Category: 8. Health

A rare cell in the lining of lungs is fundamental to the organwide response necessary to repair damage from toxins like those in wildfire smoke or respiratory viruses, Stanford Medicine researchers and their colleagues have found. A similar process occurs in the pancreas, where the cells, called neuroendocrine cells, initiate a biological cascade that protects insulin-producing pancreatic islet cells from damage.

Treating the airways of mice with an experimental drug that activates the repair pathway protected their airways from damage after infection with influenza or the virus that causes COVID-19. Conversely, animals in which the pathway was blocked experienced much more severe damage to their airways.

Activating the signaling pathway initiated by airway or pancreatic neuroendocrine cells in a similar way in humans might enhance the ability of firefighters and those with respiratory illnesses to avoid permanent lung damage, the researchers believe. They also suspect it could help prevent people with metabolic syndrome from progressing to diabetes.

“This whole signaling cascade both protects and regenerates vulnerable cells in the airway and the pancreas,” said Philip Beachy, PhD, professor of urology and of developmental biology. “If this circuit is disrupted, the damage is much worse — specialized airway cells are lost, and the stem cells can’t divide to repair the damage. We think it’s likely to be important in many other tissues in the body.”

Although the study was conducted in mice, there are tantalizing clues of a similar pathway in humans: People treated with a cancer drug that blocks the pathway are twice as likely as their peers to develop diabetes after their treatment.

“The association is highly significant and gives us early hints that activating this pathway might be protective for people with metabolic syndrome who are beginning to lose beta cell function,” Beachy said.

Beachy, who is the Ernest and Amelia Gallo Professor and a member of the Stanford Stem Cell Institute, is the senior author of the research, which was published online June 9 in Cell. Research scientist William Kong, PhD, is the study’s first author.

Neuroendocrine cells are less than 1% of the total number of cells in the cells that line the airway, which is made up of a type of tissue called epithelium. Some of them cluster together in what are called neuroepithelial bodies and play an important role in sensing oxygen levels and modulating immune responses in the lungs. But others, especially those in the tracheal airway, are solitary, nestled alone among other types of epithelial cells. It’s not been clear until now exactly what function these solitary neuroendocrine cells perform.

The hedgehog family

Beachy’s laboratory has focused on the function of a protein family called Hedgehog proteins since Beachy identified the first member in fruit flies in 1992. Members of the family are best known for their critical function in embryo patterning in early development, but they also aid in the rejuvenation of many types of tissue. Desert hedgehog is one of the least studied of the three family members (the others are Sonic hedgehog and Indian hedgehog).

Previous work in Beachy’s lab showed that stem cells in the epithelial lining of the bladder respond to a signal cascade initiated by Sonic hedgehog to regenerate the bladder lining after bacterial infection. They wondered if hedgehog proteins were involved in the repair of damage in other epithelial tissues like the airway.

When Kong used a technique called bulk RNA sequencing to search for genetic messages encoding any of the hedgehog family members in the cells of the trachea, they detected a faint signal for the Desert hedgehog protein, but not for the other two family members. When they engineered mice in a way that caused cells expressing the Desert hedgehog protein to become fluorescent, they saw that the solitary neuroendocrine cells were making the Desert hedgehog protein.

Further research showed that the Desert hedgehog protein leaves the epithelium and travels into the layer of tissue beneath the epithelium, called the mesenchyme. There, it triggers cells to begin producing another protein called Gli1. When the airway cells sense damage, Gli1 induces the expression of a protein called IL-6 that triggers stem cells in the epithelium called basal cells to begin dividing and specializing to repair the damage.

This crosstalk between tissue layers, which the researchers call epithelial-mesenchymal feedback, protects and regenerates specialized cells in the lung epithelium, including multi-ciliated cells that use their feathery arms to sweep particles and viruses out of the lungs and secretory cells that make mucus to trap unwanted invaders. In the absence of these cells, viruses and toxins can penetrate much more deeply into the lungs

Protective process

The entire process happens within hours of toxin exposure in a coordinated cascade that eventually includes even non-Gli1-expressing cells of the airway.

“At each stage, the signal is amplified until the entire trachea is impacted,” Beachy said. “This rapid response not only protects the epithelial cells from dying but it also activates a regenerative response.”

The consequences of impeding this protective message are severe.

“If this signal cascade is disrupted, the damage is much worse. Ciliated and secretory cells are lost, and the basal cells don’t divide. In fact, it’s all they can do to stretch out and try to cover the injured area,” Kong said.

Both Desert hedgehog and Gli1 are critical to the repair process. Mice unable to produce Desert hedgehog or Gli1 were much more sensitive to exposure to sulfur dioxide gas, which is an environmental pollutant and mimics the damage inflicted by other inhaled toxins. While control mice lost 85% of ciliated cells and 41% of secretory cells within 24 hours, mice lacking the protein lost 96% of ciliated cells and 88% of secretory cells during the same time.

