the horizon

Related: Reflections on 40 years of HIV/AIDS: Community members compare epidemic to COVID-19 pandemic

By the mid-1980s, the first HIV blood test was developed, but Edmonds was not ready to get results himself.

"Anyone who I knew who was testing positive was dead within two years," he said. "I just wasn't ready to go there."

He moved to Los Angeles for a few years to change his environment, but moved back to San Francisco in 1988. That same year, his father died, which served as the catalyst for Edmonds getting tested. The result came back positive, and because his helper T cell count was below 200 then, he was diagnosed with AIDS. He was 33.

"It just felt like my heart sank," Edmonds recalled, though he noted he did not feel sick. "The intern who was my doctor in this clinic, I can see her emotions. I think it was a hard thing for her to do."

He began using AZT, the first drug to gain approval from the U.S. Food and Drug Administration for treating AIDS. The drug helped decrease deaths and infections among those who were diagnosed with the virus, although it had serious side effects, such as intestinal problems, nausea, vomiting and headaches. Around the time Edmonds began taking the drug, doctors decided to cut the dosage in half, which lessened those effects. As new drugs became available, he would switch to them, and he "pretty much felt sick all the time."

"But I did what I had to do," he added. "I am not a person who just easily gives up. I don't look to the worst-case scenario, I don't allow myself to."

Though things looked dark in the HIV/AIDS fight back then, Edmonds focused on living in the moment and taking his diagnosis one step at a time. As medical advancement came, like protease inhibitors, medications that help slow the progression of HIV, he would allow himself to think about the future and felt hopeful that things would be brighter.

Sure enough, the birthdays kept coming. He always dreamed of having a big party for his 50th birthday, and he got to enjoy that moment surrounded by 100 guests in a lodge on the Russian River.

Edmonds also said he had an "incredible" support system in his life. The LGBTQ community "stepped forward" and helped when no one else would. Then in February 1992, during happy hour at the San Francisco bar Midnight Sun, he met Arnie House, who had served in the Air Force.

"It really was kind of like love at first sight. I don't know that we knew that right then, but that's what it was," Edmonds said of his husband. "Once we met, we've had very few days apart."

Edmonds encouraged House to get tested for HIV, who also received a positive diagnosis. But that didn't change anything between them, as they've "always been there for each other," Edmonds said.

In August 2018, Edmonds was diagnosed with myelodysplastic syndrome, which eventually developed into acute myeloid leukemia, a cancerthat starts in the bone marrow but often moves into the blood. Those living and aging with HIV are at higher risk of developing leukemia and other blood cancers due to suppressed immune systems.

It was recommended that Edmonds start chemotherapy as soon as possible, and later undergo a stem cell transplant. At the same time, Edmonds and House were planning on moving to the Palm Springs area, and he was referred to seek treatment at City of Hope in Duarte, one of the highest-volume transplant centers in the nation.

Not only would doctors look for a donor to address his leukemia, but also one who carried a rare mutation, homozygous CCR5 delta 32 mutation, which makes people resistant to most strains of HIV infection. Only roughly 1% of people carry this mutation. The four other people who have been declared in remission of HIV have received transplants that have targeted their HIV and a type of cancer.

It took almost a month before a donor was found via the Be The Match donor registry. Before he could undergo the transplant, his acute myeloid leukemia had to go into remission. He went through three rounds of chemotherapy, and he developed a fungal infection in his lungs during one. He also had to change the antiretroviral drugs he was taking in order to minimize drug interactions with the chemotherapy.

Finally in mid-January 2019, his leukemia went into full remission thanks to a reduced intensity chemotherapy that was developed for older patients. Afterward, he received a week of chemotherapy to wipe out his immune system and prepare his body to receive his donor's healthy stem cells, which he said was the "hardest of all of them."

But despite all the pain and side effects, "I didn't have to think at all whether I wanted to move forward to get a bone marrow transplant," Edmonds said. "I didn't even see it as an option ... it was that or death."

On Feb. 6, 2019, the transplant lasted about 30 to 40 minutes via an IV transfusion. Edmonds said he didn't have any side effects and almost immediately "felt great." Nurses even gave him a medal and started singing "Happy Birthday" to celebrate the moment.

"New life came into me," he said, noting that his blood type changed to his donor's, which is common in transplants. Some recipients might also notice other changes regarding allergies or their hair texture. "I was kind of hoping I would start getting some new hair, but that didn't happen. That's OK," he joked. Among lingering side effects that Edmonds deals with are dry eyes and mouth sores.

Edmonds had to stay close to the hospital after his treatment, and many friends from across the country stayed with him and made sure he was never alone. "I just had the best time," he recalled of all the trips they took, like playing tourist in his once-home of Los Angeles.

Doctors carefully monitored Edmonds following his transplant for both his cancer and HIV status.

Dr. Jana Dickter, associate clinical professor with City of Hopes Division of Infectious Diseases, did a number of tests to see if there was any evidence of HIV found in his body. When she and her colleagues could not find any, she opened up a "second trial" and asked Edmonds to stop taking his HIV medications.

"I monitored him for any occurrence of HIV virus and this entailed getting blood tests on him every week initially and then converted to every two weeks just because we wanted to catch if there was any recurrence in the system and start him back on his medications," Dickter said. "The longer the time went, there was no evidence of circulating HIV."

Additional testing was done in labs, such as challenging his cells with HIV, but they could not be infected with the virus, and there was no evidence of an HIV reservoir found in his body.

Edmonds officially stopped taking his HIV medication in March 2021.

"I still have to remind myself that it's real," he said of his in-remission HIV status. "But I'm feeling it."

There's still a little bit of worry in the back of his mind about whether his cancer or HIV will return, but he said he's gotten to the point where "it's OK for me to let myself believe it, and I absolutely believe it." He also said the people he's told locally have been "just thrilled for me and very, very supportive."

For Dickter, witnessing the journey firsthand has been "incredibly exciting." When she entered medical school in the 1990s, she got to see the excitement when antiretroviral therapy became available and it provided patients who were so close to death with a "second life." Fast forward to today, she was one of those in the room to tell a patient they were in remission of HIV.

"I've always wanted to be able to tell a patient that there was no evidence of remaining virus in their system, and at City of Hope we were able to do just this," Dickter said. "The experiences that he encountered, especially early on and the stigma and the fear, he's a true survivor of the epidemic, and it's so wonderful to see this happy ending for him and his family."

The success of Edmonds' treatment and his unique circumstances also give Dickter hope that it could be reciprocated in others. He was unique in the sense that, compared to the four other people who underwent transplants, he was the oldest patient, had been living with HIV the longest and had received reduced intensity chemotherapy. "This case gives me hope that there might be other opportunities in the future for older people who have HIV and blood cancers that we may be able to put them in remission for both," she said.

There's also plenty of research taking place at City of Hope in hopes of potentially finding a cure for HIV. Not only are there discussions about providing transplants for other patients with HIV and blood malignancies, but Dickter said there's an upcoming clinical trial that will look at chimeric antigen receptor T cells to treat HIV. She explained there has been preclinical research that has shown these "T cells can target and kill HIV-infected cells and potentially control HIV, and this has the potential to provide HIV patients with lifelong viral suppression without antiretroviral therapy."

Edmonds also hopes to be an advocate for HIV cure research and provide support wherever he can. He currently sits on the Community Advisory Board for RID-HIV (Reversing Immune Dysfunction for HIV-1 Eradication) Collaboratory, one of 10 Martin Delaney Collaboratories for HIV Cure Research funded by the National Institutes of Health, which he is "very honored" to be a part of. He is also in contact with his peers Castillejo, who has spoken at a number of conferences, and Franke, just beginning his public journey, and hopes to do work with them.

For now, Edmonds gets to live his life on his own terms, although he still visits City of Hope for routine care and tests. He and House are avid painters and have their art showcased throughout their home Edmonds paints more abstract pieces while House does more figurative work. Edmonds wants to create collages that tell his story in some way, but they also have a bit of work to do around their Desert Hot Springs home, where they've lived for almost two years. As they emerge out of mostly sheltering-in-place during the height of the COVID-19 pandemic, there are also plans to visit San Francisco this summer.

