Propofol Neuroexcitation 

Propofol is an intravenous drug that is widely used for anesthesia and sedation in surgeries and other interventional procedures [1]. It exerts its sedative effects through interacting with GABAA receptors; at low doses, it increases GABA agonist efficiency and at higher doses it directly opens negative ion channels on GABA receptors and causes hyperpolarization [2]. Propofol is rapidly distributed from blood to tissues and then quickly metabolized in the liver to inactive metabolites (the glucuronide and corresponding quinol glucuronides); this swift process explains why the drug is favored in clinical use – rapid onset and elimination [3]. However, adverse effects can include pain upon injection, hypotension, bradycardia including asystole, and respiratory depression [1,3]. One rare but serious adverse event that has been reported in the literature is propofol neuroexcitation or “propofol frenzy”.   

Propofol is known to have anti-convulsant properties, which are thought to be because of its modulation of the GABA receptor, much like other known anticonvulsive pharmacotherapies [1]. Preclinical studies with rodent hippocampal neurons showed propofol increases the inward current produced by GABAA receptors. An analysis comparing the EC50 of propofol and GABA infusions reveal both emulsions activate GABAA receptors in similar ways [4]. Further studies on miniature inhibitory post-synaptic currents (mIPSCs) demonstrated low concentrations of propofol could have inhibitory synaptic effects on neuroexcitation, for example prolonging repetitive opening of GABAA channels [4,5]. While propofol influences other ion channels such as potassium, sodium, calcium, NMDA, and acetylcholine, its effect on the GABA receptor seems to be strongest, suggesting GABA-mediated neurotransmission is the primary cause of the drug’s neuro-depressive properties [4].   

A landmark study from 2003 found a point mutation in the β3 subunit of the GABAA receptor was sufficient to extinguish the effects of propofol in causing loss of righting reflex (the analogue for loss of consciousness in mice) [6]. Other studies suggest amino acids in the β1 and β2 subunits are also important for the receptor to interact normally with propofol. An approach involving cysteine residues provided results which suggest propofol’s binding site exists near the middle of the transmembrane domain 3 (TM3) [7].  

However, early clinical studies from the 1990s associated propofol administrations with instances of post-surgical convulsions, perhaps through a drug-induced excitation of the CNS, sometimes called “propofol frenzy” [1,8]. A systematic review found 55 reports of 70 patients without epilepsy, all of whom experienced seizure-like phenomena (SLP) after propofol; for most patients, SLP was observed during either induction of anesthesia (24 patients, 34%) or emergence (28 patients, 40%). Five patients had abnormal EEG, with generalized spiking of neural activity in two and generalized slowing in three [1]. In three patients, abnormal CT results revealed small infarcts and ventricular bleeding, as confirmed by MRI. The review also found 10 reports of 11 patients with epilepsy; their SLP manifested as general tonic-clonic seizures in 82% of patients and opisthotonos in 18%. Case reports such as these have their limitations, predominantly low validity due to selection and observer bias, nonetheless, it should be noted 13 of the 70 patients without epilepsy had no comorbidities and were not concomitantly taking any other medication, yet they too experienced similar intensities of SLP after propofol [1]. 

Propofol also seems to facilitate glutamate release from cerebrocortical glutamatergic terminals, unlike NMDA antagonists such as ketamine and phencyclidine [2]. Neuroexcitation induced by propofol is unique in that there is a lack of a stereotyped pattern in the neocortex. While there is no evidence supporting any pharmacological treatment for propofol neuroexcitation at this time, reducing stimulation and avoiding propofol in subsequent administrations is recommended.  


  1. Walder, B., Tramèr, M. R., & Seeck, M. (2002). Seizure-like Phenomena and Propofol: A Systematic Review. Neurology, 58(9), 1327–1332.  
  1. Carvalho, D. Z., Townley, R. A., Burkle, C. M., Rabinstein, A. A., & Wijdicks, E. F. M. (2017). Propofol Frenzy: Clinical Spectrum in 3 Patients. Mayo Clinic Proceedings, 92(11), 1682–1687.  
  1. Adembri, C., Venturi, L., & Pellegrini-Giampietro, D. E. (2007). Neuroprotective Effects of Propofol in Acute Cerebral Injury. CNS Drug Reviews, 13(3), 333–351.  
  1. Orser, B. A., Wang, L. Y., Pennefather, P. S., & MacDonald, J. F. (1994). Propofol Modulates Activation and Desensitization of GABAA Receptors in Cultured Murine Hippocampal Neurons. Journal of Neuroscience, 14(12), 7747–7760.  
  1. Takahashi, A., Tokunaga, A., Yamanaka, H., Mashimo, T., Noguchi, K., & Uchida, I. (2006). Two Types of GABAergic Miniature Inhibitory Postsynaptic Currents in Mouse Substantia Gelatinosa Neurons. European Journal of Pharmacology, 553(1–3), 120–128.  
  1. Jurd, R., Arrasa, M., Lambert, S., Drexler, B., Siegwart, R., Crestani, F., Zaugg, M., Vogt, K. E., Ledermann, B., Antkowiak, B., & Rudolph, U. (2003). General Anesthetic actions in vivo Strongly Attenuated by a Point Mutation in the GABA A Receptor β3 Subunit. The FASEB Journal, 17(2), 250–252.  
  1. Yip, G. M. S., Chen, Z.-W., Edge, C. J., Smith, E. H., Dickinson, R., Hohenester, E., Townsend, R. R., Fuchs, K., Sieghart, W., Evers, A. S., & Franks, N. P. (2013). A propofol Binding Site on Mammalian GABAA Receptors Identified by Photolabeling. Nature Chemical Biology, 9(11), 715–720.  
  1. Collier, C., & Kelly, K. (1991). Propofol and Convulsions—The Evidence Mounts. Anesthesia and Intensive Care, 19(4), 573–575. 