Activating the hedgehog signaling pathway with a small molecule dramatically increased cell survival after sulfur dioxide exposure: 66% of ciliated cells and 82% of secretory cells survived in treated animals, versus 9.7% of ciliated cells and 43% of secretory cells in control animals.

Kong next tested the effect of the Desert hedgehog pathway activation on mice infected with influenza and the virus that causes COVID-19. Although no mice unable to make Gli survived more than five days after infection with influenza, all mice treated with the small molecule activator survived at least eight days after infection. Mice infected with the virus that causes COVID-19 that were unable to activate the Desert hedgehog pathway suffered extensive loss of ciliated cells in the airway.

Finally, the researchers turned their attention to the pancreas, which has a similar tissue organization as the airway. They found that the insulin-producing beta cells, which are a type of neuroendocrine cell, also make Desert hedgehog and that the organ exhibits the same epithelial-mesenchymal feedback loop with IL-6 to protect the vulnerable cells.

The researchers are now exploring whether and how the hedgehog pathway could be activated in humans to prevent lung damage in people exposed to airborne toxins or who are at risk for diabetes.

“We have reasons to think it might not be a good idea to activate the hedgehog pathway long term,” Beachy said. “We are considering how to stimulate the pathway in a targeted way, either delivering it to the airway with an aerosol or targeting it to the pancreas. And we have early hints it might be possible.”

Reference: Kong W, Lu WJ, Dubey M, et al. Neuroendocrine cells orchestrate regeneration through Desert hedgehog signaling. Cell. 2025;0(0). doi:10.1016/j.cell.2025.05.012

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In our study, we evaluated the alignment of three LLMs– Gemini, Copilot, and ChatGPT-4.0– with consensus answers provided by a panel of experts. The findings indicate that Gemini consistently demonstrated a higher degree of agreement with the expert consensus compared to the other LLMs examined. Specifically, Gemini excelled in compatibility with both the majority of the consensus members’ answers and with the responses of any of the nine reviewers who participated in the consensus, regardless of majority opinion. Additionally, among the three commonly utilized LLMs, Gemini was the most aligned in queries where a perfect or excellent consensus was achieved.

The extent to which LLMs can be utilized in clinical decision-making processes remains a topic of growing interest. To shed light on this issue, several studies have been conducted—and continue to be conducted—comparing the performance of various LLMs [9,10,11,12]. In a study involving 134 clinical cases, the diagnostic, therapeutic, and management-related decision-making accuracy of three different LLMs was evaluated, and Gemini was found to have the lowest overall performance [9]. In another study focused on surgical planning in glaucoma patients, Gemini demonstrated 32% lower agreement compared to ChatGPT-4, indicating inferior performance [10]. Similarly, when assessed as an intraoperative decision-support tool in plastic surgery, Gemini again exhibited suboptimal performance relative to ChatGPT-4 [11]. Conversely, another study evaluating the ability of ChatGPT-4 and Gemini to assess diagnosis and treatment plans for patients with acute cholecystitis found comparable performances between the two models [12]. In contrast to these previous studies, our study found that, in the context of selecting the appropriate imaging modality for patients with renal colic, Gemini produced responses that were more aligned with those of the expert consensus panel.

One potential factor contributing to variability in LLM responses is the influence of different guideline sources used during model training. While our study utilized the 2019 consensus report [7] as the reference standard, it is possible that the UK NICE guidelines, which have recommended low-dose non-contrast CT as the first-line imaging modality since January 2019, were included in the training datasets of the evaluated LLMs. This difference in guideline exposure may have contributed to discrepancies in LLM recommendations.

However, this does not undermine the validity of our findings, as our study was specifically designed to assess how well LLMs align with an established expert consensus rather than to evaluate the absolute correctness of their responses based on multiple guideline sources. In clinical practice, variations in recommendations across different guidelines are well-recognized and do not indicate an inherent flaw in an individual guideline or its interpretation. Future research could further investigate how different LLMs integrate and prioritize diverse clinical guidelines, providing additional insights into their decision-making processes.

Gemini demonstrated a significantly higher level of concurrence with the consensus, providing responses that were largely similar to those of the majority of consensus participants. This suggests that Gemini may have better performance in understanding and appropriately interpreting clinical case examples consistent with expert opinions. In contrast, only 41.4% of the questions were answered by ChatGPT-4.0 and Copilot in agreement with the consensus, indicating a less robust alignment with expert guidelines. Notably, Gemini achieved an agreement rate of 82.7% when comparing its overall responses with those of the nine reviewers. These findings indicate that Gemini could be a more credible tool for applications requiring strong conformity with expert guidelines [7]. In addition, Gemini’s high rate of agreement with expert evaluations suggests that it may assist clinicians in making imaging decisions in patients with renal colic.The high level of agreement of the Gemini scale with the highest scoring responses suggests that it may have the potential for widespread adoption in professional and academic contexts if supported by future studies. In addition, Gemini and other LLMs can have more sensitive evaluation capabilities with each new update. With the use of more data sets and the development of more fine analysis capabilities with each new update, more accurate results can be achieved in the clinical context. Future studies can contribute to the increase of our knowledge and experience in this subject by focusing on how the reliability and accuracy rates of these LLMs, especially Gemini, can be improved with new updates.