Aside from encouraging the HIV-positive community, there's also a part of Edmonds that hopes the intern who informed him of his AIDS diagnosis in 1988 stumbles upon his story and sees where life has taken him. Where he stands today is a moment so many have hoped for, and one that seemed unthinkable decades ago.

"It truly is a miraculous story," he said with a smile.

Ema Sasic covers entertainment and health in the Coachella Valley. Reach her at ema.sasic@desertsun.com or on Twitter @ema_sasic.

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Desert Hot Springs man comes forward as fifth person in remission ... - Desert Sun

Effectiveness of Monovalent mRNA COVID-19 Vaccination in … – CDC

Jennifer DeCuir, MD, PhD1,*; Diya Surie, MD1,*; Yuwei Zhu, MD2; Manjusha Gaglani, MBBS3,4,5; Adit A. Ginde, MD6; David J. Douin, MD6; H. Keipp Talbot, MD2; Jonathan D. Casey, MD2; Nicholas M. Mohr, MD7; Tresa McNeal, MD3,4; Shekhar Ghamande, MD3,4; Kevin W. Gibbs, MD8; D. Clark Files, MD8; David N. Hager, MD, PhD9; Minh Phan, MS9; Matthew E. Prekker, MD10; Michelle N. Gong, MD11; Amira Mohamed, MD11; Nicholas J. Johnson, MD12; Jay S. Steingrub, MD13; Ithan D. Peltan, MD14; Samuel M. Brown, MD14; Emily T. Martin, PhD15; Arnold S. Monto, MD15; Akram Khan, MD16; William S. Bender, MD17; Abhijit Duggal, MD18; Jennifer G. Wilson, MD19; Nida Qadir, MD20; Steven Y. Chang, MD, PhD20; Christopher Mallow, MD21; Jennie H. Kwon, DO22; Matthew C. Exline, MD23; Adam S. Lauring, MD, PhD24; Nathan I. Shapiro, MD25; Cristie Columbus, MD4,5; Robert Gottlieb, MD, PhD4,5; Ivana A. Vaughn, PhD26; Mayur Ramesh, MD26; Lois E. Lamerato, MD26; Basmah Safdar, MD27; Natasha Halasa, MD2; James D. Chappell, MD, PhD2; Carlos G. Grijalva, MD2; Adrienne Baughman2; Kelsey N. Womack, PhD2; Jillian P. Rhoads, PhD2; Kimberly W. Hart, MA2; Sydney A. Swan, MPH2; Nathaniel Lewis, PhD1; Meredith L. McMorrow, MD1,; Wesley H. Self, MD2,; IVY Network (View author affiliations)

What is already known about this topic?

Waning of monovalent mRNA COVID-19 vaccine effectiveness against COVID-19associated hospitalization among adults is recognized; however, little is known about the durability of protection provided by these vaccines against COVID-19associated invasive mechanical ventilation (IMV) and in-hospital death during the Omicron variant period.

What is added by this report?

Monovalent mRNA vaccination was 76% effective in preventing COVID-19associated IMV and death <6 months after the last dose and remained 56% effective at 12 years.

What are the implications for public health practice?

Monovalent mRNA COVID-19 vaccines provided substantial, durable protection against COVID-19associated IMV and death. All adults should remain up to date with recommended COVID-19 vaccination to prevent critical outcomes of COVID-19.

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As of April 2023, the COVID-19 pandemic has resulted in 1.1 million deaths in the United States, with approximately 75% of deaths occurring among adults aged 65 years (1). Data on the durability of protection provided by monovalent mRNA COVID-19 vaccination against critical outcomes of COVID-19 are limited beyond the Omicron BA.1 lineage period (December 26, 2021March 26, 2022). In this case-control analysis, the effectiveness of 24 monovalent mRNA COVID-19 vaccine doses was evaluated against COVID-19associated invasive mechanical ventilation (IMV) and in-hospital death among immunocompetent adults aged 18 years during February 1, 2022January 31, 2023. Vaccine effectiveness (VE) against IMV and in-hospital death was 62% among adults aged 18 years and 69% among those aged 65 years. When stratified by time since last dose, VE was 76% at 7179 days, 54% at 180364 days, and 56% at 365 days. Monovalent mRNA COVID-19 vaccination provided substantial, durable protection against IMV and in-hospital death among adults during the Omicron variant period. All adults should remain up to date with recommended COVID-19 vaccination to prevent critical COVID-19associated outcomes.

Monovalent mRNA COVID-19 vaccination has been shown to prevent hospitalization and critical outcomes, including IMV and death, during SARS-CoV-2 Alpha, Delta, and early Omicron variant periods (2,3). However, rapid waning of COVID-19 VE against infection, outpatient illness, and hospitalization has been observed during Omicron variant predominance (4). Understanding the durability of protection provided by monovalent mRNA vaccination against critical outcomes is vital. Although a bivalent mRNA dose was recommended on September 1, 2022, for all persons who had completed a primary COVID-19 vaccination series, bivalent vaccination coverage among adults aged 18 years is 20%, and most adults have only received monovalent mRNA vaccines (1,5). In addition, COVID-19 VE against hospitalization might be artificially reduced by routine testing for SARS-CoV-2 at admission, which can detect SARS-CoV-2 infection in patients admitted for reasons other than COVID-19 (4,6,7). VE against critical outcomes might be less susceptible to this bias and is therefore needed to help guide COVID-19 vaccination policy regarding revaccination intervals.

Data from the Investigating Respiratory Viruses in the Acutely Ill (IVY) Network were used to conduct a case-control analysis measuring the effectiveness of monovalent mRNA COVID-19 vaccination against COVID-19associated IMV and in-hospital death. During February 1, 2022January 31, 2023, adults aged 18 years admitted to 24 hospitals in 19 U.S. states who met a COVID-19like illness case definition and received SARS-CoV-2 testing were enrolled. IVY Network methods have been described previously (2,3). Briefly, case-patients were defined as those who received a positive SARS-CoV-2 reverse transcriptionpolymerase chain reaction (RT-PCR) or antigen test result within 10 days of illness onset and within 3 days of hospital admission, and either received IMV or died in the hospital within 28 days of admission. Control patients were defined as those who received negative SARS-CoV-2 and influenza test results by RT-PCR within 10 days of illness onset and within 3 days of hospital admission. Patients who received positive influenza test results were excluded from the analysis because of potential correlation between COVID-19 and influenza vaccination behaviors (8).

Demographic and clinical data, including receipt of IMV and in-hospital death within 28 days of admission, were collected through electronic medical record (EMR) review and patient or proxy interview. COVID-19 vaccination history was ascertained from state or jurisdictional registries, EMRs, vaccination cards, and self-report. Patients were included in the analysis if they 1) received zero COVID-19 vaccines doses (unvaccinated) or 2) received 2, 3, or 4 monovalent mRNA COVID-19 vaccine doses (monovalent-vaccinated), with the last dose received 14 days before illness onset for a primary series dose or 7 days before illness onset for a booster dose. Patients were excluded from the analysis if they were immunocompromised,** received a non-mRNA COVID-19 vaccine dose, received only 1 monovalent mRNA COVID-19 vaccine dose, received a bivalent mRNA COVID-19 vaccine dose, or for other reasons that made the patient ineligible.

VE against IMV and in-hospital death was calculated using logistic regression, in which the odds of monovalent mRNA vaccination (versus being unvaccinated) were compared between COVID-19 case-patients and control patients. Logistic regression models were adjusted for U.S. Department of Health and Human Services region, calendar time in biweekly intervals, age, sex, and self-reported race and Hispanic ethnicity. VE was calculated as (1 adjusted odds ratio) x 100%. Results were stratified by age group, time since receipt of last monovalent mRNA vaccine dose, and number of monovalent mRNA vaccine doses received. Differences between VE point estimates with nonoverlapping 95% CIs were considered statistically significant. Analyses were conducted using SAS (version 9.4; SAS Institute). This activity was determined to be public health surveillance by each participating site and CDC and was conducted in a manner consistent with all applicable federal laws and CDC policy.