Aspirin is commonly used to reduce fever and/or relieve mild to moderate pain, such as from headaches, menstrual cramps, arthritis, and muscle aches, similar to other non-steroidal anti-inflammatory drugs (NSAIDs). However, it also has significant anti-platelet properties, leading to its use by many people to prevent heart attack or ischemic stroke, which are caused by a clot blocking blood flow to part of the heart and brain respectively (MedlinePlus, Mayo Clinic). Based on available data, leading medical organizations established guidelines for what populations would benefit from daily low-dose aspirin for heart attack prevention. Recent research has led to more conservative guidelines for older adults, due to a growing recognition and cautiousness of the increased bleeding risk associated with aspirin (Mayo Clinic, Zheng & Roddick). 

A physician may recommend aspirin for prevention purposes for adults aged 40 to 59 who are considered to be at high risk of experiencing a heart attack (or ischemic stroke). Risk factors include a prior heart attack, stroke, or mini-stroke, a stent, coronary bypass surgery, and angina (MedlinePlus, Mayo Clinic). However, the anticoagulant effect occurs systemically, leading to increased bleeding in cases of injury, as well as an increased risk of spontaneous bleeding (Mayo Clinic). A large meta-analysis that included data from over 160,000 patients concluded that “the use of aspirin in individuals without cardiovascular disease was associated with a lower risk of cardiovascular events and an increased risk of major bleeding” (Zheng & Roddick). This risk outweighs the benefit for many older adults. As a result, some guidelines caution that those age 60 or older without cardiovascular disease should not participate in a daily regimen of aspirin for heart attack prevention. Other guidelines continue to have a threshold of 70 years – those aged 60 to 69 should discuss the benefits and potential harms of aspirin with their physician (Mayo Clinic). 

Aspirin, also known as acetylsalicylic acid, interferes with normal clotting processes in blood. It and other NSAIDs inhibit cyclooxygenase (COX), an enzyme that leads to the production of prostaglandins, which are involved in inflammation, pain, swelling, and fever. COX is also involved in other processes, the disruption of which leads to the side effects associated with aspirin, such as gastric irritation. Though researchers aim to develop better anti-inflammatory medication that selectively targets COX-2 rather than affecting both COX-1 and COX-2 to reduce adverse gastrointestinal effects, studies show that COX-2 inhibitors may increase the risk of clots. As a result, aspirin, which is a nonselective COX inhibitor, remains important for heart attack prevention (Vane & Botting). 

As with all medication, people who take aspirin regularly must be careful not to take other drugs with interfering or compounding effects unless directed to by their physician. Such medications include anticoagulants, ACE inhibitors, beta blockers, diuretics, corticosteroids, and some antidepressants. Ibuprofen also generally should not be taken concurrently (MedlinePlus, Mayo Clinic). In addition, some herbal and dietary supplements may increase bleeding risk when taken alongside aspirin. Due to the anticoagulant properties of the drug, it is also important that surgeons are aware of patient’s ongoing aspirin therapy to preempt dangerous bleeding during surgery (Mayo Clinic). 

Current data demonstrates the benefit of aspirin as a heart attack prevention method in a select, high risk population. However, studies also highlight the potential harms of the medication. Individuals should always seek the advice of their healthcare provider before starting or stopping an aspirin regimen. Additional research will continue to improve the resources available for reducing the risk of ischemic events. 


Mayo Clinic Staff. Daily aspirin therapy: Understand the benefits and risks. Mayo Clinic. October 15, 2021. Available: 

MedlinePlus. Aspirin. Updated May 15, 2021. Available: 

Vane, J. R. & Botting, R. M. The mechanism of action of aspirin. Thrombosis Research. 2003;110(5-6):255-8. doi: 10.1016/s0049-3848(03)00379-7

Zheng, S. L. & Roddick, A. J. Association of Aspirin Use for Primary Prevention With Cardiovascular Events and Bleeding Events. JAMA. 2019;321(3):277-287. doi:10.1001/jama.2018.20578

As yet another wave of COVID-19 infections sweeps the globe, clinicians and researchers have been forced to consider reinfection as a growing area of concern. Studies have shown that reinfection is more than just an anomaly: epidemiological data collected on the omicron variant has proven that individuals infected by earlier variants remain vulnerable to COVID-19.1,2 The natural next question, then, is whether or not COVID-19 reinfection poses a major public health issue in terms of incidence and severity. The morbidity and mortality associated with reinfection has enormous implications, particularly when it comes to anticipated healthcare burden and policy regarding infectious disease control. Should we expect that with each successive wave, hospitals will be flooded with patients the same way they were in the spring of 2020?3 Or is there any protection conferred in having fought off the infection once (or even multiple times) before? 

A recent study published in January of 2022 suggests that those who have already been infected face better odds than those experiencing a primary infection.4 Authors Mensah et al. collected data from a COVID-19 surveillance system and England’s mass PCR testing services for a 16-month period ending in May of 2021. Reinfection classification was defined as previous history of a positive PCR test, with a 90-day minimum interval in between positive tests. A total of 3,860,054 first infections were recorded, along with 13,960 cases of reinfection. In order to measure overall severity of primary infection versus reinfection, the authors cross-checked COVID-19 data from both testing and surveillance with data on ICU and hospital admissions.  

The authors noted several interesting differences when it came to the demographic of reinfected individuals. For example, men were 42 percent less likely to get reinfected than women. Risk of reinfection also increased with each successive age category, in accordance with other studies which have shown senior populations to be more vulnerable to COVID-19 infection.5 

Individuals suffering from a primary infection were more likely to have an adverse health outcome when compared to individuals experiencing a repeat infection. After adjusting for age and sex, the authors found that individuals in the reinfection group died within 28 days of a positive PCR result at less than half the rate of individuals in the primary infection group. Interestingly, hospital admission rates (within 21 days of a positive PCR test) were comparable for both groups in individuals under 50 years old. However, individuals aged 50 and over showed a 48 percent relative decrease in hospital admission frequency if they were experiencing a reinfection vs. a primary infection. A similar trend was noted in high-risk populations: a 34 percent decrease in hospital admission frequency was seen in the reinfection group as compared to the primary infection group. These findings suggest that prior infection has a larger protective effect on more vulnerable populations, perhaps conferring some level of immune protection that is relatively negligible in more resilient populations.  

