We conducted a randomized, double-blind, placebo-controlled trial to explore how zinc gluconate affects migraine symptoms in women. Sixty participants, with an average age of 35, were given either 15 mg of zinc per day or a placebo for 12 weeks, allowing us to measure the impact on headache frequency, duration, and intensity.
The results were quite promising; zinc supplementation significantly reduced how often headaches occurred, shortened their duration, and decreased the severity of the migraines reported. Participants in the zinc group experienced notable improvements, as indicated by their responses to the headache severity scale and a disability assessment questionnaire.
Furthermore, we found that zinc also had a positive effect on certain health markers. The serum levels of low-density lipoprotein (LDL), total cholesterol, and high-sensitivity C-reactive protein (hs-CRP) decreased with zinc supplementation. However, we didn’t observe significant changes in triglycerides or high-density lipoprotein (HDL) levels after adjusting for baseline values.
In conclusion, zinc supplementation appears to hold beneficial effects on migraine severity and frequency, offering a potential alternative for those who seek relief from these debilitating headaches.
Read More
7
Zinc may aid migraine relief
Zinc Administration Favorably Affects Prophylactic Therapy-refractory Migraine Attacks: A Case Series.
We explored the impact of zinc on migraine headaches, particularly looking at its effectiveness for those who haven’t found relief from traditional preventive treatments. Our investigation involved four patients suffering from migraine attacks that were resistant to usual prophylactic therapies.
Each of these patients reported a notable improvement in the frequency and severity of their headaches after incorporating zinc supplements into their regimen. This suggests that zinc might serve as a beneficial alternative for those grappling with stubborn migraines.
While our findings are promising, it's crucial to recognize that further research is needed to firmly establish the efficacy of zinc replacement therapy in this context. Nevertheless, zinc administration could offer hope for individuals facing challenges with typical migraine treatment options.
Read More
8
Zinc intake may reduce migraines
Dietary zinc intake in relation to migraine among adults: a cross sectional study of NHANES 1999-2004.
We explored the connection between zinc intake and migraine through the analysis of cross-sectional data from the National Health and Nutrition Examination Survey conducted between 1999 and 2004. Our aim was to determine if higher dietary zinc could reduce the prevalence of migraines among adults.
In our analysis, we discovered that individuals consuming higher amounts of zinc experienced fewer migraines. Specifically, when comparing participants with the lowest zinc intake to those in higher intake groups, we found significant reductions in migraine occurrence. For example, adjusting for other factors, those in the second and third zinc intake groups had a 27% and 28% lower odds of experiencing migraines, respectively.
We also noted that age plays a role in how zinc intake affects headache prevalence, suggesting that the benefits of dietary zinc may differ depending on age. Interestingly, in adults aged 20 to 50, the relationship between zinc and migraines was not straightforward, indicating a complex interaction.
Overall, this research highlights the potential benefits of increasing zinc in our diets for reducing migraine frequency, and serves as a reminder that dietary choices can have significant health implications.
Read More
Most Useful Reviews
7.5
No more headaches
243 people found this helpful
This zinc is excellent. My test results after taking these pills were exceptional. However, 50 mg caused me severe headaches, which were unbearable. I contacted my doctor, who advised me to break the tablet in half and take half a tablet daily. Thankfully, I didn't experience any further headaches. The tablets are easy to swallow, and you can also break them in half effortlessly.
Read More
7.5
Headaches ceased
8 people found this helpful
Zinc = LIFE SAVER. This zinc is fantastic, and zinc in general is beneficial. My test results improved significantly after consuming these pills. However, 50 mg led to severe headaches for me, which were unbearable. I consulted my doctor, who recommended breaking the pill in half and taking half daily. Thankfully, I no longer suffered from headaches. The pills are easy to swallow and can be easily broken in half.
Read More
4
Helps with acne
85 people found this helpful
I have been taking these tablets along with my daily zinc for a few weeks now. They have significantly reduced my acne! It has cleared up slowly, and I only get the occasional pimple. Although I have some scarring, I feel softness instead of rough, scabby acne across my face. I don't expect zinc to be a cure-all, but it has helped immensely! I have noted, however, that excessive zinc can cause headaches; I've experienced this for three days recently, which is unusual for me. I will reduce my intake to approximately 40mg per day to be safe.