During February 1, 2022January 31, 2023, a total of 6,354 immunocompetent control patients and COVID-19 case-patients with IMV or in-hospital death were enrolled in the IVY Network. After exclusion of 1,933 patients,*** 4,421 (70%) were included in the analysis (362 case-patients and 4,059 control patients). Patients were most commonly excluded because of receipt of a bivalent mRNA COVID-19 vaccine dose (446 [23% of excluded patients]), receipt of a non-mRNA COVID-19 vaccine (392 [20%]), or receipt of only 1 monovalent mRNA COVID-19 vaccine dose (260 [13%]). Among included patients, the median age was 64 years (IQR=5375 years) (Table 1). Ninety-one percent of patients had one or more chronic condition, and 20% had a previous self-reported or documented SARS-CoV-2 infection. Among 362 case-patients with IMV or in-hospital death, 146 (40%) were unvaccinated, 216 (60%) were monovalent-vaccinated, 293 (81%) received IMV, and 156 (43%) died in the hospital within 28 days of admission. Among 4,059 control patients, 979 (24%) were unvaccinated, and 3,080 (76%) were monovalent-vaccinated.

Among monovalent-vaccinated patients, the median interval from receipt of last dose to illness onset was 248 days (IQR=138378 days) (Table 2). When compared with unvaccinated patients, the VE of 24 monovalent mRNA vaccine doses against IMV and in-hospital death was 62%. VE was 57% among patients aged 1864 years and 69% among patients aged 65 years. When stratified by interval since receipt of last monovalent dose, VE against IMV and in-hospital death was 76% at 7179 days, 54% at 180364 days, and 56% at 365 days. Within each interval since receipt of last monovalent dose, VE estimates did not differ significantly by number of doses received. VE point estimates were higher 7179 days since last dose compared with 180 days since last dose, although 95% CIs overlapped.

Among immunocompetent adults aged 18 years admitted to 24 hospitals in the IVY Network in 19 U.S. states, receipt of 24 monovalent mRNA COVID-19 vaccine doses provided substantial protection against COVID-19associated IMV and in-hospital death during the Omicron variant period. Protection was highest during the first 6 months after the last monovalent dose, with persistent residual protection remaining after 6 months and sustained at 12 years. Monovalent mRNA vaccination also provided substantial protection against COVID-19associated IMV and death among adults aged 65 years, the age group that remains at highest risk of severe COVID-19 (1). These findings underscore the importance of staying up to date with COVID-19 vaccination to prevent critical outcomes of COVID-19, including optional, additional bivalent mRNA booster doses for persons at highest risk of severe disease.

A previous analysis from the IVY Network showed high effectiveness of monovalent mRNA COVID-19 vaccination against COVID-19associated IMV and death during the Delta and early Omicron variant periods (2). The current analysis expands on these findings by reporting monovalent mRNA COVID-19 VE against IMV and in-hospital death for a full year during the Omicron variant period. These results suggest some waning of protection against IMV and death after 6 months from receipt of the last dose but demonstrate clinically meaningful levels of protection for 1 year (median=455 days). In stratified analyses, VE appeared to correlate more closely with time since last dose than with total number of doses received. These findings are consistent with evidence from the United Kingdom showing that among adults aged 65 years, VE of monovalent COVID-19 vaccination against COVID-19associated mortality during the Omicron variant period was 49.7% for 2 doses and 56.9% for 3 doses after 40 weeks (280 days) from vaccination (9). Together, these results suggest maximal benefit of COVID-19 vaccination during the first 6 months after receipt, which should be considered along with trends in COVID-19 incidence and risk factors for severe disease when planning COVID-19 revaccination schedules.

The findings in this report are subject to at least four limitations. First, the sample size was insufficient to generate VE estimates for each Omicron lineage period separately or to calculate some VE estimates stratified by both time since last monovalent mRNA dose and number of doses received. Second, although case-patients had evidence of acute respiratory illness and received a positive SARS-CoV-2 test result, inclusion of case-patients who died or required IMV for reasons other than COVID-19 could have reduced VE because of misclassification. Third, previous SARS-CoV-2 infection was infrequently reported or documented among patients in this analysis, which prevented evaluation of the impact of previous infection on VE against critical outcomes. Finally, although VE estimates were adjusted for patient-level demographic characteristics, calendar time, and geographic region, residual confounding, including from COVID-19 antiviral treatment, cannot be excluded.

Since the start of the COVID-19 pandemic, approximately 1.1 million COVID-19associated deaths have occurred in the United States, with the majority occurring among patients aged 65 years. Monovalent mRNA COVID-19 vaccination provided substantial, durable protection against COVID-19associated IMV and death during the Omicron variant period, including among older adults. Protection against these critical outcomes appeared to correlate more closely with time since last dose than with total number of doses received. On April 18, 2023, bivalent mRNA vaccines became the only mRNA COVID-19 vaccines authorized for use in the United States. Only 42% of adults aged 65 years have received a bivalent mRNA COVID-19 vaccine dose and are up to date with COVID-19 vaccination (1). CDC recommends that all adults remain up to date with COVID-19 vaccination, including the updated bivalent vaccine, to prevent critical outcomes of COVID-19.

1National Center for Immunization and Respiratory Diseases, CDC; 2Vanderbilt University Medical Center, Nashville, Tennessee; 3Baylor Scott & White Health, Temple, Texas; 4Texas A&M University College of Medicine, Temple, Texas; 5Baylor Scott & White Health, Dallas, Texas; 6University of Colorado School of Medicine, Aurora, Colorado; 7University of Iowa, Iowa City, Iowa; 8Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina; 9Johns Hopkins Hospital, Baltimore, Maryland; 10Hennepin County Medical Center, Minneapolis, Minnesota; 11Montefiore Healthcare Center, Albert Einstein College of Medicine, New York, New York; 12University of Washington School of Medicine, Seattle, Washington; 13Baystate Medical Center, Springfield, Massachusetts; 14Intermountain Medical Center and University of Utah, Salt Lake City, Utah; 15University of Michigan School of Public Health, Ann Arbor, Michigan; 16Oregon Health & Science University Hospital, Portland, Oregon; 17Emory University School of Medicine, Atlanta, Georgia; 18Cleveland Clinic, Cleveland, Ohio; 19Stanford University School of Medicine, Stanford, California; 20Ronald Reagan UCLA Medical Center, Los Angeles, California; 21University of Miami, Miami, Florida; 22Washington University, St. Louis, Missouri; 23The Ohio State University Wexner Medical Center, Columbus, Ohio; 24University of Michigan School of Medicine, Ann Arbor, Michigan; 25Beth Israel Deaconess Medical Center, Boston, Massachusetts; 26Henry Ford Health, Detroit, Michigan; 27Yale University School of Medicine, New Haven, Connecticut.

