All posts by medical

Deploying and evaluating a machine learning intervention to improveclinical care and patient outcomes is a key step in moving clinical deterioration models from byte to bedside, according to a June 13 editorial in Critical Care Medicine that comments on a Mount Sinai study published in the same issue. The main study found that hospitalized patients were 43 percent more likely to have their care escalated and significantly less likely to die if their care team received AI-generated alerts signaling adverse changes in their health.

We wanted to see if quick alerts made by AI and machine learning, trained on many different types of patient data, could help reduce both how often patients need intensive care and their chances of dying in the hospital. Traditionally, we have relied on older manual methods such as the Modified Early Warning Score (MEWS) to predict clinical deterioration. However, our study shows automated machine learning algorithm scores that trigger evaluation by the provider can outperform these earlier methods in accurately predicting this decline. Importantly, it allows for earlier intervention, which could save more lives."

Matthew A. Levin, MD, lead study author, Professor of Anesthesiology, Perioperative and Pain Medicine, and Genetics and Genomic Sciences, at Icahn Mount Sinai, and Director of Clinical Data Science at The Mount Sinai Hospital

The non-randomized, prospective study looked at 2,740 adult patients who were admitted to four medical-surgical units at The Mount Sinai Hospital in New York. The patients were split into two groups: one that received real-time alerts based on the predicted likelihood of deterioration, sent directly to their nurses and physicians or a "rapid response team" of intensive care physicians, and another group where alerts were created but not sent. In the units where the alerts were suppressed, patients who met standard deterioration criteria received urgent interventions from the rapid response team.

Additional findings in the intervention group demonstrated that patients:

"Our research shows that real-time alerts using machine learning can substantially improve patient outcomes," says senior study author David L. Reich, MD, President of The Mount Sinai Hospital and Mount Sinai Queens, the Horace W. Goldsmith Professor of Anesthesiology, and Professor of Artificial Intelligence and Human Health at Icahn Mount Sinai. "These models are accurate and timely aids to clinical decision-making that help us bring the right team to the right patient at the right time. We think of these as 'augmented intelligence' tools that speed in-person clinical evaluations by our physicians and nurses and prompt the treatments that keep our patients safer. These are key steps toward the goal of becoming a learning health system."

The study was terminated early due to the COVID-19 pandemic. The algorithm has been deployed on all stepdown units within The Mount Sinai Hospital, using a simplified workflow. A stepdown unit is a specialized area in the hospital where patients who are stable but still require close monitoring and care are placed. It's a step between the intensive care unit (ICU) and a general hospital area, ensuring that patients receive the right level of attention as they recover.

A team of intensive care physicians visits the 15 patients with the highest prediction scores every day and makes treatment recommendations to the doctors and nurses caring for the patient. As the algorithm is continually retrained on larger numbers of patients over time, the assessments by the intensive care physicians serve as the gold standard of correctness, and the algorithm becomes more accurate through reinforcement learning.

In addition to this clinical deterioration algorithm, the researchers have developed and deployed 15 additional AI-based clinical decision support tools throughout the Mount Sinai Health System.

The Mount Sinai paper is titled "Real-Time Machine Learning Alerts to Prevent Escalation of Care: A Nonrandomized Clustered Pragmatic Clinical Trial." The remaining authors of the paper, all with Icahn Mount Sinai except where indicated, are Arash Kia, MD, MSc; Prem Timsina, PhD; Fu-yuan Cheng, MS; Kim-Anh-Nhi Nguyen, MS; Roopa Kohli-Seth, MD; Hung-Mo Lin, ScD (Yale University); Yuxia Ouyang, PhD; and Robert Freeman, RN, MSN, NE-BC.

Source:

Journal reference:

Levin, M. A., et al. (2024). Real-Time Machine Learning Alerts to Prevent Escalation of Care: A Nonrandomized Clustered Pragmatic Clinical Trial.Critical Care Medicine. doi.org/10.1097/CCM.0000000000006243.

Link:

AI-driven alerts improve patient care escalation and survival rates in hospitals - News-Medical.Net

Cell Biology

A new way to measure ageing and disease risk with the protein aggregation clock – EurekAlert

June 18, 2024 medical

image:

Visualization of a protein aggregation clock

Credit: ill./: Nike Heinss / JGU

--JOINT PRESS RELEASE OF THE INSTITUTE OF MOLECULAR BIOLOGY (IMB) AND JOHANNES GUTENBERG UNIVERSITY MAINZ --

Could measuring protein clumps in our cells be a new way to find out our risk of getting age-related diseases? Professor Dorothee Dormann and Professor Edward Lemke of Johannes Gutenberg University Mainz (JGU), who are also adjunct directors at the Institute of Molecular Biology (IMB) in Mainz, propose the concept of a "protein aggregation clock" to measure ageing and health in a new perspective article published inNature Cell Biology.

As we age, the DNA and proteins that make up our bodies gradually undergo changes that cause our bodies to no longer work as well as before. This in turn makes us more prone to getting age-related diseases, such as cardiovascular disease, cancer, and Alzheimer's disease. One important change is that the proteins in our cells can sometimes become misfolded and clump together to form aggregates, so-called amyloids. Misfolding and aggregation can happen to any protein, but a specific group of proteins known as intrinsically disordered proteins (IDPs) are especially prone to forming amyloids. IDPs make up around 30 percent of the proteins in our cells and they are characterized by having no fixed structure. Instead, they are flexible and dynamic, flopping around like strands of cooked spaghetti.

While the molecular mechanisms are widely debated and an important aspect of basic research, scientists know that aggregates formed from IDPs tend to accumulate in many long-lived cells such as neurons or muscle cells as we age. Moreover, they can cause many age-related diseases, particularly neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Thus, having many aggregates in a cell could be an indicator of how unhealthy the cell is or if a person is likely to develop an age-related disease soon. In their recently published article, Dormann and Lemke propose that IDP aggregation could be used as a biological "clock" to measure a person's health and age.

If developed further into a sensitive diagnostic test, a protein aggregation clock could be extremely useful. Firstly, doctors could use it to help diagnose age-related diseases at very early stages or identify people who are not yet sick but have a higher risk of developing disease as they age. This would allow them to be given preventative treatments before they develop severe disease. Secondly, scientists could use it to assess the effects of new experimental treatments to reduce protein aggregation in order to prevent or delay age-related diseases.

"In practice, we are still far away from a routine diagnostic test, and it is important that we improve our understanding of the fundamental mechanisms leading to IDP aggregation", said Dormann. "However, we want to stimulate thinking and research in the direction of studying protein aggregates to measure biological ageing processes," Lemke added. "We are optimistic that in the future we will be able to overcome the current challenges of reading a protein aggregation clock through more research on IDP dynamics and making further technological developments."

