What Happens To Your Cells With Too Little Oxygen

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Oxygen is essential for the survival and proper functioning of most eukaryotic organisms, including humans [3].  It plays a vital role in cellular respiration, the process by which cells generate energy by breaking down glucose and other nutrients. Cells have highly evolved systems for sensing and responding to having too little oxygen [3]. At the cell membrane, specialized ion channels on the cell membrane, particularly K+ channels, are responsible for the detection of oxygen, while several oxygen-responsive transcription factors inside the cell drive the molecular responses to hypoxia [9]. Lack of oxygen or excessive oxygen consumption could result in inadequate oxygen supply at the tissue or cellular level to sustain appropriate homeostasis, a condition defined as hypoxia [2,3]. Several factors can contribute to hypoxia, including various conditions, such as respiratory disorders, cardiovascular diseases, anemia, and high altitudes [6,9]. If hypoxic conditions are sustained, it can lead to a metabolic crisis that is ultimately lethal to cells and results in several detrimental outcomes if left untreated. 

Reduced energy generation is one of the most direct repercussions of cells receiving too little oxygen. Cellular respiration needs oxygen to make ATP, the cell’s energy currency.4 However, during hypoxic conditions, ATP-consuming processes are inhibited, and metabolism is disrupted until oxygen homeostasis is restored [4]. When cells cannot create energy through cellular respiration, they may turn to alternate metabolic pathways that are often less effective and generate toxic byproducts [13]. These byproducts can accumulate in the cell and cause damage, leading to cell death [13].  

Too little oxygen in cells can also cause inflammation and oxidative stress [8]. Oxygen acts as the last electron acceptor in oxidative phosphorylation [8]. Reactive oxygen species (ROS) are normal byproduct of oxidative phosphorylation, but during cellular hypoxia, ROS production may become unbalanced, leading to an overabundance of these molecules [8]. ROS accumulation may increase the susceptibility of cells to degeneration, resulting in inflammation, oxidative stress, and other forms of cellular damage [8]. This damage can inhibit the cell’s ability to self-repair, which may result in cell dysfunction or death [8].  

Oxygen is also essential for the proper functioning of the immune system, including neutrophils and monocytes [7,12].  Without enough oxygen, the immune system may not function optimally, resulting in a compromised immune system and potentially leading to an increased susceptibility to infection and other disorders [5]. Hypoxia can also affect the production of cytokines, which are proteins that help to regulate the immune response [9]. When the body is hypoxic, the production of specific cytokines may be reduced, leading to an impaired immune response [9].

The effects of too little oxygen on cells and the body can vary depending on the severity and duration of the condition. In mild instances, symptoms include shortness of breath, tiredness, and headache [2]. However, severe or prolonged hypoxia requires immediate medical attention and may result in organ damage and failure, coma, and even death [2]. It is important to address and treat hypoxia as quickly as possible to minimize the potential for cellular damage and the associated negative consequences. Treatment may involve oxygen therapy, medications, or addressing any underlying conditions contributing to the hypoxia. Early diagnosis and treatment can help to prevent further complications and improve the chances of a full recovery. 

 