Abbreviations: HHS=U.S. Department of Health and Human Services; IMV=invasive mechanical ventilation.* Hospitals by HHS region included Region 1: Baystate Medical Center (Springfield, Massachusetts), Beth Israel Deaconess Medical Center (Boston, Massachusetts), and Yale University (New Haven, Connecticut); Region 2: Montefiore Medical Center (New York, New York); Region 3: Johns Hopkins Hospital (Baltimore, Maryland); Region 4: Emory University Medical Center (Atlanta, Georgia), University of Miami Medical Center (Miami, Florida), Vanderbilt University Medical Center (Nashville, Tennessee), and Wake Forest University Baptist Medical Center (Winston-Salem, North Carolina); Region 5: Cleveland Clinic (Cleveland, Ohio), Hennepin County Medical Center (Minneapolis, Minnesota), Henry Ford Health (Detroit, Michigan), The Ohio State University Wexner Medical Center (Columbus, Ohio), and University of Michigan Hospital (Ann Arbor, Michigan); Region 6: Baylor Scott & White Medical Center (Temple, Texas) and Baylor University Medical Center (Dallas, Texas); Region 7: Barnes-Jewish Hospital (St. Louis, Missouri) and University of Iowa Hospitals (Iowa City, Iowa); Region 8: Intermountain Medical Center (Murray, Utah) and UCHealth University of Colorado Hospital (Aurora, Colorado); Region 9: Stanford University Medical Center (Stanford, California) and Ronald Reagan UCLA Medical Center (Los Angeles, California); and Region 10: Oregon Health & Science University Hospital (Portland, Oregon) and University of Washington (Seattle, Washington). Other race, non-Hispanic includes American Indian or Alaska Native, Asian, and Native Hawaiian or other Pacific Islander categories, which were combined because of small counts. Other includes patients who self-reported their race and ethnicity as Other and those for whom race and ethnicity were unknown. Chronic medical condition categories include autoimmune, cardiovascular, endocrine, gastrointestinal, hematologic, neurologic, pulmonary, and renal diseases.** Previous SARS-CoV-2 infection was defined as any self-reported or documented previous SARS-CoV-2 infection. Previous Omicron infection was defined as any self-reported or documented previous SARS-CoV-2 infection that occurred during December 26, 2021January 31, 2023.

Abbreviations: IMV=invasive mechanical ventilation; VE=vaccine effectiveness.* https://www.cdc.gov/flu/vaccines-work/ivy.htm Monovalent-vaccinated patients received 24 monovalent mRNA COVID-19 vaccine doses and zero bivalent mRNA COVID-19 vaccine doses. VE was estimated by comparing the odds of monovalent mRNA vaccination among case-patients and control patients, calculated as VE=100 (1 odds ratio). Logistic regression models were adjusted for date of hospital admission (biweekly intervals), U.S. Department of Health and Human Services region (10 regions), categorical age (1849, 5064, and 65 years), sex, and race and ethnicity (Black or African American, non-Hispanic; White, non-Hispanic; Hispanic or Latino, any race; Other race, non-Hispanic; and Other, unknown) unless otherwise noted. Logistic regression models for age groupspecific VE estimates were adjusted for continuous age. Logistic regression models for VE of 4 monovalent doses were restricted to patients aged 50 years admitted during April 5, 2022January 31, 2023, and were adjusted for continuous age.** VE estimate was not reported because of insufficient sample size.

Suggested citation for this article: DeCuir J, Surie D, Zhu Y, et al. Effectiveness of Monovalent mRNA COVID-19 Vaccination in Preventing COVID-19Associated Invasive Mechanical Ventilation and Death Among Immunocompetent Adults During the Omicron Variant Period IVY Network, 19 U.S. States, February 1, 2022January 31, 2023. MMWR Morb Mortal Wkly Rep 2023;72:463468. DOI: http://dx.doi.org/10.15585/mmwr.mm7217a3.

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Effectiveness of Monovalent mRNA COVID-19 Vaccination in ... - CDC

Trajectory of the Changing GA Treatment Landscape – AJMC.com Managed Markets Network

Ryan Haumschild, PharmD, MS, MBA: Now I would like to really transition into the future considerations of geographic atrophy [GA]. Obviously, theres been a lot of excitement here recently around complement inhibitors, and I feel like the treatment of the future landscape is even more exciting. And were going to have more options for our patients to really improve outcomes, give durable responses, and ultimately, improve the quality of life. Dr Lally, I would like to start with you. What are you most excited about in the treatment landscape of GA in the next 5 years? And what are some final thoughts that you want to share with our viewing audience from todays discussion?

David Lally, MD: I think the take-home message that Im excited about is there has really been an explosion of clinical trials and different strategies of trying to tackle this disease of GA. Blocking complement is one very important part of the puzzle. But as we have seen and we have talked about earlier, complement inhibition is really just the tip and just the start of what is to come. And really our goal is we want to prevent GA from even developing, or if it develops, we want to stop it in its track. These new therapies are really the first step of showing a slowing progression, but the disease is still progressing. We do not want it to progress. We want to stop it or prevent it from even developing. There are a lot of different strategies out there beyond complement [inhibitors] looking to try to accomplish this goal. Something we look at is neuroprotection, which is a big umbrella term thats kind of even hard to define what neuroprotection means. But I think neuroprotective medicines that can protect the retina; the retina is like an outpouching of the brain. We consider it like neural tissue, an outpouching of the brain. Any medication that can really preserve neuronal health, I think is going to be an exciting place to look. I think what is exciting is there is a lot of work going into trying to design and figure out end points that can be used to see the effects of treatments at the intermediate stage of dry AMD [age-related macular degeneration] before GA develops. And I think, again, if we can find really good clinical trial outcome measures, for the development of GA, in a reasonable time frame to run a clinical trial, I think we are really going to see the field move forward. There are a lot of people working on functional outcome measures, on structural outcome measures, to really try to help us hone in there. I think regenerative medicine is interesting. Some strategies are looking at replenishing the atrophic area with pluripotent embryonic stem cells. And theres some work that is actually getting into the later stages of development. Stem cells, although we are not all the way there yet, I think are starting to make some progress in the development of hopefully getting to an FDA-approval someday, and actually restoring the loss of the photoreceptors. But to me, the most encouraging if we look at these complement inhibitors is I hope someday we have gene therapy for these complement inhibitors. Wouldnt it be wonderful if we could give one intravitreal injection with a gene therapy that went into the cells, and we had our own retina cells make the complement inhibitors themselves where it went on forever? Because, as I mentioned earlier, these patients live with this disease for the rest of their lives. The way its looking right now, in the current state, they are going to be receiving intravitreal injections, either monthly or every other month, indefinitely. I think gene therapy is a place to be watching in the future. But the take-home message is its a really exciting time if you are a patient with GA. This is really a hallmark time in our field, having our first FDA-approved treatment. Hopefully, we may have a second soon in the summertime. The knowledge is really exponentially moving forward, and I really think in 5 years we are going to have even a lot more knowledge and we are going to have a lot better treatments coming for our patients.

Ryan Haumschild, PharmD, MS, MBA: Absolutely. Great final comments. And a lot more real-world evidence to make more informed decisions. Dr Lopes, curious what are your thoughts on how you expect the treatment landscape to change in the next 5 years, and upon that, what are your final thoughts from todays discussion?

Maria Lopes, MD, MS: Its certainly an exciting time to be in this disease space and going from no treatments to several, with 1 already approved and more in the pipeline. I guess until there is a cure, there is an unmet need. Exciting to see not just slowing disease progression, but that were looking at different mechanisms of action that hopefully make a very significant impact on preserving vision and potentially, halting progression as well as maybe even reversing disease, which is really exciting and innovative. [I would] love to see maybe more personalized medicine around predictive tools because as we have more treatment options, how do we sequence those options? How do we define what success looks like in this disease state if were just looking at a rate of growth? [I would] love to see more about any predictive tools that help us, not just identify, but then have the right shared decision approach that hopefully has and meets patient expectations, as well as payer needs and budget impact, and ultimately, making a significant impact on a clinically meaningful difference, which is about vision preservation.

Ryan Haumschild, PharmD, MS, MBA: Excellent. Clinical meaningful difference is really whats going to carry us forward, I feel like, from a treatment selection standpoint. Dr Khanani, we couldnt end without your thoughts on the evolving treatment landscape in the next 5 years. And also, what are some of your final thoughts and takeaways for our viewing audience?

