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. 

Endovascular therapy (EVT) is the preferred method of treating acute ischemic stroke (AIS) [1]. The operation requires a high degree of patient cooperation, which can be difficult to achieve, given that AIS patients may have difficulty communicating [2]. Fortunately, using anesthesia during the procedure is an option. 

Past research indicates that general anesthesia for EVT leads to worse patient outcomes than conscious sedation (CS) [1, 2, 3]. Three separate studies found that patients who experienced lower levels of sedation during EVT exhibited lower mortality, better outcomes, and higher reperfusion rates [2]. Conversely, the study found that “heavy sedation…was an independent predictor of death” [2]. The reason for GA’s worse patient outcomes is unknown. One possibility is the effect of procedural delay: it takes more time for anesthesiologists to administer GA than CS [2]. Other potential explanations include GA’s association with hemodynamic instability, neurotoxicity, hypertension, and prolonged intubation [2]. 

Despite this evidence, many researchers have recently pointed out design flaws in these studies, calling into question whether GA is riskier than CS. For one, none of the aforementioned reports are randomized or prospective [1]. Each is retrospective, which could lend itself to bias concerning which studies were chosen and who their subjects were [1]. Furthermore, other experiments have encountered evidence to the contrary. Langner et al. conducted a retrospective study of all EVT patients in Germany over five years [4]. They did not find any significant difference in outcome between GA and CS patients [4]. Similarly, Wang et al. found that GA patients did not experience worse outcomes when compared to historical subgroups [5]. Further research is needed to determine which approach to anesthesia management of EVT is safer. 

Being aware of best practices can help anesthesiologists avoid adverse events associated with general anesthesia. The decision to administer GA should be based on a careful assessment of the patient’s neurological and medical status [6]. Many anesthesiologists reserve GA for patients suffering from compromised airways, bulbar dysfunction, or other complex situations, in addition to patients having major surgeries [2]. With EVT, GA may not be appropriate when delay, a lack of institutional resources, or a high risk of propagating cerebral ischemia would compromise surgical success [7]. 

Before the operation, anesthesiologists should identify preemptive strategies to avoid complications [8]. To avoid hypotension, anesthesiologists should consider administering vasopressor therapy and applying invasive monitoring [8]. Anesthesiologists should also communicate with the neurological team to establish hemodynamic parameters [2]. The team should also plan to extubate at the end of the surgery in the absence of contraindications [2]. 

During EVT, anesthesiologists must closely attend to patients’ vitals. Because GA can lower BP, anesthesiologists must monitor BP throughout the operation to mitigate any hypotensive events [8]. Ventilation and oxygenation are also of concern [9]. Because researchers have not identified the optimal ranges of either measure, anesthesiologists must observe both to prevent hypoxemia and cerebral vasoconstriction [9]. Higher end-tidal carbon dioxide levels and sustained normocapnia are associated with better outcomes, so maintaining both is recommended [9]. 

Unfortunately, the optimal approach to administering general anesthesia to patients receiving endovascular therapy is still being investigated. Regardless, following these best practices and being conscious of the ever-evolving literature on this topic are helpful first steps for promoting the best possible EVT outcomes. 

References 

[1] C. Z. Simonsen et al., “Anesthetic strategy during endovascular therapy: General anesthesia or conscious sedation? (GOLIATH – General or Local Anesthesia in Intra Arterial Therapy) A single-center randomized trial,” International Journal of Stroke, vol. 11, no. 9, p. 1045-1052, July 2016. [Online]. Available: https://doi.org/10.1177/1747493016660103. 

[2] M. T. Froehler et al., “Anesthesia for endovascular treatment of acute ischemic stroke,” Neurology, vol. 79, no. 13, p. S167-S173, September 2012. [Online]. Available: https://doi.org/10.1212/WNL.0b013e31826959c2. 

[3] A. Abou-Chebl et al., “Conscious Sedation Versus General Anesthesia During Endovascular Therapy for Acute Anterior Circulation Stroke,” Stroke, vol. 41, p. 1175-1179, April 2010. [Online]. Available: https://doi.org/10.1161/STROKEAHA.109.574129. 

[4] S. Langner et al., “[Endovascular treatment of acute ischemic stroke under conscious sedation compared to general anesthesia – safety, feasibility and clinical and radiological outcome].,” Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin, vol. 185, no. 4, p. 320-327, February 2013. [Online]. Available: https://doi.org/10.1055/s-0032-1330361. 

[5] A. Wang et al., “General Anesthesia During Endovascular Stroke Therapy Does Not Negatively Impact Outcome,” World Neurosurgery, vol. 99, p. 638-643, March 2017. [Online]. Available: https://doi.org/10.1016/j.wneu.2016.12.064. 

[6] D. Sharma et al., “Anesthetic Management of Endovascular Treatment of Acute Ischemic Stroke During COVID-19 Pandemic: Consensus Statement From Society for Neuroscience in Anesthesiology & Critical Care (SNACC),” Journal of Neurosurgical Anesthesiology, vol. 32, no. 3, p. 193-201, July 2020. [Online]. Available: https://doi.org/10.1097/ANA.0000000000000688.  