References 

  1. Abe, H., Semba, H., & Takeda, N. (2017). The Roles of Hypoxia Signaling in the Pathogenesis of Cardiovascular Diseases. Journal of atherosclerosis and thrombosis, 24(9), 884–894. https://doi.org/10.5551/jat.RV17009 
  2. Bhutta BS, Alghoula F, Berim I. Hypoxia. [Updated 2022 Aug 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482316/ 
  3. Chen, P. S., Chiu, W. T., Hsu, P. L., Lin, S. C., Peng, I. C., Wang, C. Y., & Tsai, S. J. (2020). Pathophysiological implications of hypoxia in human diseases. Journal of biomedical science, 27(1), 63. https://doi.org/10.1186/s12929-020-00658-7 
  4. Lee, P., Chandel, N. S., & Simon, M. C. (2020). Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nature reviews. Molecular cell biology, 21(5), 268–283. https://doi.org/10.1038/s41580-020-0227-y 
  5. Maggini, S., Pierre, A., & Calder, P. C. (2018). Immune Function and Micronutrient Requirements Change over the Life Course. Nutrients, 10(10), 1531. https://doi.org/10.3390/nu10101531 
  6. Mozos I. (2015). Mechanisms linking red blood cell disorders and cardiovascular diseases. BioMed research international, 2015, 682054. https://doi.org/10.1155/2015/682054 
  7. Palazon, A., Goldrath, A. W., Nizet, V., & Johnson, R. S. (2014). HIF transcription factors, inflammation, and immunity. Immunity, 41(4), 518–528. https://doi.org/10.1016/j.immuni.2014.09.008 
  8. Semenza G. L. (2012). Hypoxia-inducible factors in physiology and medicine. Cell, 148(3), 399–408. https://doi.org/10.1016/j.cell.2012.01.021 
  9. Taylor A. T. (2011). High-altitude illnesses: physiology, risk factors, prevention, and treatment. Rambam Maimonides medical journal, 2(1), e0022. https://doi.org/10.5041/RMMJ.10022 
  10. Taylor, C. T., & Colgan, S. P. (2017). Regulation of immunity and inflammation by hypoxia in immunological niches. Nature reviews. Immunology, 17(12), 774–785. https://doi.org/10.1038/nri.2017.103 
  11. Trayhurn P. (2019). Oxygen-A Critical, but Overlooked, Nutrient. Frontiers in nutrition, 6, 10. https://doi.org/10.3389/fnut.2019.00010 
  12. Zenewicz L. A. (2017). Oxygen Levels and Immunological Studies. Frontiers in immunology, 8, 324. https://doi.org/10.3389/fimmu.2017.00324 
  13. Zorov, D. B., Juhaszova, M., & Sollott, S. J. (2014). Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiological reviews, 94(3), 909–950. https://doi.org/10.1152/physrev.00026.2013 

Understanding Post-Viral Fatigue Syndrome

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Most people who contract COVID-19 recover fully within a couple of weeks. However, a minority experience long-term symptoms for weeks or even months after the acute infection. Known as “long Covid,” these patients may suffer from debilitating fatigue, headaches, muscle pain, brain fog, and depression and anxiety (5). As many as ten percent of those who are infected by SARS-CoV-2 will experience lingering symptoms by some estimates (5). However, the phenomenon of long-term, systemic illness following viral infections is not new. High incidences of similar illnesses have been recorded following infectious outbreaks throughout the twentieth century (5). These conditions can collectively be studied as post-viral fatigue syndrome. 

For instance, after the 2003 outbreak of SARS-CoV-1, 60% of patients were still experiencing fatigue at twelve months (5). And during the 1918 H1N1 influenza pandemic, many of those affected experienced long-term, neurological disorders (3). For some, post-viral fatigue syndrome progressed to a debilitating neuroinflammatory illness known as Chronic Fatigue Syndrome (2). Patients’ calls for increased research and support around these chronic conditions have often been dismissed or discredited by medical professionals. Now, new findings surrounding long Covid may offer evidence to bolster research and treatment for post-viral fatigue syndrome. 

Post-viral fatigue syndrome is defined as a multi-systemic, complex condition that is caused by an acute or chronic viral infection (4). Patients experience various physical, cognitive, and neurological disabilities that may severely impact their ability to function in daily life. Viruses that can trigger post-viral fatigue syndrome include Epstein-Barr virus, influenza, Zika virus, Ebola, and Lyme disease (3). These viruses may also be responsible for other chronic diseases. For instance, strong evidence suggests that Epstein-Barr virus can cause Multiple Sclerosis (M.S.), an autoimmune disorder in which the immune system attacks the myelin sheath around nerves (7). 

In some cases, the severity and duration of symptoms may evolve into a condition called Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS). ME/CFS patients suffer from severe fatigue that does not improve with sleep, worsening of symptoms after physical or mental exertion, insomnia, exercise intolerance, and digestive, immune, and cognitive issues (2). Despite the severity of the condition, ME/CFS remains one of the illnesses that is most underfunded for research compared to disease burden (2). In part, this may be because 75 to 85 percent of ME/CFS patients are women, and illnesses that primarily impact women have been historically overlooked (2).  