Arshad Khanani, MD: Ryan, thank you again for moderating this great discussion. I really enjoyed it. I think the bottom line for me is that GA is a devastating disease that progresses 100% of the time, in 100% of the patients. And its a really severe disease that can take your independence away. It puts our patients in really tough situations. They cannot function and they go into depression. It really impacts the quality of life, and it leads to other comorbidities because the patients cannot see. Now, its a really exciting time to have the first FDA-approved treatment in pegcetacoplan [Syfovre], and hopefully, avacincaptad pegol coming in August. As physicians, there are still big unmet needs in this space. Obviously, complement inhibitors are a great start. Its chapter 1 of a really thick book that we will write together over the next 1 to 2 decades. In the next 5 years or so, I think we have both of these approved treatments, hopefully, that we utilize in an appropriate fashion to help our patients. And I think having artificial intelligence to help us with finding the right patients, doing the right treatment interval, monitoring the growth will be important. Now, its exciting because we have so many things in the pipeline. Gene therapy programs, some of them are in phase 2 trials, where you are actually enriching a complement factor I, and kind of modulate the overactive complement system in bringing it towards normal complement activity. We have to wait for the data to see if that pans out. Treatment burden will likely be a big problem with frequent injections. Gene therapy, as Dr Lally said, with one-time treatment targeting the complement system in one way or another, whether in the operating room or in clinic, will be exciting. We have some other novel drugs and mechanisms of action that are in the pipeline. We saw some promising data from elamipretide to preserve mitochondrial function. There are other pathways we are looking at. But at this point, over the next 5 years, I think we will have to utilize the complement inhibitors in a fashion to help our patients preserve their vision. Final comments from me, it was very depressing over the last 15 years of practice for me to give the bad news of blindness to our patients with GA. Now I can give them some hope. They will be able to preserve their vision longer. Yes, we cannot reverse the disease. Yes, we cannot stop the disease. But slowing the disease down can have meaningful outcomes in the future because the treatment effect is greater the longer you treat these patients. And then, hopefully, we will have more treatments come down the pipeline and treat this disease early at the intermediate stage so we can actually tell our patients that you are not going to go blind.

Ryan Haumschild, PharmD, MS, MBA: Complement inhibitors sure are going to be a game changer in the field of GA. Thank you all so much. Thank you to our expert panelists for this rich and informative discussion, and to our viewing audience, we hope that you found this AJMC Peer Exchangeto be useful and informative.

Transcript edited for clarity.

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Trajectory of the Changing GA Treatment Landscape - AJMC.com Managed Markets Network

Brain cells are starved of energy when autophagy malfunctions, new … – University of Birmingham

Research has major implications for neurodegenerative disease treatments

Neurodegeneration in brain cells may be happening when the natural cellular cleaning process malfunctions due to falling levels of a niacin-related coenzyme and leaves cells starved of energy, new research shows.

Brain cells die from malfunction of autophagy, a process by which cells get rid of cellular waste and generate energy for their survival. In new research published in Cell Reports, researchers have found that a metabolic failure arising from loss of autophagy is detrimental to brain cells called neurons. When autophagy stops working, the levels of a coenzyme called nicotinamide adenine dinucleotide (NAD) falls, causing the cells to not be able to get enough energy to maintain normal function and to survive.

Researchers led by Dr Sovan Sarkar at the University of Birmingham along with his PhD students, Ms Congxin Sun and Dr Elena Seranova, and in collaboration with Prof. Rudolf Jaenisch at the Whitehead Institute for Biomedical Research, developed a human embryonic stem cell (hESC) model with deletion of a key gene involved in autophagy.

They generated neurons from these hESCs to understand how loss of autophagy kills brain cells. In autophagy-deficient neurons, depletion of NAD was identified to mediate cell death. The researchers found that upon loss of autophagy, NAD was consumed by hyperactivation of naturally occurring enzymes such as Sirtuins and PARPs.

Critically for brain health, dropping NAD levels resulted in undesirable electrical changes to mitochondria, leading to them not being able to function effectively and cells arent able to metabolise energy to continue to maintain homeostasis.

The researchers say that the findings of this neurotoxic pathway provide new clues about a way to combat neurodegenerative diseases, by showing that compounds boosting NAD levels can improve the survival of neurons with loss of autophagy.

....identifying that NAD levels are being depleted when autophagy malfunctions is a very important step in thinking about a way to manage decline in brain health both in older age and among at-risk populations.

Dr Sovan Sarkar, a Birmingham Fellow in the Institute of Cancer and Genomic Sciences at the University of Birmingham and lead senior author of the paper said:

We have shown a new mechanism of how brain cells are dying when autophagy stops working properly by using a hESC-derived neuronal model of autophagy deficiency. Autophagy is a critical process across all cells, especially in neurons, and identifying that NAD levels are being depleted when autophagy malfunctions is a very important step in thinking about a way to manage decline in brain health both in older age and among at-risk populations.

NAD can be boosted through the use of targeted therapeutics such as supplementation with NAD precursors like nicotinamide (NAM), nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), as well as through the consumption of vitamin B3 also called niacin.

Our research also identifies the potential for drugs that slow down the NAD-eating enzymes in the PARP and Sirtuin families, all of which could support healthy ageing and reduced risk of neurodegeneration.

The results suggest that among the many roles that autophagy plays, helping maintain the levels of NAD that supports cell metabolism is an important process for staving off neurodegeneration. It also provides new potential targets for future treatments for neurodegenerative diseases, both by targeting the enzymes (SIRT1 and 2 and PARP1 and 2) that ate up NAD and by supplementing NAD precursors.

Dr Viktor Korolchuk, Associate Professor at Newcastle University and a senior co-author of the paper said:

Both autophagy and NAD levels decline in our cells and tissues as we get older contributing to age-related diseases. Our study helps to explain how these processes are interlinked: loss of autophagy also causes depletion of NAD.

Our recent paper demonstrated this in yeast and mouse cells, and the current study in human cells unequivocally shows that this intimate link between autophagy and NAD can trigger the death of human neurons. This finding significantly adds to our understanding of ageing and age-related neurodegeneration and opens new avenues to explore.

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Brain cells are starved of energy when autophagy malfunctions, new ... - University of Birmingham

Map of spinal cord formation gives new knowledge on diseases of … – EurekAlert

Researchers at Karolinska Institutet in Sweden have mapped how cells in the human spinal cord are formed in the embryo and what genes control the process. Their findings can give rise to new knowledge on how injury to and diseases of the spinal cord arise and how they can be treated. The study has been published in the journal Nature Neuroscience.

The spinal cord is part of the central nervous system, serving as an important bridge for communication between the brain and the rest of the body. There are many different types of cells in the human spinal cord but much still remains to be understood about how these cells are formed from stem cells during embryonic development.

Many neurodegenerative diseases and injuries of the spinal cord are incurable because of the poor regeneration of human spinal cord cells, says the studys first author Xiaofei Li, assistant professor at the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet. A better grasp of how the spinal cord is formed and how different genes control this development can lead to new therapies for spinal cord injuries and diseases such as ALS or cancer of the nervous system.

User-friendly online tool

The researchers have built up an extensive map of all the cell types of the human spinal cord, showing where the cells are and what genes they express during embryonic development. The information has been gathered in a user-friendly interactive online tool that researchers or other interested parties can use to search for genes that shape how the spinal cord develops.

The study identified key genes that affect how the stem cells migrate when the spinal cord is formed and what specialisations they have. A comparison with spinal cord development in mice revealed important differences between mice and humans.

These findings are very important because much of what we already know is based on mouse studies, says Dr Li.

The study was conducted using single-cell RNA sequencing and spatial transcriptomics, which enabled the researchers to map thousands of genes in each individual cell and analyse how they are expressed at different sites of the same tissue section.

Learning more about child cancer

The researchers also studied an unusual tumour type called ependymoma, which manifests as malignant brain tumours in children or benign spinal cord tumours in adults. On identifying genes that are specific to tumour development they were thus able to demonstrate how their findings can be used to increase understanding of diseases of the nervous system.

Well now be interrogating how stem cells form different cell types and change their properties both during embryonic development and later during maturity and ageing, as well as in different kinds of pathological conditions, says the studys last author Erik Sundstrm, senior researcher at the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet.

