The security of healthcare data remains a challenge in institutions across the U.S. A recent Stanford University report estimates a 48% growth in medical data each year 1, from which stolen records can be sold for as much as $1,000 each on the black market 2. It is estimated that 50 million Americans had their sensitive health data breached in 2021 alone 3. There are many ways to protect healthcare information. This article will focus on encryption as a method for cybersecurity in the healthcare space. 

Cryptography is an indispensable tool used to protect information in any organization, enabling secure transmission over the Internet. Data encryption in healthcare specifically refers to the conversion of sensitive and confidential patient data into a coded language that can only be accessed by authorized individuals with a decryption key, improving cybersecurity. In this context, both artificial intelligence and quantum technology are transforming the health sector in regard to cybersecurity 4.  

Healthcare cloud computing, which is increasingly the norm, presents with a unique set of challenges. According to a recent meta-analytic review, data security, availability, and integrity, as well as information confidentiality and network security remain major challenges inherent to cloud security in healthcare 5.  

However, data encryption, authentication, and classification represent powerful cybersecurity solutions that are important for healthcare data. Data encryption in particular can be applied to store and retrieve data from the cloud in order to ensure secure communication.  

It remains difficult for healthcare providers and their business associates to balance delivering quality care and keeping information systems accessible to providers with protecting patient privacy and meeting the strict regulatory requirements set forth by the U.S.’ Health Insurance Portability and Accountability Act (HIPAA) or the European Union’s General Data Protection Regulation (GDPR), among other regulations. 

In light of increasing regulatory requirements for healthcare data protection, healthcare organizations that take a proactive approach to implementing best practices for healthcare cybersecurity are best equipped for continued compliance and at lower risk of suffering costly data breaches. Best practices include but are not limited to educating healthcare staff, implementing data usage controls, restricting access to data and applications, securing mobile devices, and encrypting data. Alongside data encryption and other measures though, it remains equally important to conduct regular risk assessments, use off-site data backups, and regularly test the compliance of business associates 6. 

Most recently, in the spring of 2023, Vaultree, a major player in cybersecurity, announced a leap forward in healthcare data protection, introducing its industry-first fully functional data-in-use encryption solution to the sector 7. Combined with a software development kit and an encrypted chat tool, this technology aims to provide full-scale protection of sensitive patient data, even in the event of a breach, without compromising operational efficiency. 

Additional research and development remains to be carried out in the field of cybersecurity on encryption and beyond for healthcare data in order to optimize patient privacy and well-being. Further areas of development are sure to include, among other technologies, quantum computing as it relates to data encryption 8.  

References 

1. Harnessing the Power of Data in Health. https://med.stanford.edu/content/dam/sm/sm-news/documents/StanfordMedicineHealthTrendsWhitePaper2017.pdf
2. Patient medical records sell for $1K on dark web. Available at: https://www.beckershospitalreview.com/cybersecurity/patient-medical-records-sell-for-1k-on-dark-web.html/. (Accessed: 24th June 2023)
3. Health data breaches swell in 2021 amid hacking surge, POLITICO analysis finds – POLITICO. Available at: https://www.politico.com/news/2022/03/23/health-data-breaches-2021-hacking-surge-politico-00019283. (Accessed: 24th June 2023)
4. Jayanthi, P. & Iyyanki, M. Cryptography in the Healthcare Sector With Modernized Cyber Security. in (2020). doi:10.4018/978-1-7998-2253-0.ch008
5. Mehrtak, M. et al. Security challenges and solutions using healthcare cloud computing. Journal of Medicine and Life (2021). doi:10.25122/jml-2021-0100
6. Healthcare Cybersecurity: Tips for Securing Private Health Data. Available at: https://www.digitalguardian.com/blog/healthcare-cybersecurity-tips-securing-private-health-data. (Accessed: 24th June 2023)
7. Vaultree Sets a New Benchmark in Healthcare Cybersecurity with Industry-First, Fully Functional Data-In-Use Encryption Solution | Business Wire. Available at: https://www.businesswire.com/news/home/20230523005486/en/Vaultree-Sets-a-New-Benchmark-in-Healthcare-Cybersecurity-with-Industry-First-Fully-Functional-Data-In-Use-Encryption-Solution. (Accessed: 24th June 2023)
8. Quantum Cryptography and the Health Sector. (2022). https://www.hhs.gov/sites/default/files/quantum-cryptography-and-health-sector.pdf

Hemorrhage remains a major contributor to morbidity and mortality during the perioperative period. The swift diagnosis and treatment of coagulopathy is critical to the care of severely bleeding patients. Current methods for diagnosing coagulopathy, however, remain limited by long laboratory runtimes, a lack of information on specific abnormalities of the coagulation cascade, minimal in vivo applicability, and little ability to guide the transfusion of blood products. Viscoelastic testing may allow providers to gather data related to bleeding and coagulopathy before a patient undergoes anesthesia and surgery. 

