# Foot and Mouth Disease Treatment and Control Foot and mouth disease (FMD) is a viral infection of cloven-hoofed livestock caused by foot and mouth disease virus (FMDV), a member of the genus *Aphthovirus* in the family *Picornaviridae*. There is no specific antiviral treatment for FMD. Every case is managed with supportive nursing care, and the outcome of an outbreak is decided by how quickly authorities apply control measures rather than by anything a clinician does at the bedside of a single animal. Supportive care for an affected herd takes days to weeks of hands-on labor, while outbreak control is measured in weeks to months of movement restrictions, depopulation and vaccination. This article explains what supportive care can realistically achieve, how vaccination strategies differ, and how an outbreak is contained. It does not repeat the clinical sign detail covered elsewhere. FMD is a World Organisation for Animal Health (WOAH) listed notifiable disease. That single fact shapes everything that follows. A veterinarian who suspects FMD is legally and professionally obligated to report it to the national veterinary authority, and the national authority then decides whether to stamp out, vaccinate or both. Treatment decisions at the farm level happen only inside a framework that the state has already set. This article is educational and is not a substitute for veterinary diagnosis or treatment. ## Why There Is No Specific Treatment FMDV replicates rapidly in the epithelium of the mouth, feet and teats, producing vesicles that rupture and leave painful erosions. There is no antiviral drug licensed for FMDV in livestock anywhere, and no antiviral has been shown in controlled livestock studies to shorten the course of infection or reduce shedding. Antibiotics have no activity against a virus. They are used only to treat or prevent secondary bacterial infection of open lesions, which is a genuine concern in animals standing in wet, contaminated environments. The practical consequence is that foot and mouth disease treatment is entirely supportive. The goals are to keep the animal eating and drinking, to keep lesions clean, to control pain enough that the animal will stand and feed, and to prevent secondary bacterial infection. No supportive regimen alters the fact that the animal remains infectious and that the herd remains under regulatory control. ### What Supportive Care Can and Cannot Do Supportive care can reduce weight loss, reduce the risk of secondary infection, and improve the comfort of affected animals. It cannot shorten the incubation period, stop viral shedding, or convert an infected animal into a safe one. In a country that pursues stamping out, supportive care is often withheld or limited because animals will be depopulated. In endemic settings where vaccination and treatment are the practical options, supportive care is the main clinical intervention available. ## Supportive Care of Affected Animals Supportive care is delivered at herd level, not animal by animal in isolation, because FMD moves through a group quickly. The following measures are standard veterinary practice for vesicular disease in livestock. ### Nutrition and Water Painful oral lesions make eating painful, and animals may refuse dry forage entirely. Offer soft, palatable feed such as soaked hay cubes, fresh green chop, silage or a gruel made from the animal's normal ration. Provide clean water at all times, and consider offering water in a shallow trough so animals with painful mouths and feet do not have to reach. Animals that will not drink are at risk of dehydration within a day or two, particularly lactating cows with high water demand. ### Lesion Care Clean oral and foot lesions gently with dilute antiseptic solution and keep bedding dry. Foot lesions benefit from a clean, dry standing surface. Do not apply caustic or irritant dressings to vesicular lesions. Handle animals as little as possible, because movement spreads virus and stresses already compromised animals. ### Fluids and Analgesia Fluids may be needed for animals that will not drink. Analgesia is a welfare consideration in animals with painful feet and mouths, and non-steroidal anti-inflammatory drugs are commonly used under veterinary direction. Doses are not given here because they depend on species, weight, production status and local drug availability, and because treatment must be directed by the attending veterinarian within the regulatory framework. ### Antibiotics for Secondary Infection Antibiotics are indicated when there is evidence of secondary bacterial infection of eroded lesions, such as purulent discharge, spreading cellulitis or fever that persists beyond the expected viral course. They are not indicated as routine cover for uncomplicated FMD. Any use must comply with national antimicrobial stewardship rules