
Cervical cancer is a big worry for women all over the world. It’s the fourth most common cancer in women. In 2022, there were about 660,000 new cases and 350,000 deaths. The main reason is a long-lasting infection with high-risk human papillomavirus (HPV). This usually happens through sexual contact.
It’s important to know what habits can lead to cervical cancer. We’ll look at how lifestyle choices and health habits can increase the risk. This knowledge helps in preventing and catching it early.
Uncover the habits that lead to illness. Can a man give a woman hpv? Find out how transmission works and the best way to stay protected.
Key Takeaways
- Cervical cancer is the fourth most common cancer in women worldwide.
- Persistent infection with high-risk HPV is the primary cause.
- Lifestyle choices and health habits can significantly increase the risk.
- Awareness and prevention are key to reducing the incidence of cervical cancer.
- Early detection is critical for effective treatment.
The Global Impact of Cervical Cancer

Cervical cancer is a big problem worldwide, causing a lot of sickness and death. It’s important to spread the word and take steps to prevent it. The National Cancer Institute says it’s a big health issue globally.
Current Statistics and Mortality Rates
Cervical cancer is the fourth most common cancer in women globally. Every year, about 528,000 new cases are found, leading to around 266,000 deaths. The death rates are very high in low- and middle-income countries.
We need better screening and vaccination programs. Early detection and prevention are key to fighting cervical cancer worldwide.
Key Statistics:
- 528,000 new cases annually
- 266,000 deaths per year
- Highest mortality rates in low- and middle-income countries
Geographic Distribution and Risk Patterns
The rates of cervical cancer vary by place. Sub-Saharan Africa and South Asia have the highest rates. But, North America and Europe have lower rates because of good screening.
Knowing where the risks are helps us focus on prevention and improve healthcare in those areas.
The Economic and Social Burden
Cervical cancer costs a lot in terms of money and social impact. It affects families and healthcare systems too.
Fixing this problem needs a big effort. We need to make sure everyone has access to screening, vaccines, and treatment.
By understanding cervical cancer’s global impact, we can work to lower its rates. We can do this with strong public health plans.
Understanding Human Papillomavirus (HPV)

HPV is a key factor in cervical cancer. It’s a common virus spread through sex. We’ll look at what HPV is, how it spreads, and its different types.
What Is HPV and How It Spreads
HPV is a viral infection spread through skin contact during sex. Most people will get it at some point. Even without symptoms, it can be passed to others.
HPV is not just any infection. It has many strains, some more dangerous than others. It can be spread even when there are no signs, making it a big health issue.
High-Risk vs. Low-Risk HPV Types
HPV strains vary in risk. High-risk types, like HPV 16 and 18, can cause cancer. Low-risk types, like HPV 6 and 11, lead to genital warts but not cancer.
Knowing the HPV type is key to understanding cancer risk. It helps in choosing the right treatment.
|
HPV Type |
Associated Risk |
Common Health Issues |
|---|---|---|
|
High-Risk HPV (e.g., HPV 16, 18) |
Cancer-causing |
Cervical, anal, oropharyngeal, penile cancer |
|
Low-Risk HPV (e.g., HPV 6, 11) |
Non-cancerous |
Genital warts |
The Progression from HPV Infection to Cancer
HPV infection can lead to cervical cancer in several steps. First, the virus infects cervical cells. If the immune system can’t clear it, the infection can cause precancerous changes.
These changes can turn into cancer if not treated. Not all HPV infections lead to cancer. Other factors also play a role.
Regular screening and HPV vaccines can prevent cancer. Early detection and treatment are vital to manage HPV risks.
Can a Man Give a Woman HPV? The Transmission Pathway
Men can carry HPV without showing symptoms and pass it to their female partners. This is key to understanding the risks and how to prevent it.
Male Carriers and Asymptomatic Transmission
Many men carry HPV without knowing it because they don’t show symptoms. “HPV infection in men is often asymptomatic, making it difficult for them to know they are carriers,” says a leading expert in HPV research. This means they can unknowingly spread the virus to their female partners.
HPV can spread through skin contact during sex. It can be on the penis, scrotum, or anus, even without visible warts or symptoms.
The Science of Male-to-Female HPV Transmission
HPV transmission from men to women involves complex interactions with the immune system. Research shows that this is a major way HPV spreads, leading to cervical cancer.