The study was financed by the Erling Persson Foundation, the Knut and Alice Wallenberg Foundation, Karolinska Institutet and SciLifeLab. Co-authors Zaneta Andrusivova, Ludvig Larsson and Joakim Lundeberg are consultants at 10x Genomics Inc., for which Mats Nilsson is also an advisor.

Publication: Profiling spatiotemporal gene expression of the developing human spinal cord and implications for ependymoma origin. Xiaofei Li, Zaneta Andrusivova, Paulo Czarnewski, Christoffer Mattsson Langseth, Alma Andersson, Yang Liu, Daniel Gyllborg, Emelie Braun, Ludvig Larsson, Lijuan Hu, Zhanna Alekseenko, Hower Lee, Christophe Avenel, Helena Kopp Kallner, Elisabet kesson, Igor Adameyko, Mats Nilsson, Sten Linnarsson, Joakim Lundeberg, Erik Sundstrm. Nature Neuroscience, online 24 April 2023, doi: 10.1038/s41593-023-01312-9.

Nature Neuroscience

Experimental study

Human tissue samples

Profiling spatiotemporal gene expression of the developing human spinal cord and implications for ependymoma origin

24-Apr-2023

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Map of spinal cord formation gives new knowledge on diseases of ... - EurekAlert

Developing cells likely can ‘change their mind’ about their destiny – Phys.org

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A neural crest cell (a type of stem cell) begins with the ability to differentiate into any number of specialist cell types, but it also appears to retain the capacity to "change its mind" and differentiate anew when the circumstances are right, according to new research from the University of Bath. As a result of this hyper-flexibility, the possibilities for these cells in replacing damaged human tissue is likely to be even greater than previously thought.

Neural crest cellsfound in very young embryos, and vital for determining the color of hair and skinare highly flexible by nature, giving rise to many different types of vital cells, including neurons. New research from the University of Bath suggests their flexibility remains greater than previously thought, a finding that has significant implications for regenerative medicine.

Until now, it was assumed that neural crest cells became committed to becoming a particular cell type very early, after which their fate was sealed. However, studies led by Professor Robert Kelsh from the Department of Life Sciences at Bath suggest they retain their adaptability even after they have become visibly differentiated.

This newly discovered flexibility helps explain why neural crest stem cellsan important type of stem cell that can also be readily isolated from adult skinhave immense potential as treatments to replace and repair damaged body tissue in many parts of the body.

The finding that even after choosing a destiny (for instance, developing into skin pigment cells), neural crest cells might be able to "change their mind" and choose a new destiny (perhaps becoming cartilage cells) reconciles a long-standing debate among biologists over the nature of neural crest cell differentiation.

In humans, neural crest cells are multipotent, meaning they are capable of developing into many different types of cell, including cells of the peripheral nervous system, cardiac muscle, and cartilage, as well as pigment cells in the skin and hair. These are all cells with highly specific functions.

Until now, two rival theories have sought to explain how, exactly, they pull this off.

"The question of how the fate of these cells becomes decided and restricted has been unclear and much debated for over 40 years," said Professor Kelsh.

According to the first theory, neural crest cells begin to commit to a specific role in the young embryo before leaving the place from which they arisethe neural tube (which develops into the brain and spine). The thinking goes that by the time they start migrating to their final destinationbe that the gut, skin, or connective tissuetheir destiny is already partially limited (i.e., some options are already off the table) and that more and more options become eliminated as they migrate.

The second theory posits that neural crest cells remain multipotent when they leave the neural tube and only commit to a specific differentiation path once they reach their destination.

There has been a general feeling in the field that the first model was the more accurate of the two. The new study published in Nature Communications, however, finds that neither of these "static" theories is correct.

"It would appear that these cells are choosing their fate in a much more dynamic, mobile way and are not narrowing their options irreversibly until much later than we previously thought," said Professor Kelsh. "This provides experimental biologists with a new, updated model to help them understand the behavior of neural crest cells."

It has long been known that neural crest cells use molecular signals from their environments to turn into one type of cell or another. However, Professor Kelsh's genetic work on zebrafisha freshwater fish with many genetic similarities to humansshows these steps are likely reversible: remove the signals and the cells revert to a more primitive state, where their potential to differentiate differently is restored.

Professor Kelsh said, "Our work shows these cells become biased by their environment. Take them out of that environment and they relax back to a more broadly competent state, likely capable of becoming anything."

He added, "Our findings will be of interest to other stem-cell researchers, as they give us a theoretical understanding of how neural crest cells might be used in medicine to repair any number of defects, from skin-pigmentation defects such as vitiligo to defects of the nervous system."

More information: Tatiana Subkhankulova et al, Zebrafish pigment cells develop directly from persistent highly multipotent progenitors, Nature Communications (2023). DOI: 10.1038/s41467-023-36876-4

Journal information: Nature Communications

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Developing cells likely can 'change their mind' about their destiny - Phys.org

Cell Therapy Market to Witness Rapid Growth, Driven by Growing Applications in Oncology and Regenerative Medic – openPR

Global Cell Therapy Market report from Global Insight Services is the single authoritative source of intelligence on Cell Therapy Market. The report will provide you with analysis of impact of latest market disruptions such as Russia-Ukraine war and Covid-19 on the market. Report provides qualitative analysis of the market using various frameworks such as Porters' and PESTLE analysis. Report includes in-depth segmentation and market size data by categories, product types, applications, and geographies. Report also includes comprehensive analysis of key issues, trends and drivers, restraints and challenges, competitive landscape, as well as recent events such as M&A activities in the market.

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Cell therapy is a type of treatment that uses living cells to treat a disease or condition. The cells can be from the patient's own body, or they can be from a donor. Cell therapy is also called cellular therapy, cell transplantation, or regenerative medicine.

Key Trends:

The major factors driving the growth of this market are the increasing prevalence of cancer and chronic diseases, and the growing demand for personalized medicine.

However, the high cost of cell therapy treatments and the lack of skilled professionals are the major factors restraining the growth of this market.

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Key Drivers:

The key drivers of the cell therapy market are the increasing incidence of cancer, the rise in the aging population, and the growing demand for minimally invasive treatments.

The aging population is also a major driver of the cell therapy market, as the risk of developing cancer increases with age.

The demand for minimally invasive treatments is also growing, as patients seek to avoid the side effects of traditional cancer treatments such as chemotherapy and radiation therapy.

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Market Segments:

The cell therapy market is segmented by therapy type, therapeutic area, end-user, and region. By therapy type, the market is classified into autologous, and allogenic. On the basis of therapeutic area, it is bifurcated into malignancies, autoimmune disorders, dermatology, and others. Based on end-use, it is divided into hospitals, clinics, academic, and others. Region-wise, the market is segmented into North America, Europe, Asia Pacific, and Rest of the World.

Key Players:

The global cell therapy market includes players such as Allosource, Cells for Cells, Holostem Terapie Avanzate Srl, JCR Pharmaceuticals Co Ltd, Kolon Tissuegene Inc, Medipost Co Ltd, Mesoblast Ltd, Nuvasive Inc, Osiris Therapeutics, Inc, Stemedica Cell Technologies Inc, and others.

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The first babies conceived with a sperm-injecting robot have been born – MIT Technology Review

I was calm. In that exact moment, I thought, Its just one more experiment, says Eduard Alba, the student mechanical engineer who commanded the sperm-injecting device.

The startup company that developed the robot, Overture Life, says its device is an initial step toward automating in vitro fertilization, or IVF, and potentially making the procedure less expensive and far more common than it is today.

Right now, IVF labs are staffed by trained embryologists who earn upwards of $125,000 a year to delicately handle sperm and eggs using ultra-thin hollow needles under a microscope.

But some startups say the entire process could be carried out automatically, or nearly so. Overture, for instance, has filed a patent application describing a biochip for an IVF lab in miniature, complete with hidden reservoirs containing growth fluids, and tiny channels for sperm to wiggle through.

