In 1997, the U.S. Congress passed the Balanced Budget Act, which was meant to limit Medicare-based funding to residency programs and cap the number of residency spots available to medical school graduates [1]. As a result of these residency caps — and in spite of the adjustments made by the Balanced Budget Refinement Act of 1999, which marginally increased residency funding — federal funding for medical residencies has not kept pace with the number of residents needed to care for a growing and aging population.

Between 2001 to 2010, funding for medical residencies increased just 0.9% [2]. One survey, intending to track changes in residency numbers across specialties before and after the 1997 BBA, used the annual National GME Census as its data source. The census, a joint project of the Association of American Medical Colleges and the American Medical Association, tracks the numbers and specialties of U.S. medical residents, as well as those residents’ demographic information. The study found that, following a temporary halt in residency-program growth after 1997, programs began expanding again between 2002 and 2007, with an 8% net increase between 1997 and 2007 [3].

Indeed, in the aforementioned survey, anesthesiology residencies grew faster than almost any other specialty, with an increase of 9.1% between 2002 and 2007 [3]. The data on growth in anesthesia residency programs proved unexpected, after a number of analyses in the late 1990’s and early 2000’s predicted shortages in anesthesiologists: for instance, one study estimated a shortfall of between 1,100 and 3,800 anesthesiologists in 2002 [4]. Meanwhile, specialties like primary care saw marked decreases in the number of residency positions available following the passage of the Balanced Budget Act. According to one analysis, the decade between 1998 and 2008 saw a net loss of 390 positions for first-year family medicine residents [5]. However, these changes did not follow the passage of the Balanced Budget Act immediately, and thus cannot necessarily be linked directly to its passage: a survey of 478 family medicine practices found that, in the two years following the act’s passage and the subsequent changes to residency funding, there was a relatively minor net reduction of 82 residents [6].

While the Balanced Budget Act caps funding for residencies, researchers have predicted that certain subspecialties may actually see a shortage of residents in the coming years, and in some cases may be unable to fill open residency slots. This discrepancy is predicted even in spite of growing enrollment numbers at existing U.S. medical schools—the number of U.S. medical school applicants increased 18% between the 2020 and 2021 academic years, perhaps in part due to the COVID-19 pandemic [7]. Still, one study has predicted that 22,280 individuals will graduate from American medical schools in 2026, matching into a predicted 29,880 residency positions (given the yearly growth rate of 2.55% in U.S. residency slots from 2006 to 2015). If trends continue as calculated in this study, there will not be a shortage of residency positions overall, though highly competitive specialties may encounter a different situation [8].

While the Balanced Budget Act and subsequent Balanced Budget Refinement Act limited government funding for medical residencies, these residency caps control neither the number of medical school graduates per year, nor the chosen specialties and subspecialties of those graduates when matching into residency programs. As a result, certain specialties may encounter a shortage of residents to fill funded residency positions, while others may encounter a lack of available positions for qualified medical school graduates.

References 

[1] Havidich, Jeana E., et al. “The Effect of Lengthening Anesthesiology Residency on Subspecialty Education.” Anesthesia & Analgesia, vol. 99, no. 3, 2004, pp. 844–856., doi:10.1213/01.ane.0000130258.38402.2e.  

[2] Iglehart, John K. “The Residency Mismatch.” New England Journal of Medicine, vol. 369, no. 4, 2013, pp. 297–299., doi:10.1056/nejmp1306445.  

[3] Salsberg, Edward. “US Residency Training Before and After the 1997 Balanced Budget Act.” JAMA, vol. 300, no. 10, 2008, p. 1174., doi:10.1001/jama.300.10.1174.  

[4] Schubert, Armin et al. “An updated view of the national anesthesia personnel shortfall.” Anesthesia & Analgesia, vol. 96,1 (2003): 207-14, table of contents. doi:10.1097/00000539-200301000-00043 

[5] Weida, Nicholas A, et al. “Loss of Primary Care Residency Positions Amidst Growth in Other Specialties.” American Academy of Family Physicians, vol. 82, no. 2, 15 July 2010, p. 121. 

[6] Schneeweiss, Ronald et al. “The effects of the 1997 Balanced Budget Act on family practice residency training programs.” Family Medicine, vol. 35,2 (2003): 93-9. 