Studies show the risk of transmission goes up with longer sexual activity with an infected partner. Other STIs can also raise the risk of HPV transmission.
Detection Challenges in Male Partners
Finding HPV in men is hard because many don’t show symptoms. Current tests, like looking for genital warts, aren’t always reliable.
“We need better tests for HPV in men to stop the virus from spreading,” says an expert in HPV diagnostics. Until then, awareness and prevention are the best ways to fight HPV transmission.
Understanding male carriers and the challenges in detecting HPV helps us tackle the virus’s spread. This is key to preventing cervical cancer.
Sexual Behaviors That Increase HPV Transmission Risk
Certain sexual behaviors can greatly increase the risk of getting HPV. It’s important to know these behaviors to prevent HPV. Sexual behavior is a key factor in the risk of getting infected.
Early Sexual Debut and Cervical Vulnerability
Starting sex early can lead to a higher risk of HPV. The cervix is more vulnerable at a young age. This is because the cervix is not fully developed and is more open to infection.
Young people might not use protection or know the risks of HPV. This makes them more at risk.
Multiple Sexual Partners and Cumulative Exposure
Having many sexual partners increases the risk of HPV. The more partners, the more chance of getting HPV. This is because there’s a higher chance of meeting someone with HPV.
It’s not just about the number of partners. How often you have sex with different people also matters. People with many partners over time are at higher risk of getting HPV and cervical cancer.
Unprotected Sex and Barrier Method Limitations
Unprotected sex raises the risk of HPV. While condoms help, they’re not 100% effective. HPV can infect areas not covered by condoms, like the vulva or penis.
Condoms do lower the risk of HPV, but they don’t remove it completely. So, using condoms alone is not enough. Vaccination and regular screening are also key.
Knowing about these risks can help people make safer choices. Safe sex, HPV vaccination, and regular screenings are important for health.
The Role of Smoking in Cervical Cancer Development
Smoking greatly increases the risk of cervical cancer. We look into how smoking affects cervical cancer, focusing on the science and studies that show this link.
Tobacco Carcinogens and Cervical Cell Damage
Smoking introduces harmful substances into the body. Tobacco carcinogens, like nicotine, can damage cervical cells. This damage can lead to DNA changes and cancer.
These substances can also make cervical cells more likely to get infected with HPV. This infection can then turn into cancer.
Smoking’s Effect on HPV Persistence
Smoking harms cervical cells and weakens the body’s fight against HPV. HPV persistence is key in cervical cancer development. It lets the virus keep causing damage over time.
Smoking hurts the immune system. This makes it harder for the body to get rid of HPV. So, smoking raises the risk of cervical cancer.
Quantifying the Risk: Statistics and Studies
Studies have found how much smoking increases cervical cancer risk. Smoking can double the risk of cervical cancer in women with HPV. Epidemiological studies show smoking is a big risk factor for cervical cancer.
Knowing how smoking affects cervical cancer helps us fight it better. Quitting smoking, along with HPV vaccines and screenings, is key to lowering cervical cancer rates.
Hormonal Influences on Cervical Cancer Risk
Hormonal influences, like those from oral contraceptives, can raise the risk of cervical cancer. The link between hormones and cervical cancer is complex. It involves how hormones can make cervical cells more likely to get infected with Human Papillomavirus (HPV).
Long-Term Oral Contraceptive Use
Using oral contraceptives for a long time can increase cervical cancer risk. Research shows women using them for over five years face a higher risk. The exact reason is unclear, but it might be because these contraceptives can weaken the immune system’s fight against HPV.
Key findings include:
- Increased risk with prolonged use
- Potential impact on immune response to HPV
- Need for regular cervical screening
Hormonal Changes and HPV Vulnerability
Hormonal shifts, like those from oral contraceptives, can make the cervix more susceptible to HPV. Estrogen and progesterone can change how HPV genes work. This can lead to the virus staying longer and causing cervical lesions.
The connection between hormones and HPV infection shows why we need to understand these factors for prevention.
Balancing Contraceptive Benefits and Risks
While long-term use of oral contraceptives may raise cervical cancer risk, it’s important to weigh this against their benefits. They help prevent pregnancy and regulate menstrual cycles. Women should talk to their doctors about their risks and options.