Although there are other "clocks" to measure ageing and health, most of them are based on nucleic acids like DNA. Dormann and Lemke think that a biological clock based on proteins would be a useful complement to these existing clocks, as proteins are among the most abundant molecules in cells and are crucial for all cellular functions. With the help of such a protein aggregation clock, they hope that scientists and doctors will be able to move one step closer towards helping people age healthily and preventing age-related diseases.

With their research, Dorothee Dormann and Edward Lemke contribute to the Center for Healthy Ageing (CHA), a virtual research center launched in 2021. The CHA brings together scientists in basic and clinical research from across Mainz who focus on ageing and age-related diseases. Their findings are to be used to promote healthy ageing and to find treatments that help prevent or cure age-related diseases.

How Flow Cytometry Spurred Cell Biology – The Scientist

June 18, 2024 medical

In the mid-twentieth century, Louis Kamentsky, an engineer at Columbia University at the time, searched for a convenient approach for differentiating cancerous and normal cells. He modified a cell counting device that arranged samples into a single-file line by mounting an oscilloscope to measure their absorption and scattering of light as the cells passed through a flow tube.1-4

Around the same time, Mack Fulwyler, an engineer working at Los Alamos National Laboratory, needed to separate particles, so he drew on existing techniques to create droplets to separate cells from a flow stream based upon charge that correlated to their volume.5,6 These approaches laid the foundation for flow cytometry, which is now a staple in biological research.

All of the methodology that existed before flow cytometry suddenly could be applied to the single cell, said Thomas Jovin, a biophysicist at the Max Plank Institute who developed advancements to the instruments in the 1970s as flow cytometry emerged as a major player in the research space.

Flow cytometry entered biomedical research in immunology and cancer labs out of initial interests in separating and counting cells in a mixed population, but groups also developed instruments purely to characterize cells.7,8 The flow cytometer and the flow sorter are not separate instruments, explained Jovin. The flow sorter requires that it be a flow cytometer at the same time because you have to make the same measurement. Its just that youre using it to process the cell after it has gone through the detection system. Today, instruments that both analyze and sort cells are referred to as flow sorters and those that do not are called flow analyzers.

Initially, flow measurements were based on fluorescent light emitted from dyes that researchers used to identify genetic material, but soon after, scientist also determined the cells size based on its light-scatter patterns.9, 10 These first instruments used lamps as their light source, but this soon changed. The lasers came along very quickly, Jovin said. They were important because you could focus a laser down to microns, whereas you cant do that with a large optical source like a lamp.

You can measure essentially anything in, on, or produced by a cell at a high rate of speed in a heterogeneous solution at a rapid rate.

Jonni Moore, University of Pennsylvania

Soon, researchers added more lasers to their instruments to expand the colors they could detect and developed methods to analyze and sort cells labeled with two fluorescent molecules.11,12 With the help of dichroic mirrors and bandpass filters that reflect and isolate, respectively, specific wavelengths of light to dedicated detectors, scientists could funnel the signal from multiple parameters to specific detectors to study more features of their samples.13

As the parameters that flow systems used expanded, data poured out of labs globally. You have a lot of signals that have been processed in real time, and you have to make decisions, in the case of the sorter, in real time, because otherwise your cells wont be there anymore, Jovin said. The only way to do that was by computation. Jovin and his team developed a computer-controlled flow cytometry instrument that facilitated the data analysis process.14

With the ability to rapidly assay and separate cells of interest from a mixed population based on multiple parameters, flow cytometry rivaled its predecessor, microscopy, in the study of cells. Jonni Moore, an immunologist and the director of the shared resource laboratory at the University of Pennsylvania, recalled using a flow cytometer for the first time after only having used a fluorescent microscope during graduate school. I thought I had died and gone to heaven, she said. According to Moore, classifying T lymphocytes on the microscope took several hours longer than the seconds it took her to analyze thousands of cells by flow cytometry. It really allowed me to ask a lot more questions in my research, Moore said.

While some research focused on the ability to analyze cell properties with flow systems, many groups used flow cytometry for its sorting capacity.15 However, as scientists developed new dyes, they could use flow cytometry to analyze more cellular parameters, such as mitochondrial activity and the quantity of particular receptors on cells.16-18

Flow cytometry analysis expanded into the clinical setting by helping streamline the quantification of CD4+ T cells during the human immunodeficiency virus (HIV) epidemic. Compared to microscopy, flow cytometry analysis was faster and more reliable.19, 20 Over the next 30 plus years, analytical cytometry exploded as we realized that we could measure virtually anything in, on, or produced by a cell, in multiple populations at the same time, Moore said.

Today, researchers still use flow cytometry to analyze a population of cells based on the presence of surface markers tagged with a fluorescent antibody or other probe. However, these analyzers can also use dyes and other techniques to investigate cellular functions, such as metabolism and protein secretion.21, 22 Researchers can assess cell proliferation and death with flow cytometry by measuring the dilution of dye or uptake of it.23, 24 While various individual methods exist that can measure the amount of protein or other mediators produced by cells or their activity, they require researchers to do them separately. The technology of flow cytometry, as it exists today, allows you to do all of that together, Moore said.

However, despite measuring an entire population of cells, flow cytometry is a single-cell technique. Because youve dissociated tissues and youve put these objects into kind of single file, youve lost where theyre seated next to one another, explained Lisa Nichols, the director of the flow cytometry facility at Stanford University. That level of spatial information requires microscopy. Nonetheless, flow cytometry produces high dimensional information on individual cells, and in contrast to other single cell techniques, does so more quickly on larger populations. Flow cytometry can actually go through and get you the results from millions of cells in a matter of minutes, Nichols said.

A high-throughput, single-cell method enables researchers to assess several cell parameters simultaneously with the help of lasers.

Scientists prepare samples as single cell suspensions and labels components of interest with fluorescent antibodies or other probes. The cytometer uses pumps to draw the sample through tubing to analyze it.

Using hydrodynamic focusing the instrument injects the sample into a fast-moving stream of fluid that funnels the sample single file through a narrow channel.

The channel leads to a point where the individual cells intersect with one or more lasers. The measured sample is deposited into a waste receptable after it passes this point.

As a cell begins to cross the laser beam, it scatters light. Light that mostly crosses the cell is detected as forward scatter and measures the cells size. Light that encounters obstacles in the cell changes direction and is detected by a side scatter detector, indicating the granularity of the cell. If the lasers excite fluorescent molecules in the cell, the emitted light is channeled through dichroic mirrors and bandpass filters to isolate specific wavelengths that meet detectors specific for those wavelengths.

Ashleigh Campsall

Fluorescent probes have come a long way since the 1960s. Researchers have added lasers and probes that recognize the violet and infrared range, as well as expanded probes into quantum dots, or inorganic nanocrystals.25-27 These additions greatly expanded the available colors for researchers to use, but introduced new challenges, as more color parameters increased the likelihood of overlapping spectra from these probes. As those overlaps increase, your ability to resolve very dim signals is compromised, said Nichols.