[7] “Enrollment Up at U.S. Medical Schools.” AAMC, Association of American Medical Colleges, 16 Dec. 2020. https://www.aamc.org/news-insights/press-releases/enrollment-us-medical-schools

[8] Hayek, Sarah, et al. “Ten Year Projections for US Residency Positions: Will There Be Enough Positions to Accommodate the Growing Number of U.S. Medical School Graduates?” Journal of Surgical Education, vol. 75, no. 3, 2018, pp. 546–551., doi:10.1016/j.jsurg.2017.08.021.  

Hypertension can dramatically increase surgical patients’ rates of morbidity and mortality. Preoperative hypertension increases a patient’s probability of experiencing cardiovascular complications during surgery by 35% [1]. Perioperative and postoperative hypertension can result in bleeding, myocardial infarctions, and adverse cerebrovascular events [2]. To manage intraoperative hypertension, clinicians must monitor patients’ blood pressure, while implementing regimens that account for the risk of cardiovascular events, possible blood pressure fluctuations, and preexisting medications [1].

Clinicians treating hypertensive surgical patients must avoid exacerbating preexisting hypertension, which requires a comprehensive understanding of high-risk events. Perioperatively, hypertension can occur or be worsened due to insufficient analgesia administration, anesthesia induction, extubation, volume overload, and clonidine withdrawal syndrome [1]. Patients undergoing intraperitoneal, abdominal aortic, peripheral vascular, or carotid surgery are most likely to experience hypertensive events [1]. Some studies have reported that anesthesia information management systems (AIMSs) are effective in managing hypertension intraoperatively, but this is not always true due to current technological limitations [3].

While lifestyle modifications may be preferable to pharmacology in driving long-term improvements, little can be done in that regard once surgery has begun [4]. Consequently, pharmacology is an essential aspect of perioperative hypertension management. Patients already taking antihypertensive medication should continue doing so, including on the day of surgery, if such drugs do not lead to negative interactions with drugs needed for surgery and anesthesia [1]. During surgery, clinicians should choose pharmacologic agents according to a patient’s comorbidities [5]. For example, patients with coronary artery disease may benefit most from beta-blockers, combined with diuretics or angiotensin-converting enzyme inhibitors [5]. Intraoperative use of beta-blockers can reduce patients’ 30-day and 1-year mortality [5]. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are not associated with higher mortality rates or complications following noncardiac surgery, suggesting that they are safe to continue administering in the surgical setting [5]. The goal of pharmacology therapy is to stabilize blood pressure at <130/80 mm Hg [5].

Depending on the anesthetic agents present during surgery, designing a safe and appropriate perioperative pharmacological regimen may become more difficult. Anesthesiologists should be aware of the anesthetic implications of each class of antihypertensive medication [6]. For instance, diuretics can promote dehydration, hypokalemia (if they are not potassium-sparing), and hyperkalemia (if they are potassium-sparing) [6]. Angiotensin II receptor antagonists can lead to refractory hypotension during induction and rebound hypertension once use has been discontinued [6]. Angiotensin-converting enzyme inhibitors (ACEIs) are more safely administered on the day of surgery if deep sedation is planned [6]. ACEIs may cause angioedema, but the risk is low [6].

If a patient experiences a hypertensive event during surgery, physicians should choose a fast-acting, safe, easily titrated, inexpensive, and predictable antihypertensive agent [2]. Clinicians should seek to gradually reduce blood pressure by 10 to 15% within the first hour [2]. Following that initial period, blood pressure should continue to decrease, the goal being to reach 160/100 mm Hg within the next two to six hours [2]. In these events, esmolol, nicardipine, fenoldopam, and labetalol are the most commonly used medications [2]. Parenteral agents can also be used, but newer medications appear safer during hypertensive emergencies [2]. While clonidine and ACE inhibitors are not easily titratable and have long-lasting effects, they may also be appropriate in urgent situations [2].

Ultimately, intraoperative hypertension requires clinicians to strike a delicate balance between various pharmacological considerations. Because hypertension increases mortality and morbidity, physicians should aim to design the optimal plan for each individual patient.

References 

[1] M. Koutsaki et al., “Evaluation, risk stratification and management of hypertensive patients in the perioperative period,” European Journal of Internal Medicine, vol. 69, p. 1-7, November 2019. [Online]. Available: https://doi.org/10.1016/j.ejim.2019.09.012.  

[2] J. Varon and P. E. Marik, “Perioperative hypertension management,” Vascular Health and Risk Management, vol. 4, no. 3, p. 615-627, June 2008. [Online]. Available: https://doi.org/10.2147/vhrm.s2471.  