Viscoelastic testing offers a promising solution to many of these challenges 1, helping with the care of severely bleeding patients in the context of major surgery, major trauma, or postpartum hemorrhage 2. In the perioperative period, two assays are most frequently used: kaolin thromboelastography (TEG)-based, and tissue factor–activated rotational thromboelastometry (ROTEM)-based viscoelastic monitoring. The three main goals of such viscoelastic testing assays are to predict bleeding, assess platelet function, and allow for perioperative testing to reduce transfusion 3. They thus provide a nuanced view of the elements of the coagulation system, allowing for the rapid administration of targeted therapy 3. Specifically, these assays can help guide basic decisions regarding the treatment of perioperative coagulopathy, including when the clinician should transfuse platelets, administer fibrinogen concentrate, or administer plasmatic coagulation factors 2.  

However, it is critical to note that standard TEG/ROTEM assays are neither sensitive nor specific enough to adequately detect platelet inhibition, the effects of direct oral anticoagulants, or inherited bleeding disorders, such as cases of hemophilia or von Willebrand disease. Diagnoses of these specific conditions are better made preoperatively as part of a routine diagnostic workup 4.   

While viscoelastic testing remains a relatively novel method to assess coagulation status, evidence for its use appears favorable in reducing blood product transfusions, especially in cardiac surgery patients 1. Indeed, reviews of the literature, which is primarily focused on cardiac surgery patients, have demonstrated that transfusions of packed red blood cells, plasma, and platelets are all decreased in patients whose transfusions were guided by viscoelastic testing rather than by clinical assessment or conventional laboratory tests. More recent research has further confirmed that implementing transfusion algorithms based on the results of viscoelastic point-of-care coagulation testing can reduce transfusions and lead to improved patient outcomes 2.  Finally, meta-analytic data have corroborated that the use of viscoelastic testing in cardiac surgery patients can effectively minimize allogenic blood products exposure, dampen postoperative bleeding at 12 and 24 hours postoperatively, and reduce the need for redo surgery unrelated to surgical bleeding 5.  

Overall mortality rates have also been shown to be lower in viscoelastic testing groups, while viscoelastic testing also appears to be cost-effective from a clinical standpoint 1.  

However, while results are promising, there remains a dearth of systematic, larger scale trials. Viscoelastic testing remains a relatively novel method, and further improvement and clinical validation of these broadly used basic assays in different surgery contexts are needed 2. 

References 

1. Shen, L., Tabaie, S. & Ivascu, N. Viscoelastic testing inside and beyond the operating room. J. Thorac. Dis. 9, S299–S308 (2017). doi: 10.21037/jtd.2017.03.85.
2. Erdoes, G., Koster, A. & Levy, J. H. Viscoelastic Coagulation Testing: Use and Current Limitations in Perioperative Decision-making. Anesthesiology 135, 342–349 (2021). doi: 10.1097/ALN.0000000000003814.
3. Agarwal, S. & Abdelmotieleb, M. Viscoelastic testing in cardiac surgery. Transfusion 60 Suppl 6, S52–S60 (2020). doi: 10.1111/trf.16075.
4. Koscielny, J. et al. A practical concept for preoperative identification of patients with impaired primary hemostasis. Clin. Appl. Thromb. (2004). doi:10.1177/107602960401000301
5. Meco, M. et al. Viscoelastic Blood Tests Use in Adult Cardiac Surgery: Meta-Analysis, Meta-Regression, and Trial Sequential Analysis. J. Cardiothorac. Vasc. Anesth. 34, 119–127 (2020). doi: 10.1053/j.jvca.2019.06.030. 