These findings have some reassuring implications as to the expected healthcare burden due to reinfection. While the morbidity and mortality of reinfection is non-negligible, severity appears to be significantly less concerning than that of primary COVID-19 infection. The implication is that relatively fewer resources will be necessary to manage continuing COVID-19 infection.


1 Araf, Y., Akter, F., Tang, Y. D., Fatemi, R., Parvez, M., Zheng, C., & Hossain, M. G. (2022). Omicron variant of SARS-CoV-2: Genomics, transmissibility, and responses to current COVID-19 vaccines. Journal of medical virology. Advance online publication. 

2 Ren, S. Y., Wang, W. B., Gao, R. D., & Zhou, A. M. (2022). Omicron variant (B.1.1.529) of SARS-CoV-2: Mutation, infectivity, transmission, and vaccine resistance. World journal of clinical cases, 10(1), 1–11. 

3 Miller, I. F., Becker, A. D., Grenfell, B. T., & Metcalf, C. (2020). Disease and healthcare burden of COVID-19 in the United States. Nature medicine, 26(8), 1212–1217. 

4 Mensah, A. A., Lacy, J., Stowe, J., Seghezzo, G., Sachdeva, R., Simmons, R., Bukasa, A., O’Boyle, S., Andrews, N., Ramsay, M., Campbell, H., & Brown, K. (2022). Disease severity during SARS-COV-2 reinfection: a nationwide study. The Journal of infection, S0163-4453(22)00010-X. Advance online publication. 

5 Crimmins E. M. (2020). Age-Related Vulnerability to Coronavirus Disease 2019 (COVID-19): Biological, Contextual, and Policy-Related Factors. The Public policy and aging report, 30(4), 142–146. 

During synaptogenesis, the formation of synapses among neurons, in the developing brain, exposure to drugs that antagonize NMDA glutamate receptors or agonize ʏ-amminobutyric acid-ergic (GABA-ergic) transmission, such as many anesthetic agents, can induce significant apoptosis and glutamate-induced toxicity, also known as excitotoxicity [1]. Murine models have shown this occurs through a depletion of Akt serine/threonine kinase, a protein vital to neuronal survival. Akt is phosphorylated by the plasma membrane receptors Trk and p75 neurotrophic receptor (p75NTR), which are in turn modulated by neurotrophins such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophic factors 3-5 (NT3/4/5) [2]. Neurotrophins have anti-apoptotic properties and may prevent excitotoxic death through mitochondrial regulation [3]. Dexmedetomidine, a drug used by anesthesiologists, may have beneficial neuroprotective effects in addition to its sedative effects.

Until the turn of the 20th century, the only anesthetics that were approved for use either antagonized NMDA or mimicked GABA transmission [4]. When dexmedetomidine, a highly selective α2-adrenergic receptor agonist, was introduced, researchers began discovering its neuroprotective qualities. Ma et al. demonstrated dexmedetomidine dose-dependently attenuated neuronal injury in neuronal-glial co-cultures and improved the neurological functional deficit caused by hypoxic-ischemic insult in vivo [5]. Other studies have shown dexmedetomidine reduces NMDA-induced excitotoxicity during the perinatal period in mice [6,7]. Researchers of a 2018 Chinese study suggested dexmedetomidine’s neuroprotective quality arises from its activation and maintenance of the extracellular signal-regulated kinase (ERK) pathway [8]. This pathway is known to be activated by BDNF [9].

Mice pups were used for an experiment that questioned if and through what mechanisms dexmedetomidine enhanced BDNF release [10]. On postnatal day-5 (P5), excitotoxic brain lesions were induced with intracerebral injection of ibotenate, a glutamate analog which activates both NMDA and group I metabotropic receptors. On P10, animals were sacrificed, and their brains analyzed. Mice who had been injected with BDNF (on P5) showed significantly smaller ibotenate-induced excitotoxic lesions than controls. In primary neuronal cell cultures, BDNF exerted a potent neuroprotective effect regardless of whether the cells showed any excitotoxic stress, demonstrating BDNF’s powerful anti-apoptotic effects. Dexmedetomidine demonstrated similar neuroprotection: pups which were given dexmedetomidine 1 hr before ibotenate-induced lesion had much smaller lesions. Additionally, this neuroprotective effect, measured through cell viability, was diminished when yohimbine, an α2-adrenergic antagonist, was administered, suggesting the anesthetic’s effect comes from α2-adrenergic receptor activation [10]. Creating a hierarchal relationship between the two, dexmedetomidine was found to increase BDNF expression in astrocyte, but not neuronal, cell cultures. In mice displaying excitotoxic lesions, BDNF antibody attenuated dexmedetomidine’s neuroprotective effect, indicated through increased lesion size. However, in neuronal cell cultures, dexmedetomidine’s effect persisted despite BDNF antibody injection [10].  

Interestingly, various CNS cells appear to assume different roles in models of excitotoxic lesions. In particular, astrocytes shuttle cations like K+, modulate inflammation, and produce neurotrophic factors. They are thought to be the most important cells for limiting the excitotoxic potential of glutamate because of their expression of high-affinity glutamate transporters such as EAAT1/GLAST and EAAT2/GLT-1 [11]. As previously mentioned, dexmedetomidine displays its neuroprotective effect via α2-adrenergic antagonists [12]. In the murine cortex, α2-adrenergic receptors are strongly expressed in astrocytes and oligodendrocytes [13]. This may explain why the study described above showed dexmedetomidine stimulates BDNF expression in astrocytes, but not neurons [10].

Astrocytes can release growth factors besides BDNF, including epidermal growth factor, vascular endothelial growth factor (VEGF), and glial cell-derived neurotrophic factor [13]. Future studies may examine in further detail if dexmedetomidine stimulates other pro-survival molecules.