Researchers at the Yale School of Medicine recently launched the Yale LISTEN Study in response to growing public interest in long Covid. The study aims to “learn more about long COVID, post-vaccine adverse events, and the corresponding immune responses” to illuminate some of the causes, symptoms, and effective treatments for poorly understood, chronic illnesses (2). Professors Akiko Iwasaki and Harlan Krumholz, who are leading the study, hypothesize several different causes that could be responsible for long Covid and other types of post-viral fatigue syndrome. For instance, the acute infection may trigger an autoimmune response or create an imbalance of bacteria in the gut microbiome (2). Another possibility is that irreparable tissue damage occurs during the acute infection, leading to long-term symptoms (2). 

Nevertheless, in order to better understand post-viral fatigue syndrome, a more holistic approach for management and treatment needs to be developed. Collaboration between multidisciplinary teams of doctors is necessary to treat this complex condition, and treatment should strive to improve quality of life for patients through both pharmacological and non-pharmacological methods (5). Moreover, increased funding for studying ME/CFS and other related conditions is necessary to develop treatments for these long-standing yet still poorly understood illnesses that cause great human suffering. 

 

References  

  1. Astin, Rónan et al. “Long COVID: mechanisms, risk factors and recovery.” Experimental Physiology, 2022, pp. 1-16, doi:10.1113/EP090802 
  2. Backman, Isabella. “Will Long COVID Research Provide Answers for Poorly Understood Diseases Like ME/CFS?” Yale School of Medicine, 01 Nov 2022, medicine.yale.edu/news-article/will-long-covid-research-provide-answers-for-poorly-understood-ailments-like-chronic-fatigue/ 
  3. Balfour, Hank and William Hoffman. “It’s Not Just Long COVID.” The Atlantic, 12 Aug 2022., www.theatlantic.com/ideas/archive/2022/08/long-covid-monovirus-ebv/671080/ 
  4. Kopf, Michael. “Post-viral Fatigue Syndrome: Symptoms & Treatment.” K Health, 11 April 2022, khealth.com/learn/fatigue/post-viral-fatigue-syndrome/ 
  5. Pintos-Pascual, Ilduara, et al. “Is SARS-CoV-2 the only cause of long-COVID?” Aids reviews, 25 Nov 2022, doi:10.24875/AIDSRev.22000025 
  6. “Post-viral fatigue: a guide to management.” North Bristol NHS Trust, The British Associations of Clinicians in ME/CFS, n.d., www.nbt.nhs.uk/our-services/a-z-services/bristol-me-service/post-viral-fatigue-a-guide-management/ 
  7. Tingley, Kim. “The Strange Connection Between Mono and M.S.” The New York Times Magazine, 7 March 2022, www.nytimes.com/2022/02/23/magazine/epstein-barr-virus-multiple-sclerosis.html 

New Cases of Polio in the US

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The United States experienced its largest outbreak of polio in 1952, with about 20,000 cases. Shortly after, in 1955, the availability of the inactivated poliovirus vaccine eradicated the disease in the United States 1. However, in July 2022, the New York State Department of Health reported that a person in Rockland County tested positive for polio—shortly after which it was identified in New York City’s wastewater samples. How did polio re-emerge, why, what can be done to curb the spread of new cases? 

The Centers for Disease Control (CDC) in September 2022 announced that polioviruses identified in New York met the World Health Organization (WHO)’s criteria for circulating vaccine-derived poliovirus. Indeed, the viral sequences from the polio patient and from three different wastewater specimens harbored sufficient genetic changes to meet the definition of a vaccine-derived poliovirus 2. Globally, the virus’ genetic sequences have been linked to wastewater samples from Jerusalem, Israel, and London, UK—pointing to substantial community transmission 3. Today, the United States now joins a list of approximately 30 other countries to date within which new circulating vaccine-derived poliovirus cases have been identified 4.  

Circulating vaccine-derived poliovirus occurs when local immunity to poliovirus is low enough to allow for the prolonged transmission of the original weakened virus from an oral polio vaccine in a vulnerable individual 5. As the virus circulates and accumulates genetic changes, the virus can regain its ability to infect the central nervous system and cause paralysis. Contrary to common misconceptions, circulating vaccine-derived poliovirus cases are not caused by children receiving the polio vaccine.  

The treatment of polio remains sparse and minimal. Treatment specifically addresses symptoms and signs of polio, such as fever, but also ensures a certain amount of physical therapy to improve any weakness or paralysis. To date, there remain no Food and Drug Administration (FDA) or internationally-approved antivirals against polio 6. Therefore, it is very important to prevent the emergence of polio in the first place. 