[7] D. L. McDonagh et al., “Anesthesia and sedation practices among neurointerventionalists during acute ischemic stroke endovascular therapy,” Frontiers in Neurology, vol. 1, no. 118, November 2010. [Online]. Available: https://doi.org/10.3389/fneur.2010.00118. 

[8] M. J. Davis et al., “Anesthetic Management and Outcome in Patients during Endovascular Therapy for Acute Stroke,” Anesthesiology, vol. 116, p. 396-405, February 2012. [Online]. Available: https://doi.org/10.1097/ALN.0b013e318242a5d2. 

[9] L. K. Rasmussen, C. Z. Simonsen, and M. Rasmussen, “Anesthesia practice for endovascular therapy of acute ischemic stroke in Europe,” Current Opinion in Anaesthesiology, vol. 32, no. 4, p. 523-530, August 2019. [Online]. Available: https://doi.org/10.1097/ACO.0000000000000746.  

When Joe Biden served as Vice President under Barack Obama, he was instrumental in passing the Affordable Care Act, one of the largest healthcare overhauls in the history of the country. The confluence of his history with healthcare and the COVID-19 pandemic made healthcare changes a focal point of the 2020 election. Some of Biden’s major pledges included expanding access to healthcare, simplifying the system, and lowering prescription drug prices [1]. Given that Democrats now control all three branches of government, there is a strong chance that significant parts of Biden’s planned healthcare changes will be passed. 

Within his first few days in office, Biden instituted changes to the United States’ vaccine infrastructure. The White House announced on January 27 that vaccine distribution would be increased to provide 200 million doses by the end of summer. Around the same time, Biden also indicated that he would expand the country’s testing infrastructure and authorize FEMA to create federally run community vaccination centers [2]. While the effects of these rapid changes to the country’s vaccine infrastructure will play out over the next few years, they will undoubtably result in several permanent changes, such as higher domestic production of vaccines, more attention to supply chain stability, and increased reliance on telemedicine [3]. 

Besides COVID-19, the Biden administration is facing considerable pressure from Democrats to expand insurance coverage. In February, two Democratic congressmen introduced the Medicare-X Choice Act, which would establish a public option for small businesses and individuals by 2025. The bill was first proposed in 2017 and allows the Health and Human Services secretary to negotiate drug prices for Medicare plans. It also expands subsidies and tax credits to many low- and middle-income Americans [4]. An analysis of the previous version of the bill by the American Hospital Association found that it would reduce healthcare spending by $1.2 trillion in the first decade after it goes into action. That would result in additional stresses to hospitals and other care facilities, half of which would likely see negative margins after the law goes into effect [5]. 

Regardless of whether Medicare-X passes, the Biden administration will likely take steps to reduce the cost of prescription drugs, which became a hot-button issue during the 2020 election. In 2019, prescription drugs cost Americans a collective $370 billion, a price which is expected to rise by 5% annually between 2021 and 2028 [6]. As a result, the issue has wide bipartisan support. The Biden administration’s approach will likely include allowing Medicare to negotiate drug prices and limit yearly increases on drug prices. Biden has pledged to do so by building on the ACA, a proposal that is likely to meet fierce opposition, both from Republican opponents who seek to dismantle the legislation and progressive Democrats who seek to institute a true public option [7]. 

While the Biden administration has indicated that healthcare reform is one of its top issues, the COVID-19 pandemic has taken the front seat. Additionally, while some healthcare legislation has been introduced, the Biden administration has remained focused on passing the $1.9 trillion economic stimulus package and a comprehensive immigration bill. As a result, the future and timeline of healthcare changes remains uncertain. 

References 

[1] Silberner, Joanne. “How Joe Biden Plans to Heal American Healthcare.” BMJ, 19 Jan. 2021, doi:10.1136/bmj.n142. 

[2] Morse, Susan. “Biden Ramps up Vaccine Distribution to 200 Million Doses by the End of Summer.” Healthcare Finance News, HIMSS Media, 27 Jan. 2021, www.healthcarefinancenews.com/news/biden-ramps-vaccine-distribution-200-million-doses-end-summer.   

[3] Galea, Sandro, et al. “Taking the Long View: COVID-19 Priorities for the Biden Administration.” Journal of Health Politics, Policy and Law, 2021, doi:10.1215/03616878-8970781.  

[4] Pramuk, Jacob. “Senate Democrats Push for Public Option as Biden Weighs Health-Care Reform Plans.” CNBC, CNBC, 19 Feb. 2021, www.cnbc.com/2021/02/19/democrats-kaine-and-bennet-introduce-health-care-public-option-bill.html.   

[5] Koenig, Lane. “The Impact of Medicare-X Choice on Coverage, Healthcare Use, and Hospitals: AHA.” American Hospital Association, 12 Mar. 2019, www.aha.org/position-paper/2019-04-30-impact-medicare-x-choice-coverage-healthcare-use-and-hospitals.  