Although the use of AI-enabled LLMs may attract attention with their performance in clinical case assessments, the integration of AI technologies into healthcare systems raises significant ethical and legal concerns that warrant careful consideration [13, 14]. As these complex models become increasingly embedded in critical clinical decision-making processes, it is crucial to meticulously assess the multifaceted risks and responsibilities associated with their potential impact on patient outcomes. A primary and pressing ethical issue pertains to the transparency and explainability of the decision-making mechanisms within AI systems. Healthcare providers must be able to comprehend and trust the recommendations and rationale generated by these AI systems in order to maintain patient confidence and ensure appropriate treatment. The lack of explainability can lead to profound challenges in establishing clear lines of accountability, making it profoundly difficult to determine whether the healthcare professional or the AI system bears responsibility for an erroneous or suboptimal decision that could significantly impact a patient’s well-being [15]. This adaptation is essential for safeguarding patient trust and ensuring that the integration of AI into healthcare supports, rather than undermines, the quality and reliability of patient care.

Another concern regarding the usability of LLMs in clinical case evaluations is the legal processes related to the compliance of the use of AI in healthcare with standards regarding patient privacy and data protection [16]. In Turkiye, the Law on the Protection of Personal Data (KVKK) imposes strict regulations on the management and disclosure of patient data [17]. Similarly, in the United States, the Health Insurance Portability and Accountability Act (HIPAA) sets stringent rules on patient data handling [18]. AI systems must be designed to comply with these requirements in both jurisdictions, ensuring the safeguarding of patient information against unauthorized access and breaches. This highlights the importance of ensuring that AI systems in healthcare settings are designed to comply with stringent data protection regulations—such as KVKK in Türkiye and HIPAA in the U.S.—to safeguard patient information from unauthorized access and breaches. Legally, the utilization of AI in healthcare must adhere to standards pertaining to patient confidentiality and data protection [16]. The Health Insurance Portability and Accountability Act in the United States imposes strict rules on the management and disclosure of patient data [17]. AI systems must be engineered to adhere to these requirements, guaranteeing the safeguarding of patient information against unauthorized access and breaches.

Limitations

This study has several limitations that should be considered when interpreting its findings. Firstly, the variability in the types and phrasing of questions posed to the LLMs can influence their responses, introducing variability that may affect the conclusions. However, the use of a standardized set of 29 clinical scenarios helps mitigate this variability, ensuring a consistent basis for comparison.

Secondly, the study’s generalizability is limited by the specific scenarios and questions presented. While the results may not apply to all medical inquiries, the selected scenarios are representative of common clinical situations in emergency departments. This relevance supports the applicability of the findings within the intended context. Thirdly, each vignette was presented only once in our study. Repetitive testing might increase the quality and robustness of the results of the study. Another limitation is that no power analysis was applied in our study. Instead, the study was designed using all vignettes in the consensus report. Finally, Copilot uses the infrastructure of ChatGPT-4.0. However, it also integrates the Microsoft database into its infrastructure, focusing on producing more balanced, creative and precise answers. Therefore, although they use similar infrastructures, they use different approaches to reach results on the given data, which distinguishes these two LLMs models from each other.

Despite these limitations, the study’s design and scenario selection provide a strong foundation for its conclusions. Future research can further address these limitations to enhance our understanding of LLMs in healthcare settings.

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Beth Parsons/BBC

Beth Parsons/BBC

Beth Parsons/BBC

Scientists from Cincinnati Children’s Hospital and partners in Japan have successfully grown liver tissue with its own internal blood vessels. The new development could significantly improve treatment options for people living with haemophilia and other blood-clotting disorders – while also pushing science closer to producing liver tissues suitable for transplantation.

Published in Nature Biomedical Engineering, the study was led by Dr Takanori Takebe, MD, director for commercial innovation at the Cincinnati Children’s Center for Stem Cell and Organoid Research and Medicine (CuSTOM). The research also included experts from the Institute of Science Tokyo, the Icahn School of Medicine at Mount Sinai and Takeda Pharmaceutical Co.

“Our research represents a significant step forward in understanding and replicating the complex cellular interactions that occur in liver development,” said Takebe. “The ability to generate functional sinusoidal vessels opens up new possibilities for modelling a wide range of human biology and disease and treating coagulation disorders and beyond.”

Cracking the vascular barrier

Until now, one of the main barriers to creating functional, full-sized organoids has been the absence of internal systems such as nerves and blood vessels. This latest breakthrough overcomes that hurdle by introducing blood vessels that not only form correctly but function effectively inside the growing tissue.