Getting regular cervical screenings and HPV vaccines is key, even more so for those on hormonal contraceptives for a long time.
Reproductive Factors and Cervical Health
Cervical health is affected by many factors, like how many times a woman has given birth and when she first got pregnant. We’ll look into how these factors can raise the risk of cervical cancer and affect overall health.
Multiple Childbirths and Cervical Trauma
Research shows that women with many childbirths might face a higher risk of cervical cancer. This could be because of the trauma to the cervix during childbirth. Studies found that the risk is higher for women who have had three or more full-term pregnancies.
The exact reasons are not clear, but it’s thought that childbirth’s physical changes and trauma might start or grow cervical cancer. Also, pregnancy’s hormonal changes might make it easier to get HPV, a main cause of cervical cancer.
Young Age at First Pregnancy
Getting pregnant young is also linked to a higher risk of cervical cancer. Early pregnancy might expose the cervix to HPV more, when it’s more vulnerable. The cervix changes a lot in teens and young adults, making it more open to infection and cancer.
- Early exposure to HPV due to an immature cervix
- Increased risk of cervical trauma
- Hormonal influences during early pregnancy
Childbirth-Related Immune Changes
Immune changes from childbirth can also affect cervical health. Pregnancy changes the immune system to support the fetus, which might make it harder to fight off HPV. Women with many pregnancies might have different immune responses, making them more likely to keep HPV and get cervical cancer.
It’s important to know about these reproductive factors to understand cervical cancer risk. We suggest women, and those with many births or early pregnancies, get regular cervical screenings and HPV vaccines. This can help lower these risks.
Co-Infections That Amplify Cervical Cancer Risk
Co-infections like HIV and chlamydia can change how the body fights HPV. This makes it more likely for cervical cancer to develop. We’ll look into how these infections raise the risk and why.
HIV and Immunosuppression
Women with HIV face a higher risk of cervical cancer. Their immune systems are weakened. This makes it hard for the body to get rid of HPV, leading to a higher risk of cancer.
Table 1: Cervical Cancer Risk in HIV-Positive Women
|
Population |
Cervical Cancer Risk |
Relative Risk |
|---|---|---|
|
HIV-negative women |
Standard risk |
1.0 |
|
HIV-positive women |
Elevated risk |
2.5-3.0 |
As shown in Table 1, HIV-positive women face a much higher risk of cervical cancer than HIV-negative women.
“The link between HIV and cervical cancer risk is clear. This shows we need special screening and prevention plans for HIV-positive women.”
Chlamydia and Other Sexually Transmitted Infections
Chlamydia trachomatis infection is linked to a higher cervical cancer risk. This might be because it causes chronic inflammation and changes the immune system. Other STIs might also play a role, but the evidence is not as strong.
The Synergistic Effect of Multiple Infections
Having multiple infections can make cervical cancer risk even higher. For example, HIV and other STIs together can weaken the immune system even more. This makes it harder for the body to fight off HPV.
The complex relationship between different infections and HPV highlights the need for full sexual health checks and management.
It’s key to understand how co-infections lead to cervical cancer. This knowledge helps us create better prevention and treatment plans. By tackling these infections, we can lower cervical cancer cases worldwide.
Socioeconomic Factors and Healthcare Access
The link between money status and health care is key in cervical cancer outcomes. People with less money often find it hard to get the health care they need.
Disparities in Screening and Late Diagnosis
Some groups get less chance to have cervical cancer screening. This can cause cancer to be found too late. The Illinois Department of Public Health says women from lower-income areas are more likely to have late-stage cancer.
Education and Awareness Gaps
Knowing about cervical cancer and how to prevent it is important. But, some groups don’t have this knowledge. Public health initiatives can help teach more women about the importance of screening.
Financial Barriers to Prevention and Treatment
Money is a big problem for getting cervical cancer prevention and treatment. The cost of tests and treatments is too high for many. We need to make health care cheaper and easier to get.
By tackling the money issues that affect health care, we can lessen cervical cancer’s impact. This way, everyone, no matter their money status, can get better health care.
Dietary and Nutritional Influences on Cervical Health
Nutrition is key for a strong immune system. This helps fight off HPV infections and lowers cervical cancer risk. A diet full of nutrients boosts health, including cervical health, by strengthening defenses. We’ll look at how certain foods can help cervical health and lower cancer risk.