Think of a box where sperm and eggs go in, and an embryo comes out five days later, says Santiago Munn, the prize-winning geneticist who is chief innovation officer at the Spanish company. He believes that if IVF could be carried out inside a desktop instrument, patients might never need to visit a specialized clinic, where a single attempt at getting pregnant can cost $20,000 in the US. Instead, he says, a patients eggs might be fed directly into an automated fertility system at a gynecologists office. It has to be cheaper. And if any doctor could do it, it would be, says Munn.

MIT Technology Review identified a half-dozen startups with similar aims, with names like AutoIVF, IVF 2.0, Conceivable Life Sciences, and Fertilis. Some have roots in university laboratories specializing in miniaturized lab-on-a-chip technology.

So far, Overture has raised the most: about $37 million from investors including Khosla Ventures and Susan Wojcicki, the former CEO of YouTube.

The main goal of automating IVF, say entrepreneurs, is simple: its to make a lot more babies. About 500,000 children are born through IVF globally each year, but most people who need help having kids dont have access to fertility medicine or cant pay for it.

How do we go from half a million babies a year to 30 million? wonders David Sable, a former fertility doctor who now runs an investment fund. You cant if you run each lab like a bespoke, artisanal kitchen, and that is the challenge facing IVF. Its been 40 years of outstanding science and really mediocre systems engineering.

While an all-in-one fertility machine doesnt yet exist, even automating parts of the process, like injecting sperm, freezing eggs, or nurturing embryos, could make IVF less expensive and eventually support more radical innovations, like gene editing or even artificial wombs.

But it wont be easy to fully automate IVF. Just imagine trying to make a robot dentist. Test-tube conception involves a dozen procedures, and Overtures robot so far performs only one of them, and only partially.https://wp.technologyreview.com/wp-content/uploads/2023/04/robot-procedure-notext.mp4An video showing robotic fertilization of an egg at Overture Life Sciences. A vibrating needle pierces the egg, depositing a single sperm cell.

OVERTURE

The concept is extraordinary, but this is a baby step, says Gianpiero Palermo, a fertility doctor at Weill Cornell Medical Center who is credited with developing the fertilization procedure known as intracytoplasmic sperm injection, or ICSI, in the 1990s. Palermo notes that Overtures researchers still relied on some manual assistance for tasks like loading a sperm cell into the injector needle. This is not yet robotic ICSI, in my opinion, he says.

Other doctors are skeptical that robots can, or should, replace embryologists anytime soon. You pick up a sperm, put it in an egg with minimal trauma, as delicately as possible, says Zev Williams, director of Columbia Universitys fertility clinic. For now, humans are far better than a machine, he says.

His center did develop a robot, but it has a more limited aim: dispensing tiny droplets of growth medium for embryos to grow in. Its not good for the embryos if the drop size differs, says Williams. Creating the same drops over and over againthat is where the robot can shine. He calls it a low risk way to introduce automation to the lab.

One obstacle to automating conception is that so-called microfluidicsanother name for lab-on-a-chip technologyhasnt lived up to its hype.

Jeremy Thompson, an embryologist based in Adelaide, Australia, says hes spent his career figuring out how to make the lives of embryos better as they grow in laboratories. But until recently, he says, his tinkering with microfluidic systems yielded an unambiguous result: Bollocks. It didnt work. Thompson says IVF remains a manual process in part because no one wants to trust an embryoa potential personto a microdevice where it could get trapped or harmed by something as tiny as an air bubble.

A few years ago, though, Thompson saw images of a minuscule Eiffel Tower, just one millimeter tall. It had been made using a new type of additive 3D printing, in which light beams are aimed to harden liquid polymers. He decided this was the needed breakthrough, because it would let him build a box or a cage around an embryo.

Since then, a startup he founded, Fertilis, has raised a couple of million dollars to print what it calls see-through pods or micro-cradles. The idea is that once an egg is plopped into one, it can be handled more easily and connected to other devices, such as pumps to add solutions in minute quantities.

Inside one of Fertiliss pods, an egg sits in a chamber no larger than a bead of mist, but the container itself is large enough to pick up with small tongs. Fertilis has published papers showing it can flash-freeze eggs inside the cradles and fertilize them there, too, by pushing in a sperm with a needle.

A human egg is about 0.1 millimeters across, at the limit of what a human eye can see unaided. Right now, to move one, an embryologist will slurp it up into a hollow needle and squirt it out again. But Thompson says that once inside the companys cradles, eggs can be fertilized and grow into embryos, moving through the stations of a robotic lab as if on a conveyor belt. Our whole story is minimizing stress to embryos and eggs, he says.

Thompson hopes someday, when doctors collect eggs from a womans ovaries, theyll be deposited directly into a micro-cradle and, from there, be nannied by robots until theyre healthy embryos. Thats my vision, he says.https://wp.technologyreview.com/wp-content/uploads/2023/04/better-injection.mp4A video taken through a microscope shows a microneedle penetrating eggs held in 3D-printed pods, or cradles. An egg is about 0.1 mm across.

FERTILIS

MIT Technology Review found one company, AutoIVF, a spinout from a Massachusetts General HospitalHarvard University microfluidics lab, that has won more than $4 million in federal grants to develop such an egg-collecting system. It calls the technology OvaReady.

Egg collection happens after a patient is treated with fertility hormones. Then a doctor uses a vacuum-powered probe to hoover up eggs that have ripened in the ovaries. Since theyre floating in liquid debris and encased in protective tissue, an embryologist needs to manually find each one and denude it by gently cleaning it with a glass straw.

An AutoIVF executive, Emre Ozkumur, declined to discuss the projectthe company wants to stay under the radar a little bit longer, he saysbut its grant and patent documents suggest it is testing a device that can spot and isolate eggs and then automatically strip them of surrounding tissue, perhaps by swishing them through something that resembles a microscopic cheese grater.

Once an egg is in hand, doctors need to match it with a sperm cell. To help them pick the right one, Alejandro Chavez-Badiola, a fertility doctor based in Mexico, started a company, IVF 2.0, that developed software to rank and analyze sperm swimming in a dish. Its similar to computer-vision programs that track sports players as they run, collide, and switch directions on a pitch.

The job is to identify healthy sperm by assessing their shape and seeing how well they swim. Motility, says Chavez-Badiola, is the ultimate expression of sperm health and normality. While a person can only keep an eye on a few sperm at one time, a computer doesnt face that limit. We humans are good at channeling our attention to a single point. We can assess five or 10 sperm, but you cant do 50, says Chavez-Badiola.

His IVF clinic is running a head-to-head study of human- and computer-picked sperm, to see which lead to more babies. So far, the computer holds a small edge.

We dont claim its better than a human, but we do claim its just as good. And it never gets tired. A human has to be good at 8 a.m., after coffee, after having an argument on the phone, he says.

Chavez-Badiola says such software will be the brains to command future automated labs. This year, he sold the rights to use his sperm-tracking program to Conceivable Life Sciences, another IVF automation startup being formed in New York where Chavez-Badiola will act as chief product officer. Also joining the company is Jacques Cohen, a celebrated embryologist who once worked at the British clinic where the first IVF baby was born in 1978.https://wp.technologyreview.com/wp-content/uploads/2023/04/Conceivable-720.mp4A computer system developed by IVF 2.0 tracks and grades sperm as they swim, using image-recognition software.

CONCEIVABLE

Conceivable plans to create an autonomous robotic workstation that can fertilize eggs and cultivate embryos, and it hopes to demonstrate all the key steps this year. But Cohen allows that automation could take a while to become reality. It will happen step by step, he says. Even things that seem obvious take 10 years to catch on, and 20 to become routine.

The investors behind Conceivable think they can cash in by expanding the use of IVF. Its nearly certain that the IVF industry could grow to five or 10 times its current size. In the US, fewer than 2% of kids are born this way, but in Denmark, where the procedure is free and encouraged, the figure is near 10%.