The research differentiated human pluripotent stem cells into CD32b+ liver sinusoidal endothelial progenitors (iLSEP). These progenitor cells – cells that can differentiate into specific types – were then cultivated using a novel inverted multilayered air-liquid interface (IMALI) culture system. This system allowed them to self-organise into complex liver components, which included hepatic endoderm, septum mesenchyme and arterial and sinusoidal vessel progenitors.

“The success occurred in part because the different cell types were grown as neighbours that naturally communicated with each other to take their next development steps,” explained first author Dr Norikazu Saiki of the Institute of Science Tokyo.

Key findings

• Functional human vessels: The team created “perfused blood vessels with functional sinusoid-like features,” meaning they formed hollow channels lined with the appropriate cell types to facilitate blood flow.
• Correction of coagulation disorders: The liver organoids successfully produced four blood clotting factors, including Factor VIII, the protein missing in haemophilia A. In mouse models mimicking haemophilia, the Factor VIII produced by the organoids reversed severe bleeding.
• Broader application potential: The IMALI culture method opens the door to generating organ-specific vasculature in other organoids, potentially revolutionising the field of regenerative medicine.

Toward new treatments for haemophilia and liver disease

In the United States, about 33,000 males live with haemophilia, most with haemophilia A. This inherited disorder leads to chronic joint bleeding, pain and serious risks such as seizures or paralysis due to brain haemorrhages. While treatment exists, such as coagulation factor injections, around 20 percent of patients with haemophilia A develop resistance to these therapies.

“These advanced liver organoids can secrete these coagulation factors,” said Takebe. “If they can be produced at scale, they could become a viable treatment source that would benefit people who have developed inhibitors or are not indicated for gene therapy.”

Patients with liver failure also experience deficiencies in clotting factors, putting them at increased surgical risk. A factor-secreting organoid factory – a lab-grown organoid that continuously produces and releases therapeutic proteins – could be used to support these individuals as well.

Looking forward, the researchers hope to push this technology even further – to generate complex liver tissues that might one day help repair or even replace damaged human livers.

Using data from the UK Biobank, this study systematically investigated the relationship between stillbirth and diabetes, CVD, all-cause mortality, as well as CVD mortality. Results indicated that women with a history of stillbirth had a significantly higher risk for most outcomes compared to those without. The association between stillbirth and diabetes, CVD, all-cause, and CVD mortality remained significant regardless of spontaneous abortion or pregnancy termination history. Notably, for participants with annual incomes above 31,000 £, stillbirth was not significantly linked to all-cause or CVD mortality.

This study found that women who experienced stillbirth had an increased risk of diabetes and CVD, including its various subtypes. Although a previous studies found that pregnancy loss (including miscarriage and stillbirth) was associated with a higher risk of CVD [14, 15], unfortunately, there were too few stillbirths to allow for corresponding analyses for stillbirths. Similarly, most previous studies have included pregnancy loss as a total exposure factor, which includes not only stillbirths but also spontaneous and induced abortions [4,5,6,7]. In addition, a limited number of studies have reported on the risk of developing diabetes following pregnancy loss. For example, a study from China indicated that women with a history of stillbirth had an increased risk of diabetes [16]. Consist findings were reported in a study involving a western population, where having more than two miscarriages was associated with an approximately two-fold higher risk of diabetes, however, this study did not provide evidence specific to stillbirth [17]. In addition, most of the studies relied on national registry data and were limited in scope regarding behavioral covariates and socioeconomic modifiers. Our study adds to this evidence base by using prospective cohort data with detailed lifestyle and socioeconomic variables, allowing for refined analyses of potential effect modifiers. Moreover, by evaluating multiple cardiometabolic and mortality outcomes simultaneously, we provide a broader understanding of the post-stillbirth health trajectory. Our analysis also highlights the modifying role of income and lifestyle factors, offering insights into potential intervention points to reduce health disparities among women affected by stillbirth.

Stillbirth, diabetes, CVD, and CVD mortality may involve common underlying mechanisms, such as disorders of glucose metabolism [18, 19]. In addition, stillbirth may influence the development of CVD by bypassing other pathways of diabetes. For example, antiangiogenic status may increase the risk of stillbirth [20], and antiangiogenic proteins may be a new pathogenesis of CVD in the absence of diabetes [21]. In exploring the relationship between stillbirth, diabetes, and CVD, the deficiency of nerve growth factor (NGF) plays a crucial role. Studies indicate that women who experience stillbirth may face a decrease in NGF levels, which can lead to the apoptosis of pancreatic β-cells, thereby affecting insulin secretion and glucose metabolism, ultimately increasing the risk of diabetes [22, 23]. Additionally, in diabetic patients, the reduction of NGF levels is closely associated with the apoptosis of pancreatic beta-cell, a process that results in impaired insulin secretion through the inhibition of the PI3K and AKT signaling pathways, activation of c-Jun kinase, and reduction of Bcl-Xl protein [24]. On the other hand, the decrease of NGF can also activate the C-Jun N-terminal kinase pathway, induce the expression of apoptosis-related genes, such as promoting the release of cytochrome c, and then activate the apoptotic cascade. In addition, decreased levels of NGF were accompanied by decreased expression of the anti-apoptotic protein Bcl-xL, further weakening cell survival [25]. These molecular changes eventually lead to impaired insulin synthesis and secretion function, a decrease in the number of islet beta cells, and the destruction of the islet structure, which triggers or exacerbates the development of diabetes. In terms of CVD, patients with ischemic heart disease exhibit significantly lower NGF levels compared to healthy individuals, which may correlate with myocardial cell necrosis and HF [26, 27]. Research has shown that NGF can improve cardiac function, reduce myocardial apoptosis and fibrosis, and protect the heart by promoting autophagic flux and attenuating protein ubiquitination [23]. In summary, the deficiency of NGF establishes a complex mechanistic pathway in the occurrence and development of stillbirth, diabetes, and CVD, warranting further in-depth investigation.

