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  

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/ 

Sugammadex (ORG 25969) is a unique neuromuscular blockade reversal drug. It was the first selective relaxant binding agent, which is a relatively novel class of drugs that reverse neuromuscular blockade (NMB) induced by a specific NMB agent. Sugammadex reverses the aminosteroid non-depolarizing muscle relaxants rocuronium and vecuronium, commonly used during general anesthesia. Currently manufactured by Merck & Co., Inc. under the brand name Bridion, it must be administered according to specific protocols to exert its unique effects. 

Sugammadex, named after “Su”, for sugar, and “gammadex”, for the gamma-cyclodextrin molecule inherent to its structure,¹ has a unique three-dimensional structure resembling a hollow doughnut.² On administration, it does not produce any metabolites and is mostly excreted through urine in the same form it was ingested within 24 hours.  

 The minimal reversal dose of sugammadex is 2 mg/kg (intravenous). It is to be administered as a single intravenous bolus, delivered over less than 10 seconds. As such, the drug is currently only available for intravenous administration, in vials of 200 or 500 mg, to be stored un-refrigerated.  

Sugammadex may interfere with the chemotherapeutic drug Toremifene, a selective estrogen receptor modulator; Toremifene may delay the reversal by displacing the formation of the rocuronium-sugammadex complex. Sugammadex may also theoretically bind with contraceptive steroids but has a much lower affinity for steroids compared to aminosteroid NMBs. Additional interactions have also been noted, including with fusidic acid and magnesium.³ However, further investigations are required to probe other possible drug interactions. Sugammadex is contraindicated in individuals who are hypersensitive to it or to any of its excipients.  

 Sugammadex inactivates rocuronium by encapsulating the free molecule to form a stable molecular complex.⁴ As a result, robust recovery from neuromuscular blockade has been seen across a broad variety of clinical contexts.⁵ 

By reliably and effectively reversing moderate or deep neuromuscular blockade, sugammadex has become a core drug in anesthesia practice. Older methods of reversing rocuronium and other aminosteroid muscle relaxants, such as using neostigmine, are accompanied by several shortcomings.³

A phase 3, multicenter, randomized, blinded clinical study recently demonstrated that patients treated with sugammadex achieved faster recovery of neuromuscular function following rocuronium or vecuronium administration than with neostigmine.⁶ In addition, sugammadex also avoids side-effects associated with neostigmine, including but not limited to nausea, vomiting, and undesired autonomic adverse effects.⁷ 

 Despite its benefits, the routine, global use of sugammadex remains limited by economic constraints.⁸ This said however, it was approved by the Food and Drug Administration (FDA) in 2015, marking a turning point in its clinical use and greatly facilitating its clinical adoption.⁹ 

 Sugammadex has established itself as a key drug in anesthesia,¹⁰ undoubtedly representing a clinical milestone in the safety and quality of anesthetic care. In the meantime, additional research into its implementation and regulatory advances are required for its consistent, regular, global clinical implementation.  