  1. Jevtovic-Todorovic, V., Hartman, R. E., Izumi, Y., Benshoff, N. D., Dikranian, K., Zorumski, C. F., Olney, J. W., & Wozniak, D. F. (2003). Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. Journal of Neuroscience23(3), 876–882.
  2. Lu, L. X., Yon, J.-H., Carter, L. B., & Jevtovic-Todorovic, V. (2006). General anesthesia activates BDNF-dependent neuroapoptosis in the developing rat brain. Apoptosis11(9), 1603–1615.
  3. Degos, V., Loron, G., Mantz, J., & Gressens, P. (2008). Neuroprotective strategies for the neonatal brain. Anesthesia and Analgesia106(6), 1670–1680.
  4. Kaur, M., & Singh, P. M. (2011). Current role of dexmedetomidine in clinical anesthesia and intensive care. Anesthesia, Essays and Researches5(2), 128–133.
  5. Ma, D., Hossain, M., Rajakumaraswamy, N., Arshad, M., Sanders, R. D., Franks, N. P., & Maze, M. (2004). Dexmedetomidine produces its neuroprotective effect via the α2A-adrenoceptor subtype. European Journal of Pharmacology502(1), 87–97.
  6. Laudenbach, V., Mantz, J., Lagercrantz, H., Desmonts, J.-M., Evrard, P., & Gressens, P. (2002). Effects of α2-adrenoceptor agonists on perinatal excitotoxic brain injury: Comparison of clonidine and dexmedetomidine. Anesthesiology96(1), 134–141.
  7. Paris, A., Mantz, J., Tonner, P. H., Hein, L., Brede, M., & Gressens, P. (2006). The effects of dexmedetomidine on perinatal excitotoxic brain injury are mediated by the alpha2A-adrenoceptor subtype. Anesthesia and Analgesia102(2), 456–461.
  8. Wang, K., & Zhu, Y. (2018). Dexmedetomidine protects against oxygen-glucose deprivation/reoxygenation injury-induced apoptosis via the p38 MAPK/ERK signalling pathway. Journal of International Medical Research46(2), 675–686.
  9. Maharana, C., Sharma, K. P., & Sharma, S. K. (2013). Feedback mechanism in depolarization-induced sustained activation of extracellular signal-regulated kinase in the hippocampus. Scientific Reports3(1), 1103.
  10. Degos, V., Charpentier, T. L., Chhor, V., Brissaud, O., Lebon, S., Schwendimann, L., Bednareck, N., Passemard, S., Mantz, J., & Gressens, P. (2013). Neuroprotective effects of dexmedetomidine against glutamate agonist-induced neuronal cell death are related to increased astrocyte brain-derived neurotrophic factor expression. Anesthesiology118(5), 1123–1132.
  11. Trendelenburg, G., & Dirnagl, U. (2005). Neuroprotective role of astrocytes in cerebral ischemia: Focus on ischemic preconditioning. Glia50(4), 307–320.
  12. Engelhard, K., Werner, C., Kaspar, S., Möllenberg, O., Blobner, M., Bachl, M., & Kochs, E. (2002). Effect of the α2-agonist dexmedetomidine on cerebral neurotransmitter concentrations during cerebral ischemia in rats. Anesthesiology96(2), 450–457.
  13. Hertz, L., Lovatt, D., Goldman, S. A., & Nedergaard, M. (2010). Adrenoceptors in brain: Cellular gene expression and effects on astrocytic metabolism and [Ca2+]i. Neurochemistry International57(4), 411–420.

Tuberculosis (TB) is the leading cause of death from an infectious disease worldwide (excluding COVID-19), infecting about 10 million people every year. The clinical syndrome is caused by Mycobacterium tuberculosis, which creates its own reservoir by lying latent after resolution of the primary infection so it can re-infect the host and cause more severe disease. In 2017, one research team estimated that 24% of the global population were latently infected, despite prevention protocols, diagnostic tools and treatments1.

The World Health Organization is aiming to reduce tuberculosis incidence by 10% a year by 2025; currently, the rate of decline is around 2%1. The 10% goal was based on historical data from the fifties and sixties in Western Europe, where infection was controlled by thorough prevention, diagnosis and treatment of efforts of all forms of TB, as well as by expanding healthcare coverage and welfare programs that improved socioeconomic hardships such as poor living conditions and nutrition. These efforts in London, Wales, and the Netherlands led to a significant reduction in the incidence of TB and TB-related mortality2. Interestingly, Cape Town adopted similar measures to control the spread of TB in the early 2000s, but saw less of a reduction in incidence, likely because of lack of efforts to change the social determinants of health. These contrasting results show that improving socioeconomic status for people living in high-burden places is just as important as public health measures that directly slow the spread of disease1.

Mycobacterium tuberculosis is spread in five steps. First, an individual with an active infection of TB aerosolizes the bacteria living in their lungs, by breathing, talking, shouting, singing, etc. The bacteria can survive in the air for a time, before it is breathed in by someone else who is not currently infected. Bacteria then goes to the lungs, typically the middle or lower lobes, and causes primary infection. Once the primary infection has resolved, it lies latent in calcifications in the lungs until it is reactivated by immunosuppression or other host factors1.

Not all hosts are equally infectious, and infectivity depends on many host-related and bacterial factors. For example, people with smear-positive pulmonary TB were more likely to spread it to their household and close contacts than those with smear-negative cases. Patients with HIV or otherwise similarly immunosuppressed patients were less likely than immunocompetent patients to spread the disease1. Unsurprisingly, household contacts are the most likely to get sick, and this effect is amplified in countries that also have a high burden of HIV. And finally, access and adherence to antiretroviral therapy is protective against TB infection in patients with HIV, despite this patient population being particularly vulnerable. Since much of this evidence links TB with HIV, it may be advantageous to improve access to medication, prophylaxis and diagnostic tests to HIV as well as TB2.

First-line treatment of active, drug-susceptible TB consists of a four-drug regimen: rifampin, isoniazid, pyrazinamide and ethambutol. These must be taken for six to nine months to resolve infection, and each drug carries its own adverse effects and toxicities. Furthermore, as TB spreads, the risk of multi-drug resistant TB also increases, and that is much more complicated to treat. Due to the major morbidity and mortality caused by TB, as well as the complexity of treatment, reducing the incidence of TB is a leading public health problem3. Evidence shows that the best way to do this not only to expand prevention protocols and access to TB specific healthcare, but also to improve socioeconomic risk factors and HIV prevalence.