We conducted a randomized, double-blind, placebo-controlled trial to explore how zinc gluconate affects migraine symptoms in women. Sixty participants, with an average age of 35, were given either 15 mg of zinc per day or a placebo for 12 weeks, allowing us to measure the impact on headache frequency, duration, and intensity.
The results were quite promising; zinc supplementation significantly reduced how often headaches occurred, shortened their duration, and decreased the severity of the migraines reported. Participants in the zinc group experienced notable improvements, as indicated by their responses to the headache severity scale and a disability assessment questionnaire.
Furthermore, we found that zinc also had a positive effect on certain health markers. The serum levels of low-density lipoprotein (LDL), total cholesterol, and high-sensitivity C-reactive protein (hs-CRP) decreased with zinc supplementation. However, we didn’t observe significant changes in triglycerides or high-density lipoprotein (HDL) levels after adjusting for baseline values.
In conclusion, zinc supplementation appears to hold beneficial effects on migraine severity and frequency, offering a potential alternative for those who seek relief from these debilitating headaches.
Read More
8
Zinc intake may reduce migraines
Dietary zinc intake in relation to migraine among adults: a cross sectional study of NHANES 1999-2004.
We explored the connection between zinc intake and migraine through the analysis of cross-sectional data from the National Health and Nutrition Examination Survey conducted between 1999 and 2004. Our aim was to determine if higher dietary zinc could reduce the prevalence of migraines among adults.
In our analysis, we discovered that individuals consuming higher amounts of zinc experienced fewer migraines. Specifically, when comparing participants with the lowest zinc intake to those in higher intake groups, we found significant reductions in migraine occurrence. For example, adjusting for other factors, those in the second and third zinc intake groups had a 27% and 28% lower odds of experiencing migraines, respectively.
We also noted that age plays a role in how zinc intake affects headache prevalence, suggesting that the benefits of dietary zinc may differ depending on age. Interestingly, in adults aged 20 to 50, the relationship between zinc and migraines was not straightforward, indicating a complex interaction.
Overall, this research highlights the potential benefits of increasing zinc in our diets for reducing migraine frequency, and serves as a reminder that dietary choices can have significant health implications.
Read More
8
Zinc may help reduce migraines
Dietary zinc intake and migraine in adults: a cross-sectional analysis of the National Health and Nutrition Examination Survey 1999-2004.
We explored how dietary zinc intake relates to migraines by analyzing data from the National Health and Nutrition Examination Survey conducted between 1999 and 2004. This cross-sectional study focused on adults who reported experiencing severe headaches or migraines.
Our findings indicated a noteworthy trend: higher intake of dietary zinc was associated with a lower likelihood of having migraines. Specifically, participants with greater zinc consumption—classified into various intake levels—showed a consistent decrease in the odds of experiencing migraine symptoms. For example, those in the highest quintile of zinc intake were 30% less likely to experience migraines compared to those with the lowest intake levels.
This suggests that increasing our zinc intake could be a beneficial strategy for managing migraines. While further research is needed to understand the precise mechanism, the anti-inflammatory and antioxidant properties of zinc may play a crucial role in reducing migraine occurrences.
Read More
8
Zinc chloride may reduce headaches
Epipharyngeal Abrasive Therapy (EAT) Has Potential as a Novel Method for Long COVID Treatment.
We evaluated how zinc chloride, used in epipharyngeal abrasive therapy (EAT), might alleviate headaches among patients with long COVID. EAT involves applying zinc chloride to the lining of the epipharynx, where inflammation can linger after COVID-19.
Our study involved 58 patients who received EAT weekly for a month. Before and after the treatment, we measured the intensity of common long COVID symptoms, including fatigue and headaches, using a visual analog scale.
Interestingly, our findings showed that EAT helped reduce inflammation in the epipharynx and significantly improved not only headaches but also fatigue and attention disorders. This suggests that zinc chloride might play a role in easing headache symptoms associated with long COVID.
Overall, we believe this study highlights the potential of EAT as a new treatment avenue for managing long COVID symptoms, particularly headaches, which can often be debilitating for many.
Read More
8
Zinc improves headache symptoms
Intravenous Calcium-/Zinc-Diethylene Triamine Penta-Acetic Acid in Patients With Presumed Gadolinium Deposition Disease: A Preliminary Report on 25 Patients.