Emotional and lifestyle changes may also be an important factor in the increased risk of diabetes after stillbirth. Stillbirth, especially when experienced multiple times, tends to have a negative psychological impact on women, increasing anxiety and mental stress, which in turn affects behavior and health habits [17]. Studies have shown that women who experience stillbirths are more likely to be overweight than those who experience live births [28], which may be due to psychological stress that alters eating habits. Also, about 10% of women who experience stillbirth develop acute stress disorder [29]. Repeated stress exposure may trigger chronic stress, leading to disturbances in glucose metabolism, neuroendocrine disorders, and a prolonged low-grade inflammatory response. Depression, persistent stress and early adverse experiences are strongly associated with the development of diabetes [30]. Similarly, obesity and depression can also lead to an increased risk of CVD [31]. Women with a history of stillbirth may benefit from targeted screening and prevention strategies. Higher income may reduce the risk of cardiovascular death and all-cause death associated with stillbirth through a variety of mechanisms, including access to health care, stress management, and healthy behaviors. Higher-income women often have access to better medical resources, which allows them to receive early screening, preventive interventions, and better health management, such as diabetes and hypertension [32]. High-income groups are often able to enjoy regular health checkups, medication and preventive care, which reduces the long-term risk of serious health problems such as diabetes and CVD. In addition, higher income individuals generally experience lower levels of psychological stress, which has a positive impact on cardiovascular health [33]. Stress is a known risk factor for heart disease, and chronic stress can lead to activation of the hypothalamic–pituitary–adrenal axis, promoting inflammation and endothelial dysfunction, both of which are associated with the development of CVD [34, 35]. Conversely, low-income women may face greater stress due to financial hardship, lack of social support, or limited medical resources, which may exacerbate the risk of cardiovascular death and all-cause mortality [36]. Higher-income women may also be more likely to adopt healthy lifestyles, such as regular exercise, a balanced diet and lower rates of smoking, all behaviors that help reduce the risk of CVD and early death [37].

Our findings highlight significant heterogeneity in CVD and all-cause mortality outcomes related to stillbirth across different income levels. Specifically, among participants with annual incomes above 31,000 £, stillbirth was not significantly associated with all-cause or CVD mortality, suggesting that higher income may mitigate some health risks linked to stillbirth. No significant association between stillbirth and all-cause and cardiovascular death was observed in people without hypertension, possibly because hypertension plays an important mediating or modifying role between stillbirth and subsequent health outcomes. Hypertension is closely related to vascular endothelial dysfunction, inflammation and other pathological mechanisms, which may also be involved in the occurrence of stillbirth and affect long-term health risks [38]. Therefore, in individuals without hypertension, the absence of this pathological basis may have weakened the effect of stillbirth on the risk of death, and thus did not show a statistically significant association.

This aligns with a recent global burden of disease study indicating that stillbirth rates tend to decline as socioeconomic development increases. However, the highest burden of stillbirth remains concentrated in sub-Saharan Africa and South Asia, where socioeconomic challenges persist. Furthermore, studies have shown that the majority of stillbirths in these high-burden regions occur in rural areas with low Healthcare Access and Quality indices [39, 40]. These findings suggest that low-income families or regions may bear a disproportionate burden of stillbirth-related mortality, underscoring the need for targeted interventions, which provides a scientific basis for governments and public health organizations to develop strategies and allocate resources effectively to reduce the burden of stillbirth and its associated health outcomes. Emerging evidence indicates that a proportion of unexplained stillbirths may be linked to fetal cardiac channelopathies, such as long-QT and short-QT syndromes. These conditions, often caused by mutations in genes like KCNQ1, KCNH2, and SCN5A, can result in fatal fetal arrhythmias even in the absence of structural cardiac abnormalities or fetal growth restriction. Additionally, maternal long-QT syndrome may impair placental or uterine function, thereby increasing the risk of fetal loss [41].