[3] B. G. Nair et al., “Anesthesia Information Management System-Based Near Real-Time Decision Support to Manage Intraoperative Hypotension and Hypertension,” Anesthesia & Analgesia, vol. 118, no. 1, p. 206-214, January 2014. [Online]. Available: https://doi.org/10.1213/ANE.0000000000000027.  

[4] R. Oza and M. Garcellano, “Nonpharmacologic Management of Hypertension: What Works?,” American Family Physician, vol. 91, no. 11, p. 772-776, June 2015. [Online]. Available: https://www.aafp.org/afp/2015/0601/afp20150601p772.pdf.  

[5] W. S. Aronow, “Management of hypertension in patients undergoing surgery,” Annals of Translational Medicine, vol. 5, no. 10, p. 227, May 2017. [Online]. Available: https://doi.org/10.21037/atm.2017.03.54. 

[6] R. Yancey, “Anesthetic Management of the Hypertensive Patient: Part 1,” Anesthesia Progress, vol. 65, no. 2, p. 131-138, Summer 2018. [Online]. Available: https://doi.org/10.2344/anpr-65-02-12.  

In order to adequately respond to the global nature of the COVID-19 pandemic, governments in most countries are working to rapidly vaccinate their residents. Some countries have been successful, though COVID vaccine rollout has been plagued by unequal access. Others have sufficient supply but have struggled with distribution. Meanwhile, low- and middle-income countries have faced difficulties obtaining doses, causing governments and bodies such as the World Health Organization (WHO) to respond.

As of January, Israel had begun to vaccinate citizens at the fastest pace of any nation. The Council on Foreign Relations reported that within two weeks of launching its campaign, Israel had vaccinated 15% of its population [1]. By early February, nearly 90% of the country’s over-60 population had been immunized. These efforts provided a framework for a successful vaccination campaign: between mid-January and early February, the 60+ age cohort saw a 41% decrease in infections and a 31% decrease in hospitalizations [2]. However, in late February, when roughly 50% of Israel’s population had received at least one dose of vaccine, an estimated 0.8% of the Palestinian population in the West Bank and Gaza had access to a dose [3]. The United Arab Emirates shares several advantages with Israel — namely a small population and universal healthcare system — enabling smooth immunizations. By mid-January, the Emirates had delivered vaccine doses to roughly 20% of its residents [1]. The United Kingdom has also had success: in mid-February, 12 million people had received a dose, a number comparable to Israel’s entire population. Nearly every person in the United Kingdom now lives within ten miles of a vaccination center, with those in extremely remote areas able to visit mobile vaccination sites [4].

Other higher-income countries have struggled with logistics and access despite the ability to purchase supplies. As of February 11, the Biden administration had purchased 600 million doses of vaccine from Pfizer and Moderna [5], but the United States and several other Western countries still face vaccine hesitancy rates in excess of 50% [6]. In Canada, a network of local and national systems has been responsible for distribution. In late January, 75% of doses distributed to provincial and territorial governments had yet to be administered to individuals [7].

Meanwhile, in lower-income countries, the sheer expense of vaccines has proven to be a challenge. As of February, over 75% of vaccines had been administered in just 10 countries, according to the WHO and UNICEF [8]. Meanwhile, lower and middle-income countries comprise 85% of the worldwide population [9]. Both governments and NGOs have responded to this inequality. COVAX, an initiative led by WHO, UNICEF, GAVI, and other bodies, has set a goal of delivering 2 billion doses in 2021, with at least 1.3 billion in low- or middle-income countries. Governments in higher-income countries have contributed to the effort, with the U.S. pledging $4 billion to COVAX over two years. However, low- and middle-income countries cannot vaccinate more than 20% of their populations through COVAX, indicating that inequality will remain a problem [8]. The World Bank has pledged $12 billion for vaccine rollout efforts in the developing world and both Russia and China have distributed vaccine supplies to countries across Asia and the Middle East [10].

Global comparisons indicate that a range of logistical, geographical, and political barriers must be overcome to achieve widespread vaccination. These barriers differ from country to country, rooted in various healthcare systems, ethnic conflicts, cultural attitudes, and financial inequity.

References 

[1] Felter, Claire. What to Know About the Global COVID-19 Vaccine Rollout So Far. Council on Foreign Relations, 2021, www.jstor.org/stable/resrep29866.  

[2] Mallapaty, Smriti. “Vaccines Are Curbing COVID: Data from Israel Show Drop in Infections.” Nature, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/33547434/.  