We observed the use of intravenous calcium and zinc in patients diagnosed with gadolinium deposition disease, with a focus on how this treatment affected their headaches. In our preliminary report involving 25 patients, we noted significant improvements in headache symptoms among those receiving treatment, particularly with a regime of calcium-/zinc-diethylene triamine penta-acetic acid (DTPA).
Patients underwent three courses of treatment, and we measured their urinary gadolinium levels and self-reported symptoms before, during, and after these sessions. The findings revealed a noteworthy increase in Gd content in urine, indicating an effective chelation process, as well as moderate symptomatic relief.
Specifically, 13 patients reported a decrease in headache intensity, along with improvements in other symptoms like brain fog and bone pain. For those on a monthly treatment schedule, there were more significant benefits noted compared to the weekly treatment schedule.
Overall, while there was a transient worsening of symptoms in some patients at first—a phenomenon referred to as a "flare-up"—the outcome suggests that the combination therapy shows promise in alleviating headaches among individuals suffering from this perplexing condition.
This zinc is excellent. My test results after taking these pills were exceptional. However, 50 mg caused me severe headaches, which were unbearable. I contacted my doctor, who advised me to break the tablet in half and take half a tablet daily. Thankfully, I didn't experience any further headaches. The tablets are easy to swallow, and you can also break them in half effortlessly.
Read More
7.5
Headaches ceased
8 people found this helpful
Zinc = LIFE SAVER. This zinc is fantastic, and zinc in general is beneficial. My test results improved significantly after consuming these pills. However, 50 mg led to severe headaches for me, which were unbearable. I consulted my doctor, who recommended breaking the pill in half and taking half daily. Thankfully, I no longer suffered from headaches. The pills are easy to swallow and can be easily broken in half.
Read More
4
Helps with acne
85 people found this helpful
I have been taking these tablets along with my daily zinc for a few weeks now. They have significantly reduced my acne! It has cleared up slowly, and I only get the occasional pimple. Although I have some scarring, I feel softness instead of rough, scabby acne across my face. I don't expect zinc to be a cure-all, but it has helped immensely! I have noted, however, that excessive zinc can cause headaches; I've experienced this for three days recently, which is unusual for me. I will reduce my intake to approximately 40mg per day to be safe.
Read More
2
Headache effects
Not good. I bought it to strengthen my immune system and for hair loss, but every time I took a pill, I got a headache. It didn’t have a positive effect on me.
Read More
4
Reduces hormonal acne
1 people found this helpful
Since I started taking zinc supplements, I have noticed a significant decrease in my hormonal acne. Alternatively, it could be my new skincare routine, as finding what works can be a trial and error process. I have tried many supplements before, but this has become a staple. I split the tablet because it can induce headaches, particularly on an empty stomach.
Read More
Frequently Asked Questions
A headache is a common condition characterized by pain or discomfort in the head, scalp, or neck. It can vary in intensity, frequency, and duration, and is often classified into two primary categories: primary and secondary headaches. Primary headaches, such as tension-type headaches, migraines, and cluster headaches, are not caused by other medical conditions. Instead, they are conditions in themselves, often resulting from factors like stress, hormonal changes, or environmental triggers. Secondary headaches, on the other hand, are symptoms of an underlying issue, such as an infection, injury, or other medical conditions.
The experience of a headache can differ widely among individuals. Depending on the type, headaches can be throbbing or constant and may be accompanied by other symptoms like nausea, sensitivity to light, or aura effects before the headache strikes. Effective management strategies vary by headache type and may include over-the-counter pain relievers, lifestyle changes, and in some cases, prescription medications. Understanding the specific triggers and patterns related to your headaches can be crucial for prevention and treatment, so maintaining a headache diary may be beneficial for those experiencing frequent or severe episodes.
Zinc is a versatile metal known for its various applications in industry and health. It is a bluish-white metallic element represented by the symbol Zn and atomic number 30 on the periodic table. Zinc is primarily used for galvanizing steel to prevent rusting, in the manufacturing of alloys, and as a component in batteries. Additionally, zinc plays a crucial role in biological processes, making it an essential trace element in the human diet. It is involved in immune function, protein synthesis, wound healing, and DNA synthesis, highlighting its importance in maintaining overall health and well-being.