  1. Churchyard G, Kim P, Shah SS, Rustomjee R, Gandhi N, Mathema B, Dowdy D, Kasmar A, and Cardenas A. What We Know About Tuberculosis Transmission: An Overview. The Journal of Infectious Disease, 2017; 216: S629-S635. 
  1. Lienhard C, Glaziou P, Uplekar M, Lonnroth K, Getahun H, Ravliglione M. Global tuberculosis control: lessons learnt and future prospects. Nature Reviews Microbiology, 2012; 10: 407-416. 
  1. Nahid P, Dorman SE, Alipanah N, Barry PM et al. Executive Summary: Official American Thoracic Society/CDC/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clinical Infectious Diseases, 2016; 63(7)L 853-867. 

Non-steroidal anti-inflammatory drugs (NSAIDs) are some of the most widely used medications globally, frequently administered to patients experiencing acute, chronic, and inflammatory forms of pain. However, both traditional nonselective NSAIDs, which inhibit the molecular cyclooxygenase pathway, and second-generation NSAIDs, which block cyclooxygenase-2, may cause adverse events, especially at prescription-level doses 1

First, NSAIDs can result in gastrointestinal complications. Studies since 2012 have consistently demonstrated that both traditional NSAIDs and cyclooxygenase-2 inhibitors increase the dose-dependent risk of upper gastrointestinal complications, in the form of upper gastrointestinal bleeding or perforation and peptic ulcers 2. A prior history of peptic ulcer, an older age, and concomitant aspirin use predispose individuals to such gastrointestinal complications 3.

Second, NSAIDs may yield cardiovascular complications, including in the form of myocardial infarction and stroke. A 2009 study demonstrated an increased risk of heart disease-associated hospitalization and death linked to all NSAIDs, including rofecoxib, celecoxib, ibuprofen, diclofenac, and naproxen, among others 4. This was confirmed by a landmark study in 2013 revealing that the administration of prescription NSAIDs dose-dependently increased an individual’s risk of heart failure, major vascular events, and mortality 5.

Finally, renal adverse events may result from the use of prescription-level NSAIDs. A 2006 study found that NSAID compared to non-NSAID use incurred a 3-fold greater risk of acute renal failure after adjusting for age, sex, body mass index, and several comorbidities 6. This risk was dose-dependent and increased with long-term use of NSAIDs, as confirmed since by various recent studies.

Various strategies have been put into place to help mitigate the risk of prescription-level NSAID-associated gastrointestinal, cardiovascular, and renal complications. First, cyclooxygenase-2 inhibitors, despite their slightly improved gastrointestinal safety as compared to traditional NSAIDs, have been particularly linked to an increased risk of developing cardiovascular-related events – either selective or nonselective NSAIDs should thus be selected depending on context and patient background. Second, an enteric coating may be used to protect the gastrointestinal tract of at-risk patients. This is often used with aspirin and ibuprofen to help alleviate stomach irritation. A number of different gastroprotectants have been proven effective to this end 3. Finally, some clinicians may choose to add a gastroprotective agent to a patient’s medication regimen. Gastroprotective agents have been found to result in an overall reduction in gastrointestinal complications 7. This said, additional strategies need to be developed to specifically target a reduction in cardiovascular and renal complications.

Understanding the factors predisposing individuals to adverse events from prescription-level NSAIDs is key to curbing them through heightened clinician awareness and education. For example, patients with a high gastrointestinal or cardiovascular risk should be considered for alternative therapies. In the future, additional research should seek to further specify the factors that increase a patient’s risk for adverse events in order to ensure the best patient-centric preventive medicine steps are taken. The most effective way to minimize the risk of complications is to use the minimal effective dose of NSAIDs: in 2005, the US Food and Drug Administration issued a public health advisory establishing that “NSAIDs should be administered at the lowest effective dose for the shortest duration consistent with individual patient treatment goals,” corroborated in 2007 by an additional detailed NSAID administration guide. 


1.        Fine, M. Quantifying the impact of NSAID-associated adverse events. American Journal of Managed Care (2013).

2.        Castellsague, J. et al. Individual NSAIDs and upper gastrointestinal complications: A systematic review and meta-analysis of observational studies (the SOS Project). Drug Safety (2012). doi:10.2165/11633470-000000000-00000

3.        Sostres, C., Gargallo, C. J., Arroyo, M. T. & Lanas, A. Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract. Best Pract. Res. Clin. Gastroenterol. (2010). doi:10.1016/j.bpg.2009.11.005

4.        Gislason, G. H. et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch. Intern. Med. (2009). doi:10.1001/archinternmed.2008.525

5.        Baigent, C. et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Meta-analyses of individual participant data from randomised trials. Lancet (2013). doi:10.1016/S0140-6736(13)60900-9

6.        Schneider, V., Lévesque, L. E., Zhang, B., Hutchinson, T. & Brophy, J. M. Association of selective and conventional nonsteroidal antiinflammatory drugs with acute renal failure: A population-based, nested case-control analysis. Am. J. Epidemiol. (2006). doi:10.1093/aje/kwj331

7.        Rahme, E. et al. Gastrointestinal-related healthcare resource usage associated with a fixed combination of diclofenac and misoprostol versus other NSAIDs. Pharmacoeconomics (2001). doi:10.2165/00019053-200119050-00011

            Almost two years into the Covid-19 pandemic, the question still remains: When will the pandemic end? Some believe the answer to this question lies in herd immunity. With a highly infectious disease such as Covid-19, many have argued that eradication of the virus will occur naturally once it has spread throughout the entire community, generating antibody-mediated immunity in those that recover from the disease. The reasoning is that Covid-19 will simply fade away when there are no remaining vulnerable hosts to infect. Individuals who have argued from the herd immunity perspective often advocate for the continued opening of businesses as well as loosened restrictions for mask-wearing, social distancing, and other preventative measures. These practices, they argue, serve to simply prolong the amount of time it takes to reach herd immunity. Countries like Sweden, which have remained fairly open throughout the pandemic and now reportedly have the virus “under control,”1 have been used to substantiate this argument. The availability of Covid-19 vaccines also raises the question of whether immunity gained from the shots differs from that gained from prior infection.