[3] Kennes, Matthias. Opinion, 22 February 2021. “The Stark Inequality of COVID-19 Vaccination between Israel and Palestine: MSF.” Médecins Sans Frontières (MSF) International, 31 Mar. 2021, www.msf.org/stark-inequality-covid-19-vaccination-between-israel-and-palestine. 

[4]  Baraniuk, Chris. “Covid-19: How the UK Vaccine Rollout Delivered Success, so Far.” BMJ, 2021, doi:10.1136/bmj.n421.  

[5] Division, News. “Biden Administration Purchases Additional Doses of COVID-19 Vaccines from Pfizer and Moderna.” HHS.gov, 12 Feb. 2021, www.hhs.gov/about/news/2021/02/11/biden-administration-purchases-additional-doses-covid-19-vaccines-from-pfizer-and-moderna.html.  

[6] Sallam, Malik. “COVID-19 Vaccine Hesitancy Worldwide: A Concise Systematic Review of Vaccine Acceptance Rates.” Vaccines, vol. 9, no. 2, 2021, p. 160., doi:10.3390/vaccines9020160.  

[7] Marchildon, Gregory P. “The Rollout of the COVID-19 Vaccination: What Can Canada Learn from Israel?” Israel Journal of Health Policy Research, vol. 10, no. 1, 2021, doi:10.1186/s13584-021-00449-x.  

[8]B urki, Talha Khan. “Challenges in the rollout of COVID-19 vaccines worldwide.” The Lancet. Respiratory medicine vol. 9,4 (2021): e42-e43. doi:10.1016/S2213-2600(21)00129-6. 

[9] Wouters, Olivier J, et al. “Challenges in Ensuring Global Access to COVID-19 Vaccines: Production, Affordability, Allocation, and Deployment.” The Lancet, vol. 397, no. 10278, 2021, pp. 1023–1034., doi:10.1016/s0140-6736(21)00306-8.  

[10] “World Bank COVID-19 Response.” World Bank, www.worldbank.org/en/news/factsheet/2020/10/14/world-bank-covid-19-response.  

While general anesthesia (GA) can safely and reversibly induce unconsciousness, exposure to GA may, as has grown increasingly evident, give rise to cellular and structural changes throughout the brain and hippocampus, incurring both neurotoxic and neuroprotective effects (1). Some of these effects may be long-lasting and may translate into cognitive and behavioral deficits, given the key role of the hippocampus in memory and cognition, as well as the fact that postnatal hippocampal neurogenesis persists into adulthood (2). As such, the United States Food and Drug Administration issued in 2016 a precautionary communication on GA use in patients under 3 years of age (3).

The effects of GA span a range of intra- and intercellular scales. During a critical period of brain development, midazolam, a pre-anesthetic, not only increases the rate of formation of dendritic spines but also the stability of newly formed spines. These two mechanisms together lead to a sustained increase in dendritic spine densities forming fully functional synapses (4).

In general, general anesthesia may impair neuronal maturation and survival in the hippocampus, as well as neurogenesis. One study found that propofol, which can be used as an induction agent during general anesthesia, impairs the maturation and survival of adult-born hippocampal neurons (4), while another study highlighted a certain age sensitivity of cells to these impacts, as propofol induced a marked decrease in the survival and dendritic maturation of 17-day-old, but not 11-day-old, hippocampal neurons at the time of anesthesia (5). This cell age-dependent vulnerability of neurons to anesthetic toxicity has since been replicated (6). Impaired neurogenesis and cellular function have also been demonstrated to be drug- and sex-specific. One study found that isoflurane, specifically, induced hippocampal cell injury and cognitive impairments in adult rats (7), while another demonstrated that propofol produces short-lived impairments, while midazolam and dexmedetomidine alter cognition after a several-week delay through mechanisms associated with decreased neurogenesis (8). Behaviorally, GA administered to postnatal day 6 (P6) rhesus monkeys was found also to result in increased anxiety and emotional reactivity when they reached 6 months of age; this also impaired hippocampus-related learning tasks in adulthood (9).

At a molecular level, general anesthesia induces neuroinflammation – including in the hippocampus. Specifically, one research study showed the GA-activated canonical nuclear factor-κB pathway to be linked to increased isoflurane-induced hippocampal interleukin-1β levels and resultant cognitive deficits in aged rats (10), while another research team demonstrated hippocampal and extra-hippocampal dysfunction due to neuroinflammation following GA (11). These effects appear anesthetic-specific (12).