References  

1. Kovac, A. L. Sugammadex: the first selective binding reversal agent for neuromuscular block. Journal of clinical anesthesia (2009). doi:10.1016/j.jclinane.2009.05.002
2. Naguib, M. Sugammadex: Another milestone in clinical neuromuscular pharmacology. Anesth. Analg. (2007). doi:10.1213/01.ane.0000244594.63318.fc
3. Singh, D. et al. Sugammadex: A revolutionary drug in neuromuscular pharmacology. Anesth. Essays Res. (2013). doi:10.4103/0259-1162.123211
4. Bom, A. et al. A novel concept of reversing neuromuscular block: Chemical encapsulation of rocuronium bromide by a cyclodextrin-based synthetic host. Angew. Chemie – Int. Ed. (2002). doi:10.1002/1521-3773(20020118)41:2<265::AID-ANIE265>3.0.CO;2-Q
5. Herring, W. J. et al. Sugammadex efficacy for reversal of rocuronium- and vecuronium-induced neuromuscular blockade: A pooled analysis of 26 studies. J. Clin. Anesth. (2017). doi:10.1016/j.jclinane.2017.06.006
6. Merck’s BRIDION® (sugammadex) Receives FDA Approval for the Reversal of Neuromuscular Blockade Induced by Rocuronium and Vecuronium in Adults Undergoing Surgery – Merck.com. Available at: https://www.merck.com/news/mercks-bridion-sugammadex-receives-fda-approval-for-the-reversal-of-neuromuscular-blockade-induced-by-rocuronium-and-vecuronium-in-adults-undergoing-surgery/. (Accessed: 17th August 2022)
7. Naguib, M. & Magboul, M. M. Adverse effects of neuromuscular blockers and their antagonists. Middle East journal of anesthesiology (1998). doi: 10.2165/00002018-199818020-00002.
8. Ledowski, T. et al. Introduction of sugammadex as standard reversal agent: Impact on the incidence of residual neuromuscular blockade and postoperative patient outcome. Indian J. Anaesth. (2013). doi:10.4103/0019-5049.108562
9. FDA Approves Bridion (sugammadex) to Reverse Effects of Neuromuscular Blocking Drugs. Available at: https://www.drugs.com/newdrugs/fda-approves-bridion-sugammadex-reverse-neuromuscular-blocking-4316.html. (Accessed: 17th August 2022)
10. Tayal, G., Kundra, S. & Grewal, A. Sugammadex – New neuromuscular block reversal. J. Anaesthesiol. Clin. Pharmacol. (2008). doi: 10.4103/0259-1162.123211

Initially recognized as a respiratory system disease, COVID-19 has been found to interact with and affect the cardiovascular system, resulting in a slew of cardiac ailments ranging from myocardial damage to cardiac and endothelial dysfunction (1). Cardiac damage has been noted even without clinical features of respiratory disease. Further, some cardiac symptoms have been known to persist in certain patients, greatly complicating their recovery. Recently however, a treatment has emerged in ivabradine for persistent cardiac COVID-19 symptoms.  

At the start of the COVID-19 pandemic, a surprising volume of hospitalized patients were found to have elevated levels of cardiac troponin, a marker of myocardial injury. Soon thereafter, echocardiograms confirmed cardiac functional abnormalities in many patients (2). A recent meta-analysis of studies on long COVID-19 found that up to 11% of COVID-19 patients report experiencing palpitations or an increased heart rate (3). These may include, but are not limited to, myocardial infarction, coronary artery disease, arrhythmias, and conduction system disease. While the underlying causes remain unclear, one study based on an online survey of over 2,000 adults with long COVID interestingly found that up to two thirds of patients have symptoms suggestive of an impaired autonomic nervous system, which controls “automatic” functions of the body, including blood pressure, digestion, body temperature – and heart rate. 

COVID-19-related cardiac symptoms are similar to the broader condition known as postural orthostatic tachycardia syndrome (POTS). Even prior to the COVID-19 pandemic, POTS was known to affect more than 24 million Americans, especially in patients recovering from influenza or another viral infection. POTS can impact employment and education, similar to severe cardiac ailments, and it is important to treat quickly and effectively.  

While beta blockers and calcium channel blockers may be administered, these can lower blood pressure and may make patients feel worse. Ivabradine (Procoralan), meanwhile, is a drug that selectively reduces heart rate via ion channel current inhibition in the heart’s sinoatrial node without inducing a negative effect on inotropy. Confirming results found prior to the COVID-19 pandemic, a 2021 randomized controlled clinical trial involving 22 people demonstrated that ivabradine was effective at lowering the heart rate in POTS patients, which suggests that it may be applicable to COVID-19 patients as well (4). While its precise mechanism of action remains unknown, ivabradine is now commonly prescribed, along with exercises, to hundreds of POTS patients, including many with long COVID-19 (5).  