Since the 1960s, some US states have passed and enforced certificate of need (CON) laws for healthcare entities, with regulations varying in their application procedures, the stringency of review, and coverage across states [1, 2, 3]. These laws require prospective healthcare providers aspiring to enter the healthcare industry and existing providers seeking to make major capital expenditures to receive the approval of the state’s healthcare agency before doing so [1]. The objectives of these laws are threefold: to improve the quality of healthcare services in regions with a volume-quality relationship, to expand access to healthcare by keeping providers from engaging in “cream-skimming,” and to reduce costs by eliminating unnecessary health facilities [2].  

To receive approval for operations or expenditures under CON laws, medical providers may have to expend years of effort and thousands of dollars [4]. This is because CON laws require the approving authority not to assess a particular provider’s qualifications, but rather the “needs” of the community in question [5]. A key idea behind this feature of the US healthcare certificate of need laws is to have providers prove that their services would meet a real need in the community. As a result, other providers already servicing the community are allowed to contest a pending application, potentially creating years of delays and heightening the evidentiary burden needed to achieve approval [5]. 

Consequently, the ability of CON laws to achieve their purported objectives is dubious. In terms of quality of healthcare services, empirical studies of how certificate of need laws in the US affect hospitals reveal how little they do to improve healthcare [1, 5]. Stratmann and Wille’s 2018 study found that “the quality of hospital care in states with CON laws is not systematically higher than the corresponding quality in non-CON states,” casting doubt on the laws’ ability to accomplish their first aim [1]. Furthermore, the researchers found that some CON states provide worse service to their communities, with mortality rates for heart failure, pneumonia, and heart attacks being higher in CON states than in non-CON states [1]. 

Similarly, CON laws are associated with decreased access to healthcare [5]. States with such laws tend to have fewer ambulatory surgery centers and hospitals, particularly in rural areas; dialysis clinics; and hospice care facilities [5]. Moreover, hospitals in these states tend to have fewer hospital beds and are less likely to offer CT, PET, and MRI scans to their patients [5]. And already-vulnerable communities are especially likely to suffer the negative consequences of CON laws [5]. For example, Delia et al. suggested that CON laws were to blame for Black patients’ reduced access to hospitals that could provide them with cardiac angiography [6]. 

Lastly, certificate of need regulations have an uncertain effect on US healthcare costs, so their ability to meet their third objective is unclear. In an examination of the cost-effectiveness of CON laws, Conover and colleagues estimated the expected costs of CON regulation to exceed its expected benefits by 8% (approximately $300 million) [2]. However, they also expressed that their estimation of net costs could be skewed [2]. As such, the true level of economic benefits or losses produced by CON laws remains ambiguous. 

With this class of regulations failing to achieve at least two of their three stated objectives, it is unsurprising why fourteen states have repealed their CON laws since the 1980s [2]. Nevertheless, these laws remain operational in thirty-six states and the District of Columbia [2]. When reevaluating these laws, state authorities should keep in mind the evidence suggesting that certificates of need are not as effective as they aspire to be. 

References 

[1] T. Stratmann and D. Wille, “Certificate-of-Need Laws and Hospital Quality,” Mercatus Center, Updated July 12, 2018. [Online]. Available: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3211657.  

[2] C. J. Conover and J. Bailey, “Certificate of Need Laws: A Systematic Review and Cost-Effectiveness Analysis,” BMC Health Services Research, vol. 20, no. 748, pp. 1-29, August 2020. [Online]. Available: https://doi.org/10.1186/s12913-020-05563-1.  

[3] F. J. Hellinger, “The Effect of Certificate-of-Need Laws on Hospital Beds and Healthcare Expenditures: An Empirical Analysis,” AJMC, Updated January 23, 2018. [Online]. Available: https://mhcc.maryland.gov/mhcc/pages/home/workgroups/documents/CON_modernization_workgroup/Articles/Article%208.pdf.   

[4] “Certificate-of-Need Laws: Why They Exist and Who They Hurt,” State Policy Network, Updated April 1, 2021. [Online]. Available: https://spn.org/articles/certificate-of-need-laws/.  

[5] M. Mitchell and W. Mitchell, “How more states can free up emergency health care,” The Hill, Updated April 10, 2020. [Online]. Available: https://thehill.com/opinion/healthcare/492070-how-more-states-can-free-up-emergency-health-care/.  

 [6] D. Delia et al., “Effects of regulation and competition on health care disparities: the case of cardiac angiography in New Jersey,” BMC Health Services Research, vol. 34, no. 1, pp. 63-91, February 2009. [Online]. Available: https://doi.org/10.1215/03616878-2008-992.  