In traditional cytometers, to minimize overlapping signals from multiple fluorescent probes, the instrument doesnt use all of the light energy that a molecule emits. We take that whole spectrum, and we take a slice of it. And we measure that slice, said Timothy Bushnell, the flow cytometry core director at the University of Rochester. Mirrors and bandpass filters only permit a certain range of wavelengths to reach their detectors, which usually correspond to the peak emission spectra of commonly used probes.

While this method simplifies the problem of overlapping spectra in multiparameter experiments, it eliminates potentially valuable information. This prompted the development of spectral analyzers, which capture a fluorescent molecules full emission spectrum.28, 29 We now get the whole picture of what that spectrum looks like, Bushnell said.

Using single-labeled and unlabeled controls, the instrument accesses the entire spectrum of these samples to calculate the distinct emission spectra of each color from the mixed readout. The introduction of spectral flow cytometry enabled researchers to conduct multidimensional analyses. It lets you have more flexibility in what fluorochromes you use because youre not confined to this one detector, one fluorochrome phenomenon, Bushnell said. These advancements come in tandem with improved detector technology, such as swapping out current photomultiplier tubes for silica-based models that pick up longer wavelengths better.30

While flow cytometry enables a high dimensional analysis of individual cells within a population, researchers cannot see where their target of interest is within or on the cell. Our resolution is basically a dot on a plot, Bushnell said. This type of resolution traditionally had to be done with microscopy, but at the expense of time and quantity of cells analyzed. The introduction of imaging cytometry is changing that.31

Image flow cytometers capture an image of a cell as it flows through transit. We could combine the power of knowing where something is, so seeing where it is in the cell, with the statistics that flow can give you, Bushnell said.

Anything you can actually make into a particulate solution and put a fluorescent tag on, you can now measure.

Lisa Nichols, Stanford University

You are limited by the fact that it is flow, so these things are moving, Nichols said. Youre never going to get the resolution youre going to get with a microscope where its sitting still. Although not in the resolution possible with microscopy, the photographs provide additional information about where signal originates from within and on a sample.

Additionally, having been available for flow cytometry analyzers for more than a decade, this imaging capacity is becoming available for flow cytometry sorters.32 One setback in this application is the ability to take an image rapidly and interpret that image to make a decision for a falling samples fate. Things are moving so fast, you need to do one of two things, Nichols said. You either have to have a whole bunch of predetermined features that youre looking for that can be matched to each individual cell, or you have to have AI and computing technologies.

Not only will the rapid computing power of machine learning be necessary for quick sorting decisions, but as flow cytometry becomes increasingly multiparametric, researchers forgo the traditional bivariate plots for computational analyses already used in single-cell sequencing analyses.33-35 When you look at dot plots, two by twos, you only ever see the elephant foot. You can never see the whole elephant by doing that, said Moore. This opens the opportunity to explore and interpret data in completely new ways, possibly by introducing previously overlooked findings in datasets.

Beyond crunching the numbers in individual experiments, machine learning may offer the ability to account for variations between experiments, or batch effects. Even more broadly, these intelligent tools may be imperative for comparing and combining analyses between different institutions, confidently enabling collaborations.36

Flow cytometry is not restricted to cells. Anything you can actually make into a particulate solution and put a fluorescent tag on, you can now measure, said Nichols. With the help of microfluidic technology, instruments analyze everything from metal nanoparticles and microplastics to exosomes.37-40 These droplets have also paved the way for studying materials typically released from cells, including antibodies and other proteins and may soon be compatible with existing flow systems.41-43 Meanwhile, specially developed cytometers with the ability to more accurately measure the small scale of microparticles advance the research potential of this field.44, 45 All of these developments aim to push flow cytometry to its next limit.

References

Read more from the original source:
How Flow Cytometry Spurred Cell Biology - The Scientist

Cell Biology

Building Cells from the Bottom Up – The Scientist

June 18, 2024 medical

In pursuit of a deeper understanding of cellular life, biologists use patterns in data as a springboard for probing specific elements in complex systems. Delete a gene here; express a protein there; and through these meticulous molecular manipulations, the components necessity and sufficiency emerges, bringing clues about the nuts and bolts of cellular functioning. In recent decades, scientists from fields outside of the life sciences have entered the biological arena, bringing with them a potpourri of alternative perspectives and approaches for studying complex systems.

Cees Dekker, a biophysicist at Delft University of Technology (TU Delft), is part of a growing community of synthetic biologists who are exploring the design principles of living systems by engineering cells from the bottom up.1 Just by engineering it, you are faced with certain problems that you didnt realize when you were studying the system top-down, said Dekker, echoing a sentiment put forth by the late physicist Richard Feynman, who once said, What I cannot create, I do not understand.

Just by engineering it, you are faced with certain problems that you didnt realize when you were studying the system top-down.

Cees Dekker, Delft University of Technology

In the future, synthetic cells may become factories that produce proteins and deliver drugs to treat human disease, but for now, they reside in the realm of curiosity-driven research with the goal of answering fundamental questions about biology. Dekkers dream is to create a synthetic cell from a minimal collection of functional components.2 However, en route to this goal, he needed to learn how to build biology, and how to become a biologist, from the bottom up.

What I appreciated about [Dekker] was that he was always going for the big aim, for the very juicy target, said Nicola De Franceschi, a molecular biologist at the International Institute of Molecular Mechanisms and Machines and former postdoctoral researcher in Dekkers team.

At the end of the 1990s, a 40-year-old Dekker reflected on what he wanted to do with the next 30 or so years of his career. Up until then, he researched solid-state physics and nanotechnology; he worked on superconductors, explored how electrons traverse carbon nanotubes, and developed the first carbon nanotube transistor.3 Although he found the work rewarding, his interests were changing along with the zeitgeist of the turn of the century. There was a mood that solid-state physics is 20th century, and in the 21st century, the big open questions are really in biology, said Dekker. Fascinated by the immense complexity of cellular life, he rerouted his research agenda.

Cees Dekker, a biophysicist at Delft University of Technology, started his career working on quantum effects in semiconductors. Now, he works to build fully autonomous synthetic cells from minimal components.

Wilmar Dik

A curiosity about molecular motorsproteins that gobble up energy molecules to fuel their transport throughout the celldrove him to attend an ATP synthase conference. He eagerly sat through every talk. I didnt know anything about it, but I was totally fascinated by it, said Dekker, who hit the ground running. He added, I even started studying first year cell biology books.