Besides selective heart rate reduction, ivabradine has been found to result in a number of addition beneficial effects. These include anti-inflammatory, anti-atherosclerotic, anti-oxidant and antiproliferative effects, in addition to attenuating endothelial dysfunction and neurohumoral activation (6). 

Ivabradine has emerged as a promising drug in the treatment of persistent cardiac COVID-19 symptoms, with minimal negative side effects. Additional research will be required to elucidate its precise mechanism of action and improve its administration protocol.  

References  

1. Basu-Ray I, Soos MP. Cardiac Manifestations Of Coronavirus (COVID-19). StatPearls. 2020.
2. Abbasi J. Researchers Investigate What COVID-19 Does to the Heart. JAMA – J Am Med Assoc. 2021;
3. Lopez-Leon S, Wegman-Ostrosky T, Perelman C, Sepulveda R, Rebolledo PA, Cuapio A, et al. More than 50 long-term effects of COVID-19: a systematic review and meta-analysis. Sci Rep. 2021; doi: 10.1101/2021.01.27.21250617. 
4. Taub PR, Zadourian A, Lo HC, Ormiston CK, Golshan S, Hsu JC. Randomized Trial of Ivabradine in Patients With Hyperadrenergic Postural Orthostatic Tachycardia Syndrome. J Am Coll Cardiol. 2021; doi: 10.1016/j.jacc.2020.12.029.
5. Heart-Failure Drug Used to Treat Long Covid Symptoms – Bloomberg [Internet]. [cited 2022 Jul 25]. Available from: https://www.bloomberg.com/news/articles/2022-05-25/heart-failure-drug-used-to-treat-long-covid-symptoms
6. Baka T, Repova K, Luptak I, Simko F. Ivabradine in the management of COVID-19-related cardiovascular complications: A perspective. Curr Pharm Des. 2022; doi: 10.2174/1381612828666220328114236. 

Perhaps one of the most unique characteristics of the COVID-19 pandemic has been the large variability in infection-related morbidity and mortality. Disparities have been noted on several levels: between different ethnic groups and even within relatively homogenous demographics. Questions remain as to why some healthy, young adults have asymptomatic or mild infections while others require admission to the intensive care unit. For some researchers, these trends point towards the possibility of genetic and evolutionary determinants of COVID-19 susceptibility.1 

For patients with known genetic abnormalities, deletory effects on immune response to infection might be expected. For example, inborn errors of immunity, which include primary immunodeficiencies, increase susceptibility to a number of different infections, COVID-19 included, as well as autoimmune, inflammatory, and allergic diseases.2 A study performed by the COVID Human Genetic Consortium demonstrated that a myriad of monogenic predispositions which had been previously associated with influenza susceptibility also increased susceptibility to COVID-19. By performing both exomic and genomic sequencing on a large cohort of critically ill COVID-19 patients, the Consortium revealed thirteen such genes, including core immune genes TLR3, IRF7 and IRF9.2 

However, most individuals with genetic susceptibility to COVID-19 infection likely have a more complex etiology, orchestrated by multiple genes. The growing prevalence of genetic testing, both commercially and in healthcare settings, has made large-scale GWAS studies in the COVID-19 era possible. For example, the largest meta-analysis of genetic susceptibility to COVID-19 infection included approximately 125,500 cases and over 2.5 million controls.3 As a result of this mass study, the COVID-19 Host Genetics Initiative identified almost two dozen loci significantly associated with disease susceptibility or severity. One locus which was particularly prominent in their findings was on chromosome three, location 3p21.31 – a gene thought to encode an ACE-2 interacting sodium transporter.3 Given that SARS-CoV-2 targets the ACE-2 receptor on the cell membrane, the relationship between the 3p21.31 locus and increased disease susceptibility is consistent with known mechanisms of COVID-19 infection.  