Zinc is an essential mineral known for its various health benefits, including immune support and anti-inflammatory properties. Some studies suggest that zinc may have a role in reducing the frequency and severity of headaches, particularly migraines, which can be linked to underlying nutritional deficiencies. Certain research indicates that individuals with lower levels of zinc may experience more frequent headaches, potentially due to its involvement in enzyme functions and neurotransmitter regulation.
However, while zinc supplementation could be beneficial for some, it's important to approach this method with caution. Self-diagnosing and treating headache disorders without professional guidance may lead to unintended side effects, particularly if taken in excessive amounts. If you're considering zinc as a potential remedy for headaches, consulting with a healthcare professional is advisable to determine the appropriateness based on your individual health status and specific headache type. So, while there’s a potential link between zinc and headache relief, more conclusive research is needed to establish zinc as a standardized treatment protocol.
Based on user reviews, the time it takes to see results from this supplement for headaches can vary significantly. Some users have experienced immediate adverse effects, such as severe headaches after taking a full dose, prompting them to adjust their intake. For instance, a user who initially took 50 mg reported unbearable headaches but found relief after consulting a doctor and reducing the dosage to half a tablet daily Read Review.
Meanwhile, other users did not find the supplement beneficial for their headaches, noting that each dose resulted in problematic headache symptoms instead of relief Read Review. It's evident from the reviews that results may depend on individual reactions to the supplement. Generally, if headaches occur, adjusting the dosage under medical guidance appears crucial for those looking to find relief.
Scientific research suggests that zinc supplementation may be beneficial for headache management, particularly in the context of migraines. A systematic review analyzing multiple studies found a positive indication that zinc could help alleviate migraine symptoms, albeit with a call for more extensive clinical trials to confirm its effectiveness [1]. Further investigations involving patients resistant to traditional therapies indicated notable improvements in headache frequency and severity with zinc supplementation, hinting at its potential as an alternative treatment option [2].
Moreover, a cross-sectional analysis revealed that individuals with higher dietary zinc intake reported fewer migraines, underscoring the correlation between zinc levels and headache prevalence [3]. In randomized trials, zinc supplementation has shown to significantly reduce the frequency, duration, and intensity of migraines, making it a promising candidate for individuals seeking relief [6]. While the current body of research is encouraging, it emphasizes the need for further studies to fully establish the role of zinc in headache treatment.
Many users have reported a positive improvement in their symptoms after adjusting their zinc intake. Several individuals found that their test results, whether related to health markers or overall well-being, showed significant improvement after taking zinc supplements. For instance, one user noted exceptional test results after starting the supplements and described zinc as a "LIFE SAVER" Read Review. Another user echoed similar sentiments, highlighting that despite initially experiencing severe headaches at a full dosage, reducing the intake under medical guidance led to relief and better health outcomes Read Review.
However, it’s important to note that not all experiences have been positive. One reviewer reported consistently developing headaches with each dose and did not see any beneficial effects from the supplement on their immune system or hair loss Read Review. This illustrates that while many users have benefitted from zinc supplements, individual results can vary significantly. For those who experience adverse effects, consulting with a healthcare professional and adjusting dosage is essential to achieve an optimal outcome.
Users report mixed experiences regarding the combination of this supplement with other supplements for handling headaches. Some have found that taking zinc, particularly at higher doses, can lead to severe headaches, prompting them to seek medical guidance. For instance, after experiencing unbearable headaches from a 50 mg dose, one user reduced their intake to half a tablet daily, which alleviated their headache symptoms entirely Read Review. Another user echoed similar sentiments, praising zinc and stating that after adjusting their dosage following a doctor's advice, they were able to avoid further headaches Read Review.
Conversely, there are users who reported consistently developing headaches with each dose of the supplement, indicating a lack of positive effects on their health conditions, such as immunity and hair loss problems Read Review. This varying feedback highlights the importance of dosage adjustments and professional consultation when combining this supplement with others for headache management.
Based on recent studies, zinc supplementation has shown promise in treating migraines and headaches, but determining an optimal dose remains challenging. One significant study found that a daily intake of 15 mg of zinc gluconate significantly reduced headache frequency, duration, and severity in women suffering from migraines [6]. Other trials involving different forms of zinc also hinted at benefits, with varying doses leading to a noticeable drop in the frequency of migraine attacks among participants [7].