Anesthetic drug development is experiencing a resurgence of interest given new demands in clinical practice that can potentially be met with better agents. Existing drugs each have their own drawbacks but have improved upon drugs of the past. Continuing advancements in medicine will improve patient outcomes and experiences. How, then, are new anesthesia drugs developed? 

Current efforts to develop anesthetic drugs are primarily focused on modifying the structures of existing drugs to enhance their pharmacodynamic and pharmacokinetic properties [1]. Drug metabolism and pharmacokinetic optimization strategies specifically may help improve the physical and chemical properties of drugs. The hope is to minimize the negative effects of existing anesthetics while maintaining or enhancing the desired effects. This is a particularly dynamic area of research in the context of sedatives, analgesics, and muscle relaxants, and significant developments have recently occurred. 

Two approaches are prodrug and soft drug design. Prodrugs are compounds that are activated only once in the body and may have the advantage of providing greater control over where and when the activated drug works. Soft drugs are compounds that are quickly and predictably broken down into an inactive, non-toxic form, which may result in fewer side effects. 

Prodrug design is a useful approach for augmenting the drug-like properties of a molecule to overcome formulation and delivery difficulties. Prodrug design strategies have a wide range of applications. In the case of the soft drug approach, a retrometabolic drug design strategy allows for a predictable metabolic route via a single inactivation. Soft drug design meets the unique needs of modern anesthesia practice, in which it is often good for anesthetics to be quickly broken down by the body so that the patient can recover from anesthesia faster [2]. 

Drugs recently under development using these design approaches include analogs of midazolam, propofol, and etomidate, such as remimazolam, PF0713, and cyclopropyl methoxycarbonyl-etomidate [3].  

However, tweaking existing drugs may not provide the best solution. So how are truly new anesthesia drugs developed? Another approach relies on large quantities of data to screen for potential novel drugs. Researchers rapidly screen of large molecular libraries for activity in structural or phenotypic assays that show potential for anesthetic and target receptor interactions. Such high-throughput screening may lead to the identification of entirely new classes of drugs, which can be beneficial because they would provide different angles into the same desired effects [3].  

Researchers have also recently gradually learned to apply artificial intelligence-assisted drug design strategies for drug metabolism studies [4]. As enzymes (usually cytochrome P450) are essential for drug metabolism, the three-dimensional crystal structures of various enzymes and carrier proteins have been studied,. This may facilitate the prediction of molecular interactions in the very initial stages of drug design and is an area where AI may be extremely helpful.  

In recent years, new drug development programs for analogs of anesthetics have resulted in only a handful of compounds with market approval [6]. Particularly for sedatives, hypnotics and neuromuscular blockers, there remains relatively little drug discovery activity to this day [5].  

Part of the reason for this may be that the mechanisms of action of anesthetics are still not fully understood. In addition, the industry perceives little need for new anesthetic drugs since needs are well addressed by existing agents or fail to compete with their safety profiles. For soft sedative-hypnotics in particular, abnormal excitatory activity has led to the discontinuation of drug development programs. This was the case for the etomidate and propanidid soft drug analogs.  

To compete with existing drugs, novel anesthetic drugs need a high therapeutic index and minimal side effects to optimize the benefit/risk ratio in patients. In addition, anesthesiologists need to communicate ongoing needs for new anesthetic drugs more effectively to better drive their development. Further work using existing strategies may provide improved anesthetics in the future, but it is also possible that rethinking how new anesthesia drugs are developed will open additional avenues to explore. 

References 

1. Deng, C., Liu, J. & Zhang, W. Structural Modification in Anesthetic Drug Development for Prodrugs and Soft Drugs. Frontiers in Pharmacology (2022). doi:10.3389/fphar.2022.923353
2. Stöhr, T. et al. Pharmacokinetic properties of remimazolam in subjects with hepatic or renal impairment. Br. J. Anaesth. (2021). doi:10.1016/j.bja.2021.05.027
3. Chitilian, H. V., Eckenhoff, R. G. & Raines, D. E. Anesthetic drug development: Novel drugs and new approaches. Surg. Neurol. Int. 4, S2 (2013). doi: 10.4103/2152-7806.109179
4. Smith, G. F. Artificial Intelligence in Drug Safety and Metabolism. in Methods in Molecular Biology (2022). doi:10.1007/978-1-0716-1787-8_22
5. Kilpatrick, G. J. & Tilbrook, G. S. Drug development in anaesthesia: Industrial perspective. Current Opinion in Anaesthesiology (2006). doi:10.1097/01.aco.0000236137.23475.95
6. Keam, S. J. Remimazolam: First Approval. Drugs (2020). doi:10.1007/s40265-020-01299-8