            Covid-19 vaccines are readily available in many high-income countries, including the United States. Many are asking: Is complete vaccine compliance necessary when, at the end of 2020, approximately 31 percent of the U.S. population had already been infected with Covid-19?2 Ostensibly, this would mean that roughly a third of Americans already had some sort of antibody-mediated immunity to the disease, and certainly more have been infected since the publication of the aforementioned study.

            Authors Bozio et al. sought to answer this exact question in a study published in November of 2021.3 They examined a number of hospitalized individuals over the age of 18 who had either previously tested positive for Covid-19 infection (via a rapid assay test or reverse PCR testing) or been fully vaccinated with an mRNA vaccine (two doses, given within the recommended timeframe) in the past 90-179 days. The primary outcome was the result of a Covid-19 test taken at the time of hospitalization. When the results were adjusted for pertinent sociodemographic and health factors, the authors found that individuals who had received the Covid-19 vaccine were less likely to test positive for Covid-19 than those who had been previously infected. Interestingly, further analysis revealed that recipients of the Moderna vaccine appeared to have improved immunity when compared to recipients of the Pfizer-BioNTech vaccine. This was consistent with a previous study published in September of 2021 which reported similar findings.4

            These accumulative results would suggest that vaccines confers greater immunity when compared to a prior history of Covid-19 infection. While there are some limits to this study – for example, children were excluded, as the U.S. only recently gave full approval for administration of the Pfizer vaccine to individuals aged five and up5 – the results were fairly conclusive. These findings support the CDC recommendation that all Americans eligible to receive the vaccine should do so, for the benefit of both personal and public health.


[1] Carlsson, M., & Söderberg-Nauclér, C. (2021). Indications that Stockholm has reached herd immunity, given limited restrictions, against several variants of SARS-COV-2. (preprint).

2 One in three Americans Already Had COVID-19 by the End of 2020. Columbia Public Health. (2021, August 26). Retrieved from

3 Centers for Disease Control and Prevention. (2021, November 4). Laboratory-Confirmed COVID-19 Among Adults Hospitalized with COVID-19–Like Illness with Infection-Induced or mRNA Vaccine-Induced SARS-COV-2 Immunity – Nine States, January–September 2021. Centers for Disease Control and Prevention. Retrieved from

4 Self WH; Tenforde MW; Rhoads JP; Gaglani M; Ginde AA; Douin DJ; Olson SM; Talbot HK; Casey JD; Mohr NM; Zepeski A; McNeal T; Ghamande S; Gibbs KW; Files DC; Hager DN; Shehu A; Prekker ME; Erickson HL; Gong MN; Mohamed A; Henning DJ; Steingrub JS; Peltan ID; Brown SM; Martin ET; Mo. (2021). Comparative effectiveness of Moderna, Pfizer-BioNTech, and Janssen (Johnson & Johnson) Vaccines in Preventing COVID-19 Hospitalizations Among Adults Without Immunocompromising Conditions – United States, March-August 2021. MMWR. Morbidity and mortality weekly report. Retrieved from

5 Centers for Disease Control and Prevention. (n.d.). Covid-19 Vaccines for Children and Teens. Centers for Disease Control and Prevention. Retrieved from

Atelectasis occurs when air is not able to fully expand the alveoli of the lungs. 90% of patients undergoing general anesthesia experience atelectasis (Randtke et al, 2015). This is because general anesthesia decreases muscle tone and thus functional residual capacity (FRC) — the amount of air that is left in the lungs after exhaling. Atelectasis increases the risk for hypoxemia and pneumonia and can continue into the postoperative period. Preventing and reversing atelectasis can improve patient outcomes for surgeries that require general anesthesia (Randtke et al, 2015).

There are three explanations of the physiological cause of atelectasis that are generally agreed upon. The absorption mechanism is based on oxygen balance. Often, patients undergoing anesthesia will be placed on 100% oxygen, which pushes nitrogen gas out of the lungs (nitrogen is a component of normal atmospheric air) (Randtke et al, 2015). Oxygen is absorbed by the capillary bed, leaving the alveoli with too little gas remaining inside. Since the alveoli are not supported by cartilage, only the pressure of gases against their walls, they then collapse (Randtke et al, 2015). This can also occur with a low ventilation to perfusion ratio — when the capillary beds absorb oxygen faster than the person’s breathing can provide more air. The decreased FRC with general anesthesia exacerbates this problem. It is a challenge to get the appropriate oxygen balance, as not providing enough oxygen can also lead to hypoxemia during the procedure (Randtke et al, 2015).

The compression mechanism for atelectasis occurs when the pleural pressure in the chest cavity is greater than the intrapulmonary pressure. With the reduced muscle tone that occurs under anesthesia, the weight of the chest and the patient’s organs against the diaphragm are significant contributing factors in this mechanism (Randtke et al, 2015). Inflammation and buildup of fluid in the pleural space can also contribute. The pressure can push residual air out of the lungs, further decreasing the FRC and leading to alveolar collapse (Randtke et al, 2015).

The third mechanism is related to abnormalities in surfactant. Surfactant is produced by specific cells in the alveoli and reduces surface tension, making it easier for the lungs to expand (Randtke et al, 2015). Reduced surfactant makes it more difficult for alveoli to stay open in the first place,  re-inflate once collapsed and stabilized once reopened. General anesthesia may have some impact on surfactant abnormalities but more research is needed to clarify its role in atelectasis in this context (Randtke et al, 2015).