and withdrawal periods for meat and milk. ### Milking Management Lactating animals with teat lesions are difficult to milk and at risk of mastitis. Gentle milking, teat disinfection and, where necessary, drying off affected quarters reduce the risk. A study of intradermal versus intramuscular FMD vaccination in ruminants monitored milk yield for seven days after vaccination and found that the intradermal group showed a smaller numerical reduction in milk yield than the intramuscular group, although the difference was not statistically significant [1]. That observation concerns vaccination, not treatment, but it is relevant to any discussion of milk production during an FMD response. ## Vaccination Strategies Vaccination is the most important controllable tool in FMD management. Two broad strategies exist, and they are often confused. ### Prophylactic Vaccination Prophylactic vaccination is routine, scheduled vaccination of a population at risk before any outbreak occurs. It is used in endemic countries and in high-risk border regions. Armenia has run a nationwide preventive vaccination program for cattle, small ruminants and pigs, with regular monitoring of circulating virus subtypes and updating of vaccine antigens to match emerging strains [2]. A 65-year retrospective analysis of FMD in Armenia documented the shift from early monovalent campaigns to current protocols, alongside the evolution of diagnostics from complement fixation testing to enzyme-linked immunosorbent assay (ELISA), reverse transcription [polymerase chain reaction](/knowledge/molecular-biology/polymerase-chain-reaction) (RT-PCR) and viral protein 1 (VP1) sequencing [3]. Türkiye saw a decline in reported outbreaks after 2016 that was likely attributable to expanded vaccination coverage, improved diagnostic capacity and targeted control measures [4]. ### Emergency Vaccination Emergency vaccination is reactive. It is applied to a defined population around an outbreak, usually as ring vaccination, to create an immune barrier. A simulation study of FMD in Bolivia modeled control zones, a 30-day movement ban, depopulation and ring vaccination. Combining vaccination at 50 to 90 farms per day with depopulation at 1 to 2 farms per day controlled 60.3 percent of outbreaks. Raising depopulation to 3 to 5 farms per day controlled 62.9 percent and eliminated outbreaks nine days faster. Depopulation alone controlled 56.76 percent of outbreaks but had a median duration of 63 days. The most effective combination, vaccination at 25 to 45 farms per day with depopulation at 6 to 7 farms per day, eliminated all outbreaks within a median of 3 days and a maximum of 79 days. Vaccination alone controlled only 0.6 percent of outbreaks and had a median duration of 98 days [5]. The clear message is that vaccination works as part of a package, not as a standalone measure. Emergency vaccination effectiveness is not immediate. A study of emergency vaccination in a previously FMD-free country without vaccination estimated vaccine effectiveness at one, two and three weeks post-vaccination and found that effectiveness increased over time across all zones [6]. This lag is central to outbreak planning. Vaccinated animals are not protected on the day of injection, so movement restrictions and other measures must continue while immunity develops. ### Inactivated Vaccines Most FMD vaccines are inactivated (killed) virus vaccines formulated with an adjuvant. A polyvalent inactivated vaccine containing one serotype O strain and two serotype A strains was administered to naive small ruminants in Jordan, and about half received a second dose 28 days after the first. A single administration induced a good response, but the second dose boosted immunity, increasing both the level and duration of the response [7]. This is the standard pattern for inactivated FMD vaccines. A monovalent inactivated SAT1 vaccine developed in response to an emerging serotype in Egypt induced protective antibody levels at 14 days in cattle and buffaloes and at 21 days in sheep, with immunity lasting 32 weeks in cattle and buffaloes and 28 weeks in sheep [8]. A separate evaluation of an emergency monovalent SAT1 vaccine found that vaccinated calves developed a mean homologous virus neutralization titer of 2.175 log10 TCID50, exceeding the WOAH protective threshold of at least 1.65 log10 TCID50 [9]. ### Marker Vaccines and DIVA The central limitation of conventional inactivated vaccines is that they induce antibodies against the same viral proteins that infection does, so serological tests cannot distinguish vaccinated from infected animals. This is the DIVA problem, where DIVA stands for differentiating infected from vaccinated animals. A trivalent negative marker vaccine targeting serotypes O, A and Asia 1 was evaluated in cattle and elicited virus neutralizing antibody titers