Antioxidants and Cancer Prevention
Antioxidants protect cells from damage by free radicals, which can lead to cancer. Foods high in antioxidants, like vitamin C, vitamin E, and beta-carotene, can reduce this risk. Here are some antioxidant-rich foods:
- Citrus fruits like oranges and grapefruits
- Berries such as strawberries and blueberries
- Nuts and seeds, like almonds and sunflower seeds
- Leafy green vegetables like spinach and kale
Micronutrient Deficiencies and Immune Function
Micronutrients, like vitamins and minerals, are essential for a healthy immune system. Lack of these can weaken the immune system, making us more likely to get infections, including HPV. Important micronutrients for immune function include:
- Zinc, vital for immune cell function
- Vitamin D, important for immune response regulation
- Folate, needed for DNA synthesis and repair
Eating enough of these micronutrients can boost immune function and lower cervical cancer risk.
Evidence-Based Dietary Recommendations
Research suggests eating a diet full of fruits, vegetables, whole grains, and lean proteins is best for cervical health. Here are some specific recommendations:
- Eat more foods rich in antioxidants
- Make sure to get enough essential micronutrients from a balanced diet
- Reduce intake of processed and high-sugar foods that harm health
In summary, what we eat greatly affects cervical health and can lower cancer risk. Eating a balanced diet rich in antioxidants and micronutrients supports the immune system and overall health.
Psychological Stress and Immune Suppression
Stress and how it affects our immune system is a big topic, even with viral infections like HPV. Long-term stress can make our immune system weaker. This might make it harder for our body to fight off HPV.
Stress Hormones and HPV Persistence
Stress makes our body release hormones like cortisol and adrenaline. These hormones help us react quickly, but too much can weaken our immune system. Studies show that these hormones might make it harder for our immune system to keep HPV under control.
Stress management is key here. Lowering stress can help our immune system stay strong. Activities like meditation, yoga, and deep breathing can help reduce stress hormones and boost our immune system.
Mind-Body Connection in Cancer Development
The connection between our mind and body is important in cancer. Stress can change the environment around tumors, helping cancer cells grow. While we don’t know all the details, it’s clear that stress is bad for our health and can increase cancer risk.
Research shows that people with more stress and anxiety might be at higher risk for cancer, including cervical cancer. This shows how important mental health is in preventing cancer.
Stress Management Strategies for Prevention
Managing stress is a big part of preventing cervical cancer. By reducing stress, we can boost our immune system. This can help fight off HPV and lower the risk of cervical cancer.
- Mindfulness and meditation practices
- Regular physical activity
- Adequate sleep and rest
- Social support networks
- Healthy dietary habits
By adding these stress-reducing activities to our daily lives, we can lower our risk of cervical cancer. It’s a way to improve our overall health and well-being.
Genetic Susceptibility to HPV and Cervical Cancer
Genetic factors play a big role in cervical cancer risk. They can affect how well the body fights off HPV. We’ll look into how genetics influence HPV risk and cervical cancer, including hereditary factors and immune response variations.
Hereditary Risk Factors
Some genetic changes can be passed down and raise HPV and cervical cancer risk. Research has found certain genetic markers linked to higher cervical cancer risk. For example, genes involved in the immune system can impact how well the body fights off HPV.
Genetic Variations in Immune Response
Genetic differences can change how the immune system reacts to HPV. Some people might have genes that make it harder for their immune system to fight off the virus. This can lead to long-term HPV infections, which increase cervical cancer risk. Knowing about these genetic variations is key to finding new ways to prevent the disease.
Family History Considerations
A family history of cervical cancer might suggest a genetic link. While HPV is a main cause, a family history can raise your risk. People with a family history should talk to their doctors about screening and prevention.
|
Genetic Factor |
Description |
Impact on Cervical Cancer Risk |
|---|---|---|
|
Cytokine Gene Variations |
Affect immune response to HPV |
Increased risk of persistent HPV infection |
|
HLA Alleles |
Influence antigen presentation to T-cells |
Variations can increase or decrease risk |
|
Tumor Suppressor Gene Mutations |
Impact cell cycle regulation |
Potential increase in cancer risk |
HPV Vaccination: Breaking the Transmission Cycle
HPV vaccination is key in stopping the spread of the virus that causes cervical cancer. It protects against the most common high-risk HPV types. This can greatly lower the number of cervical cancer cases and other HPV-related diseases.