As shown in a recent meta-analysis regarding prevention and treatment pathways of postoperative pulmonary complications, there is not a lot of high-quality data currently available (Odor et al, 2020). With the lower quality data that is available, interventions found to have a significant effect include postoperative continuous positive airway pressure (CPAP), mucolytic medications (specifically ambroxol) and respiratory physiotherapy (a series of muscle training and breathing exercises practiced before and after the surgery). There is moderate quality data for intraoperative lung protective ventilation, defined as using reduced tidal volumes (<8 mL/kg), positive end expiratory pressure of at least 5 cm H2O and intermittent recruitment maneuvers (high pressure applied for a short period of time to inflate the lungs more fully) (Odor et al, 2020). It is also important to look at prevention in specific patient populations, such as in pediatric patients. One newer study suggests that use of CPAP during induction and emergence in children decreases the risk of intraoperative atelectasis, as well as the risk of residual atelectasis in the postoperative period (Acosta et al, 2021). Another recent study suggests that high-flow nasal cannula oxygen in the postoperative period reduces residual atelectasis (Lee et al, 2021). Overall, more high-quality comparative research on the effectiveness of different prevention methods is needed for all patient populations.


Acosta CM, Lopez Vargas MP, Oropel F, et al. Prevention of atelectasis by continuous positive airway pressure in anaesthetised children: A randomised controlled study. Eur J Anaesthesiol. 2021;38(1):41-48. doi:10.1097/EJA.0000000000001351

Lee J-H, Ji S-H, Jang Y-E, Kim E-H, Kim J-T, Kim H-S. Application of a High-Flow Nasal Cannula for Prevention of Postextubation Atelectasis in Children Undergoing Surgery: A Randomized Controlled Trial. Anesthesia & Analgesia. 2020;133(2):474-482. doi:10.1213/ane.0000000000005285

Odor PM, Bampoe S, Gilhooly D, Creagh-Brown B, Moonesinghe SR. Perioperative interventions for prevention of postoperative pulmonary complications: systematic review and meta-analysis. BMJ. 2020;368:m540. doi:10.1136/bmj.m540

Randtke MA, Andrews BP, Mach WJ. Pathophysiology and Prevention of Intraoperative Atelectasis: A Review of the Literature. J Perianesth Nurs. 2015;30(6):516-527. doi:10.1016/j.jopan.2014.03.012

Across the United States in 2019, over 1 in 10 households were defined as being food-insecure. Food-insecure households are, according to U.S. Department of Agriculture (USDA), “uncertain of having, or unable to acquire, at some time during the year, enough food to meet the needs of all their members because they had insufficient money or other resources for food.” These food-insecure households include 5.3 million U.S. households with “very low food security,” which disrupts eating patterns and leads to food intake levels below those considered adequate.1

While rates of food insecurity have significantly declined since they spiked to nearly 15 percent of households following the 2008 stock market crash,1 preliminary data shows that the COVID-19 pandemic has dramatically worsened food insecurity, which was already considered one of “the nation’s leading health and nutrition issues.”2 Feeding America, a national anti-hunger nonprofit, estimates that 1 in 8 people may experience food insecurity in 2021, with those most impacted by the pandemic at greater risk. Notably, racial disparities in food security that existed before the COVID-19 pandemic remain severe, with 1 in 5 Black individuals in the U.S. projected to experience food insecurity in 2021 (nearly double the rate among white individuals).3

The health complications associated with food insecurity are well-documented. Among children, these include anemia, key nutrient deficiencies, behavioral problems such as aggression, and mental health challenges such as depression and suicidal ideation.2 Many of these issues persist for adults, who are also more likely to develop chronic conditions, like diabetes, chronic heart disease, chronic obstructive pulmonary disease (COPD), hypertension, and hyperlipidemia.2,4 A study from the USDA on working-age U.S. adults found that food security status is more strongly correlated with chronic disease than income, which was only associated with hepatitis, arthritis, and COPD out of 10 chronic diseases significantly associated with food insecurity.5

How food insecurity may cause many chronic conditions remains under-researched. One exception is type 2 diabetes, which is reportedly twice as common in food-insecure individuals than others. Food scarcity may trigger peripheral insulin resistance, increases in cortisol, and accumulation of central adiposity (belly fat), which are all conditions associated with diabetes. Obesity, which some studies have found to be associated with food insecurity, may also play a role in making individuals vulnerable to diabetes and other chronic conditions.2

These findings are indicative of the essential tie between food insecurity and an inability to access nutritious food, which together impact overall health. In general, the cost of a diet rich in healthy foods — including fruits and vegetables, fish, and nuts — is greater than one reliant on highly processed foods, including meats and refined grains, according to a Harvard School of Public Health meta-analysis of 27 studies.6 A USDA study likewise found that foods high in saturated fat and/or added sugars are overall less expensive, per calorie.7 The authors of the Harvard study estimate that a “healthy” diet costs on average $1.50 more per day, which amounts to $550 per year and is an appreciable investment for low-income individuals.6

Making healthier foods more accessible, the authors write, would require a reversal of many decades of policies that have created “a complex network of farming, storage, transportation, processing, manufacturing and marketing capabilities” that have generated an economy for highly processed, low-priced foods.6 While the federal government has historically invested in food initiatives for low-income people, notably the Supplemental Nutrition Assistance Program (SNAP), there has been little innovation in these programs over the past four decades, in spite of a dramatic increase in diet-related illnesses such as obesity and type 2 diabetes.8 SNAP benefits are based on a 1970s metric that represents the minimal amount of money needed to purchase a nutritious diet, and therefore do not align with modern dietary recommendations and economic circumstances. Before the pandemic, SNAP benefits averaged less than $1.40 per meal.9

The need for improving nutritional health and equity across the country is clear. Greater government coordination across federal agencies and programs, especially within the National Institutes of Health, can strengthen government research and programs.8 Beyond taxation of less healthy foods and subsidies for more nutritious options, greater governmental coordination can fuel projects to revolutionize the production, transportation and marketing of healthier foods, increasing their availability while reducing their prices.6


