Category: 8. Health

Anywhere from 6% to 12% of the US population has taken a GLP-1 agonist. But until now there hasn’t been a cohesive message among physicians for how to care for this growing patient population.

Last month the American College of Lifestyle Medicine, the American Society for Nutrition, the Obesity Medicine Association, and The Obesity Society released a joint advisory that included a list of nutritional and lifestyle priorities to help physicians guide patients on their weight-loss journey.

Published in late May in the journal Obesity, the priorities included a baseline nutritional assessment, an understanding of patient goals, management of the most common medication side effects, reduced dependence on ultra-processed foods, prevention of nutrient deficiencies, strength training to prevent muscle loss, and other lifestyle factors that might influence weight loss.

“GLP-1s are reshaping the landscape of obesity treatment, but it’s clear that medication alone is not a complete solution,” John E. Courtney, PhD, CEO of the American Society for Nutrition, said in a statement. While the medications can powerfully reduce hunger in patients who take them, they work best in conjunction with lifestyle changes, the most important of which is proper nutrition.

An Emphasis on Diet

Primary care physicians need to work with patients to better understand their diet before prescribing these medications, said lead study author and Advisory Chair Dariush Mozaffarian, MD, PhD, director of the Food is Medicine Institute of Tufts University, Boston.

“These medications are approved as an adjunct to nutrition and lifestyle therapy and right now they’re being used as a first line in most cases,” said Mozaffarian.

Asking a simple set of questions about what patients eat in a day, whether they snack, and whether they eat out at restaurants can provide physicians with a good idea of a patient’s diet pitfalls.

Other barriers to healthy eating can include cost but also knowledge of how to prepare healthy meals, proper cooking equipment, culture, and food traditions around healthy eating. Additionally, some patients might not live near grocery stores.

A study published last year in the journal Obesity Pillars found that physicians and dietitians can help patients maximize long-term weight loss results by providing them with personalized guidance. For example, apps that can help patients track nutrition and daily caloric intake as well as personalized advice that can help highlight their dietary sticking points.

Additionally, about half of all patients have significant gastrointestinal issues on these medications and eating a healthy, well-balanced diet can help them to stave off some of the most common side effects, including constipation, nausea, and vomiting, said Mozaffarian. This includes tricks of the trade like drinking ample water, eating small meals, getting enough fiber, and avoiding fatty foods. Ramping up dosages of the medications more slowly can also help patients to avoid these symptoms.

Reducing Dependence on Ultra-Processed Foods

“Many patients not only eat less but their preferences for foods change and one of the most common themes is that they no longer crave ultra-processed foods that are very sweet or contain artificial ingredients,” said Mozaffarian. These are the foods that can be high in fat and contain chemicals that make people want to keep eating them.

There’s also research to show that ultra-processed foods are increasing some of the comorbidities that go along with weight gain like diabetes and nonalcoholic fatty liver disease.

Some of the chemicals in these foods might also be driving effects on the gut microbiome and intestinal health, said Carolynn Francavilla, MD, a nationally recognized obesity physician who owns and operates Green Mountain Partners for Health and Colorado Weight Care, both in Denver.

Staving Off Nutrient Deficiencies

What’s more, some research has shown that many patients aren’t getting ample nutrition because their appetite is so suppressed. One study released in April in Frontiers in Nutrition found that patients on GLP-1s were not getting sufficient amounts of fiber, calcium, iron, magnesium, potassium, and choline as well as vitamins A, C, D, and E.

Focusing on minimally processed foods can help patients to avoid deficiencies that come with the medications. When a patient’s diet is drastically reduced, it can make it difficult to get enough protein as well as essential micronutrients. Carefully planning meals to fit in enough protein as well as fruits, vegetables, and whole grains is a great way to ensure that patients avoid deficiencies.

However, some processed foods, for example, meal replacement shakes and bars might help patients get enough nutrients when they don’t have the appetite they once did. “These should be an exception because for some patients they can help fill in the gaps,” said Francavilla.

Other Lifestyle Factors That Help Optimize Weight Loss

Patents not only lose fat on GLP-1s but also lose bone and muscle if they don’t participate in strength training at least twice weekly. And as mentioned above, protein, calcium, and vitamin D are also very important for reducing the bone and muscle loss that can lead to frailty later in life.

The advisory also names other lifestyle factors like sleep, mental stress, substance use, and social connections as important priorities that can help patients maximize long-term success on these medications.

“GLP-1s help more than all the prior generations of obesity drugs, but that doesn’t obviate the need for good physical activity and managing all the other stressors in one’s life,” said Ziyad Al-Aly, MD, an assistant professor in the Division of General Medicine & Geriatrics at Washington University School of Medicine in St. Louis.

Sleep is especially important and can often be overlooked. A wide breadth of research shows that sleep deprivation plays a role in weight loss. A study published in the April 2022 issue of the journal Nutrients found that individuals who slept for 5.5 hours per night lost less fat than those who slept for 8.5 hours per night.

Al-Aly noted that one of the lesser known side effects of these medications is that they can cause sleep disturbance. This means that sleep hygiene, for example, going to bed at the same time nightly, avoiding screen time before bed, and avoiding caffeine later in the day are particularly important for those taking these medications.

Substance use can also be problematic because while some research has shown that these medications impact the brain reward center, thereby reducing addictive behavior like alcohol abuse, patients who still drink too much are at a much greater risk for dangerous nutrient deficiencies. Physicians need to ensure that their patients are aware of these risks.

This advisory is tremendously helpful for physicians in providing a unified message, said Al-Aly. “This is exactly what prescribers and doctors in patient communities really need, not only to help patients reach dramatic weight loss but to take into account their long-term risk factors and health.”

Many women love getting acrylic nail extensions, but the UV lights used in nail dryers may pose significant health risks. These lamps emit ultraviolet rays that are linked to an increased risk of getting skin cancer. Although skin cancer is generally treatable, it is important to take precautions to protect your skin from harmful UV exposure. Nail salons should recognise the potential dangers of UV lamps and implement safety measures to protect their clients. By raising awareness and adopting safer practices, salons can help ensure that customers can enjoy beautiful nails without compromising their long-term health.

New study reveals potential skin damage from UV nail lamps

The US Food and Drug Administration considers UV nail dryers “low-risk” devices, used to dry and cure nails in salons. However, a 2023 study published in Nature Communications found that these devices can cause significant damage to skin cells over time. They work similarly to mini tanning beds for the hands, emitting UV rays that can penetrate the skin and lead to permanent damage. Although the UV spectrum is different from traditional tanning beds and the emission is less intense, the risk of damage still exists. This raises concerns about the potential long-term effects of frequent exposure to UV nail dryers.

The impact of UV nail dryers on skin cells

Researchers studying UV nail dryers found that exposure to these devices can cause significant damage to skin cells. The skin cells showed high levels of reactive molecules that disrupted normal cell function by interacting with proteins, mitochondria, and other cellular components. According to the study, one 20-minute session resulted in 20-30% cell death, three consecutive 20-minute sessions led to 65-70% cell death, and the remaining surviving cells showed mitochondrial and DNA damage. The results of the study highlight the potential risks associated with UV nail dryers and emphasise the importance of taking precautionary measures while using these devices in nail salons.

Precautions while using UV Nail dryers

To minimize the risks associated with UV nail dryers, consider the following precautions:1. Check the bulb strength: Request the manicurist to use a UV lamp with the lowest wattage (e.g., 9-watt) to reduce radiation exposure.2. Avoid frequent manicures: Limit your exposure to UV nail dryers by spacing out your manicure appointments or opting for alternative nail polish methods.3. Apply sunscreen: Use a broad-spectrum sunscreen with an SPF value higher than 30 on your hands before using the UV lamp. Look for sunscreens containing zinc oxide or titanium dioxide for added protection.4. Wear fingerless gloves: Use protective gloves with UV-protectant properties to limit exposure. Replace them after a few washes, as their effectiveness decreases over time.

This striking astronaut photo shows a unique chain of three atolls lined up side-by-side off the coast of Australia. The oval islands were once part of a colossal coral system that rivaled the Great Barrier Reef.

The trio of islands makes up Rowley Shoals, an uninhabited Australian territory located in the Timor Sea around 180 miles (290 kilometers) off the coast of Western Australia. From southwest to northeast (left to right), the islands are named Imperieuse Reef, Clerke Reef and Mermaid Reef.

Obesity often brings about, or exacerbates, depression and anxiety. Yet some of the most effective drugs for managing depression are also known to cause weight gain. Your patients, then, may worry about the cause-and-effect of popular treatments.

This pushback may be brought up early on regarding these types of medications, or a patient may express concern over drug-induced weight gain in follow-up appointments.

If you are prescribing selective serotonin reuptake inhibitors including Celexa (citalopram), Lexapro (escitalopram), Prozac (fluoxetine) or Zoloft (sertraline), which can ease symptoms of moderate-to-severe depression by keeping specific chemical messengers active in the brain, your patients likely will have questions about weight gain. Expressing candor over the possible side effects is warranted, but a discussion about what patients can do to counter such risk is important. These drugs can be life changing, so here’s how to offer your patients guidance.

Prioritizing Patient Care

Improved mood is vital to patients that experience depression, but many will be concerned about potential weight gain, or of gained weight since you first prescribed the drugs.