To support this transformation, his lab needed a makeover: ultra-high vacuum millikelvin scanning tunneling microscopes made way for polymerase chain reaction machines and protein purification reagents. However, Dekker didnt leave everything from his past behind; he leveraged his background in nanotechnology to ease his entry into the biological sphere. His team has since developed nanotechnology-based single-molecule techniques to sequence single proteins, tease apart DNA-protein interactions, and probe how bacteria organize and distribute their chromosomes during replication.4-6

In the last decade, Dekker expanded his research portfolio further into the synthetic world to get closer to understanding natures blueprint. Im intrigued to understand the spatial and temporal organization of molecules that together form a system that has the attributes of life. Single DNA molecules are not alive; single proteins are not alive; but the combination of these hundreds of components makes an object that can grow, divide, sustain itself, evolve over time, and all that. I find that intriguing, said Dekker.

In 2016, biotechnologist Craig Venter and his colleagues at the eponymous J. Craig Venter Institute stripped down the genome of Mycoplasma mycoides to the bare minimum 473 genes required to sustain a living bacterium.7,8 After chemically synthesizing the genome, they transplanted it into an empty host. And then there was life! These synthetic microbes exhibited behaviors of living bacteria, including colony formation and continuous self-replication.

This top-down approach of genetic plug and play to filter out nonessential genes gives scientists new insights into the basic biology of life and whole-genome design. However, complex systems are incompletely defined or understood, as evidenced by the 149 genes of unknown function in Venters minimal synthetic genome. Flipping the script, some scientists are building synthetic cells from the bottom-up to ask fundamental questions in biology. Dekkers current quest is to discover the minimal components a cell needs to divide, a fundamental feature of cell life.

I even started studying first year cell biology books.

Cees Dekker, Delft University of Technology

He was, from the beginning on, someone who looked at this problem really from an engineering perspective, said Oskar Staufer, a biophysicist at the Leibniz Institute for New Materials and a peer in the synthetic biology field. Staufer noted that Dekkers techniques for building synthetic cells influenced his own research.

The first step in building a synthetic cell was to create a chassis to contain the synthetic machinery.9 Liposomes fit the bill since they are versatile, efficient, and easy to assemble. To build liposomes in the lab at scale, Dekker harkened back to his physics days where he created new equipment to test hypotheses. He and his team engineered a microfluidic system to encase an aqueous solution in a lipid membrane.10 A previous study showed the potential of such an approach using the alcohol oleic acid to shuttle lipids along as they developed into an outer bilayer.11 However, oleic acid takes more than 15 hours to separate from the newly formed liposome, a timeframe that could render potential cargo useless due to molecular and enzymatic degradation.

With speed in mind, Dekker and his team explored alternative lipid-carrying solutions and landed on the alcohol 1-octanol. Like a miniaturized bubble blowing machine, a solution consisting of 1-octanol and dissolved lipids envelopes an aqueous phase, and as this passes through a second aqueous phase, a droplet gets pinched off and dumped into a sea of vesicles. Within minutes, the encasing solution begins to separate; the dissolved lipids assemble into an outer membrane and the 1-octanol pools to the side of the vesicle before separating completely from the nascent liposome. They called the method octanol-assisted liposome assembly.

[Dekker] sees molecules as machines that perform functions, and that is not the typical perspective a biologist would have, said Stauffer. Because he perceives them as a machine, he can also take a screwdriver and start to tweak them and modify them to do certain functions.

To generate synthetic cells at scale, Dekker and his team created a novel microfluidic device. The octanol-assisted liposome assembly system produces a versatile chassis for shuttling molecular machineries.

Siddharth Deshpande, Cees Dekker

Dekker has been focusing on incorporating synthetic modules for cell division into his liposomes, borrowing inspiration from living cells along the way. Dekker is not alone in his efforts; others have found that a cocktail of five proteins successfully assembled a ring-shaped structure that emerges in the build up to bacterial cell division; however, these cell mimics have not achieved autonomous cell division.12

In what Staufer said was a major breakthrough for synthetic biology, Dekker and his team recently published their findings on a simple, straightforward module capable of inducing the complete separation of synthetic daughter cells, making it the first synthetic system capable of autonomous cell division.13,14 To achieve this milestone, they incorporated external DNA nanoparticles to coerce the liposomes into the classic dumbbell formation that occurs during late-stage natural cell division.15Alongside these synthetic membrane shapers, Dekker and his team added the bacterial protein dynamin A, which accumulates at points of high curvaturesuch as the neck of the dumbbell liposomeand triggers full separation of the membrane.

He was able to focus and also helped me to focus on the real objective, and that was very inspiring, said De Franceschi, who helped build these synthetic systems for cell division.

Researchers interest in building biological complexity from the ground up has burgeoned over the last two decades. This synthetic cell effort is something that no single group can do. Its really a joint effort. Its super multidisciplinary, said Dekker, who is a member of the European Synthetic Cell Initiative, which is coordinated by TU Delft.

Molecular puppeteers are developing minimal synthetic modules to mimic other important cell functions, including chromosomal configuration, transcription and translation, and DNA replication and segregation. The next phase is going to be the most challenging one, said Dekker. On their own, each system presents a unique set of considerations and challenges. However, scientists must also find a way to integrate the different modules to maintain the spatial and temporal fidelity that is required to build a prototype synthetic cell.13 Thats our dream, said Dekker, who hopes to adopt emerging artificial intelligence and directed evolution techniques to tackle these challenges.

Given Dekkers experience with the protein mechanics of cell division and the organization of DNA, Staufer noted, That will be very important when one aims to achieve synthetic cell division, and the division of any kind of a genetic polymermost likely DNAinto daughter cells. That combination of expertise is very rare in the field.

References

The rest is here:
Building Cells from the Bottom Up - The Scientist

Cell Biology

From Code to Creature – The Scientist

June 18, 2024 medical

It began with little pieces of embryos scooting around in a dish. In 1998, these unassuming cells caught the attention of Michael Levin, then a postdoctoral researcher studying cell biology at Harvard University. He recalled simply recording a video before tucking the memory away. Nearly two decades later, Levin, now a developmental and synthetic biologist at Tufts University, experienced a sense of dj vu. He observed that as a student transplanted tissues from one embryo to another, some loose cells swam free in the dish.

Levin had a keen interest in the collective intelligence of cells, tissues, organs, and artificial constructs within regenerative medicine, and he wondered if he could explore the plasticity and harness the untapped capabilities of these swirling embryonic stem cells. At that point, I started thinking that this is probably an amazing biorobotics platform, recalled Levin. He rushed to describe this idea to Douglas Blackiston, a developmental and synthetic biologist at Tufts University who worked alongside Levin.

At the time, Blackiston was conducting plasticity research to restore vision in blind African clawed frog tadpoles, Xenopus laevis, a model organism used to understand development. Blackiston transplanted the eyes to unusual places, such as the back of the head or even the tail, to test the integration of transplanted sensory organs.1 The eye axons extended to either the gut or spinal cord. In a display of dynamic plasticity, transplanted eyes on the tail that extended an optic nerve into the spinal cord restored the tadpoles vision.2

Levin and Blackiston decided to explore this remarkable ability to adapt to changes in function and connectivity, a key feature for regenerative medicine applications. By leveraging natures proficiency in building and rebuilding, they wanted to understand the limits of cell and tissue plasticity outside of their natural contexts to perform new functions.