that peaked at 2 to 4 weeks and remained significant for six months, with protection against homologous serotype O challenge for up to six months. DIVA compliance was demonstrated by the absence of antibodies to the deleted 3A segment after repeated booster vaccination [10]. Marker vaccines let a country vaccinate and still prove freedom from infection, which matters enormously for trade. ### Vaccine Matching and Serotype Coverage FMDV exists as seven serotypes with multiple lineages and strains, and immunity against one serotype does not reliably protect against another. Vaccine selection must match circulating strains. Post-vaccination monitoring in Jordan used virus neutralization testing against a vaccine-matched serotype O strain and a recently circulating heterologous strain to confirm cross-immunity [7]. A study in Ethiopia found that a trivalent vaccine had low effectiveness, 31 percent against single serotypes and 26 percent when adjusted for mixed infections, which was insufficient to achieve herd immunity given a high transmission intensity [11]. This illustrates that a vaccine that looks adequate on paper can fail in the field if it does not match the circulating strain or if coverage is too low. ### Vaccination and Coinfection Vaccine response can be impaired by concurrent disease. A study in cattle found that infection with the liver fluke *Fasciola hepatica* after FMD vaccination significantly lowered IgG1 antibody avidity indices, indicating impaired antibody maturation, and was accompanied by diminished vaccine-induced cellular immune responses and persistent biochemical evidence of liver dysfunction during chronic infection. Triclabendazole treatment restored antibody avidity and partially recovered productive performance, although some metabolic alterations persisted [12]. Parasite control is therefore part of a functional vaccination program. ## Outbreak Control Outbreak control is a state-led process. The veterinarian's role is early recognition, immediate reporting, and support of the official response. ### Stamping Out Stamping out means depopulating infected and often in-contact premises. It is the traditional cornerstone of FMD control in countries that hold FMD-free status without vaccination. The Bolivian modeling study showed that depopulation alone controlled 56.76 percent of outbreaks but took a median of 63 days, and that combining depopulation with vaccination was more effective than either alone [5]. Stamping out removes the source of virus but is economically and ethically costly, and it is most effective when applied early and combined with other measures. ### Movement Restrictions and Zoning Movement restrictions stop infected animals and contaminated vehicles, people and products from carrying virus to new premises. The Bolivian model included a 30-day movement ban as part of the control package [5]. Zoning divides a country into control zones so that trade from free zones can continue. A modeling study of FMD in the New England milkshed tested regional zoning, earlier detection and enhanced biosecurity and found that shorter outbreak durations and reduced spread were associated with these measures, with the combination of regional zoning and earlier detection providing synergistic reduction beyond either strategy alone [13]. Zoning is what allows a country to keep exporting from regions that remain free while containing an outbreak elsewhere. ### Surveillance and Early Detection Earlier detection reduces outbreak size. The New England modeling study tested the hypothesis that earlier detection through increased passive surveillance reduces overall outbreak impact and supported it [13]. Surveillance in endemic settings often relies on abattoir sampling. A study in Lao PDR used abattoir-based surveillance and found FMD antibody seroprevalence of 43 percent in cattle and 52 percent in buffaloes, with domestic pigs potentially playing a role in transmission [14]. Serosurveillance using non-structural protein (NSP) assays distinguishes infection-induced antibodies from vaccination responses, which is essential when vaccination is ongoing [14]. ### Biosecurity Enhanced biosecurity reduces indirect transmission. The New England study tested whether reduced indirect transmission through enhanced biosecurity improves outbreak control and supported this hypothesis [13]. Practical biosecurity includes disinfection of vehicles and equipment, controlled entry to premises, and separation of personnel and animals. ### The Trade Constraint on Vaccination A synthesis of regulatory implications for FMD, lumpy skin disease and highly pathogenic [avian influenza](/knowledge/bacteria/avian-bacteria/avian-influenza-new-zealand-kerala-outbreaks-jessamine-county-updates) in European livestock found that for FMD, despite the epidemiological benefits of