Physicians should have a transparent discussion about the potential side effects of antidepressants, as weight is one of the leading reasons patients stop taking antidepressants, or decline to start altogether, said Brintha Vasagar, MD, a family physician and chief medical officer of Progressive Community Health Centers in Milwaukee. But she said it’s also important to remember that depression itself can also contribute to weight gain, and the average amount is small — < 4 lb.

When it comes to deciding on a medication, choices should be personalized by the patient.

“Many patients are worried about starting an antidepressant because they worry weight gain will worsen their mental health,” Vasagar added. “This is a very individual decision, and it can be helpful to share that the average weight gain with antidepressant use is small, though this varies from person to person.” 

She noted that duloxetine (Cymbalta) and bupropion (Wellbutrin) have shown the lowest average weight gain and can be good medication choices for patients who are anxious about this side effect.

It can also prove helpful to suggest lifestyle tips to offset potential weight gain, such as: 

• Avoiding alcohol, which is both a good choice for depression and has the added benefit of reducing caloric intake.

• Partaking in regular exercise, which has been shown to help depression and helps burn calories.

• Making healthier dietary choices, like cutting down on ultra-processed foods, which can benefit both mental health and weight.

• Trying meditation can benefit both mental health and weight.

Primary care physicians should continue with patients to find a plan that works best for each person.

“Some patients will be able to navigate weight side effects using the above tips, while others will want to change or stop medications,” Vasagar said. “It’s important to let patients decide which symptoms are intolerable and find the balance between improvement in mental health and side effects.”

If such tweaks aren’t preventing weight gain to the patient’s satisfaction, the next steps should be discussed. Your patients should have a voice in their healthcare decisions.

“I will explain the risks and benefits of medication for depression and encourage counseling. For patients who struggle with weight despite lifestyle changes, we have a candid conversation about which symptoms are most distressing to them and make a joint decision of the best path forward,” said Vasagar.

Understanding the Pivotal Role of Primary Care Doctors

Mark Loafman, MD, a family physician with Cook County Health, Chicago, said patients deserve to be counseled about medication’s side effects. But he said it’s challenging to do so without discouraging patients from giving treatment a chance to see how it works.

“We can’t help but observe how this differs when discussed in the doctor’s office vs pharmaceutical industry ads in media. The ads always include a rapid-fire list of ‘pretty scary side effects’ while the images portray a healthy-looking patient having the best time,” said Loafman. “Our doctor-patient chats about risks and benefits don’t carry that kind of marketing appeal which I am sure influences the way we discuss potential side effects.” 

As a primary care doctor, he considers weight gain and current weight when choosing medications.

“We can make adjustments in treatment if issues arise during treatment,” he said. “Patients should be open about their concerns and follow their weight during treatment, which will help their doctor include weight in the overall treatment plan.” 

How to Handle Follow-Ups 

Primary care and family doctors should be a coach and facilitator for their patients and should be ready to either make a change in treatment or include weight-loss treatment as part of the overall treatment plan, Loafman said. Considerations can include how well the medication is working from a mental health perspective, whether there are other medications that may also work without causing as much weight gain, and if there are other side effects or reasons to consider a medication change.

And if a patient does experience weight gain, there are additional options.

“We have some really good weight-loss treatment options now, so if the behavioral health treatment is working well except for weight gain, it is very appropriate to include weight-loss treatment as part of the overall treatment plan,” he added.

In his own practice, Loafman said he follows a comprehensive primary care approach outlined above, including weight, diet, and lifestyle as part of the overall treatment plan, making an effort to discuss weight, body shape, and lifestyle with compassion and empathy, and also encouraging patients to set reasonable goals and address their success or lack there-off without blame and shame.

Commonly prescribed medicines for anxiety, depression and sleep disorders may pose a heightened risk of developing amyotrophic lateral sclerosis (ALS), a progressive and fatal neurological disorder, according to a new study recently published in JAMA Neurology.

The study researched the use of anxiolytics (used to relieve anxiety), hypnotics and sedatives (used to aid sleep or calm the body), and antidepressants (which work by altering brain chemistry to improve mood) and found that individuals who were prescribed such medications were more likely to be diagnosed with ALS in the later stages of life.

The study further found that people who used these medication before being diagnosed with ALS had a poorer prognosis, which means that their disease progressed quickly and survival rate is minimal. However, experts caution that this finding is based on association, not causation.
“These medications are often prescribed for symptoms such as anxiety, sleep disturbances, or depression, which may appear during the early (prodromal) phase of ALS – well before a formal diagnosis,” explained Dr M S Panduranga, senior consultant (neurology), Dharamshila Narayana Super-specialty Hospital.

“So, the link may reflect early, subtle neurological changes rather than the harmful effect of the drugs themselves,” the doctor added.

The study, which was conducted in Sweden, analysed nationwide data from over 1,000 ALS patients and more than 5,000 healthy individuals using the Swedish Motor Neuron Disease Quality Registry. The average age of participants was 67.5 years, and just over half (53.1%) were male.Dr Manjari Tripathi, professor and head of neurology at AIIMS, told TOI that such neuropsychiatric medications act on the brain’s inhibitory pathways, which could interfere with motor neuron activity. “There could also be a toxic effect, especially with long-term, consistent use – not just occasional doses,” she said.

“Motor neuron disease leads to slow but steady progression of muscle weakness. Patients begin to struggle with everyday tasks – buttoning a shirt, combing their hair, walking. Eventually, they become wheelchair bound. Swallowing and speech become difficult, and muscles visibly shrink,” she said, adding that one type of ALS was the same condition renowned physicist Stephen Hawking lived with for decades.

However, the exact timeline between the medication and the onset of ALS remains unfound. Dr Madhukar Bhardwaj, director and head of neurology, Aakash Healthcare, said that a longer history of psychiatric symptoms and prolonged medication use appears to be associated with increased ALS risk.

“In some observational studies, individuals using anxiety or depression medications for more than 10 years showed a stronger link with ALS, especially in younger patients. It’s not yet certain whether this reflects a true biological risk or simply earlier diagnosis due to more medical attention,” he said.

“While there’s no definitive proof that these medications cause ALS, we need to be cautious, especially when prescribing them to individuals with signs of neurological disease,” Dr Anshu Rohatgi, vice-chairperson (neurology), Sir Ganga Ram Hospital told TOI.

Meanwhile, doctors say patients must not stop medications on their own and should speak with their healthcare providers if they have concerns.

(With TOI inputs)

Introduction

Syphilis relapse remains a significant clinical challenge, reportedly occurring in a percentage of patients, which can vary widely depending on factors like immune status and treatment adequacy, who receive standard therapy, with recurrence rates potentially higher among immunocompromised individuals or those with incomplete treatment.^1,2 Early relapses (≤2 years post-infection) typically manifest as recurrent mucocutaneous lesions (eg, maculopapular rashes, condylomata lata), lymphadenopathy, and neuro-ophthalmic symptoms (headaches, blurred vision), whereas late relapses may involve cardiovascular complications or gummatous lesions.^3,4 Definitive diagnosis often requires integrated serological evaluation—combining treponemal (eg, TPPA/TPHA) and nontreponemal (eg, RPR/VDRL) tests with quantitative titers—and clinical assessment to differentiate true relapse from reinfection, especially in research or complex clinical scenarios.⁵

The pathogenesis of relapse involves multifactorial interactions. First, Treponema pallidum subsp. pallidum can persist in immunoprivileged sanctuaries such as the central nervous system (CNS) and aqueous humor, where antibiotic penetration is suboptimal.⁶ Second, host immune dysregulation—prominently driven by HIV coinfection which can impair bacterial clearance—compromises therapeutic efficacy.⁷ Third, factors such as emerging antimicrobial resistance, particularly to macrolides, and high-risk sexual behaviors leading to reinfection can further complicate management and contribute to scenarios resembling relapse or actual treatment failure.

Current clinical guidelines emphasize risk-stratified therapeutic approaches, with the 2021 CDC Sexually Transmitted Infections Treatment Guidelines specifically recommending intensified regimens for recurrent early syphilis cases.⁸ For patients with recurrent secondary syphilis or those demonstrating serological persistence after initial therapy, the gold standard involves administering intramuscular benzathine penicillin G at 2.4 million units weekly for three consecutive weeks.⁸ This extended regimen aligns with both the World Health Organization’s 2021 syphilis management framework advocating enhanced therapy for high-risk recurrences,⁹ and the 2020 European guideline on the management of syphilis emphasizing CSF evaluation prior to retreatment in such complex cases.⁴ The three-dose protocol reflects contemporary understanding of potential undetected neuroinvasion in recurrent infections while maintaining practical treatment accessibility.⁸ Neuroinvasive relapse, similar to primary neurosyphilis, necessitates intravenous aqueous penicillin G (18–24 million units daily for 10–14 days) to achieve bactericidal concentrations in cerebrospinal fluid.¹⁰ In penicillin-allergic patients with neurosyphilis, ceftriaxone (2 g daily intravenously for 10–14 days) is a recommended alternative, preferred over doxycycline due to superior CNS penetration.¹⁰ The role of adjunctive immunomodulation in routine syphilis management is not established, although research continues in broader infectious disease contexts. This review aims to synthesize current advancements in clinical strategies and preclinical models pertinent to understanding and managing syphilis relapse, highlighting existing challenges and future research directions.