Its more like craftsmanship than it is science at times because youre doing very fine manipulations.

Douglas Blackiston, Tufts University

In a similar vein, Josh Bongard, an evolutionary roboticist at the University of Vermont and Levins longtime colleague, pondered how robots could evolve like animals. He wanted to apply biological evolution to a machine by tinkering with the brains and bodies of robots and explored this idea with Sam Kriegman, then a graduate student in Bongards group and now an assistant professor at Northwestern University. Kriegman used evolutionary algorithms and artificial intelligence (AI) to simulate biological evolution in a virtual creature before teaming up with engineers to construct a physical version.

Levins biology and Bongards computational work intersected for a program called Lifelong Learning Machines(L2M). With this project, the researchers aimed to understand how biological systems adapt to their environments and integrate these living algorithms into robotics. Together, the team dovetailed developmental biology using different biological tissues as the building blocks and AI programs to generate synthetic lifeforms as the blueprints for biological robots (biobots), also known as xenobots.

At the beginning of this project, the team planned to build lifelong learning machines from AI systems, which was a challenging enterprise. Kriegman used evolutionary algorithms to design and evolve synthetic lifeforms in simulation, but the major stumbling block lay in translating these designs to the physical world. During weekly virtual meetings between the biologists and roboticists, Bongard recalled explaining to the biologist group what was easy and hard for roboticists to do; the conventional materials used to construct robots werent working.

Josh Bongard, Michael Levin, Douglas Blackiston, and Sam Kriegman (left to right) teamed up to build synthetic organisms with an unlikely building material: frog stem cells.

Its really difficult to realize [this idea] in hardware; no ones figured out how to create a robot that crawls out of a 3D printer, explained Kriegman. We tried to build robots out of rubber, 3D printers, and electronics, but theres always this problem. Its very difficult.

As Kriegman presented a video of little blob-like robots running around in a virtual environment, he described this challenge to the team. Within the computer simulations, these robots could be manipulated like a video game; it was easy to simulate physics principles like friction or modulate the virtual environment. However, the roboticists didnt think that they could translate these theoretical designs and simulations into the real world with the existing tools.

Blackiston rose to the challenge. He conceptualized a virtual robot built out of a different material: cells. In developmental biology and stem cell biology, this isnt a super difficult trick because the technology exists, but no ones thought about doing this, said Blackiston.

Blackiston got to work in the laboratory using extra cells from his X. laevis project. Through delicate micromanipulations of stem cells in the microscope room, he crafted a replica of Kriegmans virtual creature. About a week after Kriegman shared his simulations, Blackiston revealed his creation, affectionately dubbed the Bongard-bot, in a Slack thread.

When Sam and I were looking at this image, we werent sure what we were looking at. It looked like Sams virtual robot that he had shown the week before, but it was clearly made of cells, said Bongard. Although it was a rough approximation, floating in freshwater at only a few millimeters wide, it matched the virtual design.

While this creation emerged as an unexpected tangent to the initial L2M goal, it quickly became clear that this approach could breathe life into their simulations. Levin and Bongard encouraged Blackiston and Kriegman to explore this whole new space, moving between running thousands of simulations and sculpting the best designs out of cells. From there on, it was off to the races, recalled Kriegman.

Since the initial biobot remained static, the team wanted to see if they could make the newer version move. Kriegman initiated the iterative design of synthetic living machines by using AI to create virtual creatures; these innocuous blobs shuffled along the floor of a virtual world before gradually developing proto-legs or -arms. Then he and Blackiston selected the most viable designs to construct out of frog cells.

Xenobots are AI-designed organisms (red) crafted from frog stem cells (green).

In his initial simulations3 for locomotion, Kriegman based the iterations on frog skin and heart cells given their propensities to aggregate and contract, respectively.3 With heart cells, they hoped to leverage motor movements from the heart muscle, like a piston, that would coordinate a form of locomotion.

Kriegman needed the computer to determine the optimal position and shape for these cellular motors in the xenobots. However, there was no guarantee that the evolved simulation would be feasible in the real world. With limited information, Kriegman sought the expertise of heart researchers to gain some insights into heart cell synchronization and to learn how unconventional shapes may influence cellular function. We know how these cells work in the heart shape, but what would happen with these cells in the context of xenobots? he wondered. Its difficult to predict ahead of time, so the AI or evolutionary algorithm must find designs that work regardless of how the motors are moving. Its making reliable machines with unreliable parts.

The team had to get creative during this process. Based on the AI, Doug would build it, and then they would modify the AI and build the next iteration, recalled Levin. Going back and forth, it was amazing because every week there was something new to look at.

Its a great reminder that when it comes to robotics and AI, humans tend to overthink things. Its better to let evolution, either biological or artificial, figure out how much complexity is needed for the task at hand.

Josh Bongard, University of Vermont

As Kriegman generated numerous iterations of xenobots, Blackiston used the 3D image as the working blueprint in his microscope room. Blackiston gathered his ingredients using different biological tissues harvested from blastula stage X. laevis embryos. Then, as if building a sandwich, he arranged the different cell layers one at a time into a cube of tissue.

When the tissue healed together, it formed a sphere. Then Blackiston sculpted the tissue using a microsurgical tool with a wire smaller than a human hair to achieve the desired shape. Each cell type differed by color, and he rotated between filters to maintain the correct orientation. Its more like craftsmanship than it is science at times because youre doing very fine manipulations, remarked Blackiston. The final product resembled a speck of pepper moving in a petri dish. These biodegradable xenobots lived for about a week, sustaining themselves on their own food source (a yolk of lipid and protein deposits) before they degraded and ceased functioning.

One of the designs featured heart muscle cells on the bottom and skin cells on top with two stumpy legs on one side. As a result, it leaned over on its chest and could walk by moving forward in a straight line. However, when flipped onto its back, the simulated design became immobile due to the alteration in shape and tissue distribution. To verify whether the computer-generated in silico matched what was created in the laboratory, Kriegman compared the trajectories of the physical xenobot and those of the virtual xenobot. To the teams surprise, the two trajectories almost perfectly overlapped with one another. It wasnt just for one trajectory; there were lots of pairs, recalled Bongard. It confirmed that what happened in simulation matched what happened in reality.

The team next wanted to see if they could make a xenobot swim. To do this, the researchers employed another type of motor: cilia.4 Instead of layering different tissues, Blackiston used whole explants from developing frog embryos.

These explants, known as animal caps, have been used to study cell differentiation and tissue formation.5 The team repurposed the animal cap to create living machines with new specific functions. Once the X. laevis explants balled up into a spherical mass, they gained motility from cilia, which propelled them through their aqueous environments.

While their movements were less predictable compared to their walking counterparts, these ciliated xenobots could navigate. The xenobots swam through open fields, mazes, and even narrow capillaries. In environments with debris or silicone-coated beads, xenobots collectively swarmed together to push the debris into piles.