As previously mentioned, significant discrepancies in the severity of SARS-CoV-2 infection have been noted across different ethnicities. Individuals of European ancestry tend to have reduced morbidity and mortality related to infection. While there is speculation that this disparity could be attributed to pervasive socioeconomic differences across racial groups, adjusting for these variables failed to fully ameliorate the difference for Black and South Asian populations, suggesting additional factors at play.4 Continued investigation revealed one unexpected predictor for susceptibility to COVID-19 infection: Neanderthal ancestry.5,6,7 A study conducted by the COVID-19 Host Genetics Initiative reported that a roughly 75kb haplotype, which is likely traceable to Neanderthal descent and is absent in African Homosapiens, is associated with a nearly 25 percent reduction in hospitalization risk due to COVID-19.6 The haplotype encodes antiviral enzymes which contribute to improved immunity. However, the beneficial effect of this haplotype may be negated by the inheritance of other, less advantageous genes: on chromosome 3, 3p21.31, a 50kb Neanderthal haplotype has been linked to increased severity of COVID-19 infection.7 This specific Neanderthal haplotype is at least three times more prevalent in South Asian populations and is associated with as much as a 60 percent increase in hospitalization.7 

Overall, much is still to be learned concerning evolutionary and genetic susceptibility to SARS-CoV-2 infection, particularly when it comes to the influence of Neanderthal ancestry on disease severity. However, continued investigation will continue to improve our understanding of the mechanisms underlying severe COVID-19 infection and may even help us to better identify at-risk populations or create more targeted curative treatments. 

References 

1 Kerner, G., & Quintana-Murci, L. (2022). The genetic and evolutionary determinants of COVID-19 susceptibility. European journal of human genetics : EJHG, 1–7. Advance online publication. https://doi.org/10.1038/s41431-022-01141-7 

2 Zhang, Q., Bastard, P., Liu, Z., Le Pen, J., Moncada-Velez, M., Chen, J., Ogishi, M., Sabli, I., Hodeib, S., Korol, C., Rosain, J., Bilguvar, K., Ye, J., Bolze, A., Bigio, B., Yang, R., Arias, A. A., Zhou, Q., Zhang, Y., Onodi, F., … Casanova, J. L. (2020). Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science (New York, N.Y.), 370(6515), eabd4570. https://doi.org/10.1126/science.abd4570 

3 COVID-19 Host Genetics Initiative (2021). Mapping the human genetic architecture of COVID-19. Nature, 600(7889), 472–477. https://doi.org/10.1038/s41586-021-03767-x 

4 Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., Curtis, H. J., Mehrkar, A., Evans, D., Inglesby, P., Cockburn, J., McDonald, H. I., MacKenna, B., Tomlinson, L., Douglas, I. J., Rentsch, C. T., Mathur, R., Wong, A., Grieve, R., Harrison, D., … Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430–436. https://doi.org/10.1038/s41586-020-2521-4 

5 Zeberg, H., & Pääbo, S. (2020). The major genetic risk factor for severe COVID-19 is inherited from Neanderthals. Nature, 587(7835), 610–612. https://doi.org/10.1038/s41586-020-2818-3 

6 Pairo-Castineira, E., Clohisey, S., Klaric, L., Bretherick, A. D., Rawlik, K., Pasko, D., Walker, S., Parkinson, N., Fourman, M. H., Russell, C. D., Furniss, J., Richmond, A., Gountouna, E., Wrobel, N., Harrison, D., Wang, B., Wu, Y., Meynert, A., Griffiths, F., Oosthuyzen, W., … Baillie, J. K. (2021). Genetic mechanisms of critical illness in COVID-19. Nature, 591(7848), 92–98. https://doi.org/10.1038/s41586-020-03065-y 

7 Zeberg, H., & Pääbo, S. (2020). The major genetic risk factor for severe COVID-19 is inherited from Neanderthals. Nature, 587(7835), 610–612. https://doi.org/10.1038/s41586-020-2818-3