vaccination, maintaining FMD-free status without vaccination remains the dominant policy objective, constraining adoption of vaccination-to-live because of trade implications [15]. This is the central tension in FMD policy. Vaccination works, but many high-value export markets will not accept products from vaccinated animals unless a DIVA strategy is in place and recognized. The same synthesis recommended shifting toward preventive vaccination tailored by country and disease, and prioritizing vaccination-to-live strategies [15]. ## Control Measures at a Glance | Measure | Purpose | Limitations | |--|--|--| | Supportive care | Maintain nutrition, hydration and comfort, prevent secondary infection | Does not shorten infection or stop shedding, often withheld if depopulation is planned | | Stamping out | Remove infected and in-contact animals as a virus source | Costly, ethically difficult, slower than combined approaches when used alone [5] | | Movement restrictions | Prevent movement of virus on animals, vehicles and products | Economically damaging, requires enforcement, must be maintained during vaccine rollout [5] | | Zoning | Contain outbreak while allowing trade from free zones | Requires clear boundaries and surveillance to maintain credibility [13] | | Enhanced biosecurity | Reduce indirect transmission between premises | Labor intensive, difficult to sustain, depends on compliance [13] | | Prophylactic vaccination | Protect at-risk populations before outbreaks | Requires strain matching, cold chain and repeated campaigns [2] | | Emergency ring vaccination | Create an immune barrier around an outbreak | Protection lags injection by weeks, so other measures must continue [6] | | Inactivated vaccines | Induce humoral immunity against matched serotypes | Do not allow differentiation of infected from vaccinated animals | | Marker (DIVA) vaccines | Allow vaccination while proving freedom from infection | Must be paired with validated DIVA-compatible diagnostic tests [10] | | Surveillance and NSP testing | Detect infection and distinguish it from vaccination | Requires laboratory capacity and consistent sampling [14] | ## Workflow of an Outbreak Response The decision path below summarizes how a suspected FMD case moves from recognition to control. Each step depends on the one before it, and reporting comes first. ```mermaid flowchart TD A[Suspect case] --> B[Report to authority] B --> C[Laboratory confirmation] C --> D{Control strategy} D --> E[Stamping out] D --> F[Emergency vaccination] D --> G[Movement restrictions] E --> H[Zoning] F --> H G --> H H --> I[Surveillance] I --> J[Review and stand down] ``` ## Expected Results and How to Read Them In a herd under supportive care, expect oral and foot lesions to begin healing within one to two weeks if no secondary infection occurs, and expect appetite and milk yield to recover gradually over two to four weeks. Weight loss is common even with good nursing. Failure to improve, spreading lesions, or persistent fever should prompt reassessment for secondary bacterial infection. In a vaccinated population, protection is not binary. Post-vaccination serology is used to estimate the probability of protection. A study in goats estimated the vaccinal antibody titer at the time of exposure that would protect against lesions after heterologous SAT1 challenge, using virus neutralization tests and solid-phase competition ELISA [16]. This kind of threshold work is how programs judge whether a vaccine is performing. A single titer value does not guarantee protection for an individual animal. In an outbreak, the metrics that matter are outbreak duration, number of infected premises and time to elimination. The Bolivian model used exactly these metrics and showed that the combination of vaccination and depopulation eliminated outbreaks fastest [5]. The New England model used daily infected premises, outbreak duration and total infected premises [13]. ## Troubleshooting | Symptom or problem | Likely cause | Fix | |--|--|--| | Animal will not eat despite soft feed | Severe oral pain | Veterinary analgesia, softer gruel, offer water in shallow trough | | Persistent fever beyond expected course | Secondary bacterial infection | Veterinary assessment and appropriate antibiotics | | Lesions spreading or new lesions appearing | Ongoing viral replication or new exposure | Reinforce isolation and biosecurity, reassess herd status | | Vaccinated animals still develop disease | Vaccine strain mismatch or insufficient coverage | Review strain matching and coverage, consider booster where permitted [11] | | Poor antibody response after vaccination | Concurrent parasitism or other immune challenge | Investigate and treat parasites under veterinary direction [12] | | Outbreak continues despite vaccination | Protection lag or incomplete ring | Maintain movement restrictions