This work has two main strengths as follows: UK Biobank is a large and long-term follow-up cohort with large sample and abundant data which enhances the statistical validity of study. In addition, we explored the association of stillbirths with multiple outcomes and enriched the study of the experience of stillbirth on women’s long-term health outcomes. However, this study also has some limitations. First, because of the small sample size of CVD mortality, the results may be affected by the complexity of the model, which may reduce its stability. Second, although the robustness of the results was enhanced by sensitivity analyses that excluded outcomes occurring within two years, causality could not be established due to the observational design of the study. The present study revealed an association between stillbirth and these outcomes, but the underlying mechanisms have not been clarified. Third, the majority of the study population was White (95.1%), which limits the extrapolation of the results to other racial groups. Differences based on race and ethnicity may lead to different health outcomes, and this area needs further research. Fourth, the study was not able to obtain specific information on the occurrence of stillbirth. Because most of stillbirths occurred many years ago, changes in an individual’s health status, for example BMI measurement or lifestyle estimates at recruitment rather than the onset of stillbirths, and environment may affect the association between stillbirths and health outcomes, limiting the interpretation of temporal relationships. Fifth, because it is difficult to confirm whether participants had gestational diabetes at each pregnancy, some residual confounding may persist. However, we further excluded participants with pre-enrollment diabetes to minimize this potential bias. Sixth, likewise, specific information of medical services during pregnancy and frequency of medical visits is unavailable. In order to minimize the impact of these factors, we further added TDI and income level covariates to evaluate associations of stillbirths with target outcomes and obtained consistent results. Seventh, the number of stillbirths occurring among the participants in this study was concentrated at a low frequency, with a smaller sample experiencing multiple stillbirths, which limited the precision of our stratified analysis and quantitative assessment of the association between the number of stillbirths and health outcomes. Eighth, stillbirth history was obtained through self-report, which may be subject to recall bias, particularly for events that occurred many years prior to baseline. This introduces the potential for both underreporting and misclassification of exposure. If the accuracy of recall is associated with the participant’s health status, differential misclassification could occur and may bias the observed associations in either direction. However, in the absence of such systematic differences, any misclassification is likely to be non-differential and may have attenuated the true associations. Ninth, we acknowledge that certain important obstetrical and reproductive health variables, such as gestational age at the time of stillbirth, history of recurrent pregnancy loss, use of assisted reproductive technologies, and specific pregnancy complications (including preeclampsia and gestational diabetes), were not available in current dataset. These unmeasured factors are biologically linked to both stillbirth and long-term health outcomes and may have introduced residual confounding. Therefore, their absence should be considered when interpreting the findings of this study.

Given the significant associations found in this study between stillbirth and the risk of diabetes, CVD, and death, more aggressive health management for women with a history of stillbirth is recommended. This group of people should be included in the high-risk group after childbirth for systematic metabolic and cardiovascular health assessment. Diabetes screening recommends a fasting blood glucose or glucose tolerance test every 1 to 3 years, depending on the individual’s weight, family history and other risk factors. For CVD, blood pressure, lipids, and lifestyle factors should be assessed annually, combined with an electrocardiogram or echocardiogram if necessary. In addition to medical screening, psychological intervention and lifestyle management, including weight loss, nutritional guidance and exercise intervention, should be strengthened to reduce the long-term risk of chronic diseases.

Study design

An 8-week parallel, randomized, double-blinded, placebo-controlled clinical trial was conducted to investigate the effect of Zn supplementation on atherogenic indices from September 2018 to September 2019 at the Motahari and Imam Reza Clinics, Shiraz, Iran. The study protocol was in accordance with the declaration of Helsinki and good clinical practice and adhered to CONSORT guidelines. It was also approved by the Ethics Committee of Shiraz University of Medical Sciences, Shiraz, Iran (IR.SUMS.REC.1397.105), and registered in the Iranian Registry of Clinical Trials (IRCT.ir; IRCT20191015045113N1; 08/12/2019). Written informed consent was obtained from participants at the beginning of the study.

Afterward, participants received lifestyle modification recommendations over a 2-week run-in period in which they were recommended to have at least 20 min of physical activity a day, eat 5 meals per day, replace simple carbohydrates with complex carbohydrates, replace refined grains with fruits and/or vegetables, and reduce consumption of high fructose corn syrup sweetened food. After completing the run-in period, participants were randomly allocated to the intervention or control groups by the researcher, using the simple random allocation method with the random table number, in order to receive a dietary plan, in addition to a Zn supplement or placebo in the intervention or control group for 8 weeks, respectively. Demographic, anthropometric, biochemical, dietary intake, and physical activity assessments were performed before and after the study (Fig. 1). Allocations were concealed in an opaque envelope until after the baseline assessments.