Vaccine Types and Coverage
There are many HPV vaccines out there. Each one protects against different strains of the virus. The most common vaccines cover two, four, or nine types of HPV. The nonavalent vaccine protects against the most types, including the high-risk ones.
The nonavalent HPV vaccine guards against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. These types are responsible for most cervical cancers. HPV vaccines work best when given before you’re exposed to the virus, usually before you start being sexually active.
Recommended Age for Maximum Protection
The age for HPV vaccination varies based on guidelines and health status. The CDC suggests it for pre-teens aged 11 to 12. It can start as early as 9 years old. For those who missed the recommended age, catch-up vaccination is advised for females up to 26 and males up to 21.
The sooner you get vaccinated, the better you’re protected against HPV-related diseases. This is because the vaccine works best before you’re exposed to HPV, which often happens soon after you start being sexually active.
The Importance of Vaccinating Both Males and Females
Vaccinating both males and females is important for several reasons. It directly protects individuals against HPV-related diseases. This includes cervical cancer in females and genital warts and certain cancers in both sexes. It also helps lower the overall HPV transmission in the population, indirectly protecting those who are not vaccinated.
- Vaccinating males helps prevent HPV transmission to female partners, lowering cervical cancer risk.
- It also protects males against HPV-related diseases like genital warts and anal cancers.
- By vaccinating both sexes, we achieve herd immunity, further reducing HPV prevalence in the community.
In conclusion, HPV vaccination is vital for cervical cancer prevention. Knowing about the vaccines, the recommended age, and the need to vaccinate both males and females helps us fight HPV. This way, we can reduce cervical cancer worldwide.
Screening Methods for Early Detection
Early detection is key in fighting cervical cancer. We have many effective screening methods. Regular screening can greatly lower the risk of cervical cancer by catching changes early. This section will look at the screening methods, how often to get them, and the importance of following up on abnormal results.
Pap Smears and HPV Testing
The main ways to screen for cervical cancer are Pap smears and HPV testing. Pap smears take cells from the cervix to find abnormal cell changes that could turn into cancer. HPV testing looks for the human papillomavirus, a virus that can cause cervical cancer. Both tests are key in spotting those at risk and starting early treatment.
Recommended Screening Schedules by Age
Screening schedules change with age and risk factors. Women should start screening at 21. From 21 to 29, a Pap smear every three years is advised if results are normal. For women 30 to 65, co-testing (Pap smear and HPV testing) every five years is suggested, or a Pap smear alone every three years. It’s important to follow these guidelines for effective cervical cancer prevention.
Understanding and Following Up on Abnormal Results
Getting an abnormal screening result can be scary, but it doesn’t mean you have cancer. Abnormal results show cell changes that could become cancerous. Follow-up steps might include more tests, colposcopy, or biopsy. It’s vital to follow your doctor’s advice to handle any issues quickly.
Practical Steps to Reduce HPV Transmission Risk
To lower the risk of HPV, it’s important to use safe sex practices, talk openly with your partner, and live a healthy lifestyle. These steps can greatly reduce the chance of getting HPV.
Safe Sex Practices and Communication
Using condoms correctly is key to reducing HPV risk. While condoms may not cover all areas, they do lower the risk a lot. Talking openly with your partner about your sexual health is also vital. Sharing your HPV status and other health matters helps you make better choices together.
A top expert in sexual health, says, “Talking openly about HPV and other STIs makes for a healthier relationship.”
Partner Testing and Disclosure
Getting tested for HPV and other STIs is a smart move for your health and your partner’s. Regular tests can catch HPV early, leading to better treatment. It’s also key to share your test results with your partner, showing respect and understanding for each other’s health.
- Get tested for HPV and other STIs regularly.
- Discuss your test results openly with your partner.
- Consider the HPV vaccine if you’re within the recommended age range.
Lifestyle Modifications for Both Partners
Living a healthy lifestyle boosts your immune system’s fight against HPV. Quitting smoking is a big help, as it strengthens your immune system. Eating well, with lots of fruits, veggies, and whole grains, also supports your immune system. Stress management through exercise or meditation keeps your immune system strong too.