and depopulation while immunity develops [6] | | Serology cannot distinguish vaccinated from infected | Conventional vaccine in use | Consider marker vaccine and DIVA-compatible testing [10] | ## Variations and Special Situations Species differ in susceptibility and response. Small ruminants are susceptible and have been implicated in outbreaks, but data are more limited than for cattle [16]. Pigs can play an important role in transmission dynamics [14]. Vaccine responses differ by species. In the Egyptian SAT1 vaccine evaluation, protective antibody levels appeared at 14 days in cattle and buffaloes but at 21 days in sheep, and immunity lasted longer in cattle and buffaloes than in sheep [8]. Intradermal vaccination has been explored as an alternative to intramuscular delivery, inducing humoral responses comparable to intramuscular vaccination over 140 days in cattle and protecting goats against a 2025 serotype O field isolate [1]. Vaccine supply is a real constraint in endemic regions. A modeling study using data from Erzurum in Türkiye simulated four vaccine allocation strategies under limited supply and found that random allocation outperformed other strategies when the objective was to minimize average prevalence, and that all strategies performed similarly when minimizing annual incidence. The authors concluded that policymakers in endemic regions should focus more on sourcing high-quality vaccines and achieving high coverage, with risk-based targeting as a secondary concern [17]. This is a useful corrective to the assumption that clever targeting always beats broad coverage. ## Storage and Stability Notes FMD vaccines are biological products with defined cold chain requirements. Inactivated vaccines must be stored and transported within the temperature range specified by the manufacturer, and freeze-thaw cycles can damage adjuvanted formulations. Field teams should record temperature during transport and discard any vaccine that has been outside the specified range. The DIVA marker vaccine evaluation demonstrated that potency and DIVA compliance were maintained across repeated booster studies, which depends on correct storage and handling [10]. Antigen quantification, such as 146S measurement, is used in vaccine quality control to confirm that the protective antigen content is adequate [9]. Diagnostic samples for FMD testing, particularly epithelial tissue and oral swabs, require appropriate transport media and cold chain to preserve viral RNA for RT-PCR [11]. ## Clinical Relevance, Limitations and Common Mistakes The clinical relevance of this topic is straightforward. FMD is one of the most economically damaging livestock diseases in the world, and the clinician's contribution is early recognition, immediate reporting and competent supportive care within a regulatory framework. The limitations are equally clear. No treatment exists that changes the infectious status of an animal. Vaccination protects but does not instantly protect, and it does not always match the circulating strain. Control measures work as a package, and any single measure used alone tends to fail or take far longer. Common mistakes include treating FMD as a purely clinical problem and delaying the report, using antibiotics as though they addressed the virus, assuming a vaccinated animal is immediately safe to move, and assuming that a vaccine that worked last season will match this season's strain. Another frequent error is overlooking concurrent disease, such as liver fluke infection, that blunts vaccine response [12]. Programs that skip post-vaccination monitoring cannot tell whether their vaccine is working, which is why WOAH and FAO guidelines recommend assessing vaccine effectiveness [7]. Individual cases and individual herds need a veterinarian, and any suspicion of FMD needs a report to the national authority without delay. ## Frequently Asked Questions ### Is there a cure for foot and mouth disease? No. There is no specific antiviral treatment for FMD, and care is supportive only. ### What does supportive treatment for foot and mouth disease involve? Soft feed, clean water, gentle lesion cleaning, pain control, fluids when needed, and antibiotics only for secondary bacterial infection. ### Why are antibiotics used if FMD is a virus? They do not treat the virus. They treat or prevent bacterial infection of the open lesions. ### What is the difference between prophylactic and emergency vaccination? Prophylactic vaccination is routine and given before an outbreak. Emergency vaccination is given reactively around an outbreak, usually as ring vaccination. ### What is a marker vaccine? A marker vaccine is designed so that tests can distinguish vaccinated animals from infected ones, which is the DIVA principle. ### How long after vaccination does protection begin? Protection is not