Study population

According to the previous study [9], the sample size was estimated at 25 in each group, to detect a 0.18 reduction in AIP score (SD = 0.2) with a significance level of 5% (α = 0.05), a test power (1 – β) of 80%, and a probability of 10% attrition rate. Inclusion criteria include overweight or obese patients aged 18–70 years with ultrasound-confirmed NAFLD, with no alcoholic beverage consumption, lack of viral hepatitis, liver cirrhosis, Wilson’s disease, acute fatty liver of pregnancy, hepatocellular carcinoma and a history of chronic liver disease, no lipodystrophy, lack of parenteral nutrition, not suffering from diseases that affect the bile and bile ducts, no severe weight loss during the previous 6 months, lack of congenital metabolic diseases, not taking drugs that cause fatty liver (methotrexate, tamoxifen, valproate, etc.), no pregnancy and lactation, lack of serum alanine transaminase level more than 10 times the allowable limit, no history of severe systemic diseases such as CVD and kidney disease, not having chemotherapy during the past year, no drug and alcohol poisoning, not taking any supplements containing Zn. Exclusion criteria included allergies and severe side effects from taking supplements, unwillingness to continue the study, failure to follow the recommendations and diet provided, and consumption of less than 90% of the supplements provided.

Intervention

The intervention group received one 30 mg Zn capsule (zinc gluconate, Nature Made, USA) daily and the control group received one placebo capsule (starch powder) daily with a meal for 8 weeks. Considering that the tolerable upper intake level (UL) of Zn in adults is 40 mg/day and the recommended dietary allowance (RDA) is 8-11 mg/day, in addition to the lack of any complications by the dose of 30 mg/day in previous studies [22, 23], this amount of Zn was considered as the intervention dose in this trial. Both groups also received a dietary plan with a caloric deficit of 500–1000 kcal/day, consisting of 50–55% carbohydrates, 30% fat, and 15–20% proteins, based on the participant’s estimated energy requirement.

Randomization and blinding

Randomization was performed using a simple random allocation method based on the published random table number by an independent statistician. The intervention and placebo capsules were similar in shape, color, and size and were put in similar containers coded as A or B by a person out of the study. Only the principal investigator (PI) could decode the contents of each capsule. The researchers in charge of capsule delivery and conducting the study, the patients, the physician, and the outcome assessor were blinded to the coding.

Compliance assessment

Telephone calls were made every two weeks to follow up with patients, record side effects, and prevent attrition rates. At the end of the fourth week, patients attended the clinic to receive the capsules. The number of capsules consumed was recorded. If the patients consumed more than 90% of the prescribed capsules, they were considered adherent.

Dietary intake assessment

A 24-hour food record for 3 days (2 regular days and a weekend day) was used to evaluate the dietary intake of participants. Then, food records were analyzed by a modified version of Nutritionist 4 software (First Databank Inc., San Bruno, CA, USA) for Iranian food items. Total energy, macronutrients, fiber, and Zn intakes were calculated.

Physical activity assessment

The International Physical Activity Questionnaire (IPAQ) was used to assess patients’ physical activity. This questionnaire consisted of 7 questions about the intensity and duration of physical activity during the past week. The metabolic equivalent (MET) for light, moderate and vigorous activities is considered 3.3, 4, and 8, respectively. Then the intensity (MET) of physical activity was multiplied by the duration (minute) of physical activity to calculate the amount of physical activity (MET*min/week).

Anthropometric assessment

Height was measured with a tape measure attached to the wall, in a standing position, and without shoes with an accuracy of 0.5 cm. The weight of patients in the lightest possible clothing without shoes was measured by a scale (Seca, Germany) with an accuracy of 100 g. Waist circumference was measured at the midpoint between the margin of the lowest palpable ribs and the upper edge of the pelvis with an inelastic meter parallel to the ground to the nearest 0.1 cm. Body mass index (BMI) was calculated based on the standard formula (weight (kg) / [height (m)]²).

Biochemical assessment

After 10–12 h of fasting, blood samples (5 cc) were taken from the subjects at the beginning and end of the study. Blood samples were centrifuged (4000 rpm for 10 min) and sera were stored in a freezer (-70 °C) until further analysis. Blood sampling was performed at the Motahari clinic laboratory, Shiraz, Iran. Then the samples were analyzed in the laboratory of the Faculty of Nutrition and Food Sciences of Shiraz University of Medical Sciences, Shiraz, Iran. Lipid profile (TC, TG, LDL-C, and HDL-C) levels were measured by the enzymatic photometric method by auto-analyzer (BT-1500, Italy (and commercial kits (Pars Azmoun, Iran). Serum Zn was measured by colorimetric spectrophotometry assay.

Atherogenic indices assessment

Atherogenic indices (AC, AIP, Castelli risk index I, and Castelli risk index II) were calculated using the following equations at the beginning and end of the study:

AC = (TC − HDL − C)/HDL– C.

AIP = log (TG/HDL − C).

Castelli risk index I = TC/HDL– C.

Castelli risk index II = LDL − C/HDL– C.