The CDC is working closely with the WHO, the Pan American Health Organization (PAHO), and other international public health partner organizations on developing polio prevention measures. In parallel, the CDC continues to support New York State Department of Health’s investigation through ongoing wastewater testing in order to better understand the virus’ spreading dynamics and in order to support vaccination efforts across affected communities 7 

Improving vaccination coverage is the key to preventing additional cases of paralytic polio in the United States, and although no additional new polio cases have been recently identified, New York State will expand its polio vaccination and surveillance efforts. In addition, frequent hand washing, access to clean water, modern sewage systems, and efficient wastewater management further help to prevent the spread of germs, including viruses like poliovirus, and minimize its medical toll.  

Meanwhile, proactive public education efforts on the nature and spreading dynamics of the disease, as well as further clinical research on preventive and/or treatment measures for polio and related diseases will remain of the utmost importance now and into the future.  

References 

  1. United States confirmed as country with circulating vaccine-derived poliovirus | CDC Online Newsroom | CDC. Available at: https://www.cdc.gov/media/releases/2022/s0913-polio.html. (Accessed: 17th October 2022)
  2. Updated statement on report of polio detection in United States – GPEI. Available at: https://polioeradication.org/news-post/report-of-polio-detection-in-united-states/. (Accessed: 17th October 2022)
  3. Outbreak Countries – GPEI. Available at: https://polioeradication.org/where-we-work/polio-outbreak-countries/. (Accessed: 17th October 2022)
  4. Polio Investigation | CDC. Available at: https://www.cdc.gov/ncird/investigation/polio/index.html. (Accessed: 17th October 2022)

Risks of Prolonged Anesthesia for Surgery

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Surgical procedures are notoriously physiologically challenging: from the moment the patient goes under anesthesia, they incur a certain risk. The amount of risk, however, depends on a number of variables, including the invasiveness of the procedure, the patient’s pre-existing conditions and comorbidities, and – the focus of this article – the length of time spent under general anesthesia. Prolonged anesthesia is associated with significant risks. 

Surgical anesthesia induces a host of physiological changes which would not otherwise occur in healthy patients. The chief purposes of anesthesia are to provide analgesia (pain relief) and induce loss of consciousness; however, a number of other alterations occur. It has been well documented that anesthesia can have a significant impact on blood pressure, which can in turn lead to increased heart rate and tachycardia.1 Alternatively, some drugs block baroreceptor function to inhibit this automatic feedback mechanism, allowing blood pressure to drop significantly.1 Anesthesia-induced vasodilation and alterations to the autonomic thermoregulatory response reduce the efficiency of heat conservation; a 2017 study done in China reported an incidence rate of 44 percent for intraoperative hypothermia (2). Respiratory alterations are similarly common: mainly, a reduction in tidal volume and an overall increase in respiratory rate (3). Cognitive and digestive functions become heavily impaired or suppressed, albeit temporarily (1). These accumulative changes, as well as many others not mentioned, contribute to the number of side effects associated with general anesthesia: mainly, nausea, memory loss, chills, uncontrollable shivering, urinary issues, and dizziness (4). More serious side effects –  such as delirium (5)  or severe cardiac events (6) – have been reported in more vulnerable populations. Side effects and risks tend to be more prevalent after prolonged instances of anesthesia. 

Advancements in surgical techniques have led to an increased incorporation of minimally invasive techniques, which are more technically challenging and thus have led to increased anesthesia duration. While it might be intuitive that prolonged anesthesia would only increase patient exposure to these physiological changes and thus, increase the severity of the associated risks, the full extent of this risk was not well understood until the last two decades. For example, a 2008 landmark study from the Mayo Clinic was one of the first well-circulated papers to establish a clear relationship between postoperative complications and duration of anesthesia during surgery (7). The authors analyzed a total of 2,196 patients who had open radical nephrectomy or nephron-sparing surgery at the Mayo Clinic between 1989 and 2002. The patients were organized into three groups: those whose surgeries were shorter than 4 hours, those whose surgeries lasted 4-6 hours, and those whose surgeries lasted 6 or more hours. They found that the incidence rate of non-urological complications increased from 3.1, to 5.8, to 13.5 percent, respectively. The authors also noted a significant difference in outcomes for the patients whose surgeries lasted less than six hours compared to those whose surgeries were longer. Their findings suggested that there might be a certain “threshold” at which point anesthesia duration can significantly increase the risk of adverse effects.  