Since the beginning of the pandemic, at least 60% of Americans have been infected with COVID-19 (1). Contrary to initial predictions, reinfection from the virus is not uncommon, despite immunity induced by previous exposure or vaccination (2). As defined by the Centers for Disease Control and Prevention (CDC), reinfection can be diagnosed if a patient had COVID-19, recovered, and later became infected again, as confirmed by a polymerase chain reaction (PCR) test (3). Reinfections can occur from weeks to over a year since the first infection, though patients often present with mild symptoms (4). Throughout the pandemic, the rate of COVID-19 reinfection has changed over time with the emergence of each variant.

At the beginning of the pandemic, reinfections from the first variants of the virus appeared to be extremely rare (2). However, with the emergence of the delta variant in 2021, reinfections increased significantly due to the strain’s high transmissibility and ability to evade immune responses (5). Approximately 63 to 167% more transmissible than the alpha strain, the delta variant could avoid neutralization from antibodies and replicate at faster speeds, resulting in higher viral loads and more severe symptoms (6, 7). According to one major study with over 27,000 participants, delta reinfections constituted 1.16% of total cases, while alpha reinfections comprised only 0.46% (8). While higher than that of alpha, the rate of delta reinfections still remained low due to vaccinations, which demonstrated decreased but significant efficacy in preventing infection (8).  

After a decrease in COVID-19 cases, the omicron variant emerged in late 2021, causing a significant increase in infections (8). Although associated with less severe symptoms, the omicron variant had a transmissibility 2 to 4 times higher than the delta strain (9). Like delta, the omicron variant could evade immune responses due to mutations in its genome, but omicron contained novel, pernicious mutations that allowed it to prevent antibodies from binding to it (10). Due to these mutations, vaccines were significantly less effective in preventing omicron infection, with two-dose vaccine efficacy dropping to 55% after 20 weeks, compared to 88% efficacy against alpha (11). With its extremely high transmissibility and ability to evade immune responses produced by vaccines and previous infections, the omicron variant has proved to be the most common source of COVID-19 reinfection over time (8). According to the aforementioned study, omicron reinfections constituted 13% of all COVID-19 cases, but researchers estimate that the actual rate is significantly higher due to the prevalence of asymptomatic omicron reinfections and unreported at-home rapid tests (8). Additionally, the study reported that the median time from the first infection to omicron reinfection was significantly longer at 361 days compared to 204 for alpha and 291 for delta; however, omicron also constituted 96.6% of reinfections that occurred after less than one year (8). These statistics both demonstrate the power of omicron in reinfecting patients.  

As the world returns to normalcy, COVID-19 reinfection presents a critical problem that many health experts believe will compound over time. Although symptoms are typically mild, reinfections can increase the risk of adverse health events (12). With each additional reinfection, the risk of developing musculoskeletal conditions, diabetes, kidney disease, and mental health conditions increases (12). Researchers also fear that reinfections may predispose patients to “long COVID,” a condition in which COVID-19 symptoms persist for months after the patient no longer tests positive for the virus (12). As the omicron variant causes the most reinfections, researchers emphasize that individuals obtain the new Moderna and Pfizer bivalent boosters which, unlike the original vaccines, specifically target omicron (13). While the initial two-dose regimen still provides protection against severe symptoms and hospitalization, the bivalent boosters show 37% higher efficacy against severe infection than the monovalent boosters (13). In addition to bivalent boosters, researchers also recommend the continuation of COVID-19 protocols — masking, disinfecting, and social distancing (14). Although the worst of the pandemic may be over, the risk of COVID-19 reinfections presents a critical challenge in the post-pandemic world. 

References 

1: Clarke, K., Jones, J., Deng, Y., Nycz, E., Lee, A., Iachan, R., Gundlapalli, A., Hall, A. and MacNeil, A. 2022. Morbidity and mortality weekly report. MMWR 71(17):606-608. DOI: 10.15585/mmwr.mm7117e3. 