While these findings highlight zinc's potential, the consensus within the research is that further investigation is needed to solidify these recommendations and determine the most effective dosing strategies. Though results have varied slightly, it's evident that adequate zinc intake may be beneficial for those struggling with headaches, offering an alternative for individuals who have not found relief with traditional treatments [2]. Therefore, if you're considering adding zinc to your regimen for headache management, speaking with a healthcare provider for personalized advice and recommendations is wise.
7.5
No more headaches
243 people found this helpful
This zinc is excellent. My test results after taking these pills were exceptional. However, 50 mg caused me severe headaches, which were unbearable. I contacted my doctor, who advised me to break the tablet in half and take half a tablet daily. Thankfully, I didn't experience any further headaches. The tablets are easy to swallow, and you can also break them in half effortlessly.
2
Headache effects
Not good. I bought it to strengthen my immune system and for hair loss, but every time I took a pill, I got a headache. It didn’t have a positive effect on me.
7.5
Headaches ceased
8 people found this helpful
Zinc = LIFE SAVER. This zinc is fantastic, and zinc in general is beneficial. My test results improved significantly after consuming these pills. However, 50 mg led to severe headaches for me, which were unbearable. I consulted my doctor, who recommended breaking the pill in half and taking half daily. Thankfully, I no longer suffered from headaches. The pills are easy to swallow and can be easily broken in half.
7
Zinc's role in migraine management
Zinc as An Emerging Therapy in the Management of Migraine: A Systematic Review.
We explored the impact of zinc in managing migraines, which are often debilitating headaches that many people experience. This research was designed to systematically review the existing literature and gather evidence on how zinc could potentially help alleviate migraine symptoms.
Our investigation led to the analysis of five studies, including two clinical trials and three observational studies. The clinical trials showed a low risk of bias, suggesting that the findings are reliable. Overall, the review indicated a positive role for zinc in managing migraines, yet the evidence currently available is limited.
We noted that while zinc seems to offer some benefits for headache relief, more extensive and robust clinical trials are needed to firmly establish its effectiveness. As of now, the journey toward understanding the full potential of zinc for migraines continues, emphasizing the need for further investigation.
7
Zinc may aid migraine relief
Zinc Administration Favorably Affects Prophylactic Therapy-refractory Migraine Attacks: A Case Series.
We explored the impact of zinc on migraine headaches, particularly looking at its effectiveness for those who haven’t found relief from traditional preventive treatments. Our investigation involved four patients suffering from migraine attacks that were resistant to usual prophylactic therapies.
Each of these patients reported a notable improvement in the frequency and severity of their headaches after incorporating zinc supplements into their regimen. This suggests that zinc might serve as a beneficial alternative for those grappling with stubborn migraines.
While our findings are promising, it's crucial to recognize that further research is needed to firmly establish the efficacy of zinc replacement therapy in this context. Nevertheless, zinc administration could offer hope for individuals facing challenges with typical migraine treatment options.
8
Zinc intake may reduce migraines
Dietary zinc intake in relation to migraine among adults: a cross sectional study of NHANES 1999-2004.
We explored the connection between zinc intake and migraine through the analysis of cross-sectional data from the National Health and Nutrition Examination Survey conducted between 1999 and 2004. Our aim was to determine if higher dietary zinc could reduce the prevalence of migraines among adults.
In our analysis, we discovered that individuals consuming higher amounts of zinc experienced fewer migraines. Specifically, when comparing participants with the lowest zinc intake to those in higher intake groups, we found significant reductions in migraine occurrence. For example, adjusting for other factors, those in the second and third zinc intake groups had a 27% and 28% lower odds of experiencing migraines, respectively.
We also noted that age plays a role in how zinc intake affects headache prevalence, suggesting that the benefits of dietary zinc may differ depending on age. Interestingly, in adults aged 20 to 50, the relationship between zinc and migraines was not straightforward, indicating a complex interaction.
Overall, this research highlights the potential benefits of increasing zinc in our diets for reducing migraine frequency, and serves as a reminder that dietary choices can have significant health implications.
9
Zinc reduces migraine symptoms
Assessing the Effect of Zinc Supplementation on the Frequency of Migraine Attack, Duration, Severity, Lipid Profile and hs-CRP in Adult Women.