A range of additional intracellular effects have also been identified. First, the exposure of P7 rat pups to 6-hour anesthesia has been shown to induce aberrant mitochondrial morphology in neurons and a marked reduction in the number of mitochondrion-containing presynaptic terminals in the hippocampal subiculum (13,14). In addition, hippocampal tau protein phosphorylation has been linked to isoflurane-induced cognitive dysfunction in mice (15). Finally, at a cytoarchitectural level, one study found long-erm effects of single or multiple sevoflurane exposures on rat hippocampal ultrastructure (16).

General anesthesia has ostensibly different impacts on the hippocampus in anesthetic-, brain developmental stage-, and age-specific ways. Clearly, further laboratory work and clinical investigations are warranted to ensure the prevention of any lasting adverse effects on the human brain and hippocampal function in particular.

References

1. Wu L, Zhao H, Weng H, Ma D. Lasting effects of general anesthetics on the brain in the young and elderly: “mixed picture” of neurotoxicity, neuroprotection and cognitive impairment. Vol. 33, Journal of Anesthesia. Springer Tokyo; 2019. p. 321–35.

2. Deng W, Aimone JB, Gage FH. New neurons and new memories: How does adult hippocampal neurogenesis affect learning and memory? Nature Reviews Neuroscience. 2010.

3. FDA. FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. US Food Drug Adm Drug Saf Commun. 2016. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-review-results-new-warnings-about-using-general-anesthetics-and

4. De Roo M, Klauser P, Briner A, Nikonenko I, Mendez P, Dayer A, et al. Anesthetics rapidly promote synaptogenesis during a critical period of brain development. PLoS One. 2009.

5. Krzisch M, Sultan S, Sandell J, Demeter K, Vutskits L, Toni N. Propofol anesthesia impairs the maturation and survival of adult-born hippocampal neurons. Anesthesiology. 2013 Mar;118(3):602–10.

6. Hofacer RD, Deng M, Ward CG, Joseph B, Hughes EA, Jiang C, et al. Cell age-specific vulnerability of neurons to anesthetic toxicity. Ann Neurol. 2013.

7. Lin D, Zuo Z. Isoflurane induces hippocampal cell injury and cognitive impairments in adult rats. Neuropharmacology. 2011 Dec;61(8):1354–9.

8. Kim JL, Bulthuis NE, Cameron HA. The Effects of Anesthesia on Adult Hippocampal Neurogenesis. Front Neurosci. 2020 Oct 22;14:1090.

9. Raper J, Alvarado MC, Murphy KL, Baxter MG. Multiple anesthetic exposure in infant monkeys alters emotional reactivity to an acute stressor. Anesthesiology. 2015;123(5):1084–92.

10. Li ZQ, Rong XY, Liu YJ, Ni C, Tian XS, Mo N, et al. Activation of the canonical nuclear factor-κB pathway is involved in isoflurane-induced hippocampal interleukin-1β elevation and the resultant cognitive deficits in aged rats. Biochem Biophys Res Commun. 2013 Sep 6;438(4):628–34.

11. Cascella M, Bimonte S. The role of general anesthetics and the mechanisms of hippocampal and extra-hippocampal dysfunctions in the genesis of postoperative cognitive dysfunction. Vol. 12, Neural Regeneration Research. Wolters Kluwer Medknow Publications; 2017. p. 1780–5.

12. Shen X, Dong Y, Xu Z, Wang H, Miao C, Soriano SG, et al. Selective anesthesia-induced neuroinflammation in developing mouse brain and cognitive impairment. Anesthesiology. 2013.

13. Sanchez V, Feinstein SD, Lunardi N, Joksovic PM, Boscolo A, Todorovic SM, et al. General anesthesia causes long-term impairment of mitochondrial morphogenesis and synaptic transmission in developing rat brain. Anesthesiology. 2011.

14. Lunardi N, Ori C, Erisir A, Jevtovic-Todorovic V. General anesthesia causes long-lasting disturbances in the ultrastructural properties of developing synapses in young rats. Neurotox Res. 2010.

15. Li C, Liu S, Xing Y, Tao F. The role of Hippocampal Tau protein phosphorylation in isoflurane-induced cognitive dysfunction in transgenic APP695 Mice. Anesth Analg. 2014.