Since the publication of the aforementioned study, others have demonstrated a robust association between anesthesia time and adverse effects, including venous thromboembolism, increased length of stay, and additional surgery (8). It remains unclear which exact mechanisms underlie the jump in anesthesia-associated risk when duration is prolonged to around the six-hour mark. Regardless, many medical institutions and/or private practices maintain policies regarding maximum time allowable under anesthesia, particularly for elective or low-stakes procedures. 

 

References  

1 Katzung, B., Trevor, A., & Masters, S. (2018). Basic & Clinical Pharmacology. McGraw Hill Medical Publishing Division.  

2 Yi, J., Lei, Y., Xu, S., Si, Y., Li, S., Xia, Z., Shi, Y., Gu, X., Yu, J., Xu, G., Gu, E., Yu, Y., Chen, Y., Jia, H., Wang, Y., Wang, X., Chai, X., Jin, X., Chen, J., Xu, M., … Huang, Y. (2017). Intraoperative hypothermia and its clinical outcomes in patients undergoing general anesthesia: National study in China. PloS one, 12(6), e0177221. https://doi.org/10.1371/journal.pone.0177221 

3 Mills G. H. (2018). Respiratory complications of anaesthesia. Anaesthesia, 73 Suppl 1, 25–33. https://doi.org/10.1111/anae.14137 

4 NHS. (n.d.). General anaesthesia. NHS choices. Retrieved October 3, 2022, from https://www.nhs.uk/conditions/general-anaesthesia/  

5 Evered, L. A., Chan, M., Han, R., Chu, M., Cheng, B. P., Scott, D. A., Pryor, K. O., Sessler, D. I., Veselis, R., Frampton, C., Sumner, M., Ayeni, A., Myles, P. S., Campbell, D., Leslie, K., & Short, T. G. (2021). Anaesthetic depth and delirium after major surgery: a randomised clinical trial. British journal of anaesthesia, 127(5), 704–712. https://doi.org/10.1016/j.bja.2021.07.021 

6 Barker, S. J., Gamel, D. M., & Tremper, K. K. (1987). Cardiovascular effects of anesthesia and operation. Critical care clinics, 3(2), 251–268. 

7 Routh, J. C., Bacon, D. R., Leibovich, B. C., Zincke, H., Blute, M. L., & Frank, I. (2008). How long is too long? The effect of the duration of anaesthesia on the incidence of non-urological complications after surgery. BJU international, 102(3), 301–304. https://doi.org/10.1111/j.1464-410X.2008.07663.x 

8Phan, K., Kim, J. S., Kim, J. H., Somani, S., Di’Capua, J., Dowdell, J. E., & Cho, S. K. (2017). Anesthesia Duration as an Independent Risk Factor for Early Postoperative Complications in Adults Undergoing Elective ACDF. Global spine journal, 7(8), 727–734. https://doi.org/10.1177/2192568217701105  

Implications of the 2022 Inflation Reduction Act on Healthcare

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The Inflation Reduction Act (IRA), which was signed into law by President Joe Biden on August 16, seeks to fight inflation, reduce carbon emissions, and boost domestic energy production (Grovery & Orgera, 2022). However, the Inflation Reduction Act will also have a large impact on healthcare: among other provisions, the law is set to lower the cost of prescription drugs like insulin, cancer medications, and blood thinners for millions of Americans (Gustafsson & Collins, 2022). It is the most significant piece of health care legislation since the passage of the Affordable Care Act in 2010 (Gustafsson & Collins, 2022). 