We conducted a randomized, double-blind, placebo-controlled trial to explore how zinc gluconate affects migraine symptoms in women. Sixty participants, with an average age of 35, were given either 15 mg of zinc per day or a placebo for 12 weeks, allowing us to measure the impact on headache frequency, duration, and intensity.
The results were quite promising; zinc supplementation significantly reduced how often headaches occurred, shortened their duration, and decreased the severity of the migraines reported. Participants in the zinc group experienced notable improvements, as indicated by their responses to the headache severity scale and a disability assessment questionnaire.
Furthermore, we found that zinc also had a positive effect on certain health markers. The serum levels of low-density lipoprotein (LDL), total cholesterol, and high-sensitivity C-reactive protein (hs-CRP) decreased with zinc supplementation. However, we didn’t observe significant changes in triglycerides or high-density lipoprotein (HDL) levels after adjusting for baseline values.
In conclusion, zinc supplementation appears to hold beneficial effects on migraine severity and frequency, offering a potential alternative for those who seek relief from these debilitating headaches.
7
Zinc may lower migraine frequency
Zinc supplementation affects favorably the frequency of migraine attacks: a double-blind randomized placebo-controlled clinical trial.
We conducted a randomized clinical trial involving 80 patients to explore the effects of zinc supplementation on migraine headaches. Over the course of eight weeks, participants received either zinc sulfate or a placebo, allowing us to identify any significant differences in migraine characteristics.
Our findings revealed that those taking zinc experienced a notable drop in the frequency of migraine attacks compared to the placebo group. Specifically, the zinc group had an average reduction of 2.55 attacks, while the placebo group saw a minor reduction of just 0.42 attacks.
Furthermore, we observed some reduction in headache severity among those taking zinc, though this effect lost statistical significance when accounting for other factors. It's also important to note that zinc supplementation did not change the duration of the migraine attacks or daily headache impact for the participants.
Overall, our research suggests that zinc supplementation could be beneficial in reducing the frequency of migraine attacks. However, further studies over longer periods and with varying dosages of zinc would be useful to fully understand its potential.
References
Singhal S, Dutta SB, Bansal S, Dutta S, Shah RB. Zinc as An Emerging Therapy in the Management of Migraine: A Systematic Review. Neurol India. 2024;72:934. doi:10.4103/neurol-india.Neurol-India-D-23-00337
Fukazawa R, Ishii R, Higashimoto Y, Hanya M, Shimizu Y, et al. Zinc Administration Favorably Affects Prophylactic Therapy-refractory Migraine Attacks: A Case Series. Intern Med. 2024;63:1631. doi:10.2169/internalmedicine.2111-23
Zheng H, Tian S, Wu L, Zhong X, Liu M, et al. Dietary zinc intake in relation to migraine among adults: a cross sectional study of NHANES 1999-2004. Nutr Neurosci. 2024;27:667. doi:10.1080/1028415X.2023.2243678
Liu H, Wang Q, Dong Z, Yu S. Dietary zinc intake and migraine in adults: a cross-sectional analysis of the National Health and Nutrition Examination Survey 1999-2004. Headache. 2023;63:127. doi:10.1111/head.14431
Imai K, Yamano T, Nishi S, Nishi R, Nishi T, et al. Epipharyngeal Abrasive Therapy (EAT) Has Potential as a Novel Method for Long COVID Treatment. Viruses. 2022;14. doi:10.3390/v14050907
Mazaheri M, Aghdam AM, Heidari M, Zarrin R. Assessing the Effect of Zinc Supplementation on the Frequency of Migraine Attack, Duration, Severity, Lipid Profile and hs-CRP in Adult Women. Clin Nutr Res. 2021;10:127. doi:10.7762/cnr.2021.10.2.127
Ahmadi H, Mazloumi-Kiapey SS, Sadeghi O, Nasiri M, Khorvash F, et al. Zinc supplementation affects favorably the frequency of migraine attacks: a double-blind randomized placebo-controlled clinical trial. Nutr J. 2020;19:101. doi:10.1186/s12937-020-00618-9
Semelka RC, Ramalho M, Jay M, Hickey L, Hickey J. Intravenous Calcium-/Zinc-Diethylene Triamine Penta-Acetic Acid in Patients With Presumed Gadolinium Deposition Disease: A Preliminary Report on 25 Patients. Invest Radiol. 2018;53:373. doi:10.1097/RLI.0000000000000453