Not only did the xenobots demonstrate self-locomotion, but they could also be modified to record an experience. The team tested the biobots ability to sense their environments by microinjecting mRNA with a photoconvertible reporter that caused them to fluoresce green. Xenobots freely explored their surroundings, but if any xenobot passed through an area exposed to blue light, the reporter underwent a permanent conformational change, causing the xenobot to glow red. Otherwise, xenobots glowed green to indicate that they did not detect the blue light.

Xenobots also exhibited inherent robustness and could automatically self-repair after injury from surgical forceps. Every single xenobot could close a wound, resolve the injury, and reform into a spherical shape within minutes. From a robotics perspective, cells are like a technology from a thousand years in the future that have just been plopped on our desks. They work when you stick them together. They survive; theyre self-powered; and they heal, remarked Kriegman.

As they watched the xenobots scoot and shuffle across the dish and push debris into piles, the researchers envisioned adding another feature. If the debris was replaced with other materials such as stem cells or even microplastics, the ability to collect materials could open up new areas for xenobot applications. They just needed a new design.

The presence of cilia, marked in orange fluorescence, enabled xenobots to swim in their environments.

The initial spheroid shape wasnt the best for this task. When Kriegman returned to the computer drawing board, he was surprised by the simplicity of the suggested design: a C-shape. Its a great reminder that when it comes to robotics and AI, humans tend to overthink things. Its better to let evolution, either biological or artificial, figure out how much complexity is needed for the task at hand, said Bongard.

This C-shape, reminiscent of Pac-Man or a snowplow, led to an unexpected discovery. C-shaped xenobots spontaneously replicated in a manner dubbed as kinematic self-replication.6 When the team replaced debris with loose, white-colored stem cells, the xenobots immediately set to work collecting cells.

Over time, the piles of collected cells grew big enough to begin swimming themselves. These baby xenobots, although smaller than their makers, were created without evolution or genetic manipulation. Interestingly, this process occurred entirely within the dish. If there werent enough loose cells around, self-replication ceased; parent xenobots could only produce a round or two of self-replication before petering out.

The concept of kinematic self-replication was first proposed in the 1940s by a mathematician named John von Neumann.7 In this hypothetical model, a machine could assemble parts to create a duplicate of itself. However, true replication only occurs in nature, while machine replication is limited to generating computer viruses. [With xenobots], this is a new way that people havent thought about where biological systems, namely cell clusters, can replicate, said Kriegman. Maybe this will help people think differently about replication.

By leveraging existing techniques, the team built something that was not found in nature and reconfigured it to fulfill a new function. These xenobots have challenged conventional categories: Are they robots, living things, or machines? While the categorization of these synthetic living organisms may need to be redefined into a new box altogether, one thing remains certain: the team has only scratched the surface of biobots capabilities.

Its a green technology in every sense of the word. What is the probability that it will never have an application? To me, Im biased, but I think its close to zero. Its going to find a use somewhere, but who knows how many uses and how long it will take? said Bongard.

People thought this was a one-off froggy specific result, but this is a very profound thing. Whats the furthest from an embryonic frog? Well, that would be an adult human.

Michael Levin, Tufts University

Potential avenues for these biodegradable machines primarily revolve around environmental applications, from serving as biosensors to detect pollutants to gathering materials like microplastics or even sequestering and breaking down harmful chemicals.

People thought this was a one-off froggy-specific result, but this is a very profound thing, emphasized Levin. To demonstrate its translatability in a non-frog model, he wondered, Whats the furthest from an embryonic frog? Well, that would be an adult human.

He enlisted the help of Gizem Gumuskaya, a synthetic biologist with an architectural background in Levins group, to tackle this challenge of creating biological robots using human cells to create anthrobots.8 While Gumuskaya was not involved with the development of xenobots, she drew inspiration from their design. By using adult human tracheal cells, she found that adult cells still displayed morphologic plasticity.

Xenobots (C-shaped; beige) push loose stem cells (specks; white) into piles as they move through their environments.

The resulting anthrobots swam using cilia, but they unexpectedly also moved across a layer of damaged human neurons. To Gumuskayas surprise, the anthrobots aggregated and formed what she described as an ant bridge between the two damaged edges. While how they accomplished this remains unknown, the anthrobots aided in healing the neuronal tear, indicating that they may offer therapeutic potential.

There are several key differences between xenobots and anthrobots: species, cell source (embryonic or adult), and the anthrobots ability to self-assemble without manipulation. When considering applications, as a rule of thumb, xenobots are better suited to the environment. They exhibit higher durability, require less maintenance, and can coexist within the environment, said Gumuskaya.

Meanwhile, there is greater potential for the use of mammalian-derived biobots in biomedical applications. This could include localized drug delivery, deposition into the arteries to break up plaque buildup, or deploying anthrobots into tissue to act as biosensors. [Anthrobots] are poised as a personalized agent with the same DNA but new functionality, remarked Gumuskaya.

Gumuskaya hopes that this work in frogs and human cells inspires the scientific community to explore the new and unexpected functionalities of these bioconstructs. There are a lot of big challenges in this world, but were developing new kinds of technologies and tools for the next generation. I hope that these bots become one tool in that toolkit, remarked Bongard.

References

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From Code to Creature - The Scientist

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Duke School of Medicine Hosts Navy Medicine Delegation for Collaborative Research Tour – Duke University School of Medicine

June 18, 2024 medical

Duke University School of Medicine students and faculty met with a delegation of Navy Medicine senior leaders on June 6.

The teamDeputy Surgeon General Rear Admiral (RADM) Rick Freedman, along with Master Chief Petty Officer Hansen LaFoucade, Lieutenant Command Kathleen Dale, Lieutenant Aaron Abreu, and Chief Petty Officer Stephen Todrzak toured School of Medicine facilities and met with several Duke faculty and students to explore collaborative research and scholarship opportunities available within military health care.

Their tour included stops at the School of Nursing, Department of Family Medicine and Community Health, Trent Semans Center for Health Education, Duke Center for Hyperbaric Medicine and Environmental Physiology, Physician Assistant Program, Duke Surgery, and the Human Simulation and Patient Safety Center.

A key focus of the visit was to promote the Navys scholarship programs for health care professionals, including physicians, nurses, dentists, and physician assistants. Scholarships from the Navy cover tuition and offer stipends, which can provide a debt-free path to employment in Navy Medicine after graduation.

Navy Medicine has more than 44,000 highly trained military and civilian health care professionals who provide enduring expeditionary medical support to the warfighter on, below, and above sea, and ashore.

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Cumberland Healthcare announces new family medicine physician – Ashland Daily Press

June 18, 2024 medical

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Waco Family Medicine to open new headquarters next week, boosting patient care, doctor training – Waco Tribune-Herald

June 18, 2024 medical

Years of work will come to fruition next week as Waco Family Medicine opens a $65 million flagship facility bringing together medical specialty clinics, community resources and primary care physicians under one roof.