Preclinical models have been pivotal in elucidating relapse mechanisms. Rabbit infection models accurately replicate chancre progression and latent infection reactivation, enabling rigorous evaluation of antibiotic efficacy.¹¹ Humanized mouse models have uncovered T. pallidum immune evasion strategies, such as downregulation of MHC-II expression on antigen-presenting cells.¹² Breakthroughs in in vitro cultivation systems (eg, Sf1Ep epithelial cell co-culture) now permit sustained T. pallidum propagation, facilitating high-throughput drug susceptibility testing and vaccine antigen screening.^13,14 These models collectively provide a translational framework for developing relapse-prevention strategies, though, as will be discussed, their limitations necessitate careful interpretation when extrapolating findings to complex human relapse scenarios.

Overview of Syphilis Recurrence

Etiology and Epidemiology of Syphilis

Syphilis is a chronic systemic infection caused by the spirochete Treponema pallidum subsp. pallidum, a highly motile pathogen with tropism for mucocutaneous and neural tissues.¹⁴ Globally, the World Health Organization (WHO) estimates 7.1 million new syphilis cases annually, with disproportionate burdens in low-resource regions of sub-Saharan Africa and South Asia.¹⁵ Historical records trace its introduction to China via maritime trade in 1505 CE (Common Era), followed by near-elimination in the mid-20th century and a dramatic resurgence post-1980s.¹⁶ Contemporary surveillance data indicate that China now reports over 500,000 annual cases, constituting the highest incidence of bacterial sexually transmitted infections nationally.¹⁷ Transmission occurs predominantly through sexual contact (≥95% of cases), with vertical transmission, blood exposure, and iatrogenic routes accounting for minor proportions. The disease exhibits a protean clinical course, ranging from asymptomatic latency to multisystem involvement, with a percentage of adequately treated patients experiencing recurrence due to bacterial persistence or reinfection.¹⁸ The resurgence in general syphilis incidence directly increases the population base susceptible to experiencing relapse, underscoring the public health importance of understanding and managing this complication.

Figures 1 and 2 illustrate recent epidemiological patterns in Tokyo (2019–2022), revealing male predominance (male-to-female ratio: 3.8:1) and high transmission rates among men who have sex with men (MSM) (62% of cases), underscoring the role of high-risk sexual networks in syphilis resurgence.¹⁹

Figure 1 Incidence of syphilis by sex and age in Tokyo from 2019 to 2022 ((A) men, (B) women), excluding one woman patient with unknown age in 2020.

Figure 2 (Color online) Incidence of syphilis by sexual partners in Tokyo from 2019 to 2022. MSM (green), men who have sex with men; MSW (blue), men who have sex with women; WSM (red), women who have sex with men.

Definition and Clinical Manifestations of Syphilis Recurrence

Definition of Syphilis Recurrence

Syphilis recurrence is defined as the recrudescence of clinical or serological activity following documented adequate antimicrobial therapy, indicating either incomplete pathogen eradication or reinfection with distinct T. pallidum strains.²⁰ Diagnostic criteria require: (1) reappearance of pathognomonic mucocutaneous lesions (eg, chancre, condylomata lata); (2) a fourfold rise in nontreponemal antibody titers (RPR/VDRL); and (3) exclusion of reinfection through molecular typing and partner tracing (the former, molecular typing, representing an ideal approach often utilized in research settings rather than being a universally applied standard in routine clinical practice for distinguishing relapse from reinfection). Recurrence signifies treatment failure and is epidemiologically critical due to associations with enhanced transmissibility and emergence of antibiotic resistance.

Clinical Manifestations of Syphilis Recurrence

Recurrent syphilis demonstrates multisystem involvement with distinct phenotypic patterns. Primary recurrence often manifests as painless genital or anal ulcers with indurated borders. Secondary recurrence, typically occurring 4–10 weeks after latency, presents with a characteristic generalized copper-red maculopapular rash, frequently involving the palms and soles, and is often accompanied by generalized lymphadenopathy; while atypical lesions (eg, papular, vesicular) may be reported in case studies of recurrent syphilis, these macular and papular eruptions are considered typical.²¹ Neurologic complications, as detailed in systematic reviews and case series, are observed in a proportion of cases, particularly if untreated, and can include meningitis, cranial nerve palsies such as optic neuritis, and in late stages, progress to irreversible sequelae like tabes dorsalis due to central nervous system (CNS) infiltration, with imaging studies occasionally revealing rare manifestations like cranial osteomyelitis.^22,23 Systemic features such as low-grade fever, hepatosplenomegaly, and arthralgia are common, often mimicking symptoms found in autoimmune or viral syndromes, thus necessitating careful clinical differentiation aided by serological testing.²⁴ Notably, asymptomatic serological recurrence occurs, with studies in HIV-infected populations reporting a significantly higher proportion of asymptomatic cases during relapse (62.2%) compared to initial infection (21.9%), detectable only through serial serologic monitoring (using RPR titers),²⁵ emphasizing the necessity for post-treatment surveillance. The diverse clinical presentations of syphilis recurrence are summarized in Table 1.

Table 1 Key Clinical Manifestations of Syphilis Recurrence

Factors Influencing Syphilis Recurrence

Syphilis recurrence is mediated by complex host-pathogen-environment interactions. Suboptimal treatment regimens—particularly inadequate penicillin dosing (eg, less than typically recommended for the specific stage or relapse scenario) or nonadherence to the prescribed therapy duration—constitute a primary modifiable risk. This inadequacy can permit bacterial persistence in immune-privileged niches such as the central nervous system and ocular compartments, and potentially through mechanisms such as biofilm formation which allow bacteria to evade host defenses and antibiotics.^26,27 Immunocompromised hosts, prominently including HIV-coinfected individuals (who show a significantly increased risk, for example, a reported hazard ratio [HR] of 3.2, 95% CI 1.8–5.6, due to impaired CD4+ T cell function and chronic immune activation leading to dysregulated cellular immunity) and those receiving corticosteroids, exhibit impaired pathogen clearance.²⁸ This often results in poorer serological responses post-treatment, such as a serofast state (failure of RPR titers to decline adequately).⁷ Behavioral determinants are also critical; cohort studies indicate that unprotected sexual contact with untreated partners and having multiple sexual partners can increase reinfection risk two- to threefold.²⁹ Furthermore, substance use disorders, such as methamphetamine use, may act synergistically to promote transmission and thus the likelihood of reinfection.³⁰ Emerging antimicrobial resistance further complicates recurrence; for instance, surveillance studies, including data from China, report a high prevalence (eg, ranging from 85% to over 95% in some regional analyses) of clinical Treponema pallidum isolates harboring the 23S rRNA A2058G mutation.^31,32 This mutation confers high-level macrolide resistance, rendering azithromycin ineffective for salvage therapy and potentially necessitating extended or alternative antibiotic regimens, even if the initial clinical disease course caused by resistant strains appears similar to that of sensitive strains.³³

Clinical Strategies for Syphilis Recurrence

Therapeutic Drugs for Syphilis Recurrence

Syphilis recurrence management requires evidence-based antimicrobial regimens tailored to disease stage, host immunity, and antibiotic resistance patterns. While benzathine penicillin G (BPG) remains the gold standard for primary and secondary syphilis, recurrent cases demand prolonged therapy and enhanced pharmacovigilance due to risks of neuroinvasion and treatment failure.⁸

Penicillin-based regimens are first-line. For late syphilis and secondary recurrent syphilis, the recommended regimen is often 2.4 million units of intramuscular BPG administered weekly for 3 consecutive weeks.¹⁰ This long-acting formulation achieves sustained treponemicidal concentrations (>0.018 µg/mL) for an extended period, effectively penetrating skin and mucosal lesions. For neurosyphilis, intravenous aqueous penicillin G (18–24 million units daily, typically administered as 3–4 million units IV every 4 hours or by continuous infusion, for 10–14 days) is the standard regimen to achieve adequate CSF concentrations.¹⁰ Pretreatment penicillin skin testing is critical, as IgE-mediated hypersensitivity occurs in a small percentage of recipients, necessitating desensitization protocols when unavoidable.³⁴

In penicillin-allergic patients, alternative regimens require careful selection based on resistance surveillance. In penicillin-allergic patients with neurosyphilis, a recommended alternative is ceftriaxone (2 g daily intravenously or intramuscularly for 10–14 days).¹⁰ This regimen is considered to achieve sufficient CSF penetration for neurosyphilis. Doxycycline (100 mg orally twice daily for 30 days) is an alternative for non-pregnant, penicillin-allergic patients with late or recurrent syphilis, although close serological monitoring is essential.¹⁰ Macrolides like azithromycin are generally contraindicated in regions with high resistance prevalence; for instance, global surveillance, including data from China, indicates widespread 23S rRNA mutations (eg, A2058G) conferring high-level macrolide resistance, with some reports indicating MICs > 256 µg/mL for resistant strains.³⁵ Selected guideline-based treatment regimens for syphilis recurrence are outlined in Table 2.