That is the true demand, says Alan Murray, an entrepreneur with a background in software and co-working spaces who cofounded Conceivable with his business partner, Joshua Abram. The challenge is that these wonderful rich and eccentric countries can do it, but the rest of the world cannot. But they have demonstrated the true human need, he says. What they have done with money, we need to do with technology.

Murray estimates the average IVF baby in the US costs $83,000 if you include failed attempts, which are common. He says his companys objective is to lower the cost by 70%, something he says can happen if success rates increase.

But its not a given that robots will reduce the cost of IVF or that any savings will be passed on to patients. Rita Vassena, an advisor to Conceivable and CEO at Fecundis, a fertility science company, says the field has a history of introducing innovations without appreciably increasing pregnancy rates. The trend [is] toward piling up tests and technologies rather than a true effort to lower access barriers, she says.

Last fall, the researchers at Overture and doctors at New Hope published a description of their work with the robot, claiming that two patients had become pregnant. That was done after gaining ethics approval for the study, says John Zhang, founder of New Hope and senior author of the report.

Both those children have now been born, says Jenny Lu, the egg donation coordinator at New Hope. MIT Technology Review was able to speak to the father of one of the children.

Its wild, isnt it, said the father, who asked to remain anonymous. They said up until now it had always been done manually.

He said he and his partner had tried IVF several times before, without success. Both cases of robot injection involved donor eggs, which were provided to the patients for free (they can cost $15,000 otherwise). In each case, after being fertilized and grown into embryos, they were implanted in the uterus of the patient.

Donor eggs are most often used when a patient is older, in her 40s, and cant get pregnant otherwise.

Since automation wont directly solve the problem of aging eggs, an IVF lab-in-a-box wont fix this intractable reason that fertility treatments fail. However, automation could let doctors begin precisely measuring what they do, allowing them to fine-tune their procedures. Even a small increase in success rates could mean tens of thousands of extra babies every year.

Kathleen Miller, chief scientist of Innovation Fertility, a chain of clinics in the southern US, says her centers are now using computer-vision systems to study time-lapse videos of growing embryos and trying to see if any data explain why some become babies and others dont. Were putting it into models, and the question is Tell me something I dont know, she says.

Were going to see an evolution of what an embryologist is, Miller predicts. Right now, they are technicians, but theyre going to be data scientists.

For some proponents of IVF automation, an even wilder future awaits. By giving over conception to machines, automation could speed the introduction of still-controversial techniques such as genome editing, or advanced methods of creating eggs from stem cells.

Although Munn says Overture Life has no plans to modify the genetic makeup of children, he allows it would be a simple matter to use the sperm-injecting robot for that purpose, since it could dispense precise amounts of gene-editing chemicals into an egg. It should be very easy to add to the machine, he says.

Even more speculative technology is on the horizon. Fertility machines could gradually evolve into artificial wombs, with children gestated in scientific centers until birth. I do believe we are going to get there, says Thompson. There is credible evidence that what we thought was impossible is not so impossible.

Others imagine that robots could eventually be shot into outer space, stocked with eggs and sperm held in a glassy state of stasis. After a thousand-year journey to a distant planet, such machines might boot up and create a new society of humans.

Its all part of the goal of creating more people, and not just here on Earth. There are people thinking that humankind should be an interplanetary species, and human lifetimes are not going to be enough to reach out to these worlds, says Chavez-Badiola. Part of the job of a scientist is to keep dreaming.

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The first babies conceived with a sperm-injecting robot have been born - MIT Technology Review

Loss of autism-linked gene dampens social interactions in animals – Spectrum – Autism Research News

Stranger danger: Unlike wildtype mice (top row), those lacking GIGYF1 (bottom row) avoid unfamiliar mice (right) in favor of those they know (left), position heat maps show.

Mice and zebrafish that lack the autism-linked gene GIGYF1 show atypical social behaviors, according to a new study. The findings tie variations in the gene to social traits in autistic people, the researchers say.

Among the genes strongly linked to autism, GIGYF1 ranks as the second most commonly mutated one in people with autism and related neurodevelopmental conditions. But little is known about the genes contribution to autism traits, says Bo Xiong, professor of forensic medicine at Huazhong University of Science and Technology in China. Initial findings point to a role in regulating social behavior: Deleting the gene blunts social memory in mice, through mechanisms thought to be mediated by impaired insulin signaling.

GIGYF1 is also implicated in other pathways including autophagy and mRNA regulation that are often altered in people with neurodevelopmental conditions, says Jeremy Veenstra-VanderWeele, professor of developmental psychiatry at Columbia University, who was not involved in the study. But it had not previously been rigorously studied for its impact on neurodevelopment and downstream behavior, he says.

Xiong and his colleagues combed sequencing data from SPARK, a project that aims to collect genetic and clinical information from 50,000 families that have at least one child with autism. (SPARK is funded by the Simons Foundation, Spectrums parent organization).

They identified seven new GIGYF1 mutations and pooled the data with 19 previously reported variants. Cross-referencing with clinical information revealed that 86 percent of people with GIGYF1 mutations have autism. A similar proportion have communication difficulties and social phobia, alongside sleep problems and delayed speech.

Zebrafish embryos edited via CRISPR to lack GIGYF1 develop more slowly than their wildtype counterparts, Xiong and his colleagues found. As adults, the fish are more anxious and less willing to socialize.

Zebrafish are typically highly sociable: They rarely swim alone, preferring to travel in clusters called shoals. When placed in a three-chambered enclosure with a fish at one end and an empty chamber at the other, wildtype fish will opt for company. But fish lacking GIGYF1 prefer solitude and appear anxious, frequently darting around the tank. Whats more, they form looser shoals, maintaining more distance between themselves and others.

Mice engineered to express just one copy of the GIGYF1 gene also display social deficits. When the researchers tested for social novelty a mouses inclination to investigate a stranger over those it already knows the mutant mice stayed near the familiar mouse. GIGYF1 deletion also triggered repetitive behaviors, one of the core traits of autism.

The study plays to the strengths of each model, says Julia Dallman, associate professor of biology at the University of Miami in Florida, who was not involved in the study. For example, delayed embryogenesis is easier to spot in zebrafish, which develop outside their mothers body, than in mice. These different models can provide complementary windows of insight into gene function, she says.

But the fish could be tweaked to better reflect the genetics of autism, says Dallman. The study used zebrafish lacking both copies of GIGYF1, but people with the condition have one mutated copy and one functional copy.

Disrupting both gene copies is a good way to understand the biological importance of GIGYF1 but does not model the human condition, Veenstra-VanderWeele agrees.

Mice missing a copy of the gene in only their excitatory neurons still showed repetitive behaviors and impairments in social novelty. Yet deleting a copy of GIGYF1 in only inhibitory neurons triggered a different set of traits, including heightened anxiety and poorer cognition, suggesting that GIGYF1 plays distinct roles in different cell types.

The findings were published 14 March in Biological Psychiatry.

Exactly how GIGYF1 variants cause changes in social behavior remains an open question. Right now, we only know a small piece of the whole picture. We still dont know the exact molecular mechanisms by which these mutations cause behavioral defects, Xiong says.

Initial findings hint at changes in neuronal communication. By screening for transcripts and proteins that bind to GIGYF1, the researchers identified hundreds of downstream targets, including several involved in synaptic transmission. They are now harnessing electrophysiology to see how GIGYF1 deletion in mice influences neuronal chatter.

Because GIGYF1s function appears to be conserved among animal models, it would be interesting to see whether similar effects are seen in organoids and stem cells, says Ctia Igreja, a researcher at the Max Planck Institute for Biology in Tbingen, Germany, who was not involved in the study. If so, scientists may be able to pinpoint the GIGYF1s molecular mechanisms and identify potential therapeutic interventions that alleviate GIGYF1 deficiency, she adds.

Cite this article: https://doi.org/10.53053/GPMX9020

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Loss of autism-linked gene dampens social interactions in animals - Spectrum - Autism Research News

A burst of genomic innovation at the origin of placental mammals … – Nature.com

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A burst of genomic innovation at the origin of placental mammals ... - Nature.com