The one-stop shop and headquarters at 1600 Providence Drive will improve care opportunities for patients and provide family practice doctors in residency with access to greater professional development. It represents a decadelong passion project for Dr. Mike Hardin, chief clinical officer of Waco Family Medicine.

WATCH NOW: Waco Family Medicine's $65 million flagship facility on Providence Drive

So many of our patients face transportation insecurity and other challenges to their health like being food-insecure or not living in a neighborhood where they can just go outside to exercise, Hardin said. Now we wont have to send them across town to see certain specialists, and we have community partners on the first floor to offer them housing assistance, nutrition assistance or to help them pay rent and so forth. Having all this in one place will help close gaps in their care and allow them opportunities to improve their lives.

Waco Family Medicine is a Federally Qualified Health Center offering comprehensive health care services. It has more than a dozen locations that served 60,000 patients last year, primarily uninsured or underinsured patients, offering an income-based sliding fee scale.

Fundraising remains underway to pay for the new facility, with less than $13 million left to raise for the $65 million project.

WATCH NOW: Dr. Mike Hardin talks about Waco Family Medicine's new 143,000-square-foot facility, which doubles the clinical space at its Providence Drive campus. (February 2024)

The specialty clinics to be housed in the new headquarters will also give Waco Family Medicine medical residents the chance to rotate with specialists and apply what they learn in the full spectrum of family practice medicine, residency program director Dr. Burritt Hess said.

The organizations residency program already is highly rated and highly competitive, with 700 applicants for 12 positions in a recent group of residents, associate program director Dr. Ryan Laschober said.

Gloria Veracruz Guerra has been a patient at Waco Family Medicine for 42 years. She also has worked there in a variety of roles starting in nursing in 1982, transitioning through billing into patient administration and retiring more than six years ago. She has also been a member of the medical board for the practice the past five years.

Every time I walk into Waco Family Medicine, I observe how other patients are treated, Veracruz Guerra said. I look to see whether they feel heard and whether their needs are addressed.

From the first greeting when patients enter, until they leave, patients receive respect and find their needs addressed and their lives improved, she said.

Now we wont have to send them on another bus ride to another clinic in a different part of the city for specialty care, Veracruz Guerra said. Theyll be able to go to another floor or down the hall to see who they need to see.

The specialty clinics will include minor surgical care; skin care; care for muscles, bones and connective tissues; and care for long-term inflammatory ailments, officials said.

Hess said the practice may reach out to specialists who treat diabetes and glandular conditions as well as those who treat kidney diseases.

Only a portion of health can be addressed in the patient exam room. The rest is social and environmental, Laschober said.

Twenty percent of health is inside the exam room. Eighty percent is community resource, Laschober said. This new facility will provide patients access to care for the whole person. We will have medical, dental and behavioral health here along with addiction medicine.

The facility will also have indoor and outdoor exercise rooms for patients.

For some people, a physician can tell them to exercise more and they know what to do, but not everyone was a high school or college athlete and remembers how to put together an exercise training plan, Laschober said.

We will now give our patients the tools to succeed, he said. We have a fantastic wellness and fitness center, where patients will meet with a fitness specialist who will help them tailor an exercise program specific to their needs. This is not for big biceps. Its for wherever they are on their health journey.

Waco Family Medicine officials, area politicians and celebrities Chip and Joanna Gaines ceremonially broke ground Thursday on a $61 million central facility for the medical services nonprofit that will replace the current one at its existing location in the 1600 block of Colcord Avenue. (October 2022)

There will also be community-partner organizations on-site to help patients address housing challenges, and a variety of programs and resources, including Greater Waco Legal Services and even nutrition, Laschober said.

We have Shepherds Heart who will help with food distribution, but now well also have a culinary test kitchen where local partners will help patients learn to prepare nourishing meals they will eat and enjoy consistent with their culture, he said.

The range of services is aimed at addressing the social drivers of health, Hess said.

Patients will be able to meet with clinicians and community partners, lowering barriers to health and allowing them to flourish in their lives with families and employment as well, Hess said.

The easier access to specialists will also present opportunities for Waco Family Medicines residents training to specialize in family medicine, Hess said.

We have specialists who have graciously volunteered their time to serve patients who are generally uninsured and they will also oversee teams of residents, Hess said.

The specialists and the residents will collaboratively review their patients histories and develop a treatment plan together.

We are thrilled to offer the residents a state-of-the-art medical facility for training that will move training forward in huge ways beyond what the old building allowed, Hess said. And there will be a ripple effect, as these residents complete the program and go out to practice themselves. They will offer top notch care, second to none.

Friday will be the last day providers see patients in the current building next door to the new one, Hardin said. The staff will move their final items and equipment into the new building over the weekend and begin seeing patients there Monday.

Waco Family Medicine offers care from the beginning of life to the end of life, Veracruz Guerra said.

People who may be looking for a new physician should come see us and give us a chance, she said.

Waco Family Medicine plans to have a grand opening after the old building has been demolished and the campus has been put into its final form, likely in the fall, spokesperson Nick Alvarado said.

Even if people do not have a medical need, they should still come get a tour during the grand opening and see what it offers, Veracruz Guerra said.

Fundraising efforts for the new headquarters went public in December 2021, and a groundbreaking ceremony in October 2022 marked the start of construction on the 143,000-square-foot facility, with Dallas-based Beck Group as the main contractor.

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Bryan family medicine office welcomes nurse practitioner – West Bend News

June 18, 2024 medical

Tara Garza, FNP, MSN, BSN, has joined Parkview Physicians Group (PPG) Family Medicine in Bryan and is welcoming patients at the office, 442 W. High St., second floor.

Tara is an experienced nurse practitioner, and we are very glad shes chosen to serve the Williams County community as part of the Parkview family of providers, noted Sally Taylor, vice president of operations, PPG, Ohio.

Garza returns to Parkview after years serving patients at Community Memorial Hospital. As a registered nurse, she cared for the complex needs of patients in the emergency room, the medical/surgical unit, the intensive care unit (ICU) and the obstetrics (OB) department. As a family nurse practitioner, she has provided comprehensive primary care for patients from newborn to older adult and has served as a preceptor for nurses and nurse practitioners in training.

Garza began her nursing career as a telemetry nurse at Parkview Randallia Hospital, working with patients who had past or ongoing cardiac conditions.

Garza received her masters degree in nursing (Family Nurse Practitioner) from Graceland University in Independence, Missouri. She earned her bachelors degree in nursing from Indiana Wesleyan University in Marion, Indiana, after having received an associate degree from Northwest State Community College (NSCC) in Archbold, Ohio. She has been recognized among NSCCs Distinguished Alumni.