Table 2 Selected Treatment Regimens for Syphilis Recurrence (Illustrative, Based on Guidelines Like CDC/WHO)

Treatment Plan for Syphilis Recurrence

Comprehensive management of recurrent syphilis integrates stage-appropriate antibiotics, potential adjunctive measures where indicated (though not standard), and structured serological surveillance. The 2021 CDC guidelines recommend specific regimens based on syphilis stage; for instances such as late latent syphilis or syphilis of unknown duration, which can encompass some recurrence scenarios, extended BPG regimens (eg, 3 weekly doses) are advised, in contrast to the single dose for primary syphilis, partly to address potential persistence in sites like immune-privileged reservoirs.⁸ For late recurrent syphilis with cardiovascular or gummatous involvement, BPG 2.4 million units weekly for 3 weeks remains standard;¹⁰ some clinicians may consider a short course of prednisone (eg, 20 mg/day for 24 hours pre-penicillin) to mitigate Jarisch-Herxheimer reactions in a significant proportion of patients.

Adjunctive therapies play a limited and largely investigational role. Some studies on Traditional Chinese Medicine (TCM) have explored formulations like Astragalus membranaceus, reporting in vitro immunostimulatory effects, but their clinical utility in syphilis recurrence is not established.³⁶ Other experimental approaches are confined to preclinical research.

Post-treatment surveillance, as recommended by guidelines such as those from the CDC, typically involves quantitative nontreponemal testing (RPR/VDRL) at intervals like 6, 12, and 24 months, depending on the syphilis stage and HIV status, with additional follow-up for HIV-infected individuals (eg, at 3, 6, 9, 12, and 24 months for early syphilis).⁸ A fourfold decline in nontreponemal antibody titers (eg, by 6–12 months for early syphilis) is generally considered indicative of an adequate response to therapy.⁸ CSF analysis is crucial in cases of suspected neurologic involvement, treatment failure, or for patients with HIV and syphilis who have neurologic symptoms or late latent syphilis.⁸ Therapeutic failure requires repeat BPG courses or alternative regimens like ceftriaxone for salvage therapy, guided by clinical judgment and, where available, molecular resistance testing (PCR detection of 23S rRNA/16S rRNA mutations).³⁷

Preclinical Models for Syphilis Recurrence Research

Given the variable clinical manifestations of syphilis, its capacity to mimic other diseases, and the emergence of antibiotic resistance, studies on clinical strategies and preclinical models for syphilis recurrence are critically important. Preclinical models are indispensable in syphilis research, not only advancing the understanding of its pathogenesis but also providing essential platforms for developing novel therapeutics and vaccines.³⁸

Methods for Establishing Preclinical Models of Syphilis

The development and utilization of robust preclinical models are foundational to advancing our understanding of Treponema pallidum infection and for testing new interventions.^39,40

Establishment of Animal Models

Animal models remain the most widely utilized tools in preclinical syphilis studies. Successful syphilis spirochete infection models have been established in rabbits,³⁹ non-human primates (eg, macaques),⁴¹ hamsters,⁴² guinea pigs,⁴³ and mice.⁴⁴

Rabbit Model

Rabbits exhibit high susceptibility to Treponema pallidum and are extensively employed in syphilis research.⁴⁵ Experimental syphilis infections in rabbits replicate pathological changes observed in natural human infections.⁴⁶ Typically, a Treponema pallidum suspension is inoculated into rabbit testicles or other regions to establish infection. Post-inoculation, clinical symptoms, pathological changes, and serological responses are monitored to evaluate infection progression and treatment efficacy. Although genetic modification of rabbits remains challenging, advancements in gene-editing technologies such as CRISPR/Cas9 may enable future development of immunodeficient or gene-knockout rabbit models for syphilis studies.

Mouse Model

The mouse model has become a valuable tool due to low inter-individual variability, cost-effectiveness, and reagent availability. Recent establishment of a C57BL/6 mouse syphilis infection model allows evaluation of Treponema pallidum colonization, dissemination, and host immune responses.⁴⁷ However, interspecies differences in immune responses necessitate cautious extrapolation of murine findings to humans.

Non-Human Primate Model

Non-human primates (eg, macaques) offer physiological and immune systems closely resembling humans, making them ideal for syphilis research. However, ethical constraints and high costs limit their widespread use.⁴⁸

Establishment of an in vitro Culture System

In vitro culture systems are critical for investigating Treponema pallidum biology, pathogenesis, and drug susceptibility.⁴⁹ However, Treponema pallidum remains one of the most challenging pathogens to culture axenically. Recent advancements have enabled continuous in vitro growth through co-culture systems with cottontail rabbit epithelial cells.

Co-Culture System Development

Treponema pallidum is co-cultured with cottontail rabbit epithelial cells in specialized media under tightly controlled temperature, humidity, and gas composition to replicate physiological growth conditions.⁵⁰

Genetic Tool Development

Functional genetic studies using homologous recombination have identified key virulence genes in Treponema pallidum. Targeted gene replacement facilitates investigation of gene-specific roles in pathogenesis, informing therapeutic and vaccine strategies.⁵¹

Establishment of Heterologous Expression Models

Prior to in vitro co-culture systems, heterologous expression models using surrogate pathogens (eg, Borrelia burgdorferi) enabled functional characterization of Treponema pallidum proteins. These models allow expression of specific spirochetal proteins to study their biological roles and pathogenic mechanisms.⁵¹

Characteristics of Different Preclinical Syphilis Models

The choice of a preclinical model depends on the specific research question, available resources, and ethical considerations. Each model type offers unique advantages and disadvantages, as summarized in Table 3.

Table 3 Overview and Comparison of Key Preclinical Models for Syphilis Research

In vitro Culture Models

In vitro models simulate Treponema pallidum growth in human-like environments, enabling studies on microbial biology, drug susceptibility, and polymicrobial interactions.⁵² Advantages include operational simplicity, cost-effectiveness, and experimental control. Limitations include slow bacterial growth rates and incomplete replication of human host complexity, potentially affecting result accuracy.

Animal Models

Animal models are pivotal for studying syphilis infection dynamics, pathology, and immunity.⁴⁴ Mouse models are favored for acute toxicity and pharmacokinetic studies due to rapid reproduction and low cost. Rabbit models, with human-like skin architecture, are optimal for studying syphilitic dermatological manifestations. Non-human primate models provide high translational value for vaccine safety and efficacy evaluations but face ethical and financial barriers. Despite their utility, interspecies physiological and immunological differences necessitate cautious interpretation of findings.⁵³

Tissue Culture Models

Tissue culture models employ in vitro human tissues or cells infected with Treponema pallidum to study host-pathogen interactions.⁴⁸ These models elucidate syphilis pathogenesis and therapeutic responses but face challenges in tissue sourcing and culture condition standardization. Recent advances in tissue engineering have introduced artificial skin and vascular constructs as reproducible platforms for syphilis research, offering novel avenues for therapeutic development.⁵⁴

Bioinformatics-Driven Models

Advances in bioinformatics have enabled genome-, transcriptome-, and proteome-based modeling of Treponema pallidum. These high-throughput approaches integrate genomic sequences, expression profiles, and protein networks to identify therapeutic targets and vaccine candidates.⁵⁵ While offering cost and efficiency advantages, these models require rigorous validation of data quality and algorithmic accuracy.

Application Fields of Preclinical Models of Syphilis

The global resurgence of syphilis poses a significant public health challenge. While penicillin remains the first-line therapy, emerging macrolide and tetracycline resistance, coupled with the complex pathogenesis of Treponema pallidum, underscores the need for advanced preclinical models. These models are indispensable for advancing clinical diagnostics, therapeutic strategies, vaccine development, and public health policies. This section elaborates on the key applications of preclinical syphilis models.

Innovation in Syphilis Diagnostic Approaches

Preclinical models serve as critical platforms for validating novel diagnostic methodologies. Traditional serological tests, such as the Rapid Plasma Reagin (RPR) and Treponema pallidum Particle Agglutination Assay (TPPA), face limitations in sensitivity and specificity. Recent advancements in molecular biology have spurred interest in nucleic acid amplification tests (NAATs), which detect Treponema pallidum DNA in culture-resistant samples. Preclinical models enable rigorous validation of NAAT accuracy and reliability.⁵⁶ Furthermore, novel diagnostic platforms, such as the Kodecytes assay which utilizes red cell kodecytes with T. pallidum lipoprotein peptide antigens for agglutination testing, are being evaluated and show promise for routine blood center screening, with preclinical and initial clinical validation highlighting their potential utility.⁵⁷ Additionally, non-coding RNAs (ncRNAs) and microRNAs, identified as emerging diagnostic biomarkers, have undergone preliminary evaluation in preclinical settings, offering promising avenues for early syphilis detection.⁵⁸

Development of New Therapeutic Regimens and Alternative Medications

Preclinical models are pivotal for evaluating novel therapeutics and combating antibiotic resistance. Although penicillin remains effective, prolonged use risks resistance emergence. Preclinical models allow systematic assessment of antibiotic efficacy and novel treatment modalities. Furthermore, vaccines targeting Treponema pallidum outer membrane proteins (OMPs) have shown preliminary success in preclinical trials, highlighting their potential for syphilis prevention.⁵⁹