By using safe sex, testing and talking openly, and living healthy, you can greatly reduce HPV risk. This approach not only keeps you healthy but also strengthens your relationship with your partner.
Conclusion: Taking Control of Cervical Health
Knowing the risks of cervical cancer is key to keeping our health in check. We must understand how Human Papillomavirus (HPV) and other factors play a part. This knowledge helps us prevent and catch problems early.
Preventing cervical cancer starts with safe choices. This means using protection during sex, getting the HPV vaccine, and not smoking. Regular tests like Pap smears and HPV tests can also help catch issues before they get worse.
By focusing on our cervical health, we can lower the risk of cervical cancer. It’s important to educate ourselves and others. We also need to make sure everyone has access to good healthcare. This way, we can all make smart choices about our health.
Together, we can fight cervical cancer by preventing it, catching it early, and treating it well. By staying informed and taking action, we can keep our cervical health strong. This helps us live a better, healthier life.
FAQ
What causes cervical cancer?
Cervical cancer is mainly caused by the human papillomavirus (HPV). This virus is common and spread through sex. Certain habits and risk factors can also increase the chance of getting cervical cancer.
Can men transmit HPV to women?
Yes, men can pass HPV to women through sex. This includes vaginal, anal, or oral sex. Men might not show symptoms, making it hard to find the virus.
How does smoking affect cervical cancer risk?
Smoking harms cervical cells and raises the risk of cervical cancer. It lets HPV stay longer. Smoking also weakens the immune system, making it harder to fight off the virus.
What is the role of oral contraceptives in cervical cancer risk?
Long-term use of oral contraceptives might raise cervical cancer risk, mainly in HPV-positive women. But, they also prevent pregnancy. It’s important to weigh these benefits against the risks.
How do reproductive factors influence cervical health?
Having many children, starting pregnancy young, and changes in the immune system during childbirth can increase cervical cancer risk. These factors can damage cervical cells and weaken the immune system against HPV.
Can co-infections increase cervical cancer risk?
Yes, infections like HIV and other STIs can raise cervical cancer risk. They weaken the immune system, letting HPV stay longer.
How do socioeconomic factors impact cervical cancer risk?
Limited access to screening and care due to socioeconomic status can increase cervical cancer risk. It can delay finding and treating the disease.
What dietary factors influence cervical health?
Eating foods rich in antioxidants and nutrients, like fruits, vegetables, and whole grains, can boost the immune system. This can help lower cervical cancer risk.
Can stress increase cervical cancer risk?
Yes, chronic stress can weaken the immune system. This can let HPV persist and increase cervical cancer risk. Managing stress through exercise and meditation can help.
Are there genetic factors that influence cervical cancer risk?
Yes, genetic factors can affect how likely someone is to get cervical cancer from HPV. A family history of cervical cancer is important to consider.
How can HPV vaccination prevent cervical cancer?
HPV vaccination can prevent cervical cancer by protecting against high-risk HPV types. Vaccinating both males and females is key to stopping the virus’s spread.
What are the recommended screening methods for cervical cancer?
Pap smears and HPV testing are recommended for cervical cancer screening. Regular screening can catch abnormal cell changes early.
How can I reduce my risk of HPV transmission?
To lower HPV transmission risk, practice safe sex, get vaccinated, and limit partners. Talking openly with partners about HPV status and testing is also important.
References:
American Cancer Society. Key statistics for cervical cancer. https://www.cancer.org/cancer/types/cervical-cancer/about/key-statistics.html
National Cancer Institute, Surveillance, Epidemiology, and End Results Program (SEER). Cervical cancer statistics. https://seer.cancer.gov/statfacts/html/cervix.html
World Health Organization (WHO). Cervical cancer fact sheet. https://www.who.int/news-room/fact-sheets/detail/cervical-cancer
PubMed Central (PMC). Cervical cancer research article. https://pmc.ncbi.nlm.nih.gov/articles/PMC12313508/
Illinois Department of Public Health. Cervical cancer – Illinois comprehensive cancer control plan. https://dph.illinois.gov/topics-services/diseases-and-conditions/cancer/2022-2027-illinois-comprehensive-cancer-control-plan/cancer-burden-illinois/cervical-cancer.html
National Center for Biotechnology Information. Evidence-Based Medical Insight. Retrieved from https://pubmed.ncbi.nlm.nih.gov/33538338/