  1. Coleman-Jensen A, Rabbitt MP, Gregory CA, Singh A. Household Food Security in the United States in 2019. U.S. Department of Agriculture. Published 2020. 
  1. Gundersen C, Ziliak JP. Food insecurity and health outcomes. Health Aff (Millwood). 2015;34(11):1830-1839. 
  1. Hake M, Dewey A, Engelhard E, et al. The Impact of the Coronavirus on Food Insecurity. Feeding America. Published 2021. 
  1. Sun Y, Liu B, Rong S, et al. Food insecurity is associated with cardiovascular and all-cause mortality among adults in the United States. J Am Heart Assoc. 2020;9(19):e014629. 
  1. Gregory CA, Coleman-Jensen A. Food Insecurity, Chronic Disease, and Health Among Working-Age Adults. U.S. Department of Agriculture. Published 2017. 
  1. Rao M, Afshin A, Singh G, Mozaffarian D. Do healthier foods and diet patterns cost more than less healthy options? A systematic review and meta-analysis. BMJ Open. 2013;3(12):e004277. 
  1. Carlson A, Frazao E. Are healthy foods really more expensive? It depends on how you measure the price. SSRN Electron J. Published online 2012. doi:10.2139/ssrn.2199553 
  1. Fleischhacker SE, Woteki CE, Coates PM, et al. Strengthening national nutrition research: rationale and options for a new coordinated federal research effort and authority. Am J Clin Nutr. 2020;112(3):721-769. 
  1. Carlson S, Keith-Jennings B, Llobrera J. Modernizing SNAP Benefits Would Help Millions Better Afford Healthy Food. Center on Budget and Policy Priorities. Published 2021. 

Sleep allows the body and mind to recharge; without it, the human brain cannot function properly, and the body becomes more susceptible to disease. Sleep apnea involves brief stoppages in breathing that cause a person to wake repeatedly, which over time can increase risk of cardiovascular disease, depression, high blood pressure, and type 2 diabetes (O’Connor, 2019). For those with the condition, nightly sleep becomes a noisy struggle to breathe rather than a period of restoration. The most common type of sleep apnea is known as obstructive sleep apnea (OSA), which increases the risk of complications during surgery, and despite decades of research, there are no approved medications to treat the condition (Brody, 2019). However, in June of 2021, a team of researchers at Flinders University in Australia found promising results for a potential treatment. Their research, first published in the Journal of Physiology, found that a two-drug combination can reduce sleep apnea by at least 30% (Lim et al., 2021).

There are currently only a few therapies for sleep apnea patients. Continuous positive airway pressure (CPAP) therapy works to prevent a person’s airway from collapsing during sleep (Schein, 2014). CPAP machines, which are comprised of a mask, tube, and motor, use mild air pressure to keep the mask wearer’s airways open. While the CPAP therapy approach works for many, the most common side effects include nasal congestion or runny nose, feelings of claustrophobia, and difficulty falling asleep (Bakalar, 2021). Variable and bi-level positive airway pressure (VPAP and BPAP) therapies work similarly.

An alternative approach is a mandibular repositioning device; these are oral appliances designed to keep the airway open by bringing the wearer’s jaw forward or holding their tongue in place (Marques et al., 2019). However, these devices can be expensive, cause jaw pain, and are less reliable than PAP machines (Bakalar, 2021). Surgery is the last resort for sleep apnea: in the most common of these procedures, surgeons remove obstructive tissues that block the airway (Brody, 2019). Cheaper, over-the-counter approaches like nasal decongestant and breathing strips rarely work for diagnosed sleep apnea.

Researchers at Flinders University found that a combination of two medications – butylbromide and reboxetine – kept pharyngeal muscles active during sleep in people with sleep apnea, allowing for improvement in airway collapsibility and more regular and steady breathing (Lim et al., 2021). Butylbromide is an antispasmodic drug, while reboxetine is most often used to treat depression. While the medications had previously been shown to improve upper airway function during sleep for healthy individuals, its effect on sleep apnea severity was unknown until the Flinders researchers completed their study (Flinders Newsdesk, 2021). Out of fifteen original volunteers, twelve otherwise healthy individuals with OSA completed a double-blind, randomized, placebo-controlled trial (Lim et al., 2021). The research team observed participants for two nights. Each participant received either the two-drug combination or placebo immediately prior to sleep; using nasal masks, pneumotachographs (devices that record the rate of airflow), epiglottic pressure sensors, and more, researchers captured data to create estimates of OSA severity between the two groups. “Almost everyone we studied had some improvement in sleep apnea,” said Professor Danny Eckert, lead researcher and Director of Adelaide Institute for Sleep Health at Flinders (Flinders Newsdesk, 2021). “People’s oxygen intake improved. Their number of breathing stoppages was a third or more less.”

The research team will next look at the long-term effects of this drug combination and similar medications. For now, the findings of the recent study bode well for future developments in pharmacological treatment for OSA.


Bakalar, Nicholas. (2021, May 31). For Sleep Apnea, a Mouth Guard May be a Good Alternative to CPAP. The New York Times. 

Brody, Jane E. (2019, May 27). Sleep Apnea Can Have Deadly Consequences. The New York Times. 

Flinders Newsdesk. (2021, July 7). Drug combo cuts severity of sleep apnoea. Flinders University. 

Lim, R., Messineo, L., Grunstein, R.R., Carberry, J.C. and Eckert, D.J. (2021), The noradrenergic agent reboxetine plus the antimuscarinic hyoscine butylbromide reduces sleep apnoea severity: a double-blind, placebo-controlled, randomised crossover trial. J Physiol. 

Marques, M., Genta, P.R., Azarbarzin, A., Taranto-Montemurro, L., Messineo, L., Hess, L.B., Demko, G., White, D.P., Sands, S.A. and Wellman, A. (2019), Structure and severity of pharyngeal obstruction determine oral appliance efficacy in sleep apnoea. J Physiol, 597: 5399-5410. 

O’Connor, Anahad. (2019, April 10). A Guide to Sleep Apnea. The New York Times 

Schein, A. S., Kerkhoff, A. C., Coronel, C. C., Plentz, R. D., & Sbruzzi, G. (2014). Continuous positive airway pressure reduces blood pressure in patients with obstructive sleep apnea; a systematic review and meta-analysis with 1000 patients. Journal of Hypertension, 32(9), 1762–1773.