Investigation of Pathogenesis

Preclinical models elucidate the mechanisms underlying Treponema pallidum pathogenicity. By replicating infection dynamics, researchers observe spirochetal proliferation, migration, and host immune interactions. Rabbit models reveal that components of T. pallidum, such as inner flagella, can modulate lesion severity, emphasizing immune regulation in disease progression.⁶⁰ Additionally, studies using these models uncover immune evasion strategies, such as antigenic variation of TprK membrane proteins, advancing our understanding of syphilis persistence.⁴⁵

Validation Platform for Vaccine Development

Preclinical models are indispensable for evaluating vaccine candidates. Despite challenges in syphilis vaccine development due to pathogen complexity, preclinical trials assess vaccine-induced immune responses and protective efficacy. Recent focus on OMPs and peripheral membrane lipoproteins as immunogens has yielded promising preclinical results, informing clinical trial design.⁶¹

Formulation of Public Health Policies

Insights from preclinical research inform evidence-based public health strategies. By analyzing syphilis epidemiology, pathogenesis, and therapeutic outcomes, researchers provide actionable recommendations to policymakers, facilitating the design of targeted prevention programs to reduce syphilis incidence and mortality.⁶² The resurgence of syphilis has been recognized as a public health emergency in several regions, including the United States, and is a growing concern globally, underscoring the urgent need for effective public health interventions informed by robust surveillance and research.⁶³ For instance, recent data from Eastern India highlight the re-emergence of syphilis among blood donors, signaling a looming threat to public health and transfusion services that demands policy attention.⁶³

Limitations of Preclinical Models of Syphilis

Despite their utility, preclinical models face significant constraints that hinder translational progress in syphilis research.

Discrepancies Between Model Organisms and Humans

Interspecies physiological and immunological differences limit the translatability of preclinical findings. For example, murine models exhibit attenuated inflammatory responses and lack overt clinical manifestations, failing to fully recapitulate human syphilis pathology.⁶⁴

Difficulties in the in vitro Cultivation of Treponema Pallidum

Treponema pallidum’s fastidious growth requirements, including microaerophilic conditions and a fragile outer membrane, complicate in vitro cultivation. Although advances like the Sf1Ep co-culture system enable limited propagation, challenges such as prolonged culture duration and technical complexity hinder large-scale applications.⁶⁵

Challenges in Vaccine Development

Vaccine development is hampered by low expression and heterogeneity of OMPs, primary vaccine targets. Additionally, the intricate interplay between Treponema pallidum and host immune components necessitates multifactorial vaccine design, increasing developmental uncertainty.⁶⁶

Ethical and Moral Concerns

Ethical constraints arise from the use of animal models in invasive procedures, necessitating adherence to welfare guidelines. Furthermore, societal sensitivities surrounding sexually transmitted infections pose challenges in study design and public engagement.⁶⁷

Difficulty in Clinical Translation

Biological disparities between models and humans, combined with syphilis’s heterogeneous clinical presentation, complicate the extrapolation of preclinical results. Individualized optimization is required to bridge the gap between experimental findings and clinical applications.⁶⁸

Conclusion and Research Prospects

Syphilis relapse presents a persistent and complex challenge in clinical practice, compounded by factors such as host immunocompromise, pathogen persistence mechanisms, and emerging antimicrobial resistance. This review has synthesized the current understanding of clinical management strategies, emphasizing guideline-recommended therapies and the critical role of serological monitoring. Furthermore, it has highlighted the indispensable contributions of preclinical models, including rabbit and mouse systems, as well as in vitro techniques, in dissecting pathogenesis, evaluating therapeutics, and guiding vaccine development. While significant progress has been made, the translational gap between preclinical findings and human clinical outcomes remains a key hurdle. Addressing this requires ongoing innovation in model development to better mimic human disease and a continued commitment to integrated research.

In the expansive domain of clinical strategies and preclinical model research addressing syphilis relapse, future investigations should prioritize multifaceted approaches to advance global syphilis prevention and control. Critical research directions must focus on elucidating the underlying mechanisms of relapse, refining therapeutic protocols, developing novel diagnostic modalities, and enhancing public health interventions. These efforts aim to establish evidence-based, targeted solutions for mitigating syphilis recurrence and transmission.

Mechanistic Elucidation of Syphilis Relapse

Syphilis relapse constitutes a multifactorial process involving pathogen persistence, host immune modulation, suboptimal treatment efficacy, and reinfection risks. Future studies should emphasize three interconnected domains:

First, the molecular mechanisms governing Treponema pallidum latency and reactivation warrant systematic exploration. Advanced genomic and transcriptomic methodologies, including high-throughput sequencing and single-cell RNA sequencing, could delineate spatiotemporal patterns of pathogen sequestration, gene regulatory networks during dormancy, and host-microbe interactions at cellular resolution.⁶⁹ Such insights may inform strategies to disrupt bacterial reservoirs.

Second, longitudinal analyses of host immune dynamics are critical. Investigations should characterize the durability and plasticity of pathogen-specific cellular (eg, T-cell memory subsets) and humoral immune responses post-treatment.⁷⁰ Particular emphasis should address how immune evasion mechanisms facilitate relapse and whether therapeutic immunomodulation could reinforce protective immunity.

Third, antimicrobial resistance surveillance requires expansion. Genomic characterization of treatment-failure cases must evaluate emergent macrolide resistance mutations (eg, 23S rRNA A2058G) and assess penicillin tolerance mechanisms.⁷¹ These efforts will guide antimicrobial stewardship and next-generation drug development.

Therapeutic Optimization and Innovation

While penicillin remains the therapeutic cornerstone, limitations persist regarding hypersensitivity risks and treatment failures.⁷² Three strategic priorities emerge:

First, antimicrobial discovery programs should leverage T. pallidum’s unique metabolic vulnerabilities, such as its reliance on host-derived lipids and limited biosynthetic pathways.⁷³ Novel compounds targeting membrane integrity (eg, engineered lipopeptides) or essential enzymes (eg, TP0319 redox proteins) show preclinical promise.

Second, combination therapies merit rigorous evaluation. The potential for synergistic antibiotic combinations or carefully selected adjunctive therapies to enhance pathogen clearance and reduce relapse risks warrants further investigation in appropriate preclinical and clinical studies for syphilis.

Third, personalized treatment algorithms should integrate host biomarkers (eg, CSF-VDRL status, CD4+ T-cell counts) and pathogen load dynamics to stratify therapeutic intensity.⁷⁴ Machine learning models incorporating serological trajectories may optimize retreatment decisions.

Advanced Diagnostic Development

Precision diagnostics are paramount for relapse prevention. Key innovations should address:

First, ultrasensitive molecular detection. Digital PCR platforms capable of identifying T. pallidum DNA in whole blood could enable earlier relapse identification compared to conventional RPR testing.⁷⁵

Second, noninvasive sampling validation. Salivary IgA assays and urine-based lateral flow assays demonstrate high concordance with serum testing in pilot studies, offering advantages for resource-limited settings.⁷⁶

Third, predictive biomarker discovery. Multi-omics profiling may identify relapse-associated signatures, such as elevated CXCL13 levels in CSF or skewed Th17/Treg ratios, facilitating preemptive interventions.

Data Sharing Statement

Data is provided within the manuscript files, further enquiries can be directed to the corresponding author.

Ethics Approval and Consent to Participate

Ethical approval was waived by the Ethics Committee of Chengdu Second People’s Hospital because the present study does not involve any human participants or animals. Informed consent to participate was waived because the present study does not involve any human participants.

Funding

There is no funding to report.

Disclosure

The author declares no competing interests in this work.

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Could a simple advisory or alert in the electronic medical record (EMR) be the key to more frequent diagnosis and effective treatment of high blood pressure (BP)? While it could help, some physicians say it’s not sufficient to solve the persistent problem of hypertension.

However, such alerts could be part of an effective approach to catching more cases of hypertension and helping people manage their high BP.

Tackling High BP

Hypertension is well-known as a “silent killer.” Left untreated, it raises the risk for heart attack, stroke, and other life-threatening events without causing any symptoms.

Hypertension is also a widespread problem. The CDC estimates that about 120 million adults in the US have high BP, defined as having a systolic BP higher than 130 mm Hg or a diastolic BP greater than 80 mm Hg (or taking medication to lower their BP).

However, only about 1 in 4 adults with high BP actually have their BP under control.

According to the results of a recent quality improvement study in JAMA Network Open, using technology to prompt team-based care can improve primary care hypertension control and diagnosis in the ambulatory setting.

The researchers tested an intervention consisting of a high BP advisory in the EMR, along with team training, audit, and feedback. If an elevated BP reading (systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg) was entered into the EMR, the medical assistant received an advisory to recheck the patient’s BP. If the BP continued to be elevated, the EMR prompted a clinician-facing advisory, along with an order panel link.

“This study demonstrates that a paired human-technology intervention focused on team-based care and EMR integration is a fruitful approach to improving population health metrics,” the authors wrote.

“Anything that is done to alert the clinician is appropriate because of clinical inertia,” said Luke Laffin, MD, co-director of the Cleveland Clinic’s Center for Blood Pressure Disorders in Cleveland, Ohio. “There’s a lot of clinical inertia in hypertension care. It breaks that inertia. I’m not surprised that this intervention works.”

The Value of an Alert

The idea of incorporating this type of alert into the EMR system is feasible, according to Brian Barr, MD, cardiologist at the University of Maryland Medical Center and assistant professor of medicine at the University of Maryland School of Medicine in Baltimore.