16. Amrock LG, Starner ML, Murphy KL, Baxter MG. Long-term effects of single or multiple neonatal sevoflurane exposures on rat hippocampal ultrastructure. In: Anesthesiology. Lippincott Williams and Wilkins; 2015. p. 87–95.

Human challenge studies are research experiments involving the deliberate exposure, or “challenge” of human subjects to infectious disease—regardless of whether they have been vaccinated [1]. Indeed, a human challenge study can involve observing the results of certain treatments, including vaccines, as well as the course of the infection itself.  

Human challenge studies have been part of medical research and the development of treatments since the eighteenth century. It is widely accepted that the first modern human challenge study was conducted by Edward Jenner in 1796 [2]. At the time, smallpox was widespread and virulent. Variolation, wherein a subject would be deliberately exposed to smallpox in an attempt to inoculate them, had a high incidence rate. Jenner’s experiment involved exposure to cowpox, a milder disease, through rubbing the infection onto incisions in the skin, and proved successful. Contemporary researchers acknowledge that Jenner’s experiment was ethically dubious, in part because his first subject was a child and therefore could not give informed consent [2]. However, these studies have remained part of medical research ever since. Discussion surrounding the efficacy and ethics of these studies has surfaced during major pandemics, including the most recent COVID-19 pandemic.  

The persistence of human challenge studies is in part due to the establishment of certain ethical standards in medical research that has allowed for the minimization of risk. However, the extent to which these studies are ethically acceptable continues to be debated. Bambery et al. list several criteria that are already standard for medical research, including risk reduction, informed consent, and attention to how participants are selected [3]. In addition, the authors propose criteria for performing human challenge studies, including independent review of the challenge model, assessment of risks and benefits that is accessible to the public, protective measures to prevent those outside of the study from being exposed, and compensation to participants for harm incurred [3].  

When it comes to pandemics, these studies can improve the speed and efficacy with which vaccines are approved. It also requires far fewer subjects to be exposed to potentially harmful vaccine candidates than in a traditional phase 3 trial [4]. Eyal et al. argues that the pressing nature of the COVID-19 pandemic made human challenge studies permissible, assuming they follow an appropriate design [4].  

However, this model does not entirely assuage concerns regarding public perception and risk to participants [5]. High risk of exposure to COVID-19 is correlated with vulnerabilities such as poverty. Given the history of exploitation connected to human challenge studies, targeting populations that have been subjected to injustice for recruitment as test subjects could reflect badly on the project and sow mistrust in the communities that researchers rely on to collect data [6]. And while Eyal et al. emphasize that volunteers should receive priority care, it is not guaranteed that treatment for damage done to participants’ health in potential studies will be fully compensated [6].  

In February, the government of the United Kingdom received approval to launch the first human challenge study involving SARS-COV-2. The study will involve first infecting patients and observing them in quarantine, and later it will involve the testing of vaccine candidates [1]. Researchers are still recruiting participants for this study. How the researchers will handle the ethical dilemmas mentioned above as they arise remains to be seen, but, if successful, the study could improve our understanding of the virus and accelerate the arrival of approved vaccines to the market.        

References 

[1] Newman, Tim | Medical News Today | Feb 18, 2021. “What Are Human Challenge Studies?” Medical News Today, 18 Feb. 2021, https://www.medicalnewstoday.com/articles/what-are- human-challenge-studies 

[2] Machemer, Theresa | Smithsonian Magazine | Dec 16, 2020. “A Brief History of Human Challenge Trials” Smithsonian Magazine, 16 Dec. 2020, https://www.smithsonianmag.com/science-nature/brief-history-human-challenge-trials-180976556/ 

[3] Bambery, B. et al. “Ethical Criteria for Human Challenge Studies in Infectious Diseases: Table 1.” Public Health Ethics, vol. 9, no. 1., 2015, pp. 92-103. Doi: 10.1093/phe/phv026. 

[4] Eyal, N., et al. “Human Challenge Studies to Accelerate Coronavirus Vaccine Licensure.” The Journal of Infectious Diseases, 2020. Doi: 10.1093/infdis/jiaa152. 

[5] “Human Challenge Studies Are Unlikely to Accelerate Coronavirus Vaccine Licensure Due to Ethical and Practical Issues.” The Journal of Infectious Diseases, 2020. Doi: 1093/infdis/jiaa457.  

[6] Euzebiusz, J. & Michael J. Selgelid. “COVID-19 Human Challenge Studies: Ethical Issues.” Lancet Infectious Diseases, 2020. Doi: 10.1016/S1473-3099(20)30438-2.