[6] Keehan, Sean P., et al. “National Health Expenditure Projections, 2019–28: Expected Rebound In Prices Drives Rising Spending Growth.” Health Affairs, vol. 39, no. 4, 2020, pp. 704–714., doi:10.1377/hlthaff.2020.00094.  

[7] Gavulic, Kyle A., and Stacie B. Dusetzina. “Prescription Drug Priorities under the Biden Administration.” Journal of Health Politics, Policy and Law, 22 Jan. 2021, doi:10.1215/03616878-8970810.  

Apps and websites such as WebMD, Ada, Babylon Health, and FamilyDoctor aim to provide diagnoses and triage advice to patients, given self-reported symptom(s), demographics, and other information. Such tools have the potential to enable health screening and let patients take charge of their own health. Patients would have more information on when to administer self-care and avoid unnecessary health bills, while providers could devote more time to patients who genuinely need care. However, obstacles such as mediocre accuracy, low usability, and low awareness among potential users might hamper the adoption of these tools in the short term.  

If apps for symptom analysis and advice are less accurate than recommendations from general practitioners (GPs), patients could become misinformed about their own health or fail to pursue necessary care. One can measure accuracy in several ways: accuracy of diagnosis, accuracy of triage advice, and the breadth of symptom coverage. In a study of eight symptom analysis apps, one app had accuracy on par with GPs across all three metrics, while two other apps had on-par accuracy with respect to two metrics [1]. In another study, 23 symptom analysis apps were found to recommend emergency or primary care in cases where self-care would be appropriate [2]. Although these apps might be generally inaccurate today, their developers will continue to make improvements, and the apps will gain accuracy over time.  

Research has shown that patients also care about factors beyond accuracy. A study of young adult users of symptom analysis apps emphasized the importance of personalization, security, and privacy. Participants perceived symptom analysis apps to be more useful for triage advice than diagnosis [3]. In a separate study, participants tended to perceive Google as a more familiar and flexible tool than symptom analysis apps. After using several symptom analysis tools, they realized that Google was not as usable as they thought [4]. These findings suggest that patients would respond well to apps with strong outreach campaigns and transparency about their underlying processes.  

To summarize the aforementioned findings, symptom analysis apps for physical health are well–studied, with some being almost as effective as a general practitioner. The question remains whether symptom analysis apps for mental health are equally effective. A review of sixteen such apps found that clinical research backed fourteen of those apps, but none of the apps covered more than one or two mental disorders. Furthermore, roughly half of the apps were targeted to a specific population, like veterans or university students. This lack of breadth is a far cry from the breadth of coverage displayed in most apps for physical symptom analysis. To overcome this challenge, developers will need to release mental health apps for wider populations and types of disorders. At the same time, the proliferation of mental health apps in recent years has led researchers to urge caution. One study claims that “the majority” of mental health apps have no evidence of efficacy, calling for greater clinician involvement before the disparity between apps and practitioners widens too much [6]. As with physical health, inaccurate mental health advice might mislead or harm patients.  

By bringing medical expertise to mobile devices, apps for symptom analysis are already widening access to medical advice. With the proper technical and legal protections, trustworthy stakeholders could leverage search data from symptom analysis apps to monitor public health. From March to April 2020, such data from nearly 100,000 participants in Germany and the United Kingdom proved effective in flagging the COVID-19 pandemic as it unfolded [7]. As these apps become more popular, data-driven predictions in public health may become more accurate and more mainstream.  

References 

[1] Gilbert S., et al. How Accurate Are Digital Symptom Assessment Apps for Suggesting Conditions and Urgency Advice? A Clinical Vignettes Comparison to GPs. The BMJ 2020. DOI:10.1136/bmjopen-2020-040269.  

[2] Semigran H. L., et al. Evaluation of Symptom Checkers for Self Diagnosis and Triage: Audit Study. The BMJ 2015. DOI:10.1136/bmj.h3480.  

[3] Aboueid S., et al. Young Adults’ Perspectives on the Use of Symptom Checkers for Self-Triage and Self-Diagnosis: Qualitative Study. JMIR Public Health and Surveillance 2021; 7: 1. DOI:10.2196/22637.  

[4] Li H., and Salah H. Comparing Four Online Symptom Checking Tools: Preliminary Results. Proceedings of the 2017 Industrial and Systems Engineering Conference.  

[5] Wang K., et al. A Systematic Review of the Effectiveness of Mobile Apps for Monitoring and Management of Mental Health Symptoms or Disorders. Journal of Psychiatric Research 2018; 107. DOI:j.jpsychires.2018.10.006.  

[6] Marshall J. M., et al. Clinical or Gimmickal: The Use and Effectiveness of Mobile Mental Health Apps for Treating Anxiety and Depression. Australian & New Zealand Journal of Psychiatry 2020; 54: 1. DOI:10.1177/0004867419876700.  

[7] Mehl A., et al. Syndromic Surveillance Insights from a Symptom Assessment App Before and During COVID-19 Measures in Germany and the United Kingdom: Results From Repeated Cross-Sectional Analyses. JMIR mHealth and uHealth 2020; 8: 10. DOI:2020/10/e21364.