“Most modern EMRs — such as Epic, Cerner, Athenahealth, and others — are equipped with customizable clinical support tools that allow for automated reminders, alerts, and health maintenance prompts,” Barr said, adding that configurations could allow for notifications for missing BP readings or lack of documentation of BP within a particular time period.

Alerts could also be quite useful to busy primary care physicians who see patients for a multitude of reasons.

“It’s a reminder not to get distracted by the chief complaint syndrome,” said Brent Smith, MD, a family physician in Greenville, Mississippi and member of the board of directors for the American Academy of Family Physicians. “It forces us not to overlook hypertension when there are other things that brought them into the doctor’s office.”

Using this type of tool could also identify patients with multiple elevated BP readings but no formal hypertension diagnosis, said Barr. That information could also allow physicians to follow patients more closely and confirm elevated BP in multiple settings — not just in the office, according to Blair Suter, MD, cardiologist with The Ohio State University Wexner Medical Center.

“It could be the canary in the coal mine,” he said. “It could really be the sign of things to come or to progress to.”

However, healthcare organizations must also be cautious about the possibility of contributing to electronic health record alert fatigue and instead find a balance that allows the use of technology to improve patient care without increasing the alert burden on clinicians.

The authors of the study also acknowledged that some clinic managers had sustainability concerns about the time needed for BP rechecks. “[A]fter the rollout, some clinics piloted scheduling patients 10 minutes ahead of the clinician visit to increase previsit time for [medical assistants] to manage this and other population health initiatives,” they wrote.

“I think that rather than just having alerts, where people tend to get alarm fatigue, it might be more useful to focus on how we’re collecting the data and how reliable it is and how much of a true reflection it is of the patient’s true blood pressure when they’re not in the office,” said Jeremy Bock, MD, interventional cardiologist and endovascular specialist at VHC Health in Arlington, Virginia.

At-Home Monitoring

Indeed, even if alerts do help, the challenge of getting patients to monitor their BP regularly at home does persist. At-home checks can seem nonurgent to them, especially if they are already taking an antihypertensive medication and feel fine.

Kristen Trom, DO, family physician with Inspira Health in Mullica Hill, New Jersey, said that her organization’s EMR uses an alert, but it’s still a challenge to get patients to monitor their BP at home and take their medication. “Resistance to starting medication can be a major challenge,” she said. “Many of these patients have never been on medication before and prefer not to start.” 

“It’s trying to find that balance between being nonintrusive and also being part of their daily routine,” said Laffin.

Physicians may need to spend more time emphasizing the importance of at-home BP monitoring and ensure patients know how to do it correctly. Prevention efforts can be time-consuming, noted Bock, but they can also improve patient-provider relationships and patient satisfaction.

One important element of that process is reminding patients to use a validated BP cuff. Suter recommends directing patients to the website validateBP.org, which is also suggested by the American Heart Association.

Future Possibilities

Time is often the biggest impediment for primary care providers. Eventually EMRs may be configured — along with AI — to incorporate the most effective cues and advisories, and then filter the information that would be most helpful for the physician, Smith said.

“It is getting better, and it has potential for the future,” he said.

Barr added that other efforts could bolster such improvements. For example, clinic-level interventions also play a major role.

“Standardized blood pressure measurement protocols, routine use of home blood pressure monitoring, automated follow-up scheduling, and nurse-led hypertension visits can all support timely diagnosis and management,” Barr said.

“Engaging patients through portal alerts, educational messaging, and self-reported blood pressure entries adds another layer of protective care. Together, these strategies help close care gaps and support earlier identification and treatment of hypertension, ultimately improving long-term cardiovascular outcomes.”

A person diagnosed with dementia has improved survival outcomes in recent years amid significant progress in dementia diagnosis and care, according to a recent multinational study led by a University of Waterloo researcher. 

The study analyzed data from more than 1.2 million people over the age of 60 living with dementia in eight global regions between 2000 and 2018. It found that in five of those regions, including Ontario, a lower risk of death exists today than in previous years. 

Dementia is a global public health priority. Understanding how survival among people living with dementia varies over time and across health systems can help policy makers assess its real-world impact on health and social care services.” 

Dr. Hao Luo, assistant professor in the School of Public Health Sciences and lead author of the study

She said the increase in survival probability is likely due to factors such as progress in dementia prevention and care in recent years, as well as more effective drug treatments and psychosocial interventions tailored to an individual’s needs. 

“Knowledge of survival after the diagnosis of dementia is important for people living with dementia and their family members for making informed decisions about the subsequent care arrangement, for clinicians to improve their prognosis and care for people living with dementia and for policy makers to improve estimation of the real-world disease burden currently carried by health systems,” Luo said. 

Of the eight regions in the study (Ontario, United Kingdom, South Korea, Taiwan, Hong Kong, Finland, Germany and New Zealand), only New Zealand showed an increase in the risk of death following the first hospital record of dementia diagnosis. Data from Finland and Germany were inconclusive. 

“We were surprised to observe a steady increase in mortality risk in New Zealand between 2014 and 2018,” Luo said. “We later found that this coincided with a national effort to shift the diagnosis and management of uncomplicated dementia to primary care to free up specialist services. With greater involvement of primary care, people living with dementia are more likely to present to hospitals at a more advanced stage of the disease, leading to a higher risk of mortality following the first hospital record of dementia diagnosis.” 

The consistently observed decrease in mortality risk across five of the regions accounted for 84 per cent of all participants. Canada, the U.K., South Korea, Taiwan, Finland and Germany have national dementia strategies already in place or in development. 

Luo said her future research will look at the role comorbidities play. “To analyze multinational data using a standardized approach, some compromises were made, including not accounting for the impact of comorbid conditions on dementia survival,” she said. “One of my future research directions is to understand the patterns of comorbidity and how comorbidities affect survival among persons with dementia.” 

Leading global doctors, researchers, and lawyers have joined forces with patient representatives and created the first-ever information guide to better support and protect patients across the world who are considering pioneering, but also potentially risky, surgery.

The comprehensive seven-step set of essential information, co-led by the National Institute for Health and Care Research (NIHR) Bristol Biomedical Research Centre (BRC) and the University of Bristol, was published today in the British Journal of Surgery. 

It sets out clearly what patients must be told by their surgeon or clinician before undergoing innovative procedures and coincides with the fifth anniversary of the UK Government’s ‘First Do No Harm’ Independent Medicines and Medical Devices Safety Review, which highlighted unacceptable harm experienced by patients and families due to various medical devices and medications.

This is a vital step forward in learning from past mistakes and could be a game changer for improved patient safety and communication. It establishes robust, consistent, and fully transparent processes to make sure patients are given all the important and relevant information they need, including possible associated risks and other available alternatives, before deciding whether to proceed with a new procedure.

We engaged with a wide range of medical experts, lawyers, ethicists, regulatory and policy bodies, and most crucially patients themselves globally as well as the wider public. Combining their skills, insights and experience with evidence-based research, we have produced core standards which – if adopted internationally – will mean surgical innovation can still advance without potentially compromising safety or transparency for anyone.” 

Angus McNair, Co-Lead Author, Professor in Colorectal Surgery, University of Bristol Medical School

While new surgical techniques and devices are constantly being developed to improve treatment options for patients, unlike medicines, they are not required to undergo a rigorous approval process before being used on patients.

Establishing a Core Information Set (CIS), as presented in this study, was a key recommendation of the UK inquiry’s report which considered various controversial medical interventions, including pelvic mesh implants used to treat conditions like pelvic organ prolapse and stress urinary incontinence.

The CIS states that surgeons must discuss:

1. What’s new and different about the procedure
2. Possible conflicts of interest
3. Reasons for the innovation, including why it’s being recommended for the patient
4. Alternative treatments
5. Unknowns, including uncertainties about safety, how effective it is, and that the surgeon might abandon or modify the procedure during surgery
6. The surgeon’s level of expertise and experience with the innovation
7. Governance, oversight and accountability, including how safety will be monitored and how the patient will be compensated if anything goes wrong.

The study analysed more than 200 research publications and involved dozens of global surgeons, anaesthetists, medical directors, regulators, lawyers, and policy makers as well as more than 130 patients.

Its findings highlighted systemic failures to obtain informed consent before patients agreed to be operated on using new surgical techniques and medical devices, such as implanted pelvic mesh which resulted in complications, in some cases life-altering, for scores of women.

The UK inquiry, prompted by public and patient outcry, quoted a woman directly affected by the procedure, who said: “I feel as though I am an unsuspecting, unwilling participant in a cruel experiment that has gone wrong.”

Professor McNair, who is also a Consultant Colorectal Surgeon at North Bristol NHS Trust, explained: “Research shows surgeons often don’t tell patients they are using a pioneering technique, leaving them unaware that the procedure isn’t yet fully tried and tested. When surgeons do say it’s new, findings also show they may overstate its benefits or patients can assume that it must be better simply because it’s new.”

“The study aims to address these shortcomings by providing surgeons and clinicians with a step-by-step guide of the specific conversations they must have with patients before and after any new surgical procedure. It captures all the different areas of discussion they need to cover so their patients can make informed choices and, if necessary, know how to seek help and support should anything subsequently go wrong.”