Statistical analysis

Data analysis was performed by Statistical Package for Social Sciences (SPSS) software (version 19.0, SPSS Inc., Chicago, IL, USA). P < 0.05 was considered significant. Data were reported as mean ± standard deviation (SD). The normality of data distribution was assessed using the Shapiro-Wilk test. The chi-square test was used to test the homogeneity of qualitative variables between groups. Within-group and between-group comparisons of variables were performed by Paired t-test and Independent Sample t-test for normally distributed data, respectively. ANCOVA (analysis of covariance) test was also used to adjust confounder variables.

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Addis Ababa, 4 July 2025 — A new study carried out by the Africa Centres for Disease Control and Prevention (Africa CDC) and the UK Public Health Rapid Support Team (UK-PHRST) confirms the critical role international health teams have played in strengthening outbreak response across the African continent. The study also highlights the need for more strategic and locally tailored support models to ensure long-term sustainability and effectiveness.

Presented and validated during a high-level virtual workshop held from 23 to 24 June 2025, the study offers one of the most comprehensive assessments to date of international technical deployments and their impact on national outbreak preparedness and response systems in African Union (AU) Member States between 2020 and 2023.

The findings show that international teams provided crucial short-term surge capacity across several public health domains, including surveillance, laboratory systems, epidemiology, infection prevention and control, clinical care, and risk communication. Notably, nearly half of all deployments supported two or more of these areas, underscoring their value in addressing multifaceted outbreak challenges.

Beyond emergency response, the study details how international teams supported countries through the provision of equipment and infrastructure, the development of operational systems and protocols, the transfer of skills through training, the enhancement of coordination structures, and rapid deployment of human resources during critical capacity gaps.

“These deployments have delivered vital expertise, resources, and rapid response capacity at crucial moments,” said Dr Radjabu Bigirimana, Programme Lead for Africa CDC’s African Volunteers Health Corps (AVoHC). “However, they also raise important questions about sustainability, coordination, and how we strengthen long-term national preparedness systems.”

While national stakeholders widely appreciated the contributions of international teams, the study also captured reflections from international partners on the importance of aligning deployments with local needs, existing national capacities, and longer-term health security goals. Effectiveness, the study found, often depended on the expertise of deployed personnel and their integration into existing national response systems.

“This workshop reinforces the need for global partnerships to evolve—where international deployments are not just reactive measures, but deliberate investments in national systems, tailored to local realities and long-term goals,” said Dr Edmund Newman, Director of the UK-PHRST.

“Evidence-informed learning must guide how we improve emergency public health deployments,” added Dr Femi Nzegwu, Assistant Professor at the London School of Hygiene & Tropical Medicine and Monitoring, Evaluation and Learning lead at UK-PHRST. “The findings of the report validate experiences across Africa but also point to what must change to ensure deployments are more effective, context-specific, equitable, and empowering for Member States.”

The workshop resulted in the collaborative development of a roadmap to operationalise the report’s recommendations, serving as a good practice guide on how to enable sustainable solutions in outbreak management among AU Member States. In turn, the report lays a foundation for reducing long-term reliance on external surge capacity by strengthening national health systems.

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About Africa CDC

The Africa Centres for Disease Control and Prevention (Africa CDC) is the autonomous continental public health agency of the African Union, mandated to support Member States in strengthening health systems, and enhancing disease surveillance, prevention, and emergency response capabilities. Learn more at: https://africacdc.org and connect with us on LinkedIn, Twitter, Facebook and YouTube

About UK-PHRST

The UK Public Health Rapid Support Team partners with low- and middle-income countries to prevent disease outbreaks from escalating into global health emergencies. 

They work closely with international organizations, partner country governments and non-governmental organizations to:

• Rapidly investigate and respond to disease outbreaks at their source in LMICs eligible for UK Official Development Assistance, with the aim of stopping a public health threat from becoming a broader health emergency.
• Conduct research to generate an evidence base for best practice in epidemic preparedness and response.
• Strengthen capacity for improved national response to disease outbreaks in LMICs.

They are an innovative partnership between the UK Health Security Agency and the London School of Hygiene & Tropical Medicine, funded with UK aid by the UK Department of Health and Social Care. 

The views expressed in this press release are those of the author and not necessarily those of the Department of Health and Social Care.

Media contacts

For Africa CDC

Margaret Edwin, Director of Communication and Public Information / Email: EdwinM@africacdc.org

For UK-PHRST

UKHSA press office / Email: ukhsa-pressoffice@ukhsa.gov.uk

Islamabad  –  A delegation from the Polio Oversight Board (POB), led by Dr. Chris Elias of the Gates Foundation, met with Federal Health Minister Syed Mustafa Kamal on Thursday to discuss Pakistan’s polio eradication efforts.

The minister reaffirmed the government’s commitment to eliminating polio, emphasizing cross-border coordination with Afghanistan and targeted campaigns for mobile populations. He praised health workers’ dedication, calling their sacrifices a symbol of national resolve. The delegation, which includes senior representatives from WHO, UNICEF, Rotary International, and KS Relief, commended Pakistan’s progress and pledged continued support. The visit follows the delegation’s stop in Afghanistan and includes planned meetings with the Prime Minister and top officials.