2: Hall, V., Foulkes, S., Charlett, A., Atti, A., Monk, E., Simmons, R., Wellington, E., Cole, M., Saei, A., Oguti, B., Munro, K., Wallace, S., Kirwan, P., Shrotri, M., Vusirikala, A., Rokadiya, S., Kall, M., Zambon, M., Ramsay, M., Brooks, T., Brown, C., Chand, M. and Hopkins, S. 2021. SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN). Lancet 397(10283):1459-1469. DOI: 10.1016/S0140-6736(21)00675-9. 

3: Centers for Disease Control and Prevention. 2023. Reinfection. URL: https://www.cdc.gov/coronavirus/2019-ncov/your-health/reinfection.html.  

4: Abu-Rabbad, L., Chemaitelly, H. and Bertollini, R. 2021. Severity of SARS-CoV-2 reinfections as compared with primary infections. New England Journal of Medicine 2021(385):2487-2489. DOI: 10.1056/NEJMc2108120.  

5: Planas, D., Veyer, D., Baidaliuk, A., Staropoli, I., Guivel-Benhassine, F., Rajah, M., Planchais, C., Porrot, F., Robillard, N., Puech, J., Prot, M., Gallais, F., Gantner, P., Velay, A., Guen, L., Kassis-Chikani, N., Edriss, D., Belec, L., Seve, A., Courtellemont, L., Pere, H., Hocqueloux, L., Fafi-Kremer, S., Prazuck, T. and Schwartz, O. 2021. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Nature 2021(596):276-280. DOI: 10.1038/s41586-021-03777-9. 

6: Earnest, R., Uddin, R., Matluk, N., Renzette, N., Turbett, S., Siddle, K., Loreth, C., Adams, G., Tomkins-Tinch, C., Petrone, M., Rothman, J., Breban, M., Koch, R., Billig, K., Fauver, J., Vogels, C., Bilguvar, K., Kumar, B., Landry, M., Peaper, D. and Grubagh, N. 2022. Comparative transmissibility of SARS-CoV-2 variants Delta and Alpha in New England, USA. Cell Reports Medicine 3(4):100583. DOI: 10.1016/j.xcrm.2022.100583. 

7: Mlcochova, P., Kemp, S., Dhar, M., Papa, G., Meng, B., Ferreira, I., Datir, R., Collier, D., Albecka, A., Singh, S., Pandey, R., Brown, J., Zhou, J., Goonawardene, N., Mishra, S., Whittaker, C., Mellan, T., Marwal, R., Datta, M., Sengupta, S., Ponnusamy, K., Radhakrishnan, V., Abdullahi, A., Charles, O. and Gupta, R. 2021. SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion. Nature 2021(599):114-119. DOI: 10.1038/s41586-021-03944-y.  

8: Ozudogru, O., Bache, Y. and Acer, O. 2022. SARS CoV-2 reinfection rate is higher in the Omicron variant than in the Alpha and Delta variants. Irish Journal of Medical Science 2022:1-6. DOI: 10.1007/s11845-022-03060-4.  

9: Liu, Y. and Rocklov, J. 2022. The effective reproductive number of the Omicron variant of SARS-CoV-2 is several times relative to Delta. Journal of Travel Medicine 29(3):taac037. DOI: 10.1093/jtm/taac037.  

10: Syed, A., Ceiling, A., Taha, T. and Doudna, J. 2022. Omicron mutations enhance infectivity and reduce antibody neutralization of SARS-CoV-2 virus-like particles. PNAS 119(31):e2200592119. DOI: 10.1073/pnas.2200592119.  

11: Zeng, B., Gao, L., Zhou, Q., Yu, K. and Sun, F. 2022. Effectiveness of COVID-19 vaccines against SARS-CoV-2 variants of concern: a systematic review and meta-analysis. BMC Medicine 20(2022):200. DOI: 10.1186/s12916-022-02397-y. 

12: Bowe, B., Xie, Y. and Al-Aly, Z. 2022. Acute and postacute sequelae associated with SARS-CoV-2 reinfection. Nature Medicine 28(2022):2398-2405. DOI: 10.1038/s41591-022-02051-3. 

13: Reynolds, S. 2023. Bivalent boosters provide better protection against severe COVID-19. National Institutes of Health. URL: https://www.nih.gov/news-events/nih-research-matters/bivalent-boosters-provide-better-protection-against-severe-covid-19.  

14: Berg, S. 2023. What doctors wish patients knew about COVID-19 reinfection. American Medical Association. URL: https://www.ama-assn.org/delivering-care/public-health/what-doctors-wish-patients-knew-about-covid-19-reinfection.