The study, funded by the NIHR Bristol Biomedical Research Centre (BRC) at the at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, has been submitted to MP Sharon Hodgson, Chair of the cross-party All Parliamentary Group (APPG) First Do No Harm – Mesh, Promodos, Valproate.

Next steps for the study include exploring how to implement the CIS most effectively and integrate it into the Shared Decision Making (SDM) process. This could entail making health service leaders accountable and responsible for embedding it into their organisation in addition to ensuring surgeons and clinicians skills are supported through continual professional development.

Background

Childhood immunization remains one of the most cost-effective public health interventions for reducing morbidity and mortality from vaccine-preventable diseases.^1,2 Globally, immunization prevents an estimated four to five million deaths annually, primarily from diseases such as measles, diphtheria, pertussis, tetanus, and polio.^3–5 Despite its well-documented benefits, immunization coverage remains suboptimal in many low- and middle-income countries (LMICs), including Nigeria, where disparities in vaccine uptake persist across socioeconomic, geographic, and demographic groups.^6–8

Nigeria accounts for a significant proportion of the global burden of vaccine-preventable diseases, with immunization coverage consistently falling below recommended targets.⁹ According to the Nigeria Demographic and Health Survey (NDHS) 2018, only 31% of children aged 12–23 months received all basic vaccines, far below the 90% global target set by the WHO.¹⁰ Immunization coverage in Nigeria is characterized by wide regional and socioeconomic disparities, with children in northern, rural, and low-income households facing the greatest barriers to vaccine uptake.^11,12 These disparities contribute to Nigeria’s persistently high rates of infant and child mortality, which remain among the highest globally.^13,14

Several factors influence childhood immunization coverage, including maternal education, socioeconomic status, geographic location, cultural beliefs, and healthcare access.^11,12,15 Maternal education is particularly important, as higher levels of education have been associated with greater vaccine awareness, improved health-seeking behaviors, and higher immunization uptake.¹⁶ Economic status also plays a crucial role, with children from wealthier households being more likely to receive complete immunization due to fewer financial barriers to healthcare access.¹⁷

Geographic and infrastructural challenges further hinder immunization efforts in Nigeria. Children residing in rural and remote areas often experience limited access to healthcare facilities, long travel distances, and inadequate vaccine supply chains, all of which contribute to missed immunization opportunities.^18,19 In northern Nigeria, sociocultural and religious beliefs also play a significant role, with some communities exhibiting vaccine hesitancy due to misconceptions about vaccine safety and efficacy.^20,21 Past incidents of vaccine boycotts and misinformation campaigns have exacerbated these concerns, further reducing vaccine acceptance in certain regions.^22–24

In addition to individual and household-level factors, systemic challenges within Nigeria’s healthcare system contribute to low immunization coverage.²⁵ Inconsistent vaccine supply chains, weak health infrastructure, and inadequate funding for immunization programs have been persistent issues.^26,27 The country also faces poor data collection and monitoring systems, which hinder effective tracking of immunization defaulters and planning for targeted interventions.^14,28,29 Addressing these barriers requires a multifaceted approach, including improving maternal education, expanding healthcare infrastructure, engaging community leaders, and implementing financial support programs for low-income families.²⁹

While previous studies have explored sociodemographic determinants of childhood immunization in Nigeria, gaps remain in understanding how these factors interact across different regions and socioeconomic groups. Our focus on maternal sociodemographic factors was guided by existing evidence linking maternal characteristics to child health outcomes and by the data availability in the NDHS, which primarily collects information from mothers. This study aims to examine the prevalence, regional disparities, and sociodemographic predictors of full immunization coverage among children aged 12–23 months in Nigeria. The findings will provide evidence-based insights to inform policies and interventions aimed at improving immunization coverage and reducing preventable childhood deaths”.

Methods

Study Setting, Design, and Data Source

This study utilized data from the 2018 Nigeria Demographic and Health Survey (NDHS), a nationally representative survey conducted across Nigeria’s six geopolitical zones: North Central, North East, North West, South East, South South, and South West. The NDHS is part of the Demographic and Health Surveys (DHS) program, which collects comprehensive health and demographic data from women of reproductive age (15–49 years) and children under five years. The study employed a cross-sectional design, analyzing data from the Kids Recode (KR) dataset of the 2018 NDHS. The KR dataset contains detailed information on child health indicators, including immunization status, as well as maternal sociodemographic and reproductive health data.

Study Population and Sampling

The study population included women aged 15–49 years from the 2018 NDHS who had given birth in the past five years. While the unit of analysis was the child aged 12–23 months, data were obtained from their mothers. Therefore, the study population comprised women aged 15–49 years with eligible children, while the target population for the study’s outcomes was children aged 12–23 months, totalling 2453 children, as they are expected to have completed the full vaccination schedule.

Survey Instrument and Data Collection

The 2018 NDHS employed a structured Woman’s Questionnaire to gather data on sociodemographic characteristics, reproductive health, service utilization, and child health indicators, including immunization status. Information on vaccination coverage was collected using two methods: verification of vaccination cards when available, where interviewers recorded vaccination dates directly onto the questionnaire, and mothers’ verbal reports when cards were unavailable or incomplete. This dual approach allowed for a comprehensive assessment of vaccination status among children. The structured Woman’s Questionnaire used in the 2018 NDHS is publicly available via the DHS Program website (https://dhsprogram.com/Methodology/Survey-Types/DHS-Questionnaires.cfm)”.

Study Variables

The dependent variable in this study was full immunization coverage (FIC), defined according to World Health Organization (WHO) guidelines.³⁰ A child was considered fully immunized if they had received the following vaccines: one dose of Bacillus Calmette-Guérin (BCG) for tuberculosis, three doses of diphtheria-pertussis-tetanus (DPT) vaccine, at least three doses of polio vaccine, and one dose of measles vaccine. The immunization status variable was recoded into a binary outcome: “fully immunized” (1) if the child had received all recommended vaccines, and “not fully immunized” (0) if the child had missed one or more doses. Responses such as “vaccination date on card” were categorized as “fully immunized”, while “no vaccination” or “don’t know” responses were categorized as “not fully immunized”. Responses based solely on maternal recall or marked cards without dates were excluded from the analysis due to potential inaccuracies.

The independent variables included sociodemographic characteristics of the mothers, such as age, educational attainment, marital status, religion, wealth index, distance to the nearest health facility, employment status, number of living children, sex of the household head, place of residence (urban/rural), and region of residence.

Statistical Analysis

Descriptive statistics were used to summarize the sociodemographic characteristics of the study population and the prevalence of FIC. Bivariate and multivariable logistic regression analyses were conducted to examine the associations between sociodemographic factors and immunization status. Crude odds ratios (CORs) and adjusted odds ratios (AORs) with 95% confidence intervals (CIs) were calculated to quantify the strength and significance of these associations. A p-value of <0.05 was considered statistically significant.

All analyses were performed using Stata version 17, with sampling weights applied to account for the complex survey design. Data visualization tools, including pie charts, bar charts, and geographical maps, were generated using GeoPandas in Python with GADM map data for Nigeria. These visualizations were used to illustrate regional disparities in immunization coverage and the spatial distribution of immunization rates across Nigeria.

Results

Sociodemographic Characteristics of Mothers

The study analyzed data from 2453 mothers with children aged 12–23 months, and their sociodemographic characteristics are summarized in Table 1. The majority of mothers (27.9%) were aged 25–29 years, followed by those aged 30–34 years (21.7%) and 20–24 years (20.2%). The smallest proportion of mothers (1.7%) were aged 45–49 years. Education levels varied, with 37.8% of mothers having no formal education, while 14.9% had primary education, 37.1% had secondary education, and 10.3% had higher education. Most mothers were married (92.3%), while 3.3% were cohabiting, 2.2% had never been in a union, and 1.4% were divorced or separated.

Table 1 Sociodemographic Characteristics of Mothers (N=2453)

Regarding socioeconomic status, 19.7% of mothers belonged to the poorest wealth quintile, whereas 21.1% were in the richest quintile. A majority of mothers (69.3%) were currently employed. In terms of residence, 54.9% lived in rural areas, while 45.1% resided in urban settings.

Prevalence of Full Immunization Coverage

The overall prevalence of full immunization coverage among children aged 12–23 months was 26.0%, indicating that 74.0% of children were not fully immunized (Figure 1).

Figure 1 Full Immunization Coverage in Nigeria.

Regional Disparities in Full Immunization Coverage (FIC)

There were substantial regional variations in full immunization coverage (Figure 2). The North West had the lowest coverage at 13.0%, followed by the North East (18.0%) and North Central (22.0%). The highest immunization rates were observed in the South East (41.50%), South South (41.0%), and South West (34.0%). The geographic disparities in full immunization coverage are further illustrated in Figure 3.

Figure 2 Immunization coverage across Regions of Nigeria.

Figure 3 Map of Nigeria showing Full Immunization Coverage across Regions of Nigeria.

Bivariate Analysis of Maternal Characteristics and Full Immunization Coverage

Bivariate analysis showed significant associations between FIC and maternal characteristics such as age, education, wealth index, employment, distance to a health facility, and religion (Table 2). Full immunization rates increased with maternal age, with mothers aged 35–39 years having the highest immunization rates (33.98%), while those aged 15–19 years had the lowest coverage (11.27%). Compared to younger mothers, older mothers had significantly higher odds of fully immunizing their children (COR: 3.66, 95% CI: 1.88–7.15, p < 0.001).