Board certified by the American Association of Nurse Practitioners, Garza is a member of the AMDA The Society for Post-Acute and Long-Term-Care Medicine as well as the Sigma Theta Tau International Honor Society of Nursing.

Drawn to a medical career in childhood, Garza found satisfaction in nursing and has challenged herself to perform at a higher level for the benefit of her patients.

I loved bedside nursing, but I felt I had the skills to help community members even more as a nurse practitioner, so I obtained further education, she said. Being a family medicine nurse practitioner enables me to build a trusting medical relationship with people from birth until their final days. I like that Im able to take the time to get to know my patients not just their medical conditions, but who they are and what they enjoy so I can individualize their plan of care and find what will work best for them. I have experience with the elderly and enjoy the stories my older patients share; helping them live their best lives is very important.

Outside of work, Garza enjoys reading and family time with her spouse, four children and three grandchildren. She finds travel therapeutic, especially the sun and ocean breezes of cruising.

A believer in community support through volunteerism, in recent years, she has served on the Four County Career Center Health Occupations Advisory Board, as a board member of Community Memorial Hospital Rural Health Clinic and as a Gateway Woods mentor to a teen mother.

Garza is welcoming patients of all ages. To schedule an appointment, call 419-636-4517.

Garzas office hours are 8:00 a.m.4:00 p.m. Monday, 8:00 a.m. 6:00 p.m. Tuesday, 8:00 a.m. 1:00 p.m. Wednesday, 8:00 a.m. 4:00 p.m. Thursday, and 8:00 a.m. 4:00 p.m. Friday.

Lab and imaging services are also available at the PPG Family Medicine office. Lab hours are 7:30 a.m. 5:00 p.m. MonFri. Imaging is open 8:00 a.m.5:00 p.m. MonFri.

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CalOptima commits over $500M to increase the rates paid to medical providers – New Santa Ana

June 18, 2024 medical

ORANGE, Calif. (June 17, 2024) The CalOptima Health Board of Directors has approved an investment of $526.2 million to increase rates paid to hospitals, physicians, community clinics, behavioral health providers and ancillary services providers in Orange County. It is the largest provider rate increase of its kind in CalOptima Healths nearly 30-year history. This investment is intended to support timely access to critical health care services for members and promote longer-term financial stability of the managed care network over a 30-month period from July 2024 to December 2026.

This unprecedented provider rate increase comes at a much-needed time to counteract some of the financial uncertainty due to the California state budget deficit and its likely impact on health programs, including Medi-Cal. The complex nature of the ongoing budget negotiations underscores why CalOptima Healths action to deliver a separate provider rate increase is so significant. Based on prior fiscal prudence and in accordance with its founding ordinance, CalOptima Health is using unallocated reserve funds to expand access and augment provider reimbursement.

CalOptima Health provides health insurance benefits to nearly one in three Orange County residents. It serves more than 928,000 low-income children, adults, seniors and people with disabilities through a managed care delivery model, including health network partners, hospitals, physician groups, community health centers, skilled nursing facilities, behavioral health providers and other ancillary service providers. Together, these organizations are the health care safety net for Orange County.

Historically, Medi-Cal reimbursement has been a barrier to access for patients and their families, said Michael Hunn, CEO of CalOptima Health. We ask a lot of our hospitals, doctors and others who provide life-saving care to our members. During the public health emergency, CalOptima Health supported providers with temporary, short-term supplemental payments. These new rate increases will help ensure member access, provider financial stability, network access and medical care for CalOptima Health members throughout Orange County over the next two and a half years.

A county organized health system, CalOptima Health provides quality health care coverage for low-income children, adults, seniors and people with disabilities in Orange County, California. CalOptima Healths mission is to serve member health with excellence and dignity, respecting the value and needs of each person. CalOptima Health serves more than 928,000 members with a network of 10,900 primary care doctors and specialists and 39 acute and rehab hospitals.

Reactions from health care leaders across Orange County

These rate increases by CalOptima Health put members health care needs first and foremost. All of the hospitals, community clinics, physicians and others who care for CalOptima Health members appreciate the recognition and validation of our important role in supporting the health care safety net in Orange County. We thank CalOptima Health for its historic investment. Robert Braithwaite, President and CEO of Hoag Memorial Hospital Presbyterian and Chair of the Orange County Area for the Hospital Association of Southern California

On behalf of the physician community, the Orange County Medical Association applauds this important action by CalOptima Health in making a substantial investment in the health care delivery system in Orange County. Not only does this help support the providers, but more importantly, it will help to increase access to care in the network that serves one out of every three residents in our community. Jim Peterson, Executive Director, Orange County Medical Association

This landmark decision underscores CalOptima Healths unwavering commitment to enhancing the quality of care for the communities we serve. The increased funding will significantly bolster the ability of the Behavioral Health and Applied Behavior Analysis provider community to attract and retain behavior therapists, and ultimately provide the highest standard of care to our patients. The increase means more comprehensive and accessible mental health services and behavioral interventions. It will allow us to expand our reach to underserved populations, reduce wait times, and deliver individualized, evidence-based care that addresses the unique needs of each patient. We are excited about the opportunities this rate increase brings. Junie Lazo-Pearson, Ph.D., BCBA-D, Chief Clinical Officer, Advanced Behavioral Health

Orange County pediatricians appreciate that CalOptima Healths rate increase is designed to ensure that physicians are adequately reimbursed for the excellent care they deliver. Also, the increase will serve to improve health care disparities for the population served, resulting in better health outcomes and decreased overall costs. We applaud CalOptima Health for understanding and recognizing the importance of the patient-centered medical home as well as assuring continuity of care for our patients. Reshmi Basu, M.D., FAAP, President, American Academy of PediatriciansOrange County Chapter

As a family physician working at a training program within a Federally Qualified Health Center, our goal is to provide high-quality clinical care to our community while training future physicians to dedicate their careers to caring for the underserved. Ultimately, we aim to train physicians who expand their services to meet the needs of the community they serve, including services such as medication-assisted treatment of opioid use disorder, treatment of Hepatitis C, and complex prenatal care. Provider rate increases represent an opportunity for us to be appropriately compensated for the significant impact broadly trained primary care physicians have on the health care system, and for us to continue to focus our efforts on providing our patients timely access to the highest standards of needs-focused care. Matteo Leveroni, M.D., Medical Director of Family Medicine, UCI Family Health CenterSanta Ana

Family Choice Health Services fully supports the provider rate increases being implemented by CalOptima Health, starting July 1, 2024. Family Choice expects that the added upfront monthly capitation provided will be sufficient to pay for the higher provider rates being implemented. With the proper balance in increased funding between physicians, hospitals, health networks, FQHCs and other health care providers, quality patient care and access throughout Orange County will be improved and ensured. Toan Tran, M.D., Chief Executive Officer, Family Choice Health Services

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CalOptima commits over $500M to increase the rates paid to medical providers – New Santa Ana