High prescription drug costs pose an intractable problem for many Americans (Lovelace Jr., 2022). A Kaiser Family Foundation (KFF) poll published in July 2022 found that “about a quarter of adults say they or a family member in their household have not filled a prescription, cut pills in half, or skipped doses of medicine in the last year because of the cost” (Montero et al., 2022). Additionally, nearly 1 in 2 adults overall reported difficulty affording health care expenses, included prescription medications (Montero et al., 2022). The IRA allows Medicare for the first time to negotiate prices on the most expensive prescription drugs (Abrams, 2022). The new law caps out-of-pocket costs for people on Medicare, limits the monthly cost of insulin for seniors, and extends the expanded subsidies for individuals buying their own health insurance through the ACA, which were set to expire this year (Lovelace Jr., 2022). Here, some of the provisions are explained in more depth: 

 Medicare will be able to negotiate prices 

The Inflation Reduction Act empowers the federal government to negotiate prices for some of the medications that Medicare spends the most money on, which has been a goal decades in the making for Democrats and some Republicans within healthcare policy (Abrams, 2022). Starting in 2026, Medicare will begin negotiating the price of 10 drugs. That will increase by an additional 15 drugs in 2027, and then to an additional 20 drugs in 2029 and beyond (Abrams, 2022). 

Curbing insulin costs 

Starting in 2023, the cost of insulin will be capped at $35 per month for Medicare beneficiaries, though the cost will not be capped for those with private health insurance. The monthly cap will help millions: a study published in Health Affairs in July found that 14.1% of people who use insulin in the U.S. (almost 1.2 million individuals) reach “catastrophic” spending over the course of one year, meaning that after paying for essentials like food and housing, at least 40% or more of their remaining income is spent on insulin (Bakkila et al., 2022). 

$2,000 out-of-pocket cap 

Starting in 2025, the law will cap out-of-pocket spending on prescription drugs at $2,000 annually. Previously, Medicare beneficiaries had to spend about $7,000 out of pocket before qualifying for “catastrophic coverage,” under which patients are only charged a copayment or coinsurance percentage (Medicare.gov, n.d.). Stacie Dusetzina, a health policy professor at Vanderbilt University Medical Center, says this benefit is “arguably the most significant portion of the law” (Lovelace Jr., 2022). According to the KFF, “about 1.4 million people on Medicare had annual out-of-pocket costs greater than $2,000 in 2020” (Montero et al., 2022). 

There are other notable healthcare benefits in the provisions of the Inflation Reduction Act, including free vaccines for seniors and inflation penalties for drugmakers. Dusetzina notes that the impact of the IRA will be “significant,” especially for those in need of the costliest drugs (Lovelace Jr., 2022). People on Medicare are expected to benefit the most from the new law, but some experts say that some of these changes could eventually have an impact on the commercial insurance market (Lovelace Jr., 2022). Many of the law’s provisions won’t go into effect for a few years, meaning that change won’t be immediate, but the IRA represents progress towards increasing the affordability of prescription drugs while paving the way for additional future reform. 

 

References

Abrams, Abigail. (2022, August 22). Why Americans May Soon See Lower Drug Costs. Time, 200 (7), 15. 

Bakkila, B. F., Basu, S., & Lipska, K. J. (2022). Catastrophic Spending On Insulin In The United States, 2017–18. Health Affairs, 41(7), 1053–1060. DOI:10.1377/hlthaff.2021.01788 

Catastrophic coverage | Medicare. (n.d.). Medicare.Gov.  https://www.medicare.gov/drug-coverage-part-d/costs-for-medicare-drug-coverage/catastrophic-coverage 

Grover, A., & Orgera, K. (2022, August 17). The Inflation Reduction Act will cut health care costs for some patients. But we need to do more. AAMC. https://www.aamc.org/news-insights/inflation-reduction-act-will-cut-health-care-costs-some-patients-we-need-do-more 

Gustafsson, L., & Collins, S. R. (2022, August 15). The Inflation Reduction Act is a Milestone Achievement in Lowering Americans’ Health Care Costs. To the Point, Commonwealth Fund. DOI:10.26099/M8AY-4J69 

Lovelace Jr., B. (2022, August 16). Inflation Reduction Act becomes law: How it will affect your health care. NBC News. https://www.nbcnews.com/health/health-news/inflation-reduction-act-becomes-law-will-impact-health-care-rcna43090 

Montero, A., Kearney, A., Hamel, L., & Brodie, M. (2022, July 14). Americans’ Challenges with Health Care Costs. KFF. https://www.kff.org/health-costs/issue-brief/americans-challenges-with-health-care-costs/ 

Understanding the Health Provisions in the Inflation Reduction Act. (2022, August 11). KFF. https://www.kff.org/medicare/understanding-the-health-provisions-in-the-senate-reconciliation-legislation/