Table 2 Bivariate Analysis of Mothers’ Characteristics and Immunization Coverage

Higher levels of maternal education were associated with increased immunization rates. Mothers with higher education had the highest immunization rate (45.86%), followed by those with secondary education (34.76%) and primary education (28.41%). Compared to mothers with no formal education, those with higher education were significantly more likely to fully immunize their children (COR: 6.67, 95% CI: 4.51–9.86, p < 0.001). Similarly, wealth status played a crucial role in immunization uptake. Full immunization rates were lowest among children from the poorest households (11.27%) and highest among children from the richest households (45.86%). Children from the highest wealth quintile were significantly more likely to be fully immunized than those from the lowest quintile (COR: 6.67, 95% CI: 4.61–9.65, p < 0.001).

Employment status was also associated with immunization coverage. Children of employed mothers had a higher immunization rate (28.26%) compared to those of unemployed mothers (21.14%) (COR: 1.47, 95% CI: 1.15–1.87, p = 0.002). Access to health facilities influenced immunization uptake, as mothers who reported that distance was “not a big problem” had higher immunization rates (29.27%) compared to those who considered distance a major barrier (18.17%) (COR: 1.86, 95% CI: 1.36–2.55, p < 0.001). Additionally, religious affiliation was significantly associated with immunization status. Immunization coverage was higher among Christian mothers (36.28%) compared to Muslim mothers (17.40%) (COR: 0.32, 95% CI: 0.23–0.45, p < 0.001).

Multivariable Analysis of Maternal Predictors of Full Immunization Coverage

After adjusting for confounders, maternal education, wealth index, and regional variations remained significant predictors of full immunization coverage (Table 3). Maternal education remained a strong determinant, as mothers with higher education were significantly more likely to fully immunize their children compared to those with no education (AOR: 1.87, 95% CI: 1.10–3.18, p = 0.022). Household wealth status also played a crucial role, with children from the richest households having over three times higher odds of full immunization coverage compared to those from the poorest households (AOR: 3.20, 95% CI: 1.95–5.25, p < 0.001).

Table 3 Multivariable Association Factors with Full Immunization Coverage

Regional differences persisted in the multivariable analysis. Compared to the North West, children from the South East (AOR: 2.00, 95% CI: 1.16–3.46, p = 0.013) and South South (AOR: 1.73, 95% CI: 0.99–3.02, p = 0.052) were significantly more likely to be fully immunized. These findings highlight the persistent inequities in immunization coverage across Nigeria, emphasizing the need for targeted interventions in regions with low immunization uptake.

Discussion

This study examined the factors influencing full immunization coverage among children aged 12–23 months in Nigeria, highlighting significant disparities based on sociodemographic, economic, and geographic factors. It is important to distinguish between immunization coverage—defined as the proportion of children who received all recommended vaccines—and uptake, which may refer to partial or incomplete vaccination. The findings indicate that only 26% of children were fully immunized, far below the World Health Organization (WHO) target of 90% coverage for essential childhood vaccines.³⁰ This finding is consistent with previous NDHS-based studies reporting full immunization rates between 23–31% across Nigeria. However, some regional or community-based studies report slightly higher rates due to focused interventions or sampling differences. Regional disparities were also notable, with the North West (13%) and North East (18%) having the lowest immunization rates, while the South East (41.5%) and South South (41%) had the highest. These findings reflect longstanding inequalities in healthcare access, cultural influences, and socioeconomic factors, which continue to hinder immunization uptake in Nigeria.³¹

Maternal education emerged as a key determinant of immunization coverage. The results showed that children of mothers with higher education were significantly more likely to be fully immunized compared to those whose mothers had no formal education. This aligns with previous studies in sub-Saharan Africa, which indicate that educated mothers are more likely to seek preventive healthcare services and understand the importance of immunization.^16,18,32 Education empowers women to make informed health decisions, increases awareness of vaccine-preventable diseases, and enhances trust in modern healthcare systems. Expanding access to education, particularly for girls, is essential for improving childhood immunization rates.^16,33

Wealth status also played a significant role in determining immunization uptake. The study found that children from the richest households were more than three times more likely to be fully immunized compared to those from the poorest households. This supports prior research demonstrating that financial stability improves healthcare access, allowing families to afford transportation costs and out-of-pocket expenses associated with immunization.^34,35 Conversely, poorer households often face economic constraints that limit healthcare utilization, exacerbating immunization inequities. Implementing financial support programs, such as conditional cash transfers and immunization incentives, may help increase vaccine coverage among low-income families.³⁶

Geographic disparities in immunization coverage were evident, with children in rural and northern regions being less likely to be fully immunized compared to their urban and southern counterparts. These findings are consistent with studies showing that rural areas have limited access to healthcare facilities, leading to delays in childhood vaccinations.^37–39 Distance to a health facility was a significant barrier in this study, as mothers who reported distance as a “big problem” were significantly less likely to fully immunize their children. Poor road networks, inadequate vaccination outreach programs, and security concerns in some northern regions further compound these challenges.¹¹ Strengthening community-based immunization programs, expanding mobile vaccination units, and integrating immunization services into routine child health visits could help improve coverage in hard-to-reach areas.⁴⁰

Religious affiliation was another factor influencing immunization coverage. The study revealed that children born to Christian mothers had significantly higher immunization rates than those born to Muslim mothers. This may be linked to differences in health-seeking behaviors, religious beliefs, and vaccine acceptance.^41,42 Previous studies have reported vaccine hesitancy in some religious communities, often driven by misconceptions about vaccine safety, fertility concerns, and distrust in Western medicine.^21,43 Addressing religious and cultural resistance through engagement with religious leaders, culturally appropriate health education campaigns, and targeted community outreach is critical to overcoming vaccine hesitancy.²¹

Conclusion

This study highlights the low full immunization coverage (26%) among children aged 12–23 months in Nigeria, with significant regional, socioeconomic, and demographic disparities. Maternal education, household wealth status, and geographic location were strong predictors of immunization uptake. Geographic disparities were evident, with children in northern and rural regions facing lower immunization rates compared to those in urban and southern areas. Barriers such as distance to health facilities, financial constraints, and religious or cultural hesitancy contribute to the suboptimal vaccine coverage observed in this study. Addressing these barriers through education, financial support programs, community engagement, and improved healthcare accessibility is essential to achieving Nigeria’s immunization targets. Strengthening routine immunization services and expanding outreach programs, particularly in underserved regions, will be critical in reducing vaccine-preventable diseases and improving child survival outcomes.

Recommendations

To improve childhood immunization coverage in Nigeria, several strategies are recommended based on recent findings. Expanding education programs for women is crucial, as increasing female education enhances maternal health literacy and vaccine awareness, with long-term benefits for immunization uptake. Improving healthcare access in rural and underserved areas involves strengthening primary healthcare infrastructure, expanding mobile vaccination units, and integrating immunization services into routine child health visits. Implementing financial support programs, such as conditional cash transfers and immunization incentives, can assist low-income families in accessing vaccination services. Enhancing community-based immunization outreach through community health workers can improve coverage, especially in regions with vaccine hesitancy. Engaging religious and community leaders is vital for addressing vaccine hesitancy by promoting culturally appropriate campaigns. Strengthening immunization data systems with electronic records and improved surveillance will ensure accurate tracking of vaccinated children. By implementing these strategies, Nigeria can improve immunization coverage, move closer to the WHO-recommended target of 90% vaccine coverage, and reduce childhood morbidity and mortality from vaccine-preventable diseases.

Study Limitations

This study has some limitations. First, its cross-sectional design prevents causal inferences, as only associations between predictors and immunization coverage were examined. Additionally, the study relied on self-reported immunization data, which may be subject to recall bias. Moreover, the use of secondary data limits control over variable definitions, measurement accuracy, and missing data. Some vaccinations may have been misclassified due to reliance on maternal recall or incomplete health cards. Future research should incorporate longitudinal data and immunization registry validation to improve data accuracy. Despite these limitations, this study provides valuable insights into the determinants of immunization coverage in Nigeria and offers evidence-based recommendations for improving vaccine uptake.

Data Sharing Statement

The datasets supporting the findings of this study are derived from the 2018 Nigeria Demographic and Health Survey (NDHS), which is publicly available. These data can be accessed directly from The DHS Program website: https://dhsprogram.com/.

Ethical Consideration

This study involved the secondary analysis of publicly available and de-identified data from the 2018 Nigeria Demographic and Health Survey (NDHS). The research was reviewed and deemed exempt from full ethical review by the Federal University Birnin Kebbi Research Ethics Committee, in accordance with national guidelines for secondary data use. The 2018 NDHS, as the primary data source, was conducted following established ethical standards and originally approved by the National Health Research Ethics Committee (NHREC) and the ICF Institutional Review Board. During the original data collection, written informed consent was obtained from all participants aged 15 years and older, with consent for minors obtained from their guardians. All data utilized in this study were analyzed in a manner that ensured participant anonymity and maintained strict confidentiality.

Acknowledgment

The authors acknowledge the DHS Program for making the data available for this research.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the revision to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

There is no funding to report.

Disclosure

The authors declare no competing interest in this work.

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