immediate. Emergency vaccination effectiveness increases over the first three weeks after injection. ### Why is FMD a notifiable disease? Because it spreads rapidly, causes severe economic loss and must be reported so authorities can start control measures. ### Can a vaccinated animal still spread FMD? Vaccination reduces but does not instantly eliminate transmission risk, which is why movement restrictions continue during a vaccination campaign. ## Related Articles - [Bovine Foot Rot: Diagnosis, Treatment, Recurrence, and Pasture Risk Control](/knowledge/veterinary-medicine/clinical-methods/bovine-foot-rot-diagnosis-treatment-recurrence-pasture-risk-control) - [Aquarium Fish Mouth Fungus (Columnaris): Identification and Treatment](/knowledge/veterinary-medicine/aquarium-fish-care/aquarium-fish-mouth-fungus-columnaris-identification-treatment) - [Equine Hoof and Foot Conditions: Diagnosis and Treatment](/knowledge/veterinary-medicine/equine-care/equine-hoof-foot-conditions-diagnosis-treatment) - [Bearded Dragon Care: Respiratory infection open mouth breathing treatment](/knowledge/veterinary-medicine/exotic-small-animals/bearded-dragon-care-respiratory-infection-open-mouth-breathing-treatment) - [Canine Heartworm Disease: Prevention and Treatment with Heartworm and Flea Control](/knowledge/parasites/pet-parasites/canine-heartworm-disease-prevention-treatment-heartworm-flea-control) - [What To Do If Your Dog Is Stung By A Bee In The Mouth](/knowledge/veterinary-medicine/dental-care/what-to-do-if-your-dog-is-stung-by-a-bee-in-the-mouth) - [How to Treat Foot and Mouth Disease in Animals](/knowledge/veterinary-medicine/toxicology-and-food-safety/how-to-treat-foot-and-mouth-disease-in-animals) - [Foot and Mouth Disease Symptoms in Animals](/knowledge/veterinary-medicine/food-animal-medicine/foot-and-mouth-disease-symptoms-in-animals) ## Sources 1. [Intradermal Vaccination Induces Protective Immunity Against Foot-and-Mouth Disease While Mitigating Milk Yield Reduction in Ruminants.](https://pubmed.ncbi.nlm.nih.gov/42646716/) 2. [Evaluation of applied foot and mouth disease-providing measures in the Republic of Armenia: A retrospective study.](https://pubmed.ncbi.nlm.nih.gov/41630719/) 3. [Foot-and-mouth disease in Armenia (1958-2003): Historical epidemiology, serotype dynamics, and evolving vaccination strategies.](https://pubmed.ncbi.nlm.nih.gov/41113226/) 4. [Assessment of Foot-and-Mouth Disease Trends in Türkiye Between 2005 and 2025.](https://pubmed.ncbi.nlm.nih.gov/41287802/) 5. [Foot-and-Mouth Disease in Bolivia: Simulation-Based Assessment of Control Strategies and Vaccination Requirements.](https://pubmed.ncbi.nlm.nih.gov/41048213/) 6. [Effectiveness of emergency vaccination in controlling a foot-and-mouth disease epidemic in a previously FMD-free without vaccination country.](https://pubmed.ncbi.nlm.nih.gov/42342025/) 7. [Robust cross-immunity against a heterologous field strain of foot-and-mouth disease virus achieved in small ruminants following commercial vaccination in Jordan.](https://pubmed.ncbi.nlm.nih.gov/42577523/) 8. [Preparation and evaluation of a monovalent foot and mouth disease vaccine as a rapid response to the emerging serotype SAT1 in Egypt.](https://pubmed.ncbi.nlm.nih.gov/42705099/) 9. [Comprehensive evaluation of an emergency monovalent SAT1 foot-and-mouth-disease vaccine: Antigen quality, product consistency, and protective efficacy.](https://pubmed.ncbi.nlm.nih.gov/42455825/) 10. [Evaluation of a DIVA compliant trivalent negative marker vaccine for foot-and-mouth disease in cattle.](https://pubmed.ncbi.nlm.nih.gov/42409078/) 11. [Serotype Characterization and Transmission Modelling of Foot-and-Mouth Disease in Dairy Farms, Bishoftu, Ethiopia.](https://pubmed.ncbi.nlm.nih.gov/42334036/) 12. [Timing of Fasciola hepatica infection selectively impairs antibody avidity after foot-and-mouth disease vaccination in cattle.](https://pubmed.ncbi.nlm.nih.gov/42643874/) 13. [Testing Control Strategies for Foot-and-Mouth Disease in New England Using the InterSpread Plus Model: Impacts of Regional Zoning, Early Detection, and Enhanced Biosecurity.](https://pubmed.ncbi.nlm.nih.gov/42043269/) 14. [Epidemic Patterns of Foot and Mouth Disease in the Lao People's Democratic Republic.](https://pubmed.ncbi.nlm.nih.gov/42584029/) 15. [Regulatory Implications and Control Measures for Lumpy Skin Disease, Highly Pathogenic Avian Influenza, and Foot-and-Mouth Disease in European Livestock.](https://pubmed.ncbi.nlm.nih.gov/42515628/) 16. [Post-vaccination serological status predicts protection against heterologous SAT1 foot-and-mouth disease virus challenge in goats.](https://pubmed.ncbi.nlm.nih.gov/42030596/) 17. [Assessing the effects of limited vaccine supply on risk-based vaccination strategies in regions of endemic foot-and-mouth disease.](https://pubmed.ncbi